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 6

1.3.4 Guidance Documents 7

1.3.5 Pharmacopoeia 7

1.4 Basic Legislation 7

1.4.1 EU Legislation 7

1.4.2 US Legislation 12

1.5 Scope of the Legislation 15

1.6 Chapter Review 20

1.7 Further Reading 21

2 Regulatory Strategy 23

2.1 Chapter Introduction 23

2.2 Basic Regulatory Strategy 23

2.2.1 Product Development 23

2.2.2 Product Manufacture 23

2.2.3 Market Vigilance 24

2.3 Quality Assurance Systems 25

2.3.1 Personnel 25

2.3.2 Documentation 25

2.3.3 Facilities and Equipment 26

2.3.4 Corrective and Preventative Action 27

2.4 Validation 27

2.5 Regulatory Bodies 29

2.5.1 European Commission 29

2.5.2 The EMA 30

2.5.3 National Competent Authorities 32

2.5.4 Notified Bodies 34

2.5.5 The FDA 35

2.5.6 US Department of Agriculture (USDA) 39

2.5.7 Pharmacopoeia Authorities 39

2.6 International Harmonisation Bodies 40

2.7 International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use 41

2.7.1 VICH 43

2.7.2 The International Medical Device Regulators Forum (IMDRF) 43

2.8 Pharmaceutical Inspection Cooperation Scheme (PICS) 44

2.9 The World Health Organisation (WHO) 45

2.10 Chapter Review 45

2.11 Further Reading 46

3 Drug Discovery, Classification and Early Stage Development 47

3.1 Chapter Introduction 47

3.2 Drug Categorisation 47

3.2.1 Prescription Status 47

3.2.2 Physical Properties 48

3.2.3 Mode of Action 48

3.2.4 Therapeutic Use 49

3.3 Drug Discovery 51

3.3.1 Target Discovery and Validation 52

3.3.2 Lead Discovery, Validation and Optimisation 57

3.4 Drug Development 58

3.4.1 Manufacture and Control 59

3.5 Drug Delivery 59

3.5.1 Location 60

3.5.2 Drug Characteristics 60

3.5.3 Speed and Duration of Therapeutic Effect 62

3.5.4 Stability 63

3.6 Chapter Review 63

3.7 Further Reading 63

4 Non-clinical Studies 65

4.1 Chapter Introduction 65

4.2 Non-clinical Study Objectives and Timing 65

4.3 Pharmacological Studies 69

4.3.1 Pharmacodynamic Studies 70

4.3.2 Pharmacokinetic/Toxicokinetic Studies 72

4.4 Bioavailability and Bioequivalence 73

4.5 Toxicology Studies 74

4.5.1 Toxicity Studies 74

4.5.2 Genotoxicity Studies 75

4.5.3 Carcinogenicity Studies 76

4.5.4 Reproductive Toxicology Studies 76

4.6 Chemistry, Manufacturing and Control Development (CMC) 77

4.7 Quality by Design (QbD) 77

4.8 Quality of Biotech Products 78

4.8.1 Stability Studies 78

4.9 Good Laboratory Practice (GLP) 78

4.10 Chapter Review 80

4.11 Further Reading 83

5 Clinical Trials 85

5.1 Chapter Introduction 85

5.2 Clinical Trials 85

5.2.1 Phase I Trials 86

5.2.2 Phase II Trials 86

5.2.3 Phase III Trials 87

5.3 Clinical Trial Design 88

5.4 Good Clinical Practice 90

5.5 Clinical Trials in the EU 90

5.5.1 Sponsor 93

5.5.2 Investigator's Brochure (IB) 93

5.5.3 Investigator 94

5.5.4 Trial Protocol 94

5.5.5 Investigational Medicinal Product Dossier (IMPD) 94

5.5.6 Informed Consent 94

5.5.7 Manufacture of Investigational Medicinal Product 95

5.5.8 Clinical Trial Authorisation 95

5.5.9 Independent Ethics Committee Opinion 96

5.5.10 Amendments to Clinical Trials 97

5.5.11 Case Report Forms (