The Emerging Role of Postmarketing Clinical Research: Regulatory issues, strategic drivers and overall trends

Table of Contents

• Background to postmarketing research
• Mandatory postmarketing trial requirements
• Phase IV trials for market development
• Impact of competitive pressures and pipeline strength on phase IV trials
• Appropriate trial design

• Summary
• Introduction
• The clinical trial landscape
• Priorities and end-points in clinical development
  • Safety and full market approval
  • Health-economic arguments
  • Life cycle management
  • Product positioning and differentiation

• Summary
• FDA regulations for postmarketing trials
• Postmarketing commitment trials (PMC)
• Direct and indirect drivers for PMC conduct
  • Indirect driver: Public health priorities
  • Direct driver: Orphan drugs
  • PMC Case Study: Iressa
  • PMC Case study: Vioxx
• Postmarketing surveillance studies (PMS)
  • PMS study drivers
  • PMS design limitations
• FDA Amendment Act (FDAAA)
• Industry implications of FDAAA
• Public submission of datasets

• EMEA
• Terms of marketing approval agreement
• Joint FDA-EMEA drug monitoring initiatives
• Trials for improved clinical guidance

• Summary
• Introduction
• Phase IV trials for formulary access
• US - the importance of comparative effectiveness
• EU - the importance of added therapeutic value

• Postmarketing trials for indication expansion
  • The Rx to OTC switch
  • Off-label physician use and risk management
• Product development for indication expansion
  • Line extensions
  • Case Study: Line extension launch profiles
  • Case study: Zoloft (sertraline)
  • Reformulations
  • Follow-on compounds
• Phase IV trials for multiple indication expansion strategies
  • Case study: Zyprexa
  • Case study: Alimta (Pemetrexed)

• Enhanced market positioning
• Marketing regulations
• Head to Head trials
  • Case study: Zyprexa vs Risperdal
  • US Direct to Consumer (DTC) regulations
  • EU marketing regulations
• Influence of sponsorship on trial endpoint
• Impact of budget constraints
  • Big pharmaceutical firms
  • Mid tier biopharma and biotechnology firms
• Big pharma' s scale advantage
  • Case study: Novartis
  • Case study: Glivec (Imatinib mesylate)
  • Case study: Aclasta (zoledronic acid)
• Misuse of phase IV trials and regulator scrutiny

• Summary
• The impact of competition
• Market scenario: Cardiovascular
  • Case study: Diovan
• Market scenario: oncology
  • Antineoplastics - market drivers for phase IV trials

• Summary
• Introduction
• Endpoint designation and trial purpose
• Patient and physician recruitment
• Recruitment bottlenecks

• Design limitations
• Study design

• Data management and adaptive clinical trial designs
• Operational management

• Primary research methodology
• Glossary
• Index

• Figure 2.1: Projected R&D spend by phase 2005-2009 ($bn),
• Figure 2.2: Postmarketing research and product lifecycle
• Figure 3.3: NDA and ANDA requirements for postmarketing status reports
• Figure 3.4: Biological product reporting requirements for postmarketing status reports
• Figure 3.5: Sales of Iressa in the US, 2003-2007 ($m)
• Figure 3.6: Vioxx sales in the US, 2003-2004 ($m)
• Figure 3.7: Implication of FDA requirement of REMS
• Figure 3.8: Implications of tightened FDA policies
• Figure 4.9: Market drivers for postmarketing research
• Figure 4.10: Declining return on R&D investment (US, 1990-2004)
• Figure 4.11: Payor' s influence gain in prescribing decisions; US market, share of voice, 2007
• Figure 4.12: Marketing and product development strategies using phase IV trials
• Figure 4.13: Phase IV for product lifecycle management
• Figure 4.14: Sales summary for Zoloft in the US, 2000-2006
• Figure 4.15: Use of postmarketing trials for lifecycle management of Zyprexa, US and EU5, 2000-2007($m)
• Figure 4.16: Effect of indication expansion on sales of Alimta in the US, 2004-2007 ($m)
• Figure 4.17: Big pharma phase IV trials by strategic purpose, USA, 1998-2007
• Figure 4.18: Number of phase IV trials by different ' Big pharma' companies
• Figure 5.19: Impact of market competition on phase IV trial design and objective
• Figure 5.20: Global cardiovascular product pipeline, Q1 2008
• Figure 5.21: Diovan sales in the US, 1998-2007 ($m)
• Figure 5.22: Global cancer product pipeline, Q1 2008
• Figure 5.23: Number of phase IV trials vs sales growth, USA, 2003-2007
• Figure 6.24: Factors influencing successful Phase IV conduct
• Figure 6.25: Advantages and disadvantages posed by phase IV study designs

• Table 2.1: Phase IIIb vs Phase IV postmarketing studies
• Table 4.2: On-label indication expansion drivers
• Table 4.3: Declining incremental sales revenue return with subsequent line extension launches
• Table 4.4: Zyprexa- Pivotal phase IV trials for indication expansion and formulary access
• Table 4.5: Industry vs non-industry trial objectives
• Table 4.6: Trial characteristics by commissioning organization, 1998-2008*
• Table 6.1: Influence of study participation on subsequent drug prescribing
• Table 6.2: Advantages and disadvantages of using adaptive clinical trial designs