Drug Safety in the Post-Vioxx Era: New legislation, regulation and company strategies in Europe and the US

Table of Contents

Executive Summary 10

• Overview of drug safety issues 10
• Regulation of drug safety in the US and Europe 11
• New legislation and regulation in the US and Europe 12
• Industry initiatives 13
• Pharmaceutical company strategies 14
• Analysis & predictions for the future 15

Chapter 1 Overview of drug safety issues 18 Summary 18 Introduction 19 Drug safety risks 20 Managing drug safety risk 21 Unmanageable risk: drug withdrawals 23 Vioxx 24 Regulatory reforms 25 Impact on drug development 26 Link between US and European regulatory processes 28

Chapter 2 Regulation of drug safety in the US and Europe 32

• Summary 32
• Introduction 33
• US regulations 33
• Evolution of drug safety testing 34
• Pre-launch mechanisms to ensure drug safety 37
  • Drug approval process 38
  • Manufacturing plant inspections 41
• Post-launch mechanisms to ensure drug safety 41
  • MedWatch 41
  • Adverse Event Reporting System 43
  • Controls on drug usage 44
  • Post-marketing studies 47
  • Drug Safety and Risk Management Drugs Advisory Committee 48
  • Manufacturing plant inspections 48
  • Criminal sanctions 49
• European regulations 50
• History of European drug regulation 50
  • The formation of the EMEA and the MRP 52
• Pre-launch mechanisms to ensure drug safety 53
  • The EMEA 53
  • The Mutual Recognition Procedure 54
• Post-launch mechanisms to ensure drug safety 57
  • Warnings 57
  • Recalls 60
  • Inspections 61
• Conclusion 63

Chapter 3 New legislation and regulation in the US and Europe 66

• Summary 66
• Introduction 67
• Factors that raise the stakes for improving drug safety 67
• Rising adverse drug reactions 68
  • US 68
  • Europe 70
• Growing sourcing of drugs through the Internet 72
  • US 72
  • Europe 77
• Rising lawsuits against manufacturers 79
  • US 79
  • Europe 82
• Impact of DTC advertising in the US 83
• New US legislation and regulation 85
• US legislative response (Congress) 85
  • Bills proposed for drug safety 86
• US regulatory response (FDA) 91
  • Institute of Medicine Drug Safety Study 92
  • Drug Safety Oversight Board 93
  • FDA culture 95
  • Speeding drugs to market 95
  • Approval delays for risky applications 96
  • Increased investigation into counterfeiting 98
  • Heightened scrutiny of DTC advertising 99
  • Budget issues 101
• Other regulators 102
  • New York State Attorney General Eliot Spitzer vs. GSK and Paxil 102
  • State legislative initiatives 105
• New European legislation and regulation 106
• EU level legislation 106
  • Pediatric drug testing 106
  • Production of Active Pharmaceutical Ingredients 107
  • Labeling 108
• Country level legislation 109
• EU level regulation (EMEA) 110
  • EudraVigilance 110
  • Restrictions on use of COX-2 inhibitors 111
  • Restructuring to eliminate conflicts of interest 112
• Country level regulation (Competent Authorities) 112
  • Expanded collection and publication of drug safety data 112
  • Restructuring 113
  • Tightening of controls on consumer drug advertising 114
  • Delayed drug approvals 115
• Conclusion 115

Chapter 4 Industry initiatives 118

• Summary 118
• Introduction 119
• Trade group initiatives 120
  • Pharmaceutical Research and Manufacturers of America (PhRMA) 120
• Consumer group initiatives 122
• Public Citizen 122
• Consumers Union 124
• Institute for Safe Medication Practices 124
• Europe and international industry initiatives 125
• Trade group initiatives 125
  • Association of the British Pharmaceutical Industry 125
• World Health Organization 126
• Managed care companies 127
• Restrictions on usage of unsafe drugs 129
• Drug safety databases 130
• Leveraging data to shape public health care policy 130
  • Medco Institute at UMDNJ for Drug Safety, Policy and
  • Epidemiology 130
• Retailers 131
• Discontinuing of secondary market purchasing by CVS 131
• Conclusion 132

Chapter 5 Pharmaceutical company

• strategies 134
• Summary 134
• Introduction 135
• Marketing and business strategies 136
• Reductions in use of wholesalers 136
  • Pfizers European supply chain reorganization 137
• Adjustments to advertising campaigns 138
• Management strategies 141
• Executive changes 141
  • Replacement of Mercks CEO 141
  • Reorganization of drug development group at AstraZeneca 142
  • Resignation of Able Labs CEO and manufacturing reorganization 143
• Strengthening of government affairs capabilities 144
• Technology programs 146
• Using genomics to predict toxicity 146
• Expanding use of technology to track drug shipments 147
  • Bar-coding 147
  • Radio frequency identification (RFID) 148
• Labeling enhancements 150
• Regulatory responses 151
• Providing more drug data 151
  • GSK 152
  • Forest Laboratories 152
  • AstraZeneca 153
  • Eli Lilly 154
  • Merck 154
• Withdrawals of drug applications 154
• Conclusion 155

Chapter 6 Analysis & predictions for the future 158

• Summary 158
• Introduction 159
• Rising imperatives for drug safety 159
• Rising numbers of adverse reactions 159
• More lawsuits with higher payouts 160
• Wait-and-see stance from congress 161
• FDA overhaul 162
• No meaningful impact from other regulators 163
• Continuing trade group proactivity 163
• Europe trails US in reform 164
• Inconsistent approach to safety by Competent Authorities 164
• EMEA Looks to FDA 165
• Pharmas lead the charge 165
• Rising initiatives address drug counterfeiting 165
• Adjustment of DTC campaigns 166
• Increasing action against errant executives 166
• Greater provision of drug data 167
• Higher clinical trial standards 167
• Increasing involvement from managed care and retail companies 168

Chapter 7 Appendix 172

• Primary research methodology 172
• Glossary 173
• Index 174

List of Figures

• Figure 1.1: The drug safety risk spectrum 22
• Figure 1.2: Average approval time for New Chemical Entities, 1993-2003 26
• Figure 1.3: Impact of drug development pressures on drug safety 28
• Figure 2.4: Sources of FDA-reported adverse events 44
• Figure 2.5: New applications finalized by RMS, 2004 56
• Figure 2.6: Number of public drug safety warnings by country, 2002-2005* 59
• Figure 2.7: Human drugs sampled and tested by EMEA 62
• Figure 3.8: Growth in reported adverse drug events in the US, 1995-2004 68
• Figure 3.9: Consumer responses to rising drug safety risks 70
• Figure 3.10: EU and non-EU adverse drug reaction reports, 2002-2004 71
• Figure 3.11: Drivers of drug re-importation 73
• Figure 3.12: Overall susceptibility of top 5 European drug markets to counterfeiting 77
• Figure 3.13: DTC ad spending ($bn), 2001-2004 84
• Figure 3.14: NDAs and NMAs approved by the FDA, 1997-2004 97
• Figure 3.15: Number of new counterfeit drug cases opened by the FDA, 1997-2004 98
• Figure 3.16: Warning letters sent to drug marketers since expansion of DTC advertising rules, 1997-2003 99
• Figure 3.17: FDA budget, 2001-2006 102
• Figure 5.18: Pressures on drug developers 136
• Figure 5.19: Marketing & advertising expenses, Q4 2004 & Q1 2005 140

List of Tables

• Table 1.1: Potential safety risks of popular drug classes 23
• Table 1.2: Recent drug recalls and affected patients, 1997-2005 24
• Table 2.3: Timeline of key FDA legislation 34
• Table 2.4: CDER advisory committees 37
• Table 2.5: Drugs subject to FDA controls 45
• Table 2.6: Leading national Competent Authorities 57
• Table 2.7: EMEA human drug recalls, 2000-2005 60
• Table 3.8: Pending US legislation 87