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CCT Seminar: September 1, 2010

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  • 1. Tales of Avandia: Evidence, Regulation, and Clinical Practice Harry M Marks Institute of the History of Medicine Johns Hopkins University Center for Clinical Trials, JHSPH September 1, 2010
  • 2.  
  • 3. Avandia Issues
    • How well is the FDA balancing drug safety and efficacy?
    • What kinds of studies count as evidence of risk and benefit?
    • Did Glaxo SmithKline suppress evidence of avandia’s harm?
  • 4. Pre-Avandia Issues
    • What is the disease for which a drug is used?
    • How is therapeutic benefit measured?
    • How does the FDA adjudicate evidence of drug hazards?
    • What is the FDA’s role in regulating clinical practice?
  • 5. ROAD MAP
    • Disease Concepts: Diabetes
    • Surrogate Endpoints at the FDA
    • Drug labels and drug regulation
    • Avandia
  • 6. The Spectrum of Diabetes, c 1967 Camerini-Davalos Excerpta Medica (1967)
  • 7. “ What may be regarded as prediabetic today will later be shown to be a clear manifestation that the disease is present.” -JW Conn, The Banting Memorial Lecture 1958 Diabetes 7 (1958), 355
  • 8. The Spectrum of Diabetes, c 1967 Camerini-Davalos Excerpta Medica (1967)
  • 9.  
  • 10. Orinase Ad: Annual Increases in Rx
  • 11. Oral Hypoglycemic Agents
    • Biguanides (metformin)
    • Sulfonylureas
      • Orinase (tolbutamide)
      • Second generation sulfonylureas
    • Thiazolidinediones (including Avandia)
  • 12. FDA’s Rules for Surrogate Endpoints
    • Sponsor must demonstrate that the surrogate endpoint is plausibly linked to clinical outcomes
      • Biologically plausible
      • Predictor of disease progression and regression
    • FDA may require studies to demonstrate clinical benefit/validity of surrogate endpoint
    Federal Register 57 (1992): 58942-58958
  • 13. 1962 Drug Amendments "No person shall introduce into interstate commerce any drug, unless they have demonstrated whether or not the drug is safe and effective for use under the conditions prescribed, recommended or suggested in the proposed labeling thereof."
  • 14. FDA: Action options
    • Remove drug from market (may be FDA- or company-initiated)
    • Restrict use (e.g. l-dopa)
    • Modify drug labeling to include warnings
  • 15. “ He said, she said”
  • 16. Limitations of Nissen meta-analysis
    • Studies not intended to monitor CV effects of avandia
    • No patient-level data
    • Heterogeneity of study designs (all RCTs)
    • No central adjudication of CV events in most studies
  • 17. Limitations of RECORD study
    • Open-label design (ascertainment bias?)
    • Non-inferiority design
    • Different practices among sites in referral to hospital for clinical endpoints
  • 18.  
  • 19. “ These sponsored [web] links make representations and/or suggestions about the efficacy of avandia … but fail to communicate any risk information. This omission of risk information is particularly concerning as… Avandia [has a] boxed warning.” -Michael Sauers [FDA] to GSK, March 26, 2009
  • 20. GSK’s Proposed Labeling 7/09
  • 21. Avandia Vote, July 14, 2010
    • 3 No changes
    • 7 Add new warnings to label
    • 10 Revise label and restrict use
    • 12 Withdraw from market
  • 22. “ He said, she said”
  • 23. Questions and Answers

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