Building on the success of its predecessor, this second edition of the hands-on guide to how pharmaceutical and medical devices are regulated within the major global markets has an even wider scope and now features case studies. The new EU-framework and US regulations are also fully integrated.
The textbook is based on a module prepared by the authors for an MSc course. This and its broad coverage make it an ideal resource for training purposes in both industry and academia. It is equally a valuable reference for all scientists needing to familiarize themselves with the topic.

J.J. Tobin worked for many years and in various capacities within Olympus diagnostica GmbH, a company employing several 100 people who develop and manufacture in vitro diagnostic reagents. Dr. Tobin therefore has extensive experience of working within an FDA and European medical device regulatory framework.

Gary Walsh is an associate professor of industrial biochemistry at the University of Limerick, Ireland. He has direct industrial experience within the pharmaceutical industry, as well as extensive teaching and non-laboratory based research interests in the pharmaceutical biotechnology arena. He has published a number of books, book chapters and journal articles relevant to this publication. He also has taught elements of pharmaceutical science and regulatory affairs on an annual course provided by the University of Limerick to an international medical device company with a manufacturing facility based in the region.

Contents
Preface XIII
1 The Aims and Structure of Regulations 1
1.1 Introduction 1
1.2 Purpose and Principles of Regulation 1
1.3 The Legal Framework for Regulation 3
1.3.1 National Legislative Process 3
1.3.2 EU Legislative Process 4
1.3.3 Working with Legal Texts 5
1.3.4 Guidance Documents 6
1.3.5 Pharmacopoeia 7
1.4 Basic Legislation 7
1.4.1 EU Legislation 7
1.4.2 US Legislation 11
1.5 Scope of the Legislation 16
1.6 Chapter Review 19
1.7 Further Reading 19
2 Regulatory Strategy 21
2.1 Chapter Introduction 21
2.2 Basic Regulatory Strategy 21
2.2.1 Product Development 21
2.2.2 Product Manufacture 21
2.2.3 Market Vigilance 22
2.3 Quality Assurance Systems 22
2.3.1 Personnel 23
2.3.2 Documentation 24
2.3.3 Facilities and Equipment 25
Medical Product Regulatory Affairs. John J. Tobin and Gary Walsh
Copyright 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
ISBN: 978-3-527-31877-3
V
2.3.4 Corrective and Preventive Action 25
2.4 Validation 26
2.5 Regulatory Bodies 27
2.5.1 European Commission 27
2.5.2 The EMEA 29
2.5.3 National Competent Authorities 30
2.5.4 Notified Bodies 32
2.5.5 The FDA 32
2.5.6 US Department of Agriculture 35
2.5.7 Pharmacopoeia Authorities 36
2.6 International Harmonisation Bodies 36
2.7 International Conference on Harmonisation 36
2.7.1 VICH 39
2.7.2 The Global Harmonisation Task Force 39
2.8 Pharmaceutical Inspection Cooperation Scheme 40
2.9 The World Health Organization (WHO) 42
2.10 Chapter Review 42
2.11 Further Reading 42
3 Drug Discovery and Development 43
3.1 Chapter Introduction 43
3.2 Drug Categorisation 43
3.2.1 Prescription Status 43
3.2.2 Physical Properties 44
3.2.3 Mode of Action 44
3.2.4 Therapeutic Use 45
3.3 Drug Discovery 45
3.4 Drug Development 50
3.5 Drug Delivery 52
3.5.1 Location 52
3.5.2 Drug Characteristics 52
3.5.3 Speed and Duration of Therapeutic Effect 53
3.5.4 Stability 55
3.6 Chapter Review 55
3.7 Suggested Reading 55
4 Non-Clinical Studies 57
4.1 Chapter Introduction 57
4.2 Non-Clinical Study Objectives and Timing 57
4.3 Pharmacological Studies 58
4.3.1 Pharmacodynamic Studies 59
4.3.2 Pharmacokinetic/Toxicokinetic Studies 62
4.4 Bioavailability and Bioequivalence 64
4.5 Toxicology Studies 65
VI Contents
4.5.1 Toxicity Studies 65
4.5.2 Genotoxicity Studies 66
4.5.3 Carcinogenicity Studies 67
4.5.4 Reproductive Toxicology Studies 67
4.6 Chemistry, Manufacturing and Control Development
(CMC) 67
4.7 Quality of Biotech Products 68
4.7.1 Stability Studies 68
4.8 Good Laboratory Practice (GLP) 69
4.9 Chapter Review 69
4.10 Further Reading 71
5 Clinical Trials 73
5.1 Chapter Introduction 73
5.2 Clinical Trials 73
5.2.1 Phase I Trials 74
5.2.2 Phase II Trials 74
5.2.3 Phase III Trials 75
5.3 Clinical Trial Design 76
5.4 Good Clinical Practice 78
5.5 Clinical Trials in the EU 78
5.5.1 The Sponsor 80
5.5.2 The Investigator.s Brochure 80
5.5.3 The Investigator 81
5.5.4 The Trial Protocol 81
5.5.5 The Investigational Medicinal Product Dossier 82
5.5.6 Informed Consent 82
5.5.7 Manufacture of Investigational Medicinal Product 82
5.5.8 Competent Authority Clinical Trial Application 84
5.5.9 Independent Ethics Committee CTA 85
5.5.10 Amendments to Clinical Trials 87
5.5.11 Case Report Forms 87
5.5.12 Adverse Event Reporting 87
5.5.13 Annual Safety Report 88
5.5.14 Monitoring of Trials 88
5.5.15 End of Trial 88
5.5.16 Trial Master File 88
5.6 Clinical Trials in The US 89
5.6.1 Investigational New Drug Application (IND) 89
5.6.2 Institutional Review Board 91
5.6.3 Communication with the FDA 94
5.6.4 Labelling of Investigational Drugs 95
5.7 Chapter Review 95
5.8 Further Reading 95
Contents VII
6 Marketing Authorisation 97
6.1 Chapter Introduction 97
6.2 The Application Dossier 97
6.3 CTD 98
6.3.1 Module Structure 101
6.3.2 Module 3: Quality 101
6.3.3 Drug Master Files 104
6.3.4 Module 4: Non-Clinical Study Reports 105
6.3.5 Module 5: Clinical Study Reports 105
6.3.6 Module 2: Summaries 107
6.3.7 Module I: Region-Specific 110
6.3.8 Module 1: EU 110
6.3.9 Module 1: US 113
6.4 Submission and Review Process in the EU 114
6.4.1 Community Authorisation 114
6.4.2 Scientific Evaluation Process 119
6.4.3 Decision-Making Process 120
6.4.4 National Authorisations 121
6.4.5 Decentralised Procedure 121
6.4.6 Mutual Recognition Procedure 123
6.4.7 Plasma Master Files and Vaccine Antigen Master Files 124
6.5 Submission and Review Process in the US 124
6.6 Chapter Review 127
6.7 Further Reading 127
7 Authorisation of Veterinary Medicines 129
7.1 Chapter Introduction 129
7.2 Overview of Development Process for Veterinary
Medicines 129
7.2.1 Pre-Clinical Studies 130
7.2.2 Clinical Trials 131
7.2.3 Good Clinical Practices 131
7.3 Authorisation of Clinical Trials in the EU 134
7.4 Authorisation of Clinical Trials in the US 135
7.5 Maximum Residue Limits 136
7.6 Authorisation of Veterinary Medicines in the EU 138
7.6.1 Applications to Establish MRLs 138
7.6.2 Review of Applications and Establishment of MRLs 138
7.6.3 Marketing Authorisations 142
7.6.4 Presentation of the Dossier 143
7.7 Approval of Veterinary Medicines in the US 144
7.7.1 New Animal Drug Application 144
7.7.2 Approval of Veterinary Biological Products 147
7.8 Chapter Review 148
7.9 Further Reading 148
VIII Contents
8 Variations to the Drug Authorisation Process 149
8.1 Chapter Introduction 149
8.2 Provisions in Support of Special Drug Applications 149
8.2.1 Orphan Drugs 149
8.3 Accelerated Access to New Drug Therapies 151
8.3.1 EMEA Accelerated Review 151
8.3.2 Compassionate Use 151
8.3.3 Fast-Track Products 152
8.3.4 Treatment INDs 152
8.3.5 Paediatric Applications 152
8.4 Approval of New Drugs when Human Efficacy Studies are
not Ethical or Feasible 153
8.5 Animal Drugs for Minor Use and Minor Species 153
8.5.1 Conditional Approval 153
8.5.2 Indexing 154
8.5.3 Designation 154
8.6 Use of Non-Authorised Drugs for Animal Treatment in the EU 154
8.7 Changes to an Authorised Drug 154
8.8 EU System for Processing Changes 154
8.8.1 Extension Applications 155
8.8.2 Major Variation (Type II) 155
8.8.3 Minor Variation (Type IA or IB) 156
8.9 Processing Changes in the US 156
8.9.1 Manufacturing Change Supplements 156
8.9.2 Major Changes 157
8.9.3 Moderate Changes 157
8.9.4 Minor Changes 157
8.10 Authorisation of Generic Drugs 158
8.10.1 EU Regulations 158
8.10.2 US Regulations 159
8.11 Reference Drug Exclusivity 159
8.12 Other Authorisation Procedures 161
8.12.1 Well-Established Medical Use Products 161
8.12.2 Combination Products 161
8.12.3 Homeopathic Medicines 161
8.12.4 Traditional Herbal Medicines 162
8.12.5 US Regulation of OTC Drugs 162
8.13 Chapter Review 164
8.14 Further Reading 164
9 Medical Devices 167
9.1 Chapter Introduction 167
9.2 Regulatory Strategy for Medical Devices in the EU 167
9.2.1 Use of Standards to Establish Conformity 168
9.2.2 Classification of Devices 170
Contents IX
9.3 Regulatory Strategy for Medical Devices in the US 173
9.3.1 Classification of Devices 173
9.3.1.1 Class I Devices 176
9.3.1.2 Class II Devices 177
9.3.1.3 Class III Devices 178
9.3.2 Classification of New Devices 178
9.4 Development of Devices 178
9.4.1 Design Controls 180
9.4.2 Design and Development Planning 180
9.4.3 Design Input 182
9.4.4 Design Output 182
9.4.5 Design Verification and Design Validation 183
9.4.6 Design Review 183
9.4.7 Risk Analysis 184
9.4.8 Design Changes 185
9.5 Chapter Review 185
9.6 Further Reading 185
10 Authorisation of Medical Devices 187
10.1 Chapter Introduction 187
10.2 Evaluation of Medical Devices in Europe 187
10.2.1 Clinical Investigations 188
10.2.2 Performance Evaluations 190
10.3 Evaluation of Medical Devices in the US 191
10.3.1 IDE-Exempted Investigations 191
10.3.2 Abbreviated Requirement Investigations 192
10.3.3 IDE Investigations 192
10.3.4 Labelling of Devices for Investigational Use 193
10.4 Placing of Devices on the Market in the EU 194
10.4.1 Conformity Assessment Procedures 195
10.4.2 Full Quality Assurance 197
10.4.3 EC Type-Examination 197
10.4.4 Production Quality Assurance 199
10.4.5 EC Verification 199
10.4.6 Product QA 199
10.4.7 EC (Self ) Declaration of Conformity 199
10.4.8 Technical Documentation 199
10.4.9 Labelling Requirements 200
10.4.10 Competent Authority Notifications and the European Databank 201
10.5 Placing of Devices on the Market in the US 202
10.5.1 510(k) Pre-market Notification 202
10.5.1.1 Traditional 510(k) 202
10.5.1.2 Abbreviated 510(k) 203
10.5.1.3 Special 510(k) 203
10.5.1.4 De Novo 510(k) 203
X Contents
10.5.2 Notification and Review Procedures 203
10.5.3 Pre-market Approval (PMA) 203
10.5.4 Changes to a PMA-Approved Device 205
10.5.5 Humanitarian Use Devices 206
10.5.6 Labelling of Devices 206
10.6 Chapter Review 206
10.7 Further Reading 208
11 Good Manufacturing Practice (GMP) 209
11.1 Chapter Introduction 209
11.2 Drug GMP Regulations and Guidance 209
11.3 Essential GMP Requirements 212
11.3.1 Quality Assurance System 212
11.3.2 Personnel 212
11.3.3 Premises and Equipment 213
11.3.4 Documentation 221
11.3.5 Production 222
11.3.6 Quality Control 222
11.3.7 Work Contracted Out 222
11.3.8 Complaints, Product Recall and Emergency Un-Blinding 223
11.3.9 Self-Inspection 223
11.4 Validation 223
11.4.1 Facilities and Equipment Validation 225
11.4.2 Process Validation 225
11.4.3 Computer Systems Validation 226
11.4.4 Methods Validation 227
11.4.5 Cleaning Validation 229
11.4.6 Validation of Sterilisation Procedures 230
11.4.7 Water Purification System Validation 230
11.5 GMP Requirements for Devices 231
11.6 Chapter Review 234
11.7 Further Reading 235
12 Oversight and Vigilance 237
12.1 Chapter Introduction 237
12.2 Registration of Manufacturers and Other Entities 237
12.3 Manufacturing Authorisation of Medicinal Products in the EU 237
12.3.1 Wholesale Distribution of Medicinal Products 238
12.3.2 Registration of Persons Responsible for Placing Medical Devices
on the EU Market 240
12.4 Registration of Producers of Drugs and Devices in the US 241
12.4.1 Additional Licensing Requirements 242
12.5 Inspections 242
12.5.1 Inspection Techniques 245
12.5.2 Audit Findings and Consequences 248
Contents XI
12.6 Market Vigilance and Oversight of Drugs 253
12.6.1 Pharmacovigilance in the EU 254
12.6.2 Qualified Person 254
12.6.3 Reporting Requirements 254
12.6.4 Expedited Reports 255
12.6.5 Periodic Safety Update Reports 256
12.6.6 Safety Study Reports 256
12.6.7 Response to Issues 256
12.6.8 Renewal of Marketing Authorisations 258
12.6.9 Reporting Requirements in the US 258
12.6.10 Expedited Reports 258
12.6.11 Periodic Reports 262
12.7 Advertising and Promotion 262
12.8 Market Vigilance and Oversight of Devices 262
12.8.1 Market Vigilance in the EU 263
12.8.2 Medical Device Vigilance in the US 271
12.8.3 Medical Device Reporting 272
12.8.4 Reports of Corrections and Removals 273
12.8.5 Post-Market Surveillance 273
12.9 Chapter Review 274
12.10 Further Reading 274
Index 277
XII Contents