醫藥品販賣後對臨床實驗的影響

Post-marketing studies are undertaken to delineate additional clinical information concerning a drug' s risks, benefits, and optimal use. Industry stakeholders acknowledge that research undertaken in order to obtain marketing authorization (MA) does not always coincide with initiatives to ensure that the product is subsequently placed in its ideal or intended market context. Such postmarketing data can therefore prove invaluable to governing bodies like the FDA and EMEA, institutional payors and health authorities, and also to the pharmaceutical companies themselves for strategic purposes.

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