Contents:

CHAPTER 1 INTRODUCTION AND EU OVERVIEW 1 1.1 Origins and purposes of regulation 1 1.1.1 Early British regulation 2 1.1.2 Modern regulation 2 1.1.3 Development of US regulations 4 1.2 Basic elements and approaches in regulation 4 1.2.1 Safety 4 1.2.2 Quality 5 1.2.3 Efficacy 6 1.2.4 Promotion 7 1.3 EU Institutions and Legislation 7 1.3.1 Paediatric Legislation 9 1.4 Approaches to EU Registration 10 1.4.1 Centralised 10 1.4.2 Mutual Recognition 11 1.4.3 Decentralised 11 1.4.4 National 13 1.5 Role of the Regulatory Affairs professional 13 1.5.1 Interactions within the company 14 1.5.2 External Interactions 15 1.6 Conclusion 16 CHAPTER 2 US AND INTERNATIONAL OVERVIEW 17 2.1 Introduction 17 2.1.1 Modern regulation 18 2.2 US FDA Regulatory overview 19 2.2.1 Investigational New Drug (IND) application 19 2.2.2 New Drug Application (NDA) 20 2.2.3 Review 20 2.2.4 Inspection 21 2.2.5 Approval 22 2.2.6 Maintenance 22 2.3 US administrative procedure 22 2.3.1 EMEA and FDA cooperation on medicines regulation 24 2.4 FDA Good Guidance Practices 24 2.4.1 Guidance options 25 2.5 Regulatory bodies in other countries 27 2.5.1 Tripartite agreement 28 2.5.2 Hong Kong 28 2.5.3 Canada 29 2.5.4 South (or Latin) America 29 2.5.5 African Countries 30 2.5.6 Australia and New Zealand 30 CHAPTER 3 PRODUCT DEVELOPMENT 31 3.1 New product development 31 3.1.1 Steps involved in product development 31 3.1.2 Attrition rate for drugs selected for development 32 3.2 introduction to the International conference on harmonisation (ICH) 33 3.2.1 How did ICH come about? 33 3.2.2 The beginnings of ICH 34 3.3 Pre-clinical studies 35 3.3.1 What is toxicity? 36 3.3.2 Guideline for toxicity studies before clinical studies (Phase I) in healthy volunteers: 37 3.3.3 Reproductive toxicology 39 3.3.4 Mutagenicity studies 40 3.3.5 Conventional carcinogenicity studies 41 3.4 Good Laboratory Practice (GLP) 42 3.4.1 What is GLP? 42 3.5 Clinical trials and good clinical practice 43 3.5.1 So what is a clinical trial? 43 3.5.2 Post-marketing surveillance (PMS) studies 46 3.5.3 What is Good Clinical Practice? 47 3.6 EU Clinical Trials Directive 50 3.6.1 Clinical Trials Directive (2001/20/EC) 50 3.6.2 What regulatory documentation is required for a clinical trial application in the EU? 52 3.6.3 Regulatory documents required for a clinical trial application in EU Member States 52 3.7 EU Privacy Legislation 54 3.8 FDA Clinical Trials Regulation 56 3.8.1 Organisation 57 CHAPTER 4 APPLICATIONS FOR MARKETING AUTHORISATIONS: GENERAL APPROACH 59 4.1 ICH Common Technical Document 59 4.1.1 Introduction 59 4.1.2 The CTD 59 4.1.3 High-level structure of Module 1 and the CTD Modules 2, 3, 4 & 5 60 4.1.4 Presentation of the application 61 4.2 EU and US: Similarities and differences 62 4.3 Quality (CMC) 65 4.4 Safety 73 4.4.1 Module 2: overview and summaries 74 4.4.2 Guidance notes 77 4.5 Efficacy 80 4.5.1 The clinical overview 80 4.5.2 Structure of Module 5 86 4.6 Product maintenance 88 4.6.1 Variations 88 4.6.2 Renewals 92 4.6.3 Withdrawals 93 4.7 Other considerations 93 CHAPTER 5 REGULATION OF GENERICS AND INNOVATOR RIGHTS 95 5.1 Generic medicines 95 5.1.1 What is a generic? 95 5.1.2 Pricing of generics 97 5.1.3 Licensing a generic product 97 5.2 Intellectual Property law 99 5.2.1 Patent protection 99 5.2.2 Patent expiration 99 5.2.3 Patent challenge 100 5.2.4 Data exclusivity 101 5.2.5 The Bolar Clause in the EU 103 5.2.6 The US 180-day generic drug product exclusivity 103 5.2.7 Data protection 104 5.2.8 Other types of IP protection 104 5.3 Supplementary protection certificates 105 5.3.1 What is an SPC? 105 5.3.2 The need for SPCs in the EU 105 5.3.3 Obtaining and maintaining SPCs 106 5.4 US patent term restoration 106 5.4.1 Length of patent term restoration 107 5.4.2 Applying for a patent extension 107 5.4.3 Determining the length of the patent extension 107 5.5 Parallel Trade Issues 107 5.5.1 Parallel trade in the EU 107 5.5.2 Parallel trade in the US 108 5.5.3 Counterfeiting of medicinal products 109 5.5.4 Products traded over the internet 109 CHAPTER 6 OVER-THE-COUNTER DRUGS, HERBALS & HOMOEOPATHICS 111 6.1 Over-the-counter drugs 111 6.1.1 Introduction 111 6.1.2 What is an OTC drug? 111 6.1.3 The ‘2001 Review’ 112 6.1.4 Advertising and branding 112 6.1.5 Safety assessment for POM to P switches 113 6.1.6 What is involved in the reclassification of medicines from POM to P? 113 6.1.7 Switching from POM to P 113 6.1.8 Other considerations 117 6.1.9 Data requirements 118 6.1.10 Product information 119 6.1.11 Other 120 6.1.12 US OTC 120 6.1.13 Drug interactions 121 6.2 Herbal Medicines 121 6.2.1 EU Legislation 121 6.2.2 Why is there a change in the legislation with respect to herbal medicines? 123 6.2.3 An example of an EU herbal medicines registration scheme: MHRA 123 6.2.4 Product information: Labelling and the user package leaflet 124 6.2.5 Advertising 124 6.2.6 Pharmacovigilance 124 6.2.7 US legislation 124 6.3 Homeopathy 126 6.3.1 What is homeopathy? 126 6.3.2 Homeopathic preparations 126 6.3.3 Use of homeopathy around the world 126 6.3.4 Homeopathic legislation in the EU 126 6.3.5 Homeopathy in the US 127 CHAPTER 7 BIOLOGICALS, GENE THERAPY AND OTHER SPECIAL CATEGORIES 131 7.1 Biologicals, biotechnology and biosimilars 131 7.1.1 Biologicals 131 7.1.2 The history of biotechnology 131 7.1.3 Types of biological products 134 7.1.4 Licensing a biological product 135 7.1.5 Biosimilars 137 7.2 Blood and Blood Products 138 7.2.1 Introduction to blood and blood products 138 7.2.2 EU blood legislation 138 7.2.3 US blood legislation 139 7.2.4 Registering a blood product 139 7.3 Gene therapy and cloning 140 7.3.1 Gene therapy 140 7.3.2 Cloning 144 7.3.3 Regulation of cloning 147 7.4 Other special categories 147 7.4.1 Radiopharmaceuticals 147 7.4.2 Nutraceuticals 148 CHAPTER 8 SAFETY, QUALITY AND REGULATION 151 8.1 Labelling of Medicinal Products 151 8.1.1 Introduction to labelling 151 8.1.2 EU Labelling Requirements 151 8.1.3 US labelling requirements 160 8.2 Pharmacovigilance 163 8.2.1 Introduction to pharmacovigilance 163 8.2.2 When does pharmacovigilance begin? 164 8.2.3 What information is collected? 164 8.2.4 What happens to the collected data? 164 8.2.5 Changes to an MA as a result of pharmacovigilance 164 8.2.6 Periodic Safety Update Reports 165 8.2.7 Content of a PSUR 166 8.2.8 Dear Dr Letters 170 8.2.9 Reporting of suspected adverse drug reactions in the EU 170 8.2.10 Reporting of suspected adverse drug reactions in the US 171 8.2.11 Black triangle 171 8.3 Ensuring the Quality of Medicinal products 173 8.3.1 Introduction to quality 173 8.3.2 Counterfeit products 174 8.3.3 Defective products 175 CHAPTER 9 ADVERTISING AND MARKETING PRACTICES 179 9.1 The role of the pharmaceutical industry in promotion and medical education 179 9.1.1 Introduction to the promotion of medicines 179 9.1.2 Looking after the consumer 180 9.1.3 Defining promotion 181 9.1.4 EU legal requirements 182 9.1.5 Differences and similarities between countries and regions in the regulation of advertising/promotional material 183 9.2 Organisations responsible for monitoring promotional activities around the world 183 9.2.1 Introduction 183 9.2.2 Global organisations 183 9.2.3 European organisations 184 9.2.4 UK organisations 185 9.2.5 US organisations 189 9.3 Compliance Strategies 193 9.3.1 Compliance Strategies in the US 193 9.3.2 California Law 194 9.3.3 Compliance Strategies in the EU 195 CHAPTER 10 OTHER EU AND US REGULATIONS 197 10.1 Paediatric Medicines Legislation 197 10.1.1 The need for legislation 197 10.1.2 Legislation in the EU 197 10.1.3 Legislation in the US 198 10.2 Risk management 198 10.2.1 Introduction to Risk Management 198 10.2.2 Risk management outside of the EU 202 10.3 Regulation of Combination Products 202 10.3.1 US approach 202 10.3.2 EU approach 204 10.4 Medicare and Medicaid 204 10.4.1 Medicare 204 10.4.2 Problems facing Medicare 206 10.4.3 Medicaid 206 10.5 Core competencies of a RAP 207 10.5.1 Introduction 207 10.5.2 Key core competencies 207 LIST OF TABLES Table 1.1 The changing options available to applicants intending to register a medicinal product in the EU Table 2.1 The scope of FDA Good Guidance Practices Table 3.1 Examples of product failure rates as they move through developments Table 3.2 Reasons for terminating a product in development Table 3.3 Chronological events in the history of ICH Table 3.4 Guidance for toxicity studies (time of exposure) before clinical trials in patients: ICH M3 Table 3.5 Toxicology data to support Phase III trials in EU Table 3.6 The phases of clinical development Table 3.7 Guidance for patient privacy rights Table 4.1 General differences between the EU and US applications Table 4.2 Module 3: Quality Table 4.3 Module 3: CTD Organisation Table 4.4 General guidelines Table 4.5 Active substance guidelines Table 4.6 Medicinal product guidelines Table 4.7 Module 4: non-clinical Table 4.8 Relevant pharmacokinetic documents Table 4.9 Relevant toxicology documents Table 4.10 General guidelines Table 4.11 General efficacy clinical safety Table 4.12 Clinical pharmacology Table 5.1 Brufen (ibuprofen) and its associated generic versions Table 5.2 Market protection for an originator’s theoretical product in the EU Table 6.1 EU Member States and the implementation of Articles 16(1) or 16(2) Table 9.1 Type of regulation and legal requirements for advertising of medicines Table 10.1 Overview of the EU Risk Management Plan Template Produced by the EMEA Table 10.2 Core competencies required by a RAP