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The Emerging Role of Postmarketing Clinical Research: Regulatory issues, strategic drivers and overall trends
Executive Summary 8
Background to postmarketing research 8
Mandatory postmarketing trial requirements 8
Phase IV trials for market development 10
Impact of competitive pressures and pipeline strength on phase IV trials 11
Appropriate trial design 12
Chapter 1 Background to postmarketing research 16
Summary 16
Introduction 17
The clinical trial landscape 19
Priorities and end-points in clinical development 20
Safety and full market approval 22
Health-economic arguments 23
Life cycle management 23
Product positioning and differentiation 23
Chapter 2 Mandatory postmarketing trial requirements 28
Summary 28
FDA regulations for postmarketing trials 29
Postmarketing commitment trials (PMC) 29
Direct and indirect drivers for PMC conduct 33
Indirect driver: Public health priorities 33
Direct driver: Orphan drugs 34
PMC Case Study: Iressa 35
PMC Case study: Vioxx 37
Postmarketing surveillance studies (PMS) 38
PMS study drivers 39
PMS design limitations 39
FDA Amendment Act (FDAAA) 42
Industry implications of FDAAA 43
Public submission of datasets 43
EMEA 45
Terms of marketing approval agreement 45
Joint FDA-EMEA drug monitoring initiatives 45
Trials for improved clinical guidance 47
Chapter 3 Phase IV trials for market development 50
Summary 50
Introduction 51
Phase IV trials for formulary access 54
US – the importance of comparative effectiveness 56
EU – the importance of added therapeutic value 58
Postmarketing trials for indication expansion 59
The Rx to OTC switch 62
Off-label physician use and risk management 64
Product development for indication expansion 66
Line extensions 68
Case Study: Line extension launch profiles 68
Case study: Zoloft (sertraline) 69
Reformulations 71
Follow-on compounds 71
Phase IV trials for multiple indication expansion strategies 71
Case study: Zyprexa 72
Case study: Alimta (Pemetrexed) 74
Enhanced market positioning 77
Marketing regulations 77
Head to Head trials 78
Case study: Zyprexa vs Risperdal 79
US Direct to Consumer (DTC) regulations 80
EU marketing regulations 80
Influence of sponsorship on trial endpoint 81
Impact of budget constraints 82
Big pharmaceutical firms 83
Mid tier biopharma and biotechnology firms 83
Big pharma’s scale advantage 85
Case study: Novartis 86
Case study: Glivec (Imatinib mesylate) 88
Case study: Aclasta (zoledronic acid) 89
Misuse of phase IV trials and regulator scrutiny 90
Chapter 4 Impact of competitive pressures and pipeline strength on phase IV trials 94
Summary 94
The impact of competition 95
Market scenario: Cardiovascular 97
Case study: Diovan 99
Market scenario: oncology 100
Antineoplastics - market drivers for phase IV trials 102
Chapter 5 Effective phase IV trial design 106
Summary 106
Introduction 107
Endpoint designation and trial purpose 107
Patient and physician recruitment 108
Recruitment bottlenecks 110
Design limitations 110
Study design 112
Data management and adaptive clinical trial designs 113
Operational management 114
Chapter 6 Appendix 117
Primary research methodology 117
Glossary 118
Index 120
List of Figures
Figure 2.1: Projected R&D spend by phase 2005-2009 ($bn), 19
Figure 2.2: Postmarketing research and product lifecycle 20
Figure 3.3: NDA and ANDA requirements for postmarketing status reports 31
Figure 3.4: Biological product reporting requirements for postmarketing status reports 32
Figure 3.5: Sales of Iressa in the US, 2003-2007 ($m) 36
Figure 3.6: Vioxx sales in the US, 2003-2004 ($m) 38
Figure 3.7: Implication of FDA requirement of REMS 41
Figure 3.8: Implications of tightened FDA policies 43
Figure 4.9: Market drivers for postmarketing research 51
Figure 4.10: Declining return on R&D investment (US, 1990-2004) 52
Figure 4.11: Payor’s influence gain in prescribing decisions; US market, share of voice, 2007 56
Figure 4.12: Marketing and product development strategies using phase IV trials 60
Figure 4.13: Phase IV for product lifecycle management 62
Figure 4.14: Sales summary for Zoloft in the US, 2000-2006 70
Figure 4.15: Use of postmarketing trials for lifecycle management of Zyprexa, US and EU5, 2000-2007 ($m) 73
Figure 4.16: Effect of indication expansion on sales of Alimta in the US, 2004-2007 ($m) 76
Figure 4.17: Big pharma phase IV trials by strategic purpose, USA, 1998-2007 86
Figure 4.18: Number of phase IV trials by different ‘Big pharma’ companies 87
Figure 5.19: Impact of market competition on phase IV trial design and objective 95
Figure 5.20: Global cardiovascular product pipeline, Q1 2008 98
Figure 5.21: Diovan sales in the US, 1998-2007 ($m) 100
Figure 5.22: Global cancer product pipeline, Q1 2008 101
Figure 5.23: Number of phase IV trials vs sales growth, USA, 2003-2007 103
Figure 6.24: Factors influencing successful Phase IV conduct 107
Figure 6.25: Advantages and disadvantages posed by phase IV study designs 112
List of Tables
Table 2.1: Phase IIIb vs Phase IV postmarketing studies 18
Table 4.2: On-label indication expansion drivers 67
Table 4.3: Declining incremental sales revenue return with subsequent line extension launches 69
Table 4.4: Zyprexa- Pivotal phase IV trials for indication expansion and formulary access 74
Table 4.5: Industry vs non-industry trial objectives 82
Table 4.6: Trial characteristics by commissioning organization, 1998-2008* 85
Table 6.1: Influence of study participation on subsequent drug prescribing 109
Table 6.2: Advantages and disadvantages of using adaptive clinical trial designs 114
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