Handbook of Medical Device Regulatory Affairs in Asia
Second Edition 2nd Edition
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British Library Cataloguing-in-Publication Data
A catalogue record for this book is available from the British Library.
Handbook of Medical Device Regulatory Affairs in Asia (Second
Edition)
Copyright © 2018 Pan Stanford Publishing Pte. Ltd.
All rights reserved. This book, or parts thereof, may not be reproduced in any
form or by any means, electronic or mechanical, including photocopying,
recording or any information storage and retrieval system now known or
to be invented, without written permission from the publisher.
For photocopying of material in this volume, please pay a copying fee
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Danvers, MA 01923, USA. In this case permission to photocopy is not
required from the publisher.
ISBN 978-981-4774-31-4 (Hardcover)
ISBN 978-0-429-50439-6 (eBook)
Contents
Preface xxxiii
1. How to Train University Students in Regulatory Affairs 1
Raymond K. Y. Tong
1.1 Introduction 1
1.2 A Sample of Regulatory Affairs Exercises for
Students 2
1.2.1 Background 2
1.2.2 Lifelong Learning 4
Part 1: Introduction
2. The Evolution of the Regulatory Professional: Perspectives
on the Skill Sets and Capabilities That Will Define the Next
Generation of Regulatory Professionals 7
David Martin and Neil Lesser
2.1 Introduction 7
2.2 Drivers of Change 8
2.3 Historical Role and Skill Set of a Regulatory
Professional 10
2.4 Changing Role and Skill Set of the Regulatory
Professional 12
2.5 Develop as a Center of Intelligence 12
2.6 Advance toward Strategic Relationship
Management 13
2.7 Develop as a Strategic Business Partner 13
2.8 Conclusion: What Will It Take to Get There? 14
3. The Role of the Asia Regulatory Affairs Team in Relation
to the Commercial Team and Other Departments 17
Fredrik Dalborg
3.1 Introduction 17
vi Contents
3.2 Key Trends in the Asia Medical Device Industry 18
3.3 The Role of the Asia RA Team in a Global Medical
Device Organization 19
3.4 Coordination between Commercial Teams and
RA Teams 20
3.5 The Role of the RA Team during the Different
Stages of a Product Life 21
3.5.1 Product Development 21
3.5.2 Market Introduction 21
3.5.3 Product Maintenance 22
3.5.4 Product Phase-Out 22
3.6 The RA Professional: A Trusted Advisor 23
3.7 Summary 24
4. Commercial Sense and What It Means for a Regulatory
Manager or Executive 25
Annie Joseph
4.1 Know the Basics 26
4.1.1 Marketing or Commercial Plan 26
4.1.2 Priority Products and How They Are
Ranked in the Company 27
4.1.3 Know Your Commercial People 27
4.2 Maintain a Healthy Communication 27
4.3 Be Proactive and Part of the Solution 27
4.4 Remain the Expert and Provide Clarity to the
Organization 29
4.5 Be a Champion for New Product Launches 29
5. Medical Device Regulatory Strategy: Product
Development and Product Registration in Asia and
Globally 35
May Ng, Martin Ng, Ray Soh, Fadzlon Yunos, and Stephen Hsu
5.1 Introduction 35
5.2 Information in Regulatory Strategy 36
5.2.1 Device Name 36
5.2.2 Device Description 37
Contents vii
5.2.3 Intended Use 37
5.2.4 Country of Interest 38
5.2.5 Device Classification 38
5.2.6 Product Registration or Conformity
Assessment Route and Its Approval
Timeline 39
5.2.7 Technical Documentation Requirement 39
5.2.8 Quality Management System Requirement 39
5.2.9 Clinical Assessment 40
5.2.10 Reimbursement Assessment 40
5.3 Conclusion 40
6. Regulatory Affairs as a Business Partner 43
Claudette Joyce C. Perilla
7. Introduction to Regulatory Affairs Professionals’ Roles 47
Dacia Su
8. What It Means to Be a Medtech Regulatory Journalist 51
Amanda Maxwell
9. Affordable Access to Medical Devices in Developing
Countries 57
Rosanna W. Peeling and Tikki Pang
9.1 Introduction 57
9.2 Why Is Affordable Access to Medical Devices
Important for Developing Countries? 58
9.2.1 Emergency Preparedness 59
9.2.2 Efficiency and Effectiveness of Health
Systems 59
9.2.3 Health Equity 60
9.3 Case Studies 61
9.3.1 Delay in Eligibility to Treatment for HIV 61
9.3.2 Delay in Access to Early Diagnosis of
Tuberculosis 62
9.3.3 Misleading Claims of Test Performance
for Dengue Rapid Tests 62
viii Contents
9.3.4 Case Study—Access versus Performance:
Basis for FDA Approval of the First
Over-the-Counter Rapid HIV Test in the
United States 63
9.3.4.1 Background 63
9.3.4.2 Performance expectations 63
9.3.4.3 Risk benefit analysis 64
9.4 The Way Forward 65
10. Regulatory Specialists in Medical Devices in Europe:
Meeting the Challenge of Keeping Current in a Changing
Environment—How TOPRA Supports Professionals in a
Dynamic Industry 69
Lynda J. Wight
10.1 The European MedTech Environment 69
10.2 What Is TOPRA? 71
10.3 Why Be a TOPRA Member? 71
10.4 What Support Is Offered? 72
10.4.1 Competency Frameworks 72
10.4.2 Training and Development 73
10.4.3 Education 74
10.4.4 Networks and Collaborations 75
10.4.5 Information 75
10.5 Looking to the Future 75
Part 2: Medical Device Safety and Related ISO Standards
11. Biomedical Devices: Overview 79
Piu Wong
11.1 Historic Aspect of Medical Devices 79
11.2 Biomedical Market Environment 81
11.3 Orthopedics 82
11.3.1 Market 82
11.3.2 Materials 83
11.3.3 Biocompatibility 83
Contents ix
11.3.4 Fabrication 84
11.3.5 Polyethylene Fabrication 84
11.4 Vision Care 86
11.4.1 Market 86
11.4.2 Diagnostic Devices 86
11.4.3 Treatment 87
11.5 Diabetics 88
11.6 Obesity 88
11.7 Vascular Disease 88
11.8 Concluding Remarks 89
12. Labeling, Label, and Language: A Truly Global Matter 93
Evangeline D. Loh and Jaap L. Laufer
12.1 Introduction 93
12.2 Definition of Labeling 95
12.3 Elements of Labeling 97
12.4 Risk Management, Clinical Evaluation and
Labeling: The Core Triangle for Safe and Effective
Use of the Device 99
12.5 Labeling and Promotion 101
12.6 e-Labeling, Web Sites, Internet, and Social Media:
A Brave New World for Labeling 101
12.7 Language, Language Level, and Intended User 103
12.8 Conclusion 105
13. Regulatory Affairs for Medical Device Clinical Trials
in Asia Pacific 107
Seow Li-Ping Geraldine
13.1 Introduction 107
13.2 Medical Device Clinical Trials versus
Pharmaceutical Clinical Trials 108
13.3 Regulation of Clinical Trials 111
13.4 Country Regulations 117
13.4.1 Australia 117
13.4.2 China 119
Contents
13.4.3 Hong Kong 120
13.4.4 India 120
13.4.5 Malaysia 121
13.4.6 New Zealand 121
13.4.7 Singapore 122
13.4.8 South Korea 123
13.4.9 Taiwan 124
13.4.10 Thailand 125
13.5 Moving Ahead as Regulatory Affairs
Professionals 125
14. Medical Device Classification Guide 129
Patricia Teysseyre
14.1 How to Carry Out Medical Device Classification 129
14.1.1 Scope 129
14.1.2 Definitions 130
14.2 Main Classifications 131
14.2.1 Medical Devices 131
14.2.2 Active Devices 131
14.2.3 IVD Devices 132
14.2.4 IVD Case Study 134
14.2.4.1 US FDA 135
14.2.4.2 Canada 135
14.2.4.3 EU 136
14.2.4.4 Singapore 137
14.3 Medical Device Classification: Practical Examples 137
15. ISO 13485:2003/2016—Medical Devices—Quality
Management Systems—Requirements for Regulatory
Purposes 153
Gert Bos
15.1 Introduction 153
15.2 Background and Origins of ISO 13485:2003 154
15.3 Quality Management Systems 156
Contents xi
15.4 ISO 9000 and ISO 13485 Quality Management
System Family of Standards 158
15.5 Global Regulatory Footprint of ISO 13485:2003 158
15.6 Implementing an ISO 13485:2003 Quality
Management System 159
15.7 Process Approach 160
15.8 Planning the Implementation 161
15.9 Scope, Exclusions, and Non-Applicability 162
15.10 Document Control 162
15.11 Record Completion and Control 163
15.12 Management Responsibility 164
15.13 Resource Management 164
15.14 Product Realization 165
15.15 Risk Management 165
15.16 Design and Development 165
15.17 Purchasing and Supplier Control 168
15.18 Production and Service Provision 169
15.19 Monitoring and Measuring, Including Internal
Audits and Management Review 170
15.20 Control of Non-Conforming Product 170
15.21 Analysis of Data 171
15.22 Improvement: Corrective Action and Preventive
Action 171
15.23 Purpose and Goal of ISO 13485:2003 Certification 172
15.24 Achieving Certification and Continuing to
Maintain Certification 172
16. ISO 14971: Application of Risk Management to Medical
Devices 175
Tony Chan and Raymond K. Y. Tong
16.1 Introduction 175
16.2 The Foundation of a Risk Management Framework:
Policy, Plan, Team, Process, and Documentation 179
16.2.1 Policy 179
16.2.2 Plan 179
xii Contents
16.2.3 Team 179
16.2.4 Process 180
16.2.5 Documentation 180
16.3 The RM Process 180
16.3.1 Analyze Risk 180
16.3.2 Evaluate Risk 181
16.3.3 Control Risk 181
16.3.4 Feedback from Production and
Post-Production Information 183
16.4 Conclusion 184
16.5 Case Study—An Example to Illustrate Risk
Management on a Medical Device: Functional
Electrical Stimulation System for Walking 184
16.5.1 Risk Management Process 186
17. Medical Devices: IEC International Standards and
Conformity Assessment Services in Support of
Medical Regulation and Governance 193
Gabriela Ehrlich
17.1 Introduction 193
17.2 What Is an IEC International Standard? 195
17.3 How Are IEC International Standards Developed? 195
17.4 IEC International Standards for Medical Devices 196
17.5 Conformity Assessment for Medical Devices 198
17.6 Conclusion 200
18. Introduction of Good Submission Practice 201
Isao Sasaki
18.1 Introduction 201
18.2 Concept of Good Registration Management 202
18.3 Principles of Good Submission 203
18.4 Management of Submission 204
18.4.1 Planning for Submission 204
18.4.2 Preparation and Submission of
Application Dossier 205
Contents xiii
18.4.3 Quality Check 207
18.5 Communications 208
18.5.1 Communications with the Review
Authorities 209
18.5.2 Communication within Applicants’
Organization 211
18.6 Competencies and Training 212
18.6.1 Core Competency of Applicants 212
18.6.2 Training and Capacity Building 213
18.7 Conclusion 214
Part 3: Medical Device Regulatory System in the United
States, European Union, Saudi Arabia, and Latin America
19. United States Medical Device Regulatory Framework 217
James Bertram
19.1 Introduction 217
19.2 The FDA Center for Devices and Radiological
Health 218
19.3 Legislation and Device Laws 219
19.3.1 FDA Law vs. FDA Regulations vs. FDA
Guidance 219
19.4 The Regulatory Environment for Bringing a
Medical Device to Market 220
19.5 Regulatory Considerations for Medical Devices 221
19.5.1 Definition of Medical Devices 221
19.5.2 Classification of Medical Devices 222
19.5.2.1 General controls 225
19.5.2.2 Special controls 225
19.5.2.3 Premarket approval 226
19.5.3 Convenience Kits 226
19.5.4 Labeling 226
19.5.5 Adulteration and Misbranding 227
19.5.6 Establishment Registration and Medical
Device Listing 227
xiv Contents
19.5.7 Quality System Regulation/Good
Manufacturing Practices 228
19.5.8 Medical Device Reporting 229
19.5.9 Unique Device Identification 229
19.5.10 User Fees 230
19.6 Premarket Submissions for Medical Devices 231
19.6.1 eCopy Program for Medical Device
Submissions 231
19.6.2 Premarket Notification 231
19.6.2.1 Predicate device and
substantial equivalence 232
19.6.3 De Novo Request 233
19.6.4 Premarket Approval Application 234
19.6.5 Investigational Device Exemption 235
19.6.6 Presubmission: Requesting Feedback 236
19.6.7 Promoting Innovation: Expedited Access
Program 236
19.7 Summary 237
20. Regulation of Combination Products in the United States 239
John Barlow Weiner and Thinh X. Nguyen
20.1 What Products Are Considered Combination
Products 240
20.2 The Standards for Determining If a Product
Is a Combination Product 240
20.3 The Standards for Determining Which FDA
Component Has Primary Responsibility for
Regulating a Combination Product 242
20.4 Requests for Designation 243
20.5 Premarket Review Considerations 244
20.6 Post-Market Regulatory Considerations 245
20.7 Role of Office of Combination Products 246
20.8 International Harmonization and Coordination
Activities with Foreign Counterparts 246
20.9 FDA Resources for Obtaining Additional
Information 247
Contents xv
21. European Union: Medical Device Regulatory System 249
Arkan Zwick
21.1 Glossary of Terms 249
21.2 European Union: Medical Device Market and
Structure 251
21.3 New Approach: Global Approach Concepts 253
21.4 Harmonized Standards and Presumption of
Conformity 254
21.5 European Associations 256
21.6 Overview of Medical Devices Directives 259
21.7 Guidelines 260
21.8 Definitions 261
21.8.1 Medical Device 261
21.8.2 CE Mark 262
21.8.3 Competent Authority 263
21.8.4 Notified Body: Conformity Assessment
Body 264
21.8.5 Legal Manufacturer 265
21.8.6 Authorized Representative 266
21.9 Classification 267
21.9.1 Medical Devices 267
21.9.2 Active Implantable Medical Devices 268
21.9.3 In vitro and Diagnostics Medical Devices 269
21.10 Conformity Assessment Procedures 270
21.11 Essential Requirements 274
21.12 Labeling 277
21.13 Technical Documentation 278
21.14 Quality Management System 279
21.15 Risk Management 285
21.16 Clinical Evaluation 285
21.17 CE Mark Certificate and Declaration of Conformity 287
21.18 Post-Market Surveillance 288
21.19 Evolution of MDD 93/42/EEC and Impacts 289
21.20 The New EU Regulation 2017/745 on Medical
Devices 292
xvi Contents
21.21 Timetable 293
21.22 General Safety and Performance Requirements 293
21.23 Stronger Notified Body Oversight 294
21.24 Economic Operators 294
21.25 Clinical Evidence, Post-Market Follow-Up, and
Risk Reviews 294
21.26 PSUR/PMCF Reports 295
21.27 Eudamed 295
21.28 Overview of All Interactions and Key
Terminology 296
22. Regulation of Combination Products in the European
Union 299
Janine Jamieson and Elizabeth Baker
22.1 Introduction: Legal Basis 299
22.1.1 Definitions 300
22.1.1.1 Medical device 300
22.1.1.2 Medicinal product 301
22.1.1.3 Combination products:
Principal mode of action 302
22.1.1.4 Borderline products: MEDDEV
2.1/3 303
22.1.1.5 Borderline products: Manual
of decisions 303
22.2 Combination Products Regulated as Medicinal
Products 303
22.2.1 Examples of Combination Products
Regulated as Medicinal Products 304
22.3 Combination Products Regulated as Medical
Devices 304
22.3.1 Examples of Combination Products
Regulated as Drug-Delivery Devices 304
22.4 Combination Products Regulated as Devices
Incorporating, as an Integral Part, an Ancillary
Medicinal Substance 305
