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The Role of Statistics Post-Market

The Role of Statistics Post-Market. Jay Herson, Ph.D. Johns Hopkins University Sept 29, 2006. Post-Market Trials. Phase IV Label extension or modification Surveillance Investigator INDs Seeding Studies Biostatistician input much needed. Roles.

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The Role of Statistics Post-Market

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  1. The Role of Statistics Post-Market Jay Herson, Ph.D. Johns Hopkins University Sept 29, 2006

  2. Post-Market Trials • Phase IV • Label extension or modification • Surveillance • Investigator INDs • Seeding Studies • Biostatistician input much needed

  3. Roles • Role should not be described as a list of tasks • Role of the biostatistician in post-market industry trials is to be an advocate for GOOD SCIENCE.

  4. Wisdom • Good Science is Good Business but • Good Business is not necessarily good science • Credible and timely results is good business in the long run

  5. Good Science—Design Stage • Objectives • Primary and secondary endpoints • Eligibility • Power and precision • Doses, regimens • Control Group • Non-inferiority trials

  6. Good Science--Results • Results available to patients and physicians • Publication regardless of results • Clear definition of original objectives of the trial • Appropriate measures of precision, exposure • Post-hoc power

  7. Advocate • Independent Review throughout the trial

  8. Post Market Trials Then and Now

  9. Large Trials • GUSTO—t-PA vs streptokinase • ATLAS—adjuvant tamoxifen • COMMIT—acute MI asparin vs clopidogrel • CPPT—lipids, cholestiramine • CONCORDE—HIV, AZT • WHI

  10. Surprising Results • BHAT—propranalol • CAST—encainide, flecainide

  11. Cooperative Meta Analyses • ATT—antithrombolytics • EBCTCG—early breast cancer

  12. Oncology—Practice Changing Trials • Aromatase inhibators—breast cancer • bevacizumab-VEGF, colorectal • trastuzimab—breast cancer • taxanes—lung, ovarian • platinum—lung ovarian

  13. However…. • Most of the trials just referenced were not conducted by industry

  14. Industry Sponsorship • Pre-Market---Science / Regulatory driven • Post-Market—Marketing driven

  15. Marketing Influence • No trials undertaken whose results could threaten market share • Results suppressed if they threaten market share

  16. Industry Sponsorship • Phase IV—Under control of marketing • Anti-depressants—19/21 trials head-to-head sponsors product superior. • Low dose for competitor • Different schedules • Simple conditions • Not double blind

  17. The Non-Inferiority Complex • Sloppy trials • Result is under control of sponsor • Delta • Active control • Sub-potent dose • Terminate before effects • Imprecise measurement

  18. Industry Sponsorship • Publication bias • Results not matched with original objectives • Cox-2 inhibitor trials / bureaucracy

  19. Industry Sponsorship • Advertising agency purchased CRO • Seeding studies • Design problems • Organizational problems

  20. Good News • William Olson, Ortho-McNeil • Patent 6,339,105 • A regimen for the administration of tramadol for the treatment of analgesia • Slower titration rate • Reduction in side effects

  21. Opportunities • Bayesian design and analysis • Testing grounds—adaptive designs • Meta analysis • Methodology • Fixed vs Random Effects • Mixed models

  22. A. Mugglin—Medical Devices • Fine illustration of the role of statisticians • Interesting SCD-HeFT cost-effectiveness study • How do results of this information get disseminated to stakeholders—patients and their caregivers? • Should not be used as sole justification for higher prices for the product.

  23. Mugglin--Future • Globalization • Aging of populations • Cost-effectiveness • IOM recommendation • Genetics

  24. Genetics • Revisit approved but unpopular drugs due to knowledge of what DNA is associated with response, low toxicity. • bucindolol vs other beta blockers for heart failure • tamoxifen vs aromatase inhibitors in breast cancer

  25. Gould--Surveillance • fialuridine (FIAU), 1993 • Good list of limitations (Considerations and Issues) • Accumulating information of RR and the lower 5% point---how long to watch a signal? • Retrospective pharmacovigilence

  26. Gould--Bayes • Definitely a role for Bayesian methods here. The sooner the better. • Empirical Bayes a good start • Sponsor safety database • Oncology—MedDRA vs CTC 3.0

  27. Gould--Contribution • Shows the contribution a statistician can make to a difficult problem by thinking through the problem • Hope for a common ground between plaintiffs and industry • To deny the implications of this type of analysis is to deny our ability to reason

  28. Marinac-Dabic FDA/CDRH • Sources of data • Areas requiring attention • Motivate good science • Post-market surveillance for the elderly • Passive reporting system for high quality post-market surveillance data

  29. Thank You

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