Second Edition

Edited by William K. Sietsema, PhD

and Monica M. Meacham, PhD

All rights reserved; file sharing prohibited.

 Second Edition

Edited by William K. Sietsema, PhD

and Monica M. Meacham, PhD

Published by

All rights reserved; file sharing prohibited.

ii All rights reserved; file sharing prohibited.
 Dedication
This book is dedicated to Pamela A. Jones, RAPS’ publications
editor and longtime staff member who passed away on January
12, 2020. Pam was an extraordinary and wonderful person and
dear member of the RAPS family. The RAPS community benefitted
greatly from Pam’s skilled work as an editor, but it is the loss
of her wit, humor and kindness that will be felt most deeply by
those who knew her. It was a genuine privilege to have Pam in our
lives. Pam was honest and direct and did not hesitate to share her
opinions. Those of us who were fortunate to have worked with her
also know that beneath her tough, no-nonsense exterior, she had
an extremely kind heart and cared deeply about her close friends,
family and beloved pets. She will be dearly missed.

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 Copyright © 2020 by the Regulatory Affairs Professionals Society.
All rights reserved.

ISBN: 978-1-947493-42-1

Every precaution is taken to ensure accuracy of content; however,

the publisher cannot accept responsibility for the correctness of
the information supplied. At the time of publication, all Internet
references (URLs) in this book were valid. These references are
subject to change without notice.

RAPS Global Headquarters

5635 Fishers Lane
Suite 400
Rockville, MD 20852
USA

RAPS.org

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Contents
Acknowledgments .........................................................................................................................................viii
Foreword .........................................................................................................................................................ix
Chapter 1: Introduction to Regulatory Strategy.............................................................................................1
By Darin S. Oppenheimer, Jessica L. Hale, Suraj Ramachandran and George A. Cusatis

Chapter 2: The Regulatory Team....................................................................................................................9

By Naseem Kabir, Susan Capps and Grace Jiang

Chapter 3: Regulatory Intelligence Step 1: Information Collection—A Compilation of Website Addresses.....23

By William K. Sietsema, PhD

Chapter 4: The Elements of Global Regulatory Strategy—the Basics............................................................31

By Neal E. Storm

Chapter 5: Assembling and Utilizing Target Product Profiles........................................................................45

By Anastassios Retzios, PhD

Chapter 6: Preclinical Safety Guidelines Supporting International Drug Registration................................. 57

By John C. Kapeghian, PhD, DABT

Chapter 7: CMC Regulatory Strategy..........................................................................................................79

By Stephen Antonelli and Michael Craig

Chapter 8: Strategies for Clinical Development Planning.............................................................................89

By William Sietsema, PhD and Eric Brass, MD, PhD

Chapter 9: Clinical Trial Application Planning.............................................................................................99

By Sharry Arora

Chapter 10: Global Orphan Drug Regulations ............................................................................................107

By Jocelyn Jennings, MS, RAC

Chapter 11: Pediatric Strategies....................................................................................................................117

By Klaus Rose, MD, MS

Chapter 12: So Your Drug has a Friend? Companion Diagnostic Codevelopment Strategies........................133
By Catherine Lofton-Day, Dave Kern and Mya Thomae

Chapter 13: Interacting With Regulators.....................................................................................................145

By Eric Brass, MD, PhD and William Sietsema, PhD

Chapter 14: Regulatory Pathways.................................................................................................................155

By Pallavi Trivedi, MPH, RAC

Chapter 15: Global Regulatory Strategy.......................................................................................................187

By Chris Walker and Tina Soulis

Chapter 16: Preparing for an FDA Advisory Committee: High Risk, High Reward.....................................205
By Michael J. Vivion

Chapter 17: Considerations for Healthcare Products’ Lifecycle Management...............................................221

By Timothy Pang

Chapter 18: Medical Writing Strategies: Aligning Regulatory Documents with Strategic Goals....................235
By Kathy Wekselman

Index ............................................................................................................................................................243

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 Case Studies
Case Study 8-1. Teduglutide and the Selection of a Clinically Meaningful Endpoint................................................ 94
Case Study 8-2. Adverse Events of Special Interest.................................................................................................... 95
Case Study 8-3. Excluding Unacceptable Risk.......................................................................................................... 96
Case Study 13-1. Vascepa for the Treatment of Hypertriglyceridemia..................................................................... 151

Figures
Figure 5-1. Target ProductProfile (TPP) Planning Process........................................................................................ 45
Figure 5-2. Target Product Profile............................................................................................................................. 48
Figure 8-1. Clinical Development Program Reverse-Engineering Principle............................................................... 90
Figure 8-2. Sample Timeline With one Option for Displaying High-Level Information on Program Timing........... 92
Figure 10-1. Sponsor’s Guide to an Orphan Designation........................................................................................ 109
Figure 14-1. EMA Centralised Procedure Flowchart With Major Milestones......................................................... 163
Figure 14-2. Flow Chart of Drug and Device Review in Japan............................................................................... 167
Figure 14-3 Japan’s New Approval System for Commercialization of Cellular Therapy Products............................. 169
Figure 14-4. Standard Registration Process with TGA............................................................................................ 173
Figure 14-5. TGA Priority Registration Process Diagram........................................................................................ 175
Figure 14-6. TGA Provisional Registration Process Diagram.................................................................................. 177
Figure 14-7. TGA Regulation of Biologicals........................................................................................................... 179
Figure 15-1. Multidisciplinary Product Development............................................................................................. 188
Figure 15-2. Key Interactions Between Marketing and Regulatory......................................................................... 190
Figure 15-3. Clinical Development Strategy in Asia............................................................................................... 194
Figure 15-4. The CTD Triangle.............................................................................................................................. 195
Figure 15-5. Global Technology System for Safety Monitoring.............................................................................. 199
Figure 16-1. Typical Advisory Committee Meeting Seating Arrangement............................................................... 206

Tables
Table 3-1. Sources of Regulatory Intelligence........................................................................................................... 23
Table 3-2. Websites for Healthcare Product Regulations by Region.......................................................................... 24
Table 3-3. Regulatory Intelligence Databases............................................................................................................ 26
Table 3-4. Professional Associations for Regulatory Professionals.............................................................................. 26
Table 3-5. Clinical Trial Databases........................................................................................................................... 27
Table 3-6. Examples of Web Pages for Subscribing to Regulatory Updates............................................................... 28
Table 3-7. Regulatory Agency Twitter Handles......................................................................................................... 28
Table 4-1. Key Global Regulatory Plan Elements......................................................................................................... 32
Table 4-2. Changes a Global Regulatory Plan Should Anticipate, Mitigate or Manage............................................. 32
Table 4-3. Regulatory Intelligence Tool Examples to Understand the Competitive Product Landscape..................... 39
Table 4-4. Regulatory Journals for Understanding Shifting Regulatory Policy.......................................................... 40
Table 4-5. Global Regulatory Plan Components—Sample Table of Contents........................................................... 43
Table 5-1. Introductory/Top Table Presenting Certain Drug Key Elements ............................................................. 50

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Table 5-2. TPP Panel for the Clinical use and Efficacy attributes (mainly the primary endpoint) of a Liquid
Immunoglobulin G Preparation in the Treatment of Chronic Inflammatory Demyelinating
Polyneuropathy (CIDP)........................................................................................................................................... 51
Table 5-3. TPP Panel Summarizing the Safety Information a Liquid Immunoglobulin G Preparation in the
Treatment of Primary Immunodeficiency................................................................................................................. 52
Table 5-4. Specific Areas to be Covered by the TPP Asset Characterization Module................................................. 54
Table 6-1. Recommended Duration of Repeat-Dose Toxicity Studies to Support the Conduct of Clinical Trials...... 71
Table 7-1. Centralised Procedure Requirements Based on Product Type................................................................... 81
Table 7-2. Regulatory Authorities by Country.......................................................................................................... 81
Table 8-1. Study Outline Document Template......................................................................................................... 91
Table 10-1. Countries With Orphan Drug Regulations and Population Prevalence................................................ 110
Table 10-2. Overview of Orphan Drug Designation Incentives.............................................................................. 111
Table 10-3. Global Health Authority Orphan Drug Office..................................................................................... 113
Table 10-4. Orphan Drug Regulations by Country................................................................................................ 114
Table 10-5. Orphan Drug Templates and Submission Tips..................................................................................... 114
Table 13-1. Communication Objectives for Sponsor-Regulator Interactions.......................................................... 146
Table 13-2. Examples of Open vs. Content-Specific Questions to Regulators......................................................... 147
Table 13-3. Summary of Regulatory Agency Meeting Types................................................................................... 152
Table 14-1. US Pathways and Exclusivity............................................................................................................... 156
Table 14-2. FDA Drug and Biologic NDA Application Review Timeframes.......................................................... 156
Table 14-3. FDA Programs to Expedite Approval of Drug/Biologic Products Intended to Treat
Serious Conditions................................................................................................................................................. 160
Table 14-4. EU Application Procedures for Drugs and Biologics............................................................................ 162
Table 14-5. EU Standard Timelines for Centralised Applications........................................................................... 162
Table 14-6. EU Standard Mutual Recognition Procedure Timelines....................................................................... 163
Table 14-7. EU Standard Decentralised Procedure Timelines................................................................................. 164
Table 14-8. Drug MAA Types in EU...................................................................................................................... 165
Table 14-9. EU Mechanisms for Accelerated Drug and Biologics Development and Approval............................... 166
Table 14-10. Japan Drug Filing Fees....................................................................................................................... 168
Table 14-11. Human Drug (Pharmaceutical and Biological) Submission and Application Review Timeframe
and Fees as of April 1, 2019................................................................................................................................... 171
Table 14-12. TGA Application and Evaluation Fees in Australian Dollars for Prescription Medicines as of
December 2019...................................................................................................................................................... 178
Table 14-13. Overview of the TGA Application Process and Timeframes............................................................... 180
Table 14-14. TGA Fees in Australia Dollars for Sponsoring Biologicals.................................................................. 180
Table 15-1. Comparison of Regulatory and HTA Requirements............................................................................ 191
Table 15-2. Overview of Specific Country Requirements....................................................................................... 197
Table 17-1. CM Considerations by Phase of Product Lifecycle............................................................................... 223
Table 17-2. Lifecycle Evolution of Oral Antidiabetic Drugs in the US and EU...................................................... 227
Table 17-3. Remicade US Indication Expansion in the First Five Years After Launch............................................. 228
Table 18-1. Examples of Structured Regulatory Goals............................................................................................ 238
Table 18-2. Best Practice Examples for Clear Regulatory Writing........................................................................... 241

All rights reserved; file sharing prohibited. vii

 Acknowledgments
The Regulatory Affairs Professionals Society thanks Klaus Rose, MD, MS
those individuals who have shared their experience CEO
and expertise with their colleagues by contributing to klausrose Consulting, Pediatric Drug Development
this book. & More

Editors Margaret A. Hamburg, MD

Former FDA Commissioner
Monica Meacham, PhD
Associate Director, Regulatory Affairs Michael Craig
ImmunityBio Principal Consultant (CMC)
Parexel Consulting
William K. Sietsema, PhD
Vice President, Global Regulatory Affairs Michael J. Vivion, PhD
Caladrius Biosciences Principal
ECG Healthcare
Authors
Anastassios D. Retzios, PhD Mya Thomae
President Regulatory Advisor
Bay Clinical R&D Services, LLC
Naseem F. Kabir
Catherine Lofton-Day Director, Global Labeling
Formerly at Amgen, Inc. Amgen Ltd.

Chris Walker, MSc Neal E. Storm, DRSc, MBA, RAC

Vice President, European R&D, Head of Regulatory Director, Global Regulatory Affairs
Affairs & UK Sites Head Amgen Inc.
Amgen, Ltd.
Pallavi Trevedi, MPH, RAC
Darin S. Oppenheimer, DRSc Senior Associate
Executive Director Global Regulatory Affairs & Clinical Jeff Yuen and Associates, Inc.
Safety Devices and Digital Health
Merck & Company Sharry Arora
Manager
Dave Kern, MBA, RAC
Principal and Founder Stephen Antonelli, PhD
K2 Regulatory Consulting Director, Regulatory CMC
Alkermes, Inc.
Eric Brass, MD, PhD
Professor Emeritus of Medicine Suraj Ramachandran, RAC
David Geffen School of Medicine at UCLA Director Global Regulatory Affairs & Clinical Safety
Devices and Digital Health
George A. Cusatis, RAC Merck & Company
Associate Director Global Regulatory Affairs & Clinical
Safety Devices and Digital Health Susan Capps
Merck & Company Executive Director, Global Value Access & Policy
Amgen Ltd.
Jessica L Hale PharmD
Senior Specialist Global Regulatory Affairs & Clinical Timothy Pang
Safety Devices and Digital Health Senior Director, Informa Pharma Consulting
Merck & Company Informa Intelligence

Jocelyn Jennings, MS, RAC Tina Soulis, PhD

Senior Director, Regulatory Affairs CEO
Neuroscience Trials Australia
John C. Kapeghian, PhD, DAB
President Xinzhao Grace Jiang
Preclinical Safety Associates, LL Director
Amgen, Inc.
Kathryn Wekselman PhD
Vice President of Regulatory
MaxCyte, Inc.

viii All rights reserved; file sharing prohibited.

Foreword
This continues to be a remarkable time for science, medicine and public health. The rapid pace of
scientific discovery—from the so-called “omics” revolution and synthetic biology, to newly evolv-
ing cellular and gene therapies, to advances in technology such as gene-editing, nanotechnology,
3-D printing and, of course, information technology and data science—holds the promise of
truly revolutionary new therapies and interventions to prevent, treat and cure disease. Before us
is the opportunity to advance human health and well-being in ways not previously understood or
even imagined.
But, while translating new discoveries into real-world products can make an enormous
difference for individual and population health, the process is a complex and difficult one. It is
an activity fraught with challenges, requiring many steps and partners. The painstaking work to
develop, test, manufacture and distribute a new medical product successfully requires a vast range
of expertise, skills and dedication. Moreover, it demands coordinated work across disciplines,
sectors and, increasingly, across nations.
The task is not easy, but this volume provides a wonderful roadmap for those who are part
of this extraordinary enterprise seeking to realize the potential of modern medicine and public
health through enhanced regulatory science and strategy. Organized around a set of thoughtful,
authoritative and well-written chapters, the book lays out the essential elements of an inte-
grated regulatory approach. Written by a group of distinguished authors, each chapter is a clear
exposition of an important topic, ranging from the ABCs of regulatory strategy and the whys
and wherefores of interacting with regulators, to more technical aspects of the medical product
challenge such as preclinical and clinical development, expedited pathways, orphan designation,
pediatric products and product formulation, manufacturing and control. Of note, this book takes
a systematic approach, spanning the earliest stages of research and development to necessary
assessments and modifications in the postmarket period, as well as embracing globalization’s
realities for regulatory strategy and systems.
No matter how steeped one is in drug development and regulation, this book can provide
both updated information and new insights. And, for those still being initiated into this exciting
and essential realm of professional activity, this book can serve as a vital handbook for knowledge
and action.
Given the array of unmet medical care and public health needs before us, this is not an
academic exercise. There is a pressing responsibility to make sure the opportunities in science and
technology today will result in the safe, effective and high-quality medical therapeutics people
so hope for and deserve. Every effort must be made to ensure the best possible products are
delivered as swiftly and surely as possible, but never forgetting the scientific rigor and regulatory
oversight that ultimately determine failure or success.

Margaret A. Hamburg, MD
Former FDA Commissioner

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x All rights reserved; file sharing prohibited.
1 Introduction to
Regulatory Strategy

By Darin S. Oppenheimer, Jessica L. Hale, Suraj Ramachandran

1
2
3
4
and George A. Cusatis

5
Introduction products and digital health solutions), a robust
and comprehensive regulatory strategy document 6
The role of the regulatory professional has is at an all-time premium.
continued to evolve over the past several decades.
The traditional regulatory affairs role has devel-
Now that a regulatory strategy’s value in 7
a global environment is understood, a deeper
oped into more of a regulatory science-driven dive into the elements that constitute a suc-
strategist role critical for many organizational cessful strategy, including definition, scope and 8
collaborating functions. Strategy and planning objectives, roles and responsibilities and inte-
are concepts frequently discussed in many facets gration into the product lifecycle, is essential.
of the profession and continue to shed light on The Merriam-Webster Medical Dictionary 2019 9
new opportunities to highlight the regulatory defines “strategy” as “an adaptation or complex
professional’s value. In its simplest form, strategy
can be considered bringing a new product to
of adaptations (such as of behavior, metabolism,
or structure) that serves or appears to serve an
10
market, but strategy touches every product devel- important function in achieving evolutionary
opment lifecycle aspect and can ensure market success.” Therefore, regulatory strategy is an orga- 11
sustainability. A limited or inadequate strategy nization’s adaptation to progress its product from
can challenge global expansion, thus emphasizing development throughout its lifecycle.
the importance of a well-designed and executed Strategy relates to the entire development 12
regulatory strategy. program, allowing the company to identify
A regulatory strategy is a foundational doc-
ument that clearly outlines the critical regulatory
problems prospectively to avoid being surprised
when they occur. This means the company must
13
pathways and objectives to ensure adequate plan- consider CMC, nonclinical, clinical and regu-
ning to bring a new product to market, as well latory throughout the program and the impact 14
as the overall sustainability and the product end they have on each other, since change in one area
of life. Since this document is foundational, it is can seriously impact a parallel discipline. Each
expected to evolve through the product’s life- respective area should consider how regulatory 15
cycle from cradle to grave and be embedded in changes may potentially impact other functions,
the lifecycle and various review stages that occur
during organizations’ product lifecycle activities.
current operations and processes to begin plan-
ning for changes to take effect.
16
The strategy document provides clear guidance This chapter explores the requirements for
for the various participating functional teams developing a strategy for a US-centric drug 17
to ensure critical strategic regulatory elements development plan, as well as postmarketing
are considered and embedded throughout the strategy, with some global considerations, since
product lifecycle. As products continue to evolve drug development is increasingly becoming a 18
in complexity and design (such as combination global effort.

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 Chapter 1: Introduction to Regulatory Strategy

Developing the Strategic Document Goals

The strategy document format depends on the • for approved programs, provide lifecycle
company, its culture, past experiences of the management goals
regulatory professionals leading the effort and • for clinical programs, identify the prod-
the amount of detail the company wants to uct-specific target disease and patient
include in the final product. Ultimately, a strategy population from the commercial plan,
i.e., target indication or target label claim
document is an organized meld of all drug devel-
• for early programs, a single target dis-
opment facets, from pre-IND through marketing
ease may not have been selected (In this
authorization application (MAA) and into com-
case, goals should focus on the current
mercialization, agreed by multiple stakeholders. stage and diseases being considered.)
The document must capture drug development • identify major CMC goals for current
process changes, so the whole team understands program stage, e.g., new product regis-
them and their impact on the strategy. tration, new formulation, or significant
The company’s strategic output should include: manufacturing process change
• answers to development questions and • nonclinical studies needed to support
issues by phase and discipline (subject to the clinical trial application, clinical trials
change) (since patients can be dosed for the same
• exploration of accelerated approval options length of time as that of nonclinical
• product exclusivity studies) and the marketing application
• documented risks based on assumptions
Playbook Format
• planned regulator interaction timing
○ develop questions, by development This is a comprehensive outline including all
phase, to address with each agency regulatory strategy components:
• clinical endpoints and indication infor- • lays out all assumptions, regulatory
mation by investigation phase filings and timelines
• molecule history (including regulatory • captures the strategy at a point in time
actions and past precedents)
○ sections can be added or deleted as
needed
• Target Product Profile (TPP)/initial
○ can be updated as assumptions
label creation
change
• goal creation and timeline mapping
• most important document section is the
TPP
To assemble a successful strategic document, all
perspectives must be aligned toward the same Critical Elements for a Successful Strategy
goal and address everyone’s needs. This area
This section’s goal is to clarify whether the
can be a challenge when there are competing
drug’s path to registration in the target dis-
perspectives; however, team diligence is needed
ease and patient population (indication) is
to produce a first strategy document draft (which straightforward (guidelines available, precedents
may mean conducting an offsite meeting if team set, program-specific agreements with health
members are dragging their feet in producing the authorities) or will require more negotiation with
document). If agreement among all the contrib- health authorities (no guidelines or recent drug
utors cannot be reached, upper management will approvals, no validated clinical endpoints). The
need to resolve the hindering issues. following should be considered:

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
• availability of ICH, US and EU guide- including primary and secondary objectives,
lines for indication, nonclinical studies those accepted by regulators and those that are 2
or CMC (Significant differences in experimental (not necessarily accepted by regula-
these requirements should be high-
lighted (and updated when the regula-
tors, but are in published literature).
• provide information on clinical trial
3
tory landscape changes).) design, endpoints and duration of
• availability of literature to support clini- treatment 4
cal endpoints in the absence of guidance • calculate statistically what the expected
documents or previous approvals differences will be between the standard
• program-specific advice received from of care and the new product, and how 5
health authorities (This can include many subjects will be needed in each
advice previously received on other pro-
grams involving a similar product type
trial to establish efficacy, noninferiority
or superiority (depending on the stan-
6
or issue, and clinical endpoint clarity for dard of care)
regulatory approval.)
Safety Expectations
7
• route to approval for competitive drugs,
such as issues encountered by other drugs
• status of any relevant global regulatory
This section should list regulatory requirement 8
issues, e.g., transmissible spongiform assumptions to establish safety for all study phases.
• comments on safety database size,
encephalitis
need for studies in special populations, 9
Filing Expectations drug interactions and any product-

This section should provide a brief general over-

specific attributes impacting safety data
requirements
10
view of approval filing plans, including timeline, • most prevalent serious adverse events
agency review timeline and review type:
• indicate special filing mechanism eligi-
(SAEs)/adverse events (AEs) 11
bility, such as an orphan drug, acceler- Nonclinical Expectations
ated or conditional approval, fast track,
This section should list regulatory requirement
12
breakthrough designation, PRIME, etc.
• detail appropriate to the development assumptions for nonclinical studies to support
stage the TPP for clinical trial applications through- 13
• emphasis on clinical trial applications, out development, and for marketing applica-
tions, by country.
pre-IND meetings, etc., scientific advice
early in development
14
CMC Expectations
• more detail on marketing applications,
including geographic regions where This section should list assumptions related to 15
applications will be filed, submission major CMC goals:
requirements and timelines in Phase 2b
and beyond
•
•
Phase 1, 2 and 3 formulation
proposed timing for the clinical mate-
16
• plans for filing in “rest of world” markets rial, process validation and commercial
should be addressed late in development lot manufacturing campaigns 17
Efficacy Expectations • scale-up and when it will be done (Phase
1 and 2, Phase 2 to 3, or after Phase 3)
This section should list regulatory requirement • product in packaging, storage and sta- 18
assumptions to achieve the target indication, bility study conduct

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 Chapter 1: Introduction to Regulatory Strategy

• stability testing length and an overview of the when, who, what and why of
environmental conditions regulatory strategy (in the form of drug develop-
• CMC assumptions impacting clinical ment and postmarketing surveillance plans with
plans (e.g., a significant manufacturing some package insert elements) and the regulators’
change in necessitating a bioequivalence perspective on a company’s regulatory strategy or
or immunogenicity trial) lack thereof. Benefits of a strategy include:
• driving identification and management
Labeling Expectations of prospectively defined regulatory issues
or problems (some arise unexpectedly,
This section should list assumptions on label
such as an excipient not being com-
statement types supported by the current devel-
pendial in all countries or the need for
opment plan (TPP).
additional nonclinical trial requirements)
Risk Management Assessment • identifying target markets in which the
product will be commercialized; this
This section should contain a table including: will help shape the regulatory expecta-
• risk event tions necessary to meet those specific
• probability country requirements
• impact severity • identifying and mitigating risks in the
• mitigation and management plan development program
• documenting the strategic decision-
The table should be populated when risks are making process and input from all team
identified and should outline how those risks will members
be mitigated (and at what phase) or whether the • serving as the framework for evaluating
team will accept them. change
• creating awareness of key project issues
Strategy Implementation and risks within the development and
management team
As the adage says, “If you fail to plan, you plan to • ensuring efficient project resource
fail.” Implementing a strategy allows a company utilization
to chart its course forward and examine the pit- • can create credibility with regulatory
falls and mitigate any risks, challenges or issues agencies because the company has
the drug might face. Small companies tend to demonstrated a clear understanding
fail to plan, not recognizing the value of strategic of regulatory requirements and
development. They may claim to be “too busy” to has included them within the
develop an overall strategic plan; putting together comprehensive planning
the target product profile or draft package insert • can result in timely product approval,
at the end of a Phase 2 trial or during NDA thus meeting timeline objectives
preparation, only to find additional nonclinical • optimizes the opportunity to develop a
or clinical studies (such as QT prolongation or program with labeling claims superior
drug-induced liver injury) are needed to sup- to the competition’s
port the filing or claims. This is not a winning • expediting patient access to new and
strategy, and a company should plan early and improved products and therapies
evaluate all possible scenarios before proceeding • ensuring marketed product sustainability
with the program. In the long run, developing a
strategy will save both time and money, and help The ideal time to develop a strategy is before fil-
focus the development team. This book provides ing an Investigational New Drug (IND) applica-

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
tion (pre-IND stage), when the team is thinking Functional Area Subject Matter Experts’
about all drug development plan elements. Pre- Roles and Responsibilities 2
IND meeting requirements include submitting a
Typically, the global development team works
development plan with the meeting package; this
can be used to drive the team to map out a plan.
together to create the drug or biologic devel- 3
opment plan. The effort is led by a regulatory
Additionally, if the company communicates the
strategy to regulators via a TPP or other means
professional (or regulatory lead) who drafts a
plan for team discussion. Each team member
4
(usually in a meeting), the agency will gain an
brings a unique perspective to the process, acting
understanding of the company’s strategic think-
ing, thus allowing more efficient use of resources
as a Subject Matter Expert (SME) for his or 5
her respective role, and affects the ultimate
and helping keep timelines in check. This also outcome of the strategy negotiations, which in
gives the company a favorable image with the turn influences the drug or biologic development 6
regulatory agency for future product submissions. process. Some questions team members may ask
Timeline
about perspectives or a new compound typically
comprise (but are not limited to):
7
This section should present the timeline to approval,
including at least the following as appropriate:
Preclinical
8
• Is there a scientific basis or rationale for
• pre-IND meeting
this drug or biologic?
• IND/Clinical Trial Application (CTA)
filings
• Does this rationale justify moving into 9
humans?
• End-of-Phase 1 meetings (if appropri-
ate to the drug’s development)
• Do pharmacology studies demonstrate
the mechanism of action?
10
• End-of-Phase 2 meetings • Are the findings reproducible?
• planned European Medicines Agency
(EMA) or national scientific advice
• Are there any specific toxicology signals 11
of concern?
• presubmission meetings • What battery of nonclinical studies will
• registration filing (major markets and need to be conducted for an IND and 12
secondary markets) eventually for an MAA?
•
•
regulatory approvals
postmarket meetings
Manufacturing 13
• postmarketing surveillance • Can the active ingredient be made

Additional Items to be Considered

consistently, and from where will it be 14
secured?
• Are the starting materials produced
• key health authority meeting and tele-
according to GMP? 15
conference minutes • Are there any inspection issues with the
• competitive labeling table
• list of regulatory guidance documents, •
active ingredient vendor?
When was the site inspected last, and is
16
including FDA and EMA Committee the vendor willing to provide a copy of
for Medicinal Products for Human Use the last inspection? 17
(CHMP) guidelines, FDA Advisory • Does the active ingredient vendor have
Committee Meeting minutes, European a drug master file?
Public Assessment Reports, etc. • Are the drug substance excipients 18
• product exclusivity compendial in all countries in which a

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 Chapter 1: Introduction to Regulatory Strategy

clinical trial and marketing application • Has previous agency feedback on a

are planned? similar product type been received that
• Can the compound be manufactured can be leveraged?
consistently and at current facilities? • How can regulatory and/or competitive
• Will outside vendors or contract manu- intelligence be leveraged to mitigate risks?
facturers be needed?
Legal Department
• How much will it cost to produce?
• Is the formulation optimal for the • Can the company protect its intellectual
intended target population? property, or is it infringing on others?
• Is the drug or biologic stable? • Is it patentable?
• Will any analytical methods have to be • Will our confidentiality be maintained?
developed?
Medical Affairs
• What container closure method will be
used? • Is there a medical need or therapeutic
• What material changes can be value for the drug in each country
anticipated for this product? in which a clinical trial or marketing
• What are the regulatory pathways application is planned?
required for these changes? • How is the disease diagnosed and
• Will the end-user be able to use the treated currently in each country
product safely? for which there is a clinical trial and
• Will the product require the patient to marketing application planned?
travel to a provider for their medication • What is the standard of care for the
to be administered? disease in each country in which a
• Will the product be able to be manip- prospective clinical trial is planned, and
ulated in patients who do not have full how will the new drug impact this?
hand mobility? • What drugs are used off-label to treat
this disease?
Regulatory • What are the concomitant medications?
• What is the drug’s regulatory status in • What are common adverse events?
each country in which a clinical trial • Can safety and efficacy be proven?
and marketing application is planned? • What will the trial endpoints and design
• Has the drug been approved before in be, and have regulatory authorities vetted
its current or another form? these? Are the endpoints established or
• Has there ever been a recall for this type based on the literature?
of drug and why? • How many patients are in the target
• Can precedents be relied upon, or is the population (is it orphan designation)?
drug too old (i.e., pre-ICH or prior to • How many studies and patients for each
1997)? will be needed for an approvable MAA?
• What regulations or guidance docu-
ments apply? Finance/Business Development
• What FDA division will be reviewing • What is the return on investment?
the drug, and what is the division’s • How much will it cost to develop?
culture? • Can the company afford to develop it,
• What pathway should be chosen based or does it need to raise capital or find
on the pathways used by precedent a partner to complete the development
drugs, or are there no precedents? program?

6 All rights reserved; file sharing prohibited.

 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
Marketing • What patient needs are not being met
• What is the new drug’s potential market from the current design? 2
position? • Are there opportunities to implement
• What other drugs are on the market,
and what are their annual sales?
further risk mitigation as a proactive
approach? 3
• How does the new drug differ from
Conclusion
other drugs, and is there room on the 4
market for a new therapy?
In summary, regulatory strategy incorporates the
• What will patients be willing to pay for
the drug?
drug development plan, outstanding issues or
questions, background information, regulations
5
Reimbursement and/or guidance documents, strategic advice, past
• What metrics must be included in the precedents (if any), risks and proposed mitiga- 6
studies to justify the drug price? tions and recommendations on implementation.
• What will insurers be willing to pay for
the drug?
Additionally, strategy can take the form of:
• an individual question pertaining to
7
• What information is needed to ensure a development program or change in
reimbursement for this drug? regulations 8
• Will there be reimbursement issues • a review of the development plan (gap
with any payers? analysis)
• a drug development plan (US, EU or 9
Postmarketing
global)
What methods will be used to
•
implement an active postmarketing
• a clinical development plan (US, EU or 10
global)
surveillance system?
• a postmarket surveillance plan (US and/
• How will patients (end-users) report
complaints? or global) 11
• What sources will intake product

•
complaints?
Who will process the product
It is paramount for the regulatory professional
to develop a robust regulatory strategy using the
12
complaints? above guidelines as a foundation for the devel-
• Who will assess and determine the need
to voluntarily report complaints to FDA?
opment program. It is no longer enough for a 13
regulatory professional to focus only on providing
• How often will postmarket reports be
reviewed? ‘regulatory’ guidance. As products continue to
evolve in their complexity, regulatory profession-
14
• What triggers will be used to indicate
a need for changes to target product als also must adapt by taking a holistic approach
profile design? to providing the strategic direction. Strategic 15
• How is this product being used in the thinking is needed in all drug development phases,
“real-world?” from designing a molecule to the postmarketing
• Is there unintended usage by the period, and is one way regulatory professionals 16
end-users that could result in harm?
can help lead teams through this arduous process
• Are there different patient populations
utilizing the product, for whom it was
and develop a strategic “playbook” as a general 17
not intended, and could result in harm? guide. As a general rule, all “playbook” questions,
Are there opportunities for new at minimum, should be addressed to ensure the
18
•
indications for use with other patient document is comprehensive and is an asset to the
populations? development team and process.

All rights reserved; file sharing prohibited. 7

 Chapter 1: Introduction to Regulatory Strategy

8 All rights reserved; file sharing prohibited.

2 The Regulatory Team

By Naseem Kabir, Susan Capps and Grace Jiang

1
2
3
4
5
The term “regulatory team,” simply put, refers to
a group of professionals who work together on
have responsibilities in other functions also, such
as clinical research or quality assurance, on top of
6
regulated projects and activities in compliance their regulatory responsibilities. Today, however,
with the laws and regulations of a particular the profession has grown significantly, with niche 7
country or region’s governing health authorities. functions operating under the broad regulatory
Each industry (e.g., medicinal products and affairs umbrella. Larger companies will have reg-
medical devices) has its own laws and regula- ulatory departments commensurate in size with 8
tions, which are overseen and enforced by specific their size, hiring multiple regulatory professionals
regulatory authorities. For example, the US Food who specialize in niche regulatory functions such
and Drug Administration (FDA) is responsible as clinical regulatory strategy, regulatory chemistry, 9
for protecting public health in the US by ensur- manufacturing and controls (CMC), regulatory
ing the safety, efficacy and security of human and
veterinary drugs, biological products, medical
writing, device and companion diagnostics regula-
tory, regulatory operations, international/regional
10
devices, the nation’s food supply, cosmetics, prod- regulatory, advertising and promotions, labeling
ucts that emit radiation and tobacco products.1 and policy. These functions often are grouped 11
The discussion of regulatory teams in this chapter together under “global regulatory affairs,”2 which
is limited to those participating in the premarket, in turn often reports to the research and devel-
registration and postmarket regulatory activities opment function. Regulatory CMC can reside 12
of drugs and biologics (collectively referred to in quality or global operation teams in certain
hereafter as pharmaceuticals).
Regulatory professionals are highly sought
companies, depending on the company’s organiza-
tional structure. Start-up companies generally are
13
by pharmaceutical manufacturers because their more resource-constrained and thus have skeletal
expertise and experience are considered essential regulatory departments to support their needs. 14
for the successful registration, launch and main- Generally, they will outsource resource-intensive
tenance of licenses in compliance with national regulatory projects or functions to contractors
and international laws and regulations. As such, and consultants to get the specialized regulatory 15
there is clear recognition that regulatory profes- support necessary to complete projects and handle
sionals are strong, pivotal partners when creating
product strategies and plans for development,
peak resource needs.
Regulatory team membership is not always
16
commercialization and lifecycle optimization. restricted to regulatory professionals. Depending
Twenty years ago, typical regulatory profes- on each company’s organizational structure, the 17
sionals worked on all aspects of the regulatory regulatory team could comprise people from
activities necessary to support a pharmaceutical’s various departments such as clinical research,
legal and commercial success. Then, it was not manufacturing, global health technology evalu- 18
uncommon for the regulatory professional to ation, etc. In the author’s experience, at a small

All rights reserved; file sharing prohibited. 9

 Chapter 2: The Regulatory Team

company working on its first US biologic filing, centralized unit tasked with a broad and critical
the CEO, a brilliant commercial strategist, was range of responsibilities. Hence, global regulatory
an integral member of the regulatory team. This team members must be appropriately qualified
is not to suggest CEOs should be that involved and experienced to successfully meet the compa-
with regulatory activities,3 but simply illustrates ny’s business goals.
that there is no hard and fast rule about regula- Global regulatory team membership varies
tory team membership. depending on the company’s size. In smaller
This chapter provides a generalized primer companies, the regulatory professional multi-
on global regulatory team membership within tasks and, by necessity, there is an “all hands on
a biopharmaceutical company and focuses on deck” mentality. As a result, regulatory profes-
various team members’ roles and responsibili- sionals in smaller companies are generalists,
ties, with the understanding that companies are since they gain experience in a broad range of
structured very differently, so the functions and regulatory functions and sometimes even in some
descriptions will vary from company to company. non-regulatory areas, such as quality, clinical or
reimbursement. In larger companies, the global
The Global Regulatory Team regulatory team has more resources and is com-
posed of representatives from well-delineated
To market their pharmaceuticals, companies specialty regulatory functions, including mem-
must obtain approval from each country’s rele- bers who are full-time company employees and
vant health authority in which they wish to com- sometimes contractors or consultants.
mercialize their products. The regulatory team is Whatever the global regulatory team’s size,
responsible for the entire spectrum of regulatory it collectively is tasked with providing strategic
activities spanning a product’s lifecycle. This regulatory leadership and is accountable for creating
includes early development activities (such as a global regulatory strategy that will lead to the
providing input on Investigational New Drug desired label, thus positioning the pharmaceutical to
(IND)-enabling studies, pre-IND meetings meet patients’ needs and business goals in a timely
and filing the IND), manufacturing, registra- manner. Company management routinely looks to
tion (including FDA and Advisory Committee the global regulatory team to produce innovative
meetings) and postmarketing activities (includ- strategies with clearly communicated probabilities
ing postmarketing requirements, commitments of regulatory success, risks and risk mitigation strat-
and lifecycle optimization). Further, the require- egies. As such, the global regulatory team should
ments for obtaining marketing approval and develop the ability to articulate and elucidate the
maintaining those licenses are not harmonized, likelihood of regulatory success based on proposed
varying from country-to-country, thereby adding strategies and to predict regulatory agencies’ expec-
complexity and challenges to the global environ- tations and outcomes accurately.
ment. As such, the regulatory team must include The global regulatory team ideally should be
members who are intimately familiar with each a high-performing team on which each member
country’s regulations governing how to obtain possesses the right education, skills and experi-
marketing authorization and how to remain on ence and applies his or her knowledge effectively
the market in a continuous state of compliance and collaboratively to achieve common goals.4
with the country’s regulations. This regulatory The global regulatory team will have myriad
team, thus, is called the global regulatory team. tasks, some of which may be compliance-related;
While the regulatory organizational structure these regulatory activities should be documented
varies among companies, with global regulatory through standard operating procedures (SOPs),
team members likely reporting to different parts and staff should be trained appropriately to
of the organization, the team comes together as a ensure they are in a continuous “audit-ready”

10 All rights reserved; file sharing prohibited.

 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
mode. Finally, it is imperative the global regu- Additionally, the global regulatory lead is
latory team members tasked with liaising with tasked with: 2
health authorities build and maintain good • overseeing the global regulatory filing
relationships with their health authority coun-
terparts, so they earn trust and are perceived as
strategy (e.g., clinical trial applications,
marketing applications, postapproval
3
credible partners. variations such as label extensions and

The Global Regulatory Lead

safety updates, CMC changes) 4
• ensuring all projects have a clearly
defined regulatory pathway and mile-
The team is led by a global regulatory lead who,
by virtue of having worked in the particular
stones, including key regulatory timelines 5
and regulatory critical path activities, to
therapeutic area for some years, generally is
experienced with the regulations governing the
•
support successful filings and approvals
ensuring compliance with regulations to
6
therapeutic/disease space, as well as its regulatory
minimize business risk
issues and risks. The global regulatory lead gen-
erally reports to the regulatory therapeutic area
• together with the regional or 7
local regulatory representatives,
head (or, in smaller companies, the head of reg-
understanding and interpreting highly
ulatory). The global regulatory lead usually is the
regulated and complex regulatory 8
company’s point person for regulatory matters
landscapes and, importantly, staying
and provides regulatory expertise and guidance
to team members from different departments.
abreast of changes to those landscapes,
so the global regulatory strategy can be
9
For example, the global regulatory lead represents
adapted suitably
the team on the company’s key commercializa-
tion and other governance bodies. As such, the
• liaising with subject matter experts to 10
review regulatory submission dossiers,
global regulatory lead has a strong leadership
meeting requests and briefing books
role and is primarily responsible for creating and
• driving consistent, accurate product label- 11
implementing the product’s regulatory strategy
ing that is compliant with regulations, and
and driving its execution and messaging globally
and consistently. The regulatory strategy plan is
ensuring consistency in evidence-based
global product communications
12
a comprehensive document that takes world-
• participating in developing worldwide
wide regulatory requirements into account and
outlines the path to drive product development,
regulatory agency interaction strategies 13
in collaboration with regional colleagues
global registration, achievement and maintenance
• representing the company on external
of desired global and regional labeling. It also
partnership teams 14
includes a strategy for effective regulatory agency
• supervising junior regulatory staff
interactions and desired outcomes, as well as
assessing the competitive regulatory landscape.
members, developing and coaching staff
on regulatory activities and providing
15
The global regulatory lead should communicate
ongoing coaching and feedback to
well-defined, successful regulatory strategies con-
sistently throughout the organization, so expecta-
direct reports to develop the team to its 16
full potential
tions are understood. Thus, the global regulatory
lead is a strong business partner, responsible for Regulatory Chemistry, Manufacturing 17
ensuring the global regulatory team aligns com- and Controls (CMC)
mercial objectives with available and expected
scientific data, regulatory guidance and precedent A company’s regulatory CMC department may 18
and delivers on corporate goals. be a single person who works with various con-

All rights reserved; file sharing prohibited. 11

 Chapter 2: The Regulatory Team

sultants to carry out regulatory CMC activities • reviewing technical reports and sum-
or may consist of several people. In the latter mary documents for adherence to regu-
case, each product usually is assigned a regulatory latory guidelines, strategies and com-
global CMC lead. mitments, and leading CMC document
The regulatory CMC professional is an development for global filings, while
integral member of the global regulatory team keeping abreast of all pertinent laws,
and the person with expertise on the product’s regulations and guidance documents
manufacturing process development, the global and providing insight on current regula-
registration dossier’s CMC content and the man- tions and guidance documents relevant
ufacturing facilities in which the different phar- to product development projects
maceutical manufacturing steps occur. The CMC • liaising with the regional CMC staff
professional is responsible for providing input at affiliate offices (or consultants) in
to the global regulatory strategy document on various countries to generate region-
CMC strategies; providing expertise in translat- specific CMC regulatory strategy and
ing CMC regulatory requirements into practical, activities impacting the region (If a
workable plans to facilitate the drug development regulatory activity is region-specific, the
progress from pre-IND, through clinical trials regional CMC team member usually is
and successful product launch. Thereafter, the responsible for leading the activity and
CMC professional is responsible for developing must coordinate efforts with the CMC
and implementing CMC-related regulatory lead or global regulatory lead)
strategies to facilitate lifecycle management by • providing leadership, supervision and
filing CMC postmarket manufacturing change mentoring to junior CMC regulatory staff
variations globally. • communicating with business partners
Further, the CMC professional is respon- and other external collaborators
sible for planning and holding effective health • recommending regulatory policies to
authority interactions related to product manufac- ensure adherence to global regulatory
turing strategy development and implementation CMC requirements and contributing
throughout the product lifecycle. He or she also to the modification, development and
develops timelines for responding to CMC-re- implementation of CMC regulatory
lated inquiries from global regulatory agencies to company practices and policies
ensure issues are addressed in a timely manner. • scheduling and tracking project-specific
Other CMC lead responsibilities include: and operational activities relating to
• supporting health authority audits CMC goals
of manufacturing plants (In many
• ensuring compliance with regulations to
companies, regulatory CMC personnel
minimize business risk
are located at manufacturing sites; these
• supervising junior regulatory CMC staff
individuals are known as site CMC
members, developing and coaching staff
personnel. They are responsible for the
on regulatory activities and providing
plant’s regulatory activities, as well as
ongoing coaching and feedback to direct
leading or actively participating in site
reports to develop the CMC team to its
Good Manufacturing Practice (GMP)
full potential
inspections by health authorities from
around the globe and responding to Regional and Local Regulatory Leads
health authority questions pertaining to
manufacturing activities carried out at The global regulatory team generally is repre-
their facilities.) sented by either a regional regulatory lead or

12 All rights reserved; file sharing prohibited.

 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
local regulatory representative from each region where the company is headquartered or major
or country in which the pharmaceutical will markets such as US, EU or Japan. Due to the 2
be developed and/or marketed. The former are nature of their jobs and because they often are
located physically at either the company’s head-
quarters or a regional “hub” and represent two or
located in different time zones, regional regu-
latory leads and local regulatory representatives
3
more countries in that region, while the latter are must have excellent communication skills and
located in the individual countries for which they culture sensitivity awareness, which are invaluable 4
are responsible. In many companies, the regional in communicating with global, cross-functional,
regulatory leads report functionally to regulatory cross-cultural, multi-disciplinary project teams.
leadership at headquarters, with a dotted line Regional regulatory representatives and local 5
to the regional medical affairs or research and regulatory leads are responsible for several other
development head. Local regulatory represen- regulatory activities in their countries, including:
tatives often report functionally to the regional • providing guidance on regional reg- 6
regulatory group and have a dotted line to the ulatory mechanisms to optimize and
affiliate general manager. In countries where
there is no affiliate office, the local regulatory
expedite a pharmaceutical’s develop-
ment (e.g., first-in-human studies,
7
representative may be an independent consultant orphan drug framework, pediatric plan),
or employee of a different company contracted estimating the likelihood of regulatory 8
by the pharmaceutical manufacturer to perform success based on proposed strategies
country-specific functions on its behalf (e.g., and communicating to and managing
pharmaceutical warehousing and distribution). expectations of the global regulatory 9
The regional regulatory leads and local team, as well as local stakeholders
regulatory representatives are responsible for
regulatory strategy and support activities in their
• planning and managing regulatory
submissions (e.g., clinical trial and mar-
10
countries, including developing country-specific keting applications) in compliance with
regulatory strategies. They must ensure all regula- global filing plans and local regulatory 11
tory activities in their countries are aligned with requirements and providing guidance
the global regulatory team’s strategic direction. on the regional regulatory documents’
Thereafter, they are responsible for updating content in accordance with the global 12
regional regulatory strategies and implementing regulatory strategy
the strategies necessary to ensure successful new
product registrations, obtaining desired phar-
• managing regional product label
development, preferably based on
13
maceutical labeling and maintaining approved the company core data sheet for the
licenses in compliance with local requirements. pharmaceutical; generally, the regional 14
To be successful, they must have knowledge regulatory lead and/or local regulatory
and expertise of the local laws, regulations and representative will need to collaborate
guidance documents, and must advise the global with the global regulatory lead to define 15
regulatory team on the development of regional commercial objectives in the context of
regulatory product strategies, including prece-
dents, risk management, upcoming changes to
available and expected scientific data,
regulatory guidance and precedent; the
16
laws and/or policies and contingency planning. local regulatory representative also is
In implementing and optimizing corporate strat- accountable for label negotiation activi- 17
egies and messages into local regulatory plans ties with the local health authority
and labels, they must be able to think creatively, • acquiring and maintaining all required
since local regulatory frameworks and pathways licenses to support clinical trials for 18
likely are very different from those of the country investigational pharmaceuticals and

All rights reserved; file sharing prohibited. 13

 Chapter 2: The Regulatory Team

commercially approved pharmaceuticals; inside and outside the company. The regional
the local regulatory representative then regulatory lead functions as the back office that
is responsible for ensuring compliance advocates for the local regulatory representatives’
with local regulations, with a focus on needs to stakeholders in the company head-
patient safety and minimizing business quarters and otherwise provides critical support
risk that allows the local regulatory representative to
• acting as the lead contact for health function effectively and collaborate seamlessly.
authority interactions, such as lead-
ing local health authority meetings, Regulatory Writer
assembling health authority question
The regulatory writer is a core member of the
responses, supporting clinical and
global regulatory team who, working with physi-
manufacturing site inspections in their
cians, scientists, and other subject matter experts,
countries and overall building and
maintaining healthy and credible health is responsible for producing highly technical
authority relationships evidence-based regulatory documentation based
• keeping stakeholders abreast of new on scientific research and documentation. The
developments and managing expecta- writer essentially conveys the pharmaceutical’s
tions “story” (e.g., key messaging on how the phar-
• monitoring regulatory intelligence and maceutical was developed, is manufactured,
the local regulatory environment and is used, what it does and how, its side effects,
communicating the impact of new benefits and risks, etc.) while adhering to the
policies or laws or changes to existing health authority’s strict structure, format and
requirements to the global regulatory content guidelines. Regulatory writing, while
team; contributing company comments scientific in content, also largely is an art and,
to draft health authority policies and therefore, regulatory writers are in high demand.
guidance documents and participating The regulatory writers’ documents usually are
in activities promoting or influencing reviewed by subject matter experts for accuracy;
the science behind the company’s prod- by the global regulatory lead, CMC and regional
ucts or policy priorities regulatory lead for regulatory compliance to local
• advising and supporting local advertis- health authority requirements and to ensure the
ing and promotion activities messaging is appropriate; and by various other
• supervising junior regulatory staff departments (legal, etc.) for different reasons. The
members, developing and coaching staff regulatory writer is responsible for drafting each
on regulatory activities and providing document, sending it to relevant reviewers for
ongoing coaching and feedback to edits, and rewriting versions of each document
direct reports to develop the team to its until the review team is satisfied. Each document
full potential generally needs to be approved by senior man-
When both the regional regulatory and local reg- agement before it is published and submitted to
ulatory roles exist within a company, it is import- the health authority. The regulatory writer’s key
ant that the accountabilities and responsibilities activities include:
are clearly identified between them to avoid • participating in regulatory document
confusion and disagreement. In companies where study timeline development
both roles exist, they often are organized such • providing input to the regulatory sub-
that the local regulatory representative functions mission strategy
as the front office that interacts with the local • overseeing and managing contractor and
health authorities and other local stakeholders freelance contract research organization

14 All rights reserved; file sharing prohibited.

 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
activities, and content of documents photocopying or scanning documents,
written by them as requested 2
• participating in junior medical writer • training junior staff to develop their

•
training and mentoring
keeping abreast of professional informa-
electronic publishing skills and/or opti-
mize relationships with suppliers
3
tion and technology through literature, • ordering literature references for use in
symposia and conferences electronic submissions, as needed 4
• assisting with maintaining electronic
Regulatory Operations and publishing templates
Submissions 5
Regulatory Policy
The regulatory operations member of a global
regulatory team is responsible for publishing, sub- The regulatory policy group may have different 6
mitting and overseeing the archiving of regulatory names in different companies (e.g., regulatory
intelligence or government affairs). This group
documents to health authorities, using appropriate
software and programs. The submissions can be may not have a representative on the global reg- 7
electronic (such as an eCTD for FDA) or paper- ulatory team but often is consulted by the team
based; in either case, the role requires someone when a clearly defined regulatory pathway does
not exist, or intelligence is needed about how
8
with strong attention to detail to ensure submis-
sions comply with the company style guide and other companies have addressed similar prob-
health authority requirements and precise entry of lems. Generally, regulatory policy reports directly 9
submission-related data into regulatory databases. to the head of the regulatory department.
Broadly speaking, regulatory policy is
Other responsibilities may include:
• maintaining a filing system (electronic responsible for influencing health authorities 10
and paper) for the regulatory depart- and other external stakeholders on issues in
ment and assisting in preparing submis- which the company has a vested interest. It often 11
sion documents, including formatting defines and documents its priorities, and then
MS Word files to conform with the for each priority, creates messaging, a negotiation
company style guide and adding book- strategy and a plan to engage political stakehold- 12
marks and links to PDF files ers and relevant government agencies. Regulatory
• contributing to the development of
submission timelines and plans
policy’s work helps define a vision for the future
by outlining and communicating priorities and
13
• providing publishing quality control building consensus toward achieving regulatory
support by double-checking submission reform. The regulatory policy professional often 14
documents (e.g., ensuring the hyper- represents the company’s interests by sitting on
links work and pagination is accurate) working groups of trade associations (e.g., the
and maintaining QC forms Pharmaceutical Research and Manufacturers of 15
• administering and maintaining doc- America (PhRMA) and Biotechnology Industry
ument repository areas for regulatory
(both paper and electronic) in accor-
Organization (BIO)) and engages the health
authority in an effort to build and strengthen
16
dance with GMP, Good Laboratory regulatory policies, tools and institutions for the
Practice (GLP), Good Clinical Practice industry as a whole. Participation in such associa- 17
(GCP) and regulatory requirements tions helps considerably by allowing companies
• serving as a resource for company to learn from each other’s experiences and deter-
personnel, to allow appropriate access mine the types, extent and criticality of issues 18
to documents, including retrieval and facing the pharmaceutical industry. These associ-

All rights reserved; file sharing prohibited. 15

 Chapter 2: The Regulatory Team

ations also serve as “think tanks” for modernizing The labeling group’s roles and responsibili-
current regulatory pathways and developing new ties vary from company to company and are very
regulatory pathways where currently there are dependent on each company’s organizational
none. Thus, the regulatory policy professional is structure. (Note, the labeling group generally is
responsible for building and maintaining a deep not responsible for the label that accompanies
understanding and knowledge of policy topics clinical trial materials, which in most companies
impacting the company, anticipating current or is handled by a group within the clinical research
ongoing changes in the landscape, recognizing department.) Smaller companies usually do not
emerging trends (including new regulations and have a separate labeling group, and the regional
processes that can impact the company), commu- regulatory lead performs those functions. The
nicating these issues to the senior management individual responsible for a product’s labeling
of their company and collaborating with the may not be a regular global regulatory team
global regulatory team to inform product regula- member, because the labeling representative
tory strategies and planning assumptions. often works across several different products at
a time. Nonetheless, the labeling representative
Labeling works very closely with the global regulatory
team to develop and implement the global label-
Developing the pharmaceutical’s label is a com-
ing strategy, including developing target labeling,
plex process and the global regulatory team’s key
the core data sheet and core labeling materials
responsibility. Labeling generation and lifecycle
and providing expertise in translating regulatory
management fall under GMPs in most countries
labeling requirements into practical, workable
and, thus, are heavily scrutinized by inspectors
plans. Other labeling professional responsibilities
during health authority audits; further, the label
may include:
forms the basis of advertising and promotional
• creating and maintaining US, EU or other
claims the company can make about its pharma-
country-specific packaging and labeling
ceuticals and often dictates pricing reimburse-
• developing the necessary SOPs for
ment strategies. For these reasons, many compa-
labeling document review, approval and
nies have dedicated labeling groups within their
archiving (This includes contributing to
regulatory departments. The labeling process
the continuous improvement of the end-
involves multiple steps that need to be executed
to-end labeling process and managing
properly and coordinated carefully to avoid chal-
the company’s labeling review process.)
lenges that can delay patient access if the process
• ensuring the quality of labeling deliv-
is not well managed. A pharmaceutical’s labeling
erables (e.g., alignment of labeling text
is based on the product’s core data sheet, and
with data, regulatory requirements, and
the labeling group generally is responsible for
consistency between labeling documents)
developing that core data sheet and core labeling
• training other labeling staff in perform-
materials (e.g., the package insert, medication
ing labeling tasks
guide or instructions for use). The core data sheet
describes the company’s position on all the phar- Advertising and Promotion
maceutical’s aspects (e.g., its safety profile, indi-
cations studied, how it should be administered, The regulatory advertising and promotion
safe storage, etc.). It is updated periodically as professional is responsible for working with the
new data about the drug become available.5 It is global regulatory team and commercial groups to
the basis of the labeling proposed and negotiated ensure advertisements and other pieces intended
with each country’s health authority to constitute to promote the pharmaceutical’s use to health-
the product’s approved final labeling. care professionals, patients and the public are

16 All rights reserved; file sharing prohibited.

 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
truthful, balanced (based on labeling approved vide intelligence on competitor advertis-
by the health authority) and accurately commu- ing and promotional activities 2
nicated outside the company. Pharmaceuticals’ • contributing to company SOP and pol-
advertising and promotion are highly regulated,
and the advertising and promotion professional
icy creation, implementation and modi-
fication for advertising and promotional
3
must be very familiar with the regulatory and activities, and providing guidance and
legal standards and their specific application to education to the organization regarding 4
the pharmaceuticals’ advertising and promotion, promotional and advertising regulatory
which may include detailed analyses of competi- updates and climate
tor advertisements and promotional pieces. Each • keeping abreast of all pertinent laws, 5
country has its own advertising and promotion regulations and guidance documents,
policies; for example, in the US, the pharmaceu-
tical medicines’ advertising and promotion can be
and upcoming changes to them, as
well as providing insight on the impact
6
regulated by FDA, the Federal Trade Commis- of new or updated regulations on the
sion, Drug Enforcement Agency, Public Health
Service, Office of the Inspector General, state
company (The advertising and promo- 7
tion professional also must evaluate the
attorneys general and prosecutors. In addition, health authority’s promotional enforce-
organizations such as PhRMA and the Amer- ment activities and assess the changing 8
ican Medical Association provide professional regulatory environment to determine
guidelines on advertising and promotion.
Like the labeling professional, the advertis- •
the impact on the company, if any.)
perhaps managing the activities of junior
9
ing and promotion professional reports to the advertising and promotion regulatory
company’s regulatory department. Advertising
and promotion professionals work with indi-
staff or contracting support staff to per- 10
form advertising and promotional duties
vidual global regulatory teams, across several
such teams to provide expertise in translating Device and Companion Diagnostics 11
the heavily scrutinized and complex advertis-
ing and promotion requirements into practical, While this chapter focuses on regulatory team
workable plans and formulate and communicate members at companies manufacturing prescrip- 12
the regulatory promotional position for the tion medicines or biologic products, many of the
company’s approved and pipeline products. They
review each advertising and promotional piece
roles and responsibilities described also apply to
regulatory teams at medical device and generic
13
against the approved labeling and core data sheet drug companies. Where pharmaceutical manu-
and approve it for release if it meets the myriad facturers also are responsible for delivery devices 14
requirements. Additional advertising responsibil- used to administer the medicine, or where the
ities generally include: medicine is to be used in conjunction with a
• developing and implementing strategies companion diagnostic or device, the global phar- 15
to facilitate promotional materials and maceutical regulatory team includes a member
activities’ development and review, as well
as scheduling and tracking project-specific
familiar with device or companion diagnostics
law, regulation and guidance document knowl-
16
advertising and promotional activities edge and experience. Frequently, delivery devices
• representing regulatory on commercial and companion diagnostics are manufactured 17
teams that direct marketed product and marketed by a separate company, in which
activities to advise them on regulatory case the regulatory professional works very
laws and policies to ensure adherence to closely with that company to establish sustain- 18
health authority requirements and pro- able processes, ensure informed relationships

All rights reserved; file sharing prohibited. 17

 Chapter 2: The Regulatory Team

and deliver strategic outcomes. For example, the • conducting risk management and
regulatory professional will work closely on regis- scenario planning activities and driving
trations and filings and be actively involved with contingency and/or risk mitigation plan
clinical and commercial regulatory strategies, development
as well as associated health authority meetings • documenting issues, decisions and
for the delivery device or companion diagnostic. action items from team meetings and
Additionally, he or she may: escalating project issues appropriately
• support filing strategy and filing content • managing corporate governance proce-
reviews dures to ensure the company’s portfolio
• contribute to integrating the device development program and decision-mak-
or companion diagnostic into the ing procedures can move forward
company’s commercialization and
labeling documents Market Access
• support device or companion diagnostic
The regulatory leads partner closely with their
manufacturing change decisions
counterparts in market access to ensure reimburse-
Regulatory Program Manager ment requirements are appropriately included
in regulatory deliverables. Payers for this section
In mid- to large-size companies, a program are defined as organizations (e.g., government,
manager usually sits on the global regulatory hospitals, pharmacies or private health plans)
team. Due to regulatory activities’ complex- that provide insurance to patients or pay directly
ity, the program manager is key in driving the for medicines. Overall, regulatory leads need to
development and execution of complex, global, understand a basic concept about payers: payers
integrated cross-functional project plans to want to know why they should pay for a new
support the overall program strategy. The pro- medicine, given the availability of existing medi-
gram manager applies project management best cines in the market. Payers have limited budgets
practices in developing, initiating, planning, exe- and need those budget monies to cover health
cuting, controlling and closing projects, so each interventions within their populations.
step is executed in a timely manner and results Market access leads work to address payers’
in high-quality outputs. Some of the program information needs to ensure products have a
manager’s duties include: robust value proposition, maintain current reim-
• partnering with functional leads to bursement, remove inappropriate restrictions and
develop high-quality, integrated plans achieve timely access for the appropriate patient
for cross-functional sub-teams aligned population. Market access leads work with the
with the overall program strategy clinical development organization and the regu-
• identifying key deliverables and their latory leads to develop products with compelling
interdependencies for each function clinical and economic evidence to meet regula-
• ensuring cross-functional alignment and tory and payer expectations.
accountability • Product label—The label is the main
• identifying project issues or resource driver for determining payer reimburse-
gaps and facilitating resolution ment. Specific product label sections
• driving decision making have the most impact on reimbursement
• monitoring and communicating prog- decisions.
ress and adherence to timelines ○ Indication statement: Identifying
• facilitating resource planning and finan- the appropriate population for
cial capacity assessments, as needed reimbursement is a critical input

18 All rights reserved; file sharing prohibited.

 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
when planning for the indication pathway (Part B in the US)
statement. This population could and hospital (in many ex-US 2
be more-targeted than is needed countries). There is no right or
for regulatory approval. Regulatory
leads and market access leads need
wrong pathway, but the regu-
latory leads should understand 3
to discuss the patient population the implications of a product’s
payers recognize as having the administration language on its 4
greatest unmet need. For example, reimbursement strategy.
if payers are likely to accept new ○ Clinical trials sections: The market
brands as only second-line therapy access lead should be consulted if 5
because generic alternatives are a country label allows additional
viewed as sufficient first-line ther- clinical trial information to be
apy, it may be appropriate to limit included. There may be additional 6
the indication statement accord- data, such as long-term response,
ingly. In this case, this will directly
impact clinical trial design for
that would be useful for payers in
determining reimbursement.
7
registration. In another example, a • Clinical trial endpoints—Payers usually
country’s reimbursement regulations require certain endpoints or additional 8
may require setting a price based on endpoints to inform reimbursement
a competitor price, if the indication decisions. These endpoints may or may
statement for the new brand is the not align with what regulators will need 9
same as that of the competitor. In to approve a drug. It is critical that the
such instances as these, appropriate
trade-offs need to be made for the
regulatory leads have a cross-functional
discussion with the market access leads
10
overall product strategy. on the endpoints necessary for reim-
○ Dosing and administration—Lan- bursement. From the strategy discus- 11
guage used in this section could sions, the team will determine how best
affect a product’s price setting or to incorporate payer endpoints into the
reimbursement type. clinical trial program. For example, pay- 12
♦ A product’s dosing specifica- ers are largely interested in event-driven
tions, and its available SKUs
(stock keeping units), can affect
endpoints. Payers tend to put less value
on a drug that only demonstrates efficacy
13
product pricing and its SKUs. on surrogate endpoints and has no data
For example, if a product has on hard outcomes (i.e., event-driven end- 14
variable dosing and single-use points). Additionally, the regulatory leads
vials, product waste may result. may need to determine the appropriate
If the potential waste is sig- order for endpoint statistical testing, or 15
nificant enough, payers and whether endpoints should be primary or
the public could view this
negatively. One result could be
secondary to optimize reimbursement.
In another example, a patient-reported
16
payers requiring price discounts outcome measure (PRO) may be nec-
for unused medicine. essary to demonstrate a drug’s full value 17
♦ Stating that a product needs to to the payer. In this case, the PRO likely
be administered by a health- needs to be included in the Phase 2 trial
care professional may trigger to assess how the drug performs with 18
a specific reimbursement the validated PRO instrument. With

All rights reserved; file sharing prohibited. 19

 Chapter 2: The Regulatory Team

these data results, the regulatory lead and The above section is not meant to be exhaustive,
product team can determine the appro- but highlights particular areas where regulatory
priate PRO endpoint for the label and, of and market access colleagues need to collaborate.
course, inclusion in Phase 3 trial design.
• Early scientific advice—With some Conclusion
payer-related authorities, such as health
This chapter has outlined the global regulatory
technology assessment (HTA) bod-
team’s various functions and how those roles and
ies, manufacturers can obtain early
responsibilities support and enhance overall reg-
advice on data, endpoints, clinical trial
ulatory deliverables and outcomes. Regardless of
designs, etc. Manufacturers need to
their functions, a strong global regulatory team’s
follow formal processes to obtain this
members are scientifically or technically savvy in
advice. Much of the information HTA
bodies require will be similar to the their ability to understand and analyze complex
information required by regulators, who problems rapidly. It also is important that team
also provide early advice. Therefore, it members possess sound leadership skills and the
is important that the regulatory leads credibility to allow them to influence global proj-
coordinate with market access leads ect teams, line and matrix management and other
and the health economics team on the external stakeholders on strategic and operational
information packets and questions for issues and deliver on budget within agreed time-
early scientific advice, and the timelines lines. They should lead, participate and manage
for obtaining this advice. projects actively, and drive the team to solution
• Response-to-Questions (RTQs)—Reg- development and implementation. Finally, team
ulatory leads should share question members should work well as both individual
responses with market access leads for contributors and within a team environment and
new product launches. Some questions contribute strategically and operationally to their
from payers or HTA bodies can be the companies’ business goals and priorities.
same as those received by regulators. Finally, it is highly recommended that
Therefore, the payer team can use the regulatory team members grow not just linearly
regulatory team’s responses, which in their respective regulatory career functions, but
ensures consistency of response. also gain an in-depth understanding and knowl-
• Market-shaping policy activities—The edge of other regulatory functions. Ideally, reg-
regulatory policy leads need to coordi- ulatory professionals should rotate between two
nate with their health policy colleagues or more functions during their careers, since such
to ensure argumentation and evidence rotations serve to enrich and further strengthen
are aligned to address policy changes professionals’ overall regulatory understanding,
with health authorities and health poli- skills and creativity. In every company, leadership
cymakers or payers. For example, science constantly asks teams to be creative, strategic and
is continually discovering new innova- think outside the box. Creativity is a very critical
tions for serious illnesses. As such, new skill for regulatory professionals to possess.
clinical endpoints may become import- Einstein said intelligence was more creativity
ant for appropriately evaluating innova- than knowledge6 and that creativity is intelli-
tive drugs. The health policy team will gence having fun.7 Research shows creativity
need to understand the argumentation is 85% learned,8 so by rotating a regulatory
for regulators and health authorities so professional through several functions, he or she
that it can be appropriately adapted for will possess the in-depth, firsthand knowledge
policymakers and payers. to become a well-rounded, mature regulatory

20 All rights reserved; file sharing prohibited.

 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
expert. Company leadership and management References
should be cognizant of the value of hiring and 1. What Does FDA Regulate? FDA website. http://www. 2
retaining talented and creative global regulatory fda.gov/AboutFDA/Transparency/Basics/ucm194879.
htm. Accessed 4 October 2019.
team members. Management should recognize
its responsibility to nurture and build on those 2. Global Regulatory Affairs—Role in the 3
Biopharmaceutical Industry. Center Watch website.
skills and appropriately recognize and reward http://www.centerwatch.com/pdfs/s11701_ch2_sample.
such global regulatory team’s creativity, ability to
take informed risks and thoughtful, mature and
pdf. Accessed 4 October 2019. 4
3. “Sarepta CEO Gives Up Some of His Broad
business-minded leadership. Without these skills, Sway Over Management.” The Wall Street Journal
the global regulatory team may be recognized for website. http://online.wsj.com/articles/sarepta-
ceo-gives-up-some-of-his-broad-sway-over-
5
being good contributors, but their contributions management-1406661188. Accessed 4 October 2019.
may be limited in scope. 4. Kabir N. “High-Performing Regulatory Teams.”
Regulatory Focus. March 2014. Regulatory Affairs
6
Professionals Society. RAPS website. https://www.

7
raps.org/regulatory-focus%E2%84%A2/news-
articles/2014/3/essentials-of-high-performing-
regulatory-teams. Accessed 4 October 2019.

8
5. Nijveldt GJ. Introduction to Core Labeling. DIA
presentation. DIA website. https://www.diahome.org/
productfiles/27296/11022%20-%20session%201%20
nijveldt%20slides%20[compatibility%20mode].pdf.
Accessed 4 October 2019.
9
6. Einstein A. Brainy Quote website. http://www.
brainyquote.com/quotes/quotes/a/alberteins148802.
html. Accessed 4 October 2019.
10
7. Einstein A. Goodreads website. http://www.goodreads.
com/quotes/37706-creativity-is-intelligence-having-
fun. Accessed 4 October 2019.
11
8. Drucker P. “The Discipline of Innovation.” Harvard
Business Review (1999). Harvard Business School Press
website. https://hbr.org/2002/08/the-discipline-of-
innovation. Accessed 4 October 2019.
12
13
14
15
16
17
18

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 Chapter 2: The Regulatory Team

22 All rights reserved; file sharing prohibited.

3 Regulatory Intelligence Step 1:
Information Collection
A Compilation of Website Addresses
By William K. Sietsema, PhD
1
2
3
4
5
Introduction
Table 3-1. Sources of Regulatory 6
The term “regulatory intelligence” is defined by Intelligence
the Regulatory Intelligence Network Group of
the Drug Information Association as:1 • Regulatory authority websites
7
“…the act of gathering and analyzing pub- • Regulations
licly available regulatory information. This
•
•
Drug approval summaries
Advisory committee meeting materials 8
includes communicating the implications • Guidance documents
of that information, and monitoring the • Clinical trial registries
current regulatory environment for opportu- • RSS feeds 9
nities to shape future regulations, guidance, • Newsletters
• Educational conferences
policy, and legislation.” • Regulatory intelligence databases 10
(subscription)
Regulatory intelligence can come from many • Regulatory reference and information
sources. Table 3-1 provides a partial list of places sites 11
• Trade associations
to go when searching for information, which will
• Professional organizations
be the focus of this chapter.
Selected topics from Table 3-1 are discussed
•
•
Freedom of Information requests
Colleagues
12
further in the following sections, providing an • SEC filings (US)
inventory of websites and focusing on regions •
•
Warning Letters (US)
Regulatory agency presentations
13
familiar to the author (US, EU, Japan, Canada • Business intelligence websites and
and Australia).
•
databases
Online professional and scientific article 14
Regulatory Authority Websites subscriptions
• Lessons learned (knowledge
Each regulator, of course, has a website, and each management) 15
is structured very differently. The US website2 • Approved or cleared submission
is structured by “center,” with the most relevant summaries
being the US Food and Drug Administra-
• Competitor’s labeling and marketing 16
literature
tion’s (FDA) Center for Drug Evaluation and
Research (CDER),3 the Center for Biologics 17
Evaluation and Research (CBER)4 and the
Center for Devices and Radiological Health tion difficult to find and burying many of the
(CDRH).5 The FDA website was re-structured information databases several layers deep and 18
in 2019, making much of the legacy informa- impossible to find with the search function. Key

All rights reserved; file sharing prohibited. 23

 Chapter 3: Regulatory Intelligence Step 1: Information Collection — A Compilation of Website Addresses

Table 3-2. Websites for Healthcare Product Regulations by Region

Title Region Website

Electronic Code of Federal

US https://www.ecfr.gov/
Regulations
EUR-Lex. Access to European
EU https://eur-lex.europa.eu/homepage.html
Union Law

Federal Register of Legislation Australia https://www.legislation.gov.au/

Justice Laws Website (Food and

Canada https://laws-lois.justice.gc.ca/eng/acts/f-27/
Drugs Act)

Japanese Law Translation Japan www.japaneselawtranslation.go.jp/

CDER databases are listed on a page that is four “translate the web” feature provides a rudimen-
levels deep.6 CDRH maintains a list of the medi- tary translation of web pages in foreign lan-
cal devices databases.7 CBER has a page referred guages.17 There is a separate web page for Japan’s
to as the Biologics Electronic Reading Room.8 Ministry of Health, Labour and Welfare, which
The European Medicines Agency (EMA) oversees PMDA activities.18
consolidates all the human medicines links in
a single page.9 On that page, the “Topics A-Z” Regulations
provides the easiest way to navigate to the area
Each country has its own regulations that dictate
of interest.
the requirements for healthcare products’ regis-
Health Canada’s main page is located
tration. Table 3-2 provides a selection of websites
within the site for the Government of Canada.10
where laws and regulations can be accessed.
From the main page, there are links to various
areas of regulation. Drug Approval Summaries
Australia’s Therapeutic Goods Administra-
tion has a dedicated site.11 It is logically struc- The FDA website stores approval summaries
tured so topics are easy to find, and the search in various places, depending on the product
function is very good at locating areas of interest. type. For CDER, there is a database referred
Much of the information a regulatory profes- to as [email protected] CBER maintains a list of
sional would seek is found under the “industry”12 licensed biological products.20 CBER also has
or “about the TGA”13 tabs. jurisdiction over certain devices and has a sepa-
Japan’s PMDA also has a dedicated site. rate page for CBER-managed 510(k) device sub-
Whereas all information on the site can be missions21 and premarket applications (PMA).22
found in Japanese,14 only a portion is available in Vaccines licensed for use in the US are listed on
English.15 In the English version, much of the their own page.23
information of interest to a regulatory profes- In the EU, approval summaries are referred
sional is found in the “for business” section.16 For to as European Public Assessment Reports
those who do not speak Japanese, Microsoft’s (EPARs), and those resulting from a centralized

24 All rights reserved; file sharing prohibited.

 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
review can be searched from a single location.24 Australia adopts European guidelines or may
However, products approved via a national proce- adapt the European guidelines for applicability 2
dure would have to be searched on the applicable to Australia. Scientific guidelines can be searched
on the TGA site.41
national website; for example, the UK’s MHRA
site has a page for public assessment reports,25 Japan has a page for guidance documents 3
the Netherlands Medicines Evaluation Board has that also includes links to translated ministerial
a Medicines Information Bank,26 Spain’s CIMA notifications and ordinances.42 Unfortunately, only
a small number of these documents are translated.
4
has a site for searching medicines, which includes
public assessment reports where applicable,27 The International Council on Harmonisa-
and Sweden’s Medical Products Agency posts tion (ICH) also has harmonized guidances that 5
decision documents.28 are recognized by many regions.43 It divides its
guidances into four categories: Q for quality, S
Canada provides a single database of autho-
rized products that is searchable by a variety of for Safety (nonclinical), E for Efficacy (includes 6
terms, including company or product name, or human safety) and M for Multidisciplinary.
active ingredient.29 The database includes a link
Advisory Committee Meeting 7
to the product monograph. Summary Basis of
Decision (SBD) documents may be available for Materials
products authorized after 2012 and can be found The US has a very active advisory committee
8
on a separate page.30 Canada also will be provid- program that has its own web page.44 Infor-
ing clinical study reports for drugs and devices it
has approved.31
mation is available about the various advisory 9
committees and their members. The page also
Australia refers to its drug approval sum- maintains a calendar and materials used in each
maries as Australian Public Assessment Reports advisory committee, including agendas, rosters, 10
(AusPARs), and these can be searched on the presentations and briefing documents. These can
TGA website.32
Japan maintains lists of approved products
be rich sources of information.
Canada has a formal program for scientific/
11
by year in PDF format.33 Review reports from expert advisory committees.45 However, many
Japan, where available in English, are separated
by whether the product is a drug,34 a device35 or
of the committees have been canceled or have 12
completed their mandate; thus, only a few are
a regenerative medicine product.36 Full infor- still active, most notably for oncology therapies,46
mation from each marketing authorization respiratory and allergy therapies47 and health 13
application also is published on the PMDA site products for women.48
in Japanese.37 Australia has an active advisory committee
program and a page where further information
14
Guidance Documents can be obtained.49
In the US, guidance documents all can be Neither the EU nor Japan has a formal 15
searched from one location.38 advisory committee system.
The EU has a summary page for guidance39
that includes a link to a guidance document
Regulatory Intelligence Databases 16
search page. Several companies have developed databases
Canada maintains an alphabetical list of of regulatory intelligence. These databases can 17
guidance documents.40 be a tremendous resource to the regulatory
Australia does not keep all its guidance doc- professional, as they are a collection of valuable
uments in one place; rather, they are distributed information from diverse sources and are easy 18
by the medicine type. However, in many cases, to search. However, they require paid subscrip-

All rights reserved; file sharing prohibited. 25

 Chapter 3: Regulatory Intelligence Step 1: Information Collection — A Compilation of Website Addresses

Table 3-3. Regulatory Intelligence Databases

Database Name Commercial Owner Website

Tarius IQVIA https://www.tarius.com

Cortellis Regulatory https://legal.thomsonreuters.com/en/products/

Thomson Reuters
Intelligence regulatory-intelligence

MediRegs Wolters Kluwer https://lrus.wolterskluwer.com/store/mediregs

https://www.elsevier.com/solutions/pharmapendium-
PharmaPendium Elsevier
clinical-data

Worldview Clinivation http://clinivation.com/solutions/regulatory-affairs

SOFIE Graematter https://graematter.com

Table 3-4. Professional Associations for Regulatory Professionals

Association Regions of Focus Website

Regulatory Affairs Professionals
US and EU http://www.raps.org
Society (RAPS)
Asia Regulatory Professional
Asia https://www.asiaregulatory.com
Association (ARPA)
The Organization for Professionals in
Europe https://www.topra.org
Regulatory Affairs (TOPRA)

Drug Information Association (DIA) Global https://www.diaglobal.org

Canadian Association of
Professionals in Regulatory Affairs Canada https://capra.ca
(CAPRA)
Association of Regulatory and
Australia https://www.arcs.com.au
Clinical Scientists (ARCS)

tions. Table 3-3 lists some of the databases Professional associations also may keep
currently available. databases of valuable information. For exam-
ple, Friends of Cancer Research keeps a list of
Professional Associations therapies awarded Breakthrough Designations
There are several professional associations for by FDA,50 and the Alliance for Regenerative
regulatory professionals. These organizations are Medicine keeps a database of expedited approval
excellent sources for networking and informa- designations awarded to regenerative medi-
tion. Many publish their own reference works on cines.51 The list of expedited approval designa-
regulatory information. A list of these organiza- tions includes Regenerative Medicine Advanced
tions is provided in Table 3-4. Therapy, Breakthrough and Fast Track designa-

26 All rights reserved; file sharing prohibited.

 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
tions in the US, EU PRIME designations and are required to include discussion of “material
SAKIGAKE designations in Japan. events,” i.e., news or details that may reasonably 2
be expected to affect a company’s stock price.
Clinical Trial Databases Accordingly, these submissions may have detailed
information about regulatory decisions or clinical 3
Many countries maintain clinical trial databases trial results not revealed elsewhere. The US
and some, e.g., the US database, are mandated
for certain clinical trials. These databases often
Securities and Exchange Commission maintains
a database of these submissions that is searchable
4
contain valuable information, such as trial start by company name and date of filing.52
and stop dates, inclusion and exclusion criteria
and other trial design elements. They also may Freedom of Information Requests
5
list investigational site names and locations in
the trial. A list of some clinical trial databases is Many regions have freedom of information
legislation that may be used in gathering reg-
6
shown in Table 3-5.
ulatory intelligence. In the US, the Freedom of
SEC Filings Information Act provides access to many types of 7
information. Requests can be made via an online
In the US, public companies are required to form.53 The requestor may be required to pay a
make regular submissions to the Securities and fee. Note that confidential information will not 8
Exchange Commission. These submissions be released (e.g., information at the IND stage),

9
Table 3-5. Clinical Trial Databases
10
Database Name Region Website

ClinicalTrials.gov US https://www.clinicaltrials.gov/ 11
https://health-products.canada.
Clinical Trial Search Canada
ca/ctdb-bdec/index-eng.jsp 12
https://www.clinicaltrialsregister.
EU Clinical Trials Register EU
eu/ctr-search/

NIPH Clinical Trials Search Japan https://rctportal.niph.go.jp/en/

13
iyakuSearch (JAPIC Clinical Trials Information) Japan
https://www.clinicaltrials.jp/cti-
user/common/Top.jsp 14
UMIN Clinical Trials Registry Japan https://www.umin.ac.jp/ctr/
15
JMACCT (Japan Medical Association – Center https://dbcentre3.jmacct.med.
Japan
for Clinical Trials) or.jp/jmactr/Default_Eng.aspx

Australian Clinical Trials Australia

https://www. 16
australianclinicaltrials.gov.au/
ANZCTR (Australian New Zealand Clinical Australia and
Trials Registry) New Zealand
http://www.anzctr.org.au/ 17
World Health Organization International
Global http://apps.who.int/trialsearch/
Clinical Trials Registry Platform (WHO ICTRP)
18

All rights reserved; file sharing prohibited. 27

 Chapter 3: Regulatory Intelligence Step 1: Information Collection — A Compilation of Website Addresses

Table 3-6. Examples of Web Pages for Subscribing to Regulatory Updates

Regulator Web Page for Updates*

US FDA https://updates.fda.gov/subscriptionmanagement

EMA https://www.ema.europa.eu/en/news-event/rss-feeds

https://www.canada.ca/en/health-canada/corporate/social-media-health-
Health Canada
canada/rss-feeds.html

TGA https://www.tga.gov.au/subscribe-updates

*Many regulators have separate websites for subscribing to updates from each organization.

Table 3-7. Regulatory Agency Twitter Handles

Regulator Twitter Handle

EMA @EMA_News

US FDA @US_FDA

Health Canada @GovCanHealth

TGA @TGAgovau

and any information released will be redacted to Surveillance

remove sensitive information. Responses to FOI
requests are very slow and may take years. Once the regulatory professional is up to date
Health Canada operates an “access to infor- with a particular topic, he or she will want to
mation and privacy” page, although very little is stay abreast of any changes. Most regulators and
revealed about what information can or cannot many other information sources offer a subscrip-
be provided.54 tion option to receive regular updates. A selection
Australia has a well-developed system for of these is outlined in Table 3-6.
freedom of information, and TGA has its own Many regulators also have active Twitter feeds.
request page.55 Information from TGA is not Selected Twitter handles are shown in Table 3-7.
specifically exempt, but the agency has the right
Conclusions
to redact confidential information.
EMA has an “access to documents” page56 Today’s regulatory professional has an immense
that describes the types of documents that can be amount of information at his or her fingertips.
requested and the policies governing the release So much information is available that it can be
of information. Documents can be requested via difficult to determine which is actually use-
an online form.57 ful. Nonetheless, in any regulatory assessment

28 All rights reserved; file sharing prohibited.

 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
endeavor, the first step is to take inventory of the 16. About PMDA. PMDA website. https://www.pmda.
available information, and the list of sites pro- go.jp/english/pnavi_e-04.html. Accessed 27 October
2019.
2
vided in this chapter will be a good start to that
17. Web Translator. Translate the web website. http://www.
information collection. translatetheweb.com. Accessed 27 October 2019.
3
18. Ministry of Health, Labour and Welfare website. https://
www.mhlw.go.jp/english/. Accessed 27 October 2019.
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1. What is Regulatory Intelligence? (6 February 2013). The
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daf/index.cfm. Accessed 27 October 2019.
intelligence.blogspot.com/2013/02/what-is-regulatory-
intelligence.html. Accessed 27 October 2019. 20. Licensed Biological Products with Supporting 5
Documents. FDA website. https://www.fda.gov/
2. US Food and Drug Administration website. https:// vaccines-blood-biologics/licensed-biological-products-

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supporting-documents. Accessed 27 October 2019.
6
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4. Vaccines, Blood & Biologics. FDA website. https://
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vaccines-blood-biologics/substantially-equivalent-
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5. Medical Devices. FDA website. https://www.fda.gov/

medical-devices. Accessed 27 October 2019.
22. Premarket Approvals and Humanitarian Device
Exemptions with Supporting Documents. FDA
8
website. https://www.fda.gov/vaccines-blood-biologics/
6. Drug Approvals and Databases. FDA website. https://
9
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www.fda.gov/drugs/development-approval-process- and-humanitarian-device-exemptions-supporting-
drugs/drug-approvals-and-databases. Accessed 27 documents. Accessed 27 October 2019.
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7. Medical Device Databases. FDA website. https://www. website. https://www.fda.gov/vaccines-blood-biologics/
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24. Medicines. EMA website. https://www.ema.europa.eu/ 11
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website. https://www.fda.gov/about-fda/center-biologics-
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25. Public assessment reports. Medicines and Healthcare
evaluation-and-research-cber/biologics-electronic-
products Regulatory Agency website. https://www.gov.
reading-room-efoi. Accessed 27 October 2019. uk/guidance/find-product-information-about-medicines.
9. Human regulatory. European Medicines Agency Accessed 27 October 2019.
website. https://www.ema.europa.eu/en/human-
medicines-regulatory-information. Accessed 27
26. Medicines Information Bank. Dutch Medicines 13
Evaluation Board website. https://www.
October 2019. geneesmiddeleninformatiebank.nl/en/. Accessed 27
10. Drugs and Health Products. Health Canada website.
https://www.canada.ca/en/health-canada/services/
October 2019.
14
27. agencia Española de medicamentos y productos
drugs-health-products.html. Accessed 27 October 2019. sanitarias (Spanish medicines agency) website. https://
11. Therapeutic Goods Administration website. https://
www.tga.gov.au. Accessed 27 October 2019.
cima.aemps.es/cima/publico/home.html. Accessed 27
October 2019.
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12. Industry. TGA website. https://www.tga.gov.au/ 28. Swedish Medical Products Agency website. https://
industry. Accessed 27 October 2019. lakemedelsverket.se/english/product/Medicinal-
products/Decision-documents/. Accessed 27 October
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13. About the TGA. TGA website. https://www.tga.gov.au/ 2019.
about-tga. Accessed 27 October 2019.
14. Pharmaceuticals and Medical Devices Agency website
29. Drug Product Database online query. Health Canada
website. https://health-products.canada.ca/dpd-bdpp/
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( Japanese). https://www.pmda.go.jp/index.html. index-eng.jsp. Accessed 27 October 2019.
Accessed 27 October 2019.
15. PMDA website (English). https://www.pmda.go.jp/
30. The Drug and Health Product Register. Government
of Canada website. https://hpr-rps.hres.ca/reg-content/
18
english/index.html. Accessed 27 October 2019. summary-basis-decision.php. Accessed 27 October 2019.

All rights reserved; file sharing prohibited. 29

 Chapter 3: Regulatory Intelligence Step 1: Information Collection — A Compilation of Website Addresses

31. Search for clinical information on drugs and devices. 46. Oncology Therapies. Government of Canada website.
Government of Canada website. https://clinical- https://www.canada.ca/en/health-canada/services/
information.canada.ca/search/ci-rc. Accessed 27 drugs-health-products/drug-products/scientific-
October 2019. expert-advisory-committees/oncology-therapies.html.
Accessed 27 October 2019.
32. AusPAR search. TGA website. https://www.tga.gov.au/
ws-auspar-index. Accessed 27 October 2019. 47. Respiratory and Allergy Therapies. Government of
Canada website. https://www.canada.ca/en/health-
33. List of Approved Products. PMDA website. https://
canada/services/drugs-health-products/drug-products/
www.pmda.go.jp/english/review-services/reviews/
scientific-expert-advisory-committees/respiratory-
approved-information/drugs/0002.html. Accessed 27
allergy-therapies.html. Accessed 27 October 2019.
October 2019.
48. Health Products for Women. Government of Canada
34. Review Reports: Drugs. PMDA website. https://
website. https://www.canada.ca/en/health-canada/
www.pmda.go.jp/english/review-services/reviews/
services/drugs-health-products/drug-products/
approved-information/drugs/0001.html. Accessed 27
scientific-expert-advisory-committees/health-products-
October 2019.
women.html. Accessed 27 October 2019.
35. Review Reports: Medical Devices. PMDA website.
49. TGA statutory advisory committees. TGA website.
https://www.pmda.go.jp/english/review-services/
https://www.tga.gov.au/tga-statutory-advisory-
reviews/approved-information/devices/0003.html.
committees. Accessed 27 October 2019.
Accessed 27 October 2019.
50. Breakthrough Therapies. Friends of Cancer Research
36. Review Reports: Regenerative Medical Products.
website. https://www.focr.org/breakthrough-therapies.
PMDA website. https://www.pmda.go.jp/english/
Accessed 27 October 2019.
review-services/reviews/approved-information/0004.
html. Accessed 27 October 2019. 51. Expedited Approval Designations. Alliance for
Regenerative Medicine website. https://alliancerm.
37. Op cit 15.
org/expedited-approval-designations/. Accessed 27
38. Search for FDA Guidance Documents. FDA website. October 2019.
https://www.fda.gov/regulatory-information/search-
52. Filings and Forms. US Securities and Exchange
fda-guidance-documents. Accessed 27 October 2019.
Commission. https://www.sec.gov/edgar.shtml.
39. Scientific Guidelines. EMA website. https://www.ema. Accessed 27 October 2019.
europa.eu/en/human-regulatory/research-development/
53. FDA Freedom of Information Act (FOIA). FDA
scientific-guidelines. Accessed 27 October 2019.
website. https://www.accessdata.fda.gov/scripts/foi/
40. Guidance Documents—Applications and FOIRequest/requestinfo.cfm. Accessed 27 October 2019.
submissions—Drug products. Government of Canada
54. Access to Information and Privacy. Government of
website. https://www.canada.ca/en/health-canada/
Canada website. https://www.canada.ca/en/health-
services/drugs-health-products/drug-products/
canada/corporate/contact-us/access-information-
applications-submissions/guidance-documents.html.
privacy-division.html. Accessed 27 October 2019.
Accessed 27 October 2019.
55. Freedom of Information. TGA website. https://www.tga.
41. Scientific guidelines. TGA website. https://www.tga.
gov.au/freedom-information. Accessed 27 October 2019.
gov.au/ws-sg-index. Accessed 27 October 2019.
56. About Us. Access to documents. EMA website. https://
42. Regulatory Information. PMDA website. https://
www.ema.europa.eu/en/about-us/how-we-work/access-
www.pmda.go.jp/english/review-services/regulatory-
documents. Accessed 28 October 2019.
info/0002.html. Accessed 27 October 2019.
57. About Us. Send a question to the European Medicines
43. International Council for Harmonisation website.
Agency. EMA website. https://www.ema.europa.eu/en/
https://www.ich.org. Accessed 27 October 2019.
about-us/contact/send-question-european-medicines-
44. Advisory Committees. FDA website. https://www.fda. agency. Accessed 28 October 2019.
gov/advisory-committees. Accessed 27 October 2019.
45. Scientific/Expert Advisory Committees. Government
of Canada website. https://www.canada.ca/en/health-
canada/services/drugs-health-products/drug-products/
scientific-expert-advisory-committees/completed-
active.html. Accessed 27 October 2019.

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4 The Elements of Global Regulatory
Strategy — the Basics

By Neal E. Storm
1
2
3
4
5
Introduction community opinions, and must be aligned with
the company’s strategic goals. Developing a
6
For most of regulatory science’s established GRP is an iterative, cross-functional process that
history, regulations governing drug safety and
efficacy were established on a country-by-coun-
requires expert input and review from the multi- 7
ple disciplines forming the core product devel-
try basis. For instance, a US-centric framework opment team (see Chapter 2). The team’s task to
was appropriate when most US-manufactured develop a GRP is challenging due to a variety of 8
drugs were distributed and sold largely on the factors. Innovative products often pose unique
US market. Today, the pharmaceutical industry’s scientific and regulatory questions that have not
expanding global reach means drug distribu- been posed previously. Further, new information 9
tion is multinational, yet the current regulatory is fed to the core product development team
frameworks still are largely national or regional
in focus. Thus, drug manufacturers face a mul-
continuously as the product is developed and
commercialized; this information can change the
10
titude of competing local laws and regulatory assumptions on which planning has been based
requirements that, individually, may be prudent and decisions made. Guidance from drug regu- 11
and practical, but in fact may be duplicative latory authorities typically lags behind scientific
or even divergent when combined with the innovation, so available regulatory guidance
requirements to support global drug registra- may not address issues novel products raise. 12
tion. No governing body or committee has the Drug regulatory authorities’ requirements and
authority to resolve such regulatory dissonance
at the global level; it is the drug manufacturer’s
guidance also can be affected by policy decisions
based on local medical standard of care, ethical
13
responsibility, and specifically, the global reg- views and cultural values. Notably, different drug
ulatory professional’s job, to develop a globally regulatory authorities address few, if any, of these 14
integrated regulatory strategy to bridge the factors in the same manner and, not infrequently,
dissonant drug development requirements of the drug sponsor and one or more drug regula-
regional drug regulatory authorities. tory authorities may view a particular regulatory 15
A global regulatory plan (GRP) outlin- challenge differently.
ing a new drug’s proposed global strategy is
the regulatory professional’s primary tool for
The regulatory professional is responsible
for leading a global regulatory strategy’s develop-
16
bringing together all the disparate technical and ment, taking these differing rules and interpre-
regulatory information for a global launch. A tations among constituencies into consideration. 17
GRP, and the strategy it outlines, must address These considerations must be meshed with the
not only all pertinent global regulatory authori- product’s underlying science and the healthcare
ties’ requirements, but also the patients’ interests community and patients’ needs. The regulatory 18
in the drug development process and medical professional must identify common denomina-

All rights reserved; file sharing prohibited. 31

 Chapter 4: The Elements of Global Regulatory Strategy — the Basics

Table 4-1. Key Global Regulatory Plan Elements

Planning tool documenting the company’s future course of action to optimize program efficiencies
and opportunities
Tracking tool summarizing relevant regulatory events, agreements, commitments and feedback
from drug regulatory authorities, including local insights
Risk assessment tool capturing known and potential regulatory and safety risks, and identifying
mitigation and contingency plans for each

Lifecycle management (LCM) tool outlining product development opportunities

Benefit-risk assessment tool outlining current information and evidence supporting the company’s
core understanding of a product’s safety and effectiveness

Table 4-2. Changes a Global Regulatory Plan Should Anticipate, Mitigate or Manage

Evolving regulations and guidelines

Changing drug regulatory authority policies, expectations and personnel

Shifting internal company positions and business strategy (due to changing strategic imperatives,
or personnel)

Changes in local markets, or expansion or withdrawal from regions

New intelligence on competitor products

Input from patients, advocacy groups or media

New assessments of product benefit-risk or target product labeling (TPL) expectations

tors underlying global requirements to elimi- The Global Regulatory Strategy

nate, where possible, redundant or additional and Plan
regulatory requirements that may unnecessarily
increase regulatory burden. The result is an A global regulatory strategy is the roadmap for
agreed company core filing package or lifecycle obtaining drug product regulatory approvals in
desired markets. It is intended to support the
management (LCM) plan designed to maxi-
product’s clinical development phases (Phases
mize the probability of gaining approvals in as
1–3) but also may support regulatory activities
many regions as possible, based on a streamlined
throughout the product lifecycle’s duration
supporting information package. The US Food (Phase 4). Later-phase plans may include strate-
and Drug Administration’s (FDA) Dr. Jonathan gies supporting postmarketing activities or plans
Wilkin defines this concept as the “identification for continued expansion into new markets. These
of the simplest structure required for a regulatory activities include conducting required postmar-
decision” and calls it “Regulatory Elegance.”1 keting studies or pharmacovigilance activities;

32 All rights reserved; file sharing prohibited.

 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
generating periodic safety reports intended cess. Thus, a TPL must be evidence-based and
to inform global drug regulatory authorities; annotated to available data sources. It also must 2
submitting supplemental applications to obtain represent the broadest amount of regulatory
“line extensions” for secondary indications; or
introducing new delivery devices, formulations or
intelligence and the company’s best assessment
of benefit-risk at any given time, to ensure a drug
3
dosing regimens that may improve product safety candidate’s proper valuation. The global regula-
or patient treatment compliance. Global regula- tory leader, in conjunction with the core product 4
tory strategies are living documents and must be development team and its network of advisors,
versioned to support different product lifecycle must take into consideration: available drug
stages. Yet, despite these changes, a GRP is an regulatory authorities’ guidelines and standards; 5
organizational tool containing elements that can precedents established by competitor products
be used not just for tracking or planning, but also
for anticipating and managing future opportuni-
and available regulatory intelligence; mechanisms
for obtaining scientific advice and feedback from
6
ties and risks. Table 4-1 outlines the key high- one or more drug regulatory authorities; and
level GRP elements. In addition, some changes
the GRP may anticipate or mitigate are provided
opportunities for accelerated product develop- 7
ment. These all support the development of a
in Table 4-2. Common Technical Document (CTD) or pack-
Often, the first question for a regulatory age of information to support regional marketing 8
professional developing a GRP is simply “where applications and, ultimately, drug regulatory
to start?” The many possible questions and multi-
factorial considerations a GRP must address may
authority benefit-risk decision making.
A well-developed GRP also helps a sponsor
9
seem endless. Starting with the end in mind, a align company communications on specific issues
regulatory professional may start with the antici-
pated prescribing information the company seeks
relating to a product’s benefit-risk to multiple 10
regulatory authorities. An agreed GRP helps
to register. This document, the target product a sponsor develop credibility and cooperative
label (TPL), is the company’s ideal representa- partnerships with drug regulatory authorities by 11
tion of a product’s benefits and risks and drives speaking with a single, aligned voice. A GRP also
product development activities and studies (see
Chapter 5). To develop a TPL, the regulatory
helps a company transcend the constantly chang-
ing regulatory environment, anchoring company
12
professional first must understand where the positions to source data and prior agreements or
company intends to market the product and what
regulatory and clinical trial requirements must be
commitments with regulatory agencies, which 13
may counteract “regulatory drift,” defined as a shift
met in any selected region to obtain the desired in a regulatory decision that is not based on new
labeling. To develop a robust TPL, more research data or prior agreements/commitments between 14
is required. Competitor product reference labels the company and a drug regulatory authority.
from the target regions must be evaluated to
understand what drug regulatory authorities Regulations and Regulatory 15
have accepted, and to identify potential points of Guidelines
differentiation from competitor labels. The bio-
pharmaceutical industry is a high-risk enterprise Publicly available regulatory authority directives,
16
with long and often unpredictable developmental statutes, regulations and guidance documents or
cycles, making an accurate TPL an important guidelines are efficient vehicles for communicat- 17
tool that gives a company the ability to predict ing a drug regulatory authority’s current thinking
future financial risk as it forecasts clinical trial on specific regulatory topics. For instance, in the
timelines, incremental developmental costs and, US, regulations are codified under Title 21 (Food 18
ultimately, the probability of regulatory suc- and Drugs) of the Code of Federal Regulations,

All rights reserved; file sharing prohibited. 33

 Chapter 4: The Elements of Global Regulatory Strategy — the Basics

which outlines in broad strokes the legal obliga- primarily on broad, practical aspects of product
tions of drug manufacturers, clinical trial inves- registration. For instance, an early and obvious
tigators and institutional review board members. ICH success was the 2003 implementation of the
For guidance on developing a product in a CTD, which has reduced a sponsor’s adminis-
specific therapeutic area, guidance documents trative burden in multiregional regulatory filings
provide consistent, transparent, scientifically valid and facilitated faster reviews and information
and peer-reviewed regulatory recommendations exchange between regulators3 (http://www.ich.
for a particular drug class or disease indication. org/home.html). However, differences remain
They also help identify required studies, require- in the regional interpretation and implementa-
ments and ways to avoid unnecessary testing. tion of ICH guidance. Further, ICH has been
Each year, FDA publishes its new, revised and less active in harmonizing technical standards
withdrawn regulatory guidance documents on relating to clinical and labeling requirements.
a range of subjects, including those focused on Thus, it is important the GRP specifies aspects of
specific conditions.2 These guidance documents regional guidances representing a higher regula-
establish the minimum requirements needed to tory burden than in other regions, and outlines
obtain marketing approval in specific disease the regulatory strategies the company will use to
areas and, in essence, set a level playing field for address such outliers.
competing manufacturers. Although regulatory
guidance typically is nonbinding for either the Precedents and Regulatory
drug sponsor or regulatory agency, deviations Intelligence
from drug regulatory authorities’ recommended
approaches may be proposed but must be Approved drugs establish an important baseline
supported by adequate scientific and regulatory for understanding subsequent products’ future
justification and should be discussed in advance regulatory treatment and, like case law, often
with the appropriate agency(ies). serve as precedents for future drug authorities’
An important element in developing a GRP regulatory decisions. A precedent is a simi-
is understanding the guidelines that apply in lar product in the same therapeutic area that
most regions. FDA, the European Medicines has “validated” a potential regulatory pathway
Agency (EMA) and the Japanese Pharmaceu- by completing clinical studies and achieving
ticals and Medical Devices Agency (PMDA), approval. Drug development precedents are “pos-
together with experts and observers, have itive,” “negative” or “unvalidated positive.”
participated since 1990 in a series of initiatives • Positive precedent—a drug that gains
to harmonize different aspects of drug approval approval from a drug regulatory
requirements under a joint organization called authority. When studied fully, positive
the International Council on Harmonisation precedents help the regulatory profes-
of Technical Requirements for Registration of sional clarify the requirements needed
Pharmaceuticals for Human Use (ICH). Since previously to obtain regulatory approval
its formation, ICH has developed guidelines for a particular product class in a certain
successfully through a series of working groups, therapeutic area or region. A positive
harmonizing many aspects of the drug develop- drug development precedent represents
ment process, including Good Clinical Practice a drug development model of a poten-
(GCP) and Good Manufacturing Practice tial “regulatory pathway.”
(GMP) standards, aspects of Good Laboratory • Negative precedent—a drug that fails
Practice (GLP), generalizable requirements of to gain approval by one or more drug
clinical data packages and dossier format (i.e., regulatory authorities for any reason.
CTD). To date, these activities have focused Negative precedents represent industry

34 All rights reserved; file sharing prohibited.

 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
“lessons learned.” Negative precedents understand the global regulatory landscape fully.
can be as important as positive prece- Often, the information about negative precedents 2
dents because they also can illuminate is less transparent, since drug regulatory authori-
appropriate regulatory pathways; it is
possible for a product to fail develop-
ties typically do not post summary documents for
their decisions and, frequently, sponsors do not 3
ment for strictly nonregulatory reasons disclose the grounds for an applications’ rejec-
(i.e., serious side effect) and still repre- tion, or so-called regulatory deficiencies, in press 4
sent a valid regulatory pathway. If the releases.4 However, negative precedents arguably
failure is related to a regulatory issue, are richer in relevant regulatory information and
the information also is valuable because should not be dismissed. 5
it can help identify regulatory challenge Information on precedents may be
areas to be taken into consideration by obtained from multiple sources (see Chapter 3).
subsequent entrants to the field. Information on precedent drugs may be found 6
• Unvalidated positive precedent—a drug by researching regulatory authority websites,
further along in the drug development
process than the company’s own product
scientific literature and trade journals through a
process called regulatory intelligence. Perhaps the
7
but not brought forward yet for mar- best publicly available regulatory intelligence can
keting review or approval by any drug be obtained from “summary basis of approval” 8
regulatory authority. Such unvalidated documents posted on drug regulatory authority
positive precedents offer hints at what websites after a product has received marketing
generally may be considered acceptable approval (i.e., FDA Summary Basis of Approvals 9
approaches by drug regulatory authori- (SBAs), EMA European Public Assessment
ties, since it is assumed most drug spon-
sors seek regulatory advice and feedback
Reports (EPARs) and Health Canada Summary
Basis of Decisions (SBDs)). These documents
10
from drug regulatory authorities on describe the particulars of a given benefit-risk
their regulatory plans throughout the assessment leading to a regulatory decision and 11
drug development process. Precedents include data and regulatory opinion. Further,
gain more value as they move further Advisory Committee Meetings are a rich
along the drug development pathway, source of information; these are public meetings 12
because they become sources for more FDA holds midway through the drug review
complete and valuable information on
regulatory decisions and advice.
process to gain input from informed experts and
patient representatives on questions regarding
13
a drug and its intended use. This information
A single product may represent both a positive allows the regulatory professional to deduce the 14
and negative precedent, because the product may reasons a product is approved or denied market
gain approval from one drug regulatory authority access. However, FDA does not hold Advisory
and not another, or it may receive an approval for Committee Meetings for all products, so 15
one indication and not another. When positive transcripts and briefing materials to understand
and negative precedents are evaluated alongside
the recommendations contained in drug regu-
a particular precedent are not always available.
In these cases, scientific literature or conference
16
latory authority guidances, a regulatory profes- proceedings, business news reports and even
sional may develop a granular understanding of competitor Form 10-K reports and investor 17
the decision framework for future products in a briefings may offer glimpses into the rationale
specific indication. The regulatory professional for a product failing to gain approval. Other
must understand both the positive and nega- information to help understand precedents is 18
tive decisions by a drug regulatory authority to approved product labeling, which is available

All rights reserved; file sharing prohibited. 35

 Chapter 4: The Elements of Global Regulatory Strategy — the Basics

from sources such as FDA’s Drugs@FDA writing needed, or will informal (non-
webpage (http://www.accessdata.fda.gov/scripts/ binding) feedback suffice?
cder/drugsatfda/) or DailyMed (http://dailymed. • Is the needed feedback strategic in
nlm.nih.gov/dailymed/index.cfm). nature, or is the topic routine or admin-
istrative in nature? (Routine or admin-
Regulatory Interaction Strategies istrative questions may be addressed via
less resource-intensive routes of com-
Understanding the approval standards for an
munication, such as written correspon-
indication or disease state requires familiar-
dence, email or telephone conversation.)
ity with the state of the science for products
currently approved to treat the condition of
Because guidance documents and precedents
interest. However, this often is not enough
do not necessarily inform all drug develop-
to predict how regulators will approach new
ment issues novel disease treatments may raise,
products submitted for marketing authorization. biopharmaceutical companies often seek advice
Thus, an important step in the drug development directly from drug regulatory authorities on
process is to meet or correspond with the drug proposed drug testing strategies (see Chapter
regulatory authority to seek advice or approval 15). Such direct regulatory guidance ensures
for a proposed regulatory path and understand drug manufacturers are informed of the most
the drug regulatory authority’s concerns versus current scientific and regulatory standards on a
the company’s assumptions and positions. As a range of drug development areas, e.g., chemistry,
result, a GRP must contain a regulatory engage- manufacturing and controls; nonclinical testing
ment strategy identifying the points in develop- procedures; clinical trial design; and proposed
ment where drug regulatory authority advice is prescribing information. When publicly dis-
needed (regulatory decision “gates”), including closed information is insufficient to address an
the proposed objectives for each interaction and issue, the regulatory professional may advise
which regulatory authorities must be consulted. the company to seek scientific advice through a
Since all types of regulatory interactions involve meeting or written correspondence. These inter-
resource commitment by both the regulatory actions typically remain confidential between
authority and the company, and because meeting the sponsor and regulator, although the minutes
outcomes can have unexpected consequences of such meetings often are made public in the
for the company, it is important to develop a SBAs when products receive marketing approval.
structured global regulatory engagement strategy. These meetings often are held at major develop-
When approaching any drug regulatory author- ment milestones, e.g., prior to initiating clinical
ity for advice, consideration must be given to trials (pre-Investigational New Drug application,
the interaction’s proposed objectives, questions or pre-IND meeting), initiating large Phase 3
intended to be posed and an assessment of the clinical trials (i.e., End-of-Phase 2, or EoP2
possible outcomes and their impact. The follow- meeting) or submitting a marketing application
ing additional factors should be considered any (i.e., pre-filing, or pre-New Drug Application
time a regulatory professional contacts a drug (NDA) or Biologics License Application (BLA),
regulatory authority on the company’s behalf: or pre-Marketing Authorisation Application
• Will the interaction’s outcome have (MAA) meeting). Although sponsors often
long- or short-term consequences for receive spontaneous feedback from regulators in
the company? advice letters as they proceed through product
• What is the optimal timing for obtain- development, regulatory milestone meetings,
ing drug regulatory authority feedback? most often requested by the drug sponsor, consti-
• Are formal (binding) agreements in tute the most significant points at which regional

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
regulatory authorities may provide comprehen- It cannot be assumed the scientific review,
sive guidance on an entire drug development transparency level and timely access to medical 2
program. These milestones offer the sponsor the review staff will be equivalent across regions. A
opportunity to pose questions on issues requiring
prior agreement. At such meetings, the company
company seeking approval in the US can antici-
pate FDA’s scientific review quality will be rela-
3
must define its position thoroughly and trans- tively high and consistent for analogous products
parently, with a well-formulated scientific and within a given product class, that “an effective 4
regulatory rationale, to ensure a drug regulatory mechanism to discuss questions and issues with
authority has all the information it needs to the agency” exists9 and meeting outcomes will
reach an informed decision. It also is important be respected. However, these cannot be assumed 5
the drug sponsor consider any relevant drug in every region in which a company operates, as
regulatory authority guidelines in its proposals.
If the proposal deviates significantly from the
regulatory decision-making’s pace and predict-
ability across drug regulatory authorities is inher-
6
guidelines, the sponsor should anticipate agency ently uneven. A regulatory professional should
concerns by supplying an appropriate rationale
for the proposed deviation(s).5 Importantly, drug
anticipate these regulatory risks, and the GRP 7
should outline mitigation and contingency plans
sponsors that seek scientific advice meetings to avert negative consequences to the global drug
during development often benefit by improving development program. 8
the probability of their product’s approval.6
The mechanism for gaining access to regu- Benefit-Risk and Product Strategy
latory advice varies by drug regulatory authority 9
in ways related to the individual authority’s Throughout a drug product’s lifecycle, includ-
ing the postmarketing period, its benefit-risk
structure, organization, funding and expertise.
The regulatory professional must understand profile10 is refined further by data collected from 10
the implications of these differences to the broader patient populations exposed to the drug.
drug development program (e.g., development A product’s benefit-risk assessment is multifac- 11
delays, decisions made in the absence of needed eted and must reflect not only clinical experience,
advice, etc.). Some drug regulatory authorities but also its intended use, the indication’s severity
have published clear, unambiguous guidance on (ranging from “lifestyle” conditions to severely 12
the types of available meetings and their scope, debilitating or life-threatening ones), alternative
including situations in which meetings may not
be granted. For instance, FDA posts its guidance
therapies’ availability11 and the drug’s proposed
place in therapy (e.g., when a product addresses
13
on specific types of formal meetings, including an unmet medical need or is intended to be used
Type A meetings (i.e., a meeting that is necessary as a second- or third-line therapy after another 14
for an otherwise stalled product development to drug(s)). The company’s benefit-risk assessment
proceed), Type B meetings (i.e., a meeting held also must consider a range of potential off-label
to discuss the overall development program for uses (including potential abuse) once a product 15
products at different stages of development, such leaves the controlled clinical trial setting, moves
as pre-IND, EoP1, EoP2/pre-Phase 3, pre-NDA
or BLA application meetings, or post-action
into the marketplace and may be used at the
physician’s discretion. When an investigational
16
meetings) and Type C meetings intended to agent’s benefit-risk balance is sufficiently positive
accommodate specific drug development topics (equipoise), drug regulatory authorities gener- 17
not covered by either Type A and B meetings.7 ally are mandated under their own legislative
FDA explains its requirements in Formal Meet- requirements to facilitate its development. Thus,
ings Between the FDA and Sponsors or Applicants benefit-risk influences not only whether a drug 18
of PDUFA Products: Guidance for Industry.8 product is approved, but also when (the length

All rights reserved; file sharing prohibited. 37

 Chapter 4: The Elements of Global Regulatory Strategy — the Basics

of the approval process) and how (whether it granted, may lead to priority review designation
will be eligible for priority rather than stan- and allows the possibility of a “rolling” NDA or
dard approval mechanisms). Understanding a BLA submission, whereby specific application
drug’s benefit-risk, in the context of how each modules may be submitted for review prior to
drug authority is expected to view it, is critical the complete application. Additional details on
in assessing regulatory risk and developing an FDA’s expedited programs for serious conditions
informed regulatory strategy. Clearly, regulatory is available on the agency’s website.11 Although
review outcomes may not align among drug reg- these programs are available in the US, the
ulatory authorities—some may approve a product regulatory professional should become familiar
or indication, while another may not; thus, it with similar programs available in the regions in
behooves regulatory professionals to understand which the company intends to operate.
each region’s unique requirements, procedures,
policies and perspectives, including local insights Regulatory Mechanisms to Improve
that could impact benefit-risk decisions. Alignment
Assessing benefit-risk to identify whether a
Global regulatory dissonance comprises divergent
product provides meaningful therapeutic benefit
national or regional guidelines, feedback or review
compared to existing treatments for a serious or
outcomes. It may contribute significantly to an
life-threatening condition is important. Certain
unpredictable regulatory landscape and increase
regulatory authorities, including FDA, EMA and
drug development costs, and even has the poten-
PMDA, have accelerated review and approval
tial to indirectly increase costs to patients and
provisions for such products (see Chapter 16).
healthcare systems. It is the regulatory profession-
These have ethical implications, because reducing
al’s role to seek out and utilize available mecha-
time-to-market allows patients access to import-
nisms to reduce regulatory dissonance in decisions
ant new treatment options when they need it. For among drug regulatory authorities.
example, in the US, a product possibly offering a Although programs to reduce global regula-
therapeutic advantage for a serious disease may tory dissonance generally are new, few and, thus,
qualify for an accelerated approval designation inherently more unpredictable in their applica-
allowing product approval based on early clinical tion, they are being introduced with increasing
study results (i.e., nonpivotal) with surrogate regularity to improve drug regulatory authorities’
rather than clinical outcome endpoints. Drug cooperation and communication. The regulatory
approval based on such endpoints is conditional, professional should be aware of programs to
since postmarketing clinical trials must verify the reduce global regulatory dissonance, including
anticipated clinical benefit. participation in new drug regulatory authority
Other expedited development programs pilot programs to achieve this aim. Examples
with different incentives exist and may be of such mechanisms include Mutual Recogni-
requested at appropriate points in a product’s tion Agreements (MRAs), which streamline
development, including priority review and fast- drugs’ access to certain markets by individual
track designations. Similar to FDA’s accelerated drug regulatory authorities’ acceptance of other
approval designation, these programs apply to authorities’ regulatory decisions or approvals.12
products intended to treat conditions that are Other programs, such as the EU Voluntary
both serious (life-threatening (21 CFR 312.82(a) Harmonisation Procedure (VHP) pilot program,
and severely debilitating (21 CFR 312.81(b)) established the procedures to mitigate the need
and address an unmet medical need compared to for drug sponsors to interact separately with mul-
existing therapies. A priority review designation tiple Competent Authorities to obtain advice on,
could reduce the product review process from 12 and approval to conduct, clinical trial protocols.13
months to eight, or even less, from the date of Based on experience gathered through this pro-
application submission. Fast-track designation, if gram, harmonized clinical trial review procedures

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
Table 4-3. Regulatory Intelligence Tool Examples to Understand the Competitive Product 2
Landscape

WHO International Clinical Trials Portal: http://www.who.int/ictrp/network/primary/en/index.html

3
EudraCT: https://www.clinicaltrialsregister.eu/
ClinicalTrials.gov (NIH): www.clinicaltrials.gov 4
Current Controlled Trials: www.controlled-trials.com
Competitor websites (pipeline information) examples:
• http://www.merck.com/research/pipeline/home.html
5
• https://www.pfizer.com/science/drug-product-pipeline
• https://www.novartis.com/our-work/research-development/clinical-pipeline#ui-id-1=0
TrialTrove Clinical Trials Intelligence: https://citeline.com/products/trialtrove/
6
7
are now formalized through the implementation The challenge remains that “each agency will
of the Clinical Trials Regulation (536/2014),
further coordinating multinational clinical trial
retain its individual regulatory decision-making
authority regarding drug development issues and
8
assessments within the EU.14 Other initiatives marketing applications,” although the agencies
between FDA and EMA provide the framework will strive to provide “convergent guidance.”17 9
to accept common submission formats, such The GRP should consider available mechanisms
as those proposed for a “Single Orphan Drug that align scientific or regulatory feedback from
Designation Annual Report” and the ICH E2F drug regulatory authorities or improve coopera- 10
guidance Development Safety Update Report.15 tion among authorities, and the regulatory pro-
fessional should advocate their use if conditions
These mechanisms all offer benefits such as
reduced cost, better information-sharing and are right for the company’s products. 11
more efficient submission dossier approaches.
Regulatory Intelligence Tools and
In another development, EMA and FDA
joined efforts in 2009 to develop a combined Resources
12
EMA-FDA parallel scientific advice (PSA)
program. The program was originally piloted in
Other tools available to the regulatory
professional include dedicated websites for
13
limited areas, termed “clusters of interest” (i.e.,
applied to limited areas such as advanced thera- regulatory intelligence and for requirements that
pies, orphan drugs, new technologies, etc.), with can reduce the time needed to gather regulatory 14
the goal “to optimize product development and intelligence. These include The IDRAC (https://
www.pharmaceuticalonline.com/doc/the-idrac-
avoid unnecessary testing replication or unnec-
essary diverse testing methodologies.”16 The database-0001), Cortelis (https://clarivate.com/ 15
limited uptake of parallel interactions resulted in cortellis/solutions/regulatory-intelligence-solutions/)
a review and update of the General Principles for
PSA (April 2017). This procedure now is more
and Tarius (www.tarius.com) databases, which
offer subscription-based access to regulatory
16
broadly available for drug candidates seeking information and perspectives. Useful features
indications “lacking development guidelines, or include quick reference tables comparing regional 17
if guidelines do exist, those for which EMA’s and requirements, national regulatory documentation,
FDA’s guidelines differ significantly,” as well as expert reviews of issues and cross-regional
in areas of unmet need, as before (e.g., oncol- requirement comparisons. Additional tools 18
ogy, rare diseases, pediatric populations, etc.).16 are outlined in Table 4-3. It also is possible in

All rights reserved; file sharing prohibited. 39

 Chapter 4: The Elements of Global Regulatory Strategy — the Basics

Table 4-4. Regulatory Journals for Understanding Shifting Regulatory Policy

Regulatory Rapporteur. The Organisation for Professionals in Regulatory Affairs (TOPRA) www.topra.org
Regulatory Focus. Regulatory Affairs Professionals Society (RAPS) www.raps.org
Therapeutic Innovation & Regulatory Science. Drug Information Association (DIA) www.diaglobal.org
PharmaTimes. http://www.pharmatimes.com/Magazine.aspx
The Pink Sheet Daily. Informa https://www.pharmamedtechbi.com/publications/the-pink-sheet-daily
Discussion Groups, e.g., Orange Country Regulatory Affairs (OCRA) discussion group
(http://www.ocra-dg.org/)
or
Regional Chapters of Regulatory Professional Organizations (e.g., San Francisco Chapter of RAPS
http://connect.raps.org/sanfrancisco/home)

some regions to request non-public information ents can delay access to new products, often by
through what is called a “Freedom of years in some markets, if no feasible path can be
Information” request, though this approach often identified to address these requirements as part
is impeded by long administrative procedures to of the main multi-regional clinical trials. Thus, a
obtain needed information. GRP must address the needs of regulators from
Regulatory journals also can also be used regions where local data requirements are most
by the regulatory professional to understand pronounced. Importantly, a GRP should focus
the regulatory policy landscape better and are not just on certain regions such as the EU or
especially useful in keeping current on possible US, as these lapses in planning can impact global
shifts in regulatory thinking. Some examples of product launches significantly.
key regulatory journals, available by subscription
or membership, are described in Table 4-4. Potential Hazards for a Global
Regulatory Strategy
Local Insights and Impact on the
Global Strategy Regulatory professionals face several potential
pitfalls when considering all global regulatory
Regulatory capacity in some regions still is strategy elements. Often, companies duplicate
developing and varies in its level of sophisti- a successful precedent but may not fully under-
cation.18 Local populations for whom treat- stand all the assumptions or rationale support-
ments are intended often are not represented in ing it. It always is important to assess as many
pivotal clinical studies supporting approval in regulatory and competitive landscape variables as
more-mature markets, yet some drug regulatory possible and not become complacent or reliant
authorities increasingly are requiring participa- on others to do the work. In fact, the regulatory
tion of patients representing their local popula- history of related products often is incomplete
tion in such studies. When such studies are not or outdated, so information may be interpreted
conducted, ethnic bridging data or sensitivity incorrectly. As a result, the regulatory profes-
analyses may be needed in local populations sional and the team must conduct a thorough
to satisfy drug regulatory authorities who are gap analysis on a regulatory pathway’s possible
reluctant to approve a product based on ‘foreign’ permutations through scenario analysis and
clinical data. The logistical challenges this pres- simulation. On occasion, time constraints force

40 All rights reserved; file sharing prohibited.

 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
regulatory decisions to be made for a specific regulatory risk often are complex, multifactorial
product with incomplete information, e.g., and, by extension, may be difficult to resolve and 2
situations where emerging market competition even could be controversial. In such cases, the
require quick action. It is important for such
decisions to be well-documented and commu-
regulatory professional may be able to gather
more information by convening a regulatory
3
nicated transparently to stakeholders within the advisory board, consisting of external regulatory
company. Under ideal circumstances, the GRP or clinical thought leaders (or other disciplines, 4
should evaluate multiple options, especially for as needed) to advise the company on a given
an important decision that can impact the orga- topic. This approach may be particularly helpful
nization; include a full analysis of each option’s when a company is facing important decisions 5
pros and cons; and identify a decision tree map- that may, for instance, inform questions relating
ping how the final decision will be reached.
It also is important to realize the GRP does
to a product’s benefit-risk, result in drug devel-
opment delay or even program abandonment,
6
not address all areas likely to be relevant to drug or help guide decisions about escalating an issue
development. These may include health technol-
ogy assessment (HTA) bodies’ payer, pricing and
through a particular drug regulatory authority’s 7
dispute resolution mechanism. Seeking outside
reimbursement decisions, often made by HTA consultation through a regulatory advisory board
agencies. Although these agencies are not always may help the company understand exactly where 8
considered part of regulatory purview, they the point of no return exists in the negotiation
represent a “fourth regulatory hurdle,”19 since
their decisions have practical implications for
process for an intractable regulatory question,
thus helping the company be more efficient and
9
the evidence required during drug development judicious in its decision making. It also may
to ensure broad market access. Studies needed
to support these efforts should be incorporated
allow the company to redirect resources quickly 10
to newer opportunities and, most importantly,
into regulatory and clinical development plan- help the company uphold positive drug regu-
ning. Further, certain markets’ reimbursement latory authority relationships. Thus, GRPs aid 11
policies may shape the choice of countries in regulatory professionals in presenting all options
which marketing is sought and, thus, impact the
countries in which clinical trials and regulatory
clearly, articulating the most important regu-
latory messages to management and/or a drug
12
activities are conducted. Alternatively, regional regulatory authority and mediating dialogue
labels with differing interpretations for indicated
populations can affect the type of access HTAs
cross-functionally or between the company and a 13
drug regulatory authority. A robust GRP aids the
permit and affect local pricing decisions. As these regulatory professional’s effective and efficient
examples illustrate, developing a robust GRP is decision making and, in fact, supports every 14
an extramural activity, since outside bodies’ and aspect of her role.
organizations’ decisions can impact global regula-
tory strategy significantly. Use of Real-World Evidence in 15
Although it is important for the GRP to Regulatory Strategy Development
characterize regulatory risks and provide the
rationale and information to support regula- Following the 21st Century Cures Act being signed
16
tory pathways, it never will eliminate all drug into law in December 2016, new attention has
development risks. Decisions to seek marketing been given to the use of what is termed real- 17
approval seldom are based solely on regulatory world data (RWD) and real-world evidence
considerations; in some cases, regulatory risk is (RWE) in regulatory decision making in the
just one factor in a company’s decision-mak- US, which is gaining acceptance worldwide. 18
ing process. Additionally, questions involving The Duke Margolis Center for Health Pol-

All rights reserved; file sharing prohibited. 41

 Chapter 4: The Elements of Global Regulatory Strategy — the Basics

icy (2017)20 defines RWD as the data relating RWE is able to inform many types of decisions
to patient health status and/or the delivery of relevant to patient healthcare, coverage decisions,
healthcare routinely collected from a variety of regulatory decision questions, including under-
sources delivery (i.e., electronic health records), standing disease, patient populations, standard of
and RWE as the evidence derived from RWD care, questions relating to clinical trial feasibility,
through the application of specific research and the use and impact of a particular therapy in
methods. This approach is based on researchers’ clinical practice; thus, RWE is informative both
ability to analyze electronic patient data residing pre- and post-approval and offers many novel
in public or private electronic healthcare system uses for regulatory professionals to explore. To
databases or other sources to inform questions provide regulatory frameworks to better integrate
relevant to drug development and patient safety. RWE/RWD into study designs, drug develop-
The evolving science’s value to drug develop- ment plans and regulatory applications, regula-
ers is that real-world patient experience offers tors are rapidly developing guidance documents
new opportunities to evaluate the use, safety to guide drug development strategies, an import-
and effectiveness of therapies in actual clinical ant reference being FDA’s “Framework for FDA’s
practice.21 Unlike randomized controlled clinical Real-World Evidence Program.27 These tools are
trials, RWE allows drug developers to study a just the beginning in exploring how RWE may
specific research question relating to drug devel- be utilized to address novel questions in drug
opment in a truly representative patient popula- development, and should be considered early in
tion, including patient types often excluded from the development of a team’s global regulatory
traditional clinical trials. This allows researchers strategy in conjunction with advice from the
to evaluate a drug in a heterogenous popula- team’s observational research scientist.
tion, regardless of a spectrum of factors such as
disease severity, patient socioeconomic status, Summary
co-morbidities and clinical practice patterns,
and potentially enables the characterization As this chapter developed, a fuller picture of the
of outcomes most relevant to patients. Even basic global regulatory strategy’s elements began
before 2016, RWE had been used for a variety to emerge. The elements outlined in this chap-
of regulatory decision-making purposes and use ter correspond to a GRP’s content, which may
cases, most commonly as a means to monitor include, but is not limited to, those contained in
and surveil adverse events in the postmarketing Table 4-5. This table of contents is flexible, and
setting, for instance as postmarketing commit- each section’s level of detail may vary depending
ment requirements (PMRs) agreed with FDA.22 on a product’s development status, circumstance
However, other strategies have included utilizing or company preference. For example, the GRP
RWE as historical controls in small rare disease information for legacy products, with an abun-
populations, safety labeling revisions and indi- dance of product history and minimal new LCM
cation expansions.23 As one of the 21st Century opportunities, may be weighted toward simple
Cures Act’s stated purposes was to “facilitate, tracking of prior regulatory events or due dates
when scientifically appropriate, expedited and for regulatory commitments for easy reference.
efficient development and review”24 of new drugs, On the other end of the scale, the GRP informa-
one strategy supporting accelerated approval tion for products early in development may be
is to approve a drug on the basis of a surrogate weighted primarily toward future drug develop-
endpoint, and then use RWE/RWD to confirm ment planning and risk assessment. These GRP
earlier results to obtain full approval,25 as was sections may be delineated further by region or
achieved for the accelerated (US) and condi- indication; however, it is important they fully
tional (EU) approval of blinatumomab.26 In fact, integrate regional information at the global level

42 All rights reserved; file sharing prohibited.

 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
Table 4-5. Global Regulatory Plan Components—Sample Table of Contents 2
Executive Summary
Product Profile, Including Product Description and Proposed Indications
3
• Product description
• Proposed indications 4
• Core product benefit-risk assessment (by indication)
Risk Mitigation and Contingency Plans
• Regulatory
5
• Safety
• Technical
Regulatory Landscape
6
• Applicable regional regulatory guidance and policy
• Applicable regional regulatory intelligence and information from competitor products 7
Regulatory Pathways
• Available programs or opportunities for development or review acceleration (i.e., use of real-
world evidence)
8
• Available programs or opportunities for expanded access
Regulatory Interactions With Drug Regulatory Authorities 9
• Proposed regulatory interactions with drug regulatory authorities
• Summary of outcomes of regulatory interactions
• Program implications 10
Lifecycle Management (LCM) Planning
•
•
Pharmacovigilance and surveillance plan
Pediatric development plan
11
• Device or companion diagnostic development plan
• Lifecycle management opportunities
12

to enable a comprehensive global regulatory References

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and scope is at the discretion of the regulatory Issues and Opportunities (Pharmaceutical Science
Advisory Committee, 12 March 2003). FDA website.
14
professional, who must organize the informa-
http://wayback.archive-it.org/7993/20170404080001/
tion to make it useful to the team and serve as
a foundation for effective decision making. This
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htm. Accessed 1 November 2019.
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chapter provides the reader with the basic GRP
2. Guidance Agenda New & Revised Draft Guidances
and strategy development framework. CDER Plans to Publish During Calendar Year 2019.
FDA website. https://www.fda.gov/media/124386/
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3. The Value and Benefits of ICH to Drug Regulatory
Authorities—Advancing Harmonization for Better Health
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(2010). International Council on Harmonisation. ICH
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benefits-ich-drug-regulatory-authorities. Accessed 1
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 Chapter 4: The Elements of Global Regulatory Strategy — the Basics

4. Lurie P, Chahal HS, Sigelman DW, et. al. “Comparison 15. Guidance for Industry: E2F Development Safety
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Safety Signals. Reports of CIOMS Working Group 375:2293-2297. NEJM website. https://www.nejm.
IV. 1998 (Reprinted 2000, 2004). CIOMS website org/doi/pdf/10.1056/NEJMsb1609216. Accessed 28
(password required). http://www.cioms.ch/publications/ October 2019.
g4-benefit-risk.pdf. Accessed 28 October 2019.
22. Op cit 19.
11. Guidance for Industry: Expedited Programs for Serious
23. Ibid.
Conditions—Drugs and Biologics. FDA. May 2014. FDA
website. https://www.fda.gov/regulatory-information/ 24. 21st Century Cures Act. congress.gov website. https://
search-fda-guidance-documents/expedited-programs- www.congress.gov/bill/114th-congress/house-bill/34/
serious-conditions-drugs-and-biologics. Accessed 28 text#toc-HF4DFF8B9C70B4DC8984506C3257564
October 2019. BF. Accessed 28 October 2019.
12. Michor S, Diaz S. “Mutual Recognition Agreements in 25. Op cit 19.
the EU, Canada and Other Countries.” Regulatory Focus.
26. Kantarjian H, Stein A, Goekbuget N, et al.
March 2010; 16-20. RAPS.
Blinatumomab versus Chemotherapy for
13. Clinical Trials Facilitation Groups – Guidance document Advanced Acute Lymphoblastic Leukemia. NEJM
for a Voluntary Harmonisation Procedure (VHP) for the website. https://www.nejm.org/doi/full/10.1056/
assessment of multinational Clinical Trials Applications NEJMoa1609783. Accessed 28 October 2019.
Version 2 (March 2010). (CTFG//VHP/2010/Rev 1).
27. Framework for FDA’s Real-World Evidence Program.
Heads of Medicines Agencies website. http://www.
FDA website. https://www.fda.gov/media/120060/
hma.eu/fileadmin/dateien/Human_Medicines/01-
download. Accessed 28 October 2019.
About_HMA/Working_Groups/CTFG/2010_03_
VHP_Guidance_v2.pdf. Accessed 28 October 2019.
14. Clinical Trials Facilitation Groups – Guidance document
for sponsors for a Voluntary Harmonisation Procedure
(VHP) for the assessment of multinational Clinical
Trial Applications ( June 2016) (Doc. Ref.: CTFG//
VHP/2016/Rev6). HMA website. https://www.hma.
eu/392.html. Accessed 15 November 2019.

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5 Assembling and Utilizing Target
Product Profiles

By Anastassios Retzios, PhD

1
2
3
4
5
Target Product Profiles and Their Utility properties, its likely indications and its safety
and efficacy profile. It should inform how these
6
Target product profiles (TPPs) are the essential attributes compare to the competitive landscape
guides and key strategy documents in developing
novel drugs, biologics or devices. Considering
in which this agent would be launched. In addi- 7
tion, having defined the acceptable range for the
pharmaceutical development costs,1 it makes
sense to document clearly what the stakeholders drug’s key attributes facilitates detailed planning
and assists in regulatory strategy.
8
and the organization envision as the develop-
ment effort’s final product and its position in the Creating a comprehensive TTP should
marketplace. A novel drug, biologic or device’s be the definitive start of the planning process. 9
TPP must detail the therapeutic agent or device’s Figure 5-1 illustrates the TPP’s position in the
10
Figure 5-1. Target ProductProfile (TPP) Planning Process
11
Conceptual Target
Product Profile
12
Risk Assessment/
RiskMitigation

Portfolio Discovery 13
Assessment
Asset Description/ Quality Target
Characterization Product Profle
(QTTP)
14
Target Product Profile
(TPP)
Manufacturing/ 15
Clinical Preclinical Controls
Development Development

Marteting Research
16
Interactions with
Interactions With
Regulatory Agencies Key Opinion Leader
17
Approval/Marketing
18

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 Chapter 5: Assembling and Utilizing Target Product Profiles

development effort. The TTP should supply pre-NDA or pre-BLA meeting. These authors
both that efforts’ target and bounds; it should speculated that introducing the TPP at an earlier
provide the necessary clarity of what needs to stage would have provided the opportunity for
be accomplished at every development stage more effective FDA assistance. It should be men-
for every drug or device key property to achieve tioned, however, that in that 2007 draft guidance,
regulatory approval and enjoy a successful launch FDA noted that the use of the TPP is especially
in a competitive marketplace. Unfortunately, for important in pre-NDA or pre-BLA meetings.
many reasons,2 the practice of assembling a useful, This chapter explores TTP requirements
detailed drug, biologic or device TPP usually falls in regulatory guidances. It provides an effective
quite short of what might be defined as “best template for assembling a comprehensive TTP
practice,” especially in smaller biotech companies, and details the effort and the resources neces-
although larger organizations are not immune sary for an effective document. This chapter also
to deficiencies in this area. Occasionally, a very highlights some examples where the absence of
abbreviated TPP is assembled, easily forgotten and a TTP or an incomplete TTP led to significant
not updated. Even if TPPs are assembled properly, and noticeable failures in the development and
many in the organization are not familiar with effective marketing of new therapeutic entities
them; relevant documentation is not updated with and devices, and discusses associated document
information from the development effort and the development methodologies and practices, such
competition, despite the fact a TPP is supposed to as asset description and risk assessment.
be a dynamic document in any product’s lifecy-
cle. Further, the TTP frequently fails to become TPPs in Regulatory Guidances
the key element of pivotal “go/no-go” decisions.
Stakeholders and advocates tend to minimize The TPP may be utilized for interactions with
excursions from the allowable attribute range and key regulatory agencies such as FDA. The afore-
competitor drugs’ impact. mentioned 2007 draft TPP guidance includes
The TTP should be the key document for information on these documents’ optional
discussions with regulatory agencies. This was utilization in agency interactions.6 FDA strongly
the intention of the US Food and Drug Admin- suggests that the TPP should be incorporated in
istration’s (FDA) March 2007 draft guidance.3 the End-of-Phase-2 (EOP2) meeting brief-
In addition, the TTP is discussed in the Inter- ing document. This is sensible, since the TPP
national Council for Harmonisation’s (ICH) would (or, at least, should) contain the sponsor’s
Quality-by-Design (QbD) initiative, embraced potential claims in labeling concept terms. FDA
by key regulatory agencies, with the objective of then would be able to provide a direct input on
establishing effective pharmaceutical develop- these claims’ feasibility based on the information
ment “best practices,” in which a detailed and collected and the pivotal program outlined. The
effective TPP compilation is the core constit- draft guidance includes an appendix in which
uent.4 Despite this, effective TPPs are utilized the agency presents a series of interesting case
only in a minority of development projects. studies highlighting the advantages of utilizing a
Tyndal et al. (2017)5 examined the Summary TPP and the disadvantages of not compiling one.
Basis of Approval (SBoA) of 2,138 approved The last case study presented in the draft guid-
New Drug Applications (NDAs) and Biolog- ance is especially interesting because it highlights
ics License Applications (BLAs) from 1999 to typical weaknesses in biotech development, in
2015 for references to TPP utilization. Of these, which ideas are pursued by stakeholders without
only 91 referenced a TPP. Further, this report’s properly vetting the information and providing
authors revealed that the TPPs were introduced the necessary clarity required on endpoints and
at the late stages of development, usually in the claims based on them.

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
The FDA guidance also includes a TPP is expected to be approved for marketing with
sample. The sample does not vary substantially specific claims. The TPP would need to list these 2
from what is presented in this chapter, although in detail and affix an expected value range in
the organization of the information is different
and the suggested annotations more copious.
product label terms. Further, if desired, the TPP
can be extended to cover marketing and sales 3
TPP elements also are described in ICH’s targets after launch. Thus, a well-developed TPP
Q8(R2) 2009 guidance on pharmaceutical should attempt to define, as precisely as possible, 4
development.7 This guidance (and associated the following:
ICH guidances Q9 and Ql0) introduces the • physical and chemical properties
pharmaceutical development Quality-by-Design • indications 5
(QbD) concept and contrasts it to minimalist • target population
dosage and route of administration
approaches (see guideline Annex II). There is
little doubt the QbD effort faces an uphill task
•
• shelf life and storage conditions 6
in overcoming institutional norms. In its detailed • preclinical animal pharmacology and
treatise on various QbD elements, Cook et al.
•
toxicology
clinical efficacy and safety
7
(2014)8 provide a good summary of the initiative
and implementation progress. • regulatory process elements (if desired)
In terms of the TPP, the guidance advo- • marketing and sales (if desired) 8
cates creating a Quality Target Product Profile
The TPP’s key constituent element is a property
(QTPP) and defining the critical quality attri-
butes (CQAs). CQAs are defined as “physical, or attribute of the new chemical or biologic 9
chemical, biological, or microbiological property entity or device under development. In a prop-
or characteristic that should be within an appro- erly developed TPP, each key product attribute
followed during development is expected to
10
priate limit, range, or distribution to ensure the
desired product quality.” The CQA would need correspond to a value or a value range. The
to be defined for not only the drug substance attribute’s value (or value range) may be struc- 11
and product, but also the excipients, intermedi- tured as follows: maximal (the highest expected
value likely to be reached during manufacturing,
ates and closure system. Since the term “qual-
ity”—and, by extension, the term QTPP—refers development or marketing), base (or target) and 12
broadly to activities typically aggregated under minimal (the lowest acceptable value reached
chemistry, manufacturing and controls (CMC), in development). To avoid unnecessary failure,
the “minimal acceptable value” must be carefully
13
a QTPP is just one overall TPP component,
concentrating on the product’s physicochemical determined. The value should be set based on
description, including formulation, purification,
solid regulatory precedent, data to be obtained 14
during preclinical or clinical development or by
production and testing attributes. The QTTP’s
marketing research on competitor products.
CQAs can be effectively regarded as the specifi-
cations of the product under development.
A given attribute’s maximal-target-mini- 15
mal-value defines the space within which each
Key TPP Elements property or attribute and may vary during devel-
opment. The TPP authors should be expected to
16
A novel pharmaceutical or device has specific provide copious notes to justify their selections.
physical, chemical, pharmacological and tox- The detailed notes would certainly assist redi- 17
icological properties. In addition, the drug or recting the development effort in the case of
device is expected to be manufactured within regulatory or competitive environment changes.
specific parameters, its development is expected The property value on which the develop- 18
to undergo preclinical and clinical testing and it ment effort is centered, however, is defined as the

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 Chapter 5: Assembling and Utilizing Target Product Profiles

base (or target) value. Maximal property value product is stable for up to three years at room
may be attained during the development process temperature. If such an outcome is desirable
if planning allows such an eventuality.9 There is and possible (based on previous experience
no reason to enter maximal values for an attri- with the same class of compounds), it would be
bute if planning would not allow for its attain- appropriate to enter this value as this attribute’s
ment. Minimal attribute values should be entered maximum level. Conversely, previous experience
after careful consideration. If values for specific with the compound or class of compounds may
properties fall below the minimally acceptable indicate that the chemical entity may be stable
TPP entry, they should constitute triggers for go/ for only two years at 2–8° C. If this eventuality
no-go decisions. The organization should decide is acceptable to the development team, it may be
whether the development effort should continue entered as the minimal value for this attribute,
or not; if the answer to that question is affirma- the lowest acceptable storage temperature and
tive, the TPP should be amended accordingly (as shelf life value. Obviously, this range of values
well as other associated documents, such as costs for storage temperature and stability excludes
and market size projections). values for stability less than two years. If stability
For example, a particular compound’s testing indicates that the expiry period would be
development may target two-year shelf life less than two years, development effort elements
and storage at room temperature (target/base would need to be reappraised.
value), but there is a good possibility the stability In many cases, the full spectrum of distinct
program may eventually demonstrate that the attribute values for maximal, base or minimal

Figure 5-2. Target Product Profile

Top/Introductory Panel: Indications, Critical Quality

Target Population (per Indication), Attributes
Route of Administration, Dosing (CQAs)

Table 5-1
Quality Target
Product Profile
(QTTP) Critical Process
TPP Related Parameters
Documentation (CPPs)

Drug/Biologic Description/ Annotations

Asset Formulation/Storage
Description Clinical Efficacy – Indication 1

Annotations
Risk Table 5-3
Assessment/ Annotations
Risk Preclinical (Pharmacology, Indication Safety – Indication 1
Toxicology, Immunogenicity, etc.) 1
Management

Annotations

Table 5-2 Clinical Efficacy – Indication 2

Annotations

Annotations

7&)4.*'+ ,$-#%&.#/$8

Indication Safety – Indication 2

2

Annotations

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
targets is not possible (or even desirable). For ceutical presentations for the same indication.
example, if the product efficacy attribute’s target For example, an antiemetic drug may be avail- 2
value in a given indication’s primary endpoint is able as an intravenous solution, an oral tablet, an
the same as that of the pre-existing or control
product (based on the assumption that noninferi-
oral liquid or intranasally applied liquid. A TPP
that would aggregate all that information may
3
ority would be achieved), the maximal value may be too complex, considering that most of these
be higher than that of the reference product (if pharmaceutical presentations would require 4
superiority testing is planned), but the minimal their own distinct clinical development. In this
value must be identical to the target, since no case, it may be best to develop a TPP for each
marketing approval would be possible if noninfe- pharmaceutical form. In addition, the drug’s dif- 5
riority is not achieved. For primary efficacy end- ferent forms would likely mandate differences in
point attribute values, it would be helpful if they
were obtained from the drug or device control in
manufacturing. Given that fact, quality prop-
erties and their values would differ across the
6
the pivotal studies (the value for the attributes spectrum of forms. Although the manufacturing
would be the same as that of the control in case
of noninferiority).
of the active ingredient would not change, the 7
final drug manufacturing would require various
For a complete TPP, it is best to deal with QTPP versions. Thus, it may be appropriate
each targeted indication separately. Since some to compile a QTPP and the associated CQAs 8
indications may require a different dose range, for each formulation with its own CQAs and
route of administration, pharmaceutical form or
formulation, the TPP for such a multi-indication
critical process parameters (CPPs).
9
and multi-form medicinal product may be very Compiling the TPP
complex. If a number of routes of administration
are possible for a single indication, then a specific Assembling a TPP that is lucid and contains 10
“branch” of the TPP may investigate the phar- the necessary information requires a carefully
macological and safety attributes of these modes planned document outline. To annotate and 11
separately, for effective planning. For example, communicate the TPP, various product proper-
a 10% liquid immunoglobulin preparation may ties and their target, minimal and maximal values
be administered intravenously or subcutaneously may be assembled in groups based on the catego- 12
to the same type of patients (diagnosed with ries outlined in the “Key TPP Elements” section
primary immunodeficiency). Dosing varies with
the mode of administration, as does the range of
of this chapter. However, simple tables (like the
ones in the FDA guidance) or other designs can
13
acceptable safety parameters. In considering effi- be utilized. The examples included in this chapter
cacy and safety attribute ranges, it is important are not substantial departures, but they increase 14
to examine the claims of not only the reference readability and presentation. Figure 5-2 shows
or control drug, but also drugs in the develop- the outline of key TPP categories for a drug or
ing product’s competitive environment. For the biologic targeting two indications. 15
10% liquid immunoglobulin preparation, the Table 5-1 is an example of a table aggre-
sponsor may want to examine claims and safety
information posted by similar preparations and
gating several key product properties. The panel
in this table summarizes the indications, target
16
more highly concentrated liquid immunoglobu- population, dosage form and routes of adminis-
lin preparations (16% or 20% w/v). The choices tration for an intravenous liquid immunoglobulin 17
should be adequately annotated to document the preparation. The attributes and properties incor-
value selection process. porated in this panel are not exhaustive in any
It also is possible that a single active ingre- way; they have been selected simply to illustrate 18
dient may have various formulations or pharma- the process.

All rights reserved; file sharing prohibited. 49

 Chapter 5: Assembling and Utilizing Target Product Profiles

Table 5-1. Introductory/Top Table Presenting Certain Drug Key Elements (e.g., a liquid
immunoglobulin G preparation)

Indications, Target Population, Dosage and Administration

Target
Indications Dosage Form Route of Administration
Population
Primary PID: Adult and = Target PID
Immunodeficiency Pediatric • Intravenous
(PID) • Subcutaneous
CIDP: Adult
Chronic Inflammatory ITP
Demyelinating • Intravenous
Maximal Polyneuropathy
(CIDP)
CIDP
• Intravenous (Response and
maintenance phase)
• Subcutaneous
(maintenance phase)
Primary PID: Adult and Liquid 10% PID
Immunodeficiency Pediatric IgG Solution
Base/ • Intravenous
(PID)
Target • 10 mL vial • Subcutaneous
• 100 mL vial
• 200 mL vail
= Target = Target PID
Minimal
• Intravenous

The team compiling the TPP must use the to an already licensed competitor or another class
table’s annotations to provide a solid rationale for of compounds (in this case, possibly, corticoste-
the choices made. For example, several indica- roids or another immunoglobulin preparation).
tions are possible for intravenous immunoglob- Maximal values may result if the clinical studies
ulins, but not all may be sound choices for the of superiority to the reference compound are
product for a variety of reasons. These reasons proven. As noted previously, key assumptions
must be made clear in the annotations; they may and relevant information should be annotated
consist of unmet clinical need considerations, carefully in the comments for these aggregating
clinical development challenges and opportuni- and summarizing panels.
ties and even marketing or commercial issues. Table 5-3 demonstrates aggregating
Table 5-2 is an example of such a panel desirable safety information for a product in
providing greater detail on a therapeutic agent’s development. Again, these aggregating property
clinical profile in one targeted indication. This tables should not be rigid. They should be flexible
table shows a liquid immunoglobulin prepa- and informative, including attributes (in this
ration’s properties in the treatment of chronic case, clinical safety elements) that are relevant
inflammatory demyelinating polyneuropathy. indications addressed by this medicinal product
Table 5-1 shows the expected clinical response and shared by compounds or biologics of the
to primary and secondary endpoints of choice in same chemical class. In this case, immunoglobu-
detail. The target response to co-primary end- lin preparations are known to have specific safety
points may be based on achieving noninferiority concerns, which the TPP should address. Label-

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
Table 5-2. TPP Panel for the Clinical use and Efficacy Attributes (Mainly the Primary Endpoint) 2
of a Liquid Immunoglobulin G Preparation in the Treatment of Chronic Inflammatory
Demyelinating Polyneuropathy (CIDP)
3
Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
Indications
Target Route of
Dose
Dose Frequency
4
Response to Relapse Population Administration (Treatment
Treatment Prevention Regimen)
75% of 25% of = Target = Target = Target 5
subjects patient
Maximal achieve relapse after
response a treatment
period of 6 6
months
60% of
subjects
35% of
patients
PID: Adult and
Pediatric
• Diagnosed
with CIDP
• Response
Induction 7
achieve relapse after ◦ Single
• Progressive
response a treatment induction dose
motor and
period of 6
months sensory
dysfunction
of 2 mg/kg 8
◦ 1 mg/kg every
in at least one
Base/ limb no longer 3 weeks for 24
Target than 2 months weeks 9
• INCAT score of • Response
2-9 maintenance
◦ 1 mg/kg every
3 weeks for 24
10
weeks
11
= Target 50% of = Target = Target = Target
Minimal patients
relapse
12

ing concepts based on typical package inserts It is suggested that the annotations follow 13
of similar or competing products may be used a tabular format that would include columns
in this exercise. As discussed, specific attribute for the attribute or property, the value range,
the rationale for the value range selection and
14
values may “branch” into sub-TPPs.
In completing a TPP, it is important to note the sources from which the information was
that only listing the attribute value range is not
derived. The annotations make it possible for 15
this dynamic document to be understood more
adequate. Attribute values should be annotated
properly and extensively. Thus, a well-constructed
clearly by stakeholders and allow reviewers to
comprehend the rationale easily. They also facil-
16
TPP will include tables summarizing the
itate document revision, as product information
attributes, followed by substantial annotations
on each property’s values. These annotations
increases through interactions with regulatory 17
authorities, providing sharper focus on the thera-
should incorporate information considered and peutic agent’s various properties.
the rationale for setting the acceptable range TPP elements can and should have con- 18
(maximal­target-minimal). nections to the QTPP’s CQAs. For example,

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 Chapter 5: Assembling and Utilizing Target Product Profiles

Table 5-3. TPP Panel Summarizing the safety Information a Liquid Immunoglobulin G
Preparation in the Treatment of Primary Immunodeficiency

Safety (Clinical) of an Intravenous Immunoglobulin G (IVIg)

Thrombo- Hypersen- Induction Other Transmission
Hemolytic embolic sitivity Adverse Adverse of Infectious
Reactions Complica- Reactions Experiences Reactions Agents
tions
None—Very Same as Very Rare Approximately Same as Viruses:
Rare Target (< 1/10000) 10% of Target Same as
patients Target
Maximal experience
induction AEs TSEs:
Removal of
least 6 logs
Rare Very rare Very Rare Approximately Black Box Purification
(< 1/10000) (< 1/10000) 20% of warning and virus
(Black Box patients for renal reduction
Warning) experience dysfunction methodology
induction AEs adequately
Base/ (headache, removes/
Target cough, inactivates all
injection site typical model
reaction, viruses
nausea,
pharyngitis
and urticarial)
Same as = Target Same as Same as Same as Same as
Minimal Target Target Target Target Target

certain attributes in Table 5-3, in which safety Additional TPP Components

target values are discussed, can be connected to
Asset Characterization
elements of the QTTP. It is known that moderate
to higher IgA levels in immunoglobulin prepa- Depending on the organization and the number
rations increase the frequency and severity of of compounds it has in development, it always
hypersensitivity reactions. Thus, ensuring very low is helpful to provide an asset characterization
or no detectable IgA levels in the immunoglobulin
for the therapeutic agent in question. The asset
preparation also will ensure a very low frequency
characterization broadly corresponds to the
and reduced severity of hypersensitivity reactions.
Target Market Profile, a foundation element of
The IgA level CQA is an essential modifier of
the Strategic Evaluation Framework presented
the hypersensitivity reaction attribute’s value. This
CQA also should be connected to CPPs that by Tebbey and Rink (2009).10 The asset charac-
influence it. In the same vein, levels of activated terization summary (or strategic target profile)
Factor XI (FXIa) in these preparations are known provides a brief explanation of:
to be connected proportionally to the frequency • how the medicinal product fits within
and severity of thromboembolic complications, a the product categories the company or
safety element in the example TPP of the liquid institution is developing
immunoglobulin G. The proper connections • the value proposition driving the devel-
between the QTPP’s CQAs and this TPP section opment
should be established as well. • unmet clinical need the product

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
addresses are assigned to three categories: low,
• the facilities, personnel and investment medium and high 2
necessary for the product to be manu- • risk’s acceptability
risk avoidance strategy (processes to be
factured
3
•
• key dependencies and the value propo- enabled to reduce the risk’s probability)
sition • risk management mitigation (essentially,
• the intellectual property in existence or alternatives if the risk does occur)
4
likely to be acquired
• existing and future competition Several risk assessment analytical and statis-
• a brief summary of the risks tical tools exist. Applicable guidelines cover 5
• possible alternatives if the development some of these.
The risk assessment and management
of this agent is not pursued
document assembled as part of the TPP should 6
Table 5-4 shows a typical asset characterization not be confused with the Risk Management
template with explanations for its use. Certain Plan (RMP), now required in the NDA or BLA
submission process by a number of regulatory
7
template elements are organization-dependent.
agencies. However, the TPP risk assessment and
Risks Assessment and Risk Mitigation management plan may anticipate and facilitate 8
certain RMP sections.
It is typical when assembling a TPP to include
risk assessment and mitigation and management Assembling a TPP 9
documentation. Much of this is logical; putting
Team Organization
together specific product characteristics, product
quality and product efficacy and safety targets for Assembling a TPP is not (and should not be) a
10
the intended indications should allow the risks solitary exercise. It should be conducted by an ad
and probabilities of achieving these targets to be
assessed. Certain risk assessment and manage-
hoc team assembled for this purpose. The team 11
should consist of individuals who have excellent
ment concepts, such as key QbD elements, are
knowledge of the therapeutic agent in question,
discussed in the ICH Q9 guidance.11
The risk assessment should concentrate pri-
have worked with similar medicinal products 12
in the past or have expertise in the disease or
marily on risks connected with product attributes
in the TTP and the QTTP’s CQAs, as these are
syndrome the product addresses. In addition,
representatives from discovery, manufacturing,
13
critical drug properties. A risk assessment docu-
quality assurance, regulatory, preclinical testing,
ment should contain:
• risk identification (essentially, every- toxicology, clinical development and marketing 14
thing that potentially can go wrong departments (if these exist) must be invited to
participate. Outside experts and key opinion
in every development stage), which,
to properly communicate the project’s leaders may join the team either for meetings 15
risks, assesses: addressing specific issues or in all team activities.
○

○
process development risks
preclinical testing risks
It is important for the team chairperson to
fully understand the principles and process of
16
○ clinical study risks assembling adequate and workable TPPs. The
○ regulatory process risks chairperson should be capable of arbitrating any 17
○ therapeutic agent marketing risks conflicts of opinion and achieving consensus (if
• each risk’s probability and chances it consensus is impossible, the divergent opinion
may occur should be annotated and included in the risk 18
• risk’s severity, if it occurs; usually risks assessment and management document). The

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 Chapter 5: Assembling and Utilizing Target Product Profiles

Table 5-4. Specific Areas to be Covered by the TPP Asset Characterization Module

Asset/Project Name [Name of Drug Biologic] in [Indication]

Describe the full scope of the project for the asset’s development
Project Description (i.e., development, manufacturing, preclinical and clinical testing and
submission for approval in the US, EU and Rest of World (RoW)).
Describe how the product impacts the overall strategy of the company (i.e.,
Strategic Impact addition to the line of specialty pharmacy products directed to very rare
diseases).
Asset/Project
[Optional—Organization-Dependent]
Category

Project Start Date TBD

List the current project development phase (Discovery, Preclinical

Current Phase
Development, Phase 1–3).
Describe what needs to be in place for asset development to commence, if
Key Dependencies
any.
Describe the “value” proposition; for example, the specific advantages
Value Proposition the product may have in various areas; e.g., note if the therapeutic agent
addresses an area of unmet medical need.

Competition List all competitors

List all key patents and expiration dates

• constitution of matter patents
IP Position • use Patents
• formulation patents
• dosing patents
List the reasons why the corporation or institution is likely to be successful.
Why will the Likely entries include the fact the corporation has substantial previous
corporation or experience in the indication or in class of compounds to which this
institution be therapeutic agent belongs, it has specific expertise in its production, or the
successful? treatment community and the regulatory agencies may be helpful because
it addresses an area of unmet medical need or a combination of the above.
Highlight the most likely risks; this section is not a replacement for Risk
Assessment/Management, just a top-line summary of the most important
risks. It might be advisable to concentrate on risks with a higher probability
Significant Risks
of occurring and those whose impact would be severe, if they occur. Note
whether the overall risk is unacceptably high or manageable (based on
institutional operating procedures/guidelines).
[Optional—Organization-Dependent]: Enter the possible effects of the
Implications (if not project’s discontinuation. This may involve the disposition of intellectual
pursued) property, corporate alliances, corporate goals, product portfolio, product
development priorities, personnel disposition, etc.
[Optional—Organization-Dependent]: Enter possible choices of other types
Alternatives (if not
or classes of compounds that may be able to address the indication the
pursued)
therapeutic agent addresses.

54 All rights reserved; file sharing prohibited.

 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
project leader does not need to assume the role TPP would have set patient use attribute
of chair. In fact, a determined product advocate values that ought to have been tested in the 2
(many medicinal products have “champions” or development process. The multi-disciplinary
“advocates” in a corporation or institution) may
be counterproductive in this role, since alterna-
effort for a TPP compilation would have
presented more parameters than simply the
3
tives may not be explored. It also is important dynamics of deep lung delivery. Thus, it is
for team members from certain disciplines to imperative to select the correct attributes 4
question and even challenge other team mem- and properties and understand the interde-
bers’ assumptions and rationale. For example, pendencies. Such potential conflicts should
the clinical development team may propose be understood and their impact on the 5
primary endpoints and target values that are product assessed carefully. If certain property
feasible in their proposed clinical studies road-
map. However, the fact the product may be able
conflicts lead to increased risk but cannot be
altered (because of specific limitations), this
6
to achieve the target values of the suggested should be captured in the risk assessment
primary endpoint does not, in any way, correlate
with either achieving marketing authorization
document and risk mitigation strategy. 7
Although the team may disband following
or the therapeutic agent’s potential commercial TPP compilation, the TPP owner (most likely the
success. Similarly, marketing department rep- project leader) should maintain the document and 8
resentatives may challenge or dispute or object update it as necessary if new information becomes
to the target values for certain product phys-
icochemical attributes based on their under-
available, recalling the team when necessary.
9
standing of what product efficacy and patient
ease-of-use a product requires.
There are many examples of develop- References 10
ment failures caused by the poor under- 1. DiMasi JA and Grabowski HG. The cost of
standing of development goals and the biopharmaceutical R&D: Is biotech different?
Managerial and Decision Economics 2007; 28: 469–479.
11
absence of an appropriate TPP. FDA’s draft
2. Finn BM and Sutherland CF. The pharmaceutical
guidance documents a number of these
cases,12 but there are many others. The fate
industry: Where it is, how it got here, where it needs
to go, how to get there. International Journal of Medical
12
of Fluosol® from Alpha Therapeutic Cor- Marketing 2004; 4: 361–369.
poration, the only blood substitute receiving
US approval for emergency angioplasty
3. Guidance for Industry: Target Product Profile—A Strategic
Development Process Tool (March 2007). FDA website.
13
https://www.fda.gov/media/72566/download. Accessed
(1989),13 provides a vivid example of disso-
14
5 October 2019.
nance between drug properties and use in
4. Luciani F, Galluzo S, Gaggioli A, et al. Implementing
the approved indication that severely limited quality by design for biotech products: are regulators on
its commercial success. The product’s storage
15
track? mAb1 2015; 7: 451–455.
conditions (frozen) and preparation time 5. Tyndall A, Du W, Breder CD. The target product profile
conflicted with the time needed to intervene as a tool for regulatory communication: advantageous but

16
in emergency angioplasty. This fact severely underused. Nat Rev Drug Discov 2017; 16: 156.

limited the product’s usage, and it was with- 6. Op cit 3.

drawn from commercial distribution in 1996. 7. ICH Tripartite Guideline: Pharmaceutical
Similar dissonance has led to the market Development Q8 (R2) (Step 4) (August 2009). ICH
website. https://database.ich.org/sites/default/files/
17
withdrawal of Pfizer’s Exubera. There was Q8_R2_Guideline.pdf. Accessed 1 November 2019.
substantial patient resistance to the inhaler.14
Considering the inhaler was the key element
8. Cook J, Cruaňes MT, Gupta M, et al. Quality-by-
Design: Are we there yet? AAPS PharmSci Tech 2014;
18
of this drug/device combination, a proper 15:140–147.

All rights reserved; file sharing prohibited. 55

 Chapter 5: Assembling and Utilizing Target Product Profiles

9. Various clinical trials assess the results of the primary

endpoint against the control to originally define
superiority and then, if this test fails, to define
noninferiority. Obviously, superiority to the reference
compound would be a maximal attribute for the clinical
primary endpoint, and non-inferiority is going to be the
“target” and “minimal” value.
10. Tebbey PW, Rink C. Target Product Profile: a
renaissance for its definition and use. J Med Marketing
2009; 9:301–307.
11. ICH Tripartite Guideline: Quality Risk
Management-Q9 (Step 4) (November 2005). ICH
website. https://database.ich.org/sites/default/files/
Q9_Guideline.pdf. Accessed 1 November 2019.
12. Op cit 3.
13. Garrelts JC. Fluosol: an oxygen-delivery fluid for use in
percutaneous transluminal coronary angioplasty. DICP
1990; 24:1105–1112.
14. Heinemann L. The Failure of Exubera: Are We Beating
a Dead Horse? J Diab Sci Tech 2008; 2:518–529.

56 All rights reserved; file sharing prohibited.

6 Preclinical Safety Guidelines
Supporting International Drug
Registration
By John C. Kapeghian, PhD, DABT
1
2
3
4
5
Introduction come in the form of global, national or regional
health crises; international treaties impacting
6
In drug development, in principle, there should sample transport; politics of all sorts impacting
be no mystery to a highly regulated process used
every day by individual regulatory profession-
the level, timing and scope of regulatory review; 7
and project financing. On the micro scale, the list
als and pharmaceutical and biotech companies of events is endless and may include formulation
around the world. Yet, like many things, what issues, drug supply issues, overly sensitive toxicol- 8
seems simple from the outside can be more ogy species, unexpected target organ effects, poor
complex on the inside. This chapter discusses
global regulatory strategies for nonclinical
and inconsistent drug bioavailability, stability
issues, impurities, etc. The experienced regulatory
9
development programs. professional understands this when develop-
A clear nonclinical strategy allows a com-
pany to project its development program’s
ing the strategy and defining the project Gantt 10
charts, and realizes that some events may just
milestones and timelines, which are critical to be impossible to predict. Help in reaching the
setting realistic expectations and budgets. Map- destination is available in the form of regulatory 11
ping out this strategy requires the company to guidance documents, precedents in the market-
know where it stands (i.e., what nonclinical data
are in hand or, even better, what useful data are
place, all types of relevant (or irrelevant) data and
advice from experts both within and external to
12
in hand) and where it wants to go. Since drug the company. This chapter addresses strategies to
development is both a process and a business, the
destination may differ. For a virtual start-up, the
help a company achieve its goals by understand- 13
ing the regulatory landscape. It is hoped by the
destination/goal may be to generate enough data end of this chapter, regulatory professionals will
for a pre-Investigational New Drug (IND) meet- be able to read the landscape and skillfully lead 14
ing. For a small biotech, it may be to reach Phase their companies to their ultimate goals.
2 and then to partner or sell. For a large pharma-
ceutical firm, it may mean being first to market. Regulations Versus Guidance: Is there 15
The pathway in getting from point A to point B really any difference?
may differ among companies. There is a common
thread, however. Knowing there is a direct line In preclinical development, only one set of regu-
16
to be drawn—by definition, the shortest distance lations applies, regardless of where a company is
between point A and point B—does not mean it doing business. These are known as Good Labo- 17
is wise to travel that route. ratory Practice (GLP) regulations, and they gov-
Knowing the destination is not enough. ern the scope and accountability of nonclinical
The company must plan for unexpected events safety studies (toxicology, safety pharmacology) 18
along the way. On the macro scale, these may submitted to the US Food and Drug Adminis-

All rights reserved; file sharing prohibited. 57

 Chapter 6: Preclinical Safety Guidelines Supporting International Drug Registration

tration (FDA) and other drug regulatory agen- lead compound identification (pharmacology,
cies to support human clinical trials or marketing pharmacodynamics), optimization (screening
authorizations. These regulations define import- pharmacokinetics, tolerability or discovery-ori-
ant elements of conducting nonclinical studies, ented toxicology), mechanism of action or to
including establishing criteria for the study direc- investigate or follow-up on toxicology findings,
tor, the facility where the study is conducted and as well as dose-ranging studies, do not fall under
sponsor expectations. They describe test article GLP requirements.
characterization (i.e., the material being tested) In the US, only nonclinical laboratory
and test system (the model being used, e.g., cells, studies “that support or are intended to support
tissues, whole animal); study plan or protocol; applications for research or marketing permits
study assay validation expectations; and reporting for products regulated by the Food and Drug
requirements. They establish requirements for an Administration, including food and color addi-
independent quality assurance unit (QAU), test- tives, animal food additives, human and animal
ing facility standard operating procedures (SOPs) drugs, medical devices for human use, biological
and an archive for data and sample storage. products, and electronic products” are included.
The GLP regulations’ scope extends far Among these are “in vivo or in vitro experiments
beyond this general description, and it is safe to in which test articles are studied prospectively
say the regulatory professional will at some point in test systems under laboratory conditions
encounter the following GLP-related issues: to determine their safety. The term [nonclini-
• test and control article characterization cal laboratory study] does not include studies
and stability utilizing human subjects or clinical studies or
• bioanalysis of the test article in circulation field trials in animals. The term does not include
and/or in tissue (or other matrices) basic exploratory studies carried out to determine
• incorporating specialty assays or bio- whether a test article has any potential utility or
markers in the toxicology study to determine physical or chemical characteristics
• his or her potential role as the study of a test article.” International convention is that
monitor safety pharmacology studies, general toxicology
• quality assurance audit performance and studies, genotoxicity studies, reproductive and
timing in critical study phases developmental toxicology studies and carcinoge-
nicity studies are conducted under GLPs. Spe-
These regulations are not just for US drug regu- cialty studies like human tissue cross-reactivity
latory submissions. GLPs were quickly adopted studies for monoclonal antibodies, local tolerance
internationally, with Europe (through individual studies, metabolite and impurity toxicity testing
countries and the Organisation for Economic studies also generally are expected to be con-
Co-operation and Development (OECD)) and ducted under GLPs.
Japan ( Japanese Ministry of Health, Labor and Basically, all other regulatory agency pub-
Welfare (MHLW)) issuing their own GLPs. lications concerning toxicology testing scope,
There are minor differences among the lan- timing and duration expectations in support of
guage, scope and terminology used by various human trials or drug registration are ‘guidance
regulatory bodies, but their GLP requirements documents.’ Following published guidelines in
essentially are identical in detailing the frame- formulating a nonclinical testing strategy does
work to ensure nonclinical safety studies’ quality not ensure regulatory concurrence with the plan,
and integrity support human safety. In practice, but deviating from them without agency agree-
the regulatory professional must know which ment generally will result in questions during
studies fall under GLPs, and which do not. As review and could delay or derail the program’s
a general rule, nonclinical studies conducted for progress. Fortunately, avenues are available to

58 All rights reserved; file sharing prohibited.

 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
regulatory professionals to query drug regulatory wave of industry consolidation through acquisi-
agencies’ review divisions to receive additional tions and mergers. This led to a demand for more 2
guidance and feedback on testing strategies concrete and internationally accepted guidance
prior to initiating human trials (typically known
as a pre-IND or pre-Clinical Trial Application
from US, European and Japanese regulatory
agencies, and an effort was initiated to harmo-
3
(CTA) meeting) or pivotal efficacy studies and/ nize guidelines among global regulatory bodies
or registration (e.g., End-of-Phase 2 meeting). to help establish common requirements for phar- 4
These meetings are held to discuss not only maceutical companies’ drug development strate-
agency expectations for nonclinical safety study gies. In the author’s opinion, a CBER “points to
types and critical study design considerations, consider” guidance document on testing mono- 5
they also allow feedback on clinical trial design clonal antibodies, drafted initially in 1994, stoked
and important chemistry, manufacturing and
control (CMC) issues for materials to be used in
the demand for additional, much-needed guid-
ance on nonclinical testing strategies for small
6
clinical development. molecules, whether designed for general testing,
The evolution from the traditional drug
discovery model of generic receptor-driven ther-
or as a special consideration for certain disease 7
indications. Over time, additional regional
apeutics to systems and response-driven path- and international guidance documents became
ways, also forced changes in how regulators and available, and pre-IND meetings (including 8
drug companies approached preclinical safety teleconferences and written responses) expanded
testing. Largely due to advances in designing
therapeutics to selectively target disease path-
to cover a broader range of therapeutics. This
provided even the smallest companies the oppor-
9
ways where the recruitment and/or disabling of tunity to engage in drug development planning
immune function is exploited, traditional animal
models and dosing regimens were found to have
with some degree of confidence they could create 10
a virtual drug-development roadmap, custom-
little or no relevance, especially regarding safety ized for their product, and acceptable to various
endpoints. In practice, in the late 1980s and early agencies. This helped fuel the surge in IND-type 11
1990s, this led FDA to establish a mechanism submissions throughout the early 2000s until a
for face-to-face meetings with prospective drug
developers to discuss their IND plans, especially
global recession slowed things down a bit from
2008 to late 2012. Nevertheless, the numerous
12
for biologics and protein-based therapeutics, guidance documents issued during this time (and
where pharmacologic relevance was questionable
at best, in standard toxicology species like rat
still being produced) formed the foundation for 13
many innovative program strategies, especially
and dog. After internal reorganization of FDA for small start-up companies. At the same time,
agency divisions responsible for small molecules this is where the lines between nonclinical test- 14
(the Center for Drug Evaluation and Research ing strategy “guidance” and “requirements” often
(CDER)) and for biologics (the Center for Bio-
logics Evaluation and Research (CBER)), and
become blurred.
15
with industry clamoring for more broad-scope The International Council on
pre-IND meetings with FDA, the culture of out-
reach in guidance and agency division participa-
Harmonisation: ICH Guidelines 16
tion in pre-IND meetings soon were expanded. This section discusses the nature and scope of
In the 1980s and 1990s, concurrent with ICH guidelines on preclinical safety strategy, 17
the development of more large molecules (e.g., regardless of the country or region in which drug
protein-based therapeutics) arising from recom- regulatory submissions are planned. This chapter
binant technology, many large pharmaceutical will review the “S” (safety) and the “M” (multi- 18
companies expanded globally, creating a sizable disciplinary) guidelines, where applicable. The

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 Chapter 6: Preclinical Safety Guidelines Supporting International Drug Registration

ICH website (https://www.ich.org/home.html) Drug regulation in less-active markets and

lists guidance documents available in two other emerging nations’ economies more recently has
major categories (“E” and “Q” designations for become an important consideration in global
Efficacy and Quality, respectively), with Q&A drug registration. Regional harmonization initia-
documents available for many of the guidance tives (RHIs) were established for drug regulation
revisions. All ICH S, M, E and Q guidance across a defined group of non-ICH core member
documents are listed with numeric designations, countries. RHIs include the Asia-Pacific Eco-
with higher numbers representing the most nomic Cooperation (APEC), Association of
recently released guidelines. For example, S1 Southeast Asian Nations (ASEAN), East Afri-
through S11 each represent a different nonclin- can Community (EAC), Gulf Health Council
ical safety guidance document, with S11 being (GHC), Pan American Network on Drug Reg-
the most recent. The appearance of an R designa- ulatory Harmonization (PANDRH) and South
tion in parentheses, e.g., ICH S6(R1), designates African Development Community (SADC).
the first published revision of the S6 guideline, Although not recognized formally as members,
whereas M3(R2) represents the second revision organizations involved in emerging market RHIs
of the M3 guideline. have been invited to nominate permanent repre-
Looking at a brief ICH history, the EU first sentatives to participate in ICH meetings.
achieved congruence among Member States The ICH guideline establishment and
on general pharmaceutical development guide- approval process is important in understanding
lines through the European Medicines Agency its relevance and application in drug develop-
(EMA). This gave rise to a meeting in Brussels ment. The process begins when the ICH Steer-
in 1990, during which an agreement was reached ing Committee (SC) endorses an initiative and
on a mechanism to harmonize guidelines among establishes an expert working group (EWG). It
the US, EU and Japan. The harmonization includes five steps:
1. consensus building to define the need
mechanism established two meetings per year
for a guidance document (concept
of representatives from the three core regions
paper/business plan); SC approval to
(including regulatory agencies (FDA, EU and
continue; establishment of an EWG to
Japan’s MHLW and pharmaceutical trade
draft a technical document
organizations) and observers (World Health
2. six-party consensus on the draft tech-
Organization (WHO), the European Free Trade
nical document and draft guidance
Association (EFTA) and Health Canada) to har-
adopted by regulators
monize drug safety, efficacy, quality and multidis-
3. consultation and discussion among
ciplinary regulatory guidelines and to standardize stakeholders from each region impacted
the harmonization process. This meeting was by the draft guidance, resulting in a
designated as The International Conference on revised draft
Harmonisation of Technical Requirements for 4. ICH tripartite guidance document
Registration of Pharmaceuticals for Human Use adoption based on sufficient agreement
(ICH). Since that time, the core region des- among all parties
ignation has been replaced by the designation 5. implementation or regional government
“founding regulatory members,” and regulatory approval
membership has expanded to include Canada
(Health Canada), Switzerland (Swissmedic), Despite this daunting process, the guidance doc-
Brazil (ANVISA), China (NMPA), Chinese uments generated generally have been timely and
Taipei (TFDA), Republic of Korea (MFDS), and represent a broad cross-sectional perspective on
Singapore (HSA). key topics critical to developing a rational drug

60 All rights reserved; file sharing prohibited.

 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
development strategy across diverse geographic will pharmacology make in how the company’s
and cultural boundaries. Organizers and contrib- program is designed? Often, the agent’s pharma- 2
utors to this process have been very successful in cology and mechanism of action impact not only
harmonizing global pharmaceutical development,
particularly with respect to preclinical safety
efficacy but safety and are key in developing the
right preclinical drug development strategy. If 3
testing strategies. the drug candidate, for example, alters some part

Developing a Rational Preclinical

of the innate immune system versus acting as an 4
agonist on certain serotonin pathways, or works
Safety Evaluation Strategy by inhibiting protein synthesis in certain bacteria,
Step 1 Forget the Guidance Documents these hypothetical pharmacologic actions provide 5
(Well, Not Really) key information in establishing the program’s
base: e.g., what laboratory species might be most
Regulatory professionals frequently are asked relevant, what endpoints should be included that 6
to create a preclinical development plan (and typically would not be considered in standard
estimated budget) for developing a new molec-
ular or chemical entity quickly. It is assumed all
designs, and what limitations might be import-
ant in incorporating and interpreting bacterial
7
those informative guidance documents make genetic toxicology tests for certain drug classes?
it simple to develop a plan from which general Regarding the intended indication, the 8
pricing can easily be obtained from histori- same toxicology program and timelines for a
cal experience or from a reputable Contract drug intended as a sleep aid, for example, would
Research Organization (CRO). differ from one intended to treat advanced 9
However, before doing anything else, the cancer, and neither would likely be appropriate
regulatory professional should first answer the
“five whats:”
for a drug exclusively intended for metabolic
diseases in children.
10
1. What molecular entity does the com- The route of administration’s technical
pany want to develop? feasibility and challenges will be of primary 11
2. What is its pharmacologic activity? importance for an inhalation program versus a
3. What is the intended therapeutic topical eye drop program, intravenous infusion or
indication? oral capsule programs. Delivering the drug at rel- 12
4. What route and mode of administration atively high doses to species much smaller than
are intended for the clinic?
5. What does the company want to do in
humans may be limited by the necessary equip-
ment’s performance specifications and availabil-
13
its first human trial (or more commonly ity, ultimately impacting study cost and timing.
‘what does the first human trial look like’)? Last, but not least, the company must consider 14
the regimen for its initial clinical trial.
Without first addressing these five ‘whats,’ all the In most programs, two- or four-week GLP
existing published regulatory guidance will not toxicology studies are usually sufficient to initiate 15
put the company on the right path and, in fact, human trials. However, with certain programs,
may ultimately misdirect it.
Why are the five whats so important?
IND-enabling studies might require three to
six months of toxicology to support long-term
16
Molecular entities with structures as diverse as a administration in a target patient population,
simple small molecule, an antisense oligonucle- and only studies of that duration can answer 17
otide or a monoclonal antibody, for example, will safety and preliminary efficacy questions in initial
have very different concerns and issues that likely human trials. Conversely, four-week toxicology
will impact company strategy, timing, species studies to enable human trials might be con- 18
selection and, certainly, budget. What difference sidered excessive for a drug intended only for a

All rights reserved; file sharing prohibited. 61

 Chapter 6: Preclinical Safety Guidelines Supporting International Drug Registration

single dose. Guidance documents are available small molecules, or guidance on study timing to
that may be able to help with these decisions; support all clinical development phases for both
however, without a detailed product understand- small molecules and protein-based therapeutics.
ing, the individual(s) tasked with providing a
ICH M3(R2)
preclinical development strategy is at a disad-
vantage, potentially wasting company time and This may be the most widely used and refer-
resources. Even addressing the five whats will enced guideline in nonclinical safety evaluation
not fully ensure guidance documents’ usefulness and drug development because its purpose is
for the right preclinical strategy and timing, but “to recommend international standards for, and
doing so will ultimately help form the basis of a promote harmonization of, the nonclinical safety
well thought-out, rational plan. studies recommended to support human clinical
trials of a given scope and duration as well as
Knowing Where to Look for Guidance marketing authorization for pharmaceuticals.”
Step 2 Not Necessarily Where You Think The guidance’s scope includes “pharmacology
studies, general toxicity studies, toxicokinetic and
This discussion on internationally approved nonclinical pharmacokinetic studies, reproduc-
regulatory nonclinical safety (ICH “S”) guide- tion toxicity studies, genotoxicity studies and, for
lines might lead the regulatory professional to drugs that have special cause for concern or are
think ICH’s website is the first place to look for intended for a long duration of use, an assess-
published guidance to aid in formulating a test- ment of carcinogenic potential.” Whereas ICH
ing strategy. However, this depends on whether M3 guidance generally is considered more-spe-
the new therapeutic is included in a category of cific for small molecules, ICH S6(R1) covers
already approved or existing therapies. A wealth the basic preclinical safety evaluation framework
of preclinical strategy information is available for biotechnology-derived therapeutics. ICH
online in the form of US and EMA drug reg- M3(R2) provides the development strategy “big
istration approval summaries. Sifting through picture” for nonclinical safety studies and, at
FDA New Drug Application (NDA) pharmacol- the same time, covers highly detailed dose and
ogy review and approval documents can provide species selection analysis, and the use of repro-
insight into what studies were required for a ductive and developmental toxicology studies to
similar product and can be invaluable in devising support human trials in women of child-bearing
strategy. The major problem with this approach potential (WOCBP) in the various core regions.
is that pharmacology review documents may Combined with the five whats, ICH M3(R2)
be somewhat dated and include all the studies likely will form the basis for the vast majority of
conducted for market registration by study type, small molecules’ preclinical development strategy,
instead of in chronological order. Some educated along with the addition of S6(R1) for biotech-
guesses can be made about how the program nology-derived agents.
was assembled, but to understand the study
chronology, the far better option is to review the S1A–S1C(R2): Carcinogenicity Studies
relevant ICH guidelines. In this case, the most These documents discuss the circumstances
relevant guideline is not an “S” guideline, but an under which carcinogenicity studies are needed
“M” or multidisciplinary guideline: M3 Guidance (any continuous treatment in humans lon-
on Nonclinical Safety Studies for the Conduct of ger than six months) (S1A); what models are
Human Clinical Trials and Marketing Authoriza- recommended or expected—mouse and rat, or
tion; Revision 2 (M3(R2)), which can provide a perhaps transgenic mouse models (S1B); and
comprehensive view of study types expected to factors to consider in dose selection (S1C(R2)).
support Phase 1–3 trials in each core region for At the time of publication, S1 was under revision

62 All rights reserved; file sharing prohibited.

 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
to “introduce a more comprehensive and inte- Cmax, Tmax, Area Under the Curve (AUC),
grated approach to addressing the risk of human half-life, clearance, etc., regardless of which term 2
carcinogenicity of pharmaceuticals, clarify and is used. Today, toxicokinetics are considered a
update, without compromising safety, the criteria
for deciding whether the conduct of a two-year
standard component of essentially all nonclinical
safety studies conducted in support of human
3
rodent carcinogenicity study of a given pharma- trials. These studies’ (or investigations within a
ceutical would add value to this risk assessment.” larger toxicology study) designs vary, depending 4
This likely will replace S1A and S1B. on the amount of blood or tissue required for
analysis, the size of the species being evaluated,
S2(R1): Genotoxicity Testing
the route of administration, the study length, 5
This discusses genetic toxicity study types and the potential for major metabolite exposure, the
timing needed to support initiation of human
trials and further product development. It
molecule’s physicochemical properties, the rate
of systemic uptake and elimination, whether the 6
replaces two previous guidance documents, S2A drug is a small molecule or protein therapeutic
and S2B, which dealt with general topics and
specific details of the then-used genotoxicity
(note, S6 covers recombinant products), etc. The 7
list can go on and on because each molecule may
assays. They quickly became outdated, and the S2 interact differently with biological systems. S5,
revision captured the salient concepts of each. which covers reproductive toxicity studies, also 8
mentions kinetics testing. Guidance documents
S3: Toxicokinetics
or no, as toxicology studies are tracked to com-
There are two documents here: S3A covers pletion, the bioanalysis (and subsequent toxicoki- 9
toxicokinetic investigations’ scope rationale and netic analysis) data typically come together after
design features in either a toxicology study or
as a separate study; and S3B, a less commonly
the in-life portion of the study has been com-
pleted, and based on required bioanalytical assays’
10
used guidance on toxicokinetic considerations complexity and toxicokinetic analysis interpreta-
in repeat-dose tissue distribution studies. These tion, more often than not, will impact the study 11
documents provide “guidance on developing test completion date.
strategies in toxicokinetics and the need to inte-
grate pharmacokinetics into toxicity testing, in S4: Duration of Chronic Toxicity Testing 12
order to aid in the interpretation of the toxicol- This guidance document, issued in 1998,
ogy findings and promote rational study design
development,” and “guidance on circumstances
describes the expectations for chronic toxicology
studies’ duration in both rodent and nonrodent.
13
when repeat-dose tissue distribution studies The more recent (2009) multidisciplinary guid-
should be considered (i.e., when appropriate ance M3(R2) further clarifies nonclinical study 14
data cannot be derived from other sources). It duration guidance and notes exceptions. For
also gives recommendations on the conduct of example, S4 states chronic studies should be six
such studies.” For a standalone study, the term months in rodents and nine months in nonro- 15
“pharmacokinetics” generally is used more often. dents. M3(R2) proposes the same six months for
This designation also may refer to the range of
doses evaluated, which often are more in the
rodents; however, for nonrodents, the guidance
states six months for Europe and nine for the
16
pharmacologic range than the toxicologic, but US and Japan. M3(R2) also includes examples
this definition is held rather loosely. “Toxicoki- of cases in which chronic nonrodent US and 17
netics” is used when it is an investigation within a Japanese studies may not need to adhere to a
toxicology study. These two terms essentially refer nine-month duration, e.g., when immunogenicity
to the same thing, and the calculated parameters or intolerability confounds the conduct of longer 18
obtained from bioanalytical data typically include term studies; when clinical treatment regimens

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 Chapter 6: Preclinical Safety Guidelines Supporting International Drug Registration

are intermittent even though the treatment ucts like monoclonal antibodies. Briefly, all three
intervals may be repeated chronically; for drugs regions allow WOCBP in early-stage clinical
administered chronically to reduce cancer recur- trials prior to reproductive and developmental
rence; and for drugs with indications where life toxicity assessments, provided there are adequate
expectancy is short. In general, M3(R2) should and well-controlled methods of contraception
be consulted first and then, if needed, more-spe- or birth control employed and, for Europe and
cific S guidance documents should be researched, Japan, if exposure is short (for example, inten-
noting which document is either more relevant sive pregnancy risk control over a short duration
or more recent. (e.g., two weeks)). The US defers those studies
until prior to Phase 3, whereas Europe and
S5(R3): Detection of Toxicity to Reproduction
Japan require reproductive and development
This guidance, first issued in 1993, was revised toxicity studies prior to inclusion of WOCBP,
in 1995 to add male fertility assessments, and with the caveats noted here and in the guidance
amended in 2000. The most recent revision (R3) document. When conducting enhanced pre-
was still under review at the time of publication and postnatal development (ePPND) studies
but is available from the ICH website in draft in nonhuman primates, ICH S6(R1) should be
form. Among other things, the original guideline, referenced for timing. For all regions, peri- and
established new terminology and scope for the postnatal development studies are needed prior
three phases of reproductive toxicity assessments to registration.
known as Segment 1 (fertility), Segment 2
(teratology) and Segment 3 (peri- and postnatal) S6(R1): Preclinical Safety Evaluation of Bio-
technology-Derived Pharmaceuticals
toxicity studies. These designations essentially
were translated to describe nonclinical evalua- S6 was highly anticipated in the wake of FDA’s
tion studies of: 1) fertility and early embryonic ‘Points to Consider’ document dealing with
development, 2) embryo-fetal development and monoclonal antibodies and circulated to industry
3) pre- and postnatal development, including in draft form in 1994. From an historical point
maternal function. Because of the similarity in of view, the timing and content of FDA’s original
study objectives and design with the legacy seg- guidance on the general area of recombinant
ment 1, 2 and 3 terminology, these studies still products was almost revolutionary in its focus
are referred to as Segs 1, 2 or 3, especially among on preclinical development science and rational
some more-senior toxicologists. drug safety strategies, versus the more recipe- or
The draft S5(R3) guidance applies to phar- menu-driven approach used for small molecules.
maceuticals, including biotechnology-derived At a time when there seemed to be no room
pharmaceuticals, vaccines (and their novel con- to deviate from standard toxicology program
stitutive ingredients) for infectious diseases, and and study design approaches, this was a boost
novel excipients that are part of the final phar- to the concept of incorporating science-driven
maceutical product. It does not apply to cellular toxicology into drug development. In short, the
therapies, gene therapies and tissue-engineered general human specificity in therapeutic target
products. This guideline should be read in con- and pharmacology from many of the biotechnol-
junction with ICH M3(R2), ICH S6(R1) and ogy-derived products being developed in the late
ICH S9 regarding whether and when nonclinical 1980s through the early 2000s were essentially
reproductive toxicity studies are warranted. drivers of new molecular entity INDs, and these
There are subtle differences among the three programs simply did not fit the standard small
ICH regions regarding these studies’ timing to molecule rat and dog models. FDA’s monoclonal
support human trials enrolling WOCBP, as well antibody ‘Points to Consider’ document, followed
as special considerations for recombinant prod- by the more-global ICH S6 guidance (originally

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
issued in 1997), addressed not only the spec- Prior to S7 guidance formalization, these
ificity issues, but opened the door for rational types of studies were historically included under 2
program design for all types of new therapeutic the “general pharmacology” designation, the core
entities. The original S6 guidance was revised in
2011 to cover issues arising with biotechnology
of which included ligand-binding assays and in
vivo cardiovascular safety testing in anesthetized
3
product development in all three ICH regions dogs. These studies typically were done within
over the years and benefitted from face-to-face pharmaceutical companies’ research and discov- 4
agency-industry interactions. Topics relating ery units, with little standardization.
to species selection, surrogate molecule uses, The absence of critical organ function
dose selection, study duration, tissue cross-re- measures in routine toxicology testing was high- 5
activity, immunogenicity, models and timing of lighted by incidents of serious and life-threaten-
reproductive toxicity testing and other pertinent
subjects were addressed specifically for the first
ing cardiovascular, neurological (central nervous
system/CNS) and/or pulmonary human drug
6
time or given substantially more discussion in safety issues. It was clear functional measure-
the revised document. There also was reference
to guideline principles that may be applicable
ments were needed preclinically and, given the 7
impact on human safety, should be obtained
to other agents, including recombinant DNA and evaluated prior to initial human trials, and
protein vaccines, chemically synthesized peptides, under GLPs. Thus, ICH S7A recommended a 8
plasma-derived products, endogenous proteins core battery of studies, including cardiovascular,
extracted from human tissue and oligonucleotide
drugs. These latter agents often fall into a gray
CNS and pulmonary function, to address acute
changes in these major organ systems typically
9
zone somewhere between small molecule and monitored in early human trials. Often, these
biotechnology product program and study design
approaches; the revised S6 guideline can be help-
studies are conducted as standalone, single-dose 10
studies, but more recently, these measures are
ful for those product types.

S7: Safety Pharmacology

being included in general toxicology testing,
depending on the species being evaluated, the
11
nature of potential direct or indirect effects on
Two guidelines have S7 designations: S7A Safety
Pharmacology Studies for Human Pharmaceuticals,
function, and the ability to discern functional 12
changes from adverse tolerability changes, in the
issued in 2000, and S7B The Nonclinical Evalua-
toxicology study protocol or study plan. In prac-
tion of the Potential for Delayed Ventricular Repo-
larization (QT Interval Prolongation) by Human tice, standalone safety pharmacology studies his- 13
Pharmaceuticals, issued in 2005. S7A was torically have been conducted for small molecules
drafted to address and define safety pharma- administered by systemically available routes,
while a single study incorporating all three func-
14
cology study objectives and scope and to define
which studies are needed to initiate human tional safety pharmacology measures typically
trials for submission in market authorization has been used for biotechnology-derived prod- 15
applications. S7B focused on identifying agents ucts. Only a single species is needed to address
each of the three core organ system functional
that may adversely affect ventricular repolariza-
tion and prolong the QT interval as measured evaluations, and all three may be evaluated in 16
via electrocardiography. The driver for safety the same species. Unless a nonhuman primate is
pharmacology guidance was the general incon- more pharmacologically relevant, small molecule 17
sistency in the study types considered under this cardiovascular assessments are usually performed
designation, what target systems were evaluated, in dogs (with minipigs used case-by-case), while
when studies were conducted and whether they CNS and pulmonary function studies are largely 18
were conducted under GLPs. conducted in rodents (rats and/or mice).

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 Chapter 6: Preclinical Safety Guidelines Supporting International Drug Registration

Telemetry devices for electrocardiographic the immune system specifically, to produce

and other clinically important functional mea- unexpected adverse changes resulting in immu-
sures, validated for use in standard toxicology notoxicity. It is specific to small molecules, as
testing paradigms and standalone studies, have biotechnology-derived products as a class are
increased preclinical functional evaluations’ discussed in S6. The guidance provides “(1) rec-
overall quality, sensitivity and specificity. S7B ommendations on nonclinical testing approaches
expanded discussion on cardiovascular measure- to identify compounds which have the poten-
ments referred to in S7A, providing guidance tial to be immunotoxic, and (2) guidance on a
on in vitro and in vivo measurements needed weight-of-evidence decision making approach
to more-adequately evaluate potential human for immunotoxicity testing. Immunotoxicity
cardiac risk. The guidance presents a flowchart is, for the purpose of this guideline, defined as
outlining step-by-step preclinical human cardiac unintended immunosuppression or enhancement.
risk assessment and references in early in vitro Drug-induced hypersensitivity and autoimmu-
evaluations employing human ionic channel nity are excluded.”
regulatory proteins, like the human Ether-á-go- In general, standard toxicology study designs
go-related protein gene (hERG), to be incorpo- incorporate such indirect immune system
rated in safety pharmacology testing strategies. It competency measures as: hematology endpoints;
further discusses the preferred use of nonrodent organ weight and/or histologic evaluation of
cardiovascular safety monitoring to detect poten- spleen, lymph nodes (and other tissues associ-
tial adverse effects on ventricular repolarization, ated with lymph function), thymus and bone
and issues evaluating QT electrocardiogram data, marrow; total serum globulin levels calculation;
requiring a correction factor (QTc) to be applied. and, through animal husbandry and veterinary
Although the S7B guidance was focused on bet- support, monitor infection incidence within an
ter-quantifying ECG data in safety pharmacol- animal room that may relate to individual dose
ogy testing, these concepts generally have carried groups. Certain tumor types also may indicate
over to ECG evaluations in standard repeat-dose immune suppression with long-term dosing.
general toxicology testing in nonrodents, whether The guideline’s real purpose, however, is to
or not they have been addressed previously in recommend a weight-of-evidence approach on
single-dose safety pharmacology tests. follow-up immunotoxicity testing endpoints and
Overall, S7A and S7B provide a good foun- timing. Regulatory professionals should consult
dation for global regulatory agencies’ expectations this guideline if either class-related immuno-
for functional measures directly related to clin- toxicity might be a potential liability, or the test
ically measurable, vital human safety endpoints. agent’s pharmacology might suggest potential
It should be noted that although S7 principles off-target immune system effects. Otherwise,
should be followed in all relevant nonclinical func- laboratories conducting preclinical safety studies
tional evaluations, its full scope need not apply in for international drug regulatory purposes likely
all preclinical development situations. This is espe- will cover the basics in their standard toxicology
cially true for drugs intended for cancer or other testing protocols. It is always advisable to dou-
life-threatening situations (S9 guidance). Should ble-check study plans and protocols for the basic
additional functional measurements in animals endpoints described in S8.
be shown to have relevance to human safety, S7
guidance may be further revised. S9: Nonclinical Evaluation of Anticancer Phar-
maceuticals
S8: Immunotoxicity Since oncolytic agents are represented heavily
This guidance, issued in 2005, was intended to in drug development pipelines (given the high
address the potential for agents not targeting morbidity/mortality associated with cancer

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
and the aging populations of many wealthier, lished that addressed many of the questions,
pharmaceutical-centric countries), this guid- particularly regarding antibody drug conju- 2
ance, introduced in 2009, proved very helpful to gates (ADC), toxicokinetics and human starting
companies wanting to expedite their anticancer
drug candidates’ clinical trials. However, this
dose considerations.
3
S10: Photosafety Evaluation of Pharmaceuticals
guideline is specific to “pharmaceuticals that are
only intended to treat cancer in patients with late This guideline, issued in 2013, defines “factors
for initiation of and triggers for additional
4
stage or advanced disease regardless of the route
of administration, including both small molecule photosafety assessment and should be read in
and biotechnology-derived pharmaceuticals. conjunction with ICH M3(R2), Section 14 5
It describes the type and timing of nonclinical on Photosafety Testing.” Previously, M3(R2)
studies in relation to the development of anti- provided only general guidance on the need
cancer pharmaceuticals and references other for phototoxicity evaluation, based on “1) the 6
guidance as appropriate.” photochemical properties (e.g., photoabsorption
One factor driving this guidance was the
difficulty in translating standard daily toxicology
and photostability) of the molecule; 2) informa-
tion on the phototoxic potential of chemically
7
dosing regimen data, especially for small mole- related compounds; 3) tissue distribution; and
cules, to oncolytic agents’ customized or cyclic 4) clinical or nonclinical findings indicative 8
clinical dosing regimens. This guidance clarifies of phototoxicity.” FDA previously had issued
what is needed to support these clinical regimens its own photosafety testing guidance, but S10
and the often limited preclinical safety program was a much-needed international guidance and 9
scope associated with oncolytics. It also helps addressed both photo-activated tissue response
regulatory professionals draft human start-
ing dose recommendations in cancer patients,
(phototoxicity) and immune-mediated response
evaluation strategies for photochemical reactions
10
based not on traditional animal safety margins (photoallergies). Photosafety program criteria
from the No-Observed-Adverse-Effect-Level include: light absorption within the range of 11
(NOAEL), but incorporating traditional natural sunlight (290-700 nm); reactive species
oncology approaches including “a start dose generation following UV-visible light absorption;
at 1/10 the Severely Toxic Dose in 10% of the and sufficient drug distribution to light-exposed 12
animals (STD 10) in rodents. If the nonrodent tissues (e.g., skin, eye). The starting point is the
is the most appropriate species, 1/6 the Highest
Non-Severely Toxic Dose (HNSTD) is consid-
Molar Extinction Coefficient (MEC). If the
MEC is no greater than 1000 L/mol/cm at any
13
ered an appropriate starting dose. The HNSTD wavelength between 290 and 700 nm, there is
is defined as the highest dose level that does not no phototoxicity concern. This guidance provides 14
produce evidence of lethality, life-threatening a decision-tree approach to photosafety testing
toxicities or irreversible findings.” S9 essentially for systemically applied products and highlights
maintains the sound preclinical safety evaluation the importance of drug distribution data to 15
principles included in numerous other guidance photo-exposed areas (skin and eye), expectations
documents; however, it redefines the testing
nature and scope needed to treat late-stage or
for formulations applied dermally and guidance
on the use of in vitro and in vivo phototoxicity
16
advanced disease and should be consulted early test models, if needed, in the drug development
for potential application in defining oncolytic program. This issue often is overlooked, as tissue 17
preclinical strategy. distribution data may not be available until
The concepts introduced in this guideline human trials are initiated; hence, it is important
generated many technical questions, so in 2018, to generate lead molecule light-absorbing prop- 18
a follow-up ICH S9 Q&A document was pub- erty data as early as possible.

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 Chapter 6: Preclinical Safety Guidelines Supporting International Drug Registration

S11: Nonclinical Safety Testing in Support of M7(R1): Assessment and Control of DNA
Development of Pediatric Medicines Reactive (Mutagenic) Impurities in Pharmaceu-
ticals to Limit Potential Carcinogenic Risk
At the time of publication, S11 was still in draft
form (Step 2) and under review. It is intended This multidisciplinary guideline is included to
to serve as a recommended approach for the alert regulatory professionals to impurity level
nonclinical safety evaluation of drugs intended management expectations throughout the clinical
for development in pediatric populations. This program and postsubmission. M7’s purpose is to
also could include products with prior adult use, “provide a practical framework that is applicable
as well as products being considered for initial to the identification, categorization, qualifica-
human use in pediatrics. The draft guideline tion, and control of these mutagenic impurities
recommends consulting the ICH S9 guideline to limit potential carcinogenic risk.” New drug
for recommendations on whether to conduct substance and product impurities are discussed
a juvenile animal study ( JAS) for oncolytics. in ICH Q3A(R2) and Q3B(R2); however,
Whether JAS studies are warranted, and often this guidance provides sponsors with hazard
their design considerations, depends on several assessment regulatory expectations for actual
factors, including a weight-of-evidence approach or potential impurities using structure activity
for the applicability of existing pediatric and relationships (SAR) and computational models
adult human clinical data, pharmacological to predict bacterial mutagenicity outcomes. These
targets, pharmacokinetics, nonclinical safety data assessments’ timing and scope depend on the new
and feasibility of conducting a relevant study. drugs’ clinical development or postapproval stage
The guideline also references ICH E11 (Clinical and generally are driven by attempts to optimize
Investigation of Medicinal Products in the Pedi- drug substance or drug product manufacturing
atric Population) for more information on the processes, stability determination under accel-
potential need for JAS. ICH S11 also provides erated conditions and/or analytical technique
relevant study design recommendations and refinements. These hazard assessments would not
should be referenced in all cases where a JAS is be expected to factor into a typical drug develop-
considered warranted. In the US, the 2005 Pedi- ment timeline; however, impurities determined
atric Research Equity Act (PREA) gives FDA the to have genotoxic liabilities can potentially create
authority to require pediatric studies for certain costly sponsor manufacturing control issues and
drugs and biological products. Studies must use ultimately impact the drug substance or drug
product’s availability for further development or
appropriate formulations for each age group.
The studies’ goal is to obtain pediatric labeling marketing approval applications.
for the product. ICH S11 gives drug regulatory
Regional Guidance Documents
and nonclinical safety assessment professionals a
comprehensive overview of when, how and why With ICH’s success, it is possible pertinent
JAS are conducted as part of a complete package guidelines from FDA, EMA, OECD or other
addressing PREA requirements as well as other sources addressing some part or more of a com-
local, regional and international expectations in pany’s preclinical development issue at hand, may
support of pediatric safety. Although S11 still be overlooked. This may require a little searching
is under review, the draft guideline provides but should be taken seriously. Although local or
excellent examples, hypothetical cases, reference regional guidance often is congruent with ICH,
material and decision-tree approaches in its in those cases where there may be differences, the
notes and appendices, making it one of the most local or regional guidance will take precedence.
thorough and invaluable resources in the current For the US, nonclinical guidance documents
ICH safety guidance library. generally address specific cases or therapeutic

68 All rights reserved; file sharing prohibited.

 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
classes. For example, FDA’s CDER has issued One of FDA’s more valuable guidance
nonclinical guidance on testing strategies for documents, referenced in several other regions, is 2
combination products, reformulations and route Guidance for Industry: Estimating the Maximum
of administration changes, excipients, antivirals
and drug metabolites, to name just a few. CBER’s
Safe Starting Dose in Initial Clinical Trials for
Therapeutics in Adult Healthy Volunteers (2005).
3
Guidance for Industry: Preclinical Assessment of This guideline provides the basis for selecting
Investigational Cellular and Gene Therapy Products (recommending) initial human doses for Phase I 4
(2013) offers one of the few regulatory perspec- studies (in normal human volunteers) from data
tives on testing strategies for stem cells and gene obtained in IND-enabling toxicology studies for
therapy products and can be a useful guide for both small molecules and protein-based thera- 5
these products’ global regulatory expectations. peutics. In Europe, after a catastrophic Phase 1
experience resulted in multi-organ system failure
EMA and other regulatory bodies also have
issued several specific guidelines. FDA’s guide- with a pro-inflammatory monoclonal antibody 6
lines are not numbered or uniquely identified called TGN1412, EMA issued Guideline on
with any particular designation like those used Strategies to Identify and Mitigate Risks for First-
In-Human Clinical Trials With Investigational
7
by ICH, EMA or OECD; they are identified by
title and issue date only. Medicinal Products (2007), which described using
OECD guidelines are available for specific the Minimal Anticipated Biological Effect Level 8
toxicology study types for rodent or nonrodent, (MABEL) for setting starting doses in the clinic
when certain risk factors made animal-to-hu-
route of administration and study duration. For
example, general considerations in toxicology man translation of safe doses and safety margins 9
protocol (same as OECD “study plan”) design questionable. In general, however, both FDA
and scope dealing with 90-day toxicology studies and EMA starting dose considerations using the
NOAEL are similar. It is very likely the team
10
can be found in OECD Guideline 413. Like
toxicologist has experience using these guidelines
ICH guidelines, these are not meant to apply to
all situations, and one size definitely does not fit
to help bridge dose levels between the animal 11
safety studies and the doses projected for the
all. Toxicology protocols should be customized to
clinic, an exercise that should occur very early in
meet the individual lead molecule or program’s
toxicology program strategy. However, it often is 12
needs while complying with expectations from
not easy to make this translation without under-
the most relevant guidelines available. The dosing
regimen must simulate that projected for the
standing the model’s relevance and translating
the findings to human safety. Although any error
13
clinic, and the animal model should have phar- always should be on the side of safety, starting
macologic relevance for the toxicology programs’
results to translate to human safety.
with an overly conservative initial dose in the 14
clinic can be time-consuming and costly. This
In many cases, pharmacologic relevance was is where the toxicologist’s experience is invalu-
well-covered in the toxicology species, but the able. This also includes the key test facility or 15
study results had little or no relevance to humans preclinical CRO players like the study director,
due to, e.g., species-specific metabolism, differ-
ences in plasma protein binding or clearance
study pathologist, veterinary staff, principal
investigators and senior level reviewers. There is
16
rates, hypersensitivity to the drug or formulation, a reason for everything in a toxicology study, and
off-target pathways not relevant in humans and/ the degree to which the findings translate to the 17
or immunogenicity. These species differences may human dosing condition (or target patient pop-
have no impact on toxicology findings’ clinical ulation) may make the difference in whether the
relevance or may create problems for the team in clinical program progresses quickly or is diverted 18
setting reasonable human dosing safety margins. to chasing preclinical safety margins.

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 Chapter 6: Preclinical Safety Guidelines Supporting International Drug Registration

An excellent informative text on international requirements (Standard for Exchange of Non-

guidelines for safety testing is Nonclinical Safety clinical Data (SEND) that affect all NDAs,
Assessment, A Guide to International Pharmaceu- BLAs and Abbreviated New Drug Applications
tical Regulations, edited by Brock, Hastings and (ANDAs) that include nonclinical studies initi-
McGown, published by Wiley & Sons, in 2013. It ated after 17 December 2016. For INDs, SEND
covers the major regulatory agency guidelines for data requirements apply to nonclinical studies
pharmaceutical registration and discusses non- initiated after 17 December 2017. The SEND
clinical testing strategies and issues from a global Implementation Guide (SENDIGv3.0) supports
perspective, with a comprehensive look at regional single-dose general toxicology, repeat-dose
guidance as well as the role of ICH guidelines in general toxicology and carcinogenicity studies.
regional applications. The following is a partial list SENDIG v3.1 additionally supports respiratory
of regions and respective agencies responsible for and cardiovascular safety pharmacology studies.
issuing nonclinical guidelines: At the time of publication, reproductive toxi-
• US: FDA CDER and CBER guidelines cology studies were not included in the SEND
• Europe: EMA (e.g., CHMP) guide- submission requirements, and CBER was not
lines, participating EU countries; requiring SEND formatted datasets. Since FDA
OECD guidelines for study designs will update this information in the future, the
• Canada: Health Canada (Health Prod- reader is directed to the FDA webpage outlining
ucts and Food Branch (HPFB)) these requirements: https://www.fda.gov/indus-
• Japan: MHLW and Pharmaceuticals try/study-data-standards-resources/study-data-
and Medical Devices Agency (PMDA) submission-cder-and-cber.
for sponsor applications
• India: Central Drugs Standards Control Case Examples
Organization (CDSC) through the
Drugs Controller General of India Example 1—Small Molecule, No Frills
(DCGI) see Schedule Y; recombinant This example involves a hypothetical small mol-
products through Review Committee
ecule for a chronic indication. This new, orally
on Genetic Manipulation (RCGM)
active nonsteroidal anti-inflammatory agent
suggest following ICH S6(R1)
(SM-001) acting on T-lymphocytes is for use in
• China: National Medical Products
arthritis. To propose a viable nonclinical safety
Administration (NMPA, formerly
program to enable initiation of human trials, cer-
China Food and Drug Administration,
tain information is required. Using the five whats,
formerly CFDA) guidelines
• South America: MERCOSUR (South- the first four items have been addressed already:
ern Common Market) countries (Argen- 1) small molecule, 2) pharmacologic action—T-
tina, Brazil, Paraguay, Uruguay and Ven- cell inhibition, 3) chronic indication—arthritis
ezuela) MERCUSOL/GMC 1996 (act and 4) oral route of administration. The next
legislating requirements for clinical trials ‘what’ is key. The first trial is a combination single
and outlines nonclinical safety compo- ascending dose and five-day multiple ascending
nents needed); also Brazilian National dose study in healthy volunteers.
Regulatory Agency (ANVISA) The regulatory professional should start
• Australia: Therapeutic Goods Adminis- with ICH M3(R2). Table 6-1 recreates
tration (TGA), generally follows EMA M3(Rs)’s Table 1.
and ICH guidelines According to Table 6-1, a toxicity study of
at least two weeks should be conducted in two
Regulatory professionals also should be aware species, although, if there never will be a dose
of FDA’s nonclinical data submission format longer than five days, human trials could be

70 All rights reserved; file sharing prohibited.

 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
Table 6-1. Recommended Duration of Repeat-Dose Toxicity Studies to Support the Conduct 2
of Clinical Trials

Recommended Minimum Duration of Repeat-Dose Toxicity

3
Maximum Duration of Clinical Studies to Support Clinical Trials
Trial
Rodents Non-rodents 4
Up to 2 weeks 2 weeksa 2 weeksa
5
Between 2 weeks and 6
Same as clinical trial b
Same as clinical trial b
months

> 6 months 6 monthsb,c 9 monthsb,c,d

6

a. In the US, as an alternative to two-week studies, extended single-dose toxicity studies can support single-dose human trials. Clinical
7
studies of less than 14 days can be supported with toxicity studies of the same duration as the proposed clinical study.
b. In some circumstances, clinical trials of durations longer than three months can be initiated, provided the data are available from
three-month rodent and non-rodent studies and complete data from the chronic rodent and non-rodent studies are made available,
consistent with local clinical trial regulatory procedures, before extending dosing beyond three months in the clinical trial. For serious
8
or life-threatening indications or on a case-by-case basis, this extension can be supported by complete chronic rodent data and
in-life and necropsy data for the non-rodent study. Complete histopathology data from the non-rodent should be available within an

c.
additional three months.
There can be cases where a pediatric population is the primary population, and existing animal studies (toxicology or pharmacology)
9
have identified potential developmental concerns for target organs. In these cases, long-term toxicity testing starting in juvenile

10
animals may be appropriate.
d. In the EU, studies of six months duration in non-rodents are considered acceptable. However, where studies with a longer duration
have been conducted, it is not appropriate to conduct an additional study of six months. The following are examples where non-ro-
dent studies of up to six months duration can also be appropriate for Japan and the US:
• when immunogenicity or intolerance confounds conduct of longer-term studies
• repeated short-term drug exposure even if clinical trial duration exceeds six months, such as intermittent treatment of migraine,
11
erectile dysfunction, or herpes simplex

12
• drugs administered on a chronic basis to reduce the risk of recurrence of cancer
• drugs for indications for which life expectancy is short

initiated (in principle) in the US with a five-day this means dosing patients for at least two weeks
13
study (see footnote a in Table 6-1). For Europe and maybe up to one month before starting a
and Japan, 14 days typically would be required longer-term safety and efficacy program (gen- 14
for first-in-human trials for any human trial erally referred to as Phase 2b). The regulatory
duration up to 14 days. professional should ensure the toxicology
Why would toxicologists want to run studies program used to move the product into the 15
longer than five-days if that is what the initial clinic (IND-enabling) allows the company to
Phase 1 study looks like? Aside from the ‘more
is better’ argument when it comes to safety, one
continue onward into subsequent human trials
to garner key safety (and preliminary efficacy)
16
of the original five whats is whether the product signals (Phase 1b or 2a) without waiting for
deals with a chronic indication. This means the additional preclinical safety data. Following 17
IND-enabling toxicology study should support M3(R2) for SM-001, 28-day toxicology studies
repeated human dosing into Phase 2 to avoid in two species (rodent and nonrodent) would be
having to stop clinical development to wait for appropriate, ideally with toxicokinetics to estab- 18
more toxicology data. For most clinical programs, lish exposure and dose relationships (and also,

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 Chapter 6: Preclinical Safety Guidelines Supporting International Drug Registration

ultimately, to help establish safety margins) and cokinetics and toxicokinetics and, in many cases,
some period of recovery (typically 14 days for a specialty assays to assess the molecule’s specific
28-day study). properties. It takes time not only to obtain the
To complete the IND-enabling package, data, but to analyze, integrate and interpret them.
ICH M3(R2) states the need for safety pharma- This should not be rushed, although, invariably,
cology (core battery) and genotoxicity studies. As it is. Timeline stress generally occurs because
highlighted in Table 6-1’s footnotes, the guide- toxicology studies typically represent the final
line specifies the point at which reproductive tox- information needed prior to filing regulatory doc-
icity assessments for WOCBP will be included uments (e.g., INDs or CTAs) to support human
in human trials. trials. Often, original timelines may have included
Although Table 6-1 does not address the sufficient time to complete all proper assessments,
rationale behind this molecule’s study and but delays from study scheduling, analytical or
program design, ICH M3(R2) states pharmaco- formulation issues and compound or test species
logically relevant rodent and nonrodent species availability; unexpected test results requiring fur-
are needed for the general toxicity assessment. ther investigation; or, for many companies (both
Systemic exposure needs to be assessed in the large and small), limitations in available resources
toxicology models, and three dose levels should to conduct the study, invariably occur. The time
be used to assess dose-response, with the highest and resources required to satisfy SEND dataset
dose a maximally tolerated or maximal-feasible formatting should not be forgotten for INDs sub-
dose. The low dose should not produce toxicity, mitted in the US. Regulatory professionals should
and the mid dose may produce toxicity with prepare their companies for these potential set-
less incidence or severity than the high dose. backs in advance. Avoiding these delays requires
The dosing frequency should mimic the human careful planning and diligence and perhaps
trial regimen. This guideline is essentially a road additional pilot work to minimize surprises along
map to the IND or Investigator Brochure (IB) the way but, in the end, dealing with these issues
supporting the Phase 1 trial, without study may require a pause in the timeline before moving
design details. For specifics concerning individual forward. The bottom line is rushing the preclinical
protocols, FDA’s Redbook, OECD guidelines, safety study completion phase may be hazardous
ICH S2 (genotoxicity), ICH S7 (safety pharma- to the program and the health and well-being of
cology), ICH S3 (Pharmacokinetics) ICH S11 all involved, including human test subjects.
(juvenile animal studies) or a toxicologist with For SM-001, by following these steps, imag-
several years of pharmaceutical drug regulatory ine the company has done all the right things
experience should be consulted. and has the human pharmacokinetic and safety
The toxicologist will use not only the guide- data from Phase 1, as well as some preliminary
lines available for establishing the study outline efficacy signals from either pharmacodynamic
frameworks, he or she also will consider what markers or some limited work in patients. The
pharmacodynamic markers might be important, company now is considering longer-term Phase
what additional endpoints may be needed (e.g., 2 studies and beyond. Again, M3(R2) typically
ICH S8) and how to work best with the testing would be the company’s road map (Table 6-1),
facility to help ensure a quality safety assessment but reference to a second table in the guidance,
and work within established timelines. A note depicting recommended toxicology study dura-
here about timelines: toxicology studies rely on tion in rodents and nonrodents, will be required
expert safety assessments of a variety of endpoints, to support marketing registration. For most
including clinical signs, body weight and food indications that have reached Phase 3, studies
consumption, ophthalmology, electrocardiography, recommended in Table 6-1 likely have covered
clinical pathology, anatomic pathology, pharma- what is needed for market registration.

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
The path to an NDA and market registra- cies selection, duration of studies in support of
tion for a typical small molecule includes other chronic indications, immunogenicity issues in the 2
nonclinical safety assessments, some of which are test species, ADME expectations, test systems
unique or require the program to be customized
based on program- or disease state-specifics.
for reproductive and developmental toxicity
assessment and high dose selection, to name just 3
Some examples are: route and mode of admin- a few. In developing project milestone timelines,
istration; known therapeutic agent class effects; the regulatory professional should bear in mind
dosing durations may include exposures up to a
4
absorption, distribution, metabolism and excre-
tion (ADME) considerations; or metabolites week (or longer post-dose) for setting main study
specific to humans or the target patient pop- termination dates, and recovery periods may be 5
ulation, potential drug interactions and, often, lengthened to account for longer drug clearance
time, drug-antibody complexes or anti-drug
follow-up investigations of unexpected animal
findings. These are in addition to the expected antibodies if immunogenicity-related effects (or 6
reproductive and developmental toxicology complications) are suspected.
studies and carcinogenicity studies. M3(R2) Historically, in the US, when FDA regulated
recombinant proteins under CBER, the agency
7
provides specifics on the timing and scope of
these additional studies, as do local or regional was uniquely proactive in soliciting sponsor
guidelines such as those listed on the CDER and pre-IND meetings to discuss drug development 8
OECD websites. program nuances, particularly the nonclinical and
CMC sections. After reshuffling product respon-
Example 2 Recombinant Protein—Basic sibility within the agency in 2004, this approach 9
Monoclonal Antibody has carried over to CDER, and for recombinant

There really are no “typical” recombinant proteins

products within the different divisions at FDA,
pre-IND correspondence should be considered a
10
(just as there really are no typical small molecule ‘must-have’ for regulatory professionals. The rea-
test articles), but it is possible to generalize for a
theoretical example and use monoclonal antibod-
sons for including pre-IND agency interactions 11
in the development timelines, despite very clear
ies to determine what guidance is available and guidance from S6(R1), arise from such issues as
important and should be considered when devel- target specificity (or lack thereof ); relevance of 12
oping protein-based therapeutics. Once again, animal models in translation to human dosing
M3(R2) should be consulted regarding timing
of the repeat-dose toxicity studies needed to
paradigms; and potential immunogenicity, which
are generally unique to the specific biopharma-
13
support human trials; however, there is a specific ceutical and require understanding and joint
guidance for recombinant (biotechnology-de- concurrence on the most predictive pathway for 14
rived) products, ICH S6(R1). This guidance IND-enabling studies. When examining the
covers most of the biopharmaceuticals gener- types of possible responses to pre-IND agency
ally encountered; however, it does not include questions, regulatory professionals should realize 15
“antibiotics, allergenic extracts, heparin, vitamins, the pharm/tox reviewers may have seen several
cellular blood components, conventional bacterial
or viral vaccines, DNA vaccines, or cellular and
examples where sponsors developing similar
types of molecules have encountered very specific
16
gene therapies.” toxicology issues. These issues are unpublished
S6(R1) provides an international regula- and usually not discussed openly among sponsor 17
tory perspective on a broad range of issues that representatives at scientific meetings. This is not
become more or less unique to biopharmaceu- unique to biotechnology-derived products but,
ticals based on their target specificity including, given the degree to which these products are 18
for example, pharmacologic relevance in spe- customized, sometimes the off-target effects and

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 Chapter 6: Preclinical Safety Guidelines Supporting International Drug Registration

human equivalence in an efficacious dose creates rodent-only chronic toxicology model of relative
largely unanticipated safety issues for these high risk. Note, options exist regarding species
“human-specific” types of molecules. selection for longer-term studies with products
The hypothetical monoclonal antibody in under S6(R1) guidance; where these options apply,
this example is LM-001, which has a target they could impact program cost substantially
on lymphocytes conserved across species. This and perhaps reduce timelines in the nonclinical
means both rodent (rat) and nonrodent (typically development scheme.
monkey) toxicology programs will be needed. Following S6(R1) for the LM-001 anti-
Regarding the nonrodent species selection, body would include a human tissue cross-reac-
the dog generally is avoided with recombi- tivity study (and perhaps a comparable cross-re-
nant proteins, although there are exceptions to activity study in the nonrodent model), using
this. The general consensus is the dog tolerates up to two species in IND-enabling toxicology
intravenous infusion of peptides/proteins poorly studies (typically one month with toxicokinet-
and has a known sensitivity to excipients like ics and anti-drug antibody bioanalysis, and a
polysorbates, which may be added to intravenous recovery period), and that may be all for the
products for better solubility and stability. Other IND-enabling program.
nonrodent species like minipigs, in principle, can Often, recombinant product safety pharma-
be used for recombinant products. In practice, cology endpoints can be included in the general
however, this has not been mainstreamed in the toxicology study design or, at times, conducted as
toxicology community due to lack of historic standalone assessments. In principle, no geno-
experience and, hence, comfort with this species. toxicity studies are needed and no ADME other
This is especially true for longer-term applica- than toxicokinetics. On the surface, the scope of
tions where immunogenicity and/or the cost of a monoclonal antibody IND-enabling program
goods to dose animals several times the size of a appears to involve fewer studies, perhaps fewer
monkey may become prohibitive. species and, therefore, should be less expensive
Somewhat unique to S6(R1) is allowing and faster. This is rarely, if ever, the case. Bio-
longer-term studies to proceed (e.g., following analytical support for measuring blood levels
initial one-month IND-enabling studies) with a of both the drug and, potentially, anti-drug
single species (even if the rodent and nonrodent antibodies can be extremely time-consuming
both are pharmacologically relevant), provided the and expensive. Anti-drug antibodies may alter
shorter-term results are similar between rodents the toxicokinetics, requiring additional time and
and nonrodents, and are explainable by under- effort to evaluate the impact on the study. It may
standing the drug’s mechanism of action. The be necessary to determine whether the anti-drug
guidance recommends considering longer-term antibodies also are neutralizing the antibody’s
studies in only the rodent species unless there is biological effect, especially if the test species has
scientific rationale justifying the nonrodent’s use. no pharmacodynamic marker to indicate whether
This gives the sponsor an option to minimize the the drug is acting as expected in vivo. The
use of higher (and more-expensive) species in lon- recovery period also may need to be prolonged
ger-term studies for the recombinant product and substantially to allow clearance of the longer
theoretically dampens the cost of goods argument half-life antibody compared to a typical small
for using the minipig in recombinant protein molecule, and recovery animals in lower dose
nonclinical development. In practice, however, groups may need to be considered to account
there may be enough difference between rodent for possible ameliorating effects of an immune
and nonrodent responses to recombinant proteins response at higher doses. Other considerations
in IND-enabling toxicology studies to allow the would include the expense and availability of
assumption the sponsor could proceed with a nonhuman primates, if needed, and the resources

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
required if, for example, intravenous infusion is for the monoclonal antibody (or any recombinant
needed. When planning timelines, the regulatory product), the ability to conduct the reproductive 2
professional should consider the guidelines as toxicology program in a species other than nonhu-
providing a generic menu, not a relative timescale
for the types of studies involved.
man primate is reason to try, if possible, to select
molecules with relevant rodent pharmacology.
3
Another difference between S6(R1) and This obviously is easier said than done, especially
M3(R2) is nonrodent chronic study duration. For for certain immunologic disease targets. However, 4
biotechnology-derived products under S6(R1), being conscious of these issues up-front, may help
chronic nonrodent study duration is six months, save the company from a costly and extended non-
while for standard small molecules and agents clinical post-IND safety program. 5
not covered under S6(R1), it is nine months for For oncology products intended for
the US and Japan. There are exceptions, so before
assuming six months, the sponsor must to clarify
advanced disease, ICH S9 regarding the scope
and duration of toxicology studies to support that
6
this in its pre-IND discussions. One major product class, applies to both small molecules
difference likely affecting time-to-market regis-
tration is the potential waiver of carcinogenicity
and biotechnology-derived products. S6(R1) 7
addresses overall issues specific to recombinant
assessments. Again, there are many exceptions. products, while both M3(R2) and S9 address
However, S6(R1) allows a weight of evidence and issues of scope and duration that may apply for 8
case-by-case approach, acknowledging the rodent any type of molecule.
bioassay may have limited value for biotechnolo-
gy-derived products. When Guidelines Are Not Enough 9
Any potential cost- and time-savings that
This chapter was intended to provide an under-
may be gained in the six-month versus nine-
month chronic nonrodent toxicology assessment standing of how nonclinical development strate- 10
and potential waiver of carcinogenicity studies, gies and regulatory guidelines can work together,
ultimately may be consumed in supporting the building a framework for projecting the types of 11
reproductive toxicology program if the antibody studies needed and the scope of the anticipated
is not active in the rodent or rabbit. Not only program for international drug regulatory sub-
are nonhuman primate reproductive toxicology missions. What it has not done is discuss the very 12
studies expensive and time-consuming (not to real and problematic cases where available guide-
mention, higher-species-intensive), the sponsor
also may need to include sexually mature monkeys
lines do not address a sponsor’s specific needs, or
there are no pertinent guidelines. If, for example,
13
in the six-month chronic study, adding more cost the drug is an ophthalmic new molecule, would
and potential scheduling issues pending these both a rodent and nonrodent species be needed 14
animals’ availability. The regulatory professional for ocular delivery, as well as two (perhaps
should consider these issues at the outset of non- additional) species for assessing systemic effects?
clinical program design, not when the time arrives What if the drug is implanted into a local 15
to conduct those assessments, and definitely not compartment (e.g., brain or liver) and activated
based on experience with small molecule drug
development. Again, S6(R1) provides sound
externally to treat neoplastic tissue? What about
a topical dermal product meant to be applied to a
16
guidance regarding these issues; however, the discrete small area in microliter quantities; would
regulatory professional must deal with the impact it make sense to dose animals over 10% of their 17
on cost and timing, which ultimately can make body surface area? What about stem cell product
or break a drug development program. Despite development safety testing—are standard rodent
the perceived absence of an apparent downside to and nonrodent models useful? As should be clear, 18
not having a second relevant (i.e., rodent) species ICH guidance documents dealing with nonclin-

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 Chapter 6: Preclinical Safety Guidelines Supporting International Drug Registration

ical program designs offer general direction but The ultimate feedback will be from the per-
are of little value in providing advice for products tinent regulatory agency, but it is best to develop
that do not fit the mold. As discussed earlier, a well-designed program based on a strong scien-
internet searches for regional regulatory prece- tific rationale prior to approaching the agency for
dents with like molecules can be invaluable, but feedback. This is the sponsor’s product, with the
the regulatory reviews may not be available when sponsor’s scientific expertise built into it, and no
the sponsor needs them, may be outdated or sim- one should know more about how best to char-
ply may not address the situation adequately. acterize its preclinical safety. Regulatory agencies
What avenues are left? Other than enlisting expect the sponsor to have done its homework
a consultant, regulatory professionals are encour- to develop a strategy that makes sense and is in
aged to look for toxicology society meetings keeping with current thinking on the product
where such topics may be discussed in work- and its therapeutic class.
shops or symposia. Often, this is where current
regulatory agency thinking is presented, using Remember Just One Thing
real-life situations and products (likely presented
generically) as examples. Often, however, the rel- When beginning a drug development program,
evant information needed may not be presented there are several things to remember. From
anytime soon, or if there was a previous pertinent this author’s perspective, if choosing only one,
session or workshop on the issue, published pro- it would be to embrace a rational scientific
ceedings might not be available. In many cases, approach to the program strategy. This is the
regulatory professionals simply may have to look true purpose of all the guidance documents
at the lead drug candidate’s program specifics discussed here, and will likely be echoed in any
(going back to the five ‘whats’), step back and sound advice the sponsor receives from toxicol-
formulate a strategy to address human safety ogy experts, from either within the company or
concerns rationally using workable and relevant external scientists, regulatory professionals or
nonclinical models. other consultants enlisted to assist the company.
A preclinical CRO that runs, for example, a As the program strategy develops, this input
number of ophthalmic toxicology programs for should result in the type of rational program
regulatory safety support, has specialized surgical design the regulatory professional can present or
capabilities for implants in small biological defend comfortably in front of company manage-
compartments or runs several dermal programs ment and, ultimately, in front of the regulatory
for multinational pharmaceutical companies may body. It is hoped the available tools discussed in
be able to offer specific advice. These CROs often this chapter and elsewhere will lead the regula-
have individuals within their toxicology, safety tory professional to feel confident in his or her
pharmacology or surgery groups who see a fair nonclinical program strategy as the company’s
number of protocols with some potential overlap products progress through the development pro-
in the type of design your own product might cess and on to the patient population awaiting
need. The downside is that the CRO experts may the new drug.
know a great deal about specific study types but
not necessarily about how to structure the full
program. Also, CROs, of course, operate under
strict confidentiality but still may be able to sug-
gest some key study endpoints or raise important
protocol design issues the sponsor may not have
considered. They also may have the names of
consultants with whom they have worked who
have specific experience in the area of interest.

76 All rights reserved; file sharing prohibited.

 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
Recommended Reading • S10 Photosafety Evaluation of Pharmaceuticals; Step

Guidances •
4 (13 November 2013)
S11 Nonclinical Safety Testing in Support of
2
Development of Paediatric Medicines; Draft – Step 2
ICH (http://www.ich.org):
• S1A Guideline on the Need for Carcinogenicity
Studies of Pharmaceuticals (29 November 1995)
•
(18 September 2018)
E11 Clinical Investigation of Medicinal Products in 3
the Pediatric Population; Step 4 (20 July 2000)
• S1B Testing for Carcinogenicity of Pharmaceuticals; • M3(R2) Guidance on Nonclinical Safety Studies

•
Step 4 (16 July 1997)
S1C(R2) Dose Selection for Carcinogenicity Studies
for the Conduct of Human Clinical Trials and
Marketing Authorization for Pharmaceuticals; Step 4
4
of Pharmaceuticals; Step 4 (Parent guideline 27 (11 June 2009)
October 1994; Addendum on a Limit Dose 17
July 1997 and incorporated in November 2005;
Revised on 11 March 2008)
• M7(R1) Assessment and Control of DNA Reactive
(Mutagenic) Impurities in Pharmaceuticals To Limit 5
Potential Carcinogenic Risk; Step 4 (31 May 2017)
• S2(R1) Guidance on Genotoxicity Testing and Data • Q3A(R2) Impurities in New Drug Substances; Step
Interpretation for Pharmaceuticals Intended for
Human Use; Step 4 (9 November 2011) •
4 (25 October 2006)
Q3B(R2) Impurities in New Drug Products; Step 4
6
• S3A Note for Guidance on Toxicokinetics: The (2 June 2006)
Assessment of Systemic Exposure in Toxicity Studies;

•
Step 4 (27 October 1994)
S3B Pharmacokinetics: Guidance for Repeated Dose FDA (CDER) website (http://www.fda.gov/Drugs/
7
Tissue Distribution Studies; Step 4 (27 October 1994) GuidanceComplianceRegulatoryInformation/Guidances/
default.htm)
• S4 Duration of Chronic Toxicity Testing in Animals
(Rodent and Nonrodent Toxicity Testing); Step 4 (2 • Estimating the Maximum Safe Starting Dose in 8
September 1998) Initial Clinical Trials for Therapeutics in Adult
• S5 (R2) Detection of Toxicity to Reproduction for Healthy Volunteers ( July 2005)
Medicinal Products & Toxicity to Male Fertility;
Step 4 (Parent guideline 24 June 1993; Addendum FDA (CBER) website (https://www.fda.gov/regulatory-
9
9 November 2000; incorporated November 2005) information/search-fda-guidance-documents/preclinical-
• S5 (R3) Detection of Toxicity to Reproduction for
Human Pharmaceuticals; Draft – Step 2 (5 July
assessment-investigational-cellular-and-gene-therapy-
products) 10
2017) • Preclinical Assessment of Investigational Cellular and
• S6(R1) Preclinical Safety Evaluation of Gene Therapy Products (November 2013)
Biotechnology-Derived Pharmaceuticals; Step 4 (16
July 1997; Addendum12 June 2011; incorporated
11
EMA (CHMP) website (http://www.ema.europa.eu)
30 June 2011)
• Guideline on Strategies to Identify and Mitigate Risks
• S7A Safety Pharmacology Studies for Human
Pharmaceuticals; Step 4 (8 November 2000)
for First-In-Human Clinical Trials with Investigative
Medicinal Products (1 September 2007)
12
• S7B The Non-Clinical Evaluation of the Potential
for Delayed Ventricular Repolarization (QT Interval
Prolongation) by Human Pharmaceuticals; Step 4 (12
May 2005)
FDA (CDER and CBER) website relevant to SEND
• https://www.fda.gov/industry/study-data-
13
• S8 Immunotoxicity Studies for Human standards-resources/study-data-submission-cder-

•
Pharmaceuticals; Step 4 (15 September 2005)
S9 Nonclinical Evaluation for Anticancer
and-cber
14
Pharmaceuticals; Step 4 (29 October 2009) Books/Publications
• S9 Nonclinical Evaluation for Anticancer
Pharmaceuticals, Questions and Answers; Step 4 (12
June 2018)
• Nonclinical Safety Assessment, A Guide to
International Pharmaceutical Regulations, eds. Brock, 15
Hastings, and McGown. Wiley & Sons, 2013.

16
17
18

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 Chapter 6: Preclinical Safety Guidelines Supporting International Drug Registration

78 All rights reserved; file sharing prohibited.

7 CMC Regulatory Strategy

By Stephen Antonelli and Michael Craig

1
2
3
4
5
There are three key components to a pharmaceu-
tical product investigational or marketing appli-
be completely eliminated. According to ICH,
its mission is to achieve greater harmonization
6
cation. These modules, which are the basis of worldwide to ensure safe, effective and high-qual-
any application, include clinical, nonclinical and ity medicines are developed and registered in the 7
quality. The quality component is where chemis- most resource-efficient manner. This collaborative
try, manufacturing and controls (CMC) becomes regulatory group includes regulatory and industry
a significant consideration for an organization. members as well as a number of observers working 8
CMC plays an integral role, enabling nonclini- toward the globalization of medicines.
cal and clinical studies and reducing a product’s
time-to-market. Efficient planning and long-
For the most part, pharmaceutical regula-
tions are divided into five geographies:
9
range product and regulatory strategies can have • North America (US, Canada, Mexico)
lasting impacts on overall lifecycle management.
This chapter provides an overview of the
• Europe (UK, Switzerland, EU and 10
Eastern Europe)
basic considerations to facilitate and guide prod- Japan
uct development from inception to commercial-
•
• China 11
ization. CMC regulatory strategy does not start
• Rest of World (ROW) (Asia Pacific
or end with a marketing application. An effective
CMC regulatory strategy must manage the
minus Japan, Australia/New Zealand 12
(ANZ), Gulf Co-operation Council
challenging path of drug development within the
(GCC), Association of Southeast Asian
global regulatory landscape’s evolving structure.
The goal is to provide information to facili-
Nations (ASEAN), Latin America 13
(LATAM), Commonwealth Indepen-
tate interactions with technical personnel and
negotiate with regulatory authorities to refine
dent States (CIS) and Central East
Europe (CEE, non-EU countries)
14
and optimize global regulatory CMC strategies.
The main emphasis is on product registration and
postapproval changes in the US, EU and Japan, From a regulatory perspective, the world generally 15
with a separate section for emerging markets. is divided between “established” and “emerging”
markets. The established markets, with more-de-
Increased globalization has significantly
expanded the importance and need for strategic fined laws and requirements, include the US, EU, 16
product development and CMC regulatory strat- Japan, Australia, Canada and increasingly China,
egy. Increased harmonization among the major following its full ICH membership in 2017. 17
regulatory authorities, through the International Emerging markets are those with less-defined
Council for Harmonisation (ICH), has resulted laws and regulations. Approval to market pharma-
in more standardized requirements; however, it ceutical products is typically granted by a national 18
is unlikely that regional CMC differences will authority on a per country basis.

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 Chapter 7: CMC Regulatory Strategy

The EU, however, has the Centralised Proce- • strong understanding of country- or
dure, which enables pharmaceutical companies to region-specific quality requirements
submit a single marketing authorization applica- • good communication with regulatory
tion. An approval by the European Commission authorities
of a centralized application is valid in all EU • strong internal and external cross-func-
Member States and the European Economic Area tional teamwork
(EEA)-European Free Trade Association (EFTA)
states. The Centralised Procedure is required in To develop a strategic global regulatory plan,
some instances, such as those outlined in Table the first step is to understand the vision of the
7-1, and is optional for other product types. To idealized product relative to existing therapies. Is
determine whether a product should be evaluated the product being positioned as a first-in-class
under the Centralised Procedure, companies may therapy, a product being evaluated for providing
submit an ‘eligibility request’ with appropriate benefit beyond the standard of care, a generic
justification that the product falls under one of the of an existing approved product or a biosimilar?
described categories. The global product strategy is the key foundation
The EU submission procedure is important for establishing a Quality Target Product Profile
to commercialization strategies that are impacted (QTPP) and development plans to achieve the
by the submission procedure chosen, as well vision. This vision enables key CMC strategy
as regional pricing considerations, which vary development considerations and should be cap-
widely across regulatory regions. While most tured in various strategy documents. Ultimately,
new medicines use the Centralised Procedure, details such as proposed commercial image will
a sponsor could choose to follow a National, dictate container closure systems, pack sizes,
Mutual Recognition or Decentralised Procedure. expiry, labeling, manufacturing and supply chain
Since these approaches are less common, they strategies needed to complete the overall CMC
will not be discussed further. Depending on the strategy. Not having an ultimate product vision
regulatory region, additional quality requirements is comparable to assembling the most intricate
that can impact the pharmaceutical product and complicated puzzle without ever seeing the
commercialization process may apply. Table 7-2 picture on the box.
provides various countries’ or regions’ regulatory The foundation of pharmaceutical devel-
authority names. opment is establishing a therapy’s viability, as
quantified by measures of safety and efficacy,
Product Development and Global to address a medical need. The altruistic goal is
Regulatory Strategy to improve the lives of patients and potentially
develop new and innovative approaches to treat-
Planning a global regulatory strategy can start ing disease. Because human lives could hang in
as soon as the decision is made to transition a the balance, there is an underlying drive to focus
discovery candidate into development. To ensure on the fastest route to the commercial markets.
a product’s long-term clinical and commercial However, a delay to market can have an enor-
success, it is essential to develop an efficient mous financial impact in lost revenue for a com-
CMC regulatory strategy. The foundation of a pany trying to recoup the vast expense of drug
robust CMC development program and regula- development. Additionally, being first to market
tory strategy must include: is key for market exclusivity, and any delays to
• clear understanding of corporate objec- market impact the sales and revenue achievable
tives and priorities during the product’s lifecycle. This may result
• thorough understanding of the drug in business decisions that trade global planning
substance and drug product strategies for product approval in a major market,

80 All rights reserved; file sharing prohibited.

 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
Table 7-1. Centralised Procedure Requirements Based on Product Type 2
Required for: Optional for:
3
• Human medicines containing a new active • Human medicines containing a new active
substance to treat human immunodeficiency substance to treat indications other than
virus (HIV), cancer, diabetes specified as required 4
• Neurodegenerative diseases • Products providing a significant therapeutic,
• Autoimmune and other immune dysfunctions scientific or technical innovation
• Viral diseases • Products for which authorization would be in 5
the interest of public or animal health at EU
• Derived from biotechnology processes, such
level

•
as genetic engineering
Advanced-therapy medicines, gene-therapy,
• Generics of centrally authorized products and 6
applications for certain medicinal products
somatic cell therapy or tissue-engineered
for pediatric use (Pediatric Use Marketing

•
medicines
Orphan medicines
Authorisation, PUMA) 7
Table 7-2. Regulatory Authorities by Country
8
Country/Region Regulatory Authority

US FDA (Food and Drug Administration)

9
EU EMA (European Medicines Agency) and each Member State has a national
competent authority
https://www.ema.europa.eu/en/partners-networks/eu-partners/eu-member-
10
states/national-competent-authorities-human
Japan PMDA (Pharmaceuticals and Medical Devices Agency) 11
Canada HC (Health Canada)
UK Medicines and Healthcare products Regulatory Agency (MHRA)
12
Australia TGA (Therapeutic Goods Agency)

China NMPA (National Medical Product Administration)

(formerly China Food and Drug Administration - CFDA)
13
South Africa MCC (Medicines Control Council)
India CDSCO (Central Drug Standards Control Organization) 14
Brazil (LATAM) ANVISA (Agencia Nacional De Vigilancia Sanitaria)
Switzerland SwissMedic 15
Mexico COFEPRIS (Mexico Ministry of Health)
LATAM
CIS
Independent regulatory agencies
Independent regulatory agencies
16
CEE Independent regulatory agencies
ASEAN Independent regulatory agencies 17
GCC (Gulf Cooperation Independent regulatory agencies
Council)
18

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 Chapter 7: CMC Regulatory Strategy

with globalization considered later in the product 10a—Well Established Use

lifecycle. By having a clear vision of what the • expedited procedures (innovative,
ideal product will look like, a rationalized and orphan and breakthrough products)
structured development plan can be created. This • combination products
results from marrying pharmaceutical develop-
ment and CMC regulatory strategy to enable a CMC Registration Documents in the US
development candidate to become a commercial- (NDA/BLA), EU (MAA) and Japan (JNDA)
ized product. Although the three major regulatory regions
CMC Regulatory Strategy Planning have made significant strides toward harmoniza-
tion, and information regarding laws, regulations
1. identify planned and potential registration and guidance is more-readily accessible than
areas in emerging countries, differences beyond the
• applicable laws and regulations requirements for the CTD’s regional sections still
• review and approval timelines and exist. These differences are important consider-
procedures ations to incorporate into a drug development
2. product type (evaluate by region) strategy, depending on the intended registration
• small molecule or biologic regions. This long-term focus can enable study
• New Chemical Entity (NCE) and data collection efficiencies throughout
• dosage form and route of administration product development. The marketing authoriza-
• generic (Abbreviated New Drug Appli- tion name, applicable regulatory authority and
cation, ANDA, 505(j)) approval times vary across the regulatory regions.
• combination products (drug/device) All three regions have legal and regulatory pro-
• novel excipients visions to expedite drugs to treat serious condi-
• proposed container closure and com- tions, which can impact CMC content because
mercial packaging configuration, sizes of compressed development or regulatory
• product attributes and challenges authority review timelines (inspection, approval
and launch).
3. drug substance The three major regulatory regions support
• NCE, modified dosage form or generic the use of the Common Technical Document
(drug substance is a significant factor (CTD) by applicants. Module 2.3 is an overview
in determining regulatory pathway of the CMC technical information located in
(generic or modified dosage form), Module 3 and is more similar across the major
patents and exclusivity) regions than Module 3. For the Japanese New
• characteristics such as polymorphism, Drug Application ( JNDA), Module 2 should be
physical form, salts, stereoisomers, solu- written in Japanese, but figures and tables written
bility, ease of manufacture and potential originally in English and used for a US New
genotoxic impurities Drug Application (NDA) submission and/or
• ability to reference Drug Master File EU MAA are accepted. English is acceptable for
(DMF-US), Active Substance Mas- Module 3, but the table of contents should be in
ter File (ASMF-EU) or Master File Japanese. It is important to note Japan’s Pharma-
(MF-Japan) ceuticals and Medical Devices Agency (PMDA)
4. regulatory pathway and considerations utilizes Module 2 as its main review document.
• NCE The CTD sections are outlined in the ICH
• modified release dosage form guideline, Organisation of the Common Technical
• US 505(b)(2) applications, EU Article Document for the Registration of Pharmaceuti-

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
cals for Human Use: Quality (M4Q(R4) (Step 4, Pharmacopeia, European Pharmacopoeia and
2016). Additionally, each region has a location Japanese Pharmacopoeia). However, the regional 2
for regional information in Module 3. Highlights regulatory authorities support the development
of differences between regions are: of global quality standards and the submission of
harmonized compendial standards and methods,
3
Regional Information especially for excipients.
• executed batch records for primary
A significant difference between the EU 4
and both the US and Japan is use of Quali-
stability batches (US only)
fied Person documentation and batch release.
•
•
method validation package (US only)
comparability protocols (US only)
Additional differences include specifications (EU 5
release specifications, additional EU tests), the
• process validation scheme for the drug
product (EU only)
level of manufacturing process detail, the detail
level for excipients and the US requirement for
6
• certificates of suitability (EU only)
submitting a postapproval stability protocol and
materials of animal or human origin
7
•
commitment.
(EU only)
While many areas have been challenging to
• TSE compliance (EU only, located in
harmonize, recent efforts have been successful
Module 3 for US NDA)
in harmonizing approaches toward genotoxic 8
impurities (ICH M7 Assessment and Control of
The CMC regulatory professional also should be
aware of potential Module 1 regional differences.
DNA Reactive (Mutagenic) Impurities in Phar-
maceuticals to Limit Potential Carcinogenic Risk),
9
US NDA or Biologics License Application (BLA)
drug substance heavy metals specifications (ICH
CMC information includes the field copy certifi-
cation (certifying CMC information has been sent
Q3D Guideline for Elemental Impurities), drug 10
product dissolution specifications (ICH Q4B
directly to the field office for inspection purposes),
Annex 7(R2), Evaluation and Recommendation of
letters of authorization from DMF holders to
access their DMFs and the environmental assess-
Pharmacopoeial Texts for Use in the ICH Regions 11
on Dissolution Test General Chapter) and starting
ment or claim of categorical exclusion.
In all three regions, the amount of informa-
materials’ definition for drug substance synthesis
(ICH Q11 Development and Manufacture of Drug
12
tion submitted in the marketing authorization
Substances). In other, less-harmonized aspects
application may be reduced by cross-referenc-
ing to a DMF. There are differences among the
of development and commercialization, early 13
discussion and negotiation with the regulatory
regions: both EU and Japanese DMFs have an
authorities is important not only for approval,
open or applicant part and a closed or restricted
but also to maximize efficiencies and cost. 14
portion. In both these regions, the open part,
which is accessible to the applicant, is submitted CMC Regulatory Strategy Case Studies
as a component node of the MAA or NDA, 15
respectively. For the US, the regulatory author- Operative and successful CMC regulatory
ities are only required to receive the letter of
authorization to access the DMF in the appli-
strategies are typically situation-specific and
incorporate far too many variables for an effective
16
cation. In the EU, Certificates of Suitability of discussion. However, evaluating any new situation
European Pharmacopoeia monographs (CEPs) against previous regulatory authority experience, 17
may minimize Module 3 active substance or current guidance and scientific understanding can
excipient information. provide a basis for a sound approach to solve the
Each region requires adherence to its challenges of product development. The authors 18
respective pharmacopoeia for excipients (US have provided case studies for a preapproval and

All rights reserved; file sharing prohibited. 83

 Chapter 7: CMC Regulatory Strategy

postapproval CMC change in order to provide Company A has produced a solid oral
an understanding of the considerations used to tablet of a defined formulation and is using the
develop effective CMC regulatory strategies. product in a clinical investigation. The product’s
formulation is subsequently adjusted to decrease
Preapproval CMC Changes the quantity of a minor (<1.0% of total com-
position) glidant component to less than 0.5%
CMC changes are an expected part of the
of the total composition. This change includes
product development path from laboratory to
an increase in the filler component to offset
market. The amount of product understanding
the glidant decrease. This composition change
evolves as clinical development progresses from
would be considered in the US as a SUPAC-IR
initial first-in-human studies to marketing
Level 3 change in composition in a postapproval
application submission. Concomitant with
framework for the glidant (only Talc is specified
this evolution of understanding is the increas-
in SUPAC-IR). The bioequivalence requirement
ing expectation for escalated control of drug
to support this change is to conduct a full in vivo
substance and drug product manufacturing and
bioequivalence study. This could make sense in
testing and communicating this information to
a postapproval scenario; however, the scientific
the regulatory authorities.
approach is to evaluate the pre- and post-change
Preapproval Case Study products by a performance-based assay such as
in vitro dissolution and gain agreement from the
During development, the dosage form used to regulatory authority that clinical in vivo bio-
administer the intended human dose to a clinical equivalence studies would not be necessary.
subject or patient will evolve. It is not uncommon The recommended approach is to evaluate
for first-in-human dosage forms to consist of rudi- product dissolution across a range of biorelevant
mentary solutions or suspensions or capsule shells pH media. Such items as the excipient’s nature
filled with a quantity of drug substance. These and the assumption it does not significantly
preparations tend to be more akin to pharmacy impact drug substance absorption must be consid-
compounding than pharmaceutical manufacturing. ered, as well as the drug substance’s solubility and
Individual dosage units are considered more like permeability. These latter aspects (solubility and
“preparations” than “batches” but still present a permeability) are used to establish the biophar-
basis of control. The transition from these rudi- maceutics classification system (BCS) class that
mentary administrations to more-sophisticated can be used as a guide to determine the breadth
dosage forms necessitates the need to demonstrate of performance testing. For this case study, the
there is no impact on quality, safety or efficacy. drug substance is high solubility, low permeability,
It is common practice to refer to the applica- which is consistent with BCS Class 3 (Waiver of
ble postapproval guidances to glean information In Vivo Bioavailability and Bioequivalence Stud-
about evaluating the extent of a formulation ies for Immediate Release Solid Oral Dosage Forms
change. While this can be a useful approach, Based on a Biopharmaceutics Classification System:
it assumes there is a fixed (approved) starting Guidance for Industry, December 2017).
point as with a commercial product registration. The dissolution of 12 units of pre- and post-
Postapproval guidances are established from this change products demonstrate equivalent very
perspective, but many hallmark resources have rapidly dissolving profiles (85% or more of labeled
not been updated to reflect current trends, expe- amount of drug substance dissolved in 15 min-
rience or knowledge. The postapproval landscape utes) using USP Apparatus 1 in 500 mL of (1) 0.1
is far more rigid because an applicant’s engage- N HCl; (2) a pH 4.5 USP buffer; and (3) a pH
ment with a regulatory agency dramatically 6.8 USP buffer. Based on the similarity in product
decreases following development. performance, these data and the details of the gli-

84 All rights reserved; file sharing prohibited.

 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
dant identity should be sufficient to demonstrate formulations that some payers deem to be qual-
there is no impact to the product’s performance by ity and safety improvements. 2
implementing the specific formulation change and Company A decides it is prudent to refor-
gain alignment with a regulatory authority that
the formulation change does not necessitate a full
mulate to mitigate future regulatory scrutiny on
its increasingly dated formulation and to preserve
3
in vivo bioequivalence study. its product’s market share.

Postapproval CMC Changes

A change control detailing the quality changes 4
is issued, and Company A’s regulatory team joins
other company stakeholders, including supply
Familiarity with and the ability to communicate
and implement postapproval CMC changes are
chain colleagues, in regular weekly meetings. 5
A strategy is devised: the regulatory team
critical regulatory responsibility components.
Although all three regions require notification to
begins assessing the proposed changes’ regulatory
impact in each market in which the product is
6
the regulatory authorities and, potentially, prior
licensed. Affiliates in emerging countries provide
approval, depending on the change’s potential or
likelihood to impact quality, safety or efficacy, the
up-to-date information on their regulatory 7
requirements and timelines for approval. This
framework differs among the US, EU and Japan.
includes a major Prior Approval Supplement in
The regulatory submission data requirements the US and a major Type II variation in EU. 8
and reporting mechanism must be assessed for
The regulatory and documentation require-
each region. The change’s absolute nature could
be considered a supplement to the approved
ments for the variation submissions are tabulated,
along with timelines. Worst-case requirements
9
application in one region and a line extension
such as stability data, process validation data,
in another. These differences can result in very
different approval times and, thus, will greatly
bioequivalence requirements are noted, as well as 10
longer timeframes for approval. Countries where
impact the time to market. The CMC regulatory
strategy is focused more on long-term submis-
approval is dependent on prior approval in other
countries also are noted.
11
sion maintenance to enable continued manufac-
This information is shared with other key
turing of the approved product.
stakeholders, including supply chain and quality 12
Postapproval Case Study assurance colleagues, who will ensure sufficient
product supply is available while the variations
A high-impact CMC product lifecycle change can are submitted and approved and will assist in 13
include a drug product reformulation and such generating the required stability data.
associated changes as a manufacturer change.
Company A holds global licenses for a
The ultimate goal is to have all variations 14
approved at or around the same time to avoid
well-established brand leader product that also the complexity of managing different M3
is used in the pediatric population. The product documents, formulations and stock in multiple 15
is an oral suspension dosage form, and some of countries at the same time. This can be chal-
the excipients, such as colorants and flavoring
agents, no longer are considered appropriate for
lenging and is not always possible, particularly
as some countries have a much longer lead time
16
use in children. With new guidance documents for variation approval. Based on the information
in some territories on developing formula- gathered, a strategy is devised, prioritizing some 17
tions for use in pediatrics, there is increasing countries due to their commercial importance or
regulatory scrutiny on Company A’s product. the fact that approval in other countries is depen-
Additionally, some generic competitors have dent on approval in them. Variation package 18
launched comparable products with improved preparation and submission for other countries

All rights reserved; file sharing prohibited. 85

 Chapter 7: CMC Regulatory Strategy

may be prioritized due to their longer variation From a development standpoint, it is critical
approval time. to communicate to development teams and man-
The regulatory team prepares the variation agement the need for stability data to support
package documentation and submits according to Zone III, Zone IVa and Zone IVb climatic zones
the schedule agreed with key stakeholders. for emerging markets. Due to divergence in
Gradually, the team responds to questions defining long-term storage conditions for these
raised by regulators, and approval notifications hot and humid regions, the ICH Steering Com-
start arriving. Through regular meetings with mittee has withdrawn ICH Q1F, leaving the
key stakeholders, supply continuity is managed, definition to the respective regions and WHO.
batches of the previous formulation are used up WHO stability testing conditions are provided
and the new formulation is successfully intro- in WHO guidance, Annex 10, Stability Testing
duced to global markets. of Active Pharmaceutical Ingredients and Finished
Emerging Countries Pharmaceutical Products.
Additional considerations to incorporate
Commercialization in emerging countries, either into a ROW strategy are:
directly or through business partners or collab- • legal infrastructure requirements
orators, has become an increasingly important • translation requirements
corporate strategy component. Therefore, it is • corporate and manufacturing license
imperative the regulatory CMC professional requirements
understands these markets’ regulatory require- • GMP and QP certificates, CEPs
ments and can share this knowledge with the • regulatory process and review time-
technical and commercial teams. Even with an frames, including inspection
understanding of a specific region’s regulatory • country-specific requirements
requirements, unless the organization has a
local regulatory presence, using local regulatory One of the most challenging regulatory aspects
consultants is highly advisable due to the lack of international drug registration and approval
of transparency, language barriers, limited access
is managing postapproval changes, since sub-
to information and the myriad of regulatory
mission requirements and approval timeframes
complexities involved in obtaining marketing
can vary significantly (e.g., up to six years for
approval in these countries.
significant changes).
From a practical perspective, emerging
The current growth of ROW expansion is
markets are broken down further into markets
expected to continue; thus, it is paramount for
requiring independent data submission to sup-
CMC regulatory professionals to remain abreast
port approval and those requiring a Certificate
of Pharmaceutical Product or Medicinal Prod- of these regions’ current trends and requirements.
uct (CPP or CMP). In the majority of countries Conclusion
requiring a CPP, the regulatory authorities
perform only a limited review. For the latter The continued globalization and complexity
regions, approval in another country is required of the pharmaceutical industry, especially the
to support the CPP. In addition, for those coun- increased role of emerging markets, presents a
tries requiring submission data, consideration unique CMC regulatory opportunity. Success
should be given to possibly leveraging the US in this new model requires enhanced strategic
NDA or BLA or EU MAA. Most often, the planning and implementation skills, teamwork
EU MAA is utilized as the basis for developing and adaptability, in addition to knowledge of
the ROW submission. regulatory requirements.

86 All rights reserved; file sharing prohibited.

 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
Significant harmonization has occurred for Recommended Reading
the US, Japan and EU, yet it still is important for • EMA website. https://www.ema.europa.eu/en. Accessed 2
the CMC regulatory professional to understand 31 October 2019.
the similarities and differences, especially in the
postapproval change area. Supporting success-
• PMDA website. www.pmda.go.jp/english. Accessed 31
October 2019. 3
ful development, registration and postapproval • FDA website. www.fda.gov. Accessed 31 October 2019.
changes in all markets significantly expands the
scope of regulatory CMC and increases the need
• Quality Guidances. ICH website. https://www.ich.org/
page/quality-guidelines. Accessed 31 October 2019.
4
to think strategically and globally. • Industry Book of Knowledge, Practical Considerations
for eCTD Submissions: US IND Applications in
eCTD format: A CMC Perspective, V1.2, 24 March
5
2010.
• Harvey J, Fleetwood A, Ogilvie R, Teasdale A, Wilcox
P, Spanhaak S, “Management of organic impurities
6
in small molecule medicinal products: Deriving safe

7
limits for use in early development.” Reg. Tox. and
Pharmacology 84 (2017) 116–123. Science Direct
website. http://dx.doi.org/10.1016/j.yrtph.2016.12.011.
Accessed 31 October 2019.
• “A Regulatory Perspective on the Quality Overall 8
Summary: Putting the Pieces Together.” FDA website.
https://www.fda.gov/media/110657/download.

•
Accessed 31 October 2019.
Teasdale A, Elder D, Chang SJ, Wang S, Thompson
9
R, Benz N, Sanchez Flores IH. “Risk Assessment
of Genotoxic Impurities in New Chemical Entities:
Strategies to Demonstrate Control.” Organic Process
10
Research & Development, 2013, 17, 221–230. dx.doi.
org/10.1021/op300268u.
• Williams HE, Bright J, Roddy E, Poulton A, Cosgrove 11
SD, Turner F, Harrison P, Brookes A, MacDougall E,
Abbott A, Gordon C. “A comparison of drug substance
predicted chemical stability with ICH compliant
stability studies.” Drug Development and Industrial
12
Pharmacy, 45:3, 379-386, 2019. Taylor & Francis
Online website. https://doi.org/10.1080/03639045.201
8.1542707. Accessed 31 October 2019. 13
• Ramesh T, Saraven D, Khullar P. “Regulatory
Perspective for Entering Global Pharma Markets.”
Pharma Times. Vol. 43–No.09, 2011. 14
• Karlton P, Johnston D. “An Integrated Approach to the
Preparation of Global CMC Dossiers.” Ther Innov &
Regulatory Sci. Vol. 31, No. 1, 237–242. 15
• Matsuda Y. PMDA Perspectives. PMDA website.
http://www.pmda.go.jp/files/000152983.pdf. Accessed
31 October 2019. 16
• Annex 10: Stability testing of active pharmaceutical
ingredients and finished pharmaceutical products.
WHO website. http://apps.who.int/medicinedocs/ 17
en/m/abstract/Js23498en/. Accessed 1 November 2019.

18

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 Chapter 7: CMC Regulatory Strategy

88 All rights reserved; file sharing prohibited.

8 Strategies for Clinical
Development Planning

By William Sietsema, PhD and Eric Brass, MD, PhD

1
2
3
4
5
Clinical development is a very expensive under-
taking, so it is prudent to map out the most rapid
and competitive intelligence were presented in
Chapter 3. These environments are dynamic and,
6
and efficient pathway to successful global market therefore, need to be monitored on an ongoing
registrations. Reverse engineering1 is one of the basis, so the program can be adapted to respond 7
most effective ways to develop a robust plan that to significant changes.
optimizes the product’s value.2
A critical first step is to develop a vision
Initial Phase 1–3 Planning 8
for the product, consisting of specific indica- Once desired labeling claims have been iden-
tion statements similar to those that would be tified and the regulatory environment under-
9
included in a package insert or summary of
stood, Phase 3 pivotal registration trials can be
product characteristics. The target product label’s
designed to provide the evidence necessary for 10
importance was discussed in detail in Chapter 5.
those claims’ regulatory approval. Important
Indication statements have a strong influence on
clinical program design, particularly for patient
elements to consider are patient population
11
inclusion and exclusion criteria, treatment arms
populations and measurable endpoint selection,
and comparators, and primary and secondary
as well as the nature of the study’s statistical
endpoints to be measured. 12
analysis plan.
After Phase 3 trials have been designed,
Another important step in designing a supe-
rior development program is understanding both
Phase 2 data needed to enable the conduct of 13
Phase 3 trials can be determined. This allows
the regulatory environment and the competi-
tion. Understanding the regulatory environment Phase 2 trials to be designed to deliver the
required information to make optimal Phase
14
allows the program team to select the endpoints
most likely to be accepted by regulators for prod- 3 design decisions. Key Phase 2 trial elements
uct approval. A strong understanding of the com- will be dose selection studies and will explore 15
petitive environment allows the opportunity for a the breadth of endpoints being considered for
program design with elements superior to current the Phase 3 trial. Pharmacokinetic and pharma- 16
and future competitive products, optimizing the codynamic assessments also can be important
contributors to future trial design.
new product’s market value. Examples of data
that can support a marketing advantage include Defining the needs of Phase 2 and 3 trial
17
the study of more inclusive patient populations design can then influence Phase 1 trial design
and the inclusion of clinically important second- and optimize the generation of information, 18
ary endpoints. Methods for collecting regulatory which helps move the product quickly into Phase

All rights reserved; file sharing prohibited. 89

 Chapter 8: Strategies for Clinical Development Planning

Figure 8-1. Clinical Development Program Reverse-Engineering Principle

Reverse Engineering

Phase 2 Phase 2 Data Phase 3 Phase 3 Optimal

Study Needed to Pivotal Trial Clinical Market
Designs Start Design Endpoints Claims
Phase 3

2. Figure 8-1 is a graphic illustration of this In addition, databases exist for identifying
reverse engineering process. specialized clinical trial endpoints. The Medical
Outcomes Trust is a nonprofit organization that
Tools to Help Plan Clinical Development keeps a list of commonly used quality of life
instruments.7 Optum (formerly QualityMetric)
Working backward based on a conceptualized
is a commercial endeavor offering research ser-
final product, a first step would be to examine
vices related to such instruments’ use in medical
competitors’ product labeling statements. One
research and lists some available instruments.8
of the most comprehensive databases for US
Oncology study clinical trial endpoints are sum-
labeling is Daily Med, a site sponsored by the
National Institutes of Health and the National marized in an article by Slabiak.9 There also is a
Library of Medicine.3 This site can be searched web-based cardiovascular outcome inventory.10
by trade or generic name, and the advanced Another very important tool for clinical
search feature allows searches of various label development planning is examining regula-
sections. For example, indications sections can tory precedents for other products within the
be searched to identify medications approved for same therapeutic area. The US Food and Drug
specific diseases. For EU labeling, the Electronic Administration (FDA) maintains Drugs@
Medicines Compendium has similar capabil- FDA, a database of approval documents.11
ities.4 Clinical trial endpoint choices evolve Many of FDA’s medical reviews that resulted in
constantly, and no comprehensive database approval of a new medicine can be found here.
exists. Accordingly, the best option is to examine These medical reviews (and often the statistical
currently used endpoints in the therapeutic area reviews) can provide great insight into choosing
of interest. appropriate endpoints for trials. Useful informa-
An important approach to identify clini- tion also can be found in the administrative and
cal trial endpoints is searching ClinicalTrials. correspondence sections of the drug review doc-
gov.5 This website was established to increase uments, since there often are meeting minutes
clinical trial transparency, and lists each trial’s or other correspondence related to trial design
primary and secondary endpoints, thus allowing selection. Similar information is available from
identification of currently used endpoints. The the EU via the scientific discussion documents
advanced search feature allows queries by disease released for new product approvals.12 Other
or condition, as well as by development phase countries posting such information include
or outcome measure. ClinicalTrials.gov also can Canada,13 Japan14 and Australia.15
provide important intelligence on competitors’ Once information has been collected about
products currently in development; the EU has a possible endpoints, the information can be sum-
similar registry.6 marized in a target product label (see Chapter 5).

90 All rights reserved; file sharing prohibited.

 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
It is helpful to include an outline of pro- Importance of Strategic Planning
posed clinical trials in early development pro- and Avoiding a Prolonged Clinical 2
gram drafts. Useful information to include might Development Program
be a proposed title, patient population, number of
Once desired labeling language has been 3
subjects, inclusion and exclusion criteria, primary
selected, and endpoints and trial designs have
and secondary objectives and endpoints, study
design with treatment arms, key elements of
been researched, an overall program design 4
can be drafted. The overall design should try to
study execution and elements of statistical analy-
balance speed with quality and creativity. Speed
sis. Table 8-1 provides an example of a template
to market can be an important component of 5
that might be used for a clinical trial outline.
being competitive in today’s pharmaceutical
Estimated timelines are critical, and at this
stage, it is appropriate to have an overall timeline
market; thus, options for the fastest timeline 6
to gain product approvals should be explored.
showing the expected start and completion dates The development program’s length is another
for key trials, along with proposed agency meet- important total development cost determinant. 7
ings and other milestones. An example of such a Creativity in designing endpoints and outcomes
chart is shown in Figure 8-2. to highlight the new product’s advantages ver- 8

Table 8-1. Study Outline Document Template 9

Title of Study
10
Primary Objective
Secondary Objectives
Study Design
11
Dosage Regimen
Treatment Groups 12
Study Population
Subject Characteristics 13
Number of Subjects
Inclusion Criteria 14
Exclusion Criteria
Efficacy Measures
15
Primary Endpoint
Secondary Endpoints
Quality of Life Measures
16
Safety Measures
Pharmacokinetics 17
Study Conduct
Statistical Plan 18

All rights reserved; file sharing prohibited. 91

 Chapter 8: Strategies for Clinical Development Planning

Figure 8-2. Sample Timeline With one Option for Displaying High-Level Information on
Program Timing

ID Task Name Duration 2019 2020 2021 2022

Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4
1
2 Phase 1 Single Rising Dose (Europe) 12 wks
3
4 Pre-IND Meeting 0 days
5 File IND 0 days
6
7 Phase 1 14-Day Multidose Normals/Diabetics (MD#1) 12.6 wks
8 Phase 1 Bioequivalence Study 11 wks
9
10 Phase 2 12-Week BID D/R in Diabetic Neuopathy 45.6 wks
11 Phase 2 12-Week BID D/R in Post Herpetic Neuralgia 45.6 wks
12 Phase 2 - 6 Week Dose Frequency 40 wks
13
14 End of Phase 2 Meetings in US (FDA) 2 wks
15 End of Phase 2 Meetings in Europe (EMA) 2 wks
16
17 Phase 3 6-Month Diabetic Neuropathy in US 72.6 wks
18 Phase 3 6-Month Diabetic Neuropathy in Europe 72.6 wks
19 Phase 3 6-Month Post Herpetic Neuralgia in US 72.6 wks
20 Phase 3 6-Month Post Herpetic Neuralgia in Europe 72.6 wks
21
22 MAA / NDA Preparation 93 wks

sus current and near-term competitive products ics is beyond the scope of this book. Numerous
can be equally significant. books, journal articles and regulatory guidance
Taking a longer path to market may be pref- documents are available to assist companies. The
erable if it can provide stronger claims than those discussion below focuses on contemporary clini-
for competitive products. cal program design elements of particular interest
Avoiding a prolonged development pro- to the regulatory professional.
gram is critical to ensure early stage trials are
not conducted without a clear product vision. Phase 1
Such programs can proceed for many years until
Phase 1 includes first-in-human studies and
a potential path to market is identified or, worse,
other small trials designed for initial new drug
investors lose confidence in the program.
safety and tolerability testing. A robust Phase 1
Regulatory authorities increasingly recognize
program can provide important data not only to
the challenges associated with drug development
meet regulatory requirements but also to inform
for certain indications and in special populations
Phase 2 and Phase 3 study designs (Table 8-1).
and have collaborated in the development of inno-
Adequate investment to ensure complete
vative development strategies. For example, FDA
and optimized data sets generated during Phase
has issued guidance documents for developing
1 may be quite cost effective, as trial size, dura-
novel antimicrobials to treat resistant organisms16
tion and costs increase as the product progresses
and for drugs targeting rare diseases.17,18
from Phase 1 through Phase 3. Many drug-spe-
Clinical Trial Design Considerations cific programmatic considerations will be
predicated on data from the preclinical program.
A comprehensive review of clinical trial design Efforts should be made to bridge the preclinical
and drug development Phase 1, 2 and 3 specif- and clinical programs explicitly, including expo-

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
sure-response relationships for both toxicity and ments of tolerability, adverse events and efficacy
biomarker responses. This bridging will provide all are required for the integrated benefit-risk 2
confidence in the preclinical results’ predictive assessment across doses.
value. Additionally, biomarker responses can pro-
vide proof-of-concept supporting the program
The Phase 2 program also should yield
estimates of the drug’s effect on the primary 3
and aid in dose selection for Phase 2 studies, endpoint of interest to allow Phase 3 study
decreasing the size and cost of those trials. designs. Implicit in this objective is defining the 4
Expanding the Phase 1 population’s diversity primary endpoint to support the clinical indi-
in terms of race, age and sex will enhance the cation. With few exceptions (see below), Phase
predictive value of data obtained. 3 primary endpoints must be unambiguous in 5
Importantly, pharmacokinetic data obtained clinical meaning and importance. In some cases,
Phase 3 endpoint choice may be clear (e.g., all-
in initial Phase 1 studies are necessary but may
be insufficient to complete a regulatory submis- cause mortality), but the Phase 2 program may 6
sion. Pharmacokinetic data obtained in the target be too small to detect drug effects on the clinical
population during Phase 2 and Phase 3 may be endpoint. In this case, Phase 2 studies may
incorporate surrogate or biomarker endpoints
7
critical to understanding variability in exposure
as well as exposure-efficacy and exposure-toxicity whose relationship to the clinical endpoint is
relationships. Additional pharmacokinetic studies well established and quantitatively predictable. 8
in special populations, including patients with In the absence of such biomarkers, drug efficacy
uncertainty may persist until Phase 3 com-
renal disease or liver disease, may be required but
usually can be done in parallel with later-phase pletion. Currently, this is true for therapeutics 9
clinical studies to avoid programmatic delays. targeting critical limb ischemia due to periph-
Pharmacokinetic data in pediatric age eral arterial disease and has resulted in several
failed Phase 3 programs. Thus, investing early in
10
groups also may be needed, depending on the
drug’s indication. Pediatric pharmacokinetics defining useful biomarkers may be important in
also are useful in bridging efficacy data obtained decreasing investment risk for such programs. 11
in adult populations to pediatric patients (see Clinical endpoint selection for indications
not based on survival may be very challenging.
Chapter 11).
The use of a biomarker associated with clinical 12
Phase 2 status and modifiable by the drug is very attrac-

Phase 2 objectives are to define the new drug’s

tive from a developmental perspective. However,
the limitations of surrogate or biomarker end-
13
optimal dose(s), provide additional safety data points are well understood, and many examples
and confirm the drug’s hypothetical efficacy. exist where a drug was effective in changing the 14
Often, the importance of proper dose selection is biomarker as intended but was not associated
under-appreciated. A full understanding of dose with the anticipated clinical effect.20 In the US,
selection not only is required for proper Phase 3 blood pressure, hemoglobin A1C and LDL-cho- 15
design, but also is an integral part of regulatory lesterol are among the few generally accepted
evaluation. Research found 15.9% of failed first-
time applications for new molecular entities were
surrogate endpoints for full drug approval. In
other conditions, the sponsor must define a
16
due to uncertainties related to dose selection.19 measure of clinical benefit that can meet regula-
The total data (preclinical and all clinical studies) tory standards. Phase 2 provides an opportunity 17
ultimately will inform the optimal dose assess- to assess several endpoints, gain a better under-
ment. Nonetheless, Phase 2 trials should include standing of their clinical importance and inform
enough randomized dose experience to support Phase 3 endpoint selection. This process may 18
evidence-based dose selection. Rigorous assess- require additional research. For example, it may

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 Chapter 8: Strategies for Clinical Development Planning

Case Study 8-1. Teduglutide and the Selection of a Clinically Meaningful Endpoint

Patients with short bowel syndrome (SBS) may require total parenteral nutrition (TPN) to ensure
adequate nutrition and fluid delivery to address intestinal malabsorption. The TPN requirement
is recognized as substantially adversely impacting patient quality of life and is associated with
complications related to vascular access. Teduglutide is an analog of a glucagon-like peptide and has
proliferative effects on intestinal mucosa, resulting in enhanced absorption.a Based on this, teduglutide
was developed to improve SBS patients’ fluid and nutrient absorption. While teduglutide’s ability to
induce intestinal mucosa proliferation could be demonstrated in patients with SBS, how could these
histological and physiological changes’ clinical importance be demonstrated? Teduglutide’s sponsor
sought input from patients and SBS experts. This work suggested a 20% reduction in parenteral
nutrition and intravenous fluid volume would be important to SBS patients requiring TPN. These
findings were discussed with FDA, and a primary endpoint was developed using a responder definition
of at least a 20% reduction in parenteral nutrition and intravenous fluid volume. Secondary endpoints
were selected to support clinical interpretation of the primary endpoint and treatment effects. Using
these endpoints, the trials were completed successfully, and the drug was approved in both the US and
EU. This program illustrates the need for careful consideration and the value of collaborative discussion
to establish clinical meaningfulness of the Phase 3 study endpoint.

a. Gattex (teduglutide [rDNA origin]) for the treatment of adult patients with short bowel syndrome (SBS) to improve intestinal
absorption of fluid and nutrients. Briefing Information for the October 16, 2012 Meeting of the Gastrointestinal Drugs
Advisory Committee (16 October 2012). FDA website. http://wayback.archive-it.org/7993/20170113053432/http://www.fda.
gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/GastrointestinalDrugsAdvisoryCommittee/ucm323503.htm.
Accessed 4 June 2019.

be necessary to develop a validated patient-re- Thus, as was the case with Phase 1,
ported outcome tool or define the minimal clini- approaching Phase 2 trial design as an integral
cally important change for the target population component of the total development program
using a specific assessment modality. will ensure optimal data are generated to support
Innovative approaches may be required and, both Phase 3 design and the final submission.
if based on sound clinical and scientific work, can
Phase 3
support successful regulatory submissions (see
Case Study 8-1). Phase 3 trials provide definitive data on a new
Robust safety assessments also are part of drug’s efficacy and safety. These data must meet
the Phase 2 program. Phase 2 should carefully explicit regulatory standards. Thus, in addition
assess adverse events of special interest based to a high degree of study integrity, the data must
on the drug’s mechanism of action, preclinical address the need for evidence to satisfy statis-
signals, target patient population and prior expe- tical, clinical and other scientific standards. As
rience with drugs in the same class. While the discussed above, many design criteria for Phase
Phase 2 program likely will be too small to allow 3 trials, including endpoint selection, are defined
definitive quantitative assessment of these events, in Phase 2. In general, Phase 3 trials will be ran-
focusing on them will be useful in defining opti- domized, parallel group, double-blind, compar-
mal dose selection and establishing any special ator-controlled trials. While alternative designs
assessment methodologies required in Phase 3. may be necessary based on the drug or target
For example, more frequent assessment of safety population, they will have to be justified rigor-
biomarkers or establishing an event adjudication ously, and steps should be taken to mitigate any
committee may be required. biases design compromises may introduce. Study

94 All rights reserved; file sharing prohibited.

 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
Case Study 8-2. Adverse Events of Special Interest 2
Lorcaserin and the Potential Risk of Cardiac Valve Dysfunction
3
Lorcaserin is a selective serotonin-2C agonist, developed for weight management, to be used in
conjunction with diet and exercise.a However, other serotonergic agonists, including drugs for weight
loss, have been associated with increased heart valve injury rates and hemodynamically significant 4
valvulopathy. Lorcaserin’s sponsor hypothesized the valvulopathy risk would be avoided due to
the drug’s high selectivity for the 2C receptor subtype. Testing this hypothesis became an explicit
objective of the Phase 3 lorcaserin program. Patients randomized in the Phase 3 program underwent 5
echocardiography at baseline and post-randomization intervals. Pre-specified, formal noninferiority
assessment of the rate of valvulopathy after 52 weeks of loracaserin versus placebo was conducted.
A pre-specified pooled dataset from the Phase 3 trials was used to tighten the confidence intervals 6
around the point estimates for valvulopathy rates. A standardized definition of valvulopathy was used
and implemented by echocardiogram readers blinded to study assignment.
Thus, the Phase 3 program provided robust data that excluded a predefined, unacceptable
increased rate of valvulopathy due to lorcaserin and helped support FDA’s approval of lorcaserin.
7
Importantly, this intense monitoring of heart valve status would not be part of a typical Phase 3
program for an antiobesity drug. This case demonstrates how specialized safety assessments can be
incorporated into a Phase 3 program to address important clinical questions that otherwise would not
8
be answered.

a. Sponsor’s Briefing Document. Lorcaserin hydrochloride (APD356) (10 May 2012). FDA website. http://wayback. 9
archive-it.org/7993/20170113053031/http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/
EndocrinologicandMetabolicDrugsAdvisoryCommittee/ucm303193.htm. Accessed 4 June 2019.

10
results’ interpretability is facilitated by using a
placebo comparator.21,22 If an active comparator
programmatic failure. In the US, submission of a
Special Protocol Assessment (SPA; see Chapter
11
is chosen, its efficacy and safety must be well 13) can ensure alignment between the sponsor
established to allow meaningful inferences from and FDA on critical trial design considerations. 12
the trial results. This is particularly important if a The SPA process may be especially useful if a
noninferiority hypothesis is tested, as opposed to nontraditional trial design is proposed or a more
a superiority hypothesis.23 innovative methodology, such as an adaptive 13
In their review of unsuccessful initial new design, is employed.
drug approval applications in the US, Sacks,
et al. found 13% of failures were due to study
In the US, there are two important excep-
tions to the need for definitive clinical endpoint
14
endpoints of unclear clinical relevance and data prior to approval. Accelerated approval
another 13% to inconsistent results when dif- allows marketing approval based on a surrogate 15
ferent endpoints were selected.24 These results endpoint when there is an important, unmet
illustrate the importance of proper primary and
secondary endpoint selection. Primary endpoints
clinical need and high likelihood the surrogate
endpoint is predictive of clinical response.25 For
16
must be of established clinical importance, and example, in the early years of the HIV-epidemic,
secondary endpoints must support both the anti-retroviral drugs obtained approval based 17
drug’s efficacy and its clinical relevance. Failure on their ability to increase blood CD4-lympho-
to use the Phase 2 program to define endpoints cyte levels, which were believed to be predictive
and estimate effect sizes to justify Phase 3 end- of the patient’s ability to fight infections and 18
points and sample sizes will increase the risks of were associated with improved survival rates.

All rights reserved; file sharing prohibited. 95

 Chapter 8: Strategies for Clinical Development Planning

Case Study 8-3. Excluding Unacceptable Risk

Development of anti-diabetes drugs detecting an increase in the background clinical event rate
due to a drug can be extremely challenging, as observed events may be attributed to the target
population’s natural history. This bias likely contributed to delayed recognition of the association
between cyclooxygenase inhibitors use and myocardial infarctions. A 2007 meta-analysis suggested
rosiglitazone might be associated with an increase in Type II diabetes patients’ cardiovascular events.a
While the analysis suggested the increased event rate would be clinically important, individual Phase
3 clinical trials would have been too small to accrue sufficient adverse events to allow detection of the
hypothesized risk. Since multiple drug classes were available to treat Type II diabetes, FDA felt any new
anti-diabetes treatments should have little residual uncertainty with respect to their cardiovascular
risk. Thus, the agency issued guidance requiring new anti-diabetes drugs to demonstrate they were
not associated with unacceptable cardiovascular risk.b This guidance suggests sponsors provide
data excluding a relative risk of 1.3 for cardiovascular events for any new anti-diabetes drug.
This requirement can be met postapproval if preapproval data exclude a relative risk of 1.8. As a
result, Phase 3 trials for drugs to treat Type II diabetes include special procedures for identifying
and adjudicating potential cardiovascular events. Accruing sufficient adverse events to exclude a
relative risk of 1.3 requires studying higher-risk patients and/or large sample sizes. For example, the
postmarketing study examining saxagliptin and cardiovascular outcomes randomized 16,492 patients
and followed them for a median of 2.1 years.c Of note, the original signal suggesting a potential
cardiovascular risk associated with rosiglitazone may have been a false-positive signal.d

a. Nissen SE, Wolski K. “Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.” NEJM
356:2457–2471, 2007.
b. Guidance for Industry: Diabetes Mellitus—Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2
Diabetes (December 2008). FDA website. https://www.fda.gov/media/71297/download. Accessed 4 June 2019.
c. Scirica BM, Bhatt DL, Braunwald E, et al. “Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes
mellitus.” NEJM 369:1317–1326, 2013.
d. Hiatt WR, Kaul S and Smith RJ. “The cardiovascular safety of diabetes drugs–insights from the rosiglitazone experience.”
NEJM 369:1285–1287, 2013.

Currently, accelerated approvals are used most Increasingly, Phase 3 trial size is deter-
commonly for novel anti-cancer agents. Impor- mined by the need to meet safety requirements
tantly, accelerated approval is accompanied by a rather than the number of patients required to
postmarketing commitment to conduct studies demonstrate efficacy. Demonstrating safety no
to demonstrate the drug’s actual clinical benefit. longer can be viewed as failure to observe adverse
The second exception is based on the Animal effects. Rather, sponsors must demonstrate trial
Rule.26 The Animal Rule can be used to obtain procedures were adequate to recognize and
marketing approval based on demonstrating
define adverse events, especially those designated
efficacy in animal models likely to be predictive
as events of special interest (see Case Study
of response to the disease when combined with
8-2). Further, the clinical trial must be large
human drug safety data. The Animal Rule can be
used only when human clinical trials would be enough to ensure unacceptable adverse events
unethical or impractical. have been excluded using statistically appropriate
The Animal Rule was enacted to permit drug methods.27,28 Formal procedures are important,
development for conditions such as radiation particularly if a drug has the potential to increase
poisoning or infectious diseases with high the rate of serious adverse events that occur at
lethality that might be used in terrorist attacks or a background rate in the target population (see
encountered naturally (e.g., the Ebola virus). Case Study 8-3).

96 All rights reserved; file sharing prohibited.

 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
Thus, Phase 3 data must be sufficient, quan- 15. Australian Public Assessment Reports. Therapeutic
titatively and qualitatively, to provide definitive Goods Administration website. https://www.tga.gov.au/
ws-auspar-index. Accessed 4 June 2019.
2
evidence of both safety and efficacy. The totality
16. Antibacterial Therapies for Patients with an Unmet
of the data, including preclinical studies and
all clinical trials, form the basis for regulatory
Medical Need for the Treatment of Serious Bacterial
Diseases: Guidance for Industry (August 2017). FDA
3
decision making and the information ultimately website. https://www.fda.gov/media/86250/download.

4
Accessed 4 June 2019.
included in the approved product’s labeling.
17. Rare Diseases: Natural History Studies for Drug
Development: Draft Guidance for Industry (March 2019).

5
FDA website. https://www.fda.gov/media/122425/
References
download. Accessed 4 June 2019.
1. Sietsema WK. Strategic Clinical Development Planning.
18. Rare Diseases: Common Issues in Drug Development:
Designing Programs for Winning Products. FDAnews,
6
Guidance for Industry (February 2019). FDA website.
Falls Church, VA. 2005. Chapter 3, pages 9–13.
https://www.fda.gov/media/120091/download.
2. Ibid. Accessed 4 June 2019.
3. Daily Med. Current Medication Information. US 19. Sacks LV, Shamsuddin HH, Yasinskaya YI, Bouri
National Library of Medicine. https://dailymed.nlm.
nih.gov/dailymed/index.cfm. Accessed 4 June 2019.
K, Lanthier ML and Sherman RE. “Scientific and 7
regulatory reasons for delay and denial of FDA approval
4. Electronic Medicines Compendium. eMC website. of initial applications for new drugs, 2000–2012.” JAMA
https://www.medicines.org.uk/emc/. Accessed 4 June
2019.
311:378–384, 2014.
20. Fleming TR and DeMets DL. “Surrogate end points
8
5. ClinicalTrials.gov website. US National Library of in clinical trials: are we being misled?” Ann Int Med
Medicine, National Institutes of Health, Department
of Health & Human Services. http://www.clinicaltrials.
125:605–613, 1996.
21. Temple R and Ellenberg SS. “Placebo-controlled trials
9
gov/. Accessed 4 June 2019. and active-control trials in the evaluation on new
6. EU Clinical Trials Register website. https://www.
clinicaltrialsregister.eu/ctr-search/search. Accessed 4
treatments. Part 1: Ethical and Scientific issues.” Ann
Intern Med 133:455–463, 2000. 10
June 2019. 22. Ellenberg SS and Temple R. “Placebo-controlled trials
7. Medical Outcomes Trust website. http://www.
outcomes-trust.org/. Accessed 4 June 2019.
and active-control trials in the evaluation on new
treatments. Part 2: Practical issues and specific cases.” 11
Ann Intern Med 133:464–470, 2000.
8. Patient Insights. https://www.optum.com/solutions/
life-sciences/answer-research/patient-insights.html.
Accessed 4 June 2019.
23. Fleming TR. “Current issues in non-inferiority trials.”
Stat Med 27:317–332, 2008. 12
24. Op cit 19.
9. Slabiak T. “Clinical Trial Endpoints for Oncology
Studies.” Applied Clinical Trials (2 April 2012). http://
www.appliedclinicaltrialsonline.com/clinical-trial-
25. Guidance for Industry: Expedited Programs for Serious
Conditions—Drugs and Biologics (September 2017).
13
endpoints-oncology-studies. Accessed 4 June 2019. FDA website. https://www.fda.gov/media/86377/
10. Cardiovascular Outcomes, Inc. website. http://
cvoutcomes.org/. Accessed 4 June 2019.
download. Accessed 4 June 2019.
26. Guidance for Industry: Product Development Under the
14
Animal Rule (October 2015). FDA website. https://
11. Drugs@FDA. US Food and Drug Administration.
https://www.accessdata.fda.gov/scripts/cder/daf/index.
cfm. Accessed 4 June 2019.
www.fda.gov/media/88625/download. Accessed 4 June
2019. 15
27. Brass EP, Lewis RJ, Lipicky R, Murphy J and
12. European Public Assessment Reports. European
16
Hiatt WR. “Risk assessment in drug development
Medicines Agency website. https://www.ema.europa.
for symptomatic indications: A framework for the
eu/en/medicines. Accessed 4 June 2019.
prospective exclusion of unacceptable cardiovascular
13. Summary Basis of Decisions. Health Canada website. risk.” Clin Pharmacol Ther 79:165–172, 2006.
https://hpr-rps.hres.ca/reg-content/regulatory-
decision-summary.php. Accessed 4 June 2019.
28. Fleming TR. “Identifying and addressing safety signals 17
in clinical trials.” NEJM 2008; 359:1400–1402.
14. Review Reports: Drugs. Pharmaceuticals and Medical
Devices Agency website. http://www.pmda.go.jp/
english/review-services/reviews/approved-information/
18
drugs/0001.html. Accessed 4 June 2019.

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 Chapter 8: Strategies for Clinical Development Planning

98 All rights reserved; file sharing prohibited.

9 Clinical Trial Application Planning

By Sharry Arora
1
2
3
4
5
Clinical trials are prospective, organized, sys-
tematic exposures of patients to interventions
Despite the rise in clinical trials globally, the
conduct of such trials is particularly challenging
6
of some kind (drug, surgical procedure, dietary in developing countries for such reasons as rela-
change). Clinical trials advance through four tive scarcity of healthcare resources, unavailabil- 7
phases to test a treatment, find the appropriate ity of appropriate medical care and the desired
dosage and look for side effects. The health infrastructure. Globalization attracts resources to
authority (HA) typically requires Phase 1, 2 and participating countries, to provide standardized 8
3 clinical trials to be conducted to determine clinical trial conduct and procedures and to train
whether the intervention can be approved for
use. It is important for clinical trials to have
investigators and their teams.4
9
participants of different ages, sexes, races and Choosing the Countries
ethnicities to have much wider applicability
Many factors should be taken into account when 10
when the drug is in market.1 Over the last
selecting countries in which to conduct clinical
two decades, globalization of clinical trials
has increased steadily due to multiple factors,
trials, including: disease epidemiology; regulatory 11
environment and timing; speed of recruitment;
including access to well-characterized and
availability of experienced clinical trialists;
often treatment-naïve medication for willing
existence of placebos or comparator arms; patient 12
participants, resulting in expedited enrollment;
enrollment trends; and competitive information,
availability of qualified local investigators who
are eager to conduct trials; enhanced capac-
such as competing trials and/or similar products 13
ity of international sites; and the lower costs on the market.
Further, the drug’s market strategy needs to
of conducting trials in developing countries.
Economic incentives to site trials in developing be considered before choosing where to conduct 14
economies also stem from the dramatic increase the trial. Is the country a significant player in the
in clinical trial costs in developed countries such international economy and does it have a market 15
as the US and EU Member States. Further, that can afford the medication after approval?
national regulations increasingly require local, What is the current pricing and reimbursement
in-country study data to demonstrate a medic- environment?5 16
inal product or device is efficacious and safe in In choosing the countries in which to con-
that country and thus across racial and ethnic duct global clinical trials, the regulatory profes-
sional should bear in mind that a global trial’s
17
groups. These regulations propel multinational
pharmaceutical companies to consider involv- costs grow as the number of countries increases.
ing these multiregional sites early in any drug Thus, the right balance between a larger number 18
development program.2,3 of countries to enhance recruitment and facili-

All rights reserved; file sharing prohibited. 99

 Chapter 9: Clinical Trial Application Planning

tate approval versus controlling the research cost • previous human experience with the
must be determined. investigational drug
• financial disclosure
Global Dossier • letter of delegation of responsibilities/
power of attorney
Most clinical trial application (CTA) require-
• advertising
ments, around the world, are based on require-
• Qualified Person (QP) review and sign
ments of the US Food and Drug Administration
off (EU only)
(FDA) or European Medicines Agency (EMA).
• data protection declaration (EU only)
Once those requirements are understood,
• case report forms (typically, draft
applications in other countries can be similar,
acceptable)
taking individual country-specific documentation • Data Safety Monitoring Board
into account (e.g., notarized copies of business (DSMB) charter/Independent Data
licenses, draft case report forms, etc.). Monitoring Committee (iDMC)
The first step is assembling a global dossier. (typically, draft acceptable)
A global dossier is not very different from the US • clinical supply labels in country-specific
Investigational New Drug application (IND), language
as most commercial CTAs use the Common • Letter of Acceptance (LOA) of study
Technical Document (CTD) format preferred from another country (if available),
by FDA. In addition to the IND, Investigational or letter or rejection from an Ethics
Medicinal Product Dossier (IMPD) or CTA, Committee (if applicable)
completing the global submission will require
collecting and making available the:6,7 Ethics Committee
• cover sheet (Form FDA 1571) (including,
but not limited to: sponsor contact The primary scope of information assessed by
information, investigational product the EC (referred to as an institutional review
(IP) name, application date, clinical board (IRB) in the US) relates to maintaining
investigation phase(s) to be conducted, and protecting the research participants’ dignity
and commitment that the ethics and rights and ensuring their safety throughout
committee (EC) will conduct initial and their participation in a clinical trial. The EC also
continuing review and approval of each must pay special attention to reviewing informed
study proposed in the investigation) consent and protecting the welfare of certain
• table of contents participant classes deemed to be vulnerable. In
• introductory statement and general addition, the EC is responsible for ensuring a
investigational plan competent review of the research protocol, eval-
uating the possible participant risks and expected
• master Informed Consent Form
benefits and verifying the adequacy of confiden-
(ICF; typically if a country follows
tiality safeguards.8
the International Council for
Harmonisation (ICH), the same global Clinical Supply Labels
requirements apply)
• Investigator’s Brochure (IB) Clinical supply products must be appropriately
• protocol labeled to meet the following principles to:
• protocol signature page • ensure protection of the subject and
• chemistry, manufacturing and control traceability
data • enable identification of the product and
• pharmacology and toxicology data the clinical trial

100 All rights reserved; file sharing prohibited.

 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
• facilitate proper use and storage of the requirements, provided the labeling principles are
product not compromised. 2
• ensure the reliability and robustness of
Translations
data generated in the clinical trial9
3
Determining clinical supply label requirements Once a company decides to conduct clinical
and translations can be very time-consuming. trials in a country other than its home market,
key clinical documents often require transla-
4
First, the regulatory professional must develop
a table of what each country requires on the tion. Most documents will need to be certified
outer and inner packaging (bottle or vial) for translations (translated into another language, 5
both active and placebo (alternatively, Tarius or translated back and reviewed against original
Cortellis cross-country tables can be used to help
plan and manage this task). Then, the regulatory
documents to ensure the original intent has not
been lost). A certified translation will be accom-
6
professional needs to determine requirements for panied by signed and dated documentation from
a final label template, in each country’s language.
The label text must be translated, back-translated
the translator, identifying the document trans- 7
lated (stating the original language). Documents
and certified. The labels then are printed, checked
against the certified translation for quality assur- typically needing translation include: 8
ance (QA), and the drug finally can be labeled. Before Trial Initiation
This entire process can take three to six months,
depending on a variety of factors, including time • protocol synopsis
9
to compile initial requirements, translation time, • protocol (typically in countries where a
printing, QA and time to schedule investiga-
tional material labeling. Any error on the final
formal IND is not submitted) 10
• IB (typically in countries where a formal
printed label (which can happen with a variety of IND is not submitted)
languages and their unique characters) can set a
• Informed Consent Form 11
clinical program back several months.
• patient diary or questionnaires
The investigational product must be coded
and labeled in a manner that protects the
• clinical supply labels 12
• questions from regulators/answers from
blinding, if applicable, and also must be suitably
sponsors
packaged in a manner that will prevent contam-
ination and unacceptable deterioration during • ministry of health approval letters 13
transport and storage. • EC approval letters
Further, innovative approaches and technol- • investigator 1572s and curriculum vitae 14
ogy have been implemented to manage clinical (CV)
trial investigational product and auxiliary product • instructions for automatic randomization
traceability and accountability. For example, 15
computerized technologies like interactive voice After Trial Initiation
response systems (IVRS) or interactive web
response systems (IWRS) have been used to
• serious adverse events 16
• annual reports
manage randomization, investigational prod-
uct accountability at trial sites, dose titration,
• notice of study discontinuation or
close-out
17
emergency unblinding and expiry date updating
for clinical trials. A measured degree of flexi- • additional ministry of health or
bility, thus, has been included in the regulations EC communication—for protocol 18
to allow alternative approaches to the labeling amendments or IB

All rights reserved; file sharing prohibited. 101

 Chapter 9: Clinical Trial Application Planning

Maintaining the Submission to coordinate an annual report with only one or

two data cuts needed to prepare the reports, but
Once all the above documents have been that is not always the case. This means the spon-
created, collected and notarized, and the initial sor has to coordinate data analysis on an almost
submission has been made, from a regulatory monthly basis to write annual reports for multi-
perspective, the work has just begun. The sub- ple countries. In addition, some EU and Eastern
mission now needs to be maintained; following European countries require both quarterly safety
are the types of submissions required to support reports and annual reports.
the submission:
Final Report
Serious Adverse Events
An investigator must provide the sponsor with
Serious adverse events (SAEs) need to be an adequate report shortly after completion
reported in every country, meeting ICH or local of his or her participation in the investigation.
ministry of health requirements. Some of the There is no specific timeframe stipulated for
reporting challenges are:
report completion.
• Different forms—in the US, SAEs need
The investigator or institution should
to be reported on MedWatch FDA
provide the EC with a summary of the trial’s
Form 3500A,10 while the rest of the
outcome, and supply FDA or the HA with any
world uses the Council for International
additional report(s) required.
Organizations of Medical Sciences
The sponsor or its principal investigator
(CIOMS) form11 (except Canada, which
uses the ADR12 form). (PI) must submit results for applicable investi-
• Distribution—some countries and sites gational product clinical trials to ClinicalTrials.
require paper SAEs, while other sites, gov no later than one year following the study’s
ECs and countries require electronic completion date.
SAEs, which means converting the
CIOMS form into XML and obtaining
Submitting Clinical Trial Application
email addresses. (CTA)
• Timelines—all SAE reporting timelines The sponsor is responsible for submitting a CTA
need to be met, even though there or investigational new drug application (IND).
are different forms, timelines and Institutional EC review of the clinical investiga-
submission standards. tion may be conducted concurrently with FDA’s
Annual and Quarterly Reports IND or HA CTA review. However, EC approval
must be obtained prior to the sponsor being
Annual reports or Development Safety Update permitted to initiate the clinical trial.13
Reports (DSURs) are required in all major To complete the IND application package,
countries; the due date depends on the IND the sponsor must provide the following informa-
effective date and the EudraCT registration tion in paper format or electronically:
date, respectively. The IND effective date or date • cover sheet (Form FDA 1571)
of first EU approval typically is known as the (including, but not limited to: sponsor
international birthdate, which establishes the contact information, investigational
date for annual report submission. For Euro- product (IP) name, application date,
pean countries not part of the EU, the annual phase(s) of clinical investigation to
report is due on the anniversary of the first site’s be conducted, and commitment that
approval. Sometimes, countries allow sponsors the EC will conduct an initial and

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
continuing review and approval of each substantial or administrative amendment will
study proposed in the investigation) determine the review timeline. 2
• protocols IBs need to be reviewed on an annual basis
• chemistry, manufacturing and control
data
for updates. If an update is made, this will need
to be submitted to the sites, ministries of health 3
• pharmacology and toxicology data and ECs.
• previous human experience with the
investigational drug Shelf-Life Extension
4
Multicenter Studies If an investigational product expires during
trial conduct, a shelf-life extension will need to
5
In the event of multicenter clinical studies, also be filed (this submission can include: extended
known as cooperative research studies, required release statement, stability tables with stability 6
to comply with the revised Common Rule, data and an extension justification memo stating
all federally-funded or sponsored institutions the material is good for another three, six or
located in the US and engaged in multicenter 12 months), or a new study drug will need to 7
research must, by 20 January 2020, use a single be exchanged for the old material. Either way,
EC to review that study, known as the IRB
policy. This policy will streamline the EC review
this information will need to be submitted to
countries requiring this update, and there often is
8
process and eliminate duplicative reviews. The a 28–60-day timeline to review this information
exceptions to this requirement are: when mul- before the material with the new expiry date or 9
tiple-EC review is required by law (including the new material can be used. If the shelf-life
tribal law); or for research where any federal extension or information on the new lot is not
department or agency supporting or conducting submitted or reviewed in a timely manner, enroll- 10
the research determines that the use of a single ment in the study could be halted until this has
EC is not appropriate.
Designed to complement the revised Com-
been resolved.
In addition, new expiration date labels 11
mon Rule, which took effect 21 January 2019, will need to be printed and the drug packages
the National Institutes of Health (NIH) issued
a final policy requiring all institute-funded multi-
over-labeled at the site. Of course, the over-label-
ing process will need to be tracked to ensure all
12
center clinical trials conducted in the US to be sites have received the updated labeling.
overseen by a single EC, unless prohibited by any 13
federal, tribal or state law, regulation or policy. Form 1572 and Financial Disclosure
Data Safety and Monitoring Boards also are Updates
specifically required for NIH-funded multisite 14
Assuming the study is going to be conducted
clinical trials including interventions that involve
under a US IND, if investigational site informa-
potential participant risk.14
tion changes, its Form 1572 needs to be updated 15
Protocol Amendments, IB Updates and and submitted to the sponsor in a timely manner.
Informed Consent Modifications Some clinical research associates prefer to update
Form 1572 only at the end of the study; this
16
Each time a protocol amendment is made, the is not acceptable, because the information can
updated protocol and master informed consent change many times during the study, and these 17
form will need to be sent to both the ministry changes need to be captured. Also, any financial
of health and the EC, and the site will need to disclosure information changes will need to be
wait for an opinion from both before implement- captured on a new financial disclosure form and 18
ing the amendment. Whether the protocol is a evaluated to see whether it impacts the final

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 Chapter 9: Clinical Trial Application Planning

study analysis (an additional, separate efficacy IND/IP Supply, Storage, and Handling
analysis might need to be conducted for investi- Requirements
gator(s) who have exceeded financial disclosure
limits). In addition, a final financial disclosure The sponsor also must supply the investigator(s)/
form will need to be submitted no later than a institution(s) with the investigational product,
year after the study ends. including the comparator(s) and placebo, if appli-
cable. The sponsor must ensure the following:
Maintaining the US IND—Paperwork • investigational product quality and
Required stability over the period of use
• investigational product manufactured
As with most investigator submissions, the according to any applicable Good
sponsor needs to submit Form 1572 and the Manufacturing Practices (GMPs)
physician’s CV (for some products, the Inves- • proper coding, packaging and labeling
tigational Review Board (IRB) approval letter of the investigational product
and Informed Consent Form also need to be • records maintained for investigational
submitted, depending on the product and FDA product document shipment, receipt,
reviewing division). For studies conducted under disposition, return and destruction
a US IND outside the US, the following should • acceptable storage temperatures,
be submitted: conditions and times for the
• Form 1572 (in English) investigational product
• investigator CV (in English) • timely delivery of the investigational
• EC letter (if required) in native product
language, English translation and a
Record Requirements
certified translation certificate
• approved informed consent form (if The sponsor and the investigator(s) must retain
required) in English and a certified the clinical investigation records and reports for
translation certificate two years after a marketing application (known
as a New Drug Application (NDA)) is approved
What paperwork really is needed? for the investigational product; or, if an NDA is
not approved, until two years after shipment and
Collecting all the documentation, either paper
delivery of the investigational product is discon-
or electronic, from a global clinical trial some-
tinued for investigational use, and FDA has been
times can be daunting. What documentation
so notified.
really is needed?
Conducting clinical trials in multiple coun-
• regulatory authority approval, all
tries is no small feat for the clinical or regulatory
submissions, correspondence (including team, which not only supports ongoing main-
emails) and certified translations tenance but acts as the gatekeeper for initiating
• ethics (central, local, hospital, etc.) trials. Planning is essential not only to the trial
approvals, correspondence and certified initiation, but also maintenance. Mapping out
translations all the required documentation, through the
• annual report submissions and regulatory regulatory professional’s own knowledge, with
authorities’ acknowledgment receipts a CRO’s help or by utilizing Tarius/Cortellis
• SAE submissions and acknowledgements cross-country tables early, will help navigate the
• investigator Form 1572s, CVs and global clinical trial process with minimal delays
financial disclosure forms to first patient enrolled.15,16

104 All rights reserved; file sharing prohibited.

 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
References 13. Op cit 6.

1. What Are Clinical Trials and Studies? National 14. Op cit 7. 2

Institute on Aging website. https://www.nia.nih.gov/ 15. Global Regulatory Intelligence and Compliance. Tarius
health/what-are-clinical-trials-and-studies. Accessed 8
3
website. www.tarius.com. Accessed 8 October 2019.
October 2019.
16. Cortellis website. https://www.cortellis.com/
2. da Silva RE, Amato AA, Guilhem DB and Garbi intelligence/report/ri/globalregcomparison/DB/112.
Novaes MRC. Globalization of clinical trials: ethical
4
Accessed 16 October 2019.
and regulatory implications. Int J Clin Trials. 2016
Feb;3(1):1-8.
3. Li R, Barnes M, Aldinger CE and Bierer BE.
Global Clinical Trials: Ethics, Harmonization and
Commitments to Transparency. Harvard Public Health
5
Review website. http://harvardpublichealthreview.
org/global-clinical-trials-ethics-harmonization-and-
commitments-to-transparency/. Accessed 8 October 6
2019.
4.
5.
Ibid.
Meyer J. Country Selection for Your Clinical Trial:
7
There is a Method to the Madness. Covance blog

8
website. https://www.covance.com/content/dam/
covance/assetLibrary/articles/cds-country-selection-
articlefinalpdf.pdf. Accessed 8 October 2019.

9
6. 21 CFR Part 312—Investigational New Drug
Application. Electronic Code of Federal Regulations.
US Government Printing Office website. http://www.
ecfr.gov/cgi-bin/text-idx?SID=4916c39a3cd4e92fdf238
aa64bdaeab8&node=pt21.5.312&rgn=div5. Accessed 8
October 2019.
10
7. Clinical Trial Lifecycle. ClinRegs website. https://
clinregs.niaid.nih.gov/country/united-kingdom/united-
states#submission_process. Accessed 8 October 2019.
11
8. Op cit 6.
9. Health Sciences Authority Regulatory Guidance (31
January 2018). HSA website. https://www.hsa.gov.sg/
12
docs/default-source/clinical-trials/hsa_ctb_guidance_
labelling_mp_tp_31jan2018.pdf. Accessed 8 October
2019. 13
10. MedWatch Form FDA 3500A download. FDA
website. http://www.fda.gov/downloads/AboutFDA/
ReportsManualsForms/Forms/UCM048334.pdf. 14
Accessed 8 October 2019.
11. Suspect Adverse Reaction Report Form (CIOMS Form
I). CIOMS website. http://www.cioms.ch/index.php/ 15
cioms-form-i. Accessed 8 October 2019.
12. Mandatory Adverse Reporting Form for Industry.
Health Canada website. http://hc-sc.gc.ca/dhp-mps/ 16
alt_formats/pdf/medeff/report-declaration/ar-ei_indus-
form-eng.pdf. Accessed 8 October 2019.
17
18

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 Chapter 9: Clinical Trial Application Planning

106 All rights reserved; file sharing prohibited.

10 Global Orphan Drug Regulations

By Jocelyn Jennings, MS, RAC

1
2
3
4
5
During the drug or biologic development pro-
cess, a manufacturer needs to decide the indi-
Once the determination has been confirmed
that the new drug or biologic will treat a rare
6
cation(s) for the product. In other words, what disease, the regulatory professional will need
disease or disorder will the product propose to to work with the development team, including 7
treat? If the disease or disorder is a rare disease, the commercial organization, to discuss product
the regulatory professional would need to start submission strategies.
researching specific information about the dis- 8
ease or disorder to ascertain whether it meets the US Orphan Drug Designation Program
rare disease definition.
Rare diseases are diseases occurring infre-
FDA has a number of incentive programs for 9
drug, biologic and medical device manufacturers.
quently or rarely in the general population.
One such program is the Orphan Drug Desig-
Rare diseases affect a limited percentage of the
whole population; there is no set definition for
nation program. This program provides orphan 10
status to drugs and biologics that are defined
rare disease; therefore, the definition varies on a
country-by-country basis; it is country-specific as those intended for the treatment, prevention
or diagnosis of a rare disease or condition.3
11
and population-dependent. An estimated 5,000
to 8,000 (typically averaged to 7,000) distinct Whether a given medical condition constitutes
rare diseases exist today, affecting up to 10% of a distinct disease or condition for the purpose of 12
the population in total, and 50% of rare diseases orphan drug designation depends on a number of
factors, assessed cumulatively, including:
affect children,1 with as many as 250 million
people suffering from a rare disease globally.2 • disease or condition pathogenesis 13
Examples of rare diseases studied include: • disease or condition course
• genetic diseases in which enzymatic •
•
disease or condition prognosis
resistance to treatment4
14
deficiency triggers metabolic disorders
diseases that could be treated by substi-
15
•
tutive enzymes (e.g., Gaucher disease) Consequently, an orphan drug or biologic is one
• refractory digestive disorders intended for use in the treatment of a rare disease
•
•
cystic fibrosis
rare cancers (about one-third of des-
or condition.5
The Orphan Drug Act of 1983 (ODA) was
16
ignations are cancers), such as brain signed into law (Public Law 97-414) on 4 Janu-
tumors in children and young adults, or ary 1983. It provides tax incentives and exclusive 17
Merkel cell carcinoma and leukemia in licensing to encourage manufacturers to develop
adults and market drugs or biologics for diseases affect-
• neurological disorders ing relatively few people (fewer than 200,000 in 18
• hemophilia the US). The ODA defined an orphan drug as a

All rights reserved; file sharing prohibited. 107

 Chapter 10: Global Orphan Drug Regulations

drug or biologic intended to treat, diagnose or these meetings, the sponsor can discuss the rare
prevent a rare disease or disorder affecting fewer disease and ensure the prevalence information
than 200,000 people in the US, or affecting more gathered to-date meets FDA requirements.8
than 200,000 persons but not expected to recover
its developing and marketing costs.6 Prior to this EU Orphan Drug Designation Program
legislation, private industry had little economic
In June 2018, the European Medicines Agency
incentive to invest in developing treatments for
(EMA) introduced the Regulatory and Scien-
small patient populations, since the drugs were
tific Information Management Platform, named
expected to be unprofitable. The law provides
IRIS, for submitting orphan drug designation.
several incentives to promote product develop-
IRIS is a secure online portal that enables spon-
ment for these orphan populations, including
sors to submit their orphan designation applica-
seven-year marketing exclusivity for approved
tions and manage post-designation activities. The
orphan products; a clinical trial cost tax credit
regulatory professional should ensure all steps
(originally a 50% credit, but changed to 25%)7;
to gain access to IRIS are completed prior to
and waiver of the prescription drug user fee (no
submitting the orphan designation application.
other indication can be included). Marketing
EMA has released guidance and quick guides for
exclusivity prevents competition by denying
the IRIS system that should enable a smooth and
other companies marketing approval for the
successful path for registration onto the plat-
same drug for the same orphan indication.
form.9 A flow diagram of the process is shown in
“Ultra-orphan” is not an official regulatory
Figure 10-1.
term but is used by companies and investors
EMA has several webpages devoted to differ-
to designate a drug to treat fewer than 2,000
ent aspects of the orphan drug designation process.
patients in the US.
The agency’s Committee for Orphan Medicinal
Because of this legislation’s impact in
Products (COMP) is responsible for examining
helping underserved patients, other regulatory
orphan drug designation applications and provid-
authorities have recognized its value and created
ing an opinion 90 days after validation.10
their own orphan drug legislation. Japan’s
EMA offers a number of incentives for
Orphan Drug Regulation followed the US
orphan drug development similar to those in the
Orphan Drug Act 10 years later. In 1998, Aus-
US and some other countries. Additionally, EMA
tralia released its Orphan Drug Policy, and in
has annual reporting requirements for orphan
1999, the EU followed with Regulations (EC)
drug designation products. EMA and FDA had
141/2000 and 847/2000.
a process for the concurrent submission of an
The US Food and Drug Administration’s
orphan designation to both agencies. The result
(FDA) Office of Orphan Drug Development
would be a combined annual report provided to
(OOPD) is responsible for the orphan designa-
both agencies on an EMA-developed form. How-
tion program. One service OOPD provides is
ever, with the advent of IRIS, it is unclear whether
meetings with sponsors to discuss their potential
this process will continue, at least for products that
orphan drug development programs. Sponsors
were submitted prior to 19 September 2018 when
can request either an informal or formal OOPD
the use of IRIS became mandatory.11
meeting to discuss any orphan designation pro-
grams, orphan product grants and orphan prod- What other countries have orphan drug
uct outreach programs. Sponsors should note, designation regulations?
however, meeting with OOPD is not a presub-
mission meeting or interactive review meeting. To qualify for any orphan drug benefits or to
OOPD will not provide feedback on product officially call a drug an orphan product, a com-
development protocols or planned studies. At pany first must request designation. If a company

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
Figure 10-1. Sponsor’s Guide to an Orphan Designation 2
Start Not eligible*
3
No 4
Proposed Prevalence: identification
condition has distinct Condition is
Yes Yes
5
of European
pathophysiological, seriously
epidemiological
histopathological, clinical debilitating/life
resources (e.g. papers,
characterists. threatening.
registries, databases).

6
No

Yes

Subset
Prevalence is <5
in 10,000 in EU**.
Yes
The specific
product applied for
is under development
No 7
has a plausible for this
Condition is Yes link to the condition condition.
a subset of a distinct AND the product cannot exert
medical entity pharmacodynamic effects
beyond the
subset. No Yes
8
No No

9
Not ready to apply*

Data
available

10
with the specific
product in relevant No
Not eligible* Not eligible* non-clinical models or patients
affected by the proposed
condition, indicating
clinically relevant

11
outcomes.
Grounds for
potential
significant benefit Satisfactory
No based on data to support Yes authorized methods for Yes

12
clinically relevant advantage treatment, diagnosis or
and/or major contribution to prevention exist within
patient care vis-à-vis the the EU.
existing authorized
products. Identification of existing
methods of treatment,

Yes No
diagnosis or prevention
of the condition within
the EU.
13
Not ready to apply*. Consider
other frameworks (e.g. paediatrics,
advanced-therapy medicinal
products, micro-, small- and
medium-sized enterprises.
Ready to apply for an orphan
14
designation. Arrange a
pre-submission meeting.

15
Disclaimer: The flowchart presented should be interpreted as a tool to guide potential sponsors through the orphan
designation eligibility criteria. The flowchart is not used for the assessment of orphan designation, it is non-binding
and it does not preempt any of the opinions obtained by the Committee for Orphan Medicinal Products. 16
*Contact the EMA orphan medicines office for more guidance.

**Article 3(1)(a) of Regulation (EC) No 141/2000 provides an alternative criterion to the prevalence number, based
17
on evidence of insufficient return to justify the necessary investment.

Source: European Medicines Agency 18

All rights reserved; file sharing prohibited. 109

 Chapter 10: Global Orphan Drug Regulations

Table 10-1. Countries with Orphan Drug Regulations and Population Prevalence

Country Population Prevalence*

US <200,000 patients per year
EU 5 per 10,000 persons**
Canada No regulatory definition or framework for orphan drugs
Japan <50,000 patients per year (except designated intractable diseases which can be
>50,000)
Australia <2,000 patients per year
Colombia <1 per 5,000 persons
Singapore A life-threatening and severe debilitating illness affecting fewer than 20,000 persons
South Korea < 20,000 persons
Switzerland Not more than 5 in 10,000 persons in Switzerland at time of application for
designation
Taiwan < one per 100,000 people
Mexico 5 per 10,000 persons
Argentina 5 per 10,000 persons
China There is no legal definition for orphan drugs in China
Brazil 65 per 1000 persons
Panama 1 per 2,000 persons

*This is the maximum number of patients per year to be treated.

**Allows for a fluctuating population number, unlike the US Orphan Drug Act

is working on a global development plan for Curiously, Canada does not have a formal
an orphan indication, it is good to know which orphan drug act or designation process in place.
countries have orphan drug designation pro- Health Canada emphasizes that programs
grams in place, so an application in each country already are in place that can be used by manu-
can be planned accordingly. Another factor to facturers of orphan drugs, such as the compas-
consider, referencing the information in Table sionate use pathway and importation of drugs for
10-1, is if the product is an orphan in the US, personal use.12
will it also be considered an orphan product in
Orphan Drug Incentives
the EU, Australia, Japan or other countries that
have more-restrictive guidance for the number of Because an orphan drug’s use is limited, the
people required to be affected by the disease (and financial costs of developing such drugs are
smaller populations)? Also, the company should likely to be higher than probable returns, thus
plan the submission’s content and determine who discouraging research and development, since
will write the designation request, which subject there is no guarantee the money invested will
matter experts will be consulted, who will review ever be recouped. Orphan drug legislation
it and how the information can be re-used across encourages the development of such products
jurisdictions once each country’s requirements by direct or indirect financial incentives (see
and need for translations are known. Table 10-2). Most countries that have formal

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
Table 10-2. Overview of Orphan Drug Designation Incentives 2
Country Marketing Tax Credit Grants for Accelerated/ Fees Other
Exclusivity Research Priority Reductions 3
US 7 years Yes, 25% Yes Yes PDUFA* fee Protocol assistance
for clinical waiver
studies (US
only unless 4
insufficient
patient
population in
US) 5
EU 10 years Managed by Yes Yes (via the Orphan Protocol assistance
the Member Centralised designation
States Procedure) applications
are free
6
Protocol
assistance fee
reduction: 75%
Pediatric
7
related: 100%
Initial
marketing
authorization:
8
10%
Pre-
authorisation 9
inspections:
100%
Japan Up to 10
years (the re-
Yes, (tax
incentive of
Yes
(covers
Yes
10
examination 12% as a tax R&D costs
period is abatement) up to
extended
increasing
50%)
11
market
exclusivity
from 8 years
up to 10 years
12
Australia 5 years No No Yes May waive
(specific application and
indication-
unless a
evaluation fees 13
clinically

14
superior
medicine
becomes
available
during this
time) 15
Brazil No No No Shorter No • Presubmission
review times meeting required
• GMPC**
priority for the 16
manufacturing
sites involved
• Marketing
application will
17
be accepted in
ICH CTD format
18

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 Chapter 10: Global Orphan Drug Regulations

Table 10-2 (cont.)

Country Marketing Tax Credit Grants for Accelerated/ Fees Other

Exclusivity Research Priority Reductions
Canada No R&D may No Yes, there are No reduction in
qualify for a accelerated fees for orphan
tax incentive pathways, drug products
however
they are not
exclusive to
orphan drug
products
Switzerland No No No Fast track New Simplified
authorization authorization registration
procedure applications procedure
flat fees are
waived.
Mexico No No No No No
South Korea No No Possible No Possible Part of the data for
safety and efficacy
may be exempted
depending on the
reviewers
Singapore No No No No Unknown
China No No No Yes No • It is helpful to
have approval
for the orphan
drug product in
an ICH country
• Overseas clinical
data may be
accepted for
orphan drugs
on China’s new
overseas drugs
urgently needed
in Clinics
• Scientific advice
on protocols
Panama No No No Yes No
Taiwan No No Yes Yes Applicants applying
(reward for the reward must
once per submit all required
year) information to
the Review Board
for Rare Disease
and Orphan Drugs
before asking for
approval from TFDA

*PDUFA (Prescription Drug User Fee Act)

**GMPC (Good Manufacturing Practice Certification)

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
Table 10-3. Global Health Authority Orphan Drug Office 2
Country
US
Office Name
Office of Orphan Products
Link
http://www.fda.gov/ForIndustry/
3
Development (OOPD) DevelopingProductsforRareDiseasesConditions/default.htm
EU The Committee for Orphan
Medicinal Products (COMP)
http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_
us/general/general_content_000263.jsp 4
Japan Pharmaceuticals and Medical https://www.pmda.go.jp/english/index.html
Devices Agency (PMDA)
Ministry of Health Law and
http://www.mhlw.go.jp/english/policy/health-medical/
pharmaceuticals/orphan_drug.html 5
Welfare
Australia Therapeutic Goods http://www.tga.gov.au/applications-orphan-drug-designation
Administration (TGA) 6
Switzerland SwissMedic https://www.swissmedic.ch/swissmedic/en/home/services/
listen_neu.html
Singapore Health Sciences Authority
(HSA)
https://www.hsa.gov.sg/content/hsa/en.html 7
Canada Health Canada (HC) https://www.canada.ca/en/health-canada/services/licences-
authorizations-registrations-drug-health-products/regulatory-
approach-drugs-rare-diseases.html 8
Brazil Agência Nacional de Vigilância http://portal.anvisa.gov.br/regulation
Sanitária (ANVISA)

Note: Although a combined form theoretically can be used to apply for orphan drug designation in the US and EU,4 the amount
9
of information differs between the two applications. One application can be prepared and submitted, but the US application
typically is more succinct than the EU application, which requires an in-depth literature review (usually 40–50 pages more), and
the sponsor has an option for a meeting to defend its case with the COMP; so the process is a bit different. Also, a justification for
disease prevalence will need to be based on each region’s population.
10

orphan designation programs include financial Templates are always helpful, and some
11
incentives: target tax credits, lower marketing countries provide them for this application
application fees and increased regulatory assis- (Table 10-5). 12
tance from the health authority. The incentive
Orphan Drug Designation Regulatory
information needs to be factored into the drug Intelligence (RI) Tools 13
development program and strategy.
One aspect of RI is knowing where to find infor-
Health Authority Information and mation, whether for competitive analysis or to 14
Submission Requirements help with the regulatory submission strategy and

To assemble a comprehensive document check-

pulling together the information for submissions.
Because health authorities want to encourage
15
list, the regulatory professional must under- orphan drug development, a variety of databases
stand the information required for each orphan exist to aid in the search: 16
drug designation submission and the timelines • applications submitted (and by
in the markets prioritized by their company’s whom)—these databases typically
commercial or marketing team. Table 10-3
provide a summary of the drug 17
designated, the population prevalence
lists health authority names, and Table 10-4 cited, the company that applied for the
lists the regulations and/or directives, including designation and, sometimes, the basis 18
submission requirements. for the designation

All rights reserved; file sharing prohibited. 113

 Chapter 10: Global Orphan Drug Regulations

Table 10-4. Orphan Drug Regulations by Country

Country Regulation/Directive Link

US 21 CFR 316 http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/
CFRSearch.cfm?CFRPart=316
EU Regulation (EC) No 141/2000 http://www.ema.europa.eu/ema/index.jsp?curl=pages/
(the Orphan Regulation) regulation/general/general_content_000552.
jsp&mid=WC0b01ac058061ecb7
Regulation (EC) No 847/2000
Japan Article 77-2 of the http://www.mhlw.go.jp/english/policy/health-medical/
Pharmaceutical Affairs Law pharmaceuticals/dl/05.pdf
Australia Part 16h of the Therapeutic http://www.comlaw.gov.au/Details/F2014C00898
Goods Regulations 1990

Table 10-5. Orphan Drug Templates and Submission Tips

Country Link
US FDA
https://www.fda.gov/industry/designating-orphan-product-drugs-and-biological-products/
orphan-drug-designation-request-form
EU EMA
Template for sections A to E for the scientific part of the application for orphan designation
https://www.ema.europa.eu/en/human-regulatory/research-development/orphan-designation/
applying-orphan-designation

This template can only be used with the new IRIS portal. EMA encourages parallel applications
with regulatory authorities outside the EU specifically the US and Japan.
Japan MHLW
The following website has information on the orphan drug designation process. However, the
forms (templates) and guidelines are in Japanese.
https://www.mhlw.go.jp/english/policy/health-medical/pharmaceuticals/orphan_drug.html

• types of diseases for which applications be searched. Searches can be limited to specific
have been submitted dates, products, indications and drug or bio-
• timeline for when a designation logic names. Results typically can be output as a
application was submitted (some only condensed list, detailed list or Excel spreadsheet.
post those approved) and when (if ) the Both EMA and FDA have searchable orphan
marketing application was approved drug designation databases.
(this helps to see whether competitors
are serious about developing the drug) Population Prevalence and Rare Disease
• rare disease background information Databases (Free Tools)
and prevalence numbers Most applications, since they are based on the
Orphan Drug Designation Database US Orphan Drug Act, typically require similar
content. Two sections of the application are usu-
To determine which company already has a des- ally examined more critically: scientific rationale
ignation for the disease being studied, the disease and population prevalence. If these sections
state or indication in the country of choice must are not well supported, the designation may be

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
denied. Determining the population prevalence 12. Canada’s regulatory approach to drugs for rare diseases:
is a challenging process, and each company has orphan drugs. Health Canada website. https://
www.canada.ca/en/health-canada/services/licences-
2
its own approach. To help determine the pop- authorizations-registrations-drug-health-products/
ulation prevalence, it is helpful to consult the
literature and visit rare disease discussion forums,
regulatory-approach-drugs-rare-diseases.html. Accessed
1 November 2019. 3
patient advocacy group websites and rare disease
databases. Note, each region has its own policy
regarding subdividing disease indications to
4
achieve orphan designation status.
5
References
1. National Organization for Rare Disorders. NORD 6
website. https://rarediseases.org. Accessed 1 November
2019.
2. World Rare Disease Day 2011. Rare Diseases Europe 7
website. https://www.eurordis.org/content/rare-disease-
day-2011-2. Accessed 1 November 2019.
3. Developing Products for Rare Diseases & Conditions.
FDA website. https://www.fda.gov/industry/
8
developing-products-rare-diseases-conditions. Accessed

4.
1 November 2019.
Orphan Drug Regulations, Final Rule, 78 Fed
9
Reg.35117,35120 (12 June 2013). Federal Register
website. https://www.govinfo.gov/content/pkg/
FR-2013-06-12/pdf/2013-13930.pdf. Accessed 1 10
November 2019.
5. Orphan drug definition. 21 CFR 316.3(b)(10).
Electronic CFR website. https://www.ecfr.gov/cgi-bin/ 11
text-idx?SID=f6e21752b8df8c99d3c5350b01ec1b2c&
mc=true&node=se21.5.316_13&rgn=div8. Accessed 1
November 2019. 12
6. Op cit 3.
7.
8.
Ibid.
Meetings with the Office of Orphan Products Development:
13
Guidance for Industry, Researchers, Patient Groups, and
Food and Drug Administration Staff (9 July 2015). FDA
website. https://www.fda.gov/media/92815/download. 14
Accessed 1 November 2019.

15
9. Applying for orphan designation. EMA website.
https://www.ema.europa.eu/en/human-regulatory/
research-development/orphan-designation/applying-
orphan-designation. Accessed 1 November 2019.
10. Orphan designation: Overview. EMA website. https:// 16
www.ema.europa.eu/en/human-regulatory/overview/
orphan-designation-overview. Accessed 1 November
2019.
17
11. Op cit 9.

18

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 Chapter 10: Global Orphan Drug Regulations

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11 Pediatric Strategies

By Klaus Rose, MD, MS

1
2
3
4
5
Background
Pediatric laws are in place both in the US and the
EU. New findings and developments give this
6
area a high strategic importance in drug develop- The concept of children as “therapeutic orphans,” 2

ment and regulatory affairs. The term “pediatric and the call for separate PDD3 emerged as a
complex international movement after the US’
7
drug development”1 (PDD) blurs meanings of
the word “child.” Legally, humans are “children” regulatory response to the thalidomide catastro-
until they become adults; bodily, they become phe.4 It has not been a straightforward, logical, 8
planned movement, but has emerged and evolved
mature long before their 17th or 18th birthdays.
over decades as a complex interaction of advanc-
Drugs treat the body. Separate “pediatric” studies
requested or demanded by the US Food and
ing science, technology, production, medicine and 9
drug development. In short:
Drug Administration (FDA) and the Euro-
pean Medicines Agency (EMA) aim at separate
1. Preterm neonates treated with
antibiotics suffered unexpected toxicities
10
labels in minors; however, many of these studies
in the 1950s when they were treated
might be seen as driven too much by regulatory
formalism. Many studies withhold standard-of-
with antibiotics.5 11
2. Since 1962, FDA has approved
care treatment, compared to outdated treatment
drugs on the basis of clinical studies
schemes or even placebo, which is unethical
performed before submission,6 and 12
where effective treatment exists. Companies the agency oversees drug advertising.7
should try to avoid such separate pediatric stud-
ies and instead come to an agreement with the
To protect themselves against lawsuits
in the litigious US, companies added
13
authorities to include minor patients in pivotal pediatric warnings to drug labels.
regulatory efficacy studies. This also will help to
avoid potential US lawsuits. Another challenge
3. The chairman of the American 14
Academy of Pediatrics (AAP)
is that many regulatory studies in young patients committee on drugs claimed these
cannot recruit sufficiently and may take many warnings denied children the use 15
years to complete. Companies should consider of modern drugs and characterized
new ways to reach agreement with regulatory
authorities regarding requirements for these
children as “therapeutic orphans.”8 AAP
began demanding separate pediatric
16
studies. One option would be to ask involved studies9 and declared them a “moral
clinicians for help. With their support, Institu- imperative.”10 17
tional Review Boards (IRBs) and Ethics Com- 4. The term “off-label” emerged in 1988,
mittees (ECs) might ask critical questions, and describing the use of drugs outside of
revision of the respective studies might be easier the clinical description in the label.11 18
to achieve. FDA soon adopted this term.12

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 Chapter 11: Pediatric Strategies

5. The “pediatric population” was officially ment information is expected to permit quicker
and administratively created in 1979 recoveries from childhood illnesses, with fewer
when FDA defined children as less than attendant hospital stays, physician visits and
17 years of age.13 parental work days lost.”25 FDA developed clear,
6. The on-/off-label framework was imposed measurable, clinical expectations in 2001. How-
on the “pediatric” population.14-16 ever, a consequence of separate pediatric drug
7. The children-as-therapeutic-orphans approval was that drugs were officially regarded
concept became US law in 1997, as ineffective if efficacy was not proven separately
when FDA was authorized to reward in “children.” Life-saving drugs could be off-label
“pediatric” studies with additional one day before the 17th birthday and on-label the
exclusivity; since 2003, FDA has next day. This clearly makes no sense, and highly
been able to demand pediatric studies regarded pediatrician Harry C. Shirkey, MD,
without exclusivity.17 The Food and Drug noted that most physicians simply ignored the
Administration Safety and Innovation pediatric warnings, which were appropriate for
Act of 2012 (FDASIA) required earlier babies,26 but not for all “children,” now officially
pediatric study plan submission by drug defined as individuals less than 17 years old. The
manufacturers subject to the Pediatric semantic translation from vulnerable, immature
Research Equity Act (PREA) and gave preterm neonates to all administratively defined
FDA new authority to help ensure “children” blurs the meaning of the word “child.”
PREA requirements are addressed in a FDA and EMA’s administrative age limits confer
more timely fashion. an apparent but inappropriate physiological char-
8. Pediatric studies18 were conducted acteristic to the 17th or 18th birthday.27–30 It was
internationally. Initial FDA-required not a conspiracy, but a consequence of society’s
pediatric studies were being performed efforts to come to terms with the thalidomide
internationally.19 Since 2007, EMA disaster. Gradually, the desire to protect young
has demanded “pediatric investigation patients has turned into demands for separate
plans” (PIPs) as a requirement for drug pediatric studies that sometimes might be seen
approval, defining children as less than as exaggerated. Some pediatric studies mandated
18 years of age.20–23 While FDA cannot by regulatory authorities withhold standard-of-
mandate pediatric studies based on care treatment for young patients, in comparison
PREA until 2020, EMA has no such to outdated treatment schemes or even placebo.
restrictions. The EU also demands PIPs When no effective treatment exists for adults,
for rare diseases, vaccines and biologics. this might be acceptable. However, where efficacy
9. The EU approach influenced how the of treatment has been proven in adults, it is ques-
US approached PDD. Now, FDA tionable to insist on separate proof of efficacy
demands an “initial Pediatric Study in persons that legally are still children but are
Plan” (iPSP) no later than 60 days after already bodily mature.
the End-of-Phase-2 (EoP2) meeting Bodily, children and adults differ on three
for drugs without orphan designation. levels. 1) Newborns’ organs are immature
From 2020 on, the US Research to regarding absorption, distribution, metabolism
Accelerate Cures and Equity (RACE) for and excretion (ADME). To consider dosing
children act authorizes FDA also to based only on babies’ bodyweights is not enough.
apply PREA to anticancer drugs.24 ADME maturation must be taken into account.
Also, some drugs cause toxicities in newborns.
The original intention of pediatric laws was to 2) Young children cannot swallow tablets. Until
improve child healthcare: “Superior drug treat- roughly six years of age, children need special

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
oral formulations, e.g., liquids or fast-dissolving EMA-demanded pediatric studies are criticized
tablets, or other methods of administration, e.g., by academic medical science, including place- 2
intravenous or suppositories. 3) Children are bo-controlled clinical studies in minors with
smaller and weigh less than adults. After the first
months, specific newborn toxicities no longer
multiple sclerosis, allergic rhinitis or depres-
sion.37–39 The “moral imperative” for pediatric 3
occur. Dose optimization needs to be established studies, however, is still strong.40 Clinically, few
independently until the organs performing will deny that industry is continuously advancing 4
ADME are mature, which occurs well before drug treatment (see the recent separate pedi-
puberty.31 atric studies in clinical areas where FDA has
Children are not another species. They relented, including dermatology, neurology and 5
definitely are not small adults when they are oncology, and FDA’s approval of onasemnogene
born. The older they grow, the more the body abeparvovec-xioi (Zolgensma) for spinal mus-
matures. Biological basics are the same at all ages. cular atrophy).41 EMA’s contribution was a PIP 6
Children have one head, two eyes and one heart. for this truly pediatric drug.42 Overall societal
Babies with bacterial, viral or fungal infections
can and must be treated with anti-infectives in
assessments, imperatives and feelings, including
the belief that children need separate drug devel-
7
appropriate doses, keeping potential toxicities in opment, form slowly and are resistant to change.
mind. The term “extrapolation”” is appropriate They are highly demanding for those navigating 8
when used to draw conclusions from one species uncharted territories.
to another; however, it is definitely not appropri- In EMA and FDA discussions, the reg-
ate to extrapolate data from adults to adolescents: ulatory professional must remain tactful and 9
adults and adolescents are bodily mature humans diplomatic, even if the counterpart’s argument is
with different legal status. Even for younger
children, the term extrapolation is misleading;
questionable. Senior management must decide
the degree of confrontation in the discourse.
10
it overemphasizes the physiological differences Therefore, interactions with FDA and EMA that
from adults. include “pediatric” discussions provide excellent 11
In PDD, the regulatory professional’s training in diplomacy and tact.
responsibilities go beyond applying simple rules. Views of diseases are changing. Ten years
Multiple principles are involved, including those ago, FDA assumed pediatric malignancies were 12
of medical science, FDA, EMA and common fundamentally different from adult ones, with the
sense. It is a regulatory challenge, based on blur-
ring at the interface of medicine and law,32 but
exception of chronic myeloid leukemia (CML).43
Today, FDA recommends including adolescents
13
supported by large portions of academic medical with leukemia, melanoma and other malignancies
science. It could be described provocatively as in pivotal adult clinical trials.44 For an ointment 14
an intellectual aftermath of the thalidomide to treat atopic dermatitis, FDA accepted patients
disaster. It demands separate “pediatric” studies aged two to 78 years in pivotal studies without
in young people, parallel to adult development separate pediatric studies. In the past, depres- 15
studies, as if they were another species. Most of sion was thought not to exist in young patients;
these studies have limited medical value. PDD
originated in FDA and AAP’s collaboration and
however, this assumption has changed.45 Then
it was assumed that pediatric depression was
16
was augmented by bizarre EMA exaggerations fundamentally different; following 23 pediatric
that finally helped to unveil the underlying studies of antidepressants in the pediatric popu- 17
dogmatic regulatory tunnel-view logic.33–36 Such lation, FDA worked with clinical specialists and
exaggerations included the demand for studies concluded that antidepressants in young patients
in more pediatric melanoma patients than exist caused suicidality, and published a black box 18
worldwide. In several clinical areas, FDA and warning.46 This resulted in confusion and uncer-

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 Chapter 11: Pediatric Strategies

tainty among general practitioners, pediatricians the team’s internal thoughts vs. compromises to
and psychiatrists worldwide; it led to a decrease be made in negotiating with FDA and EMA.
in the vaguely defined suicidality, but the number The team should keep in mind at all times how
of suicides increased.47,48 These uncertainties still different meanings of the word “children” are
impact treatment of young patients with depres- blurred: physiological definition vs. persons that
sion.49 In studies of multiple sclerosis treatments, can legally be children but are physically mature.
FDA and EMA demand separate pediatric stud-
ies, often placebo-controlled,50 which have been Pediatric Challenges
strongly criticized by an international group of The most frequent challenges are:
clinical specialists.51 FDA is gradually retreating • safety issues preclinical testing might
from the children-are-therapeutic-orphans con- answer
cept in several clinical areas, but starting in 2020, • formulation issues: tablet vs. syrup,
the agency will demand pediatric cancer studies ointment vs. cream, particle size of
in indications different from those targeted by aerosols, etc.
the respective sponsor.52 • dosing in pre-pubertal children
EMA continues to insist on the require- • disease epidemiology per age group
ment for pediatric studies, even where FDA has • alternative treatments
relented.53–56
Against this dynamic background, it is cru- These questions are iterative; there will not be
cial for a company to understand the true clinical final answers at one time. Things change.
challenges of developing a compound for use in Some companies have a pediatric matrix
in young patients and FDA and EMA expecta- structure. Some employees may have previous
tions and demands in this area. The team should experience discussing pediatric study require-
know that all pediatric sub-disciplines emerged ments with FDA or EMA. Pediatric challenges
off-label decades before the term existed.57–61 are discussed in conferences, seminars, chat
PDD, with the exception of neonatology, is rooms and the literature. Different companies
mostly a regulatory, not a clinical challenge, have different philosophies. The lead can be an
despite PDD protagonists’ declarations.62 individual from regulatory, project management,
a contract research organization (CRO) or an
Step 1: Clinical and Common Sense
external consultant. But even if handling of pedi-
Position
atric aspects are outsourced, somebody within the
The preliminary position of a compound’s future company needs to provide oversight.
use in young patients should address:
Pediatric Expertise
• Does the targeted indication exist in
young patients, and, if so, in which age The development team’s knowledge may extend
groups? to skin, liver, kidney, cancer, eyes, joints, blood,
• Could the drug be used in another bones, infections or whatever organ or disease
indication in young patients? is targeted. Young patients are not considered
• How would the team develop a drug for a different species, but additional knowledge is
use in adult and younger populations needed to understand how to conduct internal
if “only” medical science and common preliminary assessments and later FDA and
sense are relevant? EMA discussions on pediatric drugs. A separate
pediatric advisory board usually will be unnec-
The development team needs to include inter- essary, but the team should establish a good
nal or external specialists. There will always be working relationship with one or several clinical

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
experts, who also can support the company in of pediatric master protocols is the artificial
FDA and EMA negotiations. Clinicians know definition of a pediatric population. As long as 2
the respective disease and its treatment. Team participation in such trials is voluntary, compa-
members can learn details that are not found
in medical textbooks by talking to patients or
nies can accept or reject participation.
Under the FDA Reauthorization Act of 2017
3
parents of an affected child. (FDARA), starting in 2020, applications for

Step 2: Regulatory Strategy

new drugs and biologics targeting cancer must 4
address a “molecularly targeted pediatric cancer
investigation” if FDA determines the compound
Knowing FDA and EMA pediatric require-
ments, past decisions and current trends in to be “substantially relevant.” FDA is working on 5
decision making are essential, as is searching a list of such molecular targets to help determine
FDA and EMA websites and clinicaltrials.gov when sponsors of certain cancer drugs must
conduct pediatric studies. FDA emphasizes it
6
for ongoing pediatric studies.
will handle requirements flexibly; nevertheless,
FDA pediatric studies will be mandatory. 7
There are two US laws on pediatric drug devel- EMA
opment: the Best Pharmaceuticals for Children Act
The EU Paediatric Regulation added a second
8
(BPCA) and PREA. BPCA studies are voluntary,
while PREA studies are mandatory. Both are part layer to the EU drug registration process. Before
of FDASIA. Biologics, vaccines and drugs with submitting a Marketing Authorisation Applica- 9
an orphan designation are exempt from PREA, tion (MAA), companies must submit a PIP. The
EMA Pediatric Committee (PDCO) evaluates
but starting in 2020, FDA will mandate pediatric
studies for oncology compounds. Further, com- PIPs, waivers and deferrals. A full waiver means 10
panies can offer voluntary pediatric development no pediatric development is required; a partial
in another indication. If FDA agrees, it issues a waiver exempts some age groups. A deferral 11
“Written Request” (WR). This WR is a contract means some measures, mostly clinical studies,
on required measures (pediatric formulation(s), will be performed after approval.65 The longest
juvenile animal studies, pediatric clinical stud- deferral was granted until 2031, 20 years after the 12
ies, modelling and simulation). A company that PIP decision.66
accepts the WR and fulfills its commitments
receives a six-month additional patent extension
Otherwise, the Paediatric Regulation did not
change the EU regulatory system. Once pivotal
13
(Pediatric Exclusivity, PE). trials are finalized, the company submits its
If PREA applies, the company must submit MAA, which is decided by the EMA Committee 14
an initial pediatric study plan (iPSP) to FDA for Human Medicinal Products (CHMP). Five
no later than 60 days after the End-of-Phase 2 CHMP members sit on PDCO, but the respon-
(EoP2) meeting.63 By the time of approval, the sibilities of these two committees are separate. 15
company should have a pediatric agreement.
PIP Essentials
FDA does not threaten nonapproval. FDA also
provides opportunities for early meetings to dis- PIPs are required for new drugs (including those
16
cuss pediatric drug development with sponsors. targeting pediatric diseases), vaccines, biologics
Currently, FDA recommends “pediatric and orphan designations. PIPs also are required 17
master protocols” for anticancer drugs.64 These for new indications or new pharmaceutical forms
protocols use an umbrella, basket or platform of approved drugs. EMA’s website has a list of
design that theoretically allows multiple stake- class waivers, i.e., diseases that officially do not 18
holders and sponsors to work together. The flaw exist in children. If a company develops a drug

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 Chapter 11: Pediatric Strategies

for one of these class waiver indications, it must (LoI), using the template on EMA’s website.
submit a written inquiry asking whether the class The LoI is not mentioned in the legislation but
waiver applies (a template is provided on the permits agency resource planning. In due course,
EMA website). Class waivers apply only to ther- EMA sends the names of three officers to the
apeutic drugs, not to diagnostics; for example, an applicant: the EMA pediatric coordinator, the
ultrasound contrast medium to detect coronary PDCO rapporteur and the PDCO peer reviewer.
artery disease (CAD) needs a PIP, while drugs The pediatric coordinator is the main point of
that treat CAD do not, as CAD is class-waived. contact. PIP submission deadlines are posted on
EMA wants pediatric labels in all pediatric age EMA’s website. The applicant must first submit
groups, from preterm newborns to adolescents. the PIP and additional documentation to the
EMA and PDCO do not automatically pediatric coordinator for review. If parts are
accept the company’s chosen indication. EMA insufficient, the reviewer will notify the applicant,
differentiates indication and condition to prevent with a usual deadline of two working days for
companies from focusing on adult diseases. For revision. Shorter deadlines may occur. Following
example, a company developing a compound for PIP validation, the pediatric coordinator informs
postmenopausal osteoporosis will have to justify
the applicant, who then submits the validated
its choice. Should the compound’s mechanism
PIP via the EMA eSubmission Gateway/eSub-
of action also allow its use in other osteoporosis
mission Web Client.69
types, e.g., steroid-induced osteoporosis, PDCO
will demand a PIP.67 PIP Negotiation
PIPs should be submitted after first-in-man
A presubmission meeting via teleconference is
clinical pharmacology trials (end of Phase 1),
possible between the applicant, pediatric coordi-
well before proof-of-concept. Gradually, the PIP
nator, rapporteur and peer reviewer. PDCO dis-
template has become shorter.68 The PIP must
cusses the PIP four times, at days 30, 60, 90 and
discuss the targeted disease’s epidemiology in
120 of the PIP procedure. After Day 60, there
adult and younger patients, mechanism of action,
usually is a three-month clock stop. The Day
natural course and existing therapies; a detailed
30 report is for information purposes only. The
characterization of the compound in develop-
Day 60 report requires a response. During the
ment; and an outline of all planned pediatric
clock stop, a “clarification meeting” is conducted
measures, including quality (pediatric formu-
lations); nonclinical (juvenile animal studies); via teleconference. Thereafter, modifications are
clinical trials; modelling and simulation; extrap- incorporated into the PIP and other documen-
olation; and more. Further, an application form, a tation. The Day 90 discussion shows whether
key elements form with planned studies’ details, PDCO might accept the PIP. For the Day 120
a cover letter, protocol discussion with any health meeting, the applicant has the right to an oral
authority and anything else of potential relevance explanation, the only opportunity to meet with
must be submitted. Most companies submit PDCO face-to-face.
PIPs between the end of Phase 1 and beginning PIP Modification
of Phase 3. For PIPs submitted after the end of
Phase 1, EMA requests a justification. In theory, PIPs can be modified upon applicant request.
it can issue penalties for late submission, but this The modification procedure is the same as the
has not happened to date. PIP procedure, but with only two PDCO dis-
cussions: Days 30 and 60. The PDCO decision
PIP Submission is either yes or no. EMA estimates three to five
Two months before the planned submission, modifications are required per PIP; the current
the applicant should submit a letter of intent record is 14 modifications.70

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
PIP Clinical Value on this planet for the many pediatric studies
PDCO is not involved in drug approval. This is
to which companies must commit to avoid 2
a negative PIP opinion, including diabetes;
done by the CHMP. The PIP aims at pediatric
labels for all age groups.
multiple sclerosis; juvenile idiopathic arthritis; 3
malignancies; rare kidney, heart, liver, eye and
Adolescents’ physical organs are mature. The
other organ diseases; congenital diseases; and
body does not change at the 18th birthday; only
the legal status changes. Many PIPs demand
rare endocrine disorders. Questionable pediatric 4
studies recruit worldwide.75–81
separate studies in 12- to 17-year-old patients;
medically, these lack sense. Today, many com- Other Regulatory Authorities 5
panies include adolescents and younger patients
Other regulatory authorities are aware of FDA
into pivotal regulatory studies. This is a good
and EMA pediatric requirements but have not 6
basis to argue against separate pediatric studies.
changed the drug approval process. They want to
EMA revoked the class waiver for conven-
tional melanoma in patients 12–17 years in 2008,
see pediatric documents at submission. Health 7
Canada and Japan’s Pharmaceuticals and Medical
referring to US statistics. However, only 10%
Devices Agency offer additional rewards. An
of juvenile melanoma patients need systemic initial focus on FDA and EMA requirements is 8
treatment. Most melanomas are excised without recommended. FDA and EMA exchange pedi-
affected lymph nodes or metastases, and after
the excision, the patients are healed and need no
atric information and have a monthly high-level
teleconference on pediatric issues.
9
further therapy.71–73 There now are 13 melanoma
PIP decisions on EMA’s website. Two pediatric Orphan Diseases, Rare Diseases and 10
melanoma monotherapy studies with ipilim- Rare Pediatric Diseases
umab or vemurafenib, respectively, were termi-
nated because physicians increasingly prescribed
Orphan designation was introduced in all major 11
regions, including the US, EU and Japan, to
combination treatment, and recruitment waned facilitate drug development for diseases that
(one also had been an FDA-required study). Five in the past were regarded by pharmaceutical 12
more pediatric studies demanding recruitment of companies as not offering sufficient potential
pediatric solid tumors, including melanoma, con-
tinue worldwide recruitment. After several years
profitability. Orphan drugs are defined slightly
differently in different countries or regions, as
13
of trying to recruit patients for unfeasible studies, are the regulatory procedures for these drugs.
companies can request a PIP modification and Regulatory agencies all offer a mix of administra- 14
may or may not be allowed to terminate the tive and scientific support, preferential protocol
assistance and priority review, aid for research
study. The terminated melanoma studies harmed
patients by omission, as they were exposed to
expenses, tax deductions, reduced application 15
fees and, if applicable, lesser re-examination
treatment that had become less than the stan-
dard-of-care.74
requirements. So far, orphan drugs are exempt
from pediatric requirements in the US, but not
16
The melanoma PIPs are not an exception. in the EU. Currently, FDA recommends master
Many PIPs request studies that will never
recruit enough patients. This can be due to a
protocols, and beginning in 2020, the agency will 17
require pediatric studies for anticancer drugs.
disease’s rarity, the many new drugs developed EMA facilitates orphan drug development, but
for adult diseases that occur rarely in young the sponsor carries the additional burden of the 18
patients, or both. There are not enough patients PIP procedure.

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 Chapter 11: Pediatric Strategies

FDA Rare Pediatric Disease Priority Review or more experts. Without such preparation,
Voucher Program the company risks expensive commitments and
might miss opportunities.
FDASIA included the Rare Pediatric Disease
Priority Review Voucher Incentive Program, Negotiating Only With EMA’s PDCO
which expanded the general priority review If a company deals only with EMA and PDCO,
voucher program, introduced earlier to facili- it should know PDCO is not involved in the
tate drug development for neglected tropical later approval procedure. In the best case, the
diseases and rare pediatric diseases. The pedi- PIP negotiation will result in a reasonable out-
atric voucher holder must notify FDA three come, although the negotiation may be lengthy.
months prior to using the voucher (one year In the worst case, EMA and PDCO may try
in advance for the neglected-disease voucher). to enforce as many pediatric trials and other
However, the pediatric voucher can be revoked measures as possible.
if the treatment is not marketed within a year.
Further, the company with the pediatric voucher Presubmission Meeting
must report to FDA about the treatment’s use A presubmission telephone discussion with
within five years of approval.82 the pediatric coordinator, rapporteur and peer
reviewer is now recommended by EMA and
Pediatric Strategy PDCO. It may appear as an opportunity. How-
First Considerations ever, PDCO representatives are busy and may
not be receptive to additional meetings. PDCO
The company and its team might face EMA only,
members’ opinions on presubmission meetings
or both FDA and EMA. FDA has the authority
may diverge. Substantial differences of opinion
to mandate pediatric trials only for medicines
will be documented in the Day 60 report and
used for the same indication as those used in
cannot be avoided by a presubmission meeting.
adults. Therefore, many companies will submit
No clear recommendation can be given here.
only a PIP. Nevertheless, early pediatric options
should be considered. A voluntary pediatric pro- Scenario 1: Reasonable Discussion With
gram can be negotiated with FDA for another EMA and PDCO
indication. If executed successfully, this program The company’s thoughts in the PIP reflect
results in a six-month pediatric exclusivity. Drugs current medical knowledge. The target disease is
for diseases existing only or predominantly in very rare in young patients. The company pro-
children are special challenges. FDA cannot poses inclusion of adolescents and older prepu-
mandate pediatric studies for orphan drugs until bertal children into the pivotal studies, proposes
2020. If the disease is relatively frequent, the a dose-finding study in an “opportunistic” setting
company will have to negotiate with both EMA for younger children83,84 and proposes a waiver for
and FDA on pediatric study requirements. babies and infants. The pediatric coordinator has
transformed the PIP into a reasonable internal
Drug Development, Pediatric Development
EMA document, PDCO rapporteur and peer
and Negotiations With EMA/FDA
reviewer comments make sense, and the Day 30
Initial Company Pediatric Thoughts and Day 60 reports reflect a convergent discus-
Well before EoP1, the regulatory professional sion. While the Day 30 report is for the sponsor’s
should have an idea about the compound’s information only, the company must respond to
future use in treating young patients. He or PDCO requests in the Day 60 report.
she should discuss initial thoughts on the use When PDCO requests have been read,
of the drug in pediatric populations with one processed and discussed, the applicant arranges a

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
clarification teleconference via the pediatric coor- and which are not. At the end, the applicant may
dinator. The applicant must produce a briefing agree in some areas and disagree in others. 2
document with questions and tentative answers, The applicant also must be aware that
a short presentation, a list of participants and a
toll-free phone number for the pediatric coordi-
at Day 120, PDCO can come up with new
ideas or can re-introduce an idea discussed but
3
nator and PDCO representatives. The external rejected earlier. If the team is physically pres-
expert(s) should participate at the meeting. A ent at the Day 120 meeting, it can discuss this 4
senior team member moderates the meeting and face-to-face with PDCO. If not, the team may
indicates who addresses what. A second senior receive a phone call from the pediatric coordi-
person should participate and step in if the dis- nator with a one-hour deadline to reply to new 5
cussion becomes unproductive. PDCO requests. The applicant can accept these
It takes three to six weeks to arrange the requests, withdraw the PIP or accept a negative
opinion. The applicant can request a re-exam-
6
clarification teleconference. In the scenario
ination with the same pediatric coordinator,
discussed here, requests in the Day 60 report
express misunderstandings and can be answered
different rapporteur and peer reviewer. If the 7
re-examination corrects the PIP opinion, the
during the teleconference, and both sides come
applicant has an acceptable PIP. If the re-ex-
to reasonable conclusions. At the beginning and
the end, the pediatric coordinator emphasizes
amination confirms the original PIP opinion, 8
the negative opinion remains, is published on
that the meeting’s purpose is not to achieve bind-
ing conclusions, that all participants express only
EMA’s website, and the company must either
submit a new PIP or abandon the compound.
9
their personal opinions, and that PDCO may
Scenario 3: Unfeasible EMA and PDCO
overturn conclusions.
In this scenario, the sponsor modifies the Requests 10
PIP, releases the clock stop by re-submission, The applicant is well prepared. The submitted
discusses final details after the Day 90 report and PIP reflects current medical literature. Because 11
submits final modifications. The pediatric coor- the disease is very rare in young patients, the
dinator sends a draft positive opinion in which applicant has proposed to include adolescents
the sponsor corrects a few typos. If there are no and older pre-adolescent children into the pivotal 12
strongly conflicting views, the applicant may studies and include a dose-finding study with an
decide not to ask for an oral explanation; at Day opportunistic framework in young patients.85,86
However, the pediatric coordinator claims that
13
120, the PIP is approved in a way the applicant
can accept. the targeted disease is very frequent in young

Scenario 2: Mixed EMA and PDCO

patients. The Day 60 report demands dou- 14
ble-blind, placebo-controlled clinical studies in
Feedback different pediatric age groups. Both rapporteur
This is probably the most frequent scenario. and peer reviewer support this. PDCO also 15
Some PDCO requests are based on misun- demands juvenile animal studies.
derstandings; others are based on exaggerated
assumptions about the disease’s frequency in
At the clarification teleconference, the
rapporteur is not present, but an alternate from
16
young patients, the lower age limit of young the same national authority is. This “new” rap-
patients with the disease, and the medical need porteur has limited understanding of the disease 17
or potential therapeutic benefit compared to and the PIP but supports the Day 60 demands.
other treatment options. In the clarification tele- The applicant can accept unfeasible pediat-
conference, the senior team representative must ric studies, juvenile animal studies and other 18
decide which PDCO requests are acceptable, studies the applicant considers to be question-

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 Chapter 11: Pediatric Strategies

able and potentially harmful to young patients but EMA and PDCO representatives remain
because of placebo or substandard treatment. If adamant, the applicant might consider yield-
the company’s policy is never to challenge EMA ing to their demands, and then prepare for the
and PDCO, the regulatory professional will studies, including writing the protocol, case
accept PDCO’s demands. For several years, the report forms, site selection, etc. When the study
applicant will try to recruit patients. With just is submitted to the responsible IRBs or ECs,
a few patients recruited, it returns and requests the applicant might explain its doubts about the
a PIP modification. EMA and PDCO might proposed study. The applicant might suggest that
allow more time for study recruitment or might the IRB or EC ask EMA or the PDCO chair-
find it necessary to terminate the demanded man to provide an explanation for how the study
studies. Even if the applicant has better argu- was mandated.
ments, EMA and PDCO will make the final After the Food and Drug Administration
decision. However, there are ways to balance Modernization Act (FDAMA) was enacted,
EMA and PDCO’s demands with institutions pharmaceutical companies had comparable
protecting patients. experiences with FDA. Written request (WR)
Suing EMA discussions could take years. At a certain point,
further discussions were not productive. Some-
Nycomed, the first company to sue EMA in the
times, companies accepted the WR, submitted
EU Court of Justice (ECJ), failed twice.87,88 In
the studies to the IRBs or ECs, and returned to
the first verdict, the judge ruled that Nycomed
FDA when the IRBs or ECs refused them.
could have accepted the PIP and, in parallel,
Some ECs read and consider carefully the
could have sued EMA.89 ECJ judges may not
proposed study documents. Others trust in offi-
be an ideal sounding board to challenge EMA
cial regulatory authority documents. Some might
assumptions; however, many peer-reviewed
not listen to a pharmaceutical company but
papers critically discuss PIPs.90–98 There also is a
will listen to a high-ranking academic clinician.
way to formally comply with EMA and PDCO,
When the applicant returns to the EMA and
while avoiding executing questionable studies.
PDCO with an overwhelming majority of IRBs
Oral Explanation or ECs rejecting the pediatric study and asks for
Every applicant has the right to request an a PIP modification, EMA and PDCO may think
oral explanation at the last PDCO discussion. twice before rejecting the request. EMA and
Although this is described as occurring at the PDCO will avoid open controversies with many
Day 120 meeting, it usually occurs at Day 118 or IRBs and ECs, which increases the chance for
119. The regulatory professional is asked to sub- a reasonable compromise. Such a strategy needs
mit a short presentation electronically and bring to consider first PIP negotiation, IRB and EC
60 printed copies. The applicant also must submit discussions and requesting one or several PIP
a list of participants. Good preparation is crucial. modifications, i.e., more than the relatively short
The applicant should bring its external experts one-year period for negotiating the first PIP.
to the meeting, as clinicians’ opinions carry more Should EMA and PDCO remain adamant,
weight. A good pre-meeting rehearsal is essen- litigation at the ECJ might be an option. Judges
tial: each applicant team member must know will listen to clinicians and other IRB and
what to say. The applicant needs one moderator EC members whose task is to protect patients
and a senior company officer to be available if the against unfeasible and unethical trials. That two
moderator requires assistance in the debate. pediatric melanoma studies had to be termi-
If the sponsor does not want to spend years nated (one was demanded by FDA, both by
trying to recruit patients into an unfeasible trial, EMA) cannot be denied.99,100

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
EMA Pediatric Scientific Advice pound in the EU. In theory, companies must dis-
EMA Pediatric Scientific Advice is provided free
cuss pediatric submissions first with EMA and 2
PDCO. Most companies submit the PIP con-
of charge. Although the advice is not binding,
the sponsor may present a reasonable argument
siderably later than EoP1. It is very important
to consider young patients early in development. 3
that PDCO might accept. On the other hand,
If the company plans to conduct pivotal trials
the risk of seeking Pediatric Scientific Advice
is that the recommendations—e.g., running
with young patients, this should be discussed 4
at one of the early FDA general meetings. This
a double-blind placebo-controlled safety and effi-
dialogue always takes place with the responsible
cacy clinical trial—cannot be ignored during the
ensuing development.
FDA reviewing division. If children are to be 5
considered in pivotal studies, the company might
Other EMA Committees and request participation of a representative from
Departments FDA’s Office of Pediatric Therapeutics (OPT). 6
There are several additional EMA committees Various FDA divisions have different working
with which the sponsor might interact, e.g., the relationships with OPT.
There is no standard for whom to approach
7
Committee on Advanced Therapies (CAT) or
the Small and Medium Enterprise (SME) office. first. In general, FDA can be assumed to be
If the sponsor is registered as an SME (infor- more reasonable. EMA and FDA are inde- 8
mation on EMA’s SME office and a list of all pendent, but they share information and have
limited inter-agency pediatric discussions in
EU-approved SMEs are on EMA’s website), the
office might assist with protocol writing, offer monthly teleconferences. 9
reduced fees and facilitate negotiations with var- There is no guarantee an agreement with
ious committees. Generally, any interaction with FDA also will be accepted by EMA. If a com-
pany thinks its compound might be granted fast
10
any other committee increases the chance the
applicant will find counterparts who might find track registration based on promising Phase 2
ways to influence PDCO positions, but there is data, the one-year PIP procedure might delay 11
no guarantee. registration, and the company should start the
PIP negotiation as soon as possible.
Negotiating With FDA 12
A sponsor must submit an iPSP to FDA at
Clinical Examples
no later than 60 days after the End-of-Phase
2 (EoP2) meeting.101 The template on FDA’s
Ivacaftor treats cystic fibrosis (CF) caused by
mutations that affects about 5% of CF patients.
13
website shows the fundamental differences In patients with the relevant mutations, ivacaftor
between EMA and FDA: the iPSP is shorter and considerably improves lung and other organ 14
allows an easier discussion of the key issues. For function. Both FDA and EMA approved it in
compounds falling under PREA, the sponsor is 2012, using the same clinical data. The initial
expected to submit a document describing where PIP was from 2008; since then, the PIP has 15
and how it thinks its compound should be devel- been modified 12 times.102 EMA and PDCO
oped in children. If proposals are based on good
medicine, science and ethics, reasonable feedback
aim at labels in persons younger than 18 years, as
though they were another species.
16
can be expected. Allergen-specific immunotherapy (SIT)

Negotiating With Both EMA and FDA

has been recognized as an effective therapy for 17
more than 100 years. Nevertheless, based on
There is no likely scenario in which a company new German legislation and the EU pediat-
would have to discuss pediatric plans only with ric legislation in force since 2007, EMA and 18
FDA, unless it decides not to market its com- PDCO collaborated with the German Paul-Eh-

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 Chapter 11: Pediatric Strategies

rlich-Institute to develop a “standard PIP” that press, in social media and eventually in politics.
demands separate pediatric placebo-controlled Industry tries to ease the pediatric workload on
efficacy studies that would, if executed, recruit an operational level. Large companies thus far
tens of thousands of patients with allergic rhini- have been able to afford additional expenses,
tis. Patients in the placebo group would be left but not all pharmaceutical companies are large,
untreated for five years, exposing them to the and even a large company can be bankrupted
risk of developing asthma.103 by punitive damages resulting from a lawsuit.
The EMA 10-year pediatric report claims to Questionable justifications for separate PDD
have made drugs used to treat rheumatic diseases, now are critically discussed in peer-reviewed
cardiovascular diseases, infectious diseases and publications.117–123 With stronger academic and
cancer available for children. However, many of public debates, the winds of change might gain
these drugs were available decades before EMA speed. A single US court or ECJ verdict could
and PDCO existed. By available, EMA means change the situation dramatically.
that a drug now has a label for patients younger Few drugs are used in children for com-
than 18 years.104 pletely different purposes than in adults, e.g.,
FDA- and EMA-requested or -demanded angiotensin-converting enzyme (ACE) inhibi-
studies are being performed worldwide.105–111 tion for the prevention of kidney deterioration
in Alport syndrome (AS). ACE inhibition
Potential US Lawsuits is standard therapy for hypertension, but not
Many FDA- and EMA-requested or -demanded for AS. However, there is evidence that ACE
studies require comparison to outdated treatment inhibition slows kidney deterioration, and many
or even placebo in diseases where effective treat- AS patients are treated with ACE inhibitors.
ment already exists. This might be interpreted To recruit young patients into a double-blind,
as harming patients by omission.112 US lawyers placebo-controlled study would be unethical and
might sue those that execute or sponsor such probably impossible. Parents want their chil-
studies. The medico-legal literature so far dis- dren to be treated. How can a regulatory agency
cusses only cases where something went wrong license an ACE inhibitor for AS in children?
in clinical research.113–116 The risk of being sued Even with convincing clinical data, how can they
for a study demanded by a regulatory authority be entered into the product information of drugs
is something completely new, but companies produced and marketed by disinterested generic
should be aware of this possibility. Accepting companies? FDA is working on this.
questionable studies may appear to be a simple Drug development to treat rare diseases is
business decision. However, it should be balanced occurring more frequently because the market
against the potential danger of lawsuits with high conditions have changed. It is no longer profitable
punitive damages. Companies should not accept to develop additional beta blockers, histamine
demands for separate pediatric efficacy studies receptor antagonists or proton pump inhibitors.
too easily. US, EU and Japanese orphan legislation provide
additional incentives. In the EU, EMA promotes
The Way Forward research in rare diseases, but the PIP obstacles
For FDA, EMA, US and EU lawmakers, clin- remain. Hopefully, this will be corrected.
ical academia and industry top management, Summary
several factors will come into play, including
feedback from academia, intellectual process- Today, companies must consider how new drugs
ing of PDD, pediatric study rejections by IRBs will be used in young patients. US and EU pedi-
and ECs, US lawsuits, discussion in the lay atric laws aim at pediatric labels, not improved

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
child healthcare. Without an agreed PIP, EU 6. Janssen WM. A Historical Perspective on Off-Label
drug approval is blocked. No miracle strategy
Medicine: From Regulation, Promotion, and the First
Amendment to the Next Frontiers. Food and Drug Law
2
exists to negotiate with FDA, EMA and other Institute, Levy MC (Editor). First Washington, D.C.,
USA Off-Label Communications (2008)
agencies. Companies must address each regula-
tory authority separately. 7. Donohue JA (2006) History of Drug Advertising: 3
The Evolving Roles of Consumers and Consumer
In PDD, the word “child” is used with two Protection. Milbank Q 84: 659–699.
meanings: legally, humans are children until they 8. Op cit 1. 4
become adults; bodily, they become mature long 9. AAP 1977, Committee on Drugs. Guidelines for
before their 17th or 18th birthdays. Drugs treat
5
the Ethical Conduct of Studies to Evaluate Drugs in
Pediatric Populations. Pediatrics 1977;60(1):91–101.
the body. Many separate pediatric studies may AAP website. http://pediatrics.aappublications.org/
appear to be acceptable, but companies should content/pediatrics/60/1/91.full.pdf. Accessed 13 June
try to avoid them as much as possible. Many 2019.
10. Op cit 5.
6
efficacy studies documented in www.clinicaltrials.
gov already include adults and minors, and FDA 11. Plate V. The Impact of Off-Label, Compassionate and

recently has relented considerably in accepting

Unlicensed Use on Health Care Laws in preselected
Countries. Rheinischen Friedrich-Wilhelms-
7
such studies. Universität Bonn website. http://hss.ulb.uni-bonn.

8
de/2009/1936/1936.pdf. Accessed 13 June 2019.
Where regulatory pediatric studies recruit
12. Rose K. The Challenges of Pediatric Drug
very slowly, if at all, and drag along for years, Development. Curr Ther Res Clin Exp. 2019.
companies might consider new ways to re-dis- Elsevier website. https://doi.org/10.1016/j.
cuss these studies. This could include asking curtheres.2019.01.007. Accessed 13 June 2019. 9
13. Hirschfeld S. History of Pediatric Labeling. Slide Serve
involved clinicians for help and requesting IRB
website. https://www.slideserve.com/marlin/history-of-
and EC feedback. This might facilitate changes
to the demands by regulatory authorities for
pediatric-labeling. Accessed 13 June 2019. 10
14. Rose K, Grant-Kels JM. The Meanings of “Pediatric
pediatric studies. Drug Development” A Review. Therapeutic Innovation
and Regulatory Science 2018.
15. Rose K, Neubauer D, Grant-Kels JM. Rational Use of
11
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65. Policy on the determination of the condition(s) for a 81. Rose K, Grant-Kels JM. Questionable Industry-
Paediatric Investigation Plan/Waiver (Scope of the
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87. Order of the President of the Court of First Instance
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europa.eu/juris/document/document.jsf ?text=&docid
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88. EU Court of Justice 2011: Judgment of the General
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website. http://curia.europa.eu/juris/document/
document.jsf ?text=&docid=116583&pageIndex=
12
curtheres.2019.01.003. Accessed 13 June 2019.
0&doclang=en&mode=lst&dir=&occ=first&part
74. Op cit 16.
75. Op cit 12.
=1&cid=291990. Accessed 13 June 2019.
89. Op cit 87.
13
76. Op cit 14. 90. Op cit 12.
77. Op cit 15. 91. Op cit 14. 14
78. Op cit 16. 92. Op cit 15.
79. Rose K, Neubauer D, Grant-Kels JM. Questionable
Industry-Sponsored Studies in children and
93. Op cit 16. 15
adolescents in Slovenia. Curr Ther Res Clin Exp. 2019. 94. Op cit 72.

16
ScienceDirect website. https://doi.org/10.1016/j.
95. Op cit 73.
curtheres.2019.01.002. Accessed 13 June 2019.
96. Op cit 79.
80. Rose K, Grant-Kels JM. Questionable International

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Pediatric Studies in the United States and Russia 97. Op cit 80.
Triggered by Regulatory Authorities. Asian Journal
98. Op cit 81.
of Research in Medical and Pharmaceutical Sciences
2018,3(3). Journal Repository website. http:// 99. Op cit 15.
www.journalrepository.org/media/journals/
AJRIMPS_63/2018/Apr/Rose332018AJRIMPS40776.
100. Op cit 16. 18
pdf. Accessed 13 June 2019. 101. Op cit 63.

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 Chapter 11: Pediatric Strategies

102. Ivacaftor PIP EMEA-000335-PIP01-08-M12. EMA

website. https://www.ema.europa.eu/en/documents/
pip-decision/p/0353/2018-ema-decision-22-november-
2018-acceptance-modification-agreed-paediatric-
investigation-plan_en.pdf. Accessed 13 June 2019.
103. Op cit 38.
104. 10-year Report to the European Commission. General
report on the experience acquired as a result of the
application of the Paediatric Regulation. European
Commission website. https://ec.europa.eu/health/sites/
health/files/files/paediatrics/2016_pc_report_2017/
ema_10_year_report_for_consultation.pdf. Accessed 13
June 2019.
105. Op cit 12.
106. Op cit 14.
107. Op cit 15.
108. Op cit 16.
109. Op cit 79.
110. Op cit 80.
111. Op cit 81.
112. Op cit 16.
113. Kessler DP. Evaluating the Medical Malpractice System
and Options for Reform. Journal of Economic Perspectives
2011; 25(2): 93–110.
114. Mastroianni AC. HIV, Women, And Access To Clinical
Trials: Tort Liability And Lessons From DES. Duke
J Gender Law & Policy 1998;5: 167–191. Semantic
Scholar website. https://pdfs.semanticscholar.org/
b935/fa55f13f99a89b4774790219e9202869338d.pdf.
Accessed 13 June 2019.
115. Wood AJ, Darbyshire J. Injury to research volunteers—
the CR nightmare. NEJM 2006.
116. Larkin M. Defining Compensable Injury in Biomedical
Research. 5 Health Matrix 309 (2015). Case Western
Reserve University School of Law website. https://
scholarlycommons.law.case.edu/healthmatrix/vol25/
iss1/12/. Accessed 13 June 2019.
117. Op cit 12.
118. Op cit 14.
119. Op cit 15.
120. Op cit 16.
121. Op cit 79.
122. Op cit 80.
123. Op cit 81.

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12 So Your Drug has a Friend?
Companion Diagnostic
Codevelopment Strategies
By Catherine Lofton-Day, Dave Kern and Mya Thomae
1
2
3
4
5
Introduction - The Evolving Role of
Companion Diagnostics
ing personalized therapeutics and associated
diagnostics’ scientific progress and addressing 6
the challenges in co-developing a drug candi-
In the era of personalized medicine,1 a valuable
tool to identify the therapy most beneficial to
date and its corresponding in vitro diagnostic 7
(IVD) device companion. The report highlights
a patient is the in vitro companion diagnos- the difficulty of coordinating these two distinct
tic (CoDx) test. CoDx test results are used to development processes so they converge in the 8
predict whether a patient will have a positive form of a clinical trial to validate the CoDx test’s
outcome with a particular therapy and, therefore, effectiveness in selecting patients and, in turn, the
can impact healthcare decisions significantly for therapeutic’s efficacy based on patients selected 9
that patient. Patient CoDx testing can determine for treatment.
the need to adjust treatment parameters or limit
treatment with a therapeutic to the population
In a guidance published in 2014, FDA
defines an IVD companion diagnostic device as:5
10
known to benefit. The first CoDx tests developed “an in vitro diagnostic device that provides
in conjunction with therapeutics were included information that is essential for the safe and 11
in drug labels in the late 1990s; only a few years effective use of a corresponding therapeu-
later, new concepts in these tests’ scope and tic product. The use of an IVD companion
implementation are emerging rapidly. diagnostic device with a therapeutic product 12
These changes in scope are being driven by is stipulated in the instructions for use in
the evolving worldwide medical and payer com-
munity and regulatory agency views. The stan-
the labeling of both the diagnostic device
and the corresponding therapeutic product,
13
dard paradigm for CoDx use was to develop a including the labeling of any generic equiva-
diagnostic test for each drug. Many of these tests lents of the therapeutic product.” 14
identified genetic markers specific to a patient
subgroup. With the advent of less-expensive, FDA followed up on this commitment to
high-throughput genetic and other testing meth- improve the coordination of CoDx and thera- 15
ods, CoDx panels for multiple-therapy patient peutic development by launching its Oncology
stratification have recently been developed and
approved.2 Another strategy gaining momentum
Center of Excellence (OCE). OCE expedites
oncology product drug and test development by
16
is using individual genetic profiles archived for integrating multiple FDA offices, having a single
future medical decisions.3 FDA contact working with each sponsor.6 17
In October 2013, FDA published Paving the The new EU In Vitro Device Regulation (EU
Way for Personalized Medicine—FDA’s Role in a IVDR), Regulation (EU) 2017/746 of the Euro-
New Era of Medical Product Development.4 This pean Parliament and of the Council of 5 April 18
report describes FDA’s commitment to support- 2017 on in vitro diagnostic medical devices, has

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 Chapter 12: So Your Drug has a Friend? Companion Diagnostic Codevelopment Strategies

been finalized and repeals Directive 98/79/EC cine. A record 16 personalized therapies were
and the EU Commission Decision 2010/227/ approved in 2017 alone.9
EU.7 The EU IVDR clarifies in vitro diagnostic Several new FDA draft and final guidance
devices’ scope of coverage to include CoDx tests: documents assist sponsors developing CoDx
“Companion diagnostics are essential for tests, including new communications on medical
defining patients’ eligibility for specific device clinical investigation design, investiga-
treatment with a medicinal product through tional device exemptions (IDE) for early- and
the quantitative or qualitative determination late-phase studies10 and the development of in
of specific markers identifying subjects at a vitro companion diagnostic tests, among others.
higher risk of developing an adverse reac- The European Medicines Agency (EMA) and
tion to the medicinal product in question the International Council on Harmonisation
or identifying patients in the population for (ICH) have published several reflection papers
whom the therapeutic product has been ade-
and guidelines on similar topics. The following
quately studied, and found safe and effective.
sections provide information regarding these
Such biomarker or biomarkers can be pres-
tools and how they relate to ongoing CoDx
ent in healthy subjects and/or in patients.
development changes. A list of relevant docu-
Devices that are used with a view
ments also can be found in Table 12-1.
to monitoring treatment with a medic-
inal product in order to ensure that the Regulations Controlling the Use of
concentration of relevant substances in
CoDx Tests in Clinical Trials
the human body is within the thera-
peutic window are not considered to be Companion diagnostics and personalized
companion diagnostics.” medicine have changed clinical trial design and
conduct. Biomarker assays increasingly are used
CoDx tests typically work by identifying the in early potential drug candidate development,
biomarker’s presence, absence or amount asso- not only to monitor the drug’s pharmacodynam-
ciated with a therapy’s response, or assessing ics but also to identify patient subsets that may
physiological or anatomical patient characteris-
respond differently to the therapy. Due to the
tics that might affect response. These tests can
increased patient risks associated with investiga-
potentially add value to the drug development
tional assay utilization in clinical trials, certain
process by identifying patients most likely to
criteria must be met.
respond to a specific therapy, thereby improving
In the US, using an assay to select a patient’s
treatment outcomes. If a CoDx can identify
treatment may be considered significant risk
patients who respond negatively to a therapy,
(SR) in certain situations, requiring an IDE
this can be factored into selecting those patients’
treatment regimens. In drug development, to be filed.11 When CoDx policies were being
using a biomarker to select and stratify patients formulated, FDA determined an IDE would be
can improve a clinical trial’s potential success. necessary if an assay were used to select clinical
Selecting patients with the biomarker who are study participants. More recently, however, FDA’s
more likely to respond may increase the number Center for Devices and Radiological Health
of positive outcomes and reduce study cost by (CDRH) has begun to take a more flexible view
requiring fewer patients. A 2014 publication by when assay use is considered SR, requiring an
Olsen and Jorgensen8 indicates these “bio- IDE, and when a device’s use may be considered
marker-guided” therapies have a success rate of nonsignificant risk (NSR). CDRH now utilizes
62%. Between 2014–17, one in every four drugs four questions to help make a CoDx assay SR/
approved by FDA was a personalized medi- NSR decision:

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
1. Will the investigational test results’ use expanding later to a larger cohort with FDA
lead to some trial subjects foregoing agreement. Alternatively, FDA may grant a 2
or delaying a treatment known to be staged approval with conditions, which limits

2.
effective?
Will the investigational test results’
the subjects enrolled while the sponsor addresses
identified issues. These options ensure appropri- 3
use expose trial subjects to safety risks ate human subject protection while preventing
(e.g., adverse events from the exper- clinical investigation delay. Additionally, studies 4
imental therapy) that (in some “net” investigating these candidate diagnostics’ use
sense) exceed the risks encountered with for a candidate therapy must follow regulations
control therapies or a non-trial standard pertaining to investigational new drugs (INDs). 5
of care? FDA’s 2019 Guidance for Industry: Enrich-
3. Based on a priori information about the ment Strategies for Clinical Trials to Support
investigational therapy, would incorrect Approval of Human Drugs and Biological Prod- 6
test results be likely to degrade subjects’ ucts14 outlines predictive biomarker use to

4.
treatment safety or efficacy?
Does specimen acquisition for investi-
select clinical trial subjects to study a candi-
date therapeutic’s safety and effectiveness. This
7
gational testing outside the standard of guidance describes general enrichment strategies
care require an invasive sampling proce- to decrease heterogeneity and, in section V, 8
dure that presents significant risk? describes selecting patients using a diagnostic
test to predict the likelihood they will respond
Additional detail regarding determining device to the therapy. Using a biomarker to identify 9
risk and the need for an IDE is provided in a responder population can improve both the
FDA’s Investigational IVDs Used in Clinical
Investigations of Therapeutic Products: Draft Guid-
chances for trial success and patient benefit.
Statistically, using an enriched population can
10
ance for Industry, Food and Drug Administration reduce the sample size needed to reach signifi-
Staff, Sponsors, and Institutional Review Boards cance compared to an unselected group.15 11
(December 2017).12 As pointed out in FDA’s enrichment strat-
If an IDE is required, strategies outlined in egy guidance, the ability to identify a biomarker’s
FDA Decisions for Investigational Device Exemp- predictive nature early in the therapeutic’s devel- 12
tion (IDE) Clinical Investigations: Guidance opment is not always straightforward. Often,
for Sponsors, Clinical Investigators, Institutional
Review Boards, and Food and Drug Administration
the relationship to drug response is identified
retrospectively, and additional trials must be
13
Staff13 (August 2014) are relevant to a candidate conducted to confirm results. Careful planning
CoDx trial. This guidance describes several dif- during candidate drug development is necessary 14
ferent clinical study subject enrollment mech- to ensure banked specimens are retained for
anisms after submitting an IDE application. study subjects with informed consents that allow
Following a 30-day review, the IDE application further potential diagnostic biomarker testing. 15
may be approved without conditions, approved A pivotal trial in the final codevelopment
with conditions or disapproved. Approval with
conditions allows the sponsor to correct issues
stage is needed to provide evidence the combined
use of the drug and its companion diagnostic
16
within 45 days but does not delay subject enroll- results in improved patient outcome, and the
ment so long as other requirements are met, such diagnostic device is safe and effective for its 17
as IRB approval. This guidance also includes intended use. FDA provided useful guidance on
the option of staged approval. The sponsor may these critical clinical studies in Design Con-
initiate staged approval to limit enrollment to siderations for Pivotal Clinical Investigations for 18
a patient subset, e.g., an initial feasibility trial, Medical Devices—Guidance for Industry, Clinical

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 Chapter 12: So Your Drug has a Friend? Companion Diagnostic Codevelopment Strategies

Investigators, Institutional Review Boards and Administration Staff ( July 2016).19,20 The first
Food and Drug Administration Staff.16 Although guidance explains potential CoDx development
this guidance pertains to medical devices in gen- regulatory pathways and strategies to coordinate
eral, the advice also is applicable to companion premarketing submissions for both the drug and
diagnostic studies. An important concept in this device. Central to these strategies is the CoDx
document is the need for a device benefit-risk test’s availability at the time the new therapeutic
assessment. Because a companion diagnos- is approved. If the CoDx is shown to be essen-
tic’s purpose is to allow treatment decisions to tial to the drug’s safe and effective use, another
improve patient outcomes, a positive benefit-risk important requirement is including information
ratio should be achievable. This is possible if the regarding the test’s need in the drug or biologic’s
diagnostic is demonstrated to meet the perfor- label. Drug labeling must specify the use of an
mance requirements to select patients accurately FDA-cleared or -approved CoDx for the drug or
and the drug has the expected treatment effect drug class. Similarly, the CoDx test’s labeling will
for those patients. specify the drug or drug class for which it has
FDA also has provided guidance relating been approved or cleared. The second guidance
to clinical trial data collected outside the US is a step-by-step manual to aid drug and IVD
to support medical device applications, includ- sponsors in the codevelopment process. This
ing IDEs, 510ks and PMAs. All clinical trials document includes information on specific risk
must be conducted in accordance with Good assessment and IDE requirements for CoDx
Clinical Practice (GCP), as outlined in Accep- investigational studies, expectations for IVD
tance of Clinical Data to Support Medical Device analytical validation prior to drug clinical studies,
Applications and Submissions Frequently Asked considerations for both early and late therapeutic
Questions: Guidance for Industry and FDA Staff product development, clinical trial design includ-
(21 February 2018).17 ing potential bridging studies and coordination
EMA has published a draft reflection paper of drug and device submissions.
outlining principles for obtaining sufficient EMA’s Reflection paper on co-development
evidence for prognostic or predictive genomic of pharmacogenomic biomarkers and assays in the
biomarkers intended for patient selection.18 context of drug development21 provides a helpful
This paper also provides advice on experimental overview of important biomarker assay selec-
design, ranging from exploring a biomarker’s fea- tion steps and drug and CoDx codevelopment.
sibility for its proposed intended use to prospec- EMA also provides scientific advice on novel
tive (or retrospective) clinical trials to confirm drug research and development methodologies
clinical utility. The EMA document includes through its Committee for Medicinal Products
many of the same trial design concepts outlined for Human Use (CHMP). These novel method-
in the above FDA guidance. ologies include biomarkers intended to deter-
mine therapeutic response, therapy selection,
Other Considerations Related to CoDx dose selection, etc., i.e., companion diagnostics.
Marketing Authorization CHMP can issue opinions on either a method’s
acceptability or protocol and method advice.
The two most relevant US CoDx test guidances EMA’s Qualification of novel methodologies for
are: In Vitro Companion Diagnostic Devices: drug development: guidance to applicants22 includes
Guidance for Industry and Food and Drug Admin- a draft format for requests to CHMP.
istration Staff (6 August 2014); and Principles Efforts also are underway to improve sub-
for Codevelopment of an In Vitro Companion mission consistency across multiple countries.
Diagnostic Device with a Therapeutic Product: ICH has developed a guideline that describes
Draft Guidance for Industry and Food and Drug regulatory submissions’ context, structure and

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
format for genomic biomarker qualifications to applied to CoDx devices tied to drugs on an
support biomarker use during drug develop- accelerated approval pathway, if early discussions 2
ment. ICH Guideline E1623 on genomic biomark- are held with the agency about the breakthrough
ers related to drug response: context, structure and
format of qualification submissions is intended
device program. The guidance suggests device
manufacturers submit a data development plan to
3
to improve regulatory communications’ consis- FDA and formally request breakthrough status.
tency involving biomarkers. It offers guidance If granted, the Premarket Approval (PMA) 4
for submitting biomarker data in the Common process would be shortened by moving some
Technical Document (CTD) format required by studies to postmarket status and/or postpon-
FDA, EMA and the Japanese Pharmaceuticals ing the preapproval inspection requirement to 5
and Medical Devices Agency (PMDA). Since postapproval. Related to this program, FDA has
this guidance covers biomarker use throughout
the drug development process from early- to
issued draft guidance on making benefit-risk
determinations for certain medical devices.27 The 6
late-phase, it provides general guidelines on draft guidance discusses the factors the agency
how submission content should be tailored,
whether the sponsor is seeking advice from the
will consider during the review process for a 7
breakthrough device, including the potential to
appropriate regulatory authority or the data are move certain studies to postmarket, based on the
intended to support biomarker qualification. device’s benefit-risk profile. 8
EU, US and Japanese regulatory agencies have
recommended adoption of ICH E16. As a Region-Specific Regulatory Highlights
result, FDA has provided a guidance document US
9
under the same name.24
FDA’s Center for Drug Evaluation and
Research (CDER) and Center for Biologics
The medical community’s rapid adoption of
multimarker next genome sequencing (NGS)
10
Evaluation and Research (CBER) introduced panels and the subsequent approval of several
Guidance for Industry: Expedited programs for seri- CoDx tumor mutation tests applicable to mul- 11
ous conditions—drugs and biologics (May 2014),25 tiple therapies have resulted in FDA modifying
which describes several ongoing programs to its approach to accommodate these types of
increase breakthrough therapeutics’ availability. tests. FDA has recently developed a three- 12
These programs include therapeutics’ fast track tier structure for patient result reporting and
or breakthrough therapy designations, acceler-
ated approval and priority review designation
medical decision making using these panels.28
The highest level of regulatory scrutiny applies
13
for products targeting an unmet medical need or to test markers used for guiding therapeutic use
treating a serious or life-threatening condition. (CoDx tests). To aid manufacturers of multi- 14
With no similar medical device program, drugs marker NGS panels detecting germline muta-
requiring an IVD CoDx for patient selection tions, the agency has published Considerations
could not be implemented under these programs. for Design, Development, and Analytical Valida- 15
To address CoDx development challenges linked tion of Next Generation Sequencing (NGS)-Based
to a therapeutic on an accelerated approval
timeline and to allow accelerated approval of
In Vitro Diagnostics (IVDs) Intended to Aid in the
Diagnosis of Suspected Germline Diseases: Guid-
16
other medical devices, CDRH issued a final ance for Stakeholders and Food and Drug Admin-
guidance.26 This document addresses the key istration Staff (13 April 2018).29 The published 17
issues the agency considers necessary for granting summaries of safety and effectiveness (SSED)
a breakthrough device pathway. “Breakthrough” for approved multi-gene panels for somatic gene
devices with clinically meaningful advantages mutations are helpful examples to plan these 18
over other devices could qualify. This could be tests’ analytical validation.30–32

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 Chapter 12: So Your Drug has a Friend? Companion Diagnostic Codevelopment Strategies

Using the example of tests detecting EMA by the device manufacturer’s notified body.
epidermal growth factor receptor (EGFR) More-extensive clinical evidence also is required
mutations to determine non-small-cell lung prior to applying a CE Mark. There is a five-year
carcinoma (NSCLC) patient treatment eligi- transition period prior to full enforcement of the
bility, FDA has provided guidance for develop- EU IVDR in 2022.
ment and labeling of CoDx tests applicable to The IVD regulations establish CoDx bio-
multiple therapeutic products for treatment of markers as higher-risk products (Class C) under
a specific condition.33 This approach is expected increased regulatory scrutiny. Therefore, notified
to provide healthcare providers more flexibility bodies now will be responsible for regulatory
and reduce the need for multiple tests when oversight of the companion diagnostic device
deciding therapeutic options. Depending on and will consult with EMA and/or competent
the CoDx test type, attention must be paid to authorities during the development process,
potential differences in cut-offs and other fea- thereby adding complexity and time to the CoDx
tures when considering broader labeling. approval process.
FDA is in the process of incorporating the One final consideration in the EU is the
International Organization for Standardization application of General Data Protection Regulation
(ISO) standard, Medical devices—Quality man- (GDPR) to clinical trials.37 Device manufacturers
agement systems—Requirements for regulatory and their pharma partners must keep two key
purposes (ISO 13485:2016)34 and the Medical GDPR elements in mind when planning clini-
Device Single Audit Program (MDSAP)35 into cal studies. First, under GDPR, patient consent
its inspection process, with implementation tar- forms must be written in intelligible language and
geted for the end of 2019. Although the imple- require the subject to give consent by affirmative
mentation details still are being finalized, FDA is action. The second consideration is the GDPR’s
working with organizations like the Association ‘right to erasure’ language, which allows subjects
for the Advancement of Medical Instrumenta- in commercially sponsored trials to have their data
tion (AAMI) and industry to produce technical removed from clinical studies at a future date. This
information reports and other guidance on how latter requirement can have a significant impact
it will merge CFR 820 and ISO 13485 into a on trial design and needs to be considered when
single audit program. developing statistical analysis plans.

EU China

Drug and medical device regulations are being The National Medical Products Administration
harmonized worldwide, and many countries (NMPA), the Chinese agency for regulating
have made or are implementing changes in their drugs and medical devices (formerly the China
requirements for companion diagnostic and asso- Food and Drug Administration or CFDA),
ciated trials to show clinical effectiveness. In the is currently restructuring its regulations to
EU, the In Vitro Device Directive (IVDD), which encourage innovation in medical device and
served as a guideline implemented by local law in drug development. In January 2018, the agency
the various Member States, was replaced in May published announcement no. 13 to provide guid-
2017 by the EU In Vitro Diagnostics Regulation ance on using data from medical device clinical
(EU IVDR).36 This new regulation provides trials conducted outside China.38 Since Chinese
consistency in implementing a regulated CoDx regulations make it very difficult to ship speci-
approval process not included in the IVDD. The mens outside the country, complicating clinical
EU IVDR includes a specified process for CoDx trial sample assay performance determination at
conformity assessment and interactions with centralized testing sites, these updated rules may

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
help facilitate CoDx test approval in China. The User needs and market requirements must be
regulatory environment is continuing to evolve understood thoroughly for this process to work 2
rapidly in China and may continue to create effectively. Therefore, the first step in the process
an uncertain pathway for device manufacturers,
leading to delays in the registration process.
is constructing a product concept document. Key
considerations in CoDx design include:
3
Japan Product Concept
4
A successful in vitro diagnostic device submission • regulatory and clinical strategy
in Japan requires foreign manufacturers to ensure
several critical points are met. The Japanese Min-
○

○
target market
target population and demograph-
5
istry of Health requires all foreign manufacturers ics
to engage Japanese companies to act as their ○ product support 6
Marketing Authorization Holders (MAHs). ○ reimbursement strategy
Therefore, foreign firms typically do not market predicate devices or reference
7
○

their products directly. Further, the ministry methods

requires a considerable amount of clinical testing • target population
in the Japanese population. There also is an addi-
tional set of regulatory requirements for approval,
○

○
prevalence
sample type
8
some of which are not well-aligned with US or • stakeholders
EU regulations and can lead to longer approval ○ patients 9
cycles for IVD products imported into Japan. ○ laboratories
physicians
10
○

Australia ○ payers
• device description
Also recognizing the power of personalized
medicine, Australia has proposed changes to its
○

○
intended use or indications for use
sample type
11
medical device regulations to cover CoDx tests.
○ sample collection and handling
The proposal for regulation of CoDx tests and
the required amendments to existing regulations
○ instrumentation 12
○ software
are outlined in a consultation paper published in
reagents
13
○
October 2018.39 Many of the proposed changes
○ risk analysis
are modeled after US FDA regulations and the
recent IVD regulation changes in the EU.
Assay Development 14
Developing a CoDx Strategy for the
Company’s Clinical Development
Program
Once the market analysis is complete, and the
product concept is finalized, the product can
15
begin to move through the product development
The key to a successful companion diagnostic
strategy is understanding how IVD products are
process. Going from biomarker discovery to a 16
developed, verified and validated in the clinical companion diagnostic is not a trivial process.
setting. Central to this is understanding design One of the key steps is completing feasibility
studies, where two fundamental questions need
17
control principles, the iterative process by which
products are developed in a medical device com- to be answered:
pany. Design control, as the name implies, is the 1. Is the design technically feasible? 18
use of a controlled process to develop a device. 2. Is it operationally feasible?

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 Chapter 12: So Your Drug has a Friend? Companion Diagnostic Codevelopment Strategies

Feasibility studies typically focus on establish- Class II molecular diagnostic devices and Class
ing a basic level of performance: reproducibility, III devices, the manufacturer will have to com-
sensitivity and specificity. The goal is to create pare its assay results to a gold standard method
a prototype IVD device that can demonstrate (e.g., Sanger sequencing). For most CoDx tests,
proof of concept for the CoDx test’s technical this measure of accuracy can be linked to the
and clinical viability. clinical utility of the therapeutic under investiga-
Once the prototype assay’s performance has tion. For example, the test’s ability to predict the
been established, the transition from research clinical outcome accurately (e.g., responders vs.
assay to IVD product can begin. Most regula- non-responders) provides clinical utility data for
tory bodies require some form of design control, both the drug and device.
whether it is the US Quality System Regulations During the development process, key prod-
(21 CFR 820)40 or the ISO standard, Medical uct attributes are established and verified. This
devices—Quality management systems—Require- includes testing the sample collection and han-
ments for regulatory purposes (ISO 13485:2016),41 dling process, sample processing, target prepara-
used in Europe and many other parts of the tion and target stability. Understanding the vari-
world. From the moment the design moves into ability in sample collection methods that could
development, all work must be done in a con- be utilized for the assay, such as tumor biopsy or
trolled manner, properly documented, against resection and processing methods’ effects (e.g.,
a set of design input requirements. During this formalin fixation, paraffin embedding of tissue),
process, all design elements are tested to ensure is critical to the success of subsequent clinical
the inputs (requirements) match the outputs validation studies. For example, a Phase 3 drug
(specifications). In addition, all device-associated trial often can take years, meaning samples
risks are categorized for severity and probabil- collected will need to be stable over that period,
ity, and mitigation strategies are developed to since they may not be tested until the end of the
control them. For a CoDx, many of these risks trial. Device manufacturers need to be able to
are associated with the likelihood and severity of demonstrate to regulators that sample integrity
an incorrect result, which could negatively impact was maintained during that time and that the
patient care. results obtained accurately reflect the patient’s
Demonstrating an IVD assay’s performance clinical state at the time of collection.
characteristics is centered on two key attributes: Device manufacturers also will optimize the
precision and accuracy. For precision, FDA will assay itself, making sure reagent formulations,
expect to see studies that demonstrate the test’s incubation times and temperatures and target
repeatability (single site) and reproducibility input concentrations are all within stable ranges.
(multiple sites), particularly at the assay’s limit In addition, the manufacturing and quality
of detection. The test’s ability to distinguish control processes for the reagents and other assay
between positive and negative samples consis- components are subjected to similar development
tently—the clinical decision point—is a key studies. Instrument components and subsystems,
performance metric. For quantitative tests—or as well as software modules, also are put through
for qualitative tests with a quantitative under- optimization testing. These studies’ outputs feed
pinning—the agency will expect linearity studies directly into the draft specifications that the
as well. The test will be expected to give consis- project’s subsequent verification and validation
tent quantification of known samples across the will test.
assay’s linear range. It is worth noting some sponsors have
Accuracy can be a bigger challenge for announced the intention to utilize laboratory
traditional IVD assays, since the test needs to be developed tests (LDTs) as companion diagnos-
compared to some established “truth.” For many tics to be approved alongside the drug. When

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
LDTs are submitted to FDA for approval, even IVDs used in most early stage drug trials are not
if manufacturers are not producing a distributed considered SR by FDA, as the drug’s efficacy has 2
kit, they still are subject to the same quality sys- yet to be determined. Since the drug’s benefit has
tem requirements as any other device. This can be
a challenge for some reference laboratories that
yet to be demonstrated, the investigational IVD’s
risk is minimal, particularly since it is often used 3
have never worked in a design control environ- as a tool in secondary analysis for subsequent
ment. They will need to document their devel- patient group stratification. FDA has published 4
opment and production processes to a higher draft guidance43 on using investigational IVDs
standard than required for the Clinical Laboratory to help manufacturers determine when an IDE
Improvement Amendments (CLIA), College of needs to be filed. 5
American Pathologists (CAP) or ISO’s specifi- Another Pre-Sub process use is seeking
cations for quality systems management: Medical agency feedback on clinical studies that may
laboratories—Particular requirements for quality begin with an assay version different from the 6
and competence (ISO 15189). one ultimately filed with the agency. For example,
To streamline the process of determining
when an IDE is needed and to understand both
some drugs on an accelerated approval path-
way at CDER will start a Phase 2 trial with an
7
IDE and PMA approval requirements and the LDT or prototype assay, but the final test may
development process in general, device manu- be manufactured by a different device company 8
facturers often use FDA’s pre-submission pro- or use a different instrument or assay configu-
cess (Pre-Sub).42 This informal but highly infor- ration. In these cases, the manufacturer should
mative process is designed to start a dialogue on plan for and seek FDA guidance on designing 9
the device’s design and intended use between a bridging study. It may be possible to conduct
the agency and the manufacturer. Manufacturers
often use this process to familiarize the agency
a simple analytical study to show the two test
versions perform the same. In other cases, where
10
with devices and their clinical applications. In a test’s design or manufacture has been changed
addition to a description of the device and its significantly, a bridging study may be required 11
intended use, manufacturers sometimes provide in which all samples run with the test’s clinical
analytical and clinical validation protocols to trial version need to be re-tested with the final
gain agency feedback prior to executing studies. validated test. Therefore, it is important that drug 12
This is particularly true with novel devices companies collect enough samples at the outset
whose clinical utility has yet to be established.
For companion diagnostics, the Pre-Sub process
to ensure a full bridging study can be conducted
if required.
13
can help coordinate interactions among FDA’s Finally, one other important use of the Pre-
centers (CDER, CDRH, CBER). This is Sub process is to determine how the companion 14
particularly important for drugs that could be diagnostic should ultimately be labeled when it
granted accelerated approval, so device approval can be used to support the indicated uses of mul-
does not impact the drug timeline. Although tiple drug or biological oncology products. In the 15
the Pre-Sub process is nonbinding, the agency past, FDA has tied a companion diagnostic to a
often will provide valuable feedback to the
manufacturer that can significantly improve the
specific drug through the intended use statement.
Recently, FDA published draft guidance44 stating
16
regulatory filing process. companion diagnostics that can be used with
Most investigational IVDs used in support multiple therapies could be indicated for use with 17
of therapeutic clinical investigations will need an a therapeutic product class or group. One exam-
IDE, particularly in late-stage drug trials where ple cited in the draft guidance is the use of com-
using investigational IVDs will determine which panion diagnostics that test for EGFR mutations 18
subjects are treated. However, investigational (exon 19 deletions or exon 21 (L858R) substitu-

All rights reserved; file sharing prohibited. 141

 Chapter 12: So Your Drug has a Friend? Companion Diagnostic Codevelopment Strategies

tion mutations) in NSCLC. In many cases, the throughout the drug’s lifecycle. For payers, they
same EGFR companion diagnostic test could be represent potential treatment cost and resource
indicated for use in identifying NSCLC patients reductions, particularly when transitioning from
who are eligible for treatment with multiple tyro- a one drug/one Dx model to panel tests that can
sine kinase inhibitors approved by FDA. stratify patients for multiple drugs simultane-
ously. For healthcare providers, they increase the
Other Considerations ability to make more-informed, evidence-based
decisions. Most importantly, for patients, CoDx
CoDx tests may reduce overall healthcare costs
tests increase positive treatment outcome likeli-
by more rapidly identifying an effective treat-
hood while reducing serious adverse events and
ment for a patient, thereby reducing ineffective
unnecessary therapies.
treatment costs and avoiding adverse events.
With the use of tumor panels containing multi-
ple biomarkers gaining traction, e.g., mutations References
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scans to identify polymorphisms affecting disease medicine.” NEJM 2010; 363(4):301-4. NEJM
website. http://www.nejm.org/doi/full/10.1056/
susceptibility or prognosis, these improvements
NEJMp1006304. Accessed 3 September 2019.
in effectiveness are being realized. Genetic or
2. Allegretti, Matteo, et al. “Tearing down the walls: FDA
tumor panels can cover multiple variants across
approves next generation sequencing (NGS) assays
a number of genes shown to be informative for for actionable cancer genomic aberrations.” Journal of
medical decision making. As outlined in FDA’s Experimental & Clinical Cancer Research 2018; 37:47.
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for a drug in these panels along with FDA-ap- 3. Use of Public Human Genetic Variant Databases to
Support Clinical Validity for Genetic and Genomic-
proved CoDx markers could allow evaluation in
Based In Vitro Diagnostics: Guidance for Stakeholders
clinical testing scenarios where the markers are and FDA Staff (13 April 2018). FDA website.
unmasked for investigational studies. Upon new https://www.fda.gov/downloads/MedicalDevices/
marker clinical validation and approval, the diag- DeviceRegulationandGuidance/GuidanceDocuments/
nostic manufacturer could revise the reporting UCM509837.pdf. Accessed 3 September 2019.

software to include the new marker results in the 4. “Paving the Way for Personalized Medicine—FDA’s
test report. Further, FDA has provided guidance Role in a New Era of Medical Product Development”
(October 2013). FDA website. https://www.fdanews.
on using public genetic variant databases to
com/ext/resources/files/10/10-28-13-Personalized-
establish genetic tests’ clinical validity.45 Medicine.pdf. Accessed 3 September 2019.
Many unanswered questions still remain 5. In Vitro Companion Diagnostic Devices: Guidance
when considering multi-marker panels, particu- for Industry and Food and Drug Administration
larly validation using public databases, including Staff (6 August 2014). FDA website. http://
how results will be managed to maintain patient www.fda.gov/downloads/medicaldevices/
deviceregulationandguidance/guidancedocuments/
privacy and who will pay for these broader tests.
ucm262327.pdf. Accessed 3 September 2019.
These tools are currently in use and will become
6. Oncology Center of Excellence. FDA website.
more common in the near future.
https://www.fda.gov/AboutFDA/CentersOffices/
OfficeofMedicalProductsandTobacco/OCE/default.
Conclusions htm. Accessed 3 September 2019.

CoDx tests’ emergence is exerting a huge 7. Regulation (EU) 2017/746 of the European Parliament
and of the Council of 5 April 2017. EUR-Lex website.
healthcare impact from several perspectives. For https://eur-lex.europa.eu/legal-content/EN/TXT/?qid
drug manufacturers, these tests can provide value =1562021378624&uri=CELEX:32017R0746.
through development efficiencies and, potentially, Accessed 3 September 2019.

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
8. Olsen D, Jorgensen JT. “Companion diagnostics for 17. Acceptance of Clinical Data to Support Medical Device
targeted cancer drugs – clinical and regulatory aspects.”
Front Oncol. 2014 May 16;4:105. NLM website. http://
Applications and Submissions Frequently Asked Questions
- Guidance for Industry and FDA Staff (21 February
2
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9.
Accessed 3 September 2019.
The Personalized Medicine Report 2017. Personalized
information/search-fda-guidance-documents/
acceptance-clinical-data-support-medical-device- 3
applications-and-submissions-frequently-asked.
Medicine Coalition website. http://www. Accessed 3 September 2019.
personalizedmedicinecoalition.org/Userfiles/PMC-
Corporate/file/The-Personalized-Medicine-Report1. 18. Reflection paper on methodological issues associated with 4
pdf. Accessed 3 September 2019. pharmacogenomic biomarkers in relation to clinical
development and patient selection (9 June 2011). EMA
10. Investigational Device Exemptions (IDEs) for Early
Feasibility Medical Device Clinical Studies, Including
website. http://www.ema.europa.eu/docs/en_GB/
document_library/Scientific_guideline/2011/07/
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Certain First in Human (FIH) Studies: Guidance WC500108672.pdf. Accessed 3 September 2019.
for Industry and Food and Drug Administration
Staff (1 October 2013). FDA website. http://
www.fda.gov/downloads/medicaldevices/
19. Op cit 5.
6
20. Principles for Codevelopment of an In Vitro Companion
deviceregulationandguidance/guidancedocuments/ Diagnostic Device with a Therapeutic Product:
ucm279103.pdf. Accessed 3 September 2019. Draft Guidance for Industry and Food and Drug
Administration Staff ( July 2016). FDA website. https://
7
11. Code of Federal Regulations Title 21, Subchapter
www.fda.gov/regulatory-information/search-fda-
H—Medical Devices; Part 812 Investigational Device
guidance-documents/principles-codevelopment-vitro-
Exemptions. FDA website. http://www.accessdata.
fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.
companion-diagnostic-device-therapeutic-product.
Accessed 3 September 2019.
8
cfm?CFRPart=812. Accessed 3 September 2019.
21. Reflection paper on co-development of pharmacogenomic
12. Investigational IVDs Used in Clinical Investigations of
Therapeutic Products: Draft Guidance for Industry, Food
biomarkers and Assays in the context of drug development.
EMA website. http://www.ema.europa.eu/docs/en_GB/
9
and Drug Administration Staff, Sponsors and Institutional document_library/Scientific_guideline/2010/07/

10
Review Boards (December 2017). FDA website. https:// WC500094445.pdf. Accessed 3 September 2019.
www.fda.gov/media/109464/download. Accessed 3
September 2019. 22. Qualification of novel methodologies for drug development:
guidance to applicants (Revision 3: November 2014).

11
13. FDA Decisions for Investigational Device Exemption EMA website. http://www.ema.europa.eu/docs/
(IDE) Clinical Investigations: Guidance for Sponsors, en_GB/document_library/Regulatory_and_procedural_
Clinical Investigators, Institutional Review Boards, guideline/2009/10/WC500004201.pdf. Accessed 3
and Food and Drug Administration Staff (19 August September 2019.
2014). FDA website. http://www.fda.gov/downloads/
medicaldevices/deviceregulationandguidance/
23. ICH guideline E16 Genomic biomarkers related to drug 12
response: context, structure and format of qualification
guidancedocuments/ucm279107.pdf. Accessed 3
submissions (December 2010). EMA website. http://
September 2019.
14. Enrichment Strategies for Clinical Trials to Support
www.ema.europa.eu/docs/en_GB/document_library/
Scientific_guideline/2010/09/WC500097060.pdf.
13
Approval of Human Drugs and Biological Products: Accessed 3 September 2019.
Guidance for Industry (March 2019). FDA website.
https://www.fda.gov/media/121320/download.
24. Guidance for Industry: E16 Biomarkers Related to Drug
or Biotechnology Product Development: Context, Structure,
14
Accessed 3 September 2019. and Format of Qualification Submissions (August 2011).
15. Simon R, Maitournam. “Evaluating the efficiency of
targeted designs for randomized clinical trials.” Clin
FDA website. http://www.fda.gov/downloads/drugs/
guidancecomplianceregulatoryinformation/guidances/ 15
Cancer Res 2004; 10:6759-6763. AACR website. http:// ucm267449.pdf. Accessed 3 September 2019.
clincancerres.aacrjournals.org/content/10/20/6759.long.
16
25. Guidance for Industry: Expedited Programs for Serious
Accessed 3 September 2019. Conditions—Drugs and Biologics (May 2014). FDA
16. Design Considerations for Pivotal Clinical Investigations website. http://www.fda.gov/downloads/drugs/
for Medical Devices: Draft Guidance for Industry, Clinical guidancecomplianceregulatoryinformation/guidances/
Investigators, Institutional Review Boards and Food and
Drug Administration Staff (7 November 2013). FDA
ucm358301.pdf. Accessed 3 September 2019.
17
26. Breakthrough Devices Program: Guidance for Industry and
website. https://www.fda.gov/regulatory-information/ Food and Drug Administration Staff (December 2018).
search-fda-guidance-documents/design-considerations-
pivotal-clinical-investigations-medical-devices.
FDA website. https://www.fda.gov/regulatory-information
/search-fda-guidance-documents/breakthrough-devices-
18
Accessed 3 September 2019. program/. Accessed 3 September 2019.

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 Chapter 12: So Your Drug has a Friend? Companion Diagnostic Codevelopment Strategies

27. Consideration of Uncertainty in Making Benefit-Risk 37. General Data Protection Regulation (EU) 2016/679. EU
Determinations in Medical Device Premarket Approvals, website. https://gdpr-info.eu/. Accessed 3 September
De Novo Classifications, and Humanitarian Device 2019.
Exemptions: Draft Guidance for Industry and Food and
38. Guidelines for Acceptance of Overseas Clinical Trial Data.
Drug Administration Staff (September 2018). FDA JMedTech website. http://jmedtec.com/wp-content/
website. https://www.fda.gov/regulatory-information/ uploads/2018/01/Guidelines-for-Acceptance-
search-fda-guidance-documents/consideration- of-Overseas-Clinical-Trial-Data.pdf. Accessed 3
uncertainty-making-benefit-risk-determinations- September 2019.
medical-device-premarket-approvals-de/. Accessed 3
September 2019. 39. Proposal for the regulation of IVD companion
diagnostics (October 2018). TGA website. https://www.
28. FDA Fact Sheet. CDRH’s Approach to Tumor Profiling tga.gov.au/sites/default/files/consultation-proposal-
Next Generation Sequencing Tests. FDA website. regulation-ivd-companion-diagnostics.pdf. Accessed 3
https://www.fda.gov/downloads/MedicalDevices/ September 2019.
ProductsandMedicalProcedures/InVitroDiagnostics/
UCM584603.pdf. Accessed 3 September 2019. 40. Code of Federal Regulations Title 21, Subchapter H—
Medical Devices; Part 820 Quality System Regulation.
29. Considerations for Design, Development, and Analytical FDA website. http://www.accessdata.fda.gov/scripts/
Validation of Next Generation Sequencing (NGS)-Based In cdrh/cfdocs/cfcfr/cfrsearch.cfm?cfrpart=820&showfr=1.
Vitro Diagnostics (IVDs) Intended to Aid in the Diagnosis Accessed 3 September 2019.
of Suspected Germline Diseases: Guidance for Stakeholders
and Food and Drug Administration Staff (13 April 2018). 41. Op cit 34.
FDA website. https://www.fda.gov/media/99208/ 42. Requests for Feedback and Meetings for Medical Device
download. Accessed 3 September 2019. Submissions: The Q-Submission Program: Guidance
for Industry and Food and Drug Administration Staff
30. Summary of Safety and Effectiveness Data (SSED)
(7 May 2019). FDA website. https://www.fda.gov/
P160038 Praxis Extended RAS Panel. FDA website.
media/114034/download. Accessed 3 September 2019.
https://www.accessdata.fda.gov/cdrh_docs/pdf16/
P160038B.pdf. Accessed 3 September 2019. 43. Op cit 11.
31. Summary of Safety and Effectiveness Data (SSED) 44. Op cit 33.
P160045 Oncomine Dx Target Test. FDA website.
45. Op cit 3.
https://www.accessdata.fda.gov/cdrh_docs/pdf16/
P160045B.pdf. Accessed 3 September 2019.
32. Summary of Safety and Effectiveness Data (SSED)
P170019 FoundationOne CDx. FDA website. https://
www.accessdata.fda.gov/cdrh_docs/pdf17/P170019B.
pdf. Accessed 3 September 2019
33. Developing and Labeling In vitro Companion Diagnostic
Devices for a Specific Group or Class of Oncology
Therapeutic Products: Draft Guidance for Industry
(December 2018). FDA website. https://www.fda.gov/
media/120340/download. Accessed 3 September 2019.
34. ISO 13485:2016, International Organization for
Standardization (ISO) standard, Medical devices—
Quality management systems—Requirements for regulatory
purposes. ISO website. https://www.iso.org/obp/
ui/#iso:std:iso:13485:ed-3:v1:en. Accessed 3 September
2019.
35. Medical Device Single Audit Program (MDSAP).
FDA website. https://www.fda.gov/medical-devices/
cdrh-international-programs/medical-device-single-
audit-program-mdsap. Accessed 3 September 2019.
36. Final IVDR Legislation. Regulation (EU) 2017/746
of the European Parliament and of the Council of
5 April 2017 on in vitro diagnostic medical devices
and repealing Directive 98/79/EC and Commission
Decision 2010/227/EU. Official Journal of the European
Union, Volume 60, 5 May 2017.

144 All rights reserved; file sharing prohibited.

13 Interacting With Regulators

By Eric Brass, MD, PhD and William Sietsema, PhD

1
2
3
4
5
General Approach to Regulatory
Communications
and Drug Administration (FDA) (see below). At
this stage, the sponsor typically will know more 6
about the drug and its target than the regulators.
Drug development is a multi-year process, the
ultimate success or failure of which will be
Therefore, an explicit goal should be to educate 7
the regulators about the program to establish
dependent on regulatory authorities’ decisions. to the degree possible a shared interest in the
These decisions will be based, in large part, program’s potential. 8
on sponsor-submitted data in the context of The regulators may have more experience
the regulatory authority’s established policies. than the sponsor related to drug development for
In addition, each regulator will bring its own the intended clinical indication. They also may 9
experiences and biases to the decision, as well have seen data from drugs submitted by other
as insights from proprietary data from other
submissions available to it but not the sponsor.
sponsors with similar chemical characteristics or
even directed at the same target. The sponsor, by
10
Thus, it clearly is in the sponsor’s interest to posing questions, should encourage the regulators
communicate effectively with the regulator. The to share their insights based on their expertise, 11
goal should be to ensure alignment between the not only to learn from the regulators’ experiences,
ultimate new drug submission and the regulator’s but also to understand better what concerns they
qualitative and quantitative data expectations to may have (Table 13-1). 12
support approval. These discussions also may uncover differ-
Drug developers and regulatory authori-
ties share, in part, a common goal—to approve
ences in perspectives between the sponsor and
the regulator that may have profound implica-
13
new drugs that will improve individual and tions for the development program. These can
public health. In addition, many regulatory staff range from a specific safety concern to clinical 14
members are scientists and, thus, are interested trial endpoint validity. Identifying these issues
in learning about innovative developments and early is critical for the sponsor to mitigate them
are anxious to contribute to such programs. These effectively. These issues will directly impact the 15
perspectives provide a firm foundation for com- development program’s scope, duration and
munication during the development program.
Further, they suggest that beginning communi-
cost and, in extreme cases, may make a program
uneconomical. Discovering this as early as pos-
16
cation as early as possible in development and sible clearly will be advantageous to a sponsor’s
maintaining it throughout the program can be an overall strategic planning and resource allocation. 17
asset to successful development. Implicit in this formulation is the requirement
In the US, communication often begins with that sponsors have a comprehensive development
the Pre-Investigational New Drug (Pre-IND) plan early, including a rationale for individual 18
meeting between the sponsor and the US Food studies, which can be communicated to the

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 Chapter 13: Interacting with Regulators

Table 13-1. Communication Objectives for Sponsor-Regulator Interactions

Examples of Communication Objectives to be Achieved in Sponsor-Regulator Interactions

• importance of clinical indication and unmet medical need
• basis for the intended drug target’s efficacy
• understanding the drug target’s biology and impact on potential safety liabilities
• proof of concept from preclinical studies
• justification for proposed development program’s innovative or nonclassical aspects
• identification of informative biomarkers (as related to both safety and efficacy) to be monitored
during clinical development
• sponsor’s commitment to robust development
• sponsor’s commitment to balanced, transparent communications

Examples of Key Areas of Sponsor-Regulator Alignment to be Defined Early During Development

• preclinical development program scope
• need for clinical drug interaction studies
• requirement for special safety studies (e.g., QTc assessment)
• special populations requiring pharmacokinetic evaluation
• pivotal trials’ primary endpoint
• key secondary endpoints to support approval decision and labeling
• required study size (number of subjects and duration of exposure)
• potential safety issues of special concern
• eligibility for expedited development (Breakthrough or RMAT designation, Fast Track, Priority Review)

regulators. Often, this development plan will be Optimizing the yield from ongoing spon-
directed at not only achieving the drug’s approval sor-regulator communications requires a collab-
but also ensuring the approved labeling includes orative, non-adversarial sponsor approach. This
key information the sponsor considers important. may seem counterintuitive, since the sponsor
Published guidance documents are an has a fundamental commercial interest to which
important starting point for a sponsor trying to the regulator may be viewed as a barrier or even
understand both a regulator’s perspective and a obstructionist. However, as noted above, common
program’s likely requirements. However, these interests and values do exist and form a stronger
offer only a starting point. Often, the clinical and foundation for information sharing. Therefore, it is
regulatory science may have changed since the
important that the sponsor establish its credibility
guidances’ publication, rendering the advice out-
and commitment to a constructive exchange. The
dated. Regulator experience and changes to its
appearance of minimizing safety concerns, striving
thinking since publication may not be reflected
for unjustified program design minimalism or
in either guidance revisions or public comments.
For innovative programs, the guidance may not providing partial information all will make it more
address a sponsor’s critical questions. difficult for the sponsor to gain regulator agree-
Alternatively, the sponsor may feel the guid- ment on an innovative, scientifically sound study
ance does not reflect contemporary science and design. This is not to suggest regulatory decisions
will need to convince the regulators that alterna- reflect bias or are made on the basis of the drug’s
tive approaches are acceptable or even superior sponsor. Rather, it is central to the ability to com-
and will be more informative to the regulators municate effectively to ensure an efficient devel-
when making approval decisions. opment program with maximal utility to support

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
Table 13-2. Examples of Open vs. Content-Specific Questions to Regulators 2
Open-Ended Question
What is the regulator’s recommendation for the patient population to be included in Phase 3
3
pivotal trials?
4
Content-Specific Question
Based on the response profile in the Phase 2 trial, the disease’s pathophysiology and understanding of
the drug’s target as detailed in briefing materials, does the regulator agree only patients with Stage 3 5
skin manifestations and Grade 2 joint symptoms should be included in Phase 3 pivotal trials?

6
the regulatory decision-making process. Creating well as its scientific foundations. For later-stage
an adversarial or confrontational tone, intention- meetings (see below), relevant data developed 7
ally or inadvertently, likely will present a barrier to since previous communications can be summa-
rized. The briefing book allows the sponsor to
effective communication.
provide the bases and logic for its positions and, 8
Optimizing the Yield from Questions thus, constructively pose focused questions to the
Posed to Regulators regulator to attempt to reach alignment.
This approach is consistent with the sup-
9
A common strategy for eliciting opinions on a
position the sponsor may know more about
sponsor’s proposal or to gain insights from the
regulator’s experience is to pose specific questions
the proposed new drug and its target than 10
the regulator and has thought more about the
to the regulator. These may be in the form of
problem. This contrasts with a sponsor asking an
questions submitted to the regulator as written
open-ended question to which the regulator will 11
documents or as the basis for face-to-face meet-
respond based only on what it knows, often with
ings. While many of these questions may be pro
forma and address standard regulatory processes,
more-limited thought (Table 13-2). A regulator’s
spontaneous response to the open-ended ques-
12
they also can be used to develop sponsor-regulator
tion is unlikely to be innovative, will not reflect
alignment on core development program compo-
nents. In most cases, the sponsor will have a pre-
insights developed by the sponsor and, thus, 13
may disappoint the sponsor. This open-ended
conception as to what the “right” answer should be
approach risks introducing uncertainty to the
to each question. Thus, the sponsor should provide
program due to incomplete responses and creat- 14
the regulator with the explicit background and
ing an apparent conflict between the regulator’s
rationale for its preferred answer. Importantly, this
foundation should be built on sound science and
position and the sponsor’s.
The regulator will not always agree with the
15
data, not simply the cheapest or fastest develop- sponsor’s proposal, even when it is based on a
ment strategy. As a corollary, the question can be
structured to present the preferred answer, and the
well-thought-out scientific rationale. In this situ- 16
ation, the sponsor must probe to understand the
sponsor can ask whether the regulator agrees with basis for the regulator’s position. The regulator
this or has additional comments. may not have understood the sponsor’s rationale, 17
The briefing book submitted prior to formal may have identified a weakness in the sponsor’s
meetings is an important component of the logic or be aware of data to which the sponsor
communication strategy. The sponsor can develop did not have access. The regulator also may allude 18
the background of the program to be discussed as to written policy or unwritten precedent or other

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 Chapter 13: Interacting with Regulators

considerations. Importantly, the regulator may or a more complete response than was articulated
not be able to articulate its rationale specifically if at the meeting. A sponsor may interpret the
it is based on proprietary data it cannot share. verbal discussion one way and find the minutes
Understanding the basis for the regula- reflect a different answer. It is important that the
tor’s answer is critical for the sponsor to decide sponsor understand these apparent discrepancies
how to proceed. The sponsor can adopt the fully, which may require follow-up discussions
regulator’s advice if it agrees with the position. with the regulator to establish clarity. Written
A sponsor also may elect to adopt the advice communications usually are considered final
despite not agreeing with it, to avoid conflict and are changed only rarely, but resolving these
with the regulator if the advice’s impact on the perceived discrepancies is important for guiding
program is minimally disruptive. In contrast, sponsor actions, even if no changes are made to
if the advice is contrary to the sponsor’s view the written documents.
of sound science or medicine and would com- Attention must be paid to a regulator’s exact
promise the development program, the sponsor wording in written communication. Such syntax
can provide additional information to refute the as “we would be interested to know” or “we
regulator’s position. A sponsor may proceed with suggest” should be distinguished from statements
the program contrary to the regulator’s advice, like “we feel it is important to” or “our current
knowing the issue will need to be addressed position is there is a requirement for sponsor to.”
proactively during the remainder of the pro- The sponsor should evaluate recommendations
gram and the final submission. Obviously, this linked to the former language carefully but, if
approach will incur risk and increase uncertainty justified adequately, the consequences of not
for the sponsor, as the regulator may not change accepting the recommendation might be small.
its opinion, especially if the opinion is based In contrast, failure to follow a strongly presented
on judgment from data or policy concerns not recommendation or one linked to a regulatory
available to the sponsor. However, if following requirement might place the ultimate application
the regulatory advice would impact the program in jeopardy, even if the sponsor disagrees with the
or product adversely, and the sponsor is confident regulator for sound reasons.
a scientifically sound, data-driven rebuttal can
be developed over time, this approach cannot be Timing of Agency Meetings
dismissed. Nonetheless, regulator-sponsor align-
One important element in planning a devel-
ment is preferred, and the earlier it is reached in
opment program is timing agency interactions
the program the better. Every effort should be
around the globe. In the US, a pre-defined
made to achieve this goal.
series of milestone meetings may be held,
Importance of Written Communications beginning with the Pre-IND meeting, and
progressing to End-of-Phase 1 (EoP1), End-
The regulator’s opinion may be presented in of-Phase 2 (EoP2) and Pre-New Drug Appli-
a written communication to the sponsor. This cation (Pre-NDA) meetings.
may be in the form of written responses to a Additional meetings, such as the late-cycle
set of questions or be the minutes of a direct meeting, may be held during NDA or Biologics
sponsor-regulator interaction. These written License Application (BLA) review. Generally,
communications need to be evaluated carefully FDA grants only one of each of these milestones
and understood fully by the sponsor, as they meeting types. Thus, it is important to consider
will represent the best statement of the regula- the questions that could be asked for each meet-
tor’s position at the time. Written minutes of a ing, when information to inform FDA recom-
sponsor-regulator meeting may provide nuance mendations will be available and the program-

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
matic timing requirements for specific answers. ment program more plausible. It might be worth
In the EU, Scientific Advice meetings can be considering the sponsor personnel’s background 2
held at the national level or with the European and interests to help identify individuals likely to
Medicines Agency (EMA) at any time and, since
the sponsor usually pays for these meetings, there
be successful in fostering an informal relation-
ship with one or more agency representatives.
3
is no formal restriction on the number of meet- One example might be for the sponsor’s medical
ings that can be held. director to become acquainted with an agency 4
For most major programs, the sponsor should medical reviewer. This often is easier said than
plan the full series of FDA meetings, sequenced done, but opportunities do arise to meet agency
among the clinical trials to avoid the meetings staff, for example at sponsor meetings or sci- 5
becoming rate-limiting for the program. For the entific conferences. In all such interactions, the
EU, a Pre-Clinical Trials Application (Pre-CTA)
meeting is uncommon, unless guidance is lacking
highest level of professionalism should be main-
tained. Written summaries of these interactions
6
for a particular situation, or the program pro- should be prepared by the sponsor to maintain an
poses an element contrary to current guidance. A historical record of conversations. 7
Scientific Advice meeting commonly is scheduled Each agency has its own “personality”
in the EU at about the same time as the US EoP2 regarding the amount of sponsor interaction out-
meeting, and there also commonly would be a side formal meetings it expects or tolerates. This 8
pre-filing meeting, analogous to the US Pre-NDA should be considered in the early planning stages,
meeting. In other countries, it also is common
to have pre-filing meetings, but other scientific
not only for developing a product approval strat-
egy. The sponsor should be prudent in avoiding
9
advice meeting types may be considered only on excessive contact with agency staff if they prefer
an as-needed basis. to maintain an “arm’s length” relationship. 10
One reason for this regional difference in
Pre-IND and Pre-CTA meetings is in the US, Who interacts with the regulators?
the FDA division reviewing the IND usually is Sponsors have widely varying policies about who
11
the same one that reviews the NDA or BLA. In should interact with regulators. Small companies
contrast, EU CTA reviews occur at the national
level; therefore, the reviewers generally will
tend to be more flexible, allowing medical and 12
regulatory staff and even other disciplines to
not be the same staff reviewing the Marketing contact regulators. In contrast, medium to large
Authorisation Application (MAA) at the central companies often develop Standard Operating 13
level. Thus, establishing an early relationship is Procedures (SOPs) that restrict contact with
less important.
To optimize global meetings’ timing usually
regulators. In many cases, only sponsor regulatory 14
staff members are allowed to make contact and
would require mapping the program’s planned will be involved in all discussions and communi-
clinical studies’ sequence and superimposing pro- cations. Including outside experts may enhance 15
posed agency interactions on the plan, making credibility when communicating key scientific
adjustments as needed to prevent a meeting from
unnecessarily becoming rate-limiting.
information or the data interpretation. However,
experts need to be extensively briefed as to their
16
Other Interactions role, since most are unfamiliar with the unique
nature of regulatory meetings. 17
Aside from formal meetings, establishing and Large sponsors with offices in multiple
maintaining a relationship with agency reviewing global locations may delegate interactions to the
staff can be important. This will make asking local level, which can be an advantage because 18
informal questions arising during the develop- local staff members speak the same language and

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 Chapter 13: Interacting with Regulators

are familiar with the culture and any unwritten The SPA process provides an opportunity to
expectations. However, it is important for the resolve any discordance between the sponsor’s
headquarters’ regulatory staff to have a well- trial design and FDA preferences prior to study
thought-out and well-communicated strategy to initiation. If no agreement can be reached, FDA
enable local office staff members to work toward will provide the bases for its concerns and recom-
the master plan. Poor communication with those mendations in writing. Under these circum-
staff members can result in local strategies that stances, the sponsor will have a clear understand-
deviate from planned program execution. ing of what FDA’s concerns will be at the time of
When agency meetings are held, the local full application review and will need to provide
staff always should be involved and, in many clear reasoning and supplemental information to
cases, will lead the interactions according to the ensure the same issues do not result in an unfa-
headquarters’ established strategy. Headquarters’ vorable final review.
staff also may attend local agency meetings, since Agreement between a sponsor and FDA,
they likely are best informed about program formalized through an SPA, can reduce regu-
strategy and can help the local staff make deci- latory uncertainty when launching a Phase 3
sions to support the program best. program. However, an SPA agreement can be
Agency meeting attendance also is disci-
changed under two circumstances: 1) written
pline-specific, and any meeting should include
agreement between the sponsor and FDA and
staff members who are experts in the discipline
2) a review decision finding that “a substantial
being discussed. For example, chemists and
scientific issue essential to determining the safety
engineers should be present when drug quality or
or effectiveness of the drug was identified after”
CMC issues are being considered.
the study began (see Case Study 13-1). Thus, it
Special Protocol Assessments (SPAs) obviously is important for the sponsor to conduct
an ongoing assessment of the program’s scientific
As clinical trial designs became more complex, validity and develop mitigation strategies should
FDA established a mechanism to provide more major changes occur.
formal, specific review of selected studies, partic-
ularly proposed Phase 3 studies. The SPA pro- Types of Regulatory Meetings
cess allows 45-day review cycles for submitted
protocols to “assess whether they are adequate Most regulatory agencies have specific meeting
to meet scientific and regulatory requirements policies and procedures. These are summarized in
identified by the sponsor.”1 This review can Table 13-3 and are discussed further here. Note,
allow sponsors to reach agreement with FDA on many regulatory agencies not listed will entertain
critical design features such as the target popu- formal or informal meetings, even if specific pro-
lation, study size requirements, endpoint clinical cedures are not published or not mentioned here.
relevance and the statistical analysis plan. To In the US, many FDA meeting types result
allow a complete evaluation, the sponsor should from the Prescription Drug User Fee Act (PDUFA)
make the submitted protocol’s role in the overall regulations and are associated with specific
program explicit. For example, will other Phase timelines and procedures. PDUFA meetings can
3 data be considered during the review, or will be divided into Type A, B and C, depending on
this be the sole dataset submitted? the meeting’s urgency in the context of program
Additionally, the protocol should be written development. Type A meetings generally are
to definitively demonstrate the rationale for crit- scheduled within 30 days of request, whereas
ical decisions so the FDA reviewer can under- Type B and C meetings generally are scheduled
stand the sponsor’s justification for its choices. within 60 and 75 days, respectively.

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
Case Study 13-1. Vascepa for the Treatment of Hypertriglyceridemia 2
Amarin Pharmaceuticals developed Vascepa (icosapent ethyl) as a treatment for lowering blood
triglyceride concentrations. In July 2012, Vascepa was approved by FDA as monotherapy to treat 3
severe hypertriglyceridemia (≥500 mg/dL). Amarin also sought approval for Vascepa’s use to treat
milder hypertriglyceridemia (200–499 mg/dL) in combination with an HMG-CoA reductase inhibitor in
patients at high risk for cardiovascular events. After discussions with FDA, Amarin developed a Phase 4
3 protocol to support the expanded indication defining the study population, lipid efficacy targets and
a 12-week study. This protocol was submitted for an SPA. Amarin’s SPA request specified a definitive
cardiovascular outcome study that would be conducted, but approval would be considered after the
outcomes trial had recruited 50% of its target enrollment.a Agreement on the SPA protocol in moderate
5
hypertriglyceridemia was received from FDA in July 2009. In 2013, Amarin submitted a supplemental
NDA for Vascepa after the 12-week study was completed successfully, meeting its pre-specified
endpoints, and the outcomes study had enrolled 50% of its target enrollment. However, after the SPA 6
agreement, additional clinical trial results became available on the impact of triglyceride-lowering on
cardiovascular outcomes. As reviewed by FDA,b these new data raised serious questions about the
validity of decreases in triglyceride concentrations as a surrogate measure of improved cardiovascular 7
outcomes. Based on this review and input from an Advisory Committee, FDA decided new scientific
data made the SPA invalid and did not approve the supplemental NDA to expand Vascepa’s target
population.c This scenario illustrates an SPA’s potential to de-risk a development program (the 2009
agreement) while emphasizing all such agreements are conditional, with regulatory decisions made
8
based on the best available scientific data at the time of the decision. Subsequently, the full outcomes
trial was completed and demonstrated that icosapent ethyl was associated with a statistically significant
25% reduction in cardiovascular events.d In 2019 FDA approved expanded labeling for Vascepa to 9
include the cardiovascular risk population.

a. Vascepa® (icosapent ethyl) for Treatment of Hypertriglyceridemia. Amarin Briefing Information for the Endocrinologic
and Metabolic Drugs Advisory Committee. Meeting Date: 16 October 2013. FDA website. http://wayback.archive-it.
10
org/7993/20170114010730/http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/
EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM370987.pdf. Accessed 14 June 2019.
b. FDA Briefing Document. Endocrinologic and Metabolic Drugs Advisory Committee Meeting (16 October 2013). FDA
website. http://wayback.archive-it.org/7993/20170114010718/http://www.fda.gov/downloads/AdvisoryCommittees/
11
CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM370985.pdf. Accessed 14
June 2019.
c. Amarin Announces FDA Review Division Response to ANCHOR SPA Agreement Reinstatement Request (21 January 2014). Amarin
website. https://investor.amarincorp.com/static-files/4af333b6-bb56-4d34-a71a-e8878ce633d2. Accessed 14 June 2019. 12
d. Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT Jr, Juliano RA, Jiao L, Granowitz C, Tardif JC,
Ballantyne CM; REDUCE-IT Investigators. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl

13
J Med. 2019 Jan 3;380(1):11-22. doi: 10.1056/NEJMoa1812792. Epub 2018 Nov 10.

Each meeting type has a specific purpose, as

outlined in Table 13-3. FDA meetings are not
90 calendar days, whereas Type 1, 2, 3 and 4
meetings are scheduled within 30, 75, 120 and 60
14
granted in every instance and, if granted, may days, respectively.
be a face-to-face meeting, a teleconference or, in The PDUFA meeting guidance documents 15
some cases, “written responses only.” provide a proposed briefing document struc-
FDA recently added guidance for biosim-
ilar meetings, per the Biosimilar User Fee Act
ture, which generally is required at the time of
requesting a Type A meeting and 30 and 47 days
16
(BsUFA) requirements. These meetings also are prior to Types B and C, respectively. In contrast,
highlighted in Table 13-3. Many of the pro- all BsUFA meeting briefing documents must 17
cedures are analogous, but biosimilar meetings be submitted as part of the meeting request. As
are referred to as Initial Advisory or Type 1, 2, discussed above, these briefing documents are
3 or 4. The timelines are different, as the Initial an important opportunity for the sponsor to 18
Advisory meeting generally is scheduled within share key background information, the rationale

All rights reserved; file sharing prohibited. 151

 Chapter 13: Interacting with Regulators

Table 13-3. Summary of Regulatory Agency Meeting Types

Country Meeting Type Notes

USa Type A Dispute resolution, clinical holds, Special Protocol Assessments
US Type B Pre-IND, End-of-Phase 1, End-of-Phase 2, Pre-NDA/BLA
US Type C Any meeting not classified as Type A or Type B; includes End-of-Phase 2a
meetingsb
USc CMC Meetings under an IND Meetings primarily to discuss chemistry, manufacturing, and control issues but
also may be multi-disciplinary
USd Biosimilar Initial Advisory General discussion as to whether a product may be considered a biosimilar
Meetings
US Biosimilar Biological Product Clinical holds, Special Protocol Assessments, important safety issues, dispute
Type 1 resolution
US Biosimilar Biological Product Discuss a specific issue where FDA is being asked to provide targeted advice on
Type 2 an ongoing program
US Biosimilar Biological Product In-depth review and advice regarding an ongoing program; includes substantial
Type 3 review of information
US Biosimilar Biological Product Discuss biosimilar biological product application or supplement format and
Type 4 content
US Late-Cycle Meetingse Implemented during the PDUFA V reauthorization in 2012, these meetings occur
toward the end of the review cycle for an NDA or BLA and allow the sponsor and
FDA to discuss any critical issues related to the product’s approval, including a
possible AdCom Meeting.
EU Centralized Meetings for Interaction with the Scientific Advice Working Party (SAWP) to provide guidance
Scientific Advice or Protocol on various aspects of a product’s development
Assistancef
EU National Meetings Any country also may hold a meeting at the national level and provide advice;
each country has its own procedures
Japan Consultation Meetings Advice on a broad array of product development and regulatory submission
issues
Australia Pre-submission Meetingsg Discuss plans for a Marketing Authorization Application submission
Canada Pre-CTA Consultationh Discuss concerns and resolution of issues; guidance on acceptability of a
proposed trial
Canada Pre-NDS Meetingsi Discuss the presentation of data in support of a submission

a. Guidance for Industry: Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products (December 2017).
FDA website. https://www.fda.gov/media/109951/download. Accessed 14 June 2019.
b. Guidance for Industry: End-of-Phase 2a Meetings (September 2009). FDA website. https://www.fda.gov/media/72211/
download. Accessed 14 June 2019.
c. Guidance for Industry: IND Meetings for Human Drugs and Biologics Chemistry, Manufacturing, and Controls Information
(May 2001). FDA website. https://www.fda.gov/media/70827/download. Accessed 14 June 2019.
d. Guidance for Industry: Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants (June
2018). FDA website. https://www.fda.gov/media/113913/download. Accessed 14 June 2019.
e. CDER 21st Century Review Process Desk Reference Guide. FDA website. https://www.fda.gov/media/78941/download.
Accessed 14 June 2019.
f. European Medicines Agency Guidance for Companies Requesting Scientific Advice and Protocol Assistance (21 May
2010). http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/
WC500004089.pdf. Accessed 14 June 2019.
g. Guidance 5: Pre-Submission Meetings with TGA (Version 2.1, March 2018). TGA website. https://www.tga.gov.au/publication/
pre-submission-meetings-tga. Accessed 14 June 2019.
h. Pre-Clinical Trial Application (CTA) Consultation Meeting. Health Canada website. https://www.canada.ca/en/health-canada/
services/drugs-health-products/drug-products/applications-submissions/guidance-documents/clinical-trials/pre-clinical-
trial-application.html. Accessed 14 June 2019.
i. Guidance for Industry: Management of Drug Submissions (20 December 2013). Health Canada website. https://www.canada.
ca/content/dam/hc-sc/migration/hc-sc/dhp-mps/alt_formats/pdf/prodpharma/applic-demande/guide-ld/mgmt-gest/
mands_gespd-eng.pdf. Accessed 14 June 2019.

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
for its positions and the specific questions to be procedures and expected meeting package con-
addressed at the meeting. tents are similar to those of other agencies. There 2
Within the EU, meetings may be held at the is less definition around request timing; however,
centralized level for scientific advice or protocol a briefing document is due 30 days prior to the
assistance. These meetings are held with the Sci- meeting. Specific guidance is provided for Pre- 3
entific Advice Working Party (SAWP) and have New Drug Submission (Pre-NDS) meetings
an established meeting schedule, with meeting
request submission deadlines.2 The procedure is
with Health Canada, for which a request should
be made no less than one month prior to the
4
initiated by submitting a letter of intent. The for- proposed meeting date. The briefing document
mal procedure starts about six weeks later, with
the meeting (if needed) occurring about eight
content is similar to that of other agencies and 5
generally is due two weeks prior to the meeting.
weeks after that. Unlike EMA and FDA, the Australian
The results then must be adopted by the Therapeutic Goods Administration (TGA) does 6
Committee for Human Medicinal Products not view itself as a development partner, so it
(CHMP) about two weeks after that. Thus, from
the time the letter of intent is submitted, it will
does not encourage meetings openly during
development unless there are specific critical
7
be about 16 weeks until the procedure is com- topics to discuss. However, a presubmission
plete. In addition to the guidance documents
referenced in Table 13-3, the SAWP provides a
meeting may be appropriate in some cases. 8
TGA advises these are most beneficial in the
template for the briefing document3 and a tem- following situations:
plate for a letter of intent to request a meeting.4 • complex therapeutic goods 9
Japan’s Pharmaceuticals and Medical • new or emerging technologies
Devices Agency (PMDA) has an active con- combination of technologies (e.g., a
sultation program, including the potential for
•
medicine/device combination product) 10
meetings before the start of Phase 1 in Japan • specific regulatory issues for therapeutic
and throughout development, including early
Phase 2, late Phase 2, EoP2 and prior to NDA
goods with multiple applications
11
submission.5 Consultation also can be requested It is necessary to complete and submit a pro
for protocol advice or safety and quality issue forma meeting request to TGA, which can be 12
discussions. Several months should be allowed sent via email. The request should be sent at
for the meeting procedures. The procedure is least four weeks (but preferably eight to 12
initiated with a meeting request, and the briefing weeks) prior to the proposed meeting date. 13
document is provided several weeks in advance Meetings may be in-person or by tele- or vid-
of the meeting date. PMDA generally provides
initial feedback on the briefing document and
eo-conference. The meeting requires a dossier
with content similar to that expected by other
14
expects a round of revisions before the meeting is agencies and often is provided two or more
held. This approach results in tentative agree- weeks prior to the meeting. 15
ment on most issues before the meeting is held.
Dispute Resolution
Due to the substantial differences in language
and culture in Japan and other Asian countries Neither sponsors nor regulators welcome a
16
versus North America and Europe, it is especially dispute over regulatory decisions. Nonetheless,
important to engage a local representative who disputes do occur, and some agencies have proce- 17
has experience working with the regulator. dures for their resolution. FDA has a number of
Health Canada offers meetings throughout a defined options for dispute resolution.
development program, beginning with a preclin- FDA recommends contacting the ombuds- 18
ical trial application consultation meeting. The man’s office first for advice on resolving a dispute.

All rights reserved; file sharing prohibited. 153

 Chapter 13: Interacting with Regulators

The ombudsman has agency-wide jurisdiction References

and will help outline options for resolving the 1. Guidance for Industry: Special Protocol Assessment
dispute. Issues related to manufacturing are (April 2018). FDA website. https://www.fda.gov/
media/97618/download. Accessed 14 June 2019.
common bases for disputes, and FDA has a
specific guidance document that provides an 2. The dates of 2020 SAWP meetings and deadlines for
submission of scientific advice, protocol assistance,
overview of how Good Manufacturing Practice qualification of biomarkers and parallel EMA/HTA
(GMP) disputes may be handled.6 The agency requests (18 September 2019). EMA website. https://
has a guidance document for resolving disputes www.ema.europa.eu/en/documents/regulatory-
procedural-guideline/dates-2020-scientific-advice-
that cannot be addressed at the review division working-party-sawp-meetings-deadlines-submission-
level.7 This process involves a series of appeals to scientific-advice/eunethta-requests_en.pdf. Accessed 14
agency personnel above the review division level. June 2019.
In general, any dispute resolution request should 3. CHMP protocol assistance scientific advice briefing
be provided in writing, with a clear presentation document template. EMA website. https://www.
ema.europa.eu/en/documents/template-form/
of the issue(s), an explanation of steps taken chmp-protocol-assistance-scientific-advice-briefing-
already to attempt a resolution and one or more document-template_en.doc. Accessed 14 June 2019.
proposed solutions. FDA often will entertain a 4. Template Letter of Intent for Request of Scientific
meeting to discuss a possible resolution. Goals Advice or Protocol Assistance. EMA website. https://
for responding to dispute resolution are in place www.ema.europa.eu/en/human-regulatory/research-
development/scientific-advice-protocol-assistance/
under PDUFA, BsUFA and the Generic Drug User scientific-advice-protocol-assistance-regulatory-
Fee Amendments. FDA will endeavor to accept or procedural-guidance. Accessed 12 September 2019.
not accept an appeal within 14 days of receipt. 5. Moriyama Y. “Clinical Trial Notifications and
Within 30 days of the dispute resolution request, Scientific Consultation System in Japan.” PMDA
FDA will either respond to the dispute resolu- website. http://www.pmda.go.jp/files/000152326.pdf.
Accessed 14 June 2019.
tion or hold a meeting. If a meeting is held, the
6. Guidance for Industry: Formal Dispute Resolution:
response will be provided within 30 days. The Scientific and Technical Issues Related to Pharmaceutical
majority of formal appeals are denied.8 CGMP_PRA ( January 2006). FDA website. https://
www.fda.gov/media/125431/download. Accessed 14
Summary June 2019.
7. Guidance for Industry: Formal Dispute Resolution: Appeals
Good science is important but, ultimately, the Above the Division Level (November 2017). FDA
sponsor’s ability to communicate good science to website. https://www.fda.gov/media/85613/download.
regulatory authorities is an essential component Accessed 14 June 2019.

of a successful program. Substantial effort is 8. Sharma K, Harrington A, Worrell S, Bertha A. An

FDA Analysis of Formal Dispute Resolution in the
required to be certain interactions with regulators Center for Drug Evaluation and Research: 2003
produce clear communication and create an open Through 2014. Therapeutic Innovation & Regulatory
door to discuss important issues. Science. Volume 50, issue 6, pages 697-704, 2016.

154 All rights reserved; file sharing prohibited.

14 Regulatory Pathways

By Pallavi Trivedi, MPH, RAC

1
2
3
4
5
US
Determining the appropriate regulatory pathway
for different geographic regions and assessing
6
Potential Pathways and Regulatory
the options available to accelerate and/or reduce
Exclusivity
product development risk are critical regulatory 7
and business considerations. Regulatory path- The US Food and Drug Administration (FDA),
way selection has implications for not only the an agency of the Department of Health and
development program but also, importantly, on Human Services (HHS), is responsible for reg- 8
exclusivity, review timeline and submission costs. ulating and approving drugs and biologics.1 The
This chapter focuses on key regulatory pathway types of product approval applications submitted 9
options for the US, EU, Japan, Canada, Australia to FDA for marketing a drug or biologic are
and Brazil. It does not address nonprescription, listed in Table 14-1, with the applicable regu-
consumer or herbal products. latory exclusivity period. Orphan and pediatric 10
In general, for all these regions, the pre- exclusivity are discussed elsewhere in this book.
scription product categories include drugs and The 505(b)(2) hybrid pathway is available for
some biologics but is rarely used and, therefore, is
11
biologics (including cell or gene therapies and
vaccines). This chapter addresses requirements not included in the table.
for drugs, biologics and combination products. Drug and Biologic Review Timeframes and
12
For the regulatory professional, the first step is Submission Costs
to determine the product type being developed 13
(e.g., drug, biologic or combination product) The Prescription Drug User Fee Act (PDUFA),2
based on its proposed use and the appropriate enacted in 1992, required sponsors to pay fees for
marketing application route. The legal definitions most New Drug Applications (NDAs) and Bio- 14
for drugs and biologics in the US, EU, Japan, and logics License Applications (BLAs) in exchange
Australia are provided in Appendix A. for FDA’s commitment to review applications
within specified timeframes (Table 14-2). On 18
15
The next step is to determine the general
approval requirements for the application type August 2017, the president signed into law the
based on the proposed indications and whether Food and Drug Administration Reauthorization 16
any exceptions to the general rules are avail- Act (FDARA), which includes the reauthoriza-
able, either by using a formal mechanism for
accelerating approval or precedents. Through-
tion of PDUFA (PDUFA VI) through September
2022. The Federal Food, Drug, and Cosmetic Act
17
out product development, it is essential to (FD&C Act), as amended by the Biosimilar User
monitor the regulatory path and putative Fee Amendments of 2017 (BsUFA II), authorizes 18
development requirements. FDA to assess and collect fees for biosimilar

All rights reserved; file sharing prohibited. 155

 Chapter 14: Regulatory Pathways

Table 14-1. US Pathways and Exclusivity

Product Type Potential Pathway Regulatory Exclusivitya

Drug 505(b)(1)—New Chemical Entity Five years
505(b)(2)—Modified dosage form/published literature Three years
505(j)—Generic 180 days for first to file
Paragraph IVb,c
Biologic 351(h)—New Biologic/New Chemical Entity 12 yearsd
351(k) - Biosimilar 12—18 monthsd
361 - human cells, tissues, and cellular and tissue-based none
product (HCT/P)

a. Under the Drug Price and Patent Restoration Act, eligible drug, biologic and device patents may be extended up to a maximum of
five years to compensate for development and regulatory approval time (Public Law 98-417, 21 CFR Part 60).
b. 180-day protection from competition from subsequent generic versions of the same drug is provided to certain applicants who
submit an ANDA with a paragraph IV certificate (challenging a patent that may be invalid).
c. Guidance for Industry: 180-Day Generic Drug Exclusivity Under the Hatch-Waxman Amendments to the Federal Food, Drug, and
Cosmetic Act (June 1998). FDA website. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/180-day-
generic-drug-exclusivity-under-hatch-waxman-amendments-federal-food-drug-and-cosmetic-act. Accessed 15 October 2019.
d. Draft Guidance for Industry: Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the PHS Act (August
2014). FDA website. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/reference-product-exclusivity-
biological-products-filed-under-section-351a-phs-act. Accessed 15 October 2019.

Table 14-2. FDA Drug and Biologic NDA Application Review Timeframes

User Fee Type FDA Review Time Cost

Application Fee – Clinical Data Required (NME, NDA Priority Review- Six months from 60- $2,942,965
and Original BLA) day filing date
Standard Review- 10 months from
60-day filing date
Application Fee – No Clinical Data Required (NME, Priority Review- Six months from 60- $1,471,483
NDA and Original BLA) day filing date
Standard Review- 10 months from
60-day filing date
Application Fee – Clinical Data Required (Biosimilar within 10 months of the 60 day filing $ 1,746,745
biological product)b date
Fee for redeeming Priority review voucher for all Priority Review- Six months from 60- $2,167,116
three programsd day filing date
Application Fee – No Clinical Data Required within 10 months of the 60 day filing $ 873,373
(Biosimi-lar biological product)b date
Application Fee (ANDA)c Standard Review- within 10 months $ 176,237
of the submission date
Priority Review- 8 months of the
submission date

a. PDUFA Reauthorization Performance Goals and Procedures Fiscal Years 2017 Through 2022. FDA website. http://www.fda.gov/
downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM270412.pdf. Accessed 21 April 2016.
b. Biosimilar Biological Product Reauthorization Performance Goals and Procedures Fiscal Years 2018 through 2022. FDA website.
https://www.fda.gov/industry/fda-user-fee-programs/biosimilar-user-fee-amendments
c. GDUFA reauthorization performance goals and procedures Fiscal years 2018-2022. FDA website. https://www.fda.gov/industry/fda-
user-fee-programs/generic-drug-user-fee-amendments
d. Federal Register Notices: Tropical Disease, Rare Pediatric Disease and Material Threat Medical Countermeasure Priority Review
Voucher Fees

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
biological products from October 2017 through The general requirement for showing effective-
September 2022. ness is “two adequate and well-controlled stud- 2
Applicants should confirm whether they ies,” as described in FDA’s Guidance for Indus-
meet small business exemption or waiver require-
ments, which may result in a one-time waiver for
try—Providing Clinical Evidence of Effectiveness
for Human Drugs and Biological Products. This is 3
a qualifying company’s first BLA or NDA. based on the legal requirement for substantial

US Approval Pathways for Drugs

evidence of the drug’s safety and effectiveness for 4
its intended use. According to the FD&C Act,3
substantial evidence consists of “adequate and
FD&C Act Section 505 identifies three drug
application types:
well-controlled investigations, including clinical 5
investigations, by experts qualified by scientific
• 505(b)(1) NDA—an application
training and experience to evaluate the effective-
containing full safety and effectiveness
ness of the drug involved, on the basis of which 6
investigation reports
it could fairly and responsibly be concluded by
• 505(b)(2) NDA—an application
containing full safety and effectiveness
such experts that the drug will have the effect
it purports or is represented to have under the
7
investigation reports, but where at least
conditions of use prescribed, recommended, or
some information required for approval
comes from studies not conducted by
suggested in the labeling or proposed labeling 8
thereof.” FDA long has interpreted “adequate
or for the applicant and for which the
and well-controlled studies” to mean a minimum
applicant has not obtained a right of
reference
of two adequate and well-controlled clinical 9
studies as defined in 21 CFR 314.126. Although
• 505(j)/Abbreviated New Drug Appli-
cation (ANDA)—an application for a
these clinical studies typically are thought of as
Phase 3 studies, Phase 2 studies also may be used
10
proposed product is identical in active
as registration studies if they meet the definition
ingredient, dosage, strength, route of
administration, labeling, quality, per- of adequate and well-controlled studies (e.g., 11
formance characteristics and intended appropriate masking, statistical power).
For some products, e.g., orphan drugs and
use, among other things, to a previously
approved product
oncology products, FDA has demonstrated 12
flexibility in the amount of efficacy data required
505(b)(1) and 505(b)(2) NDAs to support a drug’s approval (see Quantum of
Effectiveness Evidence in FDA’s Approval of
13
FDA’s Center for Drug Evaluation and Research
(CDER) has purview over new drug approval. Orphan Drugs, Sasinowski, et al4). FDA’s Guid-
Multiple divisions within CDER are charged ance for Industry: Providing Clinical Evidence 14
with NDA review and approval for drugs within of Effectiveness for Human Drug and Biological
Products contains details on the regulatory and
a specific therapeutic area, such as oncology.
The 505(b)(1) route or application is used to scientific considerations involved in the decision 15
obtain new drug approval. It requires extensive to approve an application based on a single ade-
data to establish:
• the drug’s safety and effectiveness for
quate and well-controlled clinical trial.
The 505(b)(2) route typically is used for
16
the proposed use drugs that are modifications (e.g., route of
• production methods are adequate to administration, dosage form) of off-patent drugs, 17
ensure the drug’s identity, strength, where an ANDA submission is not appropriate,
quality and purity yet duplicative studies are not needed. In some
• proposed labeling is appropriate and instances, using available and robust public 18
contains all necessary information literature, a 505(b)(2) NDA may be submitted

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 Chapter 14: Regulatory Pathways

and approved for a new chemical entity or a new tors, and cell and gene therapy products. The vast
molecular entity. majority of biologics are reviewed and approved
As described in FDA’s 505(b)(2) guidance,5 by FDA via submission of a BLA under the Public
in lieu of generating and submitting data, a Health Service Act (PHS Act) 351(h). With the
sponsor may rely on published literature specific exception of monoclonal antibodies and therapeu-
to information necessary for approval or the tic proteins (e.g., interferons and enzymes), bio-
agency’s finding of safety and effectiveness for logics are reviewed and approved by FDA’s Center
an approved application (cross-referencing an for Biologics Evaluation and Research (CBER).6
approved, off-patent NDA or ANDA for clinical Although biological products are approved
trial or nonclinical data). If an NDA is cross-ref- under PHS Act Section 351,7 most biologics also
erenced for efficacy, some type of clinical bridge are considered drugs within the legal framework
to the innovator must be established to enable and, therefore, generally are held to the same
the cross-reference. Generally, the clinical bridge efficacy standards as drugs (two adequate and
consists of a bioequivalence study and at least well-controlled clinical studies). As described
one Phase 3 adequate and well-controlled clinical previously, they also are subject to the same
study. Precedents and FDA guidance regarding FDA review timeframes and submission costs,
specific therapeutic areas should be researched to although due to biologics’ complex nature and
assess clinical data requirements. development time, they have longer regulatory
exclusivity periods than those for drugs.
Abbreviated New Drug Application
(Generics) Biosimilars
FDA’s Office of Generic Drugs (OGD) is In 2009, the US Congress passed the Biologics
responsible for ANDA (or generic product) Price Competition and Innovation Act (BPCI Act) as
review and approval. A generic application part of the Patient Protection and Affordable Care
submitted under 505(j) of the US Code is for a Act, empowering FDA to identify an abbreviated
product comparable to an innovator drug product approval pathway for biosimilars. Under PHS
in dosage form, strength, route of administration, Act Section 351(k), a biological product may be
quality, performance characteristics and intended demonstrated to be “biosimilar” if it is “highly
use. The usual data required to support a generic similar” to an already-approved biological. The first
consist of chemistry, manufacturing, and con- biosimilar was approved in the US in March 2015,
Zarxio (filgrastim-sndz), which is biosimilar to
trols (CMC) information and the results from a
Neupogen (filgrastim). FDA’s approval of Zarxio
bioequivalence study compared to the innovator
was based on the agency’s review of structural and
product. A clinical endpoint study is required in
functional characterization, animal study data,
certain circumstances where blood plasma level
human pharmacokinetic and pharmacodynamic
measurements in a pharmacokinetic study cannot
data, clinical immunogenicity and safety and
predict clinical outcomes (e.g., topical products
efficacy data. Zarxio’s approval did not encom-
such as dermatology or inhalation products).
pass the higher standard for interchangeability
On 18 August 2017, the president signed
at the pharmacy level. To meet the interchange-
the bill reauthorizing GDUFA II through 30
ability standard, a sponsor must demonstrate the
September 2022.
biosimilar product can be expected to produce the
US Approval Pathway for Biologics same clinical results as the reference product and,
for a biological product administered more than
Biologics are derived from living organisms. once, there is no increased risk from alternating or
Examples include vaccines, therapeutic proteins, switching between using the biosimilar product
monoclonal antibodies, blood-based clotting fac- and the reference or innovator product.

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Human cells, tissues, or cellular or tis- Table 14-3 summarizes the FDA programs
sue-based products (HCT/Ps) are articles in place to accelerate certain products’ develop- 2
containing or consisting of human cells or tissues ment. The regulations define a serious disease as
a disease or condition associated with morbidity
that are intended for implantation, transplanta-
tion, infusion, or transfer into a human recipient. that has substantial impact on day-to-day func- 3
Following the tiered approach, these products are tioning. Short-lived and self-limiting morbidity
solely regulated under Section 361 of PHS Act if usually will not be sufficient, but the morbidity
need not be irreversible if it is persistent or
4
they meet the criteria as follows:
• The HCT/P is minimally manipulated. recurrent. Whether a disease or condition is
• The HCT/P is intended for homolo-
serious is a matter of clinical judgment, based on 5
such factors as survival, day-to-day functioning
gous use only.
or the likelihood the disease, if left untreated,
• The manufacture of the HCT/P does
not involve the combination of the cells
will progress from a less-severe condition to a 6
more-serious one.8
or tissues with another article, except
Understanding FDA’s perspective and
for water, crystalloids, or a sterilizing, requirements for surrogate endpoints is par- 7
preserving, or storage; and either: (i) ticularly important when assessing accelerated
the HCT/P does not have a systemic
effect and is not dependent upon the
approval. Surrogate endpoints are defined as
laboratory measures or other tests with no direct
8
metabolic activity of living cells for its or obvious relationship to how a patient feels or
primary function; or (ii) the HCT/P has
a systemic effect or is dependent upon
to any clinical symptom, but on which a drug’s
beneficial effect is presumed to predict a desired
9
the metabolic activity of living cells beneficial effect on such a clinical outcome. Sur-
for its primary function, and (a) is for rogate endpoints fall into the category of either 10
autologous use; (b) is for allogeneic use “validated” or “unvalidated.” Validated surrogate
in a first-degree or second-degree blood endpoints are those tests for which adequate
relative; or (c) is for reproductive use. evidence exists that a drug’s effect on the measure 11
predicts the desired clinical benefit and may be
HCT/Ps that are marketed under Section 361
are not required to obtain premarket approval/
used as the basis for approval. Unvalidated surro-
gates are measures for which such evidence does 12
clearance from FDA. Distributors and marketers not exist. The Accelerated Approval Regulation (21
of HCT/Ps are permitted to self-designate the CFR 314.500, Subpart H, adopted 1992) permits
the approval of a treatment on the basis of its
13
tissue products as meeting the criteria set forth
effect on an unvalidated surrogate endpoint.
under 21 CFR Part 1271.
14
Regulatory Programs in the US to Expedite EU
Development of Drugs and Biologics Due to the number of countries involved and the 15
As mentioned previously, it is critical the reg- EU’s legal framework, regulatory issues arguably
are more complex in the EU. Stakeholders in
ulatory professional understands the legal and
regulatory framework that may support expe- the review and oversight of drugs and biologics 16
diting or minimizing development costs. In the include National Authorities as well as the Euro-
US, a number of formal programs are in place to pean Medicines Agency (EMA).
17
expedite the development of drugs or biologics EU Pathways for Drugs and Biologics
intended to support serious or life-threatening
conditions and/or where there is an unmet medi- Unlike the US, the EU essentially offers three 18
cal need, such as orphan drugs. options or routes to obtain approval to market

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 Chapter 14: Regulatory Pathways

Table 14-3. FDA Programs to Expedite Approval of Drug/Biologic Products Intended to Treat
Serious Conditionsa

Program/Path Criteria Timing Features

Breakthrough A drug or biologic intended Ideally, request designation no • FDA organizational
Therapy to treat a serious condition, later than End-of-Phase 2 meeting commitment and high-level
and preliminary clinical to optimize benefits involvement
evidence indicates the drug • Intensive guidance on
may demonstrate substantial efficient drug development
improvement on a clinically • Rolling NDA/BLA review
significant endpoint(s) over
available therapies • Other actions to expedite
development
Regenerative The drug is a regenerative medicine The request for RMAT • All breakthrough therapy
Medicine therapy, which is defined as a designation must be made either designation features,
Advanced cell therapy, therapeutic tissue concurrently with submission including early interactions
Therapy engineering product, human of an Investigational New Drug to discuss any potential
cell and tissue product, or any application (IND) or as an surrogate or intermediate
combination product using such amendment to an existing INDd. endpoints
therapies or products, except • Statute addresses potential
for those regulated solely under ways to support accelerated
Section 361 of the Public Health approval and satisfy post-
Service Act and part 1271 of Title approval requirements
21, Code of Federal Regulations;
The drug is intended to treat,
modify, reverse, or cure a serious
or life-threatening disease or
condition; and
Preliminary clinical evidence
indicates that the drug has the
potential to address unmet medical
needs for such disease or condition
Fast Track A drug or biologic intended to treat Ideally, no later than Pre-BLA or • Actions to expedite
a serious condition, and nonclinical Pre-NDA meeting development and review
or clinical data demonstrate the • Rolling NDA/BLA review
potential to address unmet medical
need or a drug designated as a
qualified infectious disease product
Accelerated A drug treating a serious During development to discuss • Approval based on an effect
Approval condition and generally providing endpointsb on a surrogate endpoint
a meaningful advantage or intermediate clinical
over available therapies and endpoint reasonably likely
demonstrates an effect on a to predict a drug’s clinical
surrogate endpoint reasonably benefit
likely to predict a clinical benefit or • Requires confirmatory trial(s)
on a clinical endpoint that can be to verify use of surrogate
measured earlier than irreversible endpoint and benefit
morbidity or mortality, reasonably
likely to predict an effect on an
intermediate clinical endpoint or
other clinical benefit
Priority Review A drug that treats a serious With original NDA • Reduced timelines for
condition and generally provides approval (priority and
a meaningful advantage over standard reviews reduced by
available therapies and, if two months)
approved, would provide a
significant improvement in safety
or effectiveness

Source: Adapted from Guidance for Industry, Expedited Programs for Serious Conditions—Drugs and Biologics (May 2014).
a. Guidance for Industry: Expedited Programs for Serious Conditions—Drugs and Biologics (September 2017). FDA website. http://www.
fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf. Accessed 15 October 2019.
b. 21 CFR Part 314, subpart H, Drugs for Human Use, Applications for FDA Approval to Market a New Drug. FDA website. http://www.
accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=314&showFR=1&subpartNode=21:5.0.1.1.4.8. Accessed 15
October 2019.
c. 21 CFR Part 601, subpart E, Biologics, Licensing. FDA website. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.
cfm?CFRPart=601&showFR=1&subpartNode=21:7.0.1.1.2.5. Accessed 15 October 2019.
d. Guidance for Industry: Expedited Programs for Regenerative Medicine Therapies for Serious Conditions (February 2019). FDA website.
https://www.fda.gov/media/120267/download. Accessed 15 October 2019.

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
a drug in an EU Member State (for biologics, Table 14-5 includes Centralised Procedure
only the Centralised Procedure is available). timelines, and Figure 14-1 is a Centralised Pro- 2
Regardless of whether the request is to mar- cedure flowchart.
ket a pharmaceutical product or a biologic, the
application is called a Marketing Authorization The Decentralised and Mutual 3
Recognition Procedures
Application (MAA). MAAs may be approved at
the Member State or EU level, depending on the The Decentralised and Mutual Recognition
Procedures are discussed together in this chapter
4
procedure used.
The three procedures are: the Centralised as they are very similar, except the Decentralised
Procedure; the Mutual Recognition Procedure/ Procedure is to be used when the product is not 5
Decentralised Procedure; and the National approved in any Member State, and Reference
Procedure. Summary information regarding each Member State (RMS) and Concerned Mem-
procedure’s criteria and key attributes is provided ber State (CMS) assessments are conducted 6
in Table 14-4, followed by additional details on in parallel. Both procedures are based on the
the Centralised and Mutual Recognition/Decen-
tralised Procedures. The EU procedure choice
principle of mutual recognition of national 7
authorizations. Using these procedures, the appli-
depends on the product type and the manufac- cant seeks approval in a single Member State.
turer and its commercial and business strategy. After approval is granted, that country (RMS) 8
The National Procedure is not discussed, as then refers the application to other EU Member
it is intended for products to be marketed in only
one EU Member State and results in a single
States (CMSs) chosen by the applicants. Only
in the event of a dispute among the Compe-
9
license for that country. tent Authorities will EMA be involved (for the
Centralised Procedure
purposes of arbitration). The respective licenses 10
remain under control of each Member State’s
Regulation (EC) No 726/2004 provides a Competent Authority in which the sponsor has
pan-European Centralised Procedure for sought approval. Tables 14-6 and 14-7 show 11
approval of certain product types identified standard Mutual Recognition and Decentralised
above. Centralised Procedure MAAs are submit-
ted to EMA. EMA provides the administrative
Procedure timelines.
12
support for application review and approval, Types of EU Drug Applications
with technical reviews of the applications being
conducted by scientific committees, including the Table 14-8 lists the four available drug and bio- 13
Committee for Medicinal Products for Human logics MAA types. Similar to the US and Japan,
Use (CHMP), the Committee on Orphan the amount of data to support approval will
depend on the product and the application type.
14
Medicinal Products (COMP), the Committee
for Advanced Therapies (CAT) and the Pae- EMA requires comprehensive safety, efficacy
diatric Committee (PDCO). These scientific and quality evidence, suggesting a single clinical 15
committees are comprised of regulatory agency trial might serve as sufficient evidence in the EU,
representatives from each Member State. EMA
assigns two CHMP members (rapporteur and
especially when there is “body of evidence.”10
However, in most instances, two pivotal or regis-
16
co-rapporteur) as the application’s primary tech- tration studies are required to support approval.
nical reviewers. CHMP is required to provide its Under the new data protection legislation, 17
opinion to EMA within 210 days. a drug or biologic applicant may be eligible for
As of April 2019, the application fee for a up to 11 years of data protection. This consists of
Centralised Procedure MAA was approximately an eight-year data protection period (no submis- 18
$325,000 (USD). sions allowed that leverage the applicant’s data)

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 Chapter 14: Regulatory Pathways

Table 14-4. EU Application Procedures for Drugs and Biologics

Type of Procedure Comments

Product
Drug Centralised • Mandatory for orphan drugs and products dealing with new active substances for certain types
of diseasesa
• Optional for other innovative drugs (including generics/hybrids of centrally authorized
products)
• Rapporteur and co-rapporteur assigned by EMA
• EMA reviews and maintains MA
• National Agencies have opportunity to ask question/comment on MA through CHMP
• One trademark for all EU countries
• Identical prescribing information and labeling in all EU countries
• Rapid and EU-wide authorization in 277 days (210 + 67 days)
Decentralised • Products not eligible for the Centralised Procedure or where the sponsor elects to file using the
and Mutual Mutual Recognition Procedure
Recognitionb • Sponsor selects Reference Member State (RMS)
• Assessment and approval by a single EU Member States (RMS)
• Assessment by a number of additional EU Member States
• Results in separate harmonized licenses in each Member State involved
• More than one trade name may be allowed
National • Intended for marketing in only one country
• National procedures apply (the rules of the country where the application was submitted)
Biologic Centralised • Mandatory for all biologics, including biosimilars and advanced therapy medicinal products
(gene and somatic therapy, tissue-engineered products
• Rapporteur and co-rapporteur assigned by EMA
• EMA reviews and maintains MA
• National Agencies have opportunity to ask questions, comment on MA through CHMP
• One trademark for all EU countries
• Identical prescribing information and labeling in all EU countries
• Rapid and EU-wide authorization in 277 days (210 + 67 days)

a. Acquired immune deficiency syndrome, cancer, neurodegenerative disorders, diabetes, autoimmune diseases and other immune
dysfunction diseases and viral diseases
b. The Decentralised Procedure is required for established medicinal products when the product is not approved in any EU Member
State. The Mutual Recognition Procedure is used for established medicinal products when the product has been approved previously
in at least one EU Member State.

Table 14-5. EU Standard Timelines for Centralised Applications

Day Action
1 Procedure start
80 Applicant receipt of assessment report (preliminary conclusions)
100 EMA receives comments from CHMP members
120 CHMP adopts list of questions and overall conclusions
1211 Applicant provides responses, clock starts
150 Applicant receives joint assessment report (preliminary conclusions)
170 Deadline for comments from CHMP members to rapporteur and co-rapporteur, EMA and other CHMP members
180 CHMP discussion and decision on the need for a list of outstanding questions or oral explanation by the
applicant
181 Restart of the clock and oral explanation (if needed)
181 to 210 Final draft of (English) Summary of Product Characteristics (SmPc), labeling and packaging leaflet submitted by
the applicant
215 at the Applicant provides EMA with SmPc, labeling and packaging leaflet in EU languages
latest
232 at the Applicant provides final translations of SmPc, labeling and packaging leaflet in the EU languages
latest
By 237 Opinions and annexes in all EU languages provided to applicant

Source: EMA Notice to Applicants, Volume 2A, Procedures for Marketing Authorisation, Chapter 4, Centralised Procedure

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

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Figure 14-1. EMA Centralised Procedure Flowchart With Major Milestones 2
FIRST PHASE SECOND PHASE 3
Final Scientific
List of Joint Opinion, 4
Reports Questions Report List of Report Day
Day 80 Day 120 Day 150 Issues? Day 210
5
SPC, EPAR
(public report
etc.) 6
Day 0 Day 100 Day 121 Day 180
Start of the EMA Peer Responses by Explanation by 7
Clock Review the Applicant the Applicant

Active Time: Evaluation

8
Clock Stop: e.g. time for the Applicant to prepare the reponse to questions, etc.

Source: The Centralised Procedure, Instrument for Pre-accession Assistance Program (IPA), EMA, London, UK, February 2010 9
Table 14-6. EU Standard Mutual Recognition Procedure Timelines
10
Day Action

11
Approximately 90 days Applicant asks Reference Member State (RMS) to update assessment report (AR) and allocate
before CMS submission procedure number.
- 14 Applicant submits application to Concerned Member State(s) (CMS). RMS circulates the AR
including Summary of Product Characteristics (SmPC), packaging leaflet (PL) and labeling to CMSs.

12
CMS application validation.
0 RMS starts the procedure.
50 CMSs send their comments to RMS and applicant.
60
Until Day 68
Applicant sends the response document to CMSs and RMS.
RMS circulates its assessment of the response document to CMSs
13
75 CMSs send their remaining questions to RMS and applicant. A break-out session can be organized

85
between Days 73–80.
CMSs sends any remaining comments to RMS and applicant.
14
90 CMSs notify RMS and applicant of final positions (and in case of negative position, also the CMD
secretariat of the EMA). If consensus is reached, the RMS closes the procedure. If consensus is not
reached, the points for disagreement submitted by CMSs are referred to CMD(h) by the RMS within
seven days after Day 90.
15
150 For procedures referred to CMD(h):
• If consensus is reached at the CMD(h) level, the RMS closes the procedure.
• If consensus is not reached at the CMD(h) level, the RMS refers the matter to CHMP for arbitration.
16
Five days after close of Applicant sends high-quality national translations of SmPC, PL and labeling to CMSs and RMS.

17
procedure
30 days after close of National marketing authorizations granted in CMSs, subject to submission of acceptable trans-
procedure lations.

Source: EMA Notice to Applicants, Volume 2A, Procedures for Marketing Authorisation, Chapter 2, “Mutual Recognition, Annex I,” Flow Chart
for the Mutual Recognition Procedure, February 2007. 18

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 Chapter 14: Regulatory Pathways

Table 14-7. EU Standard Decentralised Procedure Timelines

Day Action
Before Day -14 Applicant discusses with Reference Member State (RMS).
RMS allocates procedure number. Creation in Communication and Tracking System (CTS).
Day -14 Submission of the dossier to RMS and Concerned Member States (CMSs).
Application validation.
Assessment Step I
Day 0 RMS starts procedure. CMS is informed via CTS
Day 70 RMS forwards the Preliminary Assessment Report (PrAR), including comments on Summary of
Product Characteristics (SmPC), packaging leaflet (PL) and labeling to CMSs and the Applicant
Until Day 100 CMSs send their comment to RMS and applicant.
Until Day 105 Consultation between RMS and CMSs and applicant. If consensus is not reached, RMS stops the
clock to allow applicant to supplement the dossier and respond to questions.
Clock Off period Applicant may send draft responses to RMS and agree the date with the RMS for submission of
the final response. Applicant sends the final response document to the RMS and CMSs within a
recommended three-month period, which could be extended if justified.
Day 106 Valid applicant response submission received. RMS restarts the procedure.
Day 106 – 120 RMS updates the Preliminary Assessment Report to prepare Draft Assessment Report (DAR), draft
SmPC, draft labeling and draft PL to CMSs.
Day 120 RMS may close procedure if consensus is reached. Proceed to national 30-day step for granting MA.
Assessment Step II
Day 120 (Day 0) If consensus is not reached, RMS sends the Draft Assessment Report, draft SmPC, draft labeling
and draft PL to CMSs.
Day 145 (Day 25) CMSs send final comments to RMS.
Day 150 (Day 30) RMS may close procedure if consensus reached. Proceed to national 30-day step for granting MA.
Day 160 Applicant sends the response document to CMSs and RMS
Day 180 (Day 60) If consensus is not reached by Day 150, RMS to communicate outstanding issues to applicant,
receive any additional clarification and prepare a short report for discussion at Coordination Group.
Day 195 (at the latest) Breakout session (BOS) of involved Member States at EMA to reach consensus on the matter.
Between Day 195 and RMS consults with the CMSs and the applicant to discuss the remaining comments raised.
Day 210
Day 210 (Day 90) If consensus is reached:
• In case of positive position from RMS, Closure of the procedure including CMSs approval of
assessment report, SmPC, labelling and PL
and proceed to national 30 days step for granting the MA.
• In case of negative position from the RMS, Closure of the procedure negatively. The End of
Procedure letter plus final Day 210
overview AR is circulated.
If consensus is not reached:
In case of negative position from CMS, CMS notify the RMS, the other CMSs, applicant and the
secretariat of the Co-ordination group.
Referral to the Co-ordination group.
at the latest, with-in 7 If consensus was not reached at Day 210, points of disagreement will be referred to the
days after day 210 Coordination Group for resolution.
Day 270 (at the latest) Final position adopted by Coordination Group with referral to CHMP for arbitration in case of
unresolved disagreement.
National Step
7 days after close of Applicant sends high-quality national translation of SmPC, labeling and PL to CMS and RMS.
procedure
30 days after close of National MA granted in RMS and CMSs if no referral to the Coordination Group. National Agencies
the procedure will adopt the decision and issue the MA subject to submission of acceptable translations.
30 days after close of National MA granted in RMS and CMSs if positive conclusion by the Coordination Group and no
CMD referral procedure referral to CHMP. National agencies will adopt the decision and issue the MA subject to submission
of acceptable translations.

Source: CMDh, procedural guidance, CMDh/080/2005, Rev. 3, Flow Chart of the Decentralised Procedure, February 2018.

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

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Table 14-8. Drug MAA Types in EU 2
3
Types of MAAs When Required
Full MAA • Compulsory for new active substances
- Article 8(3) of Directive 2001/83/IEC
Abridged Applications • Generic applications for essentially similar medicinal products
- Article 10(1) and Part II(2) of
Directive 2001/83/IEC
• A generic authorization may be extended to cover more or additional indications,
strengths and pharmaceutical forms than the original product if the applicant 4
submits sufficient bridging data
Hybrid Applications • The product does not fall within the definition of a generic medicinal product
- Article 10(3) of Directive 2001/83/EC • Bioequivalence cannot be demonstrated
• Changes in the active substance, indication, strength, pharmaceutical form or
5
route of administration cannot be bridged
Bibliographic Applications • Detailed references to published scientific literature may be used if a medicinal
- Article 10(a) of Directive 2001/83/EC product has a well-established medicinal use, recognized safety and an acceptable
safety level 6
7
and an additional two-year period of marketing Regulatory Mechanisms in the EU to
Expedite Development of Drugs and
protection. This period can be extended to 11
years if, during the first eight, the Marketing Biologics
8
Authorization Holder (MAH) obtains an autho-
rization for one or more new therapeutic indi-
Similar to the US, the EU legal framework
provides mechanisms to support the more-rapid
9
cations that bring a significant clinical benefit in
advancement and availability of important and
comparison with existing therapies.
innovative medicinal products. Table 14-9 sum-
marizes these mechanisms, which typically are
10
Biologics
used for products to treat serious conditions and
The US and EU have distinct but overlapping for orphan products. 11
schemes for biologics’ regulation. In the EU, bio-
logics are defined largely in terms of their active Biosimilars
substances and manufacturing methods.11 Since 2005, the EU has had a legal framework in
12
The EU definition for a biologic is located in place for biosimilar or “similar biological medicinal
Appendix A of this chapter. Examples of biolog-
ics in the EU legal framework include medi-
product” approval (Directive 2001/83/EC, Direc- 13
tive 2004/27/EC or EMEA Guideline on Similar
cines derived from human blood and plasma, Biological Medicinal Products (CHMP/437/04
developed from recombinant DNA technology, London, 30 October 2005)), and a number of 14
immunologic medicines and advanced therapy biosimilars have been approved. The first EU
medicinal products (cell and gene therapies).
The vast majority of biologics fall under the
biosimilar was approved in 2005 (Omnitrope,
somatropin); to date, approximately 53 biosimilars
15
scope of the Centralised Procedure, although applications have gained EU approval.
some products, such as vaccines, are approved at 16
the Member State level. Japan
Biotechnology products’ approval stan-
dards are the same as for chemically synthesized Japan’s Ministry of Health, Labour and Welfare 17
medicines. Both product types must be safe and (MHLW), established as a governmental admin-
effective and have appropriate quality. Additional istrative body under the Japanese Constitution, is
requirements are applicable to biologics, espe- responsible for the approval and surveillance of 18
cially for advanced therapy medicinal products. drugs and biologics, and operates the country’s

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 Chapter 14: Regulatory Pathways

Table 14-9. EU Mechanisms for Accelerated Drug and Biologics Development and Approval

Procedure Feature
Conditional Approval

• For orphan disease, serious or life-threatening condition or • Allows marketing with “less than complete” data
use in emergency situations • Subject to obligations (i.e., completion of ongoing studies,
• Positive benefit-risk additional studies)
• Fulfills unmet medical needs • Temporary MAA (one year)a
• Able to provide future comprehensive data
Approval Under Exceptional Circumstancesb
• Unable to provide comprehensive data due to small patient • MAA granted subject to the applicant introducing specific
population, cannot be provided or contrary to accepted ethics procedures concerning the medicinal product’s safety
Adaptive Licensing (Pilot Status)
• Foresees initial approval in a well-defined patient subgroup Builds on regulatory processes already in place:
with a high medical need and subsequent widening of the • Scientific Advice
indication • Compassionate use
• Conditional approval
• Patient registries and pharmacovigilance tools
Accelerated Procedurec
• For medicinal products of major public health interest and, • Scientific opinion in 150 days (instead of 210)
particularly, from the viewpoint of therapeutic innovation
PRIME: priority medicinesd
• The scheme focuses on medicines that may offer a major • Through PRIME, the Agency offers early and proactive
therapeutic advantage over existing treatments, or benefit support to medicine developers to optimise the generation
patients without treatment options. These medicines are of robust data on a medicine’s benefits and risks and
considered priority medicines by EMA. enable accelerated assessment of medicines applications.
• To be accepted for PRIME, a medicine has to show its
potential to benefit patients with unmet medical needs
based on early clinical data.
Advance therapy medicinal product (ATMP) classificatione
• Advanced therapy medicinal products (ATMPs) are • Centralised procedure mandatory
medicines for human use that are based on genes, tissues • Assessment of the Quality, Safety & Efficacy
or cells. They offer groundbreaking new opportunities for • Post-authorisation vigilance; specific obligation for safety
the treatment of disease and injury. and for efficacy

a. Commission Regulation (EC) No 507/2006 of 29 March 2006 on the conditional marketing authorisation for medicinal products for
human use falling within the scope of Regulation No (EC) No 726/2004 of the European Parliament and of the Council
b. Guideline on procedures for the granting of a marketing authorisation under exceptional circumstances, pursuant to Article 14(8) of
Regulation (EC) 726/2004 (EMEA/357981/2005)
c. Guideline on the procedure for accelerated assessment pursuant to Article 14(9) of Regulation (EC) No 726/2004
d. EMA website: https://www.ema.europa.eu/en/human-regulatory/research-development/prime-priority-medicines
e. EMA website: https://www.ema.europa.eu/en/human-regulatory/overview/advanced-therapy-medicinal-products-overview

National Health System. Conceptually, MHLW and biologics. Historically, drug and biologic
is similar to the US HHS, to which FDA reports. approvals have lagged behind the US and EU,
In Japan, it is necessary to comply with the primarily due to the requirement for testing on
Pharmaceutical & Medical Device Act (PMD Act) the Japanese population.12
to manufacture, import and sell drug products
and biologics. Pathways for Drugs and Biologics
The Pharmaceuticals and Medical Devices The legal basis for drug approval is based on the
Agency (PMDA) is an independent admin- Pharmaceutical and Medical Device Act, “On Drug
istrative organization, the role of which is Approval Applications” (PFSB Notification No.
to provide consultations concerning clinical 1121-(2) dated 21 November 2014). The current
trials and conduct approval reviews for drugs categories are as follows:

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
• drugs containing new active ingredient In Japan, a patent can be extended up to five
• new prescription combination drugs years if it cannot be exploited due to governmental 2
• drugs with new route of administration examination for drug approval. A generic drug
• drugs with new indications applicant cannot refer to the innovator company’s
• prescription drugs with new dosage data until after the original drug’s reexamination 3
forms period. The timing for when these drugs should be
drugs with new doses
•
• biosimilar products
reexamined is designated by the MHLW at the
time of their approval as new drugs. The times that
4
• prescription drugs with additional
reexaminations should generally be conducted for
•
dosage forms
prescription combination drugs with
specific products are given below. 5
• Orphan drugs—reexamination 10 years
similar formulations
after the date of approval
• other prescription drugs
• Drugs containing new active ingredi- 6
MHLW’s standard new drug approval review ents—reexamination eight years after
time is one year (excluding time taken by the
•
the date of approval
Drugs with new routes of administra-
7
applicants to prepare responses). For designated
orphan drugs and other drugs considered to be tion—reexamination six years after the
especially important from a medical standpoint, date of approval 8
the drug product may be chosen for priority • New prescription combination drugs,
review after an evaluation of the target disease’s drugs with new indications, drugs with
seriousness and the product’s clinical usefulness new dosages—reexamination from four 9
(Notification No. 0122-(12) of the Eval- to within six years after the date of
uation and Licensing Division, PSEHB).
The timeline for priority reviews is nine
approval
10
months. Figure 14-2 is a drug application Marketing application fees for new drugs are
review flowchart. provided in Table 14-10. 11

Figure 14-2. Flow Chart of Drug and Device Review in Japan

12

Review Process for Drug or Medical Device Application

13

Applicant 14
Approval

Inquiry/Response Filing of
Application
Review Report
15
Minister of Health,
Labour and Welfare
External Advice Consultation
16
Experts Expert
Discussion
Pharmaceutical Affairs and
Food Sanitation Council 17
Source: PMDA website 18

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 Chapter 14: Regulatory Pathways

Table 14-10. Japan Drug Filing Fees

Application Type Total Fee (Yen)

Drug containing new ingredient, drug for a new route administration, drug with a 46,901,700
new combination, biotechnology-based existing drug

Biosimilars • The drug is indicated for serious diseases.

• The medical usefulness is high.
In 2009, biosimilars were added to the prescrip- • Confirmatory clinical trials are difficult
tion drug application categories, and policies for to conduct.
the assurance of their quality, safety and efficacy • The results of clinical trials, etc. other
were formulated (Notification No. 0304007 of
than confirmatory clinical trials suggest
the Evaluation and Licensing Division, PFSB
some efficacy and safety.
dated 4 March 2009).
SAKIGAKE Designation
Regenerative Medicine
In April 2015, the Ministry of Health, Labour
In November 2013, the Pharmaceuticals Affairs and Welfare notified the start of the SAKI-
Law (PAL), now called the PMD Act, was GAKE designation system in Japan. SAKI-
revised, and a new Regenerative Medicine Law GAKE is a system to put innovative medical
was established, providing the legal framework products, including pharmaceuticals, medical
for development and approval of cell-tissue based devices and regenerative medical products from
products (e.g., stem cell therapy) and to expedite Japan into clinical use. In order to receive a
development. This new law defines regenera- SAKIGAKE designation, the new product must
tive medicine products and enables conditional meet the following criteria:
• Innovativeness of the products, with
approval based on Phase 2 data. Figure 14-3
novel mechanism of action
is a graphic representation of the new approval
• The target medical condition should
system for cellular therapy products.
include one of the following:
Conditional Approval Pathway ○ serious or life-threatening medical
condition; or
For drugs for treating serious diseases that
○ medical condition with persistent
occur in a small number of patients and for
symptoms (conditions interfering
which effective treatment methods are limited,
with normal activities of daily
a conditional accelerated approval system was living) for which there is no other
established in which the results of confirmatory curative treatment
clinical trials are not required, but the conduct of • Highly effective treatment against the
necessary post-marketing surveys, etc., is required target medical condition. No other
as a condition for marketing approval (Notifica- therapy for the target medical condition
tion No. 1020(1) of Pharmaceutical Evaluation exists, or the symptoms of patients are
Division, PSEHB entitled “Implementation of expected to be significantly improved
conditional accelerated approval system for phar- through use of the product as compared
maceuticals” dated 20 October 2017). The drugs to existing therapies (including the case
eligible for this accelerated approval system must where safety is expected to be improved
meet all of the following conditions: significantly)

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

Figure 14-3. Japan’s New Approval System for Commercialization of Cellular Therapy Products 2
OLD PATHWAY 3
Clinical
Research
Clinical Trial
(confirmation of efficacy and safety)
Approval On
Market 4
5
Leading to Earlier Patient Access!
NEW PATHWAY 6
Conditional
Clinical
Clinical Trial
(confirmation of
Approval On Market
(further assessment of
Approval or
Expiration of On 7
Research probable benefit* (approval with efficacy and safety)
Conditional Market
condition and Approval
and the safety**)
period)
8
Informed Consent through the
explanation of possible risk with
*Probable benefit: Assumption of efficacy with small patient population taking post-market safety measures 9
**Safety: Earlier detection and evaluation of adverse events

10
Source: PMDA website

• The product is developed rapidly, and Canada 11

an application is submitted for approval
in Japan, ahead of other countries. The New drugs are regulated under Part C, Division 8
sponsor of the product intends to file an of the Food and Drug Regulations. Companies are 12
initial application for approval in Japan, granted market authorization by Health Canada
including the submission of simultaneous in several ways. Regardless of the method of
applications in Japan and other countries. authorization, a manufacturer receives a Notice 13
of Compliance (NOC) when it has met Health
Under the current framework, MHLW solicits
candidate products that satisfy the above criteria
Canada’s regulatory requirements for a product’s
safety, efficacy and quality. A Notice of Compli-
14
and conducts a hearing on the candidate prod- ance is a notification, issued pursuant to paragraph
ucts in preparatory evaluation. The potential C.08.004(1)(a), indicating that a manufacturer 15
candidates meeting these specified criteria are has complied with sections C.08.002 or C.08.003
invited to apply as candidates for a SAKIGAKE and C.08.005.1 of the Food and Drug Regulations.
designation. MHLW evaluates the applied prod- Notices of Compliance are issued to a manufacturer 16
ucts based on application review priorities set by following the satisfactory review of a submission.13
PMDA, and the products judged to be excel-
lent are selected for a SAKIGAKE designation.
Pathways for Drugs and Biologics 17
MHLW reports these selections to the Phar- The following provides a brief overview of three
maceutical Affairs and Food Sanitation Council, of the most common routes by which new drugs 18
and then designation results are made public. are authorized for sale in Canada.

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 Chapter 14: Regulatory Pathways

• Innovator drugs (“brand name drugs”): seeking Priority Review status of a drug submission
Manufacturers receive authorization must first provide a written request together with
to sell these products in Canada by a completed clinical assessment package to the
submitting a New Drug Submission appropriate Directorate. Priority Review submis-
(NDS) pursuant to section C.08.002 of sions are subject to the same quality, safety and
the Food and Drugs Regulations. efficacy requirements as non-priority submissions
• Subsequent entry drugs (“generic and, therefore, the time required to review the
drugs”): Health Canada often autho- information is the same. However, Priority Review
rizes manufacturers to market these submissions are inserted into Health Canada’s drug
drugs by requiring them to submit an submission queue in accordance with a shortened
Abbreviated New Drug Submission
review target and, as such, may be reviewed in
(ANDS) pursuant to section C.08.002.1
advance of non-priority submissions.14
of the Food and Drug Regulations. These
products will receive a declaration of Biosimilars
bioequivalence to a Canadian Reference
Product (pursuant to Section C.08.004 A biosimilar biologic drug, or biosimilar, is a bio-
(4)), which will be stated on the NOC. logic drug demonstrated to be similar to a brand
• Health Canada’s Changes in Manu- name drug already authorized for sale (known
facturer’s Name and/or Product Name as the reference biologic drug). Biosimilars were
Policy outlines another option for man- previously known in Canada as subsequent entry
ufacturers wishing to receive authoriza- biologics (SEBs). Biosimilars may enter the
tion through an NOC to market brand market after the expiry of reference biologic drug
name and generic drug products. This patents and data protections.15
policy applies to eligible drug submis- Biosimilars are regulated as new drugs
sions submitted to Health Canada for under the Food and Drugs Act and the Food and
a change in the manufacturer’s name Drug Regulations. To obtain authorization as a
and/or product name subsequent to
biosimilar, the drug manufacturer must provide
a merger, buy-out or other corporate
information to Health Canada to show that the
restructuring or the establishment of a
biosimilar and the reference biologic drug are
licensing agreement.
similar and that there are no clinically mean-
Priority Review of Drug Submissions ingful differences in terms of safety and efficacy
between them.
Priority Review is a fast-track status granted to eli- The Health Products and Food Branch
gible new drug submissions for human use, follow- (HPFB) timeframe to reach first decision on an
ing review and approval of a request submitted by application are outlined as time in average calen-
the drug sponsor. Priority Review submissions are dar days and fees in Table 14-11.
introduced into Health Canada’s drug review queue
in accordance with an accelerated review target of Notice of Compliance with Conditions
180 days. Priority Review status may be granted (NOC/c)
to drug submissions intended for the treatment, An NOC/c is authorization to market a drug
prevention or diagnosis of serious, life-threaten- (i.e., a Notice of Compliance (NOC)), with the
ing or severely debilitating illnesses, or conditions condition that the sponsor undertake additional
where a) there is no existing drug on the Canadian studies to verify the clinical benefit. The NOC,
market with the same profile or b) where the new qualifying under the NOC/c policy, is issued
product represents a significant improvement in the under section C.08.004 of the Food and Drug
benefit/risk profile over existing products. Sponsors Regulations. Market authorization under the

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

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Table 14-11. Human Drug (Pharmaceutical and Biological) Submission and Application 2
Review Timeframe and Fees as of April 1, 2019

Application Type Review Feeb 3

Timea
New Active Substance Submissions in support of a drug , excluding a disinfectant, 300 days $355,579
(NDS) that contains a medicinal ingredient not previously approved
in a drug in Canada and that is not a variation of a previously
approved medicinal ingredient such as a salt, ester,
4
enantiomer, solvate, or polymorph.
Clinical or Non-Clinical Data and
5
Submissions based on Clinical or Non-Clinical data and 300 days $180,101
Chemistry & Manufacturing Chemistry & Manufacturing data for a drug that does not
(NDS & SNDS) include a new active substance.
Clinical or Non-Clinical Data Only Submissions based only on Clinical or Non-Clinical data for a 300 days $84,059
(NDS & SNDS) drug that does not include a new active substance.
Comparative Studies (ANDS, NDS,
SANDS & SNDS)
Submissions based on comparative studies (e.g. Clinical
or non-clinical data, bioavailability, pharmacokinetic
180 days $50,808 6
and pharmacodynamic data) with or without Chemistry &
Manufacturing data for a drug that does not include a new

7
active substance.
Chemistry & Manufacturing Data Only Submissions based only on Chemistry & Manufacturing data 180 days $24,023
(ANDS, NDS, SANDS & SNDS) for a drug that does not include a new active substance.
Published Data Only Submissions based only on published clinical or non-clinical 300 days $19,921
(SANDS & SNDS)
Switch status from prescription drug
data for a drug that does not include a new active substance.
Submissions based only on data that support the $48,370 8
to non-prescription drug modification or removing of a medicinal ingredient listed in
Schedule F of the Food and Drug Regulations (i.e. identical
claim for existing drug).
Labelling Only
(ANDS, NDS, SANDS & SNDS)
Submissions of labelling material. (i.e. does not include
supporting clinical or non-clinical or Chemistry and
60 days $3,238 9
Manufacturing data.)

10
Administrative Submission Submissions in support of a manufacturer or product name 45 days $338
(ANDS, NDS, SANDS & SNDS) change.
Disinfectants Submissions and applications that include data in support of 300 days $4,480
(NDS-D & SNDS-D) a disinfectant.
Drug Identification Number
application - Labelling Standard
Applications attesting to compliance with a labelling standard 45 days
or Category IV Monograph for a drug that does not include
clinical or non-clinical data or chemistry and manufacturing
$1,797
11
data.
New Active Substance Submissions in support of a drug , excluding a disinfectant, 300 days $355,579
(NDS) that contains a medicinal ingredient not previously approved
in a drug in Canada and that is not a variation of a previously 12
approved medicinal ingredient such as a salt, ester,
enantiomer, solvate, or polymorph.
Clinical or Non-Clinical Data and
Chemistry & Manufacturing
(NDS & SNDS)
Submissions based on Clinical or Non-Clinical data and
Chemistry & Manufacturing data for a drug that does not
include a new active substance.
300 days $180,101
13
Clinical or Non-Clinical Data Only Submissions based only on Clinical or Non-Clinical data for a 300 days $84,059
(NDS & SNDS) drug that does not include a new active substance.
Comparative Studies
(ANDS, NDS, SANDS & SNDS)
Submissions based on comparative studies (e.g. Clinical
or non-clinical data, bioavailability, pharmacokinetic
180 days $50,808 14
and pharmacodynamic data) with or without Chemistry &
Manufacturing data for a drug that does not include a new

Chemistry & Manufacturing Data Only

active substance.
Submissions based only on Chemistry & Manufacturing data 180 days $24,023
15
(ANDS, NDS, SANDS & SNDS) for a drug that does not include a new active substance.
Published Data Only Submissions based only on published clinical or non-clinical 300 days $19,921
(SANDS & SNDS)
Switch status from prescription drug
data for a drug that does not include a new active substance.
Submissions based only on data that support the $48,370
16
to non-prescription drug modification or removing of a medicinal ingredient listed in
Schedule F of the Food and Drug Regulations (i.e. identical

Labelling Only
claim for existing drug).
Submissions of labelling material. (i.e. does not include 60 days $3,238 17
(ANDS, NDS, SANDS & SNDS) supporting clinical or non-clinical or Chemistry and
Manufacturing data.)
Administrative Submission
(ANDS, NDS, SANDS & SNDS)
Submissions in support of a manufacturer or product name
change.
45 days $338
18

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 Chapter 14: Regulatory Pathways

Table 14-11. (cont.)

Disinfectants Submissions and applications that include data in support of 300 days $4,480
(NDS-D & SNDS-D) a disinfectant.
Drug Identification Number Applications attesting to compliance with a labelling standard 45days $1,797
application - Labelling Standard or Category IV Monograph for a drug that does not include
clinical or non-clinical data or chemistry and manufacturing
data.

a. Service Standards for Drug Submission Evaluations (Pharmaceuticals and Biologic Products) under the Food and Drug Regulations
- Health Canada. Government of Canada website. https://www.canada.ca/en/health-canada/corporate/about-health-canada/
legislation-guidelines/acts-regulations/service-standards-high-volume-regulatory-authorizations/service-standards-drug-
submission-evaluations-pharmaceuticals-biologic-products-under-food-drug-regulations.html. Accessed 20 August 2019.
b. Fiscal 2019 fees in Canadian dollars.

NOC/c policy allows Health Canada to provide supplied in, or exported from Australia must be
earlier market access to potentially life-saving included in the Australian Register of Therapeu-
drugs. Conditions associated with market autho- tic Goods (ARTG). Sponsors must submit an
rization allow Health Canada to monitor the application to TGA for their medical products to
drug through enhanced postmarket surveillance. be included in the ARTG.
Eligibility is restricted to promising new drug Australia has a two-tiered system for the
therapies intended for the treatment, preven- regulation of medicines, including complemen-
tion or diagnosis of serious, life-threatening or tary medicines:16
severely debilitating diseases or conditions for
• Higher risk medicines must be
which a) there is no alternative therapy available
registered on the ARTG, which
on the Canadian market or b) where the new
involves individually evaluating the
product represents a significant improvement in
quality, safety and effectiveness of
the benefit/risk profile over existing products.
Sponsors of drugs authorized under the
the product.
NOC/c policy must agree to carry out additional • Lower risk medicines containing
clinical trials to verify the clinical benefit of pre-approved, low-risk ingredients
the drug. In addition, conditions will include: a and that make limited claims can be
requirement to undertake increased monitoring listed on the ARTG.
of the drug and reporting to Health Canada;
a requirement to provide educational material, Within the regulatory framework, medicines are
including the nature of the conditions of use, classified as either registered or listed as follows:
for health care practitioners and patients; and • Registered medicines are assessed by
restrictions on advertising and labeling. TGA for quality, safety and efficacy. All
prescription medicines and most over-
Australia the-counter medicines are registered.
The Therapeutic Goods Administration (TGA) Some complementary medicines are
is Australia’s regulatory authority for therapeutic registered.
goods that carries out a range of assessment and • Listed medicines are assessed by TGA
monitoring activities to ensure therapeutic goods for quality and safety but not efficacy.
available in Australia are of an acceptable standard. Some over-the-counter medicines are
The Therapeutic Goods Act 1989 (the Act) listed. Most complementary medicines
requires that medical products imported into, are listed.

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
Pathways for Drugs a change in the product specifications, a
change in the steps of manufacture or a 2
Applications to register new or existing prescrip- change in trade name.
tion medicines are accompanied by supportive
scientific data and evaluated with timeframes Sponsors may apply to register a prescription 3
underpinned by legislation and/or associated medicine under the provisional approval pathway,
business rules. The framework for prescription
medicines includes the following categories:
priority review pathway or the standard prescrip-
tion medicines registration pathway.
4
• Category 1 application—an application The standard registration pathway consists
to register a new prescription medicine of eight phases with eight milestones, allowing 5
(other than an additional trade name) effective planning and tracking by TGA and
or to make a variation to an existing applicants. Each phase has established timeframes.
medicine that involves the evaluation Figure 14-4 provides an overview of the standard 6
of clinical, preclinical or bioequivalence registration process and related timeframes.
data, e.g., new chemical entities, exten-
sions of indication and new routes of
Priority Review Designated Applications 7
administration. TGA has a formal priority review pathway for
• Category 2 application (Comparable faster assessment of vital and life-saving 8
Overseas Regulator (COR) report- prescription medicines for which a complete data
based process)—an application accom-
panied by two independent unredacted
dossier is available. The target timeframe of 150
working days is up to three months shorter than
9
assessment reports from comparable the standard prescription medicines registration
overseas regulators in whose jurisdiction
the product is approved for the same
process. A valid priority review designation must
be held in order to access the priority review
10
indication. pathway. A medicine may be eligible for priority
• Category 3 application—an application determination if all eligibility criteria listed below 11
to register or to vary the registration are satisfied (regulation 16R of the Therapeutic
of a prescription medicine where the Goods Regulations 1990 (the Regulations)).
application does not require the support • The medicine is a new prescription med- 12
of clinical, preclinical or bioequivalence icine or a new indications medicine; and
data, e.g., a change in the site of manu-
facture, a change to the synthetic route,
• An indication of the medicine (the prior-
ity indication) is the treatment, preven-
13
14
Figure 14-4. Standard Registration Process With TGA

Phase Pre-submission Submission First Round

Assessment
Consolidated
Section 31 Request Second Round
Assessment
Expert Advisory
Review Decision Post-decision
15
Response

16
Milestone MS1 MS2 MS3 MS4 MS5 MS6 MS7 MS8
Outcome of Outcome of submission Outcome of first round End of s.31 request Outcome of assessments Outcome of advisory Decision made by Administrative and
pre-submission planning consideration sent assessment sent response period sent committee sent delegate regulatory activities
sent complete
Advisory committee
meeting

Pre-ACPM

17
Dossier arrives at TGA by Applicant preparation of
COB 7th or 14th of month response to section 31 response
PPF lodged before (unless applicant advised request and first round and review AusPAR C-i-C content
first of month of alternative date) assessment reports of reports review and PI/CMI
requirements fulfilled
Major
Activities
Pre-submission Processing and First round Second round Delegate decision Documents published,
planning considering submission assessment assessment including PI/CMI/RMP new/revised ARTG entry

18
Consolidated Response received by Delegate Committee negotiation
section 31 TGA or response overview advice
request period ends prepared
compiled
Committee papers
circulated

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 Chapter 14: Regulatory Pathways

tion or diagnosis of a life-threatening or The TGA has a formal provisional approval

seriously debilitating condition; and pathway for the provisional registration of pre-
• When compared against registered scription medicines on the basis of preliminary
therapeutic goods, either: clinical data, where there is the potential for a
○ no therapeutic goods that are substantial benefit to Australian patients. A valid
intended to treat, prevent or diag- provisional determination must be held in order
nose the condition are included in to access this pathway. A medicine may be eligi-
the Register (except in the part of ble for provisional determination if all eligibility
the Register for goods known as criteria listed below are satisfied.
provisionally registered goods); or • The medicine is a new indications med-
○ if one or more therapeutic goods icine or a new prescription medicine.
that are intended to treat, prevent • An indication of the medicine is the
or diagnose the condition are treatment, prevention or diagnosis of a
included in the Register (except in life threatening or seriously debili-tating
the part of the Register for goods condition, and when compared against
known as provisionally regis- existing therapeutic goods, either:
tered goods)—there is substantial ○ no therapeutic goods that are
evidence demonstrating that the intended to treat, prevent or diag-
medicine provides a significant nose the condition are included
improvement in the efficacy or in the Register (except in the part
safety of the treatment, prevention of the Register for provisionally
or diagnosis of the condition com- registered goods); or
pared to those goods; and ○ if one or more therapeutic goods
• There is substantial evidence demon- that are intended to treat, prevent
strating that the medicine provides a or diagnose the condition are
major therapeutic advance. included in the Register (except in
Under sub regulation 16R(3) of the Regulations, the part of the Register for goods
the priority determination is specific to the known as provisionally registered
priority applicant, each active ingredient of the goods), there is preliminary clinical
medicine and the priority indication. The priority data demonstrating that the medi-
determination therefore applies to a specific cine is likely to provide a significant
medicine for a specific indication. For multiple improvement in the efficacy or
indications, one application for each indication safety of the treatment, prevention
must be submitted. or diagnosis of the condition com-
A registration submission that is a combina- pared to those goods.
tion of priority and non-priority indications will • There is preliminary clinical data
not be eligible for review under the priority review demonstrating that the medicine is
pathway. However, multiple priority determina- likely to provide a major therapeutic
tions may apply to one registration application. advance, and the person who made the
Combinations of medicines that are not fixed application under subsection 22C(1) of
dose combinations require separate applications the Act has provided sufficient evidence
(one for each component of the non-fixed dose of the plan to submit comprehensive
combination). The priority review registration pro- clinical data on the safety and efficacy
cess and timeframes are provided in Figure 14-5. of the medicine before the end of
the six years (starting on the day that
Provisional Approval Pathway provisional registration of the medicine

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

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Figure 14-5. TGA Priority Registration Process Diagram 2
Optional pre-submission meeting
(up to 3 months)
3
Part of the
determination
process
Determination application and decision
4
(1 month*)

5
No more
Phase 1
than 6
PPF submission (PPF only option)
months
6
Phase 2
Submission
(1 – 1.5 months)
7
Milestone 2

Phase 3 8
First round of assessment
with rolling questions
(3 months)
9
Milestone 3

Phase 4
Optional consolidation s31 response
(30 calendar days)
10
11
Milestone 4

150 Phase 5
working Second round of assessment
days (1 month)

Milestone 5
12
Timeframes for final
Phase 6 evaluation reports,
Expert advisory review
if required
sponsor response
and Delegate’s
13
(2 months) overview are as per
standard process
Milestone 6
14
Phase 7
Decision
(1 month)

Milestone 7
15
16
Phase 8
Post decision
(1.5 month)

Milestone 2
17
*Note: The determination assessment and decision making

18
process has a target timeframe if 20 working days

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 Chapter 14: Regulatory Pathways

would commence if the Secretary were instrument to be a biological. Products that are
to provisionally register the medicine). regulated as biologicals include, but are not lim-
ited to: tissue-based products (skin, bone, ocular,
The provisional determination for a medicine is cardiovascular, amnion), cell-based products
specific to the following (section 22D(3) of the Act): (genetically modified, in vitro cell expansion or
• the person who is the provisional appli- depletion), immunotherapy products contain-
cant ing human cells combination products (e.g.,
• the medicine cell therapy and medical device), products that
• each active ingredient of the medicine comprise or contain live animal cells, tissues or
to which the determination relates organs (e.g., pancreatic islet cells isolated from
• the provisional indication pigs), autologous human cells and tissue products
The provisional determination therefore applies (including stem cells).
All biologicals must be classified before
to a specific medicine for a specific indication.
they can be included on the ARTG. Biologicals
The indication proposed at determination
are classified according to the level of risk to
may be different to that approved at the time of
patients associated with their use. This will be
registration as a result of the assessment of the influenced by the level of processing applied to
quality, safety and efficacy data submitted with the biological and the intended use of the prod-
the provisional registration but must be a related uct, but also the level of external governance
indication. The priority review registration process and clinical oversight.
and timeframe are provided in the Figure 14-6. Class 1 biologicals are low risk and have
The application and evaluation fee for vari- an appropriate level of external governance and
ous processes are provided in Table 14-12. clinical oversight, such as accreditation or prac-
titioner’s oversight. Class 2 biologicals are low
Pathways for Biologics risk and are restricted to those that have been
subjected to only minimal manipulation and are
The regulatory framework for biologicals pro- only for homologous use. Class 3 biologicals are
vides the legislative basis for the regulation of medium risk and includes those that are either
human tissue and cell-derived products and live for homologous use but have been prepared
animal cell, tissues or organs that are supplied using more than minimal manipulation or for
in, or exported from, Australia. The framework non-homologous use, regardless of whether they
applies different levels of regulation to products have been prepared using minimal manipulation
based on the risks associated with their use. It is or more than minimal manipulation. Class 4 bio-
designed to be flexible enough to accommodate logicals are high risk that are currently defined in
emerging technologies. Schedule 16 as:
Even though a product may meet the defini- • biologicals that comprise or contain:
tion of a biological, it may not be regulated as a ○ live animal cells; or
biological. TGA applies regulation to products ○ live animal tissues; or
that meet the definition of a biological in three ○ live animal organs
ways, as described in Figure 14-7. Biologicals • biologicals to which both of the follow-
can be a) excluded from TGA regulation, b) ing paragraphs apply:
regulated as a therapeutic good, but not as a ○ the biologicals comprise, contain
biological, or c) regulated as a biological. For a or are derived from human cells
product to be regulated as a biological, it must be or human tissues that have been
a therapeutic good (as defined in the Therapeutic modified to artificially introduce a
Goods Act 1989) and either meet the definition function or functions of the cells
of a biological or be specified by legislative or tissues

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

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Figure 14-6. TGA Provisional Registration Process Diagram 2
Pre-submission meeting
Recommended 3 months prior to 3
determination application
Part of the
determination
process 4
Determination application
Recommended 3 months prior to

5
submission for registration
(1 month)

No more than

6
6 months
(unless Phase 1
determination PPF submission (PPF only option)
extension
granted)

Phase 2
7
Submission
(1.5 months)

Milestone 2
8
Phase 3
First round of assessment
(5 months)
9
Rolling
submissions
Milestone 3
10
of clinical
data accepted
Phase 4
-with stop
Consolidation s31 response
clock if not
(30 or 60 calendar days)
submitted by
the agreed
date Milestone 4 11
Phase 5 Approximately
Second round of assessment
(1 month)
220 working
days 12
Timeframes for Milestone 5
final evaluation
reports, sponsor
response and
Phase 6
Expert advisory review
13
Delegate’s (2 – 3 months)
overview are as
standard process
Milestone 6 14
Phase 7
Decision
(1.5 months)
15
Milestone 7

16
Provisional
Phase 8
registration valid
Post decision and provisional registration
for two years
(1.5 month)
unless extended
Milestone 8
17
Note: the timeframes below represent maximum timeframes
for each phase of the process as a guideline only.
18

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 Chapter 14: Regulatory Pathways

Table 14-12. TGA Application and Evaluation Fees in Australian Dollars for Prescription
Medicines as of December 2019

Application Type Application Evaluation

Fee Fee
Standard prescription medicine processes
New chemical entity* $48,800 $195,700
Extention of indication $29,100 $116,100
Major Variaion $19,000 $75,700
Minor variation applications applied for under section 23 of the Act $1,120 $4,450
(Change in formulation, composition, design specifications, type of
container or change of trade name)^
Variations to an ARTG entry involving the evaluation of clinical, pre- $1,120 $4,450
clinical or bioequivalence data, applied for under 9D(3) of the Act.
Includes applications for changes to Product Information involving the
evaluation of clinical, preclinical or bio-equivalence data*^
Additional trade name^ $3,080 $12,300
New generic product* $18,800 $74,700
Extension of indications of a generic medicine to maintain currency $1,120 $4,450
with indications already registered to the corresponding innovator
product and where clinical and/or bioequivalence data are not
required
These fees are in Schedule 9, Therapeutic Goods Regulations 1990
‘The Act’ refers to the Therapeutic Goods Act 1989
n/a: not applicable
* the fees are the same for the standard process and the comparable overseas regulator report-based process
^ the fees are the same for registered and provisionally registered medicines

Priority review pathway for prescription medicines

Priority determination of a prescription medicine $12,800 n/a
New prescription medicine in the priority pathway $51,700 $207,000
New indications medicine in the priority pathway $30,800 $123,100
Provisional approval pathway for prescription medicines
Provisional determination of a prescription medicine $12,800 n/a
Extension of provisional determination $4,610 n/a
Provisional registration of a new prescription medicine $48,900 $255,300
Provisional registration of a new indications medicine $29,200 $168,400
Extension of provisional registration $17,600 n/a
Transition from provisional registration to full registration* $29,100 $122,800
These fees are in Schedule 9, Therapeutic Goods Regulations 1990
n/a: not applicable
*: Fees for an application under Section 23 for registration of a medicine that is included in the part of part of the ARTG for goods known as
provisionally registered goods to be included in the part of the ARTG for goods known as registered goods

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
Figure 14-7. TGA Regulation of Biologicals 2
Products that meet the Definition of a biological
3

Excluded from Regulated as a therapeutic Regulated as a

4
TGA regulation good, but not as a biological biological

5
Examples: Examples: Examples:
∙ Fresh viable organs
∙ Fresh haematopoietic
progenitor cells
∙ Prescription biological
medicines: vaccines, plasma
derivatives, recombinant
∙ Human cell or tissue-based
products
∙ Products that comprise or
6
∙ Assisted reproductive products contain live animal cells,
technologies
∙ Eligible autologous human
cells and tissues products
∙ Labile blood and blood
components
∙ Haematopoietic progenitor
tissues or organs
∙ Combination products (e.g.
cell therapy and medical
7
cells used for haematopietic devices)

8
reconstitution (non-fresh
transplants)

9
○ the artificially introduced function To apply for a Class 2, 3 or 4 biological to be
or functions were not intrinsic to included in the ARTG, a dossier to support the 10
the cells or tissues when they were quality, safety and efficacy of the product must

•
collected from the donor
pluripotent stem cells
be submitted in accordance with the Australian
Regulatory Guidelines for Biologicals (ARGB),
11
• biologicals derived from pluripotent Dossier requirements for Class 2, 3 and 4 biologicals.
stem cells Overview of the application process and time- 12
frames is provided in Table 14-13, and related
Classification of biologicals is based on either of
the following:
fees are provided in Table 14-14.
Autologous human cells and tissues products
13
• mention in Schedule 16 (Class 1 and 4 regulation V2.0 ( July 2019) explains how TGA
biologicals) applies regulation based on the risk associated 14
• method of preparation and intended use with the product and outlines the criteria for
(Class 2 and 3 biologicals)
All Class 1 and Class 4 biologicals must be men-
exclusion or exemptions of some autologous
HCTs from TGA regulations.
15
tioned in Schedule 16 of the Therapeutic Goods Human cell and tissue (HCT) products are
Regulations 1990. those that comprise, contain or are derived from 16
Class 2 and Class 3 biologicals may also be human cells and tissues.
mentioned in Schedule 16 to clarify any ambi-
guity associated with classification based on
Autologous HCT products are those that
are removed from, and applied to, the same per-
17
method of preparation and intended use. son, i.e., the donor and the recipient are the same.
Sponsors can request TGA advice on bio- One group of autologous HCT products is those 18
logical form for classification. commonly referred to as “stem cell treatments.”

All rights reserved; file sharing prohibited. 179

 Chapter 14: Regulatory Pathways

Table 14-13. Overview of the TGA Application Process and Timeframes

Phase Stage Description Target Legislated

timeframes* timeframe*
1 Pre-submission Pre-submission meeting N/A –
2 Submission Submitted information/data & – 30
application fees
Notification of outcome of preliminary 30
assessment
3 First round of Evaluation Round 1 Evaluation 100 255
4 First round of request for Response to first s32JA letter from 30**
information from sponsor applicant
5 Second round of Evaluation Round 2 evaluation 20
5a Second round of request Response to second s32JA letter from 30**
for information from applicant
sponsor
5b Third round of Evaluation Round 3 evaluation 20
6 Expert advisory review Consult the Advisory Committee on 40–60
Biologicals, if required
7 Decision Decision 20
- Total evaluation timeframe 200–220 –
8 Post-decision ARTG entry and other administrative 20
processes

* Timeframes are stated in working days.

** These times represent typical timeframes given to you to respond to requests for information, but may be much longer.

Table 14-14. TGA Fees in Australia Dollars for Sponsoring Biologicals

Sponsoring biologicals Fee

Ingredient or component of a biological to be evaluated under regulation 16GF - evaluation fee $23,900

Class 1 biological - application fee for inclusion in ARTG $1,110

Class 2, 3, 4 biological - application fee for inclusion in ARTG $1,110

Variation application fee - all classes $1,110

Class 2 biological - evaluation fee for inclusion in ARTG $73,700

Class 2 biological - evaluation fee for variation to ARTG entry $6,760

Class 3 biological - evaluation fee for inclusion in ARTG $147,400

Class 4 biological - evaluation fee for inclusion in ARTG $239,500

Class 3 or 4 biological - evaluation fee for major variation to ARTG entry $34,900

Class 3 or 4 biological - evaluation fee for minor variation to ARTG entry $17,800

Safety related variations - evaluation of application under section 9D(3AA) $6,760

These fees are in Schedule 9A,Therapeutic Goods Regulations 1990

180 All rights reserved; file sharing prohibited.

 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
Some examples of human cell and tissue For autologous HCT products that are not
products that can be autologous: excluded from TGA regulation, the product will 2
• blood and blood components (red cells, be classified as one of the following:
plasma, serum, platelets, platelet-rich
plasma [PRP], platelet-rich fibrin
• a medicine, if it fits the definition of
blood, blood component or haemato-
3
[PRF], and conditioned serum) poietic progenitor cells (HPCs)
• skin grafts for treatment of burns • a biological 4
• bone grafts
• genetically-altered lymphocytes to Biosimilar Medicines Regulation
target cancers Applications for biosimilar medicines registra-
5
• adipose-derived cell extracts (including tion must meet the same requirements as for
stromal vascular fraction (SVF)) prescription medicines. TGA has adopted a 6
number of European guidelines that outline the
The level of regulation for autologous HCT quality, nonclinical and clinical data requirements
products is based on the level of risk to the specific to biosimilar medicines; and the ICH 7
public. The level may vary due to the level of guideline on the assessment of comparability.
external governance and clinical oversight or the
manufacturing processes or the intended use of Brazil
8
the autologous HCT product.
• Autologous HCT products are excluded The premarket approval is the legal act that
recognizes the suitability of a product to the
9
from TGA regulation if they meet the
following eligibility criteria: Brazilian sanitary regulation, and it is given by
○ not to be advertised to consumers Anvisa. It is a control measure prior to the com- 10
○ manufactured and used in a hos- mercialization of the product, used in the case
of products that could present possible health
○
pital
collected, manufactured and used risks. Anvisa requires premarket approval only 11
by persons under the supervision of for the categories of products that are considered
the medical or dental practitioner to be of greatest health risk. Premarket approvals
are published in the Official Gazette, and this
12
who has clinical care of the patient
Autologous HCT products are exempted publication is sufficient to prove the authoriza-
13
•
from some requirements if they meet the tion given by Anvisa, exempting the subsequent
following eligibility criteria: issuance of any documents, such as certificates or
declarations. The marketed product must neces-
○

○
manufactured outside of a hospital
collected, manufactured and used sarily correspond to what has been evaluated and 14
by persons under the supervision of approved by Anvisa, and no changes are allowed
the medical or dental practitioner without prior authorization from the Agency, 15
who has clinical care of the patient as established in Article 13 of Law 6360/1976.
Premarket approvals are valid for five years from
minimally manipulated
16
○

○ homologous use the date of their publication in the Brazilian

○ single indication in a single clinical Official Gazette and may be renewed for equal
procedure and successive periods.
17
• Autologous HCT products are fully Registration Applications
regulated by TGA (as a medicine or bio-
logical) if they do not meet the criteria RDC No. 200 of 12/26/2017 provides for the 18
for exclusion or exemption listed above criteria for granting and renewing the registra-

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 Chapter 14: Regulatory Pathways

tion of drugs with synthetic and semi-synthetic icine/originator drug is 12–14 months, with
active ingredients, classified as new, generic and fees ranging from $2,700 USD–27,000 USD,
similar, and other measures. depending on the size of manufacturer. For a
• New Medicine Product/Innovator generic drug, the timeframe for approval is 6–8
Drug—this includes branded medicines months, and the required fee is $2,000 USD.
that have patent protection and its For a similar product, the fee is approximately
efficacy, safety and quality are scientifi- $7,000 USD, and the timeframe for approval is
cally proven and can be identified by its 8–12 months.
brand.
• Generic Product (Branded Generics)— Framework for Prioritization of
medicines that are similar to a reference Registration, Variations and Clinical Trial
product or originator drug with which it Authorization
is intended to be exchangeable, generic Resolution RDC 204/2017 establishes the eligi-
products can only be produced after the bility criteria for the priority pathway:
expiry or refusal of patent protection • The product must meet at least one of
and other exclusivities, with its efficacy, the following eligibility criteria:
safety and quality having been scientif- ○ pediatric population
ically proven, and named in accordance ○ neglected diseases (rare diseases—
with the Common Brazilian Name RDC 205/2017)
Listing (DCB) or the Common Inter- ○ emerging or reemerging diseases
national Name Listing (DCI). ○ public health emergencies
• Similar Product (Non-Branded Gener- ○ serious debilitating conditions
ics)—a product containing the same ○ vaccines to be included in the
active principle or principles in the simi- National Immunization Program
lar concentration with the same pharma- ○ first three unprecedented generic
ceutical form, means of administration, drugs
dosage and therapeutic or diagnostic ○ risk of shortage in the market
indication as the reference medicine • According to Law No. 13,411/2016, the
registered with the regulatory agency. maximum deadlines for final decisions
• Clone Product—when an applicant in the registration process are:
wishes to gain approval of a similar ○ Drug product registration: 120
product for which its generic product is calendar days
already approved or vice versa, a clone ○ Variations/post-approval changes:
application can be submitted. When 60 calendar days
a registered innovator drug applicant ○ Clinical Trial Authorization: 45
wants to gain approval for its generic calendar days for first evaluation
product/similar product, a clone appli-
Biological Products
cation also is submitted.
According to Resolution RDC 55/2010, a
The application procedure consists of three parts: complete dossier shall be submitted for the
pre-registration measures, registration and post new biologic, including clinical trial data. For
registration. A clinical study protocol must be non-originator biologics, two pathways exist—a
submitted to the agency. An overview of the comparability pathway and a stand-alone path-
registration process is provided in Figure 14-8. way. The two pathways have different require-
The timeframe and fees for registering a ments for the amount of data to be submitted in
pharmaceutical drug in Brazil for a new med- the registration dossier.

182 All rights reserved; file sharing prohibited.

 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
Stand-alone Pathway References
The stand-alone pathway is used in instances 1. About FDA. What We Do. FDA website. https:// 2
www.fda.gov/about-fda/what-we-do. Accessed 21
where a non-originator biological cannot be January 2020.
compared to the originator product. With this
2. Prescription Drug User Fee Act, Pub. L. No. 102-571, 3
pathway, the applicant must submit a summary Title I, 106 Stat. 4491 (1992).
of the preclinical and clinical studies performed
on the non-originator biological product. The
3. FD&C Act, Section 505(d).
4
4. Sasinowski FJ, Panico EB, Valentine JE. “Quantum of
scope of the preclinical studies may be reduced, Effectiveness Evidence in FDA’s Approval of Orphan
and phase I/II studies can be exempted. Phase Drugs: Update, July 2010 to June 2014.” Therapeutic
Innovation and Regulatory Science (2015); pp 1–18.
5
III studies are mandatory, with exceptions, and
must be compared to ‘non-inferiority,’ ‘equiv- 5. Draft Guidance for Industry: Applications Covered by

alence’ or ‘superiority’ to the new biological

Section 505(b)(2) (October 1999). FDA website. https://
www.fda.gov/regulatory-information/search-fda-
6
product (originator biological). guidance-documents/applications-covered-section-

Comparability Pathway 6.
505b2. Accessed 21 January 2020.
Combination Products. Intercenter Agreement Between
7
CDER and CBER (effective 31 October 1991). FDA
The comparability pathway outlines an approach
in which the follow-on biological is compared
website. http://www.fda.gov/CombinationProducts/
JurisdictionalInformation/ucm121179.htm. Accessed
8
to the reference product in terms of quality and 21 January 2020.
available data. This pathway closely resembles
that of the WHO Similar Biological Product
7. 42 U.S.C. Section 262, Regulation of Biological
Products. FDA website. https://www.accessdata.fda.
9
gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=310.4.
Guidelines. A comparative dossier containing
preclinical and clinical studies is necessary to
8.
Accessed 21 January 2020.
21 CFR 312.300(b)(1), Expanded Access to
10
demonstrate comparability between the products. Investigational Drugs for Treatment Use. FDA website.
Nonclinical and clinical data can be reduced.
The pathway also allows for extrapolation of
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/
CFRSearch.cfm?fr=312.300. Accessed 21 January 2020.
11
therapeutic indications between the follow-on 9. FD&C Act, Section 515(d).
biological and the reference product.17 10. Directive 2001/83/EC of the European Parliament 12
and of the Council of 6 November 2001 on the
Conclusion Community code relating to medicinal products
for human use. EudraLex website. http://
eur-lex.europa.eu/LexUriServ/LexUriServ.
13
A solid understanding of the regulatory pathways
do?uri=OJ:L:2001:311:0067:0128:en:PDF. Accessed 21
for drug and biologics approval is fundamen-
tal for the regulatory professional to support a
January 2020.
11. Kingham R, Klasa G, Carver KH. “Key Regulatory
14
strong regulatory strategy. This chapter provides Guidelines for the Development of Biologics in the US
an overview of the available pathways, espe- and Europe,” Biological Drug Products: Development and
Strategies. Eds. Wang W and Singh M. John Wiley &
15
cially those resulting in more-rapid approval
Sons, Inc. 2014.
in a given region. Although the pathways may
appear straightforward, there are instances of
12. 2015 Information in English on Japanese Regulatory
Affairs, English Regulatory Information Task Force,
16
“borderline” products or increasing complexity Japan Pharmaceutical Manufacturers Association.
in all three regions, such as combination prod-
ucts. Where the pathway is not clear, proactive
2015. http://www.jpma.or.jp/english/parj/pdf/2015.pdf.
Accessed 21 January 2020. 17
13. Drug Product. Notice of Compliance-Drug Product.
communications with regulatory agencies should
occur, because pathway selection can have signifi-
Health Canada website. https://www.canada.ca/en/health-
canada/services/drugs-health-products/drug-products/
18
cant product development ramifications. notice-compliance.html. Accessed 21 January 2020.

All rights reserved; file sharing prohibited. 183

 Chapter 14: Regulatory Pathways

14. Guidance for Industry - Priority Review of Drug Biological Product—Directive 2001/83/EC
Submissions. Health Canada website. https://www. A biological medicinal product is a product, the active
canada.ca/en/health-canada/services/drugs-health- substance of which is a biological substance:
products/drug-products/applications-submissions/ • produced or extracted from a biological source
guidance-documents/priority-review/drug-submissions. • that needs for its characterization and the
html. Accessed 21 January 2020. determination of its quality a combination of
15. Biologics, Radiopharmaceuticals and Genetic Therapies. physic-chemical-biological testing, together with
Health Canada website. https://www.canada.ca/ the product process and its control
en/health-canada/services/drugs-health-products/ • The following shall be considered as biological
biologics-radiopharmaceuticals-genetic-therapies.html. medicine products:
Accessed 21 January 2020.
○ medicinal products derived from human
blood and human plasma as defined,
16. Medicines and TGA classifications. TGA website. respectively in paragraphs (4) and (10) of
https://www.tga.gov.au/medicines-and-tga- Article 1
classifications. Accessed 21 January 2020. ○ medicinal products falling within the scope
17. Regulatory pathways for approval of biological of Part A of the Annex to Regulation (EEC)
products in Brazil. Generic Biosimilar Initiative journal. No 2309/93
GaBi website. http://www.gabionline.net/Reports/ ○ advanced therapy medicinal products as
Regulatory-pathways-for-approval-of-biological- defined in Part IV of this Annex
products-in-Brazil. Accessed 21 January 2020.
Japan
Drug—Pharmaceutical and Medical Device Act, Article 2,
Paragraph 1
Appendix A—Definitions of Drugs and Bio- Drugs subject to the regulations in the Pharmaceutical
logics in the US, EU, Japan and Australia and Medical Device Act are defined as follows in Article
2, Paragraph 1 of the Law. The term “drugs” refers to the
US following substances:
1. Substances listed in the Japanese Pharmacopoeia.
Drug, FD&C Act, Section 201(g)(1)
2. Substances (other than quasi-drugs and
“Articles intended for use in the diagnosis, cure, mitigation,
regenerative medicine products), which are
treatment, or prevention of disease” and “articles (other than
intended for use in the diagnosis, treatment,
food) intended to affect the structure and function of the
or prevention of disease in humans or animals,
body of man or other animals.”
and which are not equipment or instruments,
Biological Product, PHS Act, Section 351 including dental materials.
“Virus, therapeutic serum, toxin, antitoxin, vaccine, blood 3. Substances (other than quasi-drugs or cosmetics)
component or derivative, allergenic product, or analogous which are intended to affect the structure of
product, or arsphenamine or derivative of arsphenamine (or functions of the body of humans or animals, and
any other trivalent organic arsenic compound), applicable to which are not equipment or instruments.
the prevention, treatment, or cure of a disease or condition
of human beings” (Public Health Service Act Sec. 351(i)), 42 Biological Products and Specified Biological Products—
USC S 262(i), also meet FD&C Act, sec 201(g) or (h). Pharmaceutical and Medical Device Act
1. Biological products—Drugs, quasi-drugs,
EU cosmetics, or medical devices using materials
manufactured from human or other organisms
Drug/Medicinal Product—Directive 2001/83/EC, Article 1(2)
(excluding plants) as raw materials or packaging
• Any substance or combination of substances
materials, which are designated as requiring special
presented for treating or preventing disease in
human beings. precautions in terms of public health and hygiene.
• Any substance or combination of substances 2. Specified biological products—Biological products
which may be administered to human beings with designated as requiring measures to prevent
a view to making medical diagnosis or restoring, the onset or spread of risk to public health and
correcting or modifying physiological functions in hygiene concerned
human beings
• Article 2(2) In cases of doubt, where, taking into Australia
account all its characteristics, a product may fall
within the definition of a medicinal product and Therapeutic goods - Therapeutic Goods Act 1989
within the definition of a product covered by other Goods that are represented in any way to be, or that are,
Community legislation the provisions of this whether because of the way in which the goods are presented
Directive should apply or for any other reason, likely to be taken to be:

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
• (i)for therapeutic use; or
• for use as an ingredient or component in the
manufacture of therapeutic goods; or
2
• for use as a container or part of a container for
goods of the kind referred to in subparagraph (i)
or (ii); or 3
• included in a class of goods the sole or principal
use of which is, or ordinarily is, a therapeutic use
or a use of a kind referred to in subparagraph (a)
(ii) or (iii); and
4
• includes biologicals, medical devices and goods
declared to be therapeutic goods under an order in
force under section 7, but does not include: 5
○ goods declared not to be therapeutic goods
under an order in force under section 7; or
○ goods in respect of which such an order is in
force, being an order that declares the goods
6
not to be therapeutic goods when used,
advertised, or presented for supply in the
way specified in the order where the goods 7
are used, advertised, or presented for supply
in that way; or
○ goods (other than goods declared to be
therapeutic goods under an order in force
8
under section 7) for which there is a
standard (within the meaning of subsection
4(1) of the Food Standards Australia New 9
Zealand Act 1991); or
○ goods (other than goods declared to be
therapeutic goods under an order in force
under section 7) which, in Australia or
10
New Zealand, have a tradition of use as
foods for humans in the form in which
they are presented. 11
12
13
14
15
16
17
18

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 Chapter 14: Regulatory Pathways

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15 Global Regulatory Strategy

By Chris Walker and Tina Soulis

1
2
3
4
5
Introduction erations that influence global strategy are the
organization’s financial situation or the product’s 6
The ultimate goal of a regulatory strategy is to intellectual property status. External examples
enable patient access, and it is within this context
that a regulatory professional must provide a
include the organization’s business partner or 7
investor community viewpoints.
regulatory strategy. A regulatory strategy can Global regulatory organizations must
be defined as a science-driven assessment of a provide comprehensive development plan input 8
product’s development options, key consider- throughout the product’s lifecycle. This input
ations and likely regulatory outcome. It should
span the earliest development stages through
starts in the preclinical development phase and
continues through postmarketing. Functional
9
further modifications planned postauthorization. regulatory units provide input on the likely
It should encompass key milestones and decision
points; consider regulatory objectives, hurdles,
acceptability of the planned evidence package 10
that will be generated for the regulator and
the regulatory landscape and precedents; and subsequent stakeholders, specific regulatory
characterize risks to potential success in deliver- requirements for product development, post- 11
ing a specific regulatory outcome. This regulatory marketing, regulatory submission management,
outcome, in turn, will have broader consideration
because it will link to the potential for patient
regulatory intelligence, product labeling and
advertising and promotion.
12
access, commercial acceptability and uptake and,
Interdisciplinary Factors and Alignment
therefore, likely business outcomes.
A global regulatory strategy should combine
13
regulatory requirements and business objectives. A global regulatory strategy cannot be planned
It often is defined by a global regulatory expert, in isolation from other factors contributing
to an innovative new product’s overall suc-
14
who must consult with a cross-functional team.
The cross-functional team should comprise cess. The most successful new products use a
experts who: provide regional regulatory require- multi-pronged development program approach, 15
ments and regulatory intelligence on expecta- addressing business, scientific and regulatory out-
comes. The integrated multidisciplinary product
tions, precedents and competition; correspond
with local regulatory authorities; enable docu- development concept is shown in Figure 15-1. 16
ment management and submission processes; Business Strategy
and provide specific functional expertise such as 17
labeling, CMC, nonclinical and clinical. There Business outcomes are defined broadly as those
also are internal and external business consider- accomplishments driving business results, includ-
ations that can drive a specific global regulatory ing revenue, earnings, cash flow, return on capital 18
strategy’s development. Examples of consid- and valuation.

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 Chapter 15: Global Regulatory Strategy

Figure 15-1. Multidisciplinary Product Development

Regulatory

Business Marketing
Finance

Target Product Profile

and Integrated Product
Strategy

Clinical Medical
Manufacturing Safety

Health
Outcomes

Regulatory decisions can affect the time- not be positive, and product divestiture may be
to-market, label claims and reimbursement considered. Ultimately, companies should seek
directly and, consequently, a new product’s sales, improved patient outcomes compared to existing
profitability and contribution to business results. therapies and, if these are positive, it is likely the
Therefore, it is critical regulatory professionals product also may provide financial return.
understand the organization’s business strategy Note, a sponsor TPP should be differen-
to plan the product development and postau- tiated from a formal regulatory TPP prepared
thorization activities within this framework and in accordance with FDA guidance1 and serving
as members of a multidisciplinary global team as a format for sponsor discussions with the
planning an integrated product strategy. regulatory authority. The relationship between
Early sponsor development of a Target the two types of product profiles is important,
Product Profile (sponsor TPP) by the multidis- as a sponsor TPP will guide the formal TPP
ciplinary team establishes key product attributes and development plan, contributing to overall
and provides an opportunity to consider financial business objectives.
factors and build a sophisticated financial model A sponsor TPP may include optimal and
to develop anticipated business outcomes. It acceptable label claims compared to currently
also will assist in determining the break-even available products and competitors in develop-
point at which no further development should ment. Similarly, it may articulate an acceptable
be undertaken, as the business outcomes will safety profile and risk-benefit analysis, as well as

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
planned product presentation. The sponsor TPP positive, but more data are required to confirm
will establish the global development plan frame- benefit post-license. 2
work, incorporating data and regulatory require- Conversely, local regulations requiring addi-
ments and strategies to gain marketing approval
in the shortest possible timeframe. Ultimately,
tional studies (aiming to ensure clinical data are
relevant to the local population) or having sig-
3
the company may ask a regulatory professional nificantly longer approval times may negatively
the likelihood of achieving the product’s targeted
influence a country’s prioritization. Increased 4
labeling claims and when it will be achieved.
development costs or delayed market entry to
Increasingly, the overall goal is a global
development program with simultaneous, mul-
generate additional data may reduce financial
returns compared to marketing a product in a
5
timarket submissions and approvals. However,
many factors can influence the need for prioritiz- country without these challenges. Ideally, a com-
ing an individual country or region, identifying pany will consider an integrated evidence gener- 6
opportunities to enable early or more cost-ef- ation strategy that considers evidence required by
fective market entry. For example, orphan drug
programs vary significantly. Some are limited to a
the healthcare system’s multiple stakeholders and
will gather such evidence in the smallest number
7
reduction in regulatory agency fees, while others, of separate studies minimizing cost while meet-
like the US, have more generous programs that ing stakeholder objectives for evidence. 8
include additional agency support and devel- Clearly articulating claims and global market
opment grants. A second important example is
FDA’s accelerated approval program that pro-
entry timing enables potential sales in key mar-
kets, development costs and return on investment
9
vides an opportunity to gain early approval based
to be modeled.
on surrogate or intermediate endpoints, thus
reducing premarket development costs and time,
In early development stages, many 10
unknowns and assumptions need to be built
and leading to early market entry.
Similar programs to support innovative into the model. Scenario planning and sensi-
tivity analysis will take these uncertainties into
11
new medicines are available in Europe, includ-
ing accelerated assessment of medicines of account, which will reduce as development
major public health interest via the Centralised progresses and challenges are overcome, creating 12
Procedure, especially ones that are therapeutic an increasingly robust financial model to support
innovations. Accelerated assessment usually takes
150 evaluation days, rather than the standard 210
business planning.
During development, decisions made by
13
days. In addition, in 2016, a program to enable the multidisciplinary team will impact poten-
accelerated assessment of PRIority MEdicines tial business outcomes, the financial return and 14
(referred to as PRIME) was introduced. PRIME subsequent patient access. Decisions should
eligibility criteria are similar to those for acceler-
ated assessment but result in additional dialogue,
be based on data available, moving the prod-
uct forward toward the overall TPP objectives.
15
support and connectivity within the EU regu-
If available data indicate deviations from the
latory network. It is intended for medicines in
development to address an unmet medical need.
planned pathway are required, a detailed TPP 16
There also are mechanisms in some jurisdictions review and business outcome impact evaluation
to allow approval based on more limited data should follow.
The sponsor TPP and development plan are
17
(e.g., Phase 2 studies or surrogate endpoints)
due to the new medicine’s promising nature. The living documents and require regular monitoring
conditional approval mechanism in Europe is and review to evaluate progress against objectives 18
intended for this purpose, where benefit-risk is and updating as appropriate.

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 Chapter 15: Global Regulatory Strategy

Figure 15-2. Key Interactions Between Marketing and Regulatory

Basic Clinical Regulatory Product

Postapproval
Research Studies Approval Launch

Product Target Product Product labelling Promotion and Product

potential Profile branding extensions
Product
Comparators presentation Advertising
Outcomes Filing strategy Postapproval
research studies

Marketing medicines’ approval is replaced by a cumulative

process based on gradual accretion of data (the
During all product development stages, the mar- ‘evidence continuum’). New therapies receive a
keting/commercial team contributes to the global conditional license based on further testing to
development strategy. To present a product to its substantiate their safety and efficacy in larger
target market, three key elements must be inte- or different populations, thus providing early
grated: product attributes, marketing decisions access to promising therapies, particularly for
and commercialization activities. Each of these unmet needs. Over time, more data are expected
may be influenced by the regulatory strategy, to be generated in the post-license setting, and
label claims and product presentation. access to technology and digital health records
The integrated product strategy will incor- will allow an environment that provides greater
porate the overall regulatory and market strat- confidence to regulators and other stakeholders
egies seamlessly. Key marketing interactions than has been possible before.
influencing regulatory strategy and vice versa are Marketing will be able to promote and
shown in Figure 15-2. build a new brand on an incremental basis.
Each territory should contribute to and take However, the opportunity for early market
into consideration the global product strategy launch also carries the risk that not all products
when developing regulatory and marketing strat- will have the anticipated benefits, as subse-
egies for local markets. quent trials may show a small treatment effect
Global regulatory environment changes or unacceptable adverse events. This risk needs
and precedence will impact marketing strategies to be communicated to patients and health-
directly. International harmonization of regula- care providers clearly and systems developed
tory requirements is increasing the opportunity to monitor new medicines in the marketplace
for companies to file and launch new products more closely. License cancellation or restriction
simultaneously in multiple markets. Further, the risks and consequences should be incorporated
introduction of live (adaptive) licensing, based on in risk management planning.
a medicine’s early approval in a restricted setting
Reimbursement
due to positive data in the limited setting and
shifting data generation in broader settings to a While significant efforts have been directed
subsequent line extension, will impact the sales toward global harmonization of regulatory
and marketing process significantly. Instead of an requirements, reimbursement processes and sys-
all-or-nothing regulatory approval approach, new tems are country-specific, with little or no har-

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
monization among jurisdictions, partly because Late-stage clinical trial design consider-
each country’s clinical, social and financial ations impacting HTA assessments include: 2
context can be so varied. However, several guid- • Active comparators—is a three-way
ing principles underpin many health technology
assessment (HTA) and reimbursement systems:
design incorporating a placebo and an
active comparator feasible? How will
3
• Is the new medicine effective in the the comparator be selected, as regional
population? standards of care may vary? 4
• Does it have advantages over currently • Are quality of life and validated instru-
available therapies? ments to evaluate patient preferences
• Will it contribute to an overall health- planned? 5
care savings (i.e., offset other costs)? • Does the trial use broader patient pop-
• Is it affordable? ulations?
6
The product value concept is incorporated in the Optimally, preapproval clinical trials will incor-
sponsor TPP, with contributions from health porate these data requirements. Increasingly, 7
outcomes, marketing and other integrated prod- postapproval studies are required. These may be
postapproval commitments as a condition of a
uct development team members.
Generally, a new product’s value and answers
live licensing program or a risk management 8
program required by a regulatory agency. In
to these questions are not forthcoming from a
addition, postapproval observational studies and
clinical development program focused solely
registries provide evidence to support reim- 9
on achieving regulatory approval. Regulatory
bursement submissions and continue to remove
requirements compared with HTA authority
requirements are shown in Table 15-1.
uncertainty in the postmarket setting. 10
On its own, the data package the regulatory Global Product Development
authority requires for marketing approval often
will be insufficient to meet HTA data require-
CMC (Chemistry, Manufacturing and 11
Controls)
ments. In countries where reimbursement
is pivotal to a product’s market success, data A CMC product development program focuses 12
required to support reimbursement must be on the drug substance and drug product’s formu-
incorporated into the product development plan
and regulatory strategy.
lation, process development and presentation as
well as the manufacturing facility. From a global
13
14
Table 15-1. Comparison of Regulatory and HTA Requirements

Regulators HTA Authorities 15

Evaluate efficacy (therapeutic effect) Evaluate effectiveness, how well a treatment works in the practice of

Homogenous data
medicine
Heterogeneous data
16
Risk/benefit Cost effectiveness
Comparator:
• placebo (FDA)
Comparator:
• current standard of practice
17
• active drug (EMA)
Focus is on the drug Focus is on population, cost and generalizing beyond data 18

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 Chapter 15: Global Regulatory Strategy

perspective, the CMC development program with a simple formulation, but later clinical
must consider many aspects, including develop- studies should be conducted with the product
ment phase and regional requirements. planned for marketing. If significant manufac-
A global CMC strategy should be inte- turing or formulation changes are made late in
grated and linked with the overall global development, bridging studies may be required to
product strategy to ensure suitably formulated confirm the changes have not altered the prod-
product is available to meet a particular devel- uct’s safety or efficacy profile.
opment stage’s requirements. Other clinical study CMC considerations
The three key factors influencing the CMC include requirements for a placebo product
development program are quality, time and cost. identical in appearance to the active product for
All these factors are related, and the chosen use in double-blind studies. Placebo development
pathway also will depend on the business’s risk may be challenging if the active drug substance
tolerance. For example, an organization initially has characteristics difficult to emulate with an
may choose to save time to get the first patient inactive substance, e.g., smell or taste.
for a given clinical study. However, in the end, Many countries are members of the Phar-
that decision may incur higher costs and addi- maceutical Inspection Convention and Phar-
tional time or even result in a product profile that maceutical Inspection Cooperation Scheme
is less acceptable to patients (e.g., short storage (PIC/S), which provides a GMP guide for
conditions due to lack of stability data). medicinal products. Annex 13 sets out require-
Initially, a non-GMP drug substance is ments for clinical trial product manufacturing
acceptable for nonclinical studies, provided the and labeling. This guide can assist the CMC
impurity profile does not increase a toxicity risk team in planning the clinical trial product man-
that might not occur at later development stages ufacturing program and core labels; however, the
when impurity limits are tighter. Frequently, only team always should be aware of the geographic
the drug substance is required for initial pharma- locations in which studies will be conducted and
cology and toxicology studies. However, formu- individual country- and study-specific require-
lation effects must be evaluated, and the drug ments. In some countries, e.g., India, patient
product may be required for nonclinical studies if labels and information are required to be in the
the product required a complex formulation due local language, meaning up to six local languages
to the drug substance’s physicochemical prop- must be accommodated. Clinical trial supply
erties, e.g., low solubility, membrane permea- availability is a key factor in study start-up
bility, stability or interactions with formulation times and should be coordinated with the
excipients. clinical development team. Batch records may
As the product moves into clinical stud- be required for study approval, but manufacture
ies, the CMC strategy must take clinical trial timing should ensure, as far as possible, sufficient
product requirements into account in countries stability data are available to avoid the need to
where studies are planned. In most countries, change batches during the study.
full GMP compliance is required for all clinical As the product development program moves
study phases. However, some countries, including closer to market, it is important the CMC team
Australia, allow use of a non-GMP product for a understands the regulatory filing strategy, desired
first-in-human study in healthy volunteers. product profile for patients and priority target
The drug product presentation also must be countries to ensure regulatory dossier CMC sec-
consistent with the clinical development strategy tions meet both the format and content require-
to ensure the dosage form and dose unit meet ments for each country. International Council
protocol requirements. Early in development, it on Harmonisation (ICH) guidelines assist and
is recognized clinical studies may be conducted enable manufacturers to develop a core CMC

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
dossier, but many individual country requirements Clinical Development
exist for non-CTD format, stability studies across 2
temperature zones, labeling and packaging. In Increasingly, the clinical development pro-
gram’s goal should not only be global but,
addition, specific product type guidelines devel-
oped by many jurisdictions may require additional essentially, simultaneous. 3
or different product specifications. Simultaneous global clinical develop-
Marketing and reimbursement teams also ment can bring many benefits to the global
regulatory strategy:
4
may have country- or region-specific require-
ments that must be accommodated to support • broader regulatory oversight—
commercial success, e.g., a pack size equivalent simultaneous submission and regulatory 5
to one month’s supply is the maximum quantity agency review allow the authorities’
views and experiences to be included in
permitted to be dispensed or reimbursed on
each occasion. the clinical development program 6
• reduced drug availability lag—successful
Nonclinical simultaneous clinical development
should result in earlier innovative drug
7
As the nonclinical plan is developed, it must therapy availability to populations in
be integrated with both the clinical and CMC
programs. Clinical studies must be supported
new markets and, ultimately, a reduction 8
in drug lag from core countries’
by appropriate nonclinical studies. For example, marketing time
nonclinical toxicology studies should use the • ethnic factors—broader clinical 9
route of administration proposed in the clinical development enables a science-based
study, of the same or longer duration. Results of
nonclinical studies conducted prior to the first
approach to define intrinsic and
extrinsic factors and identify meaningful
10
Phase 1 study should provide information to ethnic differences (In addition,
guide clinical study starting dose selection. Simi- registration dossiers will include higher 11
larly, reproduction study timing generally will be ethnic diversity.)
determined by the timing of including women of
child-bearing potential in clinical studies. Global clinical development data should satisfy
12
In countries that have adopted ICH not only US and EU requirements, but also
guidelines, the nonclinical program required to address ethnic differences and satisfy the local 13
support clinical studies generally is harmonized. data requirements for marketing applications
However, even in ICH countries, differences in countries such as Japan, China, South Korea,
exist in long-term toxicity study duration to sup- Taiwan, Mexico and India. 14
port Phase 3 trials and marketing applications. Global programs have contributed to the
For example, ICH M3(R2) on the duration of geographic shift in selecting countries for clinical 15
repeat-dose toxicity studies provides different trials. Drivers for this shift also include access
recommendations for the EU and US. In the EU, to wider, often treatment-naive populations and
a six-month repeat-dose study in two species a reduction in development costs. Increasingly, 16
(rodent and nonrodent) is required. However, the countries outside the traditional drug develop-
US requires a nine-month nonrodent study. ment core countries are offering quality sites and 17
Therefore, the nonclinical plan must meet good investigators.
local regulatory requirements to initiate clinical Organizations may set out to design a global
studies and meet global nonclinical requirements clinical development program, but whether this 18
needed to support the market application. can be truly simultaneous depends on many

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 Chapter 15: Global Regulatory Strategy

factors within each country, including regulatory ization and identifying the steps and regulatory
requirements and start-up times. requirements necessary to achieve this may
The unpredictable regulatory environment can influence program design significantly. For
be a major deterrent to global clinical development: example, if in-country clinical trials are needed
• lack of harmonized requirements and for regulatory approval, it may be possible to
processes among countries, and unique plan the clinical development program to include
data requirements outside international these countries in global trials in addition to
standards in-country trials.
• variability in acceptability of novel Some countries may require specific local
approaches, e.g., innovative clinical nonclinical studies or clinical pharmacokinetic
study designs studies prior to starting later-phase studies.
• variable and inefficient review of initial A global Phase 3 program may include local
approval and amendment processes requirements for ethnicity or a specific percent-
• data acceptance and uncertain ICH age of patients from each region.
GCP enforcement can raise doubts Failure to determine these requirements
about whether trial results will be prior to starting the registration studies could
acceptable to other agencies result in significant cost implications and delays
• intellectual property concern barriers in marketing application submissions if they are
to providing detailed information (e.g., not met.
CMC) at an early stage Figure 15-3 provides an example of the reg-
ulatory strategy to reduce approval timelines in
When planning a global clinical development key Asian markets by including these countries
program, prioritizing markets for commercial- in a global clinical development program.

Figure 15-3. Clinical Development Strategy in Asia

Marketing Approval
(US/EU)

US/EU IND or CTA Phase 1 Phase 2 NDA Launch

Phase 3

Marketing Approval
Japan IND or CTA Phase 1 Phase 2 NDA

Taiwan NDA
TW: Meet DOH Briding
Korea Dose Finding Requirement
KR: Meet KFDA Briding NDA
China Requirement
CN: Meet China NDA
Requirement
Drug Lag
Source Country CPP 2–2.5 Years
CTA: Clinical Trial Approval
CPP: Certificate of a pharmaceutical product to start NDA
application “save 2–3 years”

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
Clinical study protocol design also may Dossier
influence data acceptability in different jurisdic- Core Dossier
2
tions. Regulatory guidance on developing new
therapies for specific indications will influence
overall study design, including objectives, end-
Regulatory agencies expect an assurance of
medicines’ quality, safety and efficacy before they
3
points, use of active comparators or placebo and authorize their distribution to patients in their
study duration. In an effort to support conduct of countries. 4
clinical studies to meet requirements in both the While the information required by each
country’s regulators differs, ICH has developed
EU and US, EMA and FDA provide organiza-
tions the opportunity to seek parallel Scientific some harmonization of standards among coun- 5
tries. In addition to the three ICH regions (US,
Advice. The goal of parallel Scientific Advice is
sharing information and perspectives, rather than
Europe and Japan), many countries have adopted
ICH guidelines, including Australia, Switzerland
6
necessarily resulting in harmonization of regula-
and Canada.
tory requirements. However, for innovative new
products for which no specific guidance is avail-
ICH has developed a standard content for- 7
mat, the Common Technical Document (CTD),
able, agreement on development requirements that also is organized with consistent sections
may be a beneficial outcome. Increasingly, it and headings2 (see Figure 15-4). 8
also is desirable to obtain advice in parallel with Module 1 is for administrative information
reimbursement authorities to drive alignment
in what the regulatory authority and subsequent
and prescribing information and should con-
tain region-specific documents, e.g., application
9
reimbursement authorities would prefer to see in forms or the proposed regional label. Module 1
the overall evidence package. is outside the formal ICH guidelines, and each 10

Figure 15-4. The CTD Triangle

11
12
No
tp
art

13
of

Module 1
the

Regional
CT

Administrative
D

Information
14
CTD Table of Contents
2.1
CTD Table of Contents
15
2

2.2
le
du

Nonclinical Clinical
Mo

Quality Overview Overview

2.4 2.5
Overall 16
CT

Summary Nonclinical Written and Clinical

D

2.3 Tabulated Summaries Summary

2.6 2.7

Module 3 Module 4 Module 5 17

Quality Nonclinical Clinical Study
Study Reports Reports
18

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 Chapter 15: Global Regulatory Strategy

jurisdiction that has adopted ICH guidelines also regulatory reviewers to focus on the
has developed specific Module 1 guidance. product’s key outstanding issues
ICH publishes structure and content guide- • ensuring the messages delivered are
lines for Modules 2–5. simple, clear and succinct to aid the
Module 2 contains summaries of the organi- agency’s regulatory review and decrease
zation’s position on available data and summaries agency questions
of quality (QOS), safety (CSS, NCO) and effi-
cacy (CSE, CO). Regulators require the sponsor Organizations generate the filing documents
to provide its assessment of the product’s overall required to complete each CTD section, but
benefit-risk balance in this section, including any following initial approval, may need to modify
outstanding uncertainty in either risk or benefit specific sections using a variation, amendment or
at the time of initial regulatory review. supplement. For example, additional clinical data
Module 3 provides information related to may be generated with the intent of expanding
how the product was developed, how it is man- the product’s use, and the sponsor will be required
ufactured, evidence of product stability under to provide a new clinical study report (CSR) and
standard and stressed storage conditions and data proposed label changes to support the new use.
ensuring it can be manufactured reproducibly Companies often initially generate an ICH-
and analyzed to generate a reproducible product style dossier first and use this to generate the
meeting an appropriate release specification. dossiers for non-ICH countries.
Module 4 provides information related to
completed nonclinical analyses. Regional Dossiers
Module 5 provides the sponsor’s clinical trial
study reports demonstrating a tolerable safety The dossier’s content and structure may need to
profile and positive beneficial effect. be modified to meet each regulatory authority’s
ICH also has authored guidelines (quality, requirements in the region or country in which
safety and efficacy) clarifying expectations for the the organization wishes to register the product.
information these sections should contain. This may include a range of additional consider-
For a global organization, the goal is to gen- ations. Some examples are provided below, and
erate a core regulatory dossier efficiently that can specific requirements are called out at a high
be reused in multiple markets where it may wish level in Table 15-2.
to register the product. Generating this dossier, • Providing extra data—some regulatory
therefore, may take some regional differences and agencies require additional clinical
requirements across markets into account. For data representing the local population,
example, the core quality section may describe e.g., China, Japan, etc., or data with an
process information related to a range of man- alternative comparator representing that
ufacturing facilities supplying several markets, market’s standard of care.
allowing this information to be selected for the • Additional declarations—legal letters of
relevant local dossier. authority, Certificates of Analysis, exe-
A regulatory professional has multiple roles cuted batch manufacturing records all are
in generating the regulatory dossier: examples of country-specific additions.
• advising on content requirements • Local forms—application forms, local
• ensuring coordinated delivery of multi- language versions of clinical summa-
ple components ries, Certificates of Pharmaceutical
• ensuring a balanced benefit-risk Product (CPPs) confirming prior
assessment that acknowledges product approval in another jurisdiction (typi-
weaknesses and uncertainty, allowing cally US or EU).

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
Table 15-2. Overview of Specific Country Requirements 2
Country Global
Dossier
Local Trials Local Language CPP
Required
Specific Requirement
3
US ICH CTD Representative ethnic mix English No Patient-level data
Integrated

Summary of Safety and 4

Efficacy
EU ICH CTD Representative ethnic mix English, plus local language No
required for product
information
5
Japan ICH CTD Required Japanese No
Australia ICH CTD Generally No, except
bioequivalence studies using
English No Australian-specific Risk
Management Plan
6
local product as comparator

7
China Local format Required Chinese (Mandarin) Yes Extensive dossier
required for clinical
trial approval
South Mixed—ICH Mixed—some countries English, plus local language Mixed
America CTD and
local format
require local data, some
do not
required for product
information 8
9
• Alternate formats—some regions, like requiring alternative storage or stability
the Association of Southeast Asian data.
Nations (ASEAN) require their own • Clinical differences—intention to 10
dossier format (e.g., the ASEAN register an alternative indication or
CTD). This format incorporates both
summaries and detailed reports into
additional local data. This data inclusion
may require a new clinical review or
11
one part, e.g., Part IV includes both modification of other sections, e.g., inte-
the clinical summary and clinical grating new data into safety summaries 12
study reports. Formatting at a practical and summary tables. Some markets also
level can be as specific as the color may require clinical data comparing
of the tabs between sections or page the product to that market’s current 13
numbering, and care must be taken to standard of care.
meet these formatting requirements for
countries retaining these specific dossier
• Timing difference—depending on when
the original filing is submitted, a cur-
14
validation needs. rent dossier version incorporating the
sequence of changes that have occurred 15
An alternative commercial strategy may may be required. For this purpose, good
practice is to keep a ‘current master ver-
require tailoring the dossier, e.g., where differ-
ent data are required to register attributes for a sion’ in addition to tracking versions and 16
specific market. content registered in each market.
• Quality differences—registering Planning Filing Sequence Across Global 17
alternative presentations, manufactur- Markets
ing sites or supply routes in a specific
country, different release specifications The dossier generation and filing sequence 18
or humidity and temperature conditions planning strategy is the regulatory professional’s

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 Chapter 15: Global Regulatory Strategy

responsibility, in consultation with the global (RMPs) to be submitted as part of marketing

multidisciplinary development team. Some applications and require formal postapproval
markets do not accept applications until one of activities to ensure appropriate prescribing and
the ICH (i.e., reference) countries completes usage and to monitor and manage product safety.
its review. Once this initial review is complete, Although detailed RMP guidelines and formats
a CPP can be issued confirming a satisfactory vary across jurisdictions, the risk management
review was completed in another jurisdiction. principles articulated in the International Stan-
This can mean other markets can do a slightly dard ISO 31000 generally apply.3
abbreviated review based on the fact the prior From early planning and as product devel-
review has occurred, known as a reliance mech- opment progresses, ISO 31000’s principles can be
anism. This allows regulatory submission to take applied to enable early product risk identification
place in waves. and assessment, together with mitigation plans to
Key considerations when planning a filing minimize these risks during further development,
timeline include: at product launch and postapproval.
• availability of required filing data, e.g., When planning and preparing marketing
local market data
applications for each jurisdiction, the residual
• prior reviews, e.g., in an ICH country
risks and management strategies identified in
(US, EU, Japan) (including an ability
a global RMP can be customized to produce
to leverage responses to these questions
jurisdiction-specific RMPs.
elsewhere)
• launch time commercial driver During the evaluation process, the regula-
(impacted by market dynamics), e.g., tory agency may identify new risks or request
when does the organization want to alternate management strategies. These may be
initiate distribution, as soon as possible country-specific issues, such as those associated
or at a defined time with prescribing patterns or healthcare practices.
• resource availability to complete the In these instances, country-specific responses are
filing (including responding to agency required. Alternatively, these may potentially be
questions) issues relevant around the globe. Coordinating
• desired filing sequence (knowing agen- global risk management planning and incorpo-
cies discuss reviews with each other, and rating these issues into RMPs and postapproval
agreement on specific label language activities provide the opportunity to maintain
in one region can impact the review a globally harmonized lifecycle maintenance
outcome in another) approach. Issues initially restricted to one country
Lifecycle Management or jurisdiction may, in time, be applicable to other
countries, and the understanding and knowledge
Postapproval Commitments gained then can be shared for mutual benefit.
At the time of initial registration, a company The need to globally coordinate postapproval
will have limited experience and exposure with commitments will increase as adaptive licenses
its drug and some uncertainty. In the past, are granted. Adaptive licenses acknowledge data
regulatory approval was ‘all or nothing.’ When a continue to accumulate after a license is granted,
product is approved for marketing, a regulatory and access is best addressed by repeat cycles of
agency has relied almost exclusively on sponta- learning and confirming (re-licensing) over the
neous adverse reporting programs to monitor a product lifecycle continuum.
new product’s safety in the marketplace. Increased monitoring of real-world perfor-
More recently, an increasing number of mance (Real World Evidence, RWE), including
jurisdictions require Risk Management Plans postauthorization efficacy and safety studies

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

Figure 15-5. Global Technology System for Safety Monitoring 2

Clinical Data
System 3
Central
Clinical Trial Laboratory

4
Management System
Site Data Entry System

Global Safety
Signal
Detection
External
Regulatory
5
Incoming System Database Database
ADR

6
Reports
Literature and
Spontaneous ADR
Reports

7
Routine
Reporting

Significant

8
Alert
Case Case Series Signals Queries
Reports Regulators

Product Safety Monitoring

9

and registries, will be required. This is especially Safety Monitoring 10

true when smaller data packages were initially
relied upon to gain regulatory approval and this
evidence may be required by other stakeholders
Clinical product development risk assessment
must be thorough and rigorous. However, it is
11
such as reimbursement authorities. For countries impossible to identify all safety concerns during
with relatively small populations, global coop- controlled clinical trials. Once a product is mar- 12
eration among regulatory agencies and global keted, the number of patients exposed generally
studies are required to provide the breadth and increases dramatically, including those with
depth of additional data required to support co-morbid conditions and/or taking concomitant 13
ongoing approval. Overall, this lifecycle man- medications. Therefore, postmarketing safety data
agement approach is expected to lead to lower collection and clinical risk assessment are critical
for evaluating and characterizing a product’s risk
14
patient risks compared to the current approach,
despite smaller early data packages.4 profile and making informed risk minimization
The International Coalition of Medicines decisions. The growing trend for early approvals 15
Regulatory Authorities (ICMRA), formed in based on less-extensive clinical trial data further
increases this imperative.
December 2013, provides a forum for develop-
ing a cooperative approach among regulators on Postmarket safety data monitoring now 16
many topics, including postapproval commit- is a universal regulatory authority requirement
ments. This group and other such coalitions of for marketing approval and may include formal 17
authorities in multiple jurisdictions can utilize postapproval clinical studies, monitored release
reliance mechanisms, working together to share programs and spontaneous reporting programs.
reviews, guidelines and best practices, and can be Although these postapproval obligations are 18
useful tools when considering filing strategies. mandated by agencies at the jurisdiction level,

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 Chapter 15: Global Regulatory Strategy

reporting requirements are predicated on both drawn from the market many years after initial
local and global monitoring programs. launch due to long-term safety studies initiated
Safety scientists, therefore, must find ways after a series of spontaneous reports alerted regu-
to capture, record and analyze huge amounts lators to potential concerns.
of safety information across different studies, Opportunities exist for greater international
systems and jurisdictions and coordinate this collaboration among regulators who potentially
information globally to meet reporting require- have access to bigger pharmacovigilance datasets
ments, make informed recommendations and and data mining capabilities, as well as increased
implement decisions. collaboration and harmonization on regulatory
Global pharmacovigilance processes and decisions. The next wave in this workflow is the
workflow are supported most effectively by introduction of artificial intelligence to enhance
using a global pharmacovigilance system as data mining and uncover new insights from large
a technology tool for drug safety detections, data sets.
data mining, results interpretation and deci-
sion-making support. Such systems are trans- Maintenance and Compliance
forming industry’s capability to detect safety
Throughout the lifecycle, product registration
signals early as a key component of meeting
must be maintained in accordance with regula-
regulatory authorities’ postapproval require-
tions in each jurisdiction in which it is approved.
ments and demonstrating a commitment to
safety that transcends regulatory compliance. Variations to the current approved product may
An example of a global technology system require a submission and regulatory authority
supporting improved safety monitoring is shown approval, depending on the nature of the pro-
in Figure 15-5.5 posed change. Similarly, the approval timelines,
It is important to acknowledge a global and such provisions as grace periods (for imple-
technology system is a support tool and must mentation), vary widely in different regions.
be used within the global policy and procedure Whenever proposed changes are planned,
framework to establish a culture of safety and e.g., a quality change such as a packaging change,
quality and provide the expertise and resources at they ideally should be planned well in advance
both the global and local level. of implementation. A global plan is required,
Globally, these will include: including an understanding of region-specific
• establishing functional groups and requirements for the proposed variation, e.g.,
expertise data requirements, submission format, time-
• developing and aligning integrated lines and costs. It is good practice to assess the
operational procedures change’s intended impact and benefit, e.g., a
• developing and implementing well-de- minor change in manufacturing may take more
fined decision-making models, esca- time and effort to introduce than the savings in
lation processes and communication efficiency intended locally in the plant.
channels Similarly, changes relating to new clinical
• incorporating continuous improvement data availability to extend the approved indica-
activities tions may be planned well ahead of time at both
the global and local levels.
These principles apply regardless of the organiza- As with new product submissions, a spon-
tion’s size, the number of products or number of sor may elect to compile a core global variation
jurisdictions. Newly launched products generally dossier, accessible via a central database, with
are the focus of key postapproval monitoring. local requirements added at a regional or country
There are notable examples of products with- level. The submission then is managed at the

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
local level, with local regulatory staff responsible • creating customized reports interpreting
for regulatory agency interactions. regulations and ensuring the regulatory 2
Other changes, such as safety-related updates function is the ultimate authority on all
following unexpected serious adverse events and
signals detected through postmarketing surveil- •
regulatory compliance aspects
tracking regulatory key performance
3
lance, often are accompanied by tight regulatory indicators with a balance of lagging
timelines for notifying the regulatory agency and
updating product information documentation to
indicators (e.g., issues generated after 4
product launch) and leading indicators
ensure new risks are communicated promptly to (e.g., revenue at risk from potential
patients and healthcare professionals. Although it
is not possible to plan specific regulatory interac-
regulation changes) 5
tions in advance, global planning for such events is
vital to enable rapid implementation if these occur.
Regulatory functions within organizations,
especially those with global programs, should not
6
A multidisciplinary team including experts in reg-
be merely reactive and tactical, but more proac-
ulatory and safety, compliance, risk management,
communications and marketing should document tive and aligned with the organization’s global 7
procedures and ensure all key staff (and backups) product strategy to ensure minimal regulatory
are trained and ready to implement the plan, compliance challenges and timely mitigation of
if necessary. A local plan should be developed, nonconformance risks. 8
consistent with each region and country, that links
Regulation Database
into the global plan.
9
Companies need to have reliable, current
Knowledge Management
knowledge databases to track technical and legal
Knowledge management is one of the most requirements for each country in which they 10
significant regulatory challenges. Regulatory intend to submit regulatory dossiers. Commercial
expertise often is comprised of knowledge of
what is written in regulation, knowledge of
databases are available, and/or companies can
utilize staff to provide local intelligence. Local
11
precedence and actual personal experience and direct intelligence advantages include supple-
a set of relationships with the relevant authority menting local published guidance with practical 12
that help the regulatory professional collectively insights and experience of what actually was
provide advice on what is ‘required’ and what is required in addition to what was published. If
‘expected’ to deliver a positive outcome. using a commercial database, the information’s 13
currency should be confirmed, as regulations
Experience Capture change frequently, especially in countries with
evolving regulatory frameworks.
14
Properly captured knowledge and centralized
information sources yield process efficiencies. Knowing the Regulatory Authority
Actions taken by companies for proper knowl- 15
edge codification and dissemination include: Organizations need to know not only the written
• creating an “expert tracker” database for
knowledge residing with the organiza-
regulatory requirements, they also should have a
good understanding of unwritten requirements
16
tion’s employees and attempting to cen- and the personal preferences of any agency
tralize and disseminate that information reviewers who may review their dossiers. 17
• disseminating information through If possible, regulatory personnel should be
multi-level training at different career encouraged or advised to interact with the regu-
stages for regulatory and affiliated lators during new product development, although 18
personnel it is not possible or efficient to meet with all

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 Chapter 15: Global Regulatory Strategy

agencies. These interactions can help the orga- Therapeutic Goods Administration or others. Key
nization get to know the future agency review agency meeting considerations may include:
team, help that team become familiar with the • data reporting impacting benefit-risk
product’s innovative aspects and gain input on conclusion and requiring review before
the proposed strategy. advancing to the next phase
All regulatory agencies expect companies • clinical design issues requiring discussion
to be truthful, transparent, collaborative, sci- (e.g., where there is an intention
ence-based and patient-focused in all interactions. not to follow regional guidance and
expectations or where a specific
Language, Culture and Local Insights innovation is intended in the trial design)
To be successful, it is important companies • defining milestone meetings, e.g., End-
understand which documents must be presented in of-Phase 2 (EoP2)
the local language. This might include packaging, • technical reviews with specific
patient or physician leaflets, clinical summaries, etc. committees, e.g., biotechnology
Holding meetings in the local language can products or advanced therapies
show respect for the culture, especially where facil- • preapproval reviews, e.g., Advisory
itated by a representative from the country who is Committee Meeting
aware and respectful of specific expectations. For • presubmission interactions to familiarize
global companies, this step can be cumbersome. the review team with the dossier
Local language negotiations or discussion and allow in-person discussion and
of highly scientific dossier review aspects also clarification ahead of dossier submission
may be more fruitful in the local language
if the reviewers are less comfortable with an The global product strategy team’s job is to
alternative language. define the overall corporate product development
Some countries have specific format require- strategy, assimilate the feedback from multiple
ments, which may extend to electronic format, jurisdictions (and possible stakeholders if joint
paper color for the printed dossier, signatures and HTA advice is also sought) and propose a plan
required dossier page numbering, etc. Insights that takes feedback obtained into account. It is
into each of these requirements will ensure good practice to document the advice received
speedy validation and subsequent dossier review. and capture why the company chose not to
follow that advice, as this is likely to come up
Regulatory Authority Meetings during the subsequent marketing authorization
application review.
Global organizations may plan to interact with
specific regulatory agencies to gain feedback on Electronic Submissions
available data and intended next development
process steps. In general, companies will interact To facilitate submission, navigation and review,
with only a limited number of regulators to get many countries accept electronic dossiers. To
a sense of their intended action’s likely accept- ensure presentation is in a common format,
ability. Companies intending to market in the ICH has agreed on a common format known as
US normally will interact with FDA at defined the electronic Common Technical Document
milestones; similarly, if intending to market (eCTD).6 The table of contents is consistent
elsewhere, key interactions may include meetings with the CTD, and the document is structured
with EMA (and/or specific national European in HTML format. Since this field is evolving,
regulatory authorities), Japan’s Ministry of Health, current standards should be verified via ICH or
Labour and Welfare, Health Canada, Australia’s country-specific websites prior to dossier com-

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
pilation and submission. For example, since July References
2015, eCTD submissions have been mandatory 1. Draft Guidance for Industry and Review Staff: Target 2
for all EMA centralized applications. Product Profile—A Strategic Development Process Tool.
Many countries do not accept eCTD yet, but Draft (2007). FDA website. https://www.fda.gov/
may accept a non-eCTD electronic submission
media/72566/download. Accessed 10 October 2019. 3
(NEES). NEES differs from an eCTD because it 2. Organisation of the Common Technical Document for the
Registration of Pharmaceuticals for Human Use M4(R3).
does not have an XML backbone or MD5 check-
sum, as defined by ICH. Rather, it is a collection
ICH website. https://database.ich.org/sites/default/
files/M4_R4__Guideline.pdf. Accessed 26 November
4
of electronic files organized in folders. 2019.

International Cooperation and

3. International Organization for Standardization.
ISO 31000: 2009 Risk management Principles and
5
Harmonization Guidelines.

As organizations seek to increase their drug

4. Eichler HG, Baird LG, Barker R, Bloechl-Daum B,
Borlum-Kristensen F et al. “From adaptive licensing
6
development programs’ efficiency by increasing to Adaptive Pathways: delivering a flexible life span

7
approach to bring new drugs to patients.” Clin
their focus on early and simultaneous registra- Pharmacol Ther 2015; 97: 234–246.
tion in multiple global markets, regulators also
5. Lu Z. “Information technology in pharmacovigilance:
are growing more aware of the need for global
8
benefits, challenges and future directions from industry
harmonization of requirements and processes. perspectives.” Journal of Drug Healthcare and Patient
Efforts to increase global harmonization are con- Safety. 2009:1 35–45.

tinuing through a range of activities in addition

9
6. Electronic Common Technical Document (eCTD) M8.
ICH website. https://www.ich.org/page/ich-electronic-
to ongoing ICH processes.
common-technical-document-ectd-v40. Accessed 26
November 2019.
ICMRA
10
ICMRA provides direction for a range of areas
common to many regulatory authorities’ missions.
It identifies areas for potential synergies among
11
regulators and facilitates, where possible, interna-
tional leveraging and resource savings by building 12
confidence and deeper regulator collaboration.

International Generic Drug Regulators 13

Programme (IGDRP)
IGDRP was created to promote collaboration and 14
convergence in generic drug regulatory programs
for regulatory agencies from several countries.
15
International Regulators Consortium

This consortium was formed in 2007 by like- 16

minded regulatory authorities to promote greater
regulatory collaboration and alignment of regu-
latory requirements. 17
18

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 Chapter 15: Global Regulatory Strategy

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16 Preparing for an FDA Advisory
Committee: High Risk, High Reward

By Michael J. Vivion
1
2
3
4
5
For regulatory professionals, the statement
“You’re going to have an Advisory Committee
The FDA Advisory Committee Meeting has
been called everything from the Super Bowl of
6
Meeting” can generate waves of anxiety. For FDA meetings to regulatory theater. The meeting
them, and their companies, a Food and Drug is unique—part regulatory, part science, part med- 7
Administration (FDA) Advisory Commit- ical care, part public policy and part performance.
tee Meeting1 can be a defining event. For the The first was convened by George Washington
regulatory participant, such a meeting can be in 1794 to discuss the Whiskey Rebellion. They 8
career-defining, offering the opportunity to were formalized for FDA by the Federal Advisory
demonstrate cross-functional leadership, com-
munication excellence and organizational talent.
Committee Act of 1972—and further impacted
by the Sunshine Act of 1976 and the more recent
9
For companies, the meeting’s outcome can range Physician Payment Sunshine Act. FDA relies on
from facilitating a first-cycle approval to, for a its Advisory Committees to provide advice and 10
small company, virtual death. recommendations on a wide range of matters
For those involved in the drug and biologic related to public health: from responses to biologic
approval process, the response also generates terrorism to regulating tobacco products to scien- 11
a series of challenges: months of preparation, tific issues to new drug approvals.
huge resource demands, reliance on external But the Advisory Committee that has the
most impact on American health is the meeting
12
Key Opinion Leaders (KOLs), large outlays for
expenses and high stakes. Consequently, this that focuses on a medicinal product’s approval.
chapter focuses on the Advisory Committees For that reason, the rest of this chapter will 13
directly involved in the drug approval process. focus on the elaborate and intense preparation
for an approval meeting sponsored by the Cen-
Everyone who prepares for any of these meet-
ings faces one common truth—FDA Advisory ter for Drug Evaluation and Research (CDER) 14
Committees come with a level of unavoidable risk. or the Center for Biologics Evaluation and
Because these meetings are public, compa- Research (CBER). 15
nies’ practices and research outcomes are scru-
Advisory Committee Overview
tinized. The vote and the recorded discussion
provide material for use in future discussions A product Advisory Committee is convened
16
with FDA, for sales and marketing, for com- when FDA needs external expertise to make an
petitive intelligence and for investor decision approval decision. This need for advice is gener- 17
making. FDA faces the same public scrutiny; the ally scientific or medical, e.g., a review of a first-
vote and discussion establish a public rationale in-class therapy, one that adds to or challenges
for action—and occasionally a public outcry over current general knowledge. A product’s approval 18
an unpopular decision. might establish a precedent or impact public pol-

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 Chapter 16: Preparing for an FDA Advisory Committee: High Risk, High Reward

Figure 16-1. Typical Advisory Committee Meeting Seating Arrangement

icy. In these cases, the agency might seek external the majority meet for a full day. Each committee
advice because of the impact’s significance. has its own tendencies, but there are no rules
Sometimes, approvals or rejections intersect with governing a meeting’s exact length—some end
policy or public concerns or controversy. early, some run over. Most meetings are sin-
Indeed, both the sport and theater analogies gle company2 meetings; others bring together
reflect the preparation’s nature, which has all multiple companies to participate, perhaps on the
the elements of an organized, choreographed, same day or perhaps on sequential days.
scripted, collaborative, public performance. The meeting structure also varies, although
Figure 16-1 shows typical staging for an some features generally are predictable. The
Advisory Committee Meeting. meeting is chaired by an independent panel
Advisory Committee Meetings take place member. The chair can exert considerable power.
in the Great Room at FDA’s White Oak, MD One chair of a committee discussing bladder
meeting facility or at a variety of hotels in the cancer, for example, canceled the morning
Washington, DC area. The proceedings from break and went straight through to lunch.
hotel meetings are available as live feeds sold by Several chairs have suggested that the commit-
private companies and then, after the meeting, tee rewrite FDA’s questions to the committee.
sold as videos. Videos of meetings held at White Chairs have been known to limit the agency’s
Oak are provided free on the internet in real participation in Q&A, saying, in effect, “This is
time and then posted on the appropriate FDA not the agency’s meeting.”
committee website. Of greatest importance to the company,
Advisory Committee Meetings follow a however, is the chair’s power to decide whether
variety of models, varying even in something as to allow the company to answer questions or
simple as length. Some are only a half-day, while speak outside the formal time allotted in the

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
agenda. Companies preparing for these meetings nent record of those supporting and disagreeing
should learn as much as possible about a chair’s with the opinions and interpretations presented 2
behavior and prepare accordingly. (The section on at the meeting. In addition, committee mem-
“Considering Advisory Committee Membership”
discusses the impact of other panel members.)
bers are provided the opportunity to provide
rationales for their votes, which also go into the
3
The meeting consists of an FDA statement public record.
of purpose, the obligatory statements about the FDA uses the transcript of the discussion 4
day’s requirements; then it moves into the first and vote explanations to help guide its decision.
act of the drama, a company oral presentation, It claims to not care too much about the exact
generally followed by Q&A. Then, traditionally, vote, but rather professes to value the commit- 5
the chair schedules a 10-minute break, followed tee’s comments more. Companies, however, value
by FDA’s oral presentation, also generally includ-
ing Q&A, which often includes questions for the
the votes. Shares rise or fall. The ability to raise
money increases or decreases. Future launch and
6
company. Occasionally, questions are held until detailing plans are affected by the votes. Reputa-
after both the company and FDA have presented.
The format varies from committee to committee
tions—corporate and professional—shine or dim 7
as a result of the votes.
and chair to chair. These two performances are An extra pressure point is that the meeting
followed by an intermission for lunch. is open to the public. Analysts, journalists, con- 8
After lunch, the Open Public Hearing3 cerned and curious citizens, members of Con-
(OPH) speakers take the stage to tell their sto-
ries and offer their opinions on the product being
gress, even the competition are all free to attend
the meeting. Further, the public has access to
9
considered, an activity taking on more import details of the meeting’s focus, made public on
in recent years. (This part of the meeting will be
discussed in detail later in the chapter.)
FDA’s website 48 hours before the meeting. 10
In addition, after the meeting, the content
The last act consists of panel deliberations becomes a permanent part of the public record.
on the questions FDA has posed to the commit- All the slides the sponsor and FDA show in 11
tee. This format also varies. In general, however, the presentation and the Q&A along with both
before the committee moves to considering each
formal question, the chair makes time to hear
the agency and sponsor’s briefing materials are
posted on FDA’s website. FDA also posts a
12
from panelists who have further questions for
meeting transcript including all discussion and
FDA or the company. Then, the panelists vote
on FDA’s questions—unless FDA did not ask
any vote that takes place. These materials are 13
available to everyone.
any voting questions. In those cases, the com-
mittee simply discusses the questions. If there is Initiating Preparation 14
a vote, the chair surveys the committee members
and gives them an opportunity to explain their One pervasive question for a company devel-
votes. During this period, committee members oping a new product is whether it will require 15
rarely ask questions of either FDA (unless there an Advisory Committee Meeting. Companies
is confusion about a question), external experts
or the sponsor. Consequently, misunderstood
frequently must decide whether to initiate
preparation for a meeting before they have been
16
information or incomplete responses in the told whether they will actually have a meeting.
minds of committee members can be accepted as Deciding whether to proceed “at risk” depends 17
fact, highlighting the Q&A’s importance to the on whether there will be a meeting. The answer is
meeting’s final outcome. unpredictable, depending as it does on a variety
Voting is electronic and recorded publicly of factors outside the company’s control—FDA’s 18
by committee member name, forming a perma- internal and “private” knowledge of other prod-

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 Chapter 16: Preparing for an FDA Advisory Committee: High Risk, High Reward

ucts or other research, the agency’s workload, the for an Advisory Committee Meeting. Companies
tolerance level for inconclusive data and FDA’s also realize they can repurpose the material they
actual product expertise. have created—scripts, briefing document and
In addition, Congress has made it more dif- slides—as useful material for sales, marketing
ficult for FDA to decide not to hold a meeting. and medical affairs.
“Under section 505(s) of the Federal Food, Drug,
and Cosmetic Act, before approving a drug no Meeting Preparation
active ingredient of which has been approved,
Because the stakes are so high, companies fre-
FDA must either refer that drug to an advisory
quently spend as much as a million dollars on
committee or provide in the action letter for
the preparation process, a process often requir-
the drug a summary of the reasons why FDA
ing approximately six months of steady training
did not refer the drug to an advisory committee
and rehearsing. The process is both time- and
before approval.”
resource-intensive. It involves coordinating an
When management asks regulatory about
internal team to construct briefing materials,
the probability of a meeting and the need to
developing a 60–90-minute presentation, planning
initiate preparation, the answer should be based
for 60–150 minutes of Q&A—including creating
on this guidance and on the recent product types
and organizing slides—managing external experts
appearing before an Advisory Committee in the
and synchronizing the many activities associated
company’s therapeutic area. The unpredictability
with Advisory Committee preparation.
of the answer, however, always should be part of
the discussion and the decision. Preparation Process Overview
At-Risk Preparation: Message Matrix Advisory Committee conduct is governed more
by precedent than by guidelines or rules. The
Some companies have chosen to initiate at-risk
only FDA guidance focuses largely on timelines
preparation, starting the Advisory Commit-
and material that can be redacted. It gives one
tee presentation before receiving notice from
piece of advice: focus on the issues at hand. FDA
FDA. Indeed, a few initiate preparations even
provides no specific advice on exactly what the
before filing.
sponsor should present in its briefing materials,
In the case of the pre-filing preparation,
how long they should be or how the presentation
companies use a process called frontloading. A
should be shaped. There are no rules on using
series of meetings creates a knowledge man-
outside experts or slides or whether to bring in
agement matrix to drive explicit messages and
patients to speak. A knowledgeable sponsor must
identify potential issues that might arise during
make these decisions based on its strategy and its
review; then the company develops positions on
understanding of how to succeed at an Advisory
these issues to ensure the program can support the
Committee Meeting.
messages and opinions. The filing team then can
A complete plan will include details about
use this matrix to shape submission sections that
the following:
call for discussion, including clinical study reports,
• strategy for obtaining desired outcomes
the preclinical (2.4) and clinical (2.5) overviews. • meeting preparation timeline
If created post-filing, the message matrix • preparation and meeting roles and
can contribute to a variety of filing and review responsibilities
requirements, e.g., company responses to the • company’s role in the Open Public
inquiries it receives from health authorities. In a Hearing
few cases, a company’s ability to respond effec- • profiles of recent Advisory Committee
tively to these requests has eliminated the need actions and current committee members

208 All rights reserved; file sharing prohibited.

 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
• regulatory review timeline, including Clearly, all companies want favorable discussions
need to answer questions from other and votes, but the wisest consider the outcome’s 2
health authorities impact on labeling, uptake, indication and sci-
management buy-in entific and medical community responses. They
3
•
• decision on external help necessary for want a positive vote and a rational discussion of
preparation the product.
• message matrix to align team on
company’s positions on content
The preparation process should proceed 4
with the potential outcomes in mind. For some
• list of experts, internal and external,
companies, that outcome is almost a foregone
needed to give presentations and
respond to questions
conclusion. Some know they have a small chance 5
for a positive vote; others have such excellent
• briefing document and core presentation
data that they understand that their meeting’s
message/issue prototypes
outcome is pro forma. Nevertheless, Advisory 6
• briefing document and core presentation
reviews and final approval Committee Meeting outcomes are nuanced.
• Q&A organized into useful format for Commenting on an article about correspon-
dence between Advisory Committee votes and
7
rehearsal and answer retrieval
• slides developed, reviewed and FDA decisions, a professor from Yale noted that
organized into retrievable format the only factor clearly correlating to FDA not 8
• speaker training and coaching following a committee’s recommendation was
the failure of a committee to reach consensus.4 In
• rehearsals, including mock committee
meetings, their timing and location other words, the closer the vote, the more leeway 9
• meeting and hotel logistics for both FDA has in making a decision contrary to the

•
mocks and the meeting
travel arrangements for team and
one reported publicly.
However, it is not about just the vote; it
10
external support also is about the panel discussion’s tone and the
• logistics for compensating external
experts
nature of the comments. 11
Consider these alternatives:
• plan for integrating late-cycle meeting negative vote with helpful comments
12
•
• plan for implementing interaction with
• positive vote with helpful comments
committee industry representative
• positive vote with potentially harmful
• profiles of temporary voting members
posted on FDA website two days before
•
reservations
negative vote with harmful comments
13
the meeting

The following sections provide details on the

Another consideration is that the Advisory 14
Committee Meeting is like a pre-launch meet-
process involved in preparing for the meeting, ing. The public hears the key data and FDA’s
focusing on the most important considerations. It position. During the Open Public Hearing, con- 15
is by no means exhaustive. Regulatory profession- cerned members of the public provide endorse-
als participating in one of these meetings for the ments—or not—that become part of the public
first time face considerable research to ensure they record and often are highlighted by the media. 16
develop an appropriate roadmap and action plan. Media representatives are in attendance and
report in great detail what they find most news-
Developing an Outcomes-Based Strategy worthy from the proceedings. Analysts attend 17
the meeting and form opinions and forecasts.
After deciding to prepare for a meeting, one of In short, much of what occurs at the meeting
the key preparation steps is to develop a strategy potentially can influence a product’s sales and the 18
that considers the desired outcome in depth. company’s success.

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 Chapter 16: Preparing for an FDA Advisory Committee: High Risk, High Reward

Finally, a company cannot forget that FDA Implementing a Strategy

is also an audience, and it has the final vote for
approval and the label. In addition, FDA has a After developing a strategy, the next step is plan-
good memory. A company’s performance has the ning its implementation. Most companies do not
potential to make a lasting impression. have sufficient internal resources to handle such a
complex, intense process, so deciding on the need
Influences on Strategy for external support for both process and content
becomes a critical path activity that needs to be
Frequently, determining an overall strategy
completed early. Experts who might support the
involves several functions, each representing an
company’s position need to be engaged as soon
essential voice in the development, approval and
as dates become available because they often are
marketing processes.
booked months in advance. Starting this complex
Most important, meeting-associated issues
preparation process as much as six months before
can lead to internal disagreements, sometimes
the meeting date can pay high dividends.
gentle but at other times vigorous. The potential
for disagreement exists in all types of Advisory Considering Advisory Committee
Committee Meetings, but approval meetings ele- Membership
vate those odds. For example, regulatory, clinical
and marketing do not always have mutually com- An important tactic to accomplish the team’s
patible goals. Regulatory could be determined goals is to construct purposeful communication
to obtain a positive vote, but marketing wants with a particular Advisory Committee audi-
a positive vote peppered with committee com- ence in mind. Companies applying this tactic
ments to support product launch. Clinical might spend considerable time early in the preparation
want both but maintains a strong opinion that process developing an understanding of their
the company’s data support a stretch indication, a Advisory Committee’s membership. Accord-
desire sometimes so risky it puts the entire filing ing to FDA, Advisory Committee members
at stake. are selected based on their expertise and their
Occasionally, the disagreement is more ability to review scientific and medical materials
fundamental. For example, data may support to provide the agency with advice on one of the
one dosing regimen, but the marketplace needs issues described in the guidance. Indeed, this is
a variation on the supported dose. A well-pre- Advisory Committees’ remit.
pared sponsor constructs its strategy with a clear In reality, however, the expert committee
understanding of the risks involved and the member selection process presently is under
consequences of losing. strain. To avoid both real and apparent conflicts
FDA’s meeting role also merits consider- of interest, FDA is forced to exclude many
ation. Like the sponsor, FDA makes its opinion top experts because of their financial interests,
known via a presentation, briefing materials and direct and indirect, in either the products being
Q&A. The agency also listens astutely to every- reviewed or competitive products.5 FDA can
thing the sponsor presents or claims and will use obtain a waiver under certain circumstances;
that information in subsequent action as it and however, recent pressure has made it more diffi-
the company move toward the Prescription Drug cult, politically, for the agency to do so.6,7
Use Fee Act (PDUFA) decision date. Accordingly, some committees fail to have
A successful strategy must include an aware- the rigor originally built into the Advisory
ness of potential data interpretations, the com- Committee member selection process. Pediatri-
pany’s needs and FDA’s positions as expressed in cians are frequent panel members because they
pre-meeting documents and meeting minutes. have medical expertise but rarely are involved

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
with clinical trials. FDA also regularly draws on its own stage. Symbolically, committee members
a population of experts who have been approved sit around a horseshoe-shaped table with its 2
for Advisory Committee service already because opening to the public reflecting the spirit of the
of their previous clearance and their status as
“government employees.” National Cancer
Sunshine Act, a public meeting designed for the
public protection.
3
Institute, National Institutes of Health, Centers Although the exact arrangements might
for Disease Control and Prevention and Veter- vary, certain features of the staging are consistent 4
ans Affairs hospital employees frequently serve (Figure 16-1). Projectors are not the highest
as members or temporary members of Advisory quality. Screen placement makes communication
Committees regardless of their expertise level. awkward. There is limited eye contact between 5
Consequently, company experts and external individual committee members and sponsor
advisors occasionally have a specialized expertise
superior to most committee members, sometimes
speakers and responders. FDA has seats at the
table; the company does not. Sponsor partici-
6
making communicating the intricacies of a prod- pants sit on one side of the room, FDA’s on the
uct and its development a challenge. other. Microphones are fixed; no lavaliere micro- 7
By the preparation’s kick-off, the sponsor phones are used.
team should be armed with standing commit- Because these committee rooms are so
tee member profiles to analyze its audience. In different from venues common to most present- 8
addition to more traditional research sources, the ers and responders, anxious presenters frequently
sponsor should consider LinkedIn, Facebook and
science blogs. Some paid services also can supply
are uncomfortable. Accordingly, rehearsals using
the room design, or even the actual room, help
9
pieces of this information. In addition, sponsors mitigate potential nervousness and increase the
can obtain videos of previous Advisory Commit- team’s comfort and performance levels. 10
tee Meetings and watch particular committees
and committee members in action. The more the Matching Strategy and Tactics:
team knows about Advisory Committee mem- Messaging 11
bers’ backgrounds, voting histories and particular
The best way to mitigate an Advisory Committee
interests or concerns, the better able it will be
to address process, content and comprehension
Meeting’s associated risks and obtain the best 12
result possible is to develop a clear compendium,
issues, and focus its briefing document, core
presentation and Q&A book on not only those
usually in a searchable matrix, of the company’s
messages: its hypotheses, claims, conclusions and
13
issues, but also responses to them. Successful
interpretations. This matrix resembles the matrix
communication demands a clear understanding
of both audience analysis and audience focus.
described earlier but has the committee mem- 14
bers as its audience. All the steps in messaging
Companies must tailor their materials for a
are done with the advisory committee members’
wide level of expertise, which means they have
to develop strategies and tactics to inform and
expertise and experience providing guidance 15
about what might be the most effective approach
persuade everyone from generalists to broadly
published KOLs.
to presenting the company’s data.
Simultaneously, the company must honestly
16
Impact of Advisory Committee Venues and fully assess the issues inherent in its product
and the messages they’ve identified—particularly 17
As noted previously, the most common sites for in light of the audience it has profiled. The team
Advisory Committee Meetings are Washington, then must determine how it plans to respond to
DC-area hotels and FDA’s facility in White the issues identified, analyze its positions and 18
Oak, MD. Each meeting and each division has assess whether it has the appropriate support

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 Chapter 16: Preparing for an FDA Advisory Committee: High Risk, High Reward

for their messages and responses. At that point, of organizations provide testimony by patients,
it can begin the preparation, which should start doctors, caregivers and healthcare workers—all of
early and maintain momentum throughout the whom are experts in their own experiential way.
process, always keeping in mind effective com- This testimony often develops the medical need
munication is that which leads the audience to picture in a way the company cannot. In addi-
accept the communicator’s purpose or prem- tion, the testimony can provide concrete exam-
ise—in this case, the company and its advisory ples with human faces of the disease treatment’s
committee team—and to act on it. clinical relevance and importance.

Engaging External Support Developing Briefing Materials

Companies also must consider who can best Developing effective briefing materials (referred
implement the strategy, given both content and to variously as briefing document, background
committee membership. Can company experts document, briefing package or briefing book)
persuade the committee, or does the knowledge presents a number of challenges. First, this
and credibility needed for persuasion require package is submitted about a month before the
external experts? Even after making this deter- meeting, before the company receives FDA’s
mination, companies have to ask what level materials and before the late-cycle meeting.
of expertise actually can be presented with- Often, the important issues and the company’s
out leaving the committee either confused or response to them change significantly during this
unpersuaded. Once again, to increase the chances interval. Second, there are no FDA rules for this
of success, the team must develop approaches document. In its guidance, it recommends only
designed for the committee it is facing. that the document should focus on the issue at
Another expert who often can be useful to hand, and the material in the document should
a company is the committee’s industry rep- not be misleading
resentative. The sponsor provides its briefing The most successful briefing materials take
materials to the industry representative. It the demands they place on committee mem-
also can discuss the meeting with the industry bers into account. They make the sponsor’s case
representative. It is permitted for the sponsor to to the committee in a document structured to
meet with the representative before the meeting facilitate reading, presenting strong and clear
to discuss any concerns the sponsor has about messages supported by persuasive evidence.8 Yet
the meeting process and its ability to be heard, another consideration is the briefing materials
if necessary, on particular issues. The range of are public; everything given to committee mem-
openness for this kind of discussion varies from bers is available to the public except redactions
committee to committee and from representa- made to protect certain proprietary information.
tive to representative, but it is an opportunity The materials are posted on FDA’s website two
that should be explored. days before the meeting; analysts, the media,
Another potential avenue for the company advocacy groups and all other interested parties
is the Open Public Hearing. Companies can may access the materials. Often, there are
inform key disease groups like the National MS significant stock fluctuations based on FDA
Society, Alliance for Aging Research, National and sponsor briefing materials and the public
Foundation for Infectious Diseases or patient response. For these reasons, most briefing doc-
advocacy groups like Conquer Cancer Founda- uments do not follow the FDA advice to limit
tion, American Nurses Association, Asthma and discussion to the issue at hand. Companies want
Allergy Foundation of America of the upcoming the committee to accept the arguments pre-
meeting. Often, representatives from these kinds sented, but they also want the wider audience to

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
do the same—and to understand the product’s as possible so the following Q&A can focus on
complete story, not just an excerpt that deals unresolved issues. It therefore sets the stage for 2
with one issue. Context serves understanding. the Q&A by providing the committee with the
Therefore, the best documents often are
written with this wider audience in mind while
company’s intellectual framework for the dis-
cussion. It also should create the impression of a 3
keeping the primary focus on the committee credible, thoughtful and thorough company.
members. As mentioned above, the readers’ The company’s strategy also dictates the
presentation’s shape. For example, if a company
4
expertise levels vary from committee to com-
mittee and within each committee. In addition, decides to review the entire product development
the amount of attention committee members path, perhaps because it wants the committee 5
give the document varies. Many members have and the public to understand how difficult deci-
sions were made, the presentation might empha-
active clinical practices or intense university
demands and only minimal time to prepare. size medical need and program design. If FDA 6
Other members come with the materials has agreed there are no safety issues that need to
marked with extensive tabs and sticky notes. be discussed, the sponsor might choose to give a
presentation heavily weighted toward efficacy. If
7
Briefing packages that are too complex or sim-
there are clearly defined issues, a sponsor might
ply too long run the risk of being either largely
unread or simply skimmed.
choose to craft an issue-oriented presentation. 8
The wise company recognizes the special
Because both the sponsor and FDA prepare
conditions imposed by the room structure and
briefing materials, for a multiple topic or product
meeting that may run three days, for example,
the committee composition. The room makes it 9
difficult to use many of the standard techniques
committee members often have six documents to
of presentation excellence. Because most of the
read before the meeting—three from the sponsor
committee members are faced away from the 10
and three from FDA. At a recent meeting to speaker, both body language and eye contact
discuss risks associated with Opioid-Induced
Constipation ( June 2014), five sponsors pre-
range from difficult to impossible. Speakers must
rely on vocal variety, pace, significant pauses
11
sented briefing documents in addition to one and language structured for the ear, not the eye.
from FDA. Six 150-page briefing documents
mean 900 pages of reading for committee mem-
Companies should also accept that less is more. 12
Giving a 90-mimute presentation both stretches
bers, who most often work fulltime schedules in the attention span of the committee and takes
their “real” jobs. away from Q&A—where the issues have the 13
greatest chance of being resolved.
Developing the Core Presentation
Preparing for Q&A 14
Because not every committee member reads the
sponsor’s briefing book, the core presentation A sponsor’s performance in Q&A often is the
given at the meeting can be the first time the most important part of the meeting. It is where 15
sponsor has the opportunity to present its case.9 the committee gets to deal with its open issues.
Time allotted for the presentation ranges from
45 to 90 minutes, depending on decisions made
During Q&A, the sponsor has the opportunity
to hear the committee members’ concerns, i.e.,
16
before the meeting by FDA and the committee what they think and feel about the medical prod-
chair. It is the most personal and most direct uct under consideration. Only during Q&A can 17
communication between the company and the a company respond directly to those concerns.
committee. It rarely provides the final convinc- All preparation to this point has been based on
ing evidence for a positive response, but one of FDA’s responses and a series of knowledgeable 18
its goals is to take as many issues off the table hypotheses about how the committee will react.

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 Chapter 16: Preparing for an FDA Advisory Committee: High Risk, High Reward

Consequently, Q&A forms a central part similar therapeutic areas. Most of all, it antici-
of the meeting’s choreography. At an approval pates questions and prepares for all concerns that
meeting, sponsors must have back-up slides to might obstruct a positive discussion and vote.
support their responses to almost any possi- Finally, the team rehearses—and rehearses.
ble question or concern a panelist might have.
Although the number of slides shown to the Q&A Back-Up Slides
committee is limited, usually around five–25,
Advisory Committee members expect the
the number prepared can be in the thousands.
sponsor to show back-up slides supporting its
For a $300 billion investment, a company wants
assertions and expect these slides to be shown
to ensure all possible approval recommendation
almost simultaneously as it begins its answer.
obstacles can be overcome.
To meet these expectations, the team deals with
The sponsor’s seating section includes
three primary considerations: slide creation, slide
employees to retrieve slides, send them to the
effectiveness and slide retrieval.
speaker’s preview monitor and project them on
A team needs to produce only enough
the committee’s screen within five seconds. The slides to support answers requiring visual data
speaker responding to questions might preview representation or to serve as notes for some-
five–10 slides for each one actually shown. one responding during Q&A. Slides should
Q&A materials the team will use in its be created only after a question and answer
preparation also must be designed with con- have been identified. To be efficient, a team
sideration for the audience. The Q&A book, should make messaging its priority, followed
whether in paper or electronic form, functions by slide production. In no case should it begin
much like a script. It forms a complete Q&A to produce slides before the presentation and
performance plan. Traditionally, it develops briefing book preparation have begun. Teams
out of the message matrix and consists of a with the discipline to create slides in the context
compendium of issues a company foresees, its of developing Q&A often produce fewer than
planned responses and the data it will use to 1,500 slides. Their slides are connected clearly
support those responses. In its most complete to Q&A book items and, although they might
form, it also records the supporting slides’ iden- be revised during preparation, become central
tification numbers, content source and respon- Q&A process components because the slides
sible personnel at the meeting. The Q&A book are relatively easy to access.
provides an intellectual snapshot of the compa- Teams that prioritize slide creation will
ny’s messages, issues, responses and support at a reformat and repurpose slides from congresses,
given time in the preparation process. symposia, advisory boards, internal presentations
At its best, it provides the sponsor team and marketing decks. These teams produce thou-
the ability to sort through a large amount sands of slides; the record is said to be more than
of material in seconds to provide both an 10,000 back-up slides. Such an overwhelming
appropriate response to a question and the number of slides greatly strains a team’s resources
correct back-up slide to support the response and makes rapid access difficult.
if needed. It is an essential component of both Compressed timelines and slide volume,
rehearsals and the meeting. even at the lower end, require adequate pro-
An effective team updates the Q&A book cessing and frequently heroic effort to keep the
throughout the preparation process. It generates schedule on track; therefore, estimating and
comprehensive material by considering the litera- establishing production capacity drives slide
ture, practitioners’ concerns in the medical area, development tactics.
advisory board material, Advisory Committee As the Q&A slides are developed, they must
member profiles and other drugs’ experiences in be organized and indexed for easy retrieval. This

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
process operates most smoothly when integrated preparation team a fresh view on its strategy and
with an electronic search function and software implementation. It provides an assessment of 2
designed specifically for an Advisory Committee the speakers and, particularly, of the responders
during Q&A. It is not uncommon after a mock
Meeting. Ideally, the indexing system and mes-
saging process are integrated. for a company to decide to switch team roles and 3
The most impactful slides are those that engage different experts. A mock provides a team
illustrate an answer, supporting the team with a strong dose of reality and suggests strong
next steps.
4
member’s response. They tend to be simple,
one-message slides. Complex slides appropriate To get the most out of such a meeting, mock
for prominent journals are unlikely to be effective panelists should be selected carefully. To help the 5
with most Advisory Committees, especially given team understand best who its audience will be on
the committee membership limitations discussed the day of the meeting, the mock panel should
above. Further, a slide presenting too much infor- reflect standing committee members’ exper- 6
mation or providing support to more than one tise and even their manner. To maximize that
insight’s quality and quantity, the sponsor should
answer often leads to further questions.
populate each mock with different panelists. 7
Performance Each mock should be conducted as though

For issues involving products and approval

it were an actual meeting. The mock panelists
receive the briefing materials. The setting reflects
8
meetings, preparation typically begins four to six that of the actual meeting, including screens and
months before the meeting. Most speakers and table shape. Someone plays the chair. The agenda 9
responders to questions have significant experi- reflects a typical meeting. Both the panel and
ence in scientific communication, but, because sponsor team play their roles until the feedback
this meeting is so different, presenters often are session begins. 10
stunned and even slightly overwhelmed by an During the feedback session, a facilitator
asks panelists to comment on the briefing docu-
Advisory Committee’s special communication
demands. Consequently, an important part ment’s content, structure and clarity as well as its 11
of preparation will be customized training in relevance to the presentation. In addition, panel-
Advisory Committee performance, followed by ists comment on the presentation and Q&A. The
facilitator also makes time for the team to ask
12
ongoing coaching.
Performance coaching occurs in a series of questions, should it have any specific concerns
internal rehearsals and mock Advisory Com- that have not been covered. Through observation 13
mittee Meetings where the entire committee of and interaction with mock panelists, team
members will be able to get a feel for concerns,
meeting process is replicated.
comments and question content and style, and 14
Mock Advisory Committee Meetings committee members’ thought processes.
During a separate, team-only debrief, the
Mocks are like off-Broadway openings, import- team should assess comments and suggestions 15
ant milestones in any preparation. They are and choose which ones to incorporate into
structured to reflect the processes of an actual
meeting using a panel of external experts chosen
the presentation, responses and slide deck. It
should discuss any key concerns or themes that
16
to reflect the panel’s likely expertise. They have a emerged from panelists’ feedback and deter-
draft briefing document, a core presentation and mine whether and how to address them. It also 17
several Q&A sessions. They offer the company should capture any new questions (or responses)
outsider experts’ perspective on company data in the Q&A books.
and strategy, presented in the context of an actual Finally, the best-prepared teams record each 18
Advisory Committee. This structure gives the mock and review the recording to critique mem-

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 Chapter 16: Preparing for an FDA Advisory Committee: High Risk, High Reward

bers’ performances. They should examine presen- critics and speak against approval, including rep-
tations and responses for clarity and persuasive resentatives from citizen action groups, and even
delivery, assess slide retrieval speed and accuracy lawyers who might be suing the company. Their
and examine slides to ensure each provides presentations may range from overtly supportive
persuasive data and is well-designed. The team to intensely negative. The testimony ranges from
should address any areas in need of improvement. first-hand experience to PowerPoint presenta-
It then can fold that knowledge into presentation tions of evidence from observational trials to
and response revisions. academic treatises.
In this high stakes’ theater, the best prepared A company presenting the results of its
ensemble leaves nothing to chance: rehearse, development program for an Advisory Com-
review, revise and rehearse again. mittee cannot afford to dismiss the potential
importance of an OPH.
Preparing for the Open Public Hearing
Logistics
Commonly lasting one hour immediately fol-
lowing lunch, this offers members of the public The process complexity described above is only
who register the opportunity to comment on the what participants can see. Underlying this pro-
product and the disease the meeting is consid- cess are thousands of small details and tasks, all
ering. For those who cannot attend in person, of which must be performed to a high standard
FDA offers the opportunity to submit written for smooth preparation. These additional details
comments that are included in the committee can include:
briefing package. The chair encourages partici- • scouting and choosing facilities
pants to state their connection to the topic and appropriate to the team’s size and needs
the level of the company’s financial support. • transporting people to and from airports
In general, the testimony gives committee and hotels
members a chance to see the approval process • contacting and booking hotel rooms
from a more emotive point of view. Hearing from • transportation
patients and caregivers about their quality of life • external experts
and need for a better treatment has occasionally • copying services
induced tears from the committee. On the other • audiovisual equipment
hand, it also gives the floor to health industry • security
watchdogs who show up with their own analyses • understanding potential venues’
and interpretations of a company’s data. limitations
A team should prepare a strategy and an
implementation plan for this session. The best Even making sure the team has water, 3x5 note-
practice for a team is to provide publicity to a cards and tissues are important.
wide variety of potential supporters for its prod-
uct. Work to ensure the makeup of the OPH Challenges to Advisory Committee
participants reflects potential issues the commit- Credibility and Integrity
tee and temporary voting members will address. Political Pressure
The most successful OPHs hear from a mosaic
of patients, caregivers, physicians and repre- As suggested earlier, the Advisory Committee
sentatives from professional organizations. This occurs in a public venue,10 putting both the
mixture is important to ensure the committee company and FDA at risk of social and political
hears a balanced and complete view of the prod- influence shaping some of the discourse both
uct because it regularly hears from those who are outside and inside the meeting.11 Companies

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
have learned that members of Congress, the try’s level of support for patient and disease
press, health advocacy organizations and other advocacy groups.15 2
influential forces can be moved by external pres- However, the testimony does give com-
sures and public campaigns. mittee members the opportunity to see the
approval process from a more emotive point of
3
Committee Membership view. No strong research has investigated a pos-
Earlier in the chapter, the problem with the sible cause-and-effect relationship between the 4
efforts to avoid bias while ensuring expertise tenor of the OPH and its impact on the final
vote; however, in private conversations, com-
in committee membership was discussed.12
FDA has responded to this problem in a vari- mittee members have expressed that testimony 5
ety of ways, beginning as early as 2007 when it often has caused them to assess benefit-risk
published “Measuring Conflict of Interest and more closely in their deliberations.
As mentioned earlier, the OPH has become
6
Expertise on FDA Advisory Committees” by
Nancy Gieser of the agency’s Office of Policy, an opportunity to put pressure on FDA. The
Planning and Preparedness.13 flibanserin advisory committee brought out 7
Lately, several investigative journalists have hundreds of women supporting the product, a
treatment for female sexual dysfunction, and
written about the indirect influence the phar-
maceutical industry is having on committee publicly introducing gender discrimination as an 8
members though a post hoc process. For example, underlying motif at the meeting. Similarly, at the
a committee member has no conflicts of interest eteplirsen committee, dozens of boys and their
parents came together to lobby for its approval.
9
and no apparent bias. During the meeting, he
or she proves to be an articulate supporter of Although the panel voted “No,” the public
the product. After the meeting, the company support had an impact. “I assure you, we listened 10
hires the committee member to attend Advi- very carefully and will take the information we
heard here today under serious consideration,”
sory Boards, speak at satellite symposium, and
support the product in physician education. This Dr. Billy Dunn said, addressing the OPH par- 11
practice is gaining traction, and it is quite likely ticipants.16 FDA approved the drug despite the
that knowledge of the practice circulates among negative vote.
Despite these controversies, which are likely
12
chains of physicians and researchers in multiple
therapeutic areas.14 to continue, a company presenting the results of
its development program cannot afford to ignore 13
Open Public Hearing the OPH.
The OPH has become increasingly important, Conclusion 14
and controversial. At the beginning of an OPH,
the committee chair encourages participants to A study published in 2019 reported that,
state their connection to and the level of finan- between 2008 and 2015,17 FDA’s approval 15
cial support from the company participating in decision matched the committees’ votes approx-
the meeting. Their connections, when expressed,
are varied. In addition, expressing these connec-
imately 80% of the time. Drawing a conclusion,
however, about the influence of the committees’
16
tions is optional. Consequently, it is difficult to votes would be inappropriate because an approval
assess potential testimony bias. Some speakers decision includes many different variables: public 17
have been prepared by firms with some connec- health considerations, political pressure, medical
tion to the sponsor. Even the testimony from need, interpretations of data and recognition of
professional organizations has been called into other products in the approval pipeline. Fur- 18
question because of the pharmaceutical indus- ther, these numbers are averages; the correlation

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 Chapter 16: Preparing for an FDA Advisory Committee: High Risk, High Reward

varies considerably from year to year. A study (OPH) session, during which interested persons may
present relevant information or views orally or in
conducted by ECG, exploring the correlation
writing (21 CFR 14.25(a)). 21 CFR 14.29 requires a
in 2018, found that in only two of 29 products minimum of 60 minutes per meeting to be dedicated
with a voting question did FDA make a decision to an OPH session for oral presentations, unless public
against the committee votes, both going against participation does not last that long. For meetings
that extend more than one day and/or meetings with
positive committee votes. One vote was 12–11 multiple topics, the OPH session can be divided
“Yes,” the other 10–7 “Yes.”18 into multiple parts. If the Advisory Committee has
In addition, at every meeting, FDA makes overwhelming interest in a specific topic, the committee
chair may extend the OPH session. The time and
a statement that the discussion of the reasons location of the meeting and the OPH session are
for the vote are more important than the votes published in the Federal Register (21 CFR 14.20) at
themselves. Nevertheless, FDA employees also least 15 days before a meeting.
have made public statements indicating that they 4. DeArment A. “FDA often goes against advisory
recognize the vote’s importance to sponsors. committee recommendations when votes are divided,
study finds” (19 July 2019). MedCity News website.
Despite the limitations and controversies https://medcitynews.com/2019/07/fda-often-goes-
inherent in the process, Advisory Committee against-advisory-committee-recommendations-
members’ votes and comments during discus- when-votes-are-divided-study-finds/. Accessed 16
September 2019.
sions can have a major impact on scientific and
medical practice, clinical trial design, product 5. Cooper J and Golec J. “Conflicts of Interest on Expert
Committees: The Case of FDA Drug Advisory
approvals, labeling and product uptake. They Committees.”(University of Connecticut School of
influence the reputations of both individuals and Business Research Paper No. 17-02; George Mason
companies. To ensure a successful outcome, all Law & Economics Research Paper No. 18-10) SSRN.
Posted: 4 Apr 2017, Last revised: 27 Apr 2018.)
the parts of an Advisory Committee Meeting
6. Public Availability of Advisory Committee Members’
must be carefully coordinated and produced. The
Financial Interest Information and Waivers: Guidance for
briefing book must be a credible advocate for the the Public, FDA Advisory Committee Members, and FDA
product. Content must be refined and delivered Staff (March 2014). FDA website. http://www.fda.gov/
by well-rehearsed speakers. Interaction with RegulatoryInformation/Guidances/ucm391034.htm.
Accessed 16 September 2019.
the committee members during Q&A must be
7. Food and Drug Administration Amendments Act of
direct, forceful and credible. In short, an Advisory
2007(FDAAA) Title VII, Section 701: Conflicts of
Committee Meeting is a major production from Interest. FDA website. https://www.govinfo.gov/
top to bottom, from concept to implementation, content/pkg/PLAW-110publ85/html/PLAW-
and its influence makes it a major player in the 110publ85.htm. Accessed 16 September 2019.

approval process.19 8. Guidance for Industry: Advisory Committees—Preparation

and Public Availability of Information Given to Advisory
Committee Members (August 2008). FDA website.
https://www.fda.gov/media/75436/download. Accessed
References 16 September 2019
1. Advisory Committees. FDA website. https://www.fda.
9. Fenichel R and Garvey T. “Writing a Briefing Book
gov/advisory-committees. Accessed 16 September 2019.
for a CDER Advisory Committee.” Dr. R. Fenichel
2. In much of the material discussing Advisory website. http://www.fenichel.net/papers/briefing%20
Committees, the word “sponsor” may be used instead of book.pdf. Accessed 19 June 2019.
“company” and “agency” instead of “FDA.”
10. I recently worked with a development team that
3. The Open Public Hearing at FDA Advisory Committee was told it would not need an Advisory Committee
Meetings: Guidance for the Public, FDA Advisory Meeting. At the mid-cycle meeting, FDA told the
Committee Members, and FDA Staff (15 May 2013). sponsor that instead, Special Government Employees
FDA website. https://www.fda.gov/regulatory- (SGEs) would be consulted during the review. In the
information/search-fda-guidance-documents/open- Summary Basis of Approval, FDA published minutes
public-hearing-fda-advisory-committee-meetings. of meetings held with the SGEs. In the process I
Accessed 16 September 2019. Every Advisory saw, the review team composed a series of questions
Committee Meeting includes an open public hearing similar to those asked during an Advisory Committee

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
Meeting and compiled a briefing document, also 18. Carillo FR. Unpublished research ( June 2019).
similar to one FDA might have composed for an
Advisory Committee Meeting. Both then were sent,
19. For one view, see Califf ’s remarks as he left the Office 2
of Commissioner in 2017. Internet Archive. https://
along with the company’s draft labeling, to SGEs for web.archive.org/web/20170118195221/http://blogs.
evaluation and discussion. The review team and the
SGEs then discussed the assessment and the answers
fda.gov/fdavoice/index.php/2017/01/fda-advisory-
committees-independent-informed-essential-and-
3
to the FDA questions. evolving/. Accessed October 8, 2019.
11. Sanders M. “Sex, Drugs, And Advisory Committees:
An Analysis of Pharmaceutical Industry Manipulation 4
of FDA Vulnerability to Sociopolitical Influences on Author’s note: Much of this chapter is based on
Matters of Women’s Health.” Columbia Law School my 20+ years’ experience—acting both within the
website. http://hrlr.law.columbia.edu/files/2018/01/ industry and as a communication consultant—of 5
MaraSandersSexDrugsandAdv.pdf. Accessed 16
September 2019.
preparing over 60 company teams to perform at
12. In 2014, researchers wrote a number of articles on
FDA Advisory Committee Meetings.
6
potential biases of FDA Advisory Committees; the
most commonly cited one was “Revisiting Financial
Conflicts of Interest in FDA Advisory Committees.”
The MilBank Quarterly: A Multidisciplinary Journal of
7
Population Health and Health Policy; Sept 2014, Vol
92, #3, pp 446-470. Since that time, research has been
sporadic, but consumer watchdog groups continue to 8
make the issue topical. On 26 November 2016, the
Patient, Consumer and Public Health organization
released a statement responding to FDA’s draft
guidance on conflicts of interest. Patient, Consumer and
9
Public Health website. https://patientsandconsumers.
org/coalition-letter-on-conflicts-of-interest/. Accessed
16 September 2019.
10
13. Gieser N. “Financial Conflict-of-Interest Disclosure
and Voting Patterns at FDA Advisory Committee
Meetings.”
11
14. Piller C and You J. “Hidden conflicts? Pharma
payments to FDA advisers after drug approvals spark
ethical concerns.” Science, 5 July 2018, 2:00 PM. Science
12
Magazine website. https://www.sciencemag.org/

13
news/2018/07/hidden-conflicts-pharma-payments-fda-
advisers-after-drug-approvals-spark-ethical. Accessed
16 September 2019.
15. Glickman A. “Conflict of Interest Among Public
Speakers at FDA Advisory Committees” (23 April 14
2018). Penn Leonard Davis Institute website. https://
ldi.upenn.edu/healthpolicysense/conflict-interest-
among-public-speakers-fda-advisory-committees.
Accessed 16 September 2019.
15
16. Pollack A. “Advisers to F.D.A. Vote Against Duchenne
Muscular Dystrophy Drug.” The New York Times,
Business, 25 April 2016.
16
17. Zhang AD, Schwartz JL and Ross JS. “Association
between Food and Drug Administration Advisory 17
Committee Recommendations and Agency Actions,
2008–2015” (14 July 2019). The Milbank Quarterly.
Wiley Online Library website. https://onlinelibrary.
wiley.com/doi/abs/10.1111/1468-0009.12403. Accessed
18
16 September 2019.

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 Chapter 16: Preparing for an FDA Advisory Committee: High Risk, High Reward

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17 Considerations for Healthcare
Products’ Lifecycle Management

By Timothy Pang
1
2
3
4
5
Introduction 2018.1 As the industry steels itself for the coming
wave of biosimilars, the need to maximize every
6
Lifecycle management (LCM) in the pharma- product’s value throughout its lifecycle is clearer
ceutical industry can be defined as those actions
taken to maximize a drug or biologic product’s
than ever. 7
value throughout its lifecycle, from prelaunch to The Cost of Developing New Molecular
patent expiry and beyond. Entities (NMEs) Continues to Grow 8
LCM sometimes has been viewed as most
The latest estimate from the Tufts Center for the
relevant to the later lifecycle stages, as the prod-
uct matures through peak sales, the plateau phase
Study of Drug Development at Tufts Univer- 9
sity for the cost of developing a New Molecular
and toward loss of exclusivity, when actions are
Entity (NME) is $2.558 billion.2 This figure per
taken to stave off the threat from branded and
generic competition. However, LCM should
approved compound is based on average out- 10
of-pocket costs estimated at $1.395 billion and
be applied across the whole product lifecycle to
maximize a product’s value most effectively in a
time costs (expected returns investors forego
while a drug is in development) estimated at a
11
proactive, planned manner (rather than through a
further $1.163 billion. In contrast, at the low end
series of reactive steps taken only when sales have
plateaued or already are falling, and the generic
of recent estimates, the cost of developing a new 12
drug has been calculated at a median of $648
threat looms large). This chapter addresses the
million (based on 10 approved oncology drugs).3
broad LCM concept.
The Tufts figure of $2.558 billion is undoubtedly 13
No Let-Up as Successive Patent Cliffs at the high end of such estimates, but it does
Threaten Billions in Revenues have the advantage of accounting for survivor- 14
ship bias—around 90% of medicines that enter
The impact of patent expirations that have clinical trials never make it to market.
affected the industry in the last decade—and Drug development cost estimate method- 15
will continue over the next several years—is ologies and sources have been the subject of no
difficult to understate. While various figures
have been cited, an idea of the scale of these
little debate, including a thoughtful perspective
piece in the New England Journal of Medicine in
16
changes is demonstrated by the fact that in 2012, 2015,4 but regardless of the absolute numbers,
an estimated $33 billion (US) of sales were lost the correct methodologies to apply, and the 17
as a result of the precipitous falls in revenues respective roles of private and public sector drug
from patent expiry. A 2013 analysis, meanwhile, development funding, there is little doubt drug
concluded more than $290 billion of sales were development remains an extremely expensive 18
at risk from patent expiries between 2012 and activity. Equally, while the absolute numbers

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 Chapter 17: Considerations for Healthcare Products’ Lifecycle Management

and the steepness of the curve may be cause for uct’s useful life. From the pharmaceutical com-
debate, few would argue the trend is inexora- pany’s perspective, LCM allows features to be
bly upwards; the Tufts estimate in 2003 was a added to an existing product to help it to com-
“mere” $802 million5 (and in 1991, a paltry $231 pete against other products in the same space;
million).6 Against this backdrop of rising drug adding new indications as a part of a planned
development costs, the need for effective LCM LCM strategy also broadens product applicabil-
is clear, as companies seek to unlock every last ity and sales potential. For the patient, features
dollar of value from those products that do make added or improved by LCM may increase
it to market. convenience and/or tolerability, improve com-
The Difficulty of Developing NMEs pliance and perhaps also lead to more consistent
Continues to Increase efficacy. Other product improvements based on
LCM decisions potentially could increase safety
While the cost of drug development continues to in a variety of ways, such as lowering exces-
rise, so apparently does the difficulty. Hay et al., sive blood concentrations, removing an isomer
noted in 2014, the “most comprehensive survey responsible for side effects or enabling a switch
of clinical success rates across the drug industry to a safer method of administration.
to date shows productivity may be even lower
than previous estimates,”7 while others, such General LCM Principles
as Cohen in 2005, have noted that “25% fewer From Intuitive Thinking to Formalized
NME and BLA drugs were approved on average Planning
in the past 10 years compared with the 1990s.”8
Indeed, taking a longer view, the number of new LCM works best if it is part of a formalized
FDA approved drugs for every billion US dollars framework. In the past, LCM activities often
of research and development (R&D) spend has were dependent on individual or project team
halved approximately every nine years since experience in a particular therapeutic area. A
1950, in inflation-adjusted terms.9 Whether as lack of strong formalized processes resulted in
a result of drug development’s progress or as a a largely intuitive LCM planning model. This
consequence of increased clinical trial complex-
LCM model generally has been replaced—at
ity or decreased entrepreneurial spirit following
least among medium to large pharmaceutical
major pharmaceutical company mergers, new
companies—by processes with formalized steps
blockbuster drugs are increasingly elusive. In this
and pre-specified lifecycle checkpoints.
context, once again, effective LCM’s importance
to industry is clear; with new blockbusters being Segmenting the Lifecycle to Determine
in short supply, the importance of existing prod- LCM Decision Points
ucts’ well-planned and executed LCM cannot be
overstated. The full value of every asset has to be While many more or less arbitrary divisions can
maximized; hence, LCM is indispensable. be made in the product lifecycle, the segments
below can form a strong basis for a formalized
LCM Can Be Considered an Opportunity to LCM process with predefined decision points:
Improve the Product Profile
• early development
In addition to the strategic imperatives consid- • late development
ered above, LCM also provides the opportunity • launch
to improve the product profile, with the poten- • growth
tial to bring benefits to both pharmaceutical • pre-genericization
companies and patients throughout the prod- • post-genericization

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
How the product lifecycle is divided is less Table 17-1 gives a broad overview of key LCM
important than having a process in place to pro- considerations at each phase. 2
vide an LCM planning structure. At each phase,
LCM Tactics
different primary and secondary issues should
be considered and decisions made and recorded
3
The range of LCM options available for a
as part of the LCM process (and to safeguard product depends on multiple factors, including
against loss of institutional memory). What is both commercial aspects (e.g., competition and 4
appropriate will depend on the product, company, the level of product success, and the resources
therapy area and specific market environment. available) and technical considerations (e.g., the
5
Table 17-1. CM Considerations by Phase of Product Lifecycle 6
Phase Priority Issues for
Consideration
Secondary Issues for
Consideration
Influencing Factors
7
Early • Explore most appropriate • Consider potential • Indication potential
development primary indication and additional indications and (addressable patient
(preclinical to
Phase 2)
formulation formulations universe, unmet needs,
etc.)
8
• Clinical study
requirements (profile that
needs to be achieved) 9
Late • Confirm launch indication, • Conduct preparatory • Competitive environment
development formulation and dose(s) work on potential at and after launch
(Phase
2 to pre-
additional indications and
formulations
(including existing
and future players and
10
registration) products)
• Regulatory and pricing
and market access
environment at and after
11
launch
Launch (pre-
registration
• Execute medical
marketing program for
• Initiate secondary
indication program
• Market reaction to product
including stakeholder 12
to 1 year after primary indication • Begin investigation of feedback
launch) • Formulate brand follow on product • Competitors’ actions
development plan to
maximize differentiation
• Likely market evolution
13
Growth (1 year • Execute brand • Advance secondary • Product performance
after launch to
peak sales)
development plan to
maximize differentiation
indication development
• Advance follow on product
• Brand development plan
success 14
Pre- • Launch new formulation/ • Consider post- • Remaining brand value
genericization dose/fixed dose genericization options • Degree of current and
(peak sales to
before loss of
combination/authorized
generic/OTC version/
future competition 15
exclusivity) follow on product, transfer
patients to these assets
Post- • Price adjustments where • Consider and execute • Profitability
16
genericization relevant expansion into emerging • Level of continuing
(after loss of • Complete transfer of markets investment required vs.
exclusivity) remaining patients to
new formulation/dose/
• Consider exit from
developed markets
level of return
• Presence/absence of
17
fixed dose combination/ (divestiture, out-licensing, more attractive internal or
authorized generic/OTC etc.) external assets
version/follow on product 18

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 Chapter 17: Considerations for Healthcare Products’ Lifecycle Management

feasibility of reformulation, etc.). The remainder patent-protected formulation). This example

of this chapter provides an overview of several by no means stands alone; Informa Pharma’s
commonly employed LCM tactics, to introduce Pharmaprojects database of pipeline and mar-
different options rather than cast judgment on keted drugs (part of Informa Pharma’s Citeline
which are most likely to be successful; success suite of drug development focused databases)
invariably depends on individual circumstances. contains more than 1,000 drugs that are oral
reformulations, of which a quarter are approved
Reformulation drugs,10 reflecting the ubiquity and relative ease
of oral reformulation as an LCM tactic.
Perhaps the most frequently used LCM tactic,
One of the more obvious examples of
product reformulation, serves two main purposes:
dramatic patient benefits from reformulating an
1. opportunity to differentiate the
oral solid dosage form is mesalamine in ulcer-
product from its competitors through
ative colitis. Whereas Pentasa (mesalamine)
greater convenience, improved ease of
requires four doses per day with a total daily
dosing, etc.
pill burden of eight or 16 capsules, successor
2. opportunity to increase the product
product Lialda (mesalamine) offers once daily
family’s patent-protected life (with the
dosing with two or four tablets. The Lialda tab-
assumption that patients can be switched
let core contains mesalamine with hydrophilic
from an older formulation to a new
and lipophilic excipients and provides extended
formulation with a longer patent life) active ingredient release, thus once-a-day
dosing. Using an advanced formulation with a
Reformulations may involve: venerable molecule provides benefits to patients
• formulation change but same route of suffering from a chronic disease and also ben-
administration efits the marketing company, which has been
• formulation and route of administration able to use Lialda’s simple dosing schedule as an
changes important differentiator against other brands of
mesalamine on the market.
The first category includes multiple examples Important examples also exist in the cat-
of products reformulated to improve patient egory of lifecycle managed products through
convenience, particularly in terms of dosing changes to both the formulation and route of
regimen. Perhaps the most common pattern is administration. While the studies required to
reformulations designed to reduce pill burden support such a change usually are more onerous,
and/or improve dosing schedule. Examples in major benefits can be generated.
this category include Glucophage (metformin), FDA first approved Imitrex (sumatriptan)
approved in the US in 1995 as an immediate in 1992 as a subcutaneous injection for migraine.
release tablet to be taken twice or even three As the first-in-class triptan for a condition where
times a day, and Glucophage XR (metformin), the drug’s onset of action speed is crucial, and a
approved in 2000 as an extended release tablet significant number of patients suffer nausea as a
suitable for once-a-day dosing. In the Type 2 symptom, the injection formulation of Imitrex
diabetes population, in which polypharmacy is originally was targeted at the more severe end of
common, the benefits of once-a-day dosing are the migraine market, particularly those patients
self-evident, and the dual hydrophilic polymer willing to trade an injection’s pain and inconve-
matrix system of Glucophage XR provided a nience for fast relief of symptoms.
clear benefit to patients in terms of convenience As physicians became more comfortable
by enabling a single daily dose (and allowed with the product, and as competitor AstraZeneca
original Glucophage patients to switch to a new prepared to launch a tablet formulation of sec-

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
ond-in-class Zomig (zolmitriptan), the natural • gliptins such as Januvia (sitagliptin)
LCM step was approval of the tablet formulation with the FDCs Janumet (sitagliptin and 2
of Imitrex in 1995, thus significantly broadening metformin) and Janumet XR (sitagliptin
the potential patient population and keeping
Imitrex a step ahead of Zomig, which would be •
and metformin)
gliflozins such as Invokana (canagli- 3
approved in tablet formulation in 1997. Further flozin) with the FDC Invokamet (cana-
efforts at Imitrex reformulation were made with gliflozin and metformin) 4
the 1996 approval of Imitrex STATdose Sys-
While FDC LCM tactics are most commonly
tem, a prefilled syringe and auto-injector pen
to replace vials and regular syringes, and, finally,
applied to oral solid dosage (OSD) products, 5
where they can improve dosing regimens and
the 1997 approval of a nasal spray aimed to offer
patient convenience, FDCs are arguably most
faster onset without the inconvenience of an
beneficial when a non-oral route of administra- 6
injection. Zomig, for its part, countered with the
tion is involved. In insulin dependent diabetics,
2001 approval of an orally disintegrating tablet
and a nasal spray in 2003.
for example, insulin combination products such
as Ryzodeg (insulin degludec and insulin aspart)
7
With both Imitrex and Zomig, the range help to reduce the burden of multiple injections
of formulations provided patients with a variety and thus increase quality of life and potentially 8
of choices to suit their personal preferences and compliance. A combination of Tresiba (insulin
clinical profiles, while also allowing both prod- degludec) and NovoLog (insulin aspart), Ryzo-
ucts to compete against each other for new and deg allows patients to inject a premixed combi- 9
switched patients. Put another way, if a direct nation of ultra-long acting and rapid acting insu-
competitor has an active LCM program, it is dif-
ficult for a company to remain relevant without
lins in a single injection. This FDC formulation
provides clear convenience benefits over admin-
10
its own program. istering multiple single component injections,

Fixed-Dose Combinations (FDCs)

while also offering benefits over other existing 11
premixed insulin products, including 24 hour
basal insulin coverage and less late post-pran-
Because FDCs are so ubiquitous in certain ther-
dial and nocturnal hypoglycemia. Ryzodeg thus 12
apy areas, they have become standard LCM prac-
provides both an effective LCM solution for
tice in the product lifecycle pre-genericization
phase. By providing a single pill to replace two or
NovoLog, and clear benefits to the patient.
It is worth noting that while Ryzodeg can
13
more pills treating the same condition, FDCs are
be seen as an FDC LCM tactic for NovoLog,
an effective way to reduce pill burden, increasing
convenience and, thus, potentially improving
the FDC was in fact submitted to FDA for 14
approval in September 2011, at the same time
patient compliance and treatment outcomes. as the single component Tresiba; Ryzodeg and
FDCs perhaps are most common in diabetes Tresiba were subsequently approved simulta- 15
treatment, where metformin combinations are an neously in September 2015. This reflects an
expected part of oral antidiabetic drugs’ (OADs)
product lifecycle. Multiple generations of OADs
important LCM option even for new prod-
ucts—the simultaneous launch of single com-
16
with metformin have been used to improve ponent and FDC products to maximize patient
patient convenience, including: choice and access to new therapies. Particularly 17
• glitazones such as Actos (pioglitazone) in cases where one component of an FDC has
with the FDCs ACTOplus met (piogli- been available for some time, the failure to
tazone and metformin) and ACTOplus launch an FDC at the same time as the newer 18
met XR (pioglitazone and metformin) single component might, depending on the

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 Chapter 17: Considerations for Healthcare Products’ Lifecycle Management

circumstances, be seen as an overly cynical tactic it arises, based on the prevailing commercial
that fails to prioritize patient welfare. situation. In the US, once-daily Invokana was
As in other LCM areas, FDCs often involve followed by the twice-daily FDC Invokamet,
the simultaneous or phased application of more approved by FDA in 2014 as the first-in-class
than one tactic to the same product. In the case gliflozin plus metformin combination; the
of Actos, for example, both FDC and extend- presence of Invokamet appears to have led the
ed-release reformulation tactics have been used Farxiga (dapagliflozin) team to skip the twice
to extend the product lifecycle. daily FDC stage in its US LCM program for
Actos already was available for once-a-day once daily Farxiga. Instead, the Farxiga team
dosing when the FDC ACTOplus met was went straight to once daily Xigduo XR (dapagli-
introduced as part of the Actos LCM program flozin and metformin), which was approved two
in 2005. While the ACTOplus met prescribing months later than Invokamet but now has an
information mentions circumstances in which important dosing schedule convenience advan-
the product can be used once daily, most patients tage over Invokamet.
will have to use it twice daily, particularly after In the EU, however, Xigduo (dapagliflozin
the initial titration period. The product was and metformin) is sold as an immediate release,
something of a mixed blessing for patients twice daily product, putting it on a par with twice
already taking Actos and metformin in separate daily Vokanamet (canagliflozin and metformin),
pills; while ACTOplus met reduced the pill possibly reflecting a less-pressing need for Forxi-
burden, it did nothing to improve the dosing ga’s (dapagliflozin) LCM tactics to surpass those
schedule. For patients already taking once daily of Invokana in the EU. This may reflect the fact
Actos and once daily Glucophage XR, ACTO- that Forxiga and Xigduo were first-in-class prod-
plus met actually was a step backward to twice-a- ucts in the EU, and Invokana and Vokanamet
day dosing. were second-in-class, opposite the US situation,
It was a little surprising when ACTOplus where Invokana and Invokamet beat Farxiga and
met XR (pioglitazone and metformin) was Xigduo XR, respectively, to market. These prod-
approved in 2009 with a claim to be the first, and
ucts are summarized in Table 17-2.
at that time, only FDC OAD incorporating an
extended-release metformin formulation (using Indication Expansion
a formulation developed by Watson and licensed
to Takeda). Indication expansions are another LCM program
Whether twice-a-day FDCs are sensible mainstay. They perhaps can be categorized best
choices when a single molecule drug already is according to the therapeutic “distance” between
available with once-a-day dosing varies depend- the initial and subsequent indications:
ing on the therapeutic area and commercial land- • expansion within the same disease, e.g.,
scape. While introducing a twice-a-day FDC as from inducting remission in Crohn’s
an interim step toward an eventual once-a-day disease to maintaining remission
FDC potentially extends the product family’s • expansion from one disease to another,
patent life further, the multiple switches involved e.g., from Crohn’s disease to rheumatoid
in moving patients from the original product to arthritis
a twice-a-day FDC, then to a once-a-day FDC
increase the risk patients will be lost to generics While indication expansions broadening the
or other competitors. label within the same disease, e.g., from acute to
Each pharmaceutical company stakeholder chronic treatment, from treatment to prevention
team will make its own decision on the FDC or from adult to pediatric use, are relatively com-
versus extended-release conundrum, where mon, the feasibility of expanding to an unrelated

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
Table 17-2. Lifecycle Evolution of Oral Antidiabetic Drugs in the US and EU 2
US Brand Name
Invokana
Generic Name
canagliflozin
Approval Date
March 2013
Dosing Schedule
Once daily
3
Farxiga dapagliflozin January 2014 Once daily
Invokamet canagliflozin and metformin August 2014 Twice daily 4
Xigduo XR dapagliflozin and metformin October 2014 Once daily
EU Brand Name Generic Name Approval Date Dosing Schedule 5
Forxiga dapagliflozin November 2012 Once daily
Invokana canagliflozin November 2013 Once daily
Xigduo dapagliflozin and metformin January 2014 Twice daily
6
Vokanamet canagliflozin and metformin April 2014 Twice daily
7
indication will depend largely on the product’s possible by an understanding of TNF-alpha’s role 8
mechanistic properties and the originally indi- in other immune-mediated diseases.
Remicade is now approved in the US for:
cated disease mechanisms and any diseases that
are indication expansion candidates. • Crohn’s disease 9
Thus, while indication expansions broad- • pediatric Crohn’s disease
ening the label within the same disease or to a
related disease (such as from asthma to chronic
•
•
ulcerative colitis
pediatric ulcerative colitis
10
obstructive pulmonary disease) often are a • rheumatoid arthritis
matter of proactive choice and established LCM • ankylosing spondylitis 11
planning, expansion to an unrelated indication • psoriatic arthritis
is not always an option or may be revealed to be plaque psoriasis
12
•
an option only as a result of a later scientific or
(sometimes serendipitous) medical discovery. Most products have little to no label expansion
The tumor necrosis factor alpha (TNF-al-
pha) inhibitors provide multiple examples of
possibility to six different diseases, for both
mechanistic reasons and because most product
13
both expansion within the same disease and from lifecycles simply will not allow enough time
one disease to another. to generate such extensive clinical trial data 14
Remicade (infliximab), originally approved prior to patent expiry. Therefore, to simulate
in 1998 with a narrow label specifying induction what may be possible for a more “normal” drug,
of remission (i.e., acute, not chronic, treatment) particularly a small molecule, Table 17-3 shows 15
in Crohn’s disease, has gone through an extensive Remicade indication expansions in the first five
indication expansion program both within and
beyond Crohn’s disease. While expansion beyond
years after launch.
Of note is the steady expansion from
16
Crohn’s disease into ulcerative colitis might have narrow to broader patient populations in both
been considered an obvious next step, given the the original indication of Crohn’s disease and 17
frequent use of the same drugs in both inflam- the first additional indication of rheumatoid
matory bowel disease indications, the addition arthritis. This pattern was repeated in the four
of rheumatoid arthritis, ankylosing spondylitis, other diseases later added to the Remicade label, 18
psoriatic arthritis and plaque psoriasis was made and indeed by many of the other TNF-alpha

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 Chapter 17: Considerations for Healthcare Products’ Lifecycle Management

Table 17-3. Remicade US Indication Expansion in the First Five Years After Launch

Indication Approval
Reduction of signs and symptoms of Crohn’s disease and induction of clinical August 1998
remission in patients with moderately to severely active Crohn’s disease who
have had inadequate response to conventional therapy
Reduction of number of draining enterocutaneous fistulas in patients with
fistulizing Crohn’s disease
In combination with methotrexate for reduction of signs and symptoms of November 1999
rheumatoid arthritis in patients with moderately to severely active rheumatoid
arthritis who have had inadequate response to methotrexate
In combination with methotrexate for inhibition of progression of structural December 2000
damage in patients with moderately to severely active rheumatoid arthritis who
have had inadequate response to methotrexate
In combination with methotrexate for improvement of physical function in February 2002
patients with moderately to severely active rheumatoid arthritis who have had
inadequate response to methotrexate
Maintenance of clinical remission in patients with moderately to severely active June 2002
Crohn’s disease who have had inadequate response to conventional therapy
Reduction of number of rectovaginal fistulas in patients with fistulizing Crohn’s April 2003
disease
Maintenance of fistula closure in patients with fistulizing Crohn’s disease
Expansion within the same disease as the original indication shown in italics
Expansion into a separate disease shown in plain type

inhibitors, although exceptions do exist, such Pharmaceuticals and Medical Devices Agency
as Simponi (golimumab), approved by FDA in (PMDA), which often approves much broader
2009 for rheumatoid arthritis, psoriatic arthritis initial labeling language than that approved in
and ankylosing spondylitis. Clearly, launching the US and EU, leaving relatively little need for
a product with the widest possible label allows further expansion.
capturing the greatest number of patients from This phenomenon usually is understood as
the outset, but, for practical and other reasons, reflecting the prohibition on drug reimbursement
launching with multiple indications usually is not for unapproved indications under the Japanese
viable, leaving room for gradual LCM expansion, National Health Insurance system; to facilitate
both as a form of endogenous growth and to reimbursement, approved indications generally
compete effectively with similar products. are written somewhat less restrictively in Japan.
Finally, when planning LCM indication Thus, while indication expansions can and do
expansion tactics, the relevance of such expan- play an important LCM planning role in the
Japanese market, they tend to be of greater rele-
sions can vary markedly by geography. While
vance in the US and EU.
FDA tends to approve tightly worded indications
reflecting the submitted clinical data in a fairly Chiral Switches and Active Metabolites
literal way, other regulators can and do approve
comparatively broad indications from the outset. A racemate drug is a mixture of a pair of enan-
Most notable in this regard is the Japanese tiomers. Such drugs present the opportunity

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
for a “chiral switch” as part of an LCM strategy, Threatened by the impending genericization
whereby a single enantiomer of an existing race- of Prilosec, AstraZeneca gained FDA approval 2
mate is developed as the line extension to the of Nexium in 2001, before Prilosec had been
racemic mixture. A single enantiomer developed
from an existing racemate is a New Chemical
exposed to generics. This timing element perhaps
is the single most important factor in determin- 3
Entity (NCE), but as a line extension usually ing a chiral switch’s success, as it also often is
is considered part of the racemate’s “product with other LCM tactics such as reformulation. 4
family” and very much part of the racemate’s The Nexium launch before Prilosec patients had
LCM program. been lost to generics meant AstraZeneca could
Theoretically (but sometimes not in prac- shepherd patients from the racemate to the line 5
tice), stereochemically pure drugs offer certain extension, aided in many markets by a Nexium
advantages over racemic drugs, including the launch price that made it cheaper than Prilosec,
potential for:11 another key successful chiral switch element (or 6
• smaller doses key element of any other LCM-driven switch).
•
•
simpler dose-response relationship
less inter-subject variability
When Nexium sales hit $5.22 billion in 2007,
AstraZeneca had achieved peak sales that were
7
• less toxicity if one stereoisomer is 83% of Prilosec’s peak, with a successor product
disproportionately responsible for the employing clever chemistry but offering little to 8
racemate’s toxicity commend it over Prilosec in terms of genuine
clinical benefit. If a chiral switch is timed and
While certain chiral switches may feature a priced correctly, it has a chance of protecting 9
single enantiomer drug offering genuine clin- significant product family value.
ical benefits over the racemate, there also are Finally, while chiral switches remain
popular—and indeed have been executed more
10
examples of both commercially successful and
unsuccessful chiral switch single enantiomer recently in the same class as Prilosec/Nexium
drugs that have provided little or no additional in the form of Takeda’s Prevacid (lansoprazole) 11
clinical benefit compared to the racemate. Such to Dexilant (formerly Kapidex; dexlansopra-
zole) switch—there is some evidence the chiral
cases may encourage the perception that chiral
switches essentially are exercises in extending a switch well may be running dry. Agranat et al., 12
estimated as early as 2002, single enantiomer
product family’s patent life by switching patients
from a soon-to-be-genericized racemate to a sin-
drugs were accounting for an increasing pro-
portion of new drugs introduced to the market,
13
gle enantiomer line extension with a much longer
increasing from approximately 20% of new
remaining patent life.
Nevertheless, major blockbusters have used
drugs 10 years earlier to almost 75%.12 While 14
some of this growth in enantiopure drugs
the chiral switch as a vital LCM component,
reflects chiral switches, over time, if the number
sometimes with extremely effective patient of new drugs launched as racemates declines, 15
retention results within the product family, even at a certain point, it stands to reason there will
in the face of generic competition to the race-
mate. A prime example of this may be Astra-
be fewer and fewer racemates from which to
switch. Since the long-term trend appears to be
16
Zeneca’s chiral switch from racemic Prilosec toward development and launch of single enan-
(omeprazole) to single enantiomer Nexium tiomer rather than racemic NCEs, the pool of 17
(esomeprazole). Launched by AstraZeneca fore- racemates to switch to enantiopure drugs may
runner Astra in 1988, Prilosec, at one point, was become somewhat shallow.
the world’s top selling drug, with annual sales of When considering a chiral switch, it also is 18
$6.26 billion in 2000. worth being cognizant of the likely payer reac-

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 Chapter 17: Considerations for Healthcare Products’ Lifecycle Management

tions to such tactics; where an active enantiomer ment, while GlaxoSmithKline gained exclusive
successor product such as Xyzal (levocetirizine) US rights to commercialize all combinations
is perceived as having little or no benefit over resulting from the deal and agreed to provide
the original product (in this example, Zyrtec formulation development and manufacturing for
(cetirizine)), payer reactions may be hostile, the new combination.
particularly once generic versions of the original While multiple approvable letters delayed
product are available. The same is true for active Treximet’s (formerly Trexima; sumatriptan and
metabolite products such as Clarinex (deslo- naproxen) launch until 2008, well past the point
ratadine), which never achieved the commercial of protecting the Imitrex product family’s value,
success of parent drug Claritin (loratadine), as the GSK-Pozen deal nevertheless was important
the drugs shared a similar clinical profile. Nev- as an example of a major pharmaceutical com-
ertheless, if an active metabolite drug has clear pany turning to outside LCM expertise for a
clinical benefits over its parent compound, such significant brand. It also is worth noting Pozen
as Allegra’s (fexofenadine) lower risk of cardiac was the Treximet NDA applicant, and the drug
arrhythmia compared to Seldane (terfenadine), was submitted to and approved by FDA via the
the active metabolite successor product can 505(b)(2) pathway (which allows NDAs where
be a viable LCM option, and may indeed be a at least some required information comes from
necessity to rescue the franchise from oblivion, studies not conducted by or for the applicant),
as in the case of Seldane, which was withdrawn rather than the 505(b)(1) pathway more typical
from markets globally. for major pharmaceutical companies.
While the Treximet story illustrates large
Outsourced and Virtual LCM pharmaceutical companies’ willingness to
collaborate and, to a degree, outsource LCM
As big pharmaceutical companies come to activities, Treximet also provides an example
understand their core strengths and weaknesses of the ultimate product outsourcing at the end
more clearly, outsourcing and collaboration grow. of its lifecycle: divestiture. Thus, US rights to
This is no different in the LCM area than in any Treximet, with 2013 sales of $78.7 million, a
other pharmaceutical industry sphere. This sec- fraction of peak Imitrex sales, were acquired
tion provides brief examples of outsourced and by specialty pharmaceutical company Pernix
other virtual LCM strategies used to supplement Therapeutics in 2014. Even with the Treximet
in-house activities. divestiture, GlaxoSmithKline was able to secure
Facing generic competition to popular an upfront payment of $250 million, executing
migraine therapy Imitrex, and already having a well-timed exit for a product that never quite
experienced the reformulations and route of lived up to expectations.
administration changes described earlier in this Finally, sumatriptan provides one more vir-
chapter, by the early 2000s, GlaxoSmithKline tual LCM example that traditionally would not
was running out of in-house LCM options for be classified as LCM, in Zecuity (sumatriptan),
the drug. At this point, the company took steps an iontophoretic transdermal system formerly
to partially outsource further Imitrex LCM by known as Zelrix (sumatriptan), developed by
signing an agreement with FDC specialist Pozen NuPathe. FDA approved Zecuity via the 505(b)
in 2003. The agreement was for the development (2) pathway in 2013. This sumatriptan patch
and commercialization of proprietary combi- had no direct GlaxoSmithKline involvement
nations of GlaxoSmithKline’s triptans Imitrex and arguably competes with the Imitrex product
and/or Amerge (naratriptan) with a nonsteroidal family. However, SR One, GlaxoSmithKline’s
anti-inflammatory drug. Pozen became respon- corporate venture capital arm, invested early in
sible for the Imitrex-naproxen FDC’s develop- NuPathe, a company with GlaxoSmithKline

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
alumni in senior leadership roles. Teva acquired eca decided to remain a branded prescription
NuPathe in January 2014 for $144 million, pro- drug company and not be involved in the switch 2
viding an exit for investors and a final full stop to directly, its choice of Procter & Gamble as the
these tangential virtual LCM activities. Prilosec OTC licensee was highly rewarding for
both companies.
3
OTC Switch: End of the Line? When FDA approved Prilosec OTC in
A switch from prescription to over-the-counter
2003, it labeled the product as inappropriate for 4
use for more than two weeks at a time without
(OTC) status, while a popular LCM tactic,
a physician’s supervision. While this might have
clearly is relevant only for certain products, usu-
ally those meeting the majority, if not all, of the
been expected to limit sales, it actually was a 5
major win for AstraZeneca, since it was able
following criteria:
• long history of use, providing reassur-
to continue selling prescription Prilosec while
Procter & Gamble sold Prilosec OTC, despite
6
ance the product can be used safely
both products having the same dose, which
without a prescription and without
physician consultation
usually would have meant withdrawing the 7
prescription version in the US. FDA’s decision
• consumers are capable of self-diagnos-
also meant Prilosec OTC could be sold without
ing their conditions and appropriately
selecting the product themselves using
generic OTC competition for three years. This 8
relatively perfect situation led Prilosec OTC
only the OTC label
• low misuse or abuse potential
sales to far exceed expectations, to the extent
that many states were affected by stock short-
9
• OTC product benefits outweigh risks
ages. FDA has taken a more encouraging stance

OTC medicines are affected by different mar-

on OTC switches in recent years, but not every 10
product switched will meet the perfect set of cir-
kets’ cultural norms and expectations, meaning
cumstances Prilosec OTC enjoyed. It is clear, for
what may be successful or even just acceptable
as an OTC switch in one market may be unsuc-
suitable products, an OTC switch is an import- 11
ant potential LCM tactic.
cessful or downright unacceptable in another
in terms of consumer response. With the rather Concluding Comments 12
wide divergence in different countries’ OTC
Caveats
regulations, it is clear decisions on switching a
drug from prescription to OTC status should This chapter has discussed a number of the more
13
be made at the local level, or at least with common LCM options available to companies
significant input from local teams; a global level planning to maximize a branded prescription 14
OTC switch plan with sufficient relevance to all drug’s lifecycle. However, it has not addressed
territories is unlikely. Generally, countries like all options or their permutations. It has concen-
the UK have the most liberal OTC switch reg- trated on areas where marketing, portfolio man- 15
ulatory approach, followed perhaps by the US agement, R&D and regulatory teams most likely
and then Japan in the major markets. Whether
a drug switched to OTC can remain simulta-
will have the greatest input. This chapter did
not address other options, including maneuvers
16
neously available as a prescription product also relating solely to legal and intellectual property
varies according to local regulations. protection issues (including patents and patent 17
The current OTC switch vogue as an LCM law), which clearly are possible. While legal
end-of-lifecycle tactic in the US perhaps can efforts clearly have their place, what is possible is
be traced back to Prilosec’s switch to Prilosec not always what is advisable; as a recent example, 18
OTC (omeprazole) in 2003. While AstraZen- Allergan’s transfer of Restasis (cyclosporine) pat-

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 Chapter 17: Considerations for Healthcare Products’ Lifecycle Management

ents to New York’s Saint Regis Mohawk Tribe, Looking at a product’s lifecycle end, generi-
which licensed the patents back to Allergan, cization’s impact in the US and EU already is so
was ultimately rejected by federal courts, while severe (and is growing more severe in Japan) that
attracting bipartisan criticism from politicians many companies have divested whole portfolios
and other parties. As in other areas of business, of “tail” products as the final LCM endgame or
reputational risk from aggressive LCM legal have even split the company into a “rump” or
tactics should be considered before execution. “tail” entity and an innovation-based entity, as in
Technical issues related to appropriate the case of Abbott and AbbVie.
Some emerging markets offer a different
pricing adjustments over the product lifecycle or
perspective, with many physicians and patients
authorized generics and other deals with generics
in such markets as China favoring multinational
companies also were not covered in this chapter
corporations’ brands over those of local manu-
but remain important potential considerations.
facturers, almost regardless of the product’s age
Such options as investigator-initiated studies, and whether a generic is available. Emerging
studies and publications not intended to sup- market end-users and prescribers often merge
port label expansions and other areas that have the notion of branded (non-generic) drugs with
attracted particular regulatory disapproval in multinational corporations’ products and perceive
recent times have not been addressed, although multinational corporations’ drugs to be superior
they may have a role if conducted under a suffi- to local products. Similarly, generics often are
ciently robust compliance regime. associated with local companies, inferior quality
and, in some markets, counterfeiting and lack of
Picking Correctly From the Buffet supply security.
As emerging markets gradually (or, in
LCM planning may be approached best in the
some cases, rapidly) mature, this practice will
same way a budget-conscious diner approaches
decline. Already, in China, as just one example,
a buffet. Both require careful consideration of
the authorities have demonstrated awareness
all choices before any decisions are made, if
of this tactic and are revising regulations to
the highest value options are to be chosen in
reward innovative drugs in an attempt to avoid
the right order and within the allotted time.
becoming a dumping ground for old products
Companies must pay close attention to rivals, to
or a tail end cash cow for western and Japanese
see which options already have been taken and
drug companies. Nevertheless, in less powerful or
which of the remaining are most attractive. The
assertive emerging markets, there likely is a five-
best solution usually will be a combination of
to 10-year window where legacy brands that have
options, chosen in a manner that maximizes the
reached their product lifecycle end can access
whole’s chances of being greater than the sum of
additional revenue streams through emerging
the parts.
market launches. Even so, this situation likely
Coda will be short-lived in many emerging markets,
leading to the next LCM frontier: emerging
Although clearly not without their individual market-specific LCM tactics executed locally to
challenges and risks, certain emerging mar- meet the market’s prescriber and patient needs.
kets’ continuing rise has the potential to alter There remain endless future LCM challenges
the LCM landscape significantly. Currently, as and opportunities to explore.
markets such as China are developing rapidly, the
prospect of gaining additional late-in-lifecycle
revenues from a broad product launch program
in emerging markets is attractive.

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References
1. Harrison C. “Patent watch.” Nat Rev Drug Discov. 2013 2
Jan;12(1):14–5.
2. DiMasi JA, Grabowski HG, Hansen RW. “Innovation
in the pharmaceutical industry: new estimates of R&D 3
costs.” J Health Econ. 2016 May;47:20–33.
3. Prasad V, Mailankody S. “Research and development
spending to bring a single cancer drug to market and 4
revenues after approval.” JAMA Intern Med. 2017 Nov
1;177(11):1569–75.
4. Avorn J. “The $2.6 billion pill--methodologic and 5
policy considerations.” N Engl J Med. 2015 May
14;372(20):1877–9.
5. DiMasi JA, Hansen RW, Grabowski HG. “The price of 6
innovation: new estimates of drug development costs.” J
Health Econ. 2003 Mar;22(2):151–85.
6. DiMasi JA, Hansen RW, Grabowski HG, Lasagna L. 7
“Cost of innovation in the pharmaceutical industry.” J
Health Econ. 1991 Jul;10(2):107–42.
7. Hay M, Thomas DW, Craighead JL, Economides 8
C, Rosenthal J. “Clinical development success rates
for investigational drugs.” Nat Biotechnol. 2014

8.
Jan;32(1):40–51.
Cohen FJ. “Macro trends in pharmaceutical innovation.”
9
Nat Rev Drug Discov. 2005 Jan;4(1):78–84.
9. Scannell J, Blanckley A, Boldon H, Warrington
B. “Diagnosing the decline in pharmaceutical
10
R&D efficiency.” Nat Rev Drug Discov. 2012 Mar
1;11(3):191–200.
10. Informa Pharma. Pharmaprojects. https://
11
pharmaintelligence.informa.com/products-and-
services/data-and-analysis/pharmaprojects. Accessed
7 November 2019. 12
11. Caldwell J. “Through the looking glass in chiral
drug development.” Modern Drug Discov. 1999 Jul-
Aug;2(4):51–60. 13
12. Agranat I, Caner H, Caldwell J. “Putting chirality to
work: the strategy of chiral switches.” Nat Rev Drug
Discov. 2002 Oct;1(10):753–68. 14
15
16
17
18

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18 Medical Writing Strategies:
Aligning Regulatory Documents
with Strategic Goals
By Kathryn Wekselman
1
2
3
4
5
Introduction those who have never been reviewers or decision
makers at a healthcare regulatory authority, it is 6
Putting any regulatory strategy into action is a useful exercise to consider what it is like to be
always going to require written documents.
Indeed, written documents are often the only
in those positions. Try considering the regulators’ 7
missions and the realities of doing their jobs.
means by which strategic regulatory goals can What are their goals? What pressures do they
be achieved. Regulatory documents are used to face? What do they worry about? When review- 8
seek required answers to questions and to secure ers read a sponsor’s document, what are they
or confirm alignment with regulatory agencies. looking for? What will they already know and
Documents are used to obtain approval for the what information will be new to them? 9
desired next step in the series of milestones A good (and undoubtedly accurate) assump-
involved in product development, approval, intro-
duction to the market and market expansion.
tion to start with is that regulators genuinely
embrace the mission of improving public health
10
Documents are used to request specific regula- while safeguarding patients from harm. They
tory designations, fulfil requirements for periodic can be expected to take seriously the challenge 11
updates or other mandated reporting, facilitate of finding the balance between making needed
treatments available to patients without undue
monitoring of patient safety and inform regula-
tors of clinical study progress and outcomes. delay and making risky decisions based on insuf- 12
Luckily, the pharmaceutical and medical ficient evidence. Whether regulators view spon-
device industries are full of highly educated, sors with skepticism or suspicion may depend
in part on the contents of submitted documents,
13
intelligent people with subject matter expertise
and well-developed writing skills. But expertise and in part on personalities or past experiences.
and previous writing experience do not guarantee But a wise sponsor regards regulators as part- 14
wisdom about strategic regulatory writing. Med- ners and approaches them with the intention of
finding common ground. The ultimate goal for
ical writers and regulatory professionals often are
required to steer teams to produce documents both parties is an adequate body of evidence to 15
that will best support regulatory goals. demonstrate a favorable benefit-risk balance of
This chapter presents some key medical
medical treatments.
Under the umbrella question of favorable or
16
writing strategies to best align regulatory docu-
unfavorable benefit-risk balance, regulators must
ments with strategic goals.
answer a long list of additional questions when 17
Consider the Regulatory Audience evaluating sponsor submissions.
Some of the big questions sponsors should
It may seem obvious that regulators are always help regulators answer are: 18
the audience for regulatory submissions. For • Is the treatment safe and effective?

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 Chapter 18: Medical Writing Strategies: Aligning Regulatory Documents with Strategic Goals

• Has the best dose or treatment regimen information.

been identified? Regardless of clinical area, the sponsor will
• Are the clinical studies appropriately always know more about the specific details of its
designed to demonstrate a treatment program and data than the reviewers. The danger
effect? in this situation is that the sponsor will neglect
• Are there data inconsistencies (e.g., to provide full information or clearly lay out
study endpoint results not aligned, the background and assumptions that will allow
studies with varying results)? reviewers to understand what they are being
• Are there identifiable data gaps (e.g., asked to decide. A regulatory professional’s abil-
populations not studied, missing data)? ity to understand the perspective of a document’s
• Are there signals of a potential safety intended readers is a real asset when framing the
issue requiring further study? argument and identifying specific content for a
• How likely are unforeseen safety risks, regulatory submission document.
even if no safety signals have been noted? Sponsors can expect regulators to strive
for impartiality when dealing with regulatory
For some treatment development programs, submissions. Consistency in regulatory decision
the sponsor will need to help regulators answer making is usually an important concern for
additional questions, such as: regulators, sometimes appearing as resistance
• Is the disease or condition being treated to change. Wise sponsors will study the public
a real medical entity? record, seeking to understand how regulators
• What is the condition’s importance to reacted to earlier submissions that are analogous
patients? in some way to their current efforts. While genu-
• What treatment benefit level is inely inconsistent regulatory decisions may occur,
meaningful to patients? these probably are far less frequent than sponsors
imagine. The suspicion that a sponsor was treated
To align a regulatory submission document with unfairly likely would prove to be unfounded if
regulators’ needs most effectively, sponsors should everything regulators see confidentially were
identify which questions regulators will be trying available for public disclosure. Certainly, accu-
to answer from the document. Sponsors then mulating knowledge and changes in treatment
can address these questions directly. Regulators paradigms will eventually supersede precedent,
always need sufficient supportive data to give when warranted, resulting in new regulatory
them reasons for granting regulatory requests. practice; however, sponsors who hope to change
It is also helpful to think explicitly about regulatory practice should understand that is a
what regulatory document reviewers can be difficult goal.
expected to know already and what information Regulators almost universally perform
is likely to be new to them. In most US Food and their tasks under time pressure, often having
Drug Administration (FDA) review divisions, large workloads and constrained staffing levels.
for example, clinical reviewers are experts in a Sponsors can help by writing clear, concise and
specific area of clinical practice and research. In focused documents (more on this below) and by
other cases, such as the European Medicines using established templates and carefully fol-
Agency (EMA) Committee on Orphan Medic- lowing guidance on specific document contents,
inal Products (COMP), reviewers may be clini- structure and format. Originality is seldom a vir-
cians with limited knowledge in a given appli- tue in regulatory writing. It is easier for reviewers
cation’s clinical area. An accurate understanding to find information in a familiar format. For-
of what knowledge reviewers are likely to have tunately, the regulatory field has moved toward
will help a sponsor provide the most appropriate increasing standardization and harmonization,

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
helping sponsors meet reviewers’ expectations Clarify the Regulatory Goal
in this regard. Regulatory document writers can 2
obtain templates from regulatory agency web- In addition to targeting a specific audience, reg-
ulatory documents are written to achieve specific
sites, purchase commercially available templates
or create their own by following agency guidance goals. As with all regulatory strategy compo- 3
nents, regulatory documents are most likely to
(e.g., orphan drug designation applications,1
agency meeting information packages,2 expe-
be successful when the writer starts with the end 4
in mind and maintains that focus throughout
dited designations,3 Development Safety Update
the writing process. Establishing clear regula-
Reports4). Guidelines, checklists or procedures to
be followed by regulators when reviewing doc-
tory goals for each document and submission 5
is crucial before writing begins. The clearer the
uments often are publicly available (e.g., FDA
Manuals of Policy and Procedures,5 Therapeutic
goal, the better the document can be crafted to
support the desired outcome.
6
Goods Administration IVD medical device
Although sometimes simple, more often,
application audit6). Where these exist, they also
can serve as valuable guides when preparing the
regulatory goals are complex or nuanced. For 7
example, a sponsor may be hoping to receive
documents. Trying to apply these guides before
submitting a document sometimes will reveal
marketing approval for a new product. But the
sponsor also may be hoping for an approval with
8
weaknesses or omissions that can be improved
just one regulatory review cycle. Certain language
before submission, rather than discovered during
regulatory review.
in the approved drug label may be very important 9
for competitive purposes or for third-party payers
While interactions between sponsors and
regulators occur within a highly structured
to agree to cover the drug.
Regulatory goals also may exist in a hier-
10
framework, with abundant guidance and prece- archy, wherein the most preferred outcome is
dent, these interactions are ultimately exercises
in communication. Being human, individual
identified, as well as a second- or even third-most 11
preferred outcome(s), in case the ideal outcome
regulators will have differing perspectives, is unachievable. Then the question arises of
experience levels and facility with written and whether to disclose the less-desired outcomes in 12
spoken language. From the sponsor’s perspec- a document or to hold those in reserve for a later
tive, regulatory responses are not always clear
or understandable. The same may be true of
discussion or document. 13
Some examples of structured regulatory
guidance documents and other formal agency goals are provided in Table 18-1.
statements. In this situation, asking for clarifi- Although it is beyond the scope of this 14
cation is almost always possible. When unsure, chapter to discuss how to choose the regulatory
wise regulatory professionals will follow the
time-honored advice not to assume anything,
goal, a typical goal-setting process will involve 15
rounds of review and refinement until the goal is
but rather keep the dialogue going until veri- clear enough to begin writing the document. Of
fying that each party to the interaction knows course, regulatory goals do not exist in isolation, 16
what the other is trying to communicate. Using but are chosen to support treatment or business
interactions with regulators to better understand
regulatory agency concerns and then deliber-
goals that are the ultimate aims of medical prod-
uct development and marketing.
17
ately addressing those concerns in subsequent Once the regulatory goals for a document
submissions is a bedrock strategy for aligning are clear, the document structure and contents 18
regulatory documents with strategic goals. can be mapped out so writing can begin.

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 Chapter 18: Medical Writing Strategies: Aligning Regulatory Documents with Strategic Goals

Table 18-1. Examples of Structured Regulatory Goals

Overall goal and subgoals:

1. Obtain agency concurrence that the planned Phase 1 clinical study may proceed.
a. Obtain agency concurrence with specific elements of the planned clinical study design
(inclusion and exclusion criteria, starting dose and dose escalation scheme, randomization
and blinding, etc.).
b. Obtain agency concurrence with specific elements of clinical study product manufacturing
(in-process testing, product labels, product release specifications, etc.).

Tiered goals:
1. Obtain agency concurrence that a marketing application, as described, is likely to contain
sufficient information about the product to enable a determination of marketability.
2. If not, obtain agency concurrence that the marketing application is likely to be accepted for full
review rather than receiving a “refuse to file” response for insufficient information.
3. If not, will the agency advise what additional information would be needed for a fileable
marketing application?

Identify Document Contents Strategically are incomplete. Taking time to think through the
planned document contents more than once is
To map a regulatory document’s contents and likely to save time overall by reducing the need
structure, it is important to focus on what regu- for re-writing later. Further reflection usually
lators need to know to provide what the sponsor yields additional insights, resulting in a more
is seeking: meaningful responses to requests; persuasive document. Involving team members
specific answers to questions; or agreement that with additional perspectives is valuable for the
a regulatory obligation has been fulfilled. This same reason.
perspective must be applied to identify the best At this point in document planning, gaps in
possible supporting information. the available data often become apparent. If this
A sponsor should fully understand what happens, a new set of options arises:
information is available at the time the docu- • Can more information be obtained from
ment is written. Information may come from a data source that has been overlooked?
clinical study data, manufacturing data and data • Or, can the submission be postponed
extracted from shared databases, registries or until specific additional information is
available?
published literature. Useful information also may
• Or, should the submission go forward
come from treatment guidelines, medical records
but with an explicit acknowledgement
or patient advocacy groups.
of the limitations of currently available
Once available information has been
data?
identified, a team can draft “key messages” that • Or, should the submission go forward,
arise from the data and place the messages into a making the best possible case using
logical hierarchy that communicates them most available information, without drawing
clearly. Caution must be exercised at this point in attention to particular data limitations?
planning, however. Early impressions about what
conclusions can be drawn and what useful infor- The best answers to these questions will depend
mation nuggets are present in data almost always on each situation’s specific details, including how

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
much time pressure exists and how much regula- the answer changed?” While there certainly are
tory risk a sponsor is comfortable assuming. times when a particular inquiry will be premature 2
At this stage of writing the document, it is or distracting, this is best judged based on the
important to consider both its length and the
level of detail to be included. Some regulatory
development program’s progress and available
data, rather than on fear of unwelcome responses
3
documents have page limits or other guides from regulators. Luckily for recalcitrant sponsor
to determine acceptable document length, but teams, regulators sometimes will proactively 4
others do not. Experienced regulatory document address important issues that have not been
writers usually develop a “sense” of an appropriate raised in regulatory submissions.
document length and try to plan document con- Finally, sponsors should not overlook the 5
tents accordingly. The aim is to provide enough importance of checking the accuracy of both
information to achieve regulatory goals, but not
overwhelm the regulators with superfluous detail.
text and numeric data in a regulatory document.
A formal quality control and quality assurance
6
When documents are too long, regulators are review process, with specific team members iden-
likely to miss key information or fail to follow
the argument being made.
tified to perform these reviews, is recommended. 7
Document quality reviewers should check for
Once the messages and supporting data to internal consistency of documents and also check
be included in a regulatory document have been accuracy against source documents. Finding and 8
identified, a document outline can be created. eliminating content errors before submission
The key messages should be used as paragraph
topic sentences and document section titles. This
enhances the credibility of both document and
sponsor. It also saves the pain of having to issue a
9
is intended to make it as easy as possible for correction or explain an error later.
regulators to identify the conclusions the sponsor
wants them to reach, and what evidence the Seek Objectivity
10
sponsor is providing to allow them to reach those
conclusions. Without unnecessary repetition, a Although much easier to recommend than prac- 11
regulatory document should clearly emphasize its tice, objectivity in reviewing data and judging
key points. arguments helps ensure regulatory documents
When possible, regulatory documents should will be credible and persuasive. Developing and 12
employ multiple lines of evidence to support con- marketing medical treatments requires hopeful-
clusions, but should not give undue prominence
to secondary issues and less important details.
ness and creative thinking, while working on a
development or marketing team induces team
13
Document information selection and placement spirit or even groupthink. These realities make
should work together to make it easy for regula- it difficult to remain impartial and avoid tunnel 14
tors to understand the sponsor’s conclusions and vision when evaluating data and planning regula-
why those conclusions are appropriate. tory strategy.
The sponsor should bear in mind that Counteracting the subjectivity inherent in 15
regulatory issues will not disappear just because a team membership and the resulting partisan
document avoids bringing them up. One school
of thought about what to include in regulatory
viewpoint requires a conscious effort to look
at data and conclusions through the eyes of a
16
submission documents trots out the adage, “Don’t skeptical outsider. Team members should actively
ask any questions that that you don’t want to hear try to identify counterarguments and weaknesses 17
the answers to.” Those with a different perspec- in the data presented, so they are not surprised by
tive then respond, “Wouldn’t it be better to hear other points of view when their documents are
those answers now, when there is more time to read by regulators. Enlisting outsiders to review 18
figure out how to comply—or how to try to get draft documents is often very helpful, since

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 Chapter 18: Medical Writing Strategies: Aligning Regulatory Documents with Strategic Goals

outsiders can see things with fresh eyes and may is to assume the subject is uncomplicated. But
spot potential ways of strengthening documents. with or without recognition, a medical writer’s
Every medical treatment development goal always should be to present information as
program will generate some problematic data. clearly as possible. The best way to achieve this
Inconsistent, uninterpretable or even conflicting is to try to see the document from the intended
data almost always are present in a body of study readers’ perspective.
results. This is not surprising, given biology’s Best practices for clear regulatory document
complexity, measurement difficulty and the writing are identified throughout this chapter.
variability of human phenomena. Unless they are Earlier sections have emphasized the importance
truly unimportant, problematic data should not of structuring these documents to make the
be hidden. Trying to hide data lessens the regula- emphasis as clear as possible. The main points
tory submission’s credibility and invites reviewer should be obvious, with minimal reader effort
suspicion. Usually, the best course is to present required to identify them. The most emphasis
problematic data and explain how it might be should be given to the main points. Subsidiary
understood. By proactively identifying issues in or less important topics should be apparent by
their data, sponsors have an opportunity to make their placement and the amount of space devoted
the best argument they can for why these issues to them. If information on secondary topics is
should not prevent achieving regulatory goals. becoming too detailed, one option is to move the
Honesty is always a good approach. In some details into appendices, so any needed infor-
cases, the best that can be said is that data are not mation is available but does not distract readers
interpretable, or further study is required before a from the emphasis on the main points.
conclusion can be reached. Documents and document sections should
Shareholders, investors, practicing clinicians, not build to a conclusion. Rather, the conclusion
patients or third-party payers are not the audi- should be stated first, followed by the evidence
ence for regulatory documents. But writing team demonstrating how that conclusion was reached.
members who usually address non-regulatory A classic strategy is to start with an introduc-
audiences may require education about regulators’ tory paragraph stating a conclusion and listing
needs and preferences so regulatory documents the lines of evidence that will be presented in
are appropriately targeted. Overly promotional support of that conclusion. Then, the evidence is
language and content about financial consider- presented in the same order as in the introduc-
ations can undermine regulatory goals by arous- tion. Finally, the conclusion is re-stated briefly
ing suspicion that the sponsor lacks scientific under the heading, “Conclusion.” If this seems
credibility or is more focused on business success too simple-minded, remember that the goal of a
than on improving healthcare. The writing regulatory submission is to be clear and convinc-
ing, not daring or fancy.
team’s regulatory leader may need to steer team
Providing signposts throughout the doc-
members toward greater objectivity in regulatory
ument also helps readers. Sections and subsec-
document language and content.
tions should be clearly identified by headings.
Realize Clear Writing is Harder Than it Introduction and conclusion sections should be
Appears provided as well, wherever they are helpful. Paths
to related information can be provided through
A truism about the best medical writing is cross-references, with text stating what additional
that the writer of a very clear document will information is available elsewhere. Regulatory
not receive the admiration deserved for this submission documents can take advantage of the
accomplishment. Since the information is so capabilities of electronic publishing and the elec-
clearly presented, a reader’s natural inclination tronic Common Technical Document (eCTD)

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

1
Table 18-2. Best Practice Examples for Clear Regulatory Writing 2
Best Practice
Consistently use a controlled
Problematic Example
Three ascending doses of
Better Example
Three ascending doses of the
3
vocabulary of terms. Avoid the drug were given. The experimental drug were given.
using alternative terms to
identify the same thing.
experimental treatment was
well tolerated by all subjects.
The experimental drug was
well tolerated by all subjects.
4
Use direct, clear, easily The 5 mg, 10 mg and 20 mg Complete response occurred in
understood language and
sentence structure.
dose groups demonstrated
complete responses in 12%,
12% of the 5 mg dose group, 18
% of the 10 mg dose group and
5
18% and 36% of subjects, 36% of the 20 mg dose group.
respectively.
6
Avoid superfluous words. Based on information gained In the S106 study, some
in the S106 study, it has been infections were not cleared
observed that not all infections
were cleared completely by day
completely by day seven of
treatment.
7
seven of treatment.
Use parallel construction The sites performed baseline Subjects received baseline 8
in lists, sentences and CT scans, and subjects were CT scans and pre-treatment
paragraphs. pre-treated with steroids. with steroids.
Keep the tone professional and This experimental approach This experimental approach 9
scientific; avoid overstating. may prove to be an important may provide successful
requirement for successful treatment for a condition with
treatment of this difficult unmet medical need. 10
condition.
Be alert for possible multiple The surgeons knew less The surgeons knew less
meanings. about acupuncture than their about acupuncture than their 11
patients. patients did.
or
The surgeons knew less about 12
acupuncture than they knew
about their patients.
13
format, which allows cross-references within editing text can increase the clarity of regulatory 14
and between documents to be easily created by documents to a degree that may be surprising.
authors and used by readers. Regulatory submission documents should
In addition to clear document structure and always be checked for grammar and word usage. 15
content organization, clear writing at the level An editing step performed by someone other
of sentences and paragraphs is vital to convey
the intended meaning and avoid misunderstand-
than the author is advisable to correct any writ-
ing errors and clarify any ambiguous wording.
16
ing. Some of the best practices for writing clear While writers know the intended meaning of
sentences and paragraphs are presented in Table their texts, an outside reader may interpret the 17
18-2. These will not come as revelations to most same words in a different way. Such problems
writers, but these practices are overlooked too may be impossible for the original writer to rec-
often when regulatory documents are being writ- ognize. Similarly, documents should be reviewed 18
ten. Keeping them in mind when writing and for the use of jargon, unfamiliar local terms and

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 Chapter 18: Medical Writing Strategies: Aligning Regulatory Documents with Strategic Goals

uncommon abbreviations that may confuse read- information supports the action the sponsor
ers rather than aid comprehension. wants the regulators to take.
As has been suggested throughout this
chapter, writing regulatory submission docu-
References
ments often involves working with a team. In
1. Applying for Orphan Designation. EMA website.
many instances, a document is written by more
https://www.ema.europa.eu/en/human-regulatory/
than one writer, with various team members research-development/orphan-designation/applying-
writing sections about their areas of expertise. In orphan-designation. Accessed 15 August 2019.
this case, one writer should review and edit the 2. Formal Meetings Between the FDA and Sponsors or
resulting document for consistency of voice and Applicants of PDUFA Products: Guidance for Industry
(December 2017). FDA website. https://www.fda.
standardization of vocabulary and other docu- gov/regulatory-information/search-fda-guidance-
ment elements. documents/formal-meetings-between-fda-and-
The need for a regulatory expert to guide the sponsors-or-applicants-pdufa-products-guidance-
industry. Accessed 15 August 2019.
team toward best practices in writing regula-
3. Expedited Programs for Serious Conditions—Drugs
tory submission documents has been suggested
and Biologics. FDA website. https://www.fda.
throughout this chapter. To guide the team, gov/regulatory-information/search-fda-guidance-
regulatory experts may need to use diplomacy at documents/expedited-programs-serious-conditions-
some times and assert control at others. While drugs-and-biologics. Accessed 15 August 2019.

team leadership skills are not writing skills, per 4. E2F Development Safety Update Report. FDA website.
https://www.fda.gov/regulatory-information/search-
se, good team leadership by a regulatory expert fda-guidance-documents/e2f-development-safety-
often is critical to the quality of regulatory docu- update-report. Accessed 15 August 2019.
ments produced by writing teams. 5. CDER Manual of Policies & Procedures (MAPP).
FDA website. https://www.fda.gov/about-fda/center-
Conclusion drug-evaluation-and-research/cder-manual-policies-
procedures-mapp. Accessed 15 August 2019.
Industry veterans probably can point to examples 6. Application audit (technical file review) of IVD
of regulatory strategies that have achieved their medical device applications (February 2011). TGA
website. https://www.tga.gov.au/sites/default/files/ivd-
intended goals despite written documents that
application-audit.pdf. Accessed 15 August 2019.
were not particularly clear or well presented. This
can be considered a testament to the power of
convincing data and regulators’ willingness to dig
through murky presentations to find the under-
lying information. But, veterans also probably
can point to examples of regulatory strategies
that did not succeed, despite what should have
been a reasonable chance of success. Such cases
can be haunted by the question of whether the
desired outcome might have been achieved if
the regulatory documents had been clearer or
written more persuasively. A thoughtful approach
to writing regulatory documents best aligned
with a regulatory goal cannot guarantee success.
However, a thoughtful approach can maximize
the likelihood that regulators will understand the
goal a sponsor is trying to achieve, why this goal
is important and how the totality of available

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Index
Tables, figures and case studies are indicated by competitive product landscape and, 205, 210
appending “t”, “f” or “c” to the page number. conflict of interest, 217
Contents of tables are not indexed separately. Draft core presentation development, 213
guidance documents are indexed under Guidance developing briefing materials, 212–213
for Industry. Law and regulations titles are indexed external support for, 212
only by country or regulatory area. as information source, 35
initiating preparation, 207–208
A logistics, 216
meeting venue impact, 211
Abbreviated New Drug Application (ANDA) membership considerations, 210–211
in CMC planning, 82 message matrix, 206
cross-reference to off-patent drug, 157–158 messaging in strategy, 211–212
review and approval process, 158 mock meetings, 215–216
Abbreviated New Drug Submission (ANDS), 170 open public hearing, 207, 216, 217
absorption, distribution, metabolism and excretion outcome-based strategy for, 209–210
(ADME), 72, 74, 118–119 overview/purpose, 205–207
accelerated/expedited development and approval performance, 215
Animal Rule in, 95 political pressure, 216–217
Centralised Procedure, 189 preparation for, 208–209
endpoint identification for trials in, 159 preparation for meetings, 205–220
EU mechanisms for, 166t Q&A, 207, 213–215
fast-track status, 170 RI from, 35
FDA programs for, 160t RI materials for, 25
listing of, 26–27 at-risk preparation, 207–208
Next Genome Sequencing (NGS) panels, 137 team role in, 10
PRIme MEdicines (PRIME), 189 See also Food and Drug Administration
products eligible for, 38 allergen-specific immunotherapy, 127–128
strategic plan consideration of, 2, 5 Alliance for Regenerative Medicine, 26
surrogate endpoints for, 42, 95, 159
Antibody Drug Conjugates (ADC), 67
US pathways, 26–27, 159
anticancer pharmaceuticals
Active Substance Master File (ASMF-EU), 82
nonclinical evaluation of, 67
Actos (pioglitazone), 225, 226
pediatric requirements for, 121
adverse effects/events (AEs)
Q&A document for, 67
benefit-risk assessment and, 93–94
toxicology studies for, 75
in CoDx development, 135, 142
ANVISA (Agencia Nacional De Vigilancia
demonstration and definition of, 96c
Sanitaria). See Brazil
DSURs for, 102
Asia: clinical development strategy in, 194f
postmarketing surveillance for, 190, 201
Asia-Pacific Economic Cooperation (APEC), 60
in regulatory strategy development, 3, 6
Association of Southeast Asian Nations (ASEAN)
reporting of serious, 102
ICH guidelines in, 60
RWE for surveillance of, 42
regulatory geography, 79
SAEs reporting, 102
Australia
of special interest, 95c
advisory committee meeting materials, 25
special interest case study, 95
application fees, 178t, 180t
trial procedures for defining, 96
AusPARs, 25
advertising and promotion, 14, 16–17, 187
CoDx requirements for, 139
Advisory Committee meetings, 205–219
freedom of information requests, 28
approval and committee vote comparison,
guidance document access, 25
217–218
ICH guideline adoption, 195

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 Index

legal definitions for, 184 TPP utilization in, 46

Orphan Drug Policy, 108, 110 biosimilars
pharmaceutical regulation geography, 79 Canadian regulatory pathways, 170
regulatory meetings in, 153 EU legal framework for, 165
regulatory precedents for, 90 LCM for, 221
standard registration process, 173f PMDA approval, 168
TGA website, 24 US approval pathway for, 158–159
timelines for application process, 180t biotechnology-derived products
use of non-GMP products, 192 chronic nonrodent study duration, 75
Australian laws and regulations CMC for, 73
Australian Regulatory Guidelines for Biologicals preclinical evaluation guidelines for, 62, 64–65
(ARGB), 179 protein-based therapeutics, 73
Autologous human cells and tissues products Branded Generics, 182
regulation, 179 Brazil
Therapeutic Goods Act 1989, 172, 176, 184 biological products, 182–183
Therapeutic Goods Regulations 1990, 179 ICH membership, 60
Australian Public Assessment Reports (AusPARs), 25 patent protection in, 182
Australian Register of Therapeutic Goods (ARTG), regulatory agency, 70
172 regulatory authorities/agencies, 70
Australian regulatory pathways, 172–181 regulatory pathways in, 181–183
biologics, 176–181, 179f Brazilian laws and regulations
drugs, 173 RDC 205/2017, 182
HCT/Ps, 176 RDC No 200 of 12/26/2017, 181
priority review, 173–174, 175f Resolution RDC 55/2010, 182
provisional approval, 174–176, 177f Resolution RDC 204/2017, 182
registered vs. listed medicines, 172 Brazilian regulatory pathways
Australia/New Zealand (ANZ), 79 stand-alone pathway, 183
timeframe and fees for, 182
B Breakthrough Therapy designation. See accelerated/
expedited development and approval
benefit-risk assessment business strategy, 187–190
in clinical trials, 93
with CoDx, 136, 137
conditional approval and, 189 C
in CTD, 196 Canada
evaluation of, 235 adverse event reporting, 102
for GRP and TPL, 33 biosimilar regulation, 170
OPH effects on, 217 guidance document access, 25
in product strategy, 37–38, 40 ICH guideline adoption, 195
for regulatory authority meetings, 202 regulatory pathways in, 169–172
RI sources for, 35 scientific/advisory committee meeting materials, 25
biologics Summary Basis of Decision (SBD) document, 25
Australian regulatory pathways, 176–181 websites and databases, 25
Centralised Procedure application, 165 Canadian laws and regulations
regulatory exclusivity for, 155, 156t, 158 Food and Drugs Act, 170
US approval pathway for, 158 Food and Drugs Regulations, 169–170
Biologics Electronic Reading Room, 24 Canadian regulatory pathways, 169–172
Biologics License Application (BLA) HPFB timeframe, 170
approval pathway for, 158 innovator (brand name) drugs, 170
clinical success rates for, 222 Notice of Compliance (NOC), 169, 170
CMC registration documents for, 82–83 Notice of Compliance with Conditions (NOC/c),
PDUFA fee requirements, 155 170
regulatory meetings with, 36–37, 148–149 Priority Review of drug submissions, 170
RMP requirements for, 53 SEBs/biosimilars, 170
rolling submission for, 38 subsequent (generic) drugs, 170
small business exemption, 157

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

carcinogenicity testing, 62–63 requirements for success, 86–87

case studies strategy planning, 82
adverse events, 95c children-as-therapeutic-orphans, 118
clinically meaningful endpoint selection, 94c China
postapproval CMC study, 85–86c CoDx requirements for, 138–139
preapproval CMC study, 84–85c ICH status, 60
teduglutide: endpoint selection, 94 nonclinical guidelines, 70
TPP utilization, 46 regulatory geography, 79
unacceptable risk exclusion, 96c Chinese Taipei (TFDA) ICH status, 60
Center for Biologics Evaluation and Research (CBER) chiral switches, 228–229
biologics regulation, 59 chronic toxicity testing (S4), 63–64
biologics review by, 158 Clarinex (desloratadine), 230
CoDx development, 141 Claritin (loratadine), 230
expedited program guidelines, 137 clinical development planning, 89–98
nonclinical guidelines, 70 clinical development facilitation, 91
website and databases, 24 clinical trial design, 92–97
Center for Devices and Radiological Health (CDRH) endpoint identification for trials, 90–91
CoDx regulation, 141 meaningful endpoint selection, 94
CoDx use in clinical trials, 134 Phase 1-3, 89–90
guidance on Breakthrough devices, 137 reverse-engineering principal in, 90f
website and databases, 24 study document template, 91, 91t
Center for Drug Evaluation and Research (CDER) timeline for, 92f
in CoDx development, 141 tools for, 90–91
expedited product guidelines, 137 See also clinical trial design
new drug approval, 157 clinical supply labels, 100–101
nonclinical guidelines, 69–70 Clinical Trial Application (CTA) planning, 99–106
regional guidelines, 73 choosing countries for, 99–100
small molecule regulation, 59 clinical supply labels, 100–101
website and databases, 23–24 computerized technology in, 101
Central East Europe (CEE), 79 documentation needed, 104
Centralised Procedure ethics committee for, 100
accelerated assessment, 189 Form 1571, 102
MAA submission by, 80, 161 Form 1572 and financial disclosure updates,
major milestones in, 163f 103–104
requirements by product type, 81t global dossier contents, 100
Certificate of Medicinal Product (CMP), 86 investigational product requirements, 104
Certificate of Pharmaceutical Product (CPP), 86 IP supply, storage, and handling, 104
Certificates of Suitability of European Pharmacopoeia maintaining submission, 102–103
monographs (CEPs), 83 multicenter studies, 103
Chemistry, Manufacturing and Controls (CMC) pre-CTA meetings, 59
strategy, 79–88 protocol amendment requirements, 103
case studies, 83–84 record requirements, 104
centralised procedure/requirements, 81 shelf-life extension, 103
CTD use for registration, 82 submission contents, 102–103
in emerging countries, 86 translations requirements, 101–102
expectations in strategic document, 13–14 trial design, 92–97
ICH guidelines for CMC dossier, 193–194 US IND paperwork requirements, 104
postapproval CMC changes, 84–85 clinical trial design
preapproval CMC changes, 84, 85–86 clinical development planning, 92–97
pre-IND and pre-CTA meetings and, 59 clinical meaningful endpoint for, 94c
in product development, 79–80, 191 CoDx in, 134–136
regional differences in CTD, 83 endpoint identification, 90–91, 93
regulatory authorities, 81 endpoint identification for trials, 19–20
regulatory planning, 82 Phase 1, 92–93
in regulatory strategy, 80–82 Phase 2, 93–94

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 Index

Phase 3, 94–97 Council for International Organizations of Medical

See also endpoint identification for trials Science (CIOMS), 102
clinical trials Critical Process Parameters (CPPs), 49
databases for, 27 Critical Quality Attributes (CQAs), 47, 49, 51–52, 53
defined, 99
NIH policy for multicenter studies, 103 D
clinically meaningful endpoint, 94c
databases
Clone Product, 182
authorized products (Canada), 25
Code of Federal Regulations, Title 21, 33–34
clinical trials, 27
combination products. See companion diagnostic
“expert tracker”, 201
(CoDx) development
Committee for Advanced Therapies (CAT), 127, 161 orphan drug designation, 114
Committee for Medicinal Products for Human Use prevalence/rare disease, 114–115
(CHMP) product regulation tracking, 201
application review by, 161 SEC filings, 27
See also specific regulator authorities
CoDx development, 136
guidelines issued, 70, 165 Development Safety Update Reports (DSURs), 102
pediatric product evaluation, 121, 123 device and companion diagnostics, regulatory team
for, 17–18
scientific advice meetings, 153
Committee on Orphan Medicinal Products (COMP), dispute resolution, 153–154
108, 161, 236 drug approval summaries
Common Brazilian Name Listing (DCB), 182 AusPARs, 25
Common International Name Listing (DCI), 182 SBD documents, 25
Common Rule, 103 Drug Master File (DMF-US), 82–83
Common Technical Document (CTD) drug-discovery model, 59
CMC technical information, 82
electronic submissions, 202–203 E
for global dossier and CTA, 100, 195–196 East African Community (EAC), 60
regional interpretation and implementation of, 34 efficacy
Commonwealth Independent States (CIS), 79 endpoint identification for trials, 48–49, 51t
companion diagnostic (CoDx) development, 133–144 expectations in strategic document, 13
applications of, 142 ICH guidelines, 25, 68, 137
clinical development strategy, 139–142 target product profiles and, 51t
clinical trial use of, 134–136 EMA guidelines
evolution of, 133–134 Guideline on Similar Biological Medicinal
guidance documents for, 136 Products, 165
marketing authorization for, 136–137 Guideline on Strategies to Identify and Mitigate
region-specific highlights, 137–139 Risks for First- In-Human Clinical Trials With
regulatory team role with devices, 17–18 Investigational Medicinal Products, 69
role of, 133–134 Qualification of novel methodologies for drug
comparability pathway (Brazil), 183 development, 136
Competent Authority, 161 Reflection paper on co-development of
competitive product landscape pharmacogenomic biomarkers and assays in the
Advisory Committee meetings and, 205, 210 context of drug development, 136
approved drug label language and, 237 emerging markets
clinical development planning and, 91–92, 99 characteristics of, 232
in development program design, 89 climate zone stability data, 86
gap analysis on, 40 geography of, 79
for orphan drug development, 113 ICH guidelines in, 60
in regulatory intelligence, 3, 5, 6, 11, 39 regulatory decisions and, 41
TTPs for, 45, 47, 49 RHIs in, 60
understanding the landscape of, 39t enantiomer drug, 229–230
Concerned Member State (CMS), 161 End-of-Phase-1 (EOP1) meeting, 5, 148
Contract Research Organization (CRO), 61, 69, 76, End-of-Phase-2 (EOP2) meeting, 5, 46, 59, 118, 121,
120 127

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

endpoint identification for trials EPARs, 35

in accelerated approval, 159 freedom of information requests, 28
Animal Rule in exceptions to, 95 harmonized guidelines in, 34
clinical importance for, 3, 94c, 95, 145 labeling for minors, 117
correlation with approval, 55 lawsuits against, 126
defense of, 54–55 orphan drug development incentives, 108
defining of, 19–20, 90 pediatric drug development laws in, 121
exceptions for definitive clinical, 95 Pediatric Scientific Advice (EMA), 127
for generic/ANDAs, 158 pharmaceutical guideline development, 60
indication statements and, 89 PIP negotiations with, 124–126
Phase 2 data for, 93–94 preclinical regional guidance, 69–70
primary, 49, 51t, 93 product studies for minors, 117
RWE/RWD and surrogate endpoint, 42 Regulatory and Scientific Information Management
SPAs for, 150 Platform (IRIS), 108
surrogate, 42, 95, 159 Scientific Advice meetings, 149
enhanced Pre and PostNatal Development (ePPND) websites, 24, 28
studies European Public Assessment Reports (EPARs), 35
reproductive toxicity study timing, 64 European Union (EU)
established markets, 79 accelerated drug and biologics development, 166t
eSubmission Gateway/eSubmission Web Client, 122 biosimilar product approval pathway, 165
Ethics Committees (ECs) Centralised Procedure in, 60
for clinical trial application planning, 100 CoDx requirements for, 138
NIH policy for multicenter studies, 103 Decentralized Procedure timelines, 164t
pediatric studies and, 117 drug application types in, 161–165, 166t
EU laws and regulations drug/biologics pathways in, 159–165
Clinical Trials Regulation (536/2014), 39 drugs/biologics application procedures, 162t
Directive 2001/83/EC, 165, 184 EPARs, 24–25
Directive 200427/EC, 165 EU PRIME designations listing, 27
EU In Vitro Device Regulation (EU IVDR), guidance document access, 25
133–134 ICH guideline adoption, 195
EU In Vitro Diagnostics Regulation (EU IVDR), ICH membership, 60
138 Mutual Recognition Procedure timelines, 163t
General Data Protection Regulation (GDPR), 138 orphan designations, 123
Paediatric Regulation, 121 orphan drug designation program, 108–110
Regulation (EC) No 726/2004, 138 orphan drug regulations, 108
Regulations (EC)141/2000 and 847/2000, 108 pediatric drug development laws in, 121
EU regulatory pathways pediatric laws in, 117
biologics, 165 regulatory meetings in, 153
biosimilars, 165 regulatory pathways, 159–165
Centralised Procedure, 160, 163f Scientific Advice meetings, 149
Decentralized and Mutual Recognition Procedures, Scientific Advice Working Party (SAWP), 153
160–161, 163t, 164t submission procedures in, 80
expedited development, 165 European Union Member States
MAA types in, 161, 165t biologics submissions, 161
routes for approval, 159–160, 162t Centralised Procedure application in, 80
European Economic Area (EEA), 80 exclusivity
European Free Trade Association (EFTA) first marketing for, 80
Centralised Procedure application in, 80 in LCM, 221
ICH observer status, 60 marketing, 108
European Medicines Agency (EMA) orphan product development and, 108
10-year pediatric report, 128 pediatric products, 121, 124, 156t
Centralised Procedure milestones, 163t regulatory exclusivity period, 155, 158
Centralised Procedure requirements, 202 regulatory path choice and, 155, 156t
committee review of MAA, 161 strategic plan consideration of, 2, 5, 80, 82
Competent Authority disputes and, 161 US pathways and, 158t

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 Index

voluntary PIP for, 124 change anticipation and management, 32t, 37

See also patents decision making and, 40–41
experience capture, 201 functions of, 42–43
Expert Working Group (EWG), 60 key elements in, 32t
Exubera (Pfizer), 55 regulatory engagement strategy in, 36
table of contents for, 43t
F tool for development, 31
global regulatory strategy, 31–44, 187–204
Farxiga, 226 advice or approval seeking, 36–37
Fast Track status. See accelerated/expedited benefit-risk and product strategy, 37
development and approval business strategy in, 187–188
fexofenadine, 230 CMC product development, 191
“five what’s” in strategy developments clinical development, 193, 194f
application example, 70–71 nonclinical, 193
preclinical safety evaluation strategy, 61–62 CTD in, 195
Fixed-Dose Combinations (FDCs), 225–226 electronic submissions, 202–203
Fluosol® (Alpha Therapeutic Corporation), 55 experience capture, 201
Food and Drug Administration (FDA) filing sequence, 197–198
Advisory Committee meetings, 205–220 GRP as tool, 31
Breakthrough Designations listing, 26–27 harmonization, 203
formal meeting types and guidance on, 37 hazards for, 40–41
harmonized guidelines in, 34 history and overview of, 31–32
internal reorganization of, 59 improving alignment, 38–39
iPSP requirements, 118, 121, 127 key elements of, 32t
ISO 13485:2016 adoption, 138 knowledge management, 201
Next Genome Sequencing (NGS) panels, 137 language, culture, and local insights, 202
nonclinical laboratory study regulation, 58 local insights and impact on, 40
nonclinical regional guidance, 68–69 maintenance and compliance, 200–201
nonclinical safety studies, 56–57 multidisciplinary product development, 187–190,
Oncology Center of Excellence (OCE), 133 188f
OOPD services, 108 plan table of contents, 43t
orphan designation, 123 postapproval commitments, 198–199
Orphan Drug Designation program, 107 precedents and regulatory intelligence, 34–36
PDUFA meeting types, 150 regional dossiers, 196–197, 197t
pediatric drug development laws in, 121 regulation database, 201
priority review voucher program, 124 regulations/regulatory guidelines, 33–34
product studies for minors, 117 regulator interactions in, 201–202
regulatory authority website, 23, 24 regulatory authority meetings, 202
regulatory meetings with, 150–153 regulatory interaction strategy in, 35
request for written request for PIP, 126 reimbursement, 190–191
Summary Basis of Approval (SBA), 35 RWD and RWE in, 41–42
TPP sample, 47 safety monitoring, 199–200, 199f
written request for pediatric product studies, 121 strategy as roadmap, 32–33
See also Advisory Committee Meetings TPL as starting point for, 33
Form 10-K reports, 35 TPP utilization in, 188–189
freedom of information requests, 27–28 understanding regional guidelines, 34
Friends of Cancer Research, 26 globalization: emerging vs. established markets, 79
Glucophage (metformin), 224
G Good Clinical Practice (GCP), 136
generic product submissions, 158, 170 for drug development process, 34
genotoxicity testing, 63 Good Laboratory Practice (GLP)
global dossier: clinical trial application planning, 100 for drug development process, 34
global orphan drug regulations, 107–116 in nonclinical safety studies, 57–59
Global Regulatory Plan (GRP), 34–36 scope of, 56–58
anticipation of changes by, 32t Good Manufacturing Practice (GMP), 16, 104

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

for drug development process, 34 access for information, 28

guidance documents ANDS for generic drugs, 170
access for RI, 25 HPFB review timeframe, 170
See also ICH guidelines; specific country; specific human drug application review timeline, 171
regulatory agency ICH membership, 60
Guidance for Industry pediatric incentives, 123
Acceptance of Clinical Data to Support Medical Priority Review in submission queue, 170
Device Applications and Submissions Frequently website, 24
Asked Questions, 135 Health Products and Food Branch (HPFB), 70, 170
Considerations for Design, Development, and Health Technology Assessment (HTA)
Analytical principles of, 191
Validation of Next Generation Sequencing (NGS)- regulatory comparison and, 191t
Based In Vitro Diagnostics (IVDs) Intended to scientific advice for strategy, 20
Aid in the Diagnosis of Suspected Germline healthcare product lifecycle management, 221–234
Diseases, 137 Highest Non-Severely Toxic Dose (HNSTD), 67
Design Considerations for Pivotal Clinical human cellular/tissue-based products (HCT/Ps)
Investigations for Medical Devices, 135 Australian pathways, 176
Enrichment Strategies for Clinical Trials to Japanese approval system for, 169f
Support Approval of Human Drugs and TGA regulations for, 179–181
Biological Products, 135 US approval pathway for, 159
Estimating the Maximum Safe Starting Dose in
Initial Clinical Trials for Therapeutics in Adult I
Healthy Volunteers, 69
Expedited programs for serious conditions—drugs ICH guidance documents
and biologics, 137 Clinical Investigation of Medicinal Products in the
FDA Decisions for Investigational Device Pediatric Population, 68
Exemption (IDE) Clinical Investigations, 135 Development Safety Update Report, 39
Formal Meetings Between the FDA and Sponsors M3 Guidance on Nonclinical Safety Studies for the
Conduct of Human Clinical Trials and Marketing
or Applicants of PDUFA Products, 37
Authorization, 62
Investigational IVDs Used in Clinical
The Nonclinical Evaluation of the Potential for
Investigations of Therapeutic Products, 135
Delayed Ventricular Repolarization (QT Interval
Preclinical Assessment of Investigational Cellular
Prolongation) by Human Pharmaceuticals, 65
and Gene Therapy Products, 69
Organisation of the Common Technical Document
Principles for Codevelopment of an In Vitro
for the Registration of Pharmaceuticals for
Companion Diagnostic Device with a
Human Use, 82–83
Therapeutic Product, 136
Organization of the Common Technical Document
Providing Clinical Evidence of Effectiveness for
for Registration of Pharmaceuticals for Human
Human Drugs and Biological Products, 157
Use, 82–83
In Vitro Companion Diagnostic Devices, 136
Qualification of novel methodologies for drug
Waiver of In Vivo Bioavailability and
development, 137
Bioequivalence Studies for Immediate
A Safety Pharmacology Studies for Human
Release Solid Oral Dosage Forms Based on a
Pharmaceuticals, 65
Biopharmaceutics Classification System, 84
ICH guidelines: Efficacy (E)
Gulf Co-operation Council (GCC), 79
designation of, 25
Gulf Health Council (GHC), 60
JAS requirements, 68
ICH guidelines: Multidisciplinary (M)
H designation of, 25
harmonization initiatives (RHIs) M3(R2)
factors in, 59 chronic toxicity testing duration, 63–64
international groups, 203 photosafety evaluations, 67
regional, 60 protein-based therapeutics, 73
Voluntary Harmonisation Procedure (VHP), 38 purpose and scope of, 62
Health Canada repeat-dose toxicity studies, 193
Abbreviated New Drug Submission (ANDS), 170 S6(R1) comparison, 75

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 Index

toxicology studies, 71–73 Interactive Web Response Systems (IWRS), 101

mutagenic impurity assessment (M7(R1)), 68, 83 International Coalition of Medicines Regulatory
ICH guidelines: Quality (Q) Authorities (ICMRA), 199, 203
CTD sections, 82–83 International Council on Harmonisation (ICH)
dissolution specifications (Q4B), 83 core regions for, 60
drug substance development/manufacture (Q11), guideline categories and revisions, 60–61
83 guideline establishment process, 60–61
elemental impurities (Q3D), 83 guidelines, 34
Quality-by-Design concept, 47 guidelines for CMC dossier, 193–194
TPP elements in Q8/R2, 47 harmonized guidance categories, 25
ICH guidelines: Safety (S) history, 60
anticancer pharmaceuticals, 66–67 preclinical guidelines, 59–61
biotechnology-derived therapeutics, S6(R1), 62, QbD initiative by, 46
64–65, 73–74, 75 regulatory membership, 60
carcinogenicity testing (S1A–S1C(R2)), 62–63 See also specific guideline categories
chronic toxicity testing (S4), 63–64, 71t International Council on Harmonisation of Technical
genotoxicity (S2(R1)), 63 Requirements for Registration of Pharmaceuticals
genotoxicity testing (S2(R1)), 63 for Human Use (ICH), 34
immunotoxicity (S8), 66 international drug registration
nonclinical, 25 managing postapproval changes, 86
nonclinical pediatric (S11): JAS requirements, 68, preclinical safety guidelines, 57–78
72 International Generic Drug Regulators Programme
pediatric medicines development (S11), 68 (IGDRP), 203
photosafety evaluations (S10), 67–68 International Organization for Standardization (ISO)
preclinical safety M3(R2), 62 standard
reproductive toxicity (S5(R3)), 64 ISO 13485:2016, 138, 140–141
safety pharmacology (S7), 65–66 ISO 15189, 141
Safety pharmacology (S7A and S7B), 65 ISO 31000, 198
toxicokinetics (S3), 63 International Regulators Consortium, 203
ICH Steering Committee (SC), 60 Investigational Medicinal Product Dossier (IMPD),
ICH tripartite guidance document adoption, 60 100
Imitrex (sumatriptan), 224–225 Investigational New Drug application (IND)
immunotherapy, allergen-specific, 127–128 global dossier comparison, 100
in vitro companion diagnostic (CoDx) test. See pre-IND meetings, 59
companion diagnostic (CoDx) development regulatory meetings with, 36, 149
in vitro diagnostic (IVD) device. See companion regulatory team activity in, 10
diagnostic (CoDx) development Invokana (canagliflozin), 225
incentives for development Ivacaftor clinical example, 127
EMA, 108
Health Canada, 123 J
Japan, 123
Januvia (sitagliptin), 225
under Orphan Drug Act, 107–108
Japan
orphan drug designations, 111–112t
approved product lists, 25
orphan product, 110–113
biosimilar applications, 168
pediatric product, 124
CoDx requirements for, 139
priority review and fast track, 38
guidance document access, 25
India, 70, 192, 193
harmonized guidelines in, 34
initial Pediatric Study Plan (iPSP), 118, 121, 127
ICH guideline adoption, 195
Institutional Review Board (IRB)
ICH membership, 60
approval letter for US IND, 104
IVD and CoDx submissions, 139
functions of, 100
orphan designations in, 123
multicenter studies, 103
pediatric incentives, 123
oral explanation request for PIP, 126
PMDA website, 24
pediatric studies and, 117
regenerative medicine, 168
Interactive Voice Response Systems (IVRS), 101

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

regulatory approach for OTC switch, 231 loss of exclusivity and, 221
regulatory pathways, 165–169 OTC switch, 231
Japanese laws and regulations outsourced and virtual, 230
On Drug Approval Applications (PFSB Notification phases of, 223t
No 1121-(2)), 166–167 principles of, 223
Orphan Drug Regulation, 108 product profile improvement with, 222
Pharmaceutical & Medical Device Act (PMD Act), reformulation, 224–226
166, 184 scope of, 221
Pharmaceuticals Affairs Law (PAL/PMD), 168 selection for, 232
Regenerative Medicine Law, 168 tactics for, 223–224
Japanese New Drug Application (JNDA), 82
Japanese regulatory pathways M
cellular therapy product commercialization, 169f
market exclusivity. See exclusivity
conditional approval, 168
marketing, 17, 190, 190f
drug and device review process, 167f
Marketing Authorisation Application (MAA)
drug filing fees, 168t
Centralised Procedure for, 161
filing fees, 168t
for companion diagnostic (CoDx), 136–137
MHLW review timeline, 167
CTD use for, 82
patent extension in, 167
pathways for drugs and biologics, 165–169 PIP requirements for, 121
Pharmaceutical Evaluation Division (PSEHB) regulatory meetings with, 36, 149
marketing exclusivity. See exclusivity; patents
notification, 168
SAKIGAKE designation, 27, 168–169 Master File (MF-Japan), 82
juvenile animal study (JAS), 68 maximal-target-minimal-value, 47–49
Medical Device Single Audit Program (MDSAP ), 138
medical writing strategies, 235–242
K clear writing best practices, 240–242, 241t
knowledge management, 201 map regulatory documents, 238–239
objectivity in, 239
L regulatory audience composition, 235–237
regulatory goal clarification, 237
labeling development for strategic goals, 235
clinical supply labels, 100–101 structured regulatory goals, 238t
Daily Med site, 90 Medicines Information Bank, 25
endpoint summary in, 90 message matrix, 206, 209, 214
expectations in strategic document, 14 Minimal Anticipated Biological Effect Level
regulatory team in, 16 (MABEL), 69
role in reimbursement, 18–20 Ministry of Health, Labor and Welfare (MHLW)
specific claims in, 47 GLP adoption, 58
team role in, 13 Ministry of Health, Labour and Welfare (MHLW)
TPL document, 33 ICH membership, 60
large molecules, 59. See also protein-based website, 24
therapeutics See also Japan
Latin America (LATAM), 79, 81t multicenter studies, 103
Letter of Acceptance (LOA), 100 mutagenic impurity assessment, 68
lifecycle management (LCM) Mutual Recognition Agreements (MRAs), 38
antidiabetic drug evolution, 227t
Mutual Recognition Procedure/Decentralised
branded prescription maximization, 231–232
Procedure, 161
chiral switches/active metabolites, 228–230
emerging market influences on, 232
in emerging markets, 232 N
fixed-dose combinations, 225 National Institutes of Health (NIH) clinical trial
global products, 198–201 requirements, 103
global regulatory organization input in, 187 National Library of Medicine, 90
healthcare products, 221–234 National Medical Products Administration (NMPA).
indication expansion, 226–228, 228t See China

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 Index

negative precedents, 34–36 orphan drug authorities, 113t

neglected-disease voucher, 124 orphan drug designation database, 114
Netherlands Medicines Evaluation Board, 25 for pediatric products, 123
Neupogen (filgrastim), 158 programs for development, 107–108, 110t
New Chemical Entity (NCE), 82, 229 regulations by country, 114t
New Drug Application (NDA) RI tool for, 113
cross-reference to off-patent drug, 157–158 submission requirements for, 113
CTD use for, 82–83 templates for submissions, 114t
PDUFA fee requirements, 155 US orphan drug designation program, 107
record requirements for, 104 Over-The-Counter (OTC) switch, 231
regulatory meetings with, 36, 148–149
RMP requirements for, 53 P
small business exemption, 157
Paediatric Committee (PDCO)
TPP utilization in, 46
application review by, 161
New Medicine Product/Innovator Drug registration,
indication and condition differentiation, 122
182
PIP evaluation, 121
New Molecular Entity (NME)
PIP negotiation with, 124–125
clinical success rates for, 222
request for oral explanation, 126
development costs of, 221
Nexium (esomeprazole), 229 Pan American Network on Drug Regulatory
Next Genome Sequencing (NGS) panels, 137 Harmonization (PANDRH), 60
Parallel Scientific Advice (PSA) program, 39
Non-Branded Generics, 182
nonclinical strategy patents
anticipated events with, 57 chiral switches for extension, 229–230
extension in Japan, 167
GLP regulations in, 57–58
safety strategy development, 61–62 extension with WR pediatric study, 121
strategic document and, 13 impact of expiration and extensions of, 221
US definition of, 58 indication expansion for extension, 227–228, 228t
industry effects of expiration, 221
non-eCTD electronic submission (NEES), 203
modification of off-patent products, 157–158
No-Observed-Adverse-Effect-Level (NOAEL), 68, 69
protection by reformulation, 224, 228
Nycomed lawsuit, 126
See also exclusivity
Nycomed suit, 126
Patient-Reported Outcome (PRO) measure, 19–20
Pediatric Drug Development (PDD), 117
O Pediatric Exclusivity (PE). See exclusivity
Office of Generic Drugs (OGD), 158 Pediatric Investigation Plan (PIPs)
Office of Orphan Drug Development (OOPD), 108 clinical value of product, 123
Oncology Center of Excellence (OCE), 133 EMA class waivers and, 121–122
oncolytic agents. See anticancer pharmaceuticals modification of, 122–123
on-/off-label framework in pediatric population, 118 negotiation, 122
open public hearing (OPH), 217 patient ages and, 123
oral antidiabetic drugs (OADs), 224–225 products requiring, 121–122
oral solid dosage (OSD) products, 225 Small and Medium Enterprise (SME) office, 127
Organisation for Economic Co-operation and studies without exclusivity, 118
Development (OECD) submission contents and timeline, 122
GLP adoption, 58 pediatric population: definition of, 118
regional guidance documents, preclinical, 68–69, pediatric product strategies, 117–132
70, 72 assessment for use, 120–121
Orphan Drug Designation program, 107 children-as-therapeutic-orphans, 118
orphan product regulations, 107–116 discussion with EMA and PDCO, 124–125
guide to designation, 109f, 114t factors in future development, 128
health authority office for, 113t FDA/EMA negotiations, 127
incentives for development, 110–113 incentives for development, 124
marketing exclusivity, 108, 111–112t lawsuits against regulatory agencies, 126, 128
orphan diseases defined, 123 mixed EMA and PDCO feedback, 125

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

negotiation with FDA, 127–128 regional regulatory agencies for, 70

negotiations with EMA, 124–126 reproductive toxicity (S5(R3)), 64
oral explanation from PDCO, 126 safety pharmacology (S7), 65–66
PDD history, 117–120 supplements to guidelines, 75–76
Pediatric Scientific Advice (EMA), 127 toxicokinetics (S3), 63
presubmission meetings, 124 See also Good Laboratory Practice (GLP)
regulatory authorities, 123 Pre-Clinical Trials Application (Pre-CTA), 149
regulatory strategy for, 121 Prevacid (lansoprazole), 229
strategy for, 124–128 Prilosec (omeprazole), 229
unfeasible EMA/PDCO requests, 125–126 Prilosec OTC (omeprazole), 231
See also Pediatric Investigation Plan Prilosec/Prilosec OTC (omeprazole), 231
Pharmaceutical Evaluation Division (PSEHB) PRIme MEdicines (PRIME), 189
notification, 167–168 Priority Review of drug submissions, 170, 182. See
pharmaceutical regulation geographies, 79 also specific countries
Pharmaceuticals and Medical Devices Agency protein-based therapeutics, 59, 62, 69, 73
(PMDA) Public Health Service Act (PHS Act)
CTD use for, 82 biologic and biosimilar approval, 158
harmonized guidelines in, 34 biological product definition by, 184
role in development, 166 HCT/Ps regulation by, 159
scientific advice meetings, 153
website, 24 Q
pharmacokinetic data
Phase 1, 93 Qualified Person (QP)
playbook format, 12 in CMC planning, 83
positive precedents, 34–36 CTA review, 100
postmarketing activities Quality Assurance Unit (QAU), 58
benefit-risk profile updates, 37 Quality Target Product Profile (QTPP), 47, 51, 80
commitment with accelerated approval, 42, 96 Quality by Design (QbD) concept
ICH initiative on, 46, 47
later-phase strategy plans for, 32–33
in risk assessment and mitigation, 53
PMRs, 42
safety data collection, 199, 201
strategic planning for, 7, 17 R
team role in, 10 racemate drug, 228–229
verification of clinical benefit, 38 rare diseases
postmarketing commitment requirements (PMRs), 42 defined, 107
precedents (of approved drugs), 34–36 pediatric, 118, 123–124
preclinical safety guidelines Rare Pediatric Disease Priority Review Voucher, 124
anticancer pharmaceuticals (S9), 66–67 Real-World Data (RWD) in strategy development,
applicable regulations, 61–62 41–42
biotechnology-derived pharmaceuticals (S6(R1)), Real-World Evidence (RWE) in strategy development,
64–65 41–42
carcinogenicity testing (S1A–S1C(R2)), 62–63 receptor-driven therapeutics, 59
case examples of, 70–75 recombinant technology
chronic toxicity testing (S4), 63, 71t preclinical safety evaluations in, 63–65, 73–75
genotoxicity (S2(R1)), 63 protein-based therapeutics development, 59
goals of, 76 Reference Member State (RMS), 161
guidance document use, 62 reformulation
ICH M3(R2), 62 extended-release, 226
immunotoxicity (S8), 66 patent extension by, 224, 228
internation drug registration, 57–78 postapproval case study, 85
medical expert role in, 15–16 purposes and methods, 224–225
mutagenic impurity assessment (M7(R1)), 68 Regenerative Medicine Advanced Therapy
pediatric medicines development (S11), 68 designation. See accelerated/expedited development
photosafety of pharmaceuticals (S10), 67 and approval
regional guidance documents, 69–70 Regulatory and Scientific Information Management

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 Index

Platform (IRIS), 108 Australia, 173–181

regulatory authorities/agencies Brazil, 181–183
by country/region, 81t Canada, 169–172
issuing nonclinical guidelines, 70 Centralised Procedure, 161
TPPs in interaction with, 46–47 Decentralised/Mutual Recognition Procedures, 161
regulatory exclusivity. See exclusivity EU, 159–165
Regulatory Intelligence Network Group of the Drug filing expectation in strategic document, 13
Information Association, 23 Japan, 165–169
Regulatory Intelligence (RI), 23–30 US, 155–159
advisory committee meeting materials, 25 regulatory strategy
from Advisory Committee Meetings, 35 clinical development planning, 89–98
agency Twitter handles, 28t CMC regulatory strategy, 79–88
clinical trial databases, 27, 27t global, 187–204
competitive product landscape, 39t implementation of, 14–15
databases for, 25–26, 25t medical writing in, 235–242
drug approval summaries, 24–25 overview, 1–8
freedom of information requests, 27–28 pediatric products, 117–132
guidance documents, 25 role of regulatory professional in, 1
guidance documents for, 25 regulatory team, 9–10
intelligence definition/sources, 23, 23t advertising/promotional professional, 16–17
laws/regulations websites, 24 CMC professional responsibilities, 11–12
overview of sources for, 23t defined, 9–10
precedents and, 34–36 device and CoDx activities, 17–18
professional associations, 26–27, 26t global lead responsibilities, 11
regional laws and regulations, 24 global regulatory team, 10–11
regulatory journals, 40t labeling development, 16
SEC filings, 27 market access activities, 18–20
subscription update web pages, 28, 28t operations member activities, 15
surveillance, 28 organization for TPP assembly, 53–55
tools and resources for, 39–40 program manager duties, 18
websites recommendations, 20
regional product regulations, 24t recommendations for, 20
regulatory authority, 23–24 regional/local lead responsibilities, 12–14
regulatory interactions/communications, 145–154 regulatory policy role in, 15–16
agency meeting timeline, 148–149 writer’s activities, 14–15
benefits from, 145–147 reimbursement
dispute resolution, 153–154 global regulatory strategy/plan, 191
informal questions in, 149 regulatory team role in, 18–20
marketing and regulatory, 190f strategic planning for, 17
meeting types, 150–153, 152t Remicade (infliximab), 227–228, 228t
milestones for meetings, 36, 148 reproductive toxicity
objectives for sponsor-regulator, 146t biotechnology-derived therapeutics with, 62
questions types for, 147t guidelines for (S5(R3)), 64
regional differences in timing of, 148–149 reproductive toxicity studies, 64, 65, 72
regulatory meetings for global registrations, 202 Republic of Korea (MFDS) ICH status, 60
relationships in, 149 Response-to-Questions (RTQs), 20
responsibility for, 149–150 Rest of World (ROW)
Scientific Advice meetings, 149 market development in, 86
SPAs for clinical trials, 150 organizations in, 79
strategy for, 36–37 See also emerging markets
written communications, 148 Restasis (cyclosporine), 231
yield from, 147–148 risk assessment and mitigation
regulatory meetings. See Advisory Committee for CoDx use in clinical trials, 134
Meetings; regulatory interactions/communications QTTP/CQAs in, 53
regulatory pathways, 155–186 in strategic document, 14

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 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

Risk Management Plan (RMP) regulatory lead and, 11

for global products, 198 roles/responsibilities of, 235–242
requirements for, 53 team members as, 5
Ryzodeg (insulin degludec and insulin aspart), 225 Subsequent Entry Biologics (SEBs), 170. See also
biologics
summaries of safety and effectiveness (SSED), 137
S Summary Basis of Approval (SBA/SBoA), 35, 46
SAKIGAKE designations, 27 Summary Basis of Decisions (SBDs), 35
Scientific Advice meetings, 149 Sweden: Medical Products Agency, 25
Scientific Advice Working Party (SAWP), 153 Swissmedic, 60
Securities and Exchange Commission (SEC) database, Switzerland
27 ICH guideline acceptance, 195
Seldane (terfenadine), 230 ICH membership, 60
serious adverse events (SAEs) reporting, 102 regulatory geography, 79
Severely Toxic Dose, nonclinical evaluation of, 67 systems and response-driven pathways, 59
Singapore (HSA) ICH status, 60
six-party consensus (ICH guidelines), 60
T
Small and Medium Enterprise (SME) office, 127
small business exemption, 157 Target Product Label (TPL) in GRP, 33
small molecules Target Product Profiles (TPPs), 45–56
chronic toxicity testing, 75 asset characterization, 52–53, 54t
FDA divisions responsible for, 59 compiling of, 48f, 49–52, 50t
human dosing of, 69 key elements of, 47–49
immunotoxicity (S8) studies, 66–67 asset characterization, 52–53
M3(R2) guidance on, 62 properties/attribute definition in, 47
preclinical safety evaluation, 64 risk assessment and mitigation, 2
safety studies on, 65 nonclinical studies, 13
South African Development Community (SADC), 60 planning process for, 45f
Spain: CIMA website, 25 in regulatory guidance, 46–47
Special Protocol Assessments (SPAs), 150 safety information, 52t
species selection team organization for assembling, 53–55
factors in selection, 74 utility of, 45–46
ICH guidelines on, 62, 65 Tarius/Cortellis cross-country tables, 104
for nonclinical studies, 61 teduglutide: endpoint selection case study, 94
pharmacologic relevance of, 73 thalidomide disaster effects, 119
stand-alone pathway (Brazil), 183 Therapeutic Goods Administration (TGA)
Standard for Exchange of Nonclinical Data (SEND), biologicals regulation, 179f
70 biosimilar medicines regulation, 181
standard operating procedures (SOPs), 58, 149 freedom of information requests, 28
stereochemically pure drugs, 229 regulatory meetings with, 202
strategic document development scientific advice meetings, 153
critical elements of, 12–14 website, 24
development and goals of, 12 timelines
finance/business development, 16 for agency meetings, 148–149
goals and, 235–242 Australian application process, 180t
legal department, 16 Centralised applications, 162t
marketing, 17 for clinical development planning, 92f
medical affairs, 16 Decentralized Procedure, 164t
regulatory status, 16 FDA NDA review, 158t
reimbursement, 17 HPFB review timeframe, 171–172t
subject matter expert roles/responsibilities, 15 Mutual Recognition Procedure, 163t
timeline for, 14 PIP submission, 122
subject matter expert (SME) PIP submission contents and timeline, 122
document review by, 14 toxicology studies
in orphan drug designation request, 110 initiation of human trials, 61–62

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 Index

reproduction toxicity detections, 64 (FDAMA), 126

toxicokinetics (S3), 63 Food and Drug Administration Reauthorization Act
trade associations: influence on strategy, 15–16 (FDARA), 155
translations for clinical trial application planning, Food and Drug Administration Safety and
101–102 Innovation Act (FDASIA), 118, 121, 124
Treximet(formerly Trexima; sumatriptan and Freedom of Information Act, 27
naproxen), 230–231 Generic Drug User Fee Amendments, 154
Orphan Drug Act (ODA), 107–108, 114
U Patient Protection and Affordable Care Act, 158
Pediatric Research Equity Act (PREA), 68, 118,
unacceptable risk: exclusion case study, 96
121, 127
United Kingdom (UK)
Physician Payment Sunshine Act, 205
MHRA website, 25
Prescription Drug User Fee Act (PDUFA), 150,
pharmaceutical regulation geography, 79
210
regulatory approach for OTC switch, 231
Public Health Service Act (PHS Act), 158–159, 184
United States (US)
Research to Accelerate Cures and Equity (RACE),
adverse event reporting, 102
118
advisory committee meeting materials, 25
RI via Freedom of Information Act, 27
clinical trial databases, 27
Sunshine Act, 205
codification of regulations, 33–34
US regulatory pathways
CoDx requirements for, 137–138
ANDAs for drugs, 158
guidance document access, 25
approval pathway for biologics and biosimilars,
ICH guideline adoption, 195
158–159
nonclinical laboratory study regulation, 58
approval pathways for drugs, 157–159
Orphan Drug Designation program (ODD), 107
approval pathways for drugs, biologics/biosimilars,
potential lawsuits in, 128
157–159
regulatory approach for OTC switch, 231
biologics, 158
regulatory authority website, 23
biosimilars and HCT/Ps, 158–159
unvalidated positive precedents, 35
drug/biologic expedited development, 159
US 505(b)(1) and 505(b)(2) NDA submissions,
expedited development programs, 159, 160t
157–158
NDAs for drugs, 157–158
for biologics, 155
regulatory exclusivity for, 155, 156t
pathways and exclusivity, 156t
regulatory pathways, 155–159
US 505(j). See Abbreviated New Drug Submission
review timeframes and fees, 155
US Food and Drug Administration. See Food and
Drug Administration
US laws and regulations V
21st Century Cures Act, 42 vaccines
Accelerated Approval Regulation (21 CFR drug approval summaries listings, 24
314.500), 138 ICH safety guidelines for, 64–65, 73
Animal Rule, 95 PIPs for, 118, 121
Biologics Price Competition and Innovation Act PREA exemption, 121
(BPCI Act), 158 registration procedures for, 158, 165, 182
Biosimilar User Fee Act (BsUFA), 151, 155 Vascepa case study, 151
Biosimilar User Fee Amendments (BsUFA II), Vokanamet (canagliflozin and metformin), 226
155–157 Voluntary Harmonisation Procedure (VHP), 38
Clinical Laboratory Improvement Amendments
(CLIA), 141 W
FDA Reauthorization Act (FDARA), 121
Federal Advisory Committee Act, 205 Women Of Child-Bearing Potential (WOCBP)
Federal Food, Drug, and Cosmetic Act (FD&C in IND-enabling package, 72
Act), 184 regional differences in trials for, 64
Food, Drug, and Cosmetic Act (FD&C Act), 155, toxicological studies for, 62
157 World Health Organization (WHO)
Food and Drug Administration Modernization Act ICH observer status, 60
Similar Biological Product Guidelines, 183

256 All rights reserved; file sharing prohibited.

 Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition

stability testing condition guidance, 86

Written Request (WR)
for oral explanation from PDCO or FDA, 126
for PIP requirements, 121
for Priority Review, 170

X
Xigduo XR (dapagliflozin and metformin), 226
Xyzal (levocetirizine), 230

Z
Zarxio (filgrastim-sndz), 158
Zecuity (sumatriptan), 230
Zelrix (sumatriptan), 230
Zomig (zolmitriptan), 224–225
Zyrtec (cetirizine), 230

All rights reserved; file sharing prohibited. 257

All rights reserved; file sharing prohibited.
 William K. Sietsema, PhD
William K. Sietsema, PhD, is vice president, global regulatory Affairs at Caladrius
Biosciences, a company that focuses on innovative cell therapies a difficult-to-
treat diseases. Previously, he was global regulatory lead at Amgen, where he
provided strategic guidance to a portfolio of early-stage projects in oncology and
inflammation. Sietsema also was vice president, global regulatory consulting
and submissions at Kendle International/INC Research and adjunct professor
of pharmaceutical sciences at the University of Cincinnati College of Pharmacy,
where he taught evening classes in drug development. He has 35 years of
experience in the pharmaceutical industry. With Kendle/INC, Sietsema brought
leadership to several initiatives in the fields of inflammation, skeletal disease,
analgesia, gastrointestinal disease, ophthalmology and women’s health. He has
authored 40 journal articles, six book chapters, 73 presentations and posters and
holds six patents. He has published six books on regulatory topics ranging from
strategic planning to practical aspects of preparing CTAs and MAAs. Sietsema
holds a PhD in biochemistry from the University of Wisconsin, Madison. He is a
member of the American Chemical Society, the Regulatory Affairs Professionals
Society and the Association for Regenerative Medicine. He was recognized by
R&D Directions as one of the top 20 clinical research scientists in 2007.

Monica M. Meacham, PhD

Monica Meacham, PhD, is an associate director of regulatory affairs at
ImmunityBio, Inc., a privately held immunotherapy company. Previously, she
has held positions at NantKwest, Caladrius Biosciences and California Stem Cell.
Meacham has more than 11 years of experience in the development of cellular
and gene therapy products, primarily focusing on immunotherapy products for
oncology indications. She holds a PhD in biological sciences from the University
of California at Irvine (UCI), and was recruited into industry for her experience
with stem cells and cellular therapies. Meacham’s experience expanded into
the personalized medicine space as she stepped into a primary role in the
development of an autologous dendritic cell-based cancer immunotherapy.
She has established her career in the cancer immunotherapy space advancing
several cutting-edge technologies, including personalized next-generation
neoepitope cancer vaccine and an IL-15 superagonist, which was recently
granted Breakthrough Therapy Designation. Meacham has authored nine journal
articles, two book chapters and 20 presentations and posters. She also mentored
graduate students from UCI during a summer program and been an invited
speaker for biology classes at UCI. She is a member of the Regulatory Affairs
Professionals Society (RAPS) and has co-chaired preconference workshops for
the annual RAPS Convergence.

ISBN: 978-1-947493-42-1

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