Drug Development Process
Dr Shivkumar Shete
Assistant Professor
Sree Dattha Istitute of Pharmacy
Subject : Clinical Research
Pharm.D 5th Year
New Drug Development is...
Expensive 500 – 800 Million US $
Time consuming 12 – 14 years
Cumbersome 1 out of 10,000 NCE
becomes a marketable drug
… and what will the Marketing outcome be?
1. Disease Targeting
CNS
Infectious Diseases
Oncology
Metabolic Diseases
Ophthalmology
Urology
Women’s Health
Inflammation
PHARMA- THE R&D PIPELINE
File File
IND Phase I Phase II Phase III NDA
Discovery Preclinical Clinical Approval
Research Research Development Phase
$ 802 M
3.5 years 1.5 years 5 years 2 years
7.41% 4.70%
33.37% 42.35%
of R&D of R&D
of R&D Budget of R&D Budget
Budget Budget
• IND - Investigational New Drug Application Production
• &
NDA - New Drug Application
Marketing
Development Phases
Drug development consists of two phases
Preclinical
Clinical
Objective of Preclinical phase
Discover and develop patentable drug candidates on targets
of relevance
Generate data that gives reasonable estimate of clinical
efficacy and safety
Provide enough evidence to obtain regulatory approval for
“first in human testing”
Lead Generation
Target identification
Identification of new, clinically relevant, molecular targets is of
utmost importance to the discovery of innovative drugs
Choose a disease
Choose a target
Current therapy is based upon less than 500 molecular targets
45% of which are G-protein coupled receptors
28% are enzymes
11% are hormones and factors
5% ion channels
2% nuclear receptors
Many more drug targets still exist! How to identify them?
Besides classical methods of cellular and molecular biology, new
techniques are becoming increasingly important
Genomics
Bioinformatics
Proteomics
Target validation
Involved in pathogenesis of disease
Can generate experimental model of clinical disease (Proof of
concept)
Possible to have compounds bind to active site
Lead Compound Identification
Compounds are identified which interact with the target
protein and modulate its activity
Screening of natural products
Fermentation (antibiotics)
Plant extracts (anticancer agents)
Chemical modification of natural products (semisynthesis)
Screening synthetic compound ʹlibrariesʹ
75 % of drugs are synthetic chemicals
Chemical modification of existing drugs
Captopril Enalapril, cilazapril
Starting from the natural ligand or modulator compounds
Salbutamol and isoprenaline are derived from adrenalin
New technologies used in Lead Identification
High-throughput Screening
Computer-aided drug design
Combinatorial chemistry/Parallel Synthesis
De-novo synthesis/Virtual screening
Pre-Clinical Development
Efficacy data – proof of concept (GLP)
Animal models of disease
Therapeutic dose calculations
Animal PK
Rodents
Large animals
Safety Pharmacology
Toxicology/Toxicokinetics
Efficacy Data
Experimental proof-of-concept
To be established before new drug can be given IND
The animal model Should provide predictable
information that is relevant to clinical effects
Disease specific animal models
Transgenic / knock out/ knock in animals
Pharmacokinetic Information
In vivo ADME
Bioavailability
Peak plasma concentration
Duration of drug action
Metabolic stability
Safety Evaluation
Safety pharmacology studies provide a dynamic and
flexible approach of the potential functional
disturbances induced by a new chemical entity
Many studies regarding vital functions can be carried
out very early, prior to clinical study, at single dose,
with short-term design, sometimes using in vitro
methods and with small amount of product
Safety Pharmacology
CNS studies
CNS Function Tests
Motor activity
Behavioral changes
Cardiovascular studies
ECG
Hemodynamic parameters
Respiratory function tests
Gastrointestinal motility studies
Hematological Evaluations
Blood Coagulation
Hepatic and Renal functional Status
Toxicology Studies
Preliminary (Range-Finding) Toxicity
Maximum tolerated dose (MTD)
Dose limiting toxicity's (DLT)
Up/Down toxicity study
Single/multiple dose range-finding
Subacute, Subchronic Chronic toxicity
Single or multiple dose
Duration: 2, 4, 13, 26 weeks
Toxicology Studies
Reproductive & Development Toxicology
Teratogenicity, Generation Studies
Genotoxicity
Ames Salmonella Test, Reverse
Mutation assay
In vivo micronucleus Test
Chromosomal Aberrations
In vitro Chromosomal Aberrations
Gene Mutations
IND Application
Documentation that allows investigational clinical
testing of a new medicine
The main purpose is to provide the data showing that it
is reasonable to begin tests of a new drug on humans
Must be filed with FDA before drug administered to
humans
Studies may begin within 30 days of application…..if no
response from the FDA
Content and Format of IND Application
A. Cover Sheet (FDA Form-1571)
B. Table of Contents
C. Introductory Statement and General Investigational Plan
D. Investigator's Brochure
E. Protocols
F. Chemistry, Manufacturing, and Control Information
1. Chemistry and Manufacturing Information
2. Drug Substance
a. A description of the drug substance, including its physical, chemical,
or biological characteristics
b. The name and address of its manufacturer
c. The general method of preparation of the drug substance
d. The acceptable limits and analytical methods used to assure the
identity, strength, quality, and purity of the drug substance
e. Information to support the stability of the drug substance during
the toxicologic studies and the proposed clinical study(ies)
3. Drug Product
a. A list of all components, which may include reasonable
alternatives for inactive compounds, used in the manufacture
of the investigational drug product
b. Where applicable, the quantitative composition of the
investigational new drug product
c. The name and address of the drug product manufacturer
d. A brief, general description of the method of manufacturing
and packaging procedures as appropriate for the product
e. The acceptable limits and analytical methods used to assure
the identity, strength, quality, and purity of the drug product
f. Information to support the stability of the drug substance
during the toxicologic studies and the proposed clinical study
4. A brief general description of the composition, manufacture, and
control of any placebo to be used in the proposed clinical trial(s)
5. A copy of all labels and labeling to be provided to each
investigator
6. A claim for categorical exclusion from or submission of an
environmental assessment
G. Pharmacology and Toxicology Information
1. Pharmacology and Drug Distribution
2. Toxicology: Integrated Summary
1. A brief description of the design of the trials and any deviations from
the design in the conduct of the trials
2. A systematic presentation of the findings from the animal toxicology
and toxicokinetic studies
3. Identification and qualifications of the individual(s) who evaluated
the animal safety data and concluded that it is reasonably safe to
begin the proposed human study
4. A statement of where the animal studies were conducted and where
the records of the studies are available for inspection
5. Whether the GLP requirements were fulfilled during the animal
experiments – if any non-compliance during the process; how does it
affect the findings of the study – implications in clinical studies
3. Toxicology - Full Data Tabulation
4. Toxicology - GLP Certification
5. Monitoring of Effects of these Clarifications
G. Previous Human Experience with the Investigational Drug
Pharmaceutical clinical trials are commonly classified into 4
phases: (as of 2006, there are now 5)
Phase 0 – Micro dosing Studies
Phase 1 – Dose ranging Studies
Phase 2 – Efficacy and Safety Evaluation
Phase 3 – Additional Efficacy and Risk Benefit Analysis
Phase 4 – Ongoing Safety and New Use Analysis
Phase 0 Studies
A recent designation for exploratory, first-in-human trials
Designed to expedite the development of promising therapeutic
agents by establishing early on whether the agent behaves in
human subjects as was anticipated from preclinical studies
Phase 0 is a pre-IND stage in which researchers are permitted to
test small doses of a potential drug in a small human sample
before filing INDA better inform the subsequent conduct of
phase I and II trials
Characteristics of Phase 0 Trials
Conducted before initiating phase I trials, with less extensive
toxicology and preclinical study needed than to conduct a phase
I trial
No therapeutic or diagnostic intent
Testing of a single dose of an agent, or very limited dose
expansion far below the maximum tolerated dose (MTD), over a
period < 7 days
Study limited to 6-15 patients
Benefits
Evaluate pharmacokinetics and pharmacodynamics of analogs
directed at a predefined target in order to select the most
promising candidates for further development
Determine whether mechanisms of action defined in nonclinical
trials can be obtained in humans, i.e., whether a drug binds to
or inhibits the alleged target, using human tumor tissue or
surrogate markers
Drawbacks:
Patients in a phase zero trial get only too small portion of the
IND and results may not be dependable and relevant
The laboratory and other parameters are very limited and very
expensive researchers have to depend on BA/BE labs
involved in use sensitive instrument in detecting the test articles
at micro-dose level
Phase 1 Studies
A small group of healthy volunteers selected to assess the safety,
tolerability, pharmacokinetics, and pharmacodynamics of a therapy
Normally include dose ranging studies
There are 3 common kinds of phase I trials:
Single Ascending Dose (SAD) studies- small patient group single dose
of drug; monitored over a period of time no adverse effects, the dose
is escalated for new group
Multiple Ascending Dose (MAD) studies- group of patients receives
multiple low doses of the drug; body fluids are collected at various time
points to analyze processing of drugs in body subsequent dose
escalation
Food effect- to investigate differences in absorption caused by food
before the dose is given
Objectives
Determine the metabolic and pharmacological actions and the
maximally tolerated dose
Factors to be identified
Bioavailability
Bioequivalence
Dose proportionality
Metabolism
Pharmacodynamics
Pharmacokinetics
Data Focus
Vital signs
Plasma and serum levels
Adverse events
Design Features
Single, ascending dose tiers
Unblinded
Uncontrolled
Duration
Up to 1 month
Study Population
Healthy volunteers or individuals with the target disease (such as
cancer or HIV)
Sample Size
20 to 80
Example
Study of a single dose of Drug X in normal subjects
Phase 2 Studies
Objectives
Evaluate effectiveness, determine the short-term side effects and
identify common risks for a specific population and disease
Factors to be identified
Bioavailability
Drug-disease interactions
Drug-drug interactions
Efficacy at various doses
Pharmakodynamics
Pharmakokinetics
Patient safety
Data Focus
Dose response and tolerance
Adverse events
Efficacy
Design Features
Placebo controlled comparisons
Active controlled comparisons
Well-defined entry criteria
Duration
Several months
Study Population
Individuals with target disease
Sample Size
200 to 300
Example
Double-blind study evaluating safety and efficacy of Drug X vs.
placebo in patients with hypertension
Phase 2a and 2b studies
Phase 2a: Pilot clinical trials to evaluate efficacy and safety in
selected populations of about 100 to 300 subjects who have the
disease or condition to be treated, diagnosed, or prevented
Dose-response
Type of patient
Frequency of dosing
Other issues involved in safety and efficacy
Phase 2b: Well-controlled trials to evaluate safety and efficacy
in subjects who have the disease or condition to be treated,
diagnosed, or prevented
Phase 3 Studies
Objectives
Obtain additional information about the effectiveness on
clinical outcomes and evaluate the overall risk-benefit ratio
in a demographically diverse sample
Factors to be identified
Drug-disease interactions
Drug-drug interactions
Dosage intervals
Risk-benefit information
Efficacy and safety for subgroups
Data Focus
Lab Data
Adverse events
Efficacy
Design Features
Randomized
Controlled
2 – 3 treatment arms
Broader eligibility criteria
Duration
Several years
Study Population
Individuals with target disease
Sample Size
Hundreds to Thousands
Example
Study of Drug X vs. standard treatment in hypertension study
Phase 3a and 3b Studies
Phase 3a: Conducted after the drug's efficacy is demonstrated
but before regulatory submission of the New Drug Application
(NDA)
Phase 3b: Trials are conducted after regulatory submission of
the NDA but prior to the drug's approval and launch
Called as peri-approval studies and may supplement or complete
earlier trials, or they may seek different kinds of information –
QOL, Economic impacts
Phase 4 Studies
Objectives
Monitor ongoing safety in large populations and identify
additional uses of the agent that might be approved by the
FDA
Factors to be identified
Epidemiological data
Efficacy and safety within large, diverse populations
Pharmacoeconomics
Data Focus
Efficacy
Pharmacoeconomics
Epidemiology
Adverse events
Design Features
Uncontrolled
Observational
Duration
Ongoing (following FDA approval)
Study Population
Individuals with target disease, as well as new age groups,
genders, etc
Sample Size
Thousands
Example
Study of economic benefit of newly-approved Drug X vs. standard
treatment for hypertension
Essential documents
The documents that permit evaluation of the conduct of a study and
the quality of the data generated
1. Approval of the IRB/IEC on study protocol
2. Translated documents
3. Import license for trial products
4. Signed confidentiality agreement
5. Investigator brochure
6. Financial agreement
7. CV of investigator and co-investigator
8. Insurance agreement
9. CRF
10. Lab certification
Investigator
A person responsible for the conduct of the study at the study
site. Investigator is responsible for the rights, health and welfare
of the study subjects
Co Investigator
A person legally qualified to be an investigator to whom the
principal investigator delegates part of his responsibilities
Coordinator
A coordinator coordinates the trial process and acts as liaison
between the investigator, and the sponsor and study subjects in
order to complete the trial process
Investigator’s brochure
A collection of data for the investigator consisting of all the
clinical as well as non clinical information available on the
investigational products known prior to the onset of the trial
There should be adequate data to justify the nature, scale and
duration of the proposed trial and to evaluate the potential
safety and need for special precautions. If new substantially
relevant data is generated during the trial, the information in
the investigator’s brochure must be updated
Monitor
A person appointed by the sponsor or CRO for
monitoring and reporting the progress of the trial and
for verification of the data
The monitor ensures that the trial is conducted,
recorded and reported in accordance with the
Protocol, Standard Operating Procedure, Good Clinical
Practice and the applicable regulatory measurements.
Investigational Product
A Pharmaceutical product being tested or used as reference in a
clinical study. An investigational product may be an active
chemical entity or a formulated dosage form
Multi centric study
A clinical trial conducted according to one single protocol in
which the trial is taking place at different investigational sites,
therefore carried out by more than one investigator
Informed consent
Voluntary written assent of a subjects’ willingness to participate
in a particular study and in its documentation
The confirmation is sought only after information about the trial
including an explanation of its status as research, its objectives,
potential benefits, risks and inconveniences, alternative
treatment that may be available and of the subject’s rights
responsibilities has been provided to the potential subject
Inspection
An official review / examination conducted by regulatory
authority of the documents, facilities, records and any other
resources that are deemed by the authority related to the study
The inspection may be carried out at the site / at the sponsor’s /
CRO’s facility in order to verify adherence
Protocol
A document that states the background, objectives,
rationale, design, methodology and statistical considerations
of the study. It also states the conditions under which the
study shall be performed and managed
Randomization
The process of assigning study subjects to either the treatment
or the control group
Randomization gives all subjects the same choice of being in
either group in order to reduce bias
Raw data
It refers to all records or certified copies of the original clinical
and laboratory findings or other activities in a clinical study
necessary for the reconstruction and evaluation of the trial.
Final report
A complete and comprehensive description of the study after its
completion
It includes description of experimental and statistical methods
and materials presentation and evaluation of the results,
statistical analyses and a critical ethical, statistical and clinical
appraisal
References :
Textbook On Clinical Research A Guide For Aspiring
Professionals And Professionals by Guru Prasad Mohanta
Principles of Clinical Research by Authors: R. B. Ghooi
https://pharmadost.info/clinical-research-pharmd-notes/
