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Ethical issues in clinical trials

Ethical issues in clinical trials. Bernard Lo, M.D. bernie@medicine.ucsf.edu. RCT to prevent nephropathy in Type 2 diabetes (1998). ACE effective in Type I Some smaller studies in Type II Many physicians already using ACE. Ethical issues in clinical trials.

candice-chaney
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Ethical issues in clinical trials

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  1. Ethical issues in clinical trials Bernard Lo, M.D. bernie@medicine.ucsf.edu

  2. RCT to prevent nephropathy in Type 2 diabetes (1998) • ACE effective in Type I • Some smaller studies in Type II • Many physicians already using ACE

  3. Ethical issues in clinical trials • (Moving from animal to human studies) • Choice of intervention and control • Placebo or active control? • ACE inhibitor or ARB? • (Background intervention) • Is standard care adequate?

  4. Ethical issues in clinical trials • Randomization • (Design issues) • Selection of participants • Endpoints

  5. Ethical issues in clinical trials • Data and Safety Monitoring • Publication of results

  6. Ethical concerns about clinical trials • Benefits and risks uncertain • Decisions not individualized to benefit participant • Treatment by randomization and protocol • Benefit primarily to future patients • Participants misunderstand

  7. Ethical guidelines:Belmont Report (1979) • Respect for persons • Free and informed consent • Beneficence • Risks must be minimized and proportional to benefits • Independent review by IRB (and DSMB)

  8. Ethical guidelines:Belmont Report (1979) • Justice • Not exploit vulnerable populations • Access to interventions after trial

  9. What is ethical concern about randomization? • In clinical care, MD recommends what is best for individual patient • Participants do not understand

  10. When is randomization justified?Three levels of equipoise • Experts disagree or uncertain • Current evidence inconclusive or conflicting • Uncertainty about particular population • No serious harm to participants • IRB may approve

  11. Three levels of equipoise • Clinicians may not recommend or enroll participants if judges one arm superior • From evidence and judgment • For individual patient, one arm preferable • Participant must consent • Must know about standard therapy or access to study agent outside of trial

  12. Questions?

  13. VIGOR (11/2000) • Fewer GI side effects on rofecoxib than naproxen (2.1 vs. 4.5) • More Mis on refecoxib (0.4 vs 0.1) • Attributed to protective effect of naproxen

  14. VIGOR adverse effects • 3 additional MIs on refecoxib • Reported to FDA before publication • Known to 2 employee / authors • Not reported to academic authors or to NEJM

  15. Role of NEJM • NEJM aware of discrepancy 8/01 • Did not publish letter • Did not ask authors to respond • Reprint income $697,000 to NEJM

  16. APPROVe study (2/05) • Thrombotic events 1.50 on rofecoxib vs. 0.78 on placebo • Led to voluntary withdrawal of drug • Increased risk after 18 months • Defense to lawsuits

  17. Selection of endpoint in APPROVe • Count only events while on Rx or up to 14 days after stopping • Academic authors claimed they were just following the protocol

  18. APPROVe problems • Presented all events to FDA 5/06 • Curves diverge at 4 months, not 18

  19. Peer review with APPROVe • “Aggressively promotes safety of up to 18 months of use … beyond the data of the study” • “Hand of sponsor is too evident .. Written consistently in manner designed to support the company’s public positions.”

  20. Peer review with APPROVe • Journal originally asked authors to drop references to 18 months

  21. Concerns raised by APPROVe • Withholding of negative data • Bias in design and analysis • Responsibilities of sponsors, authors, journals

  22. Conflicts of interest • “Drug companies have to continue to be successful businesses… But their primary mission is products that save lives and improve lives.” • “This is an area that’s different from ice cream, bubble gum, and automobiles.”

  23. Business relationship • Self-interest in profit • Caveat emptor • Do not call attention to shortcomings • May overstate benefits

  24. Fiduciary relationship for MDs • Illness makes patients vulnerable • Physicians have expertise • Reliance and trust • Act in patient’s interest, not self-interest or interest of 3rd parties

  25. Responses to conflicts of interest • Disclose • To institution, IRB, participants, journal • Manage • Investigators in clinical trial should not have significant financial interest

  26. Responses to conflicts of interest • Forbid certain actions or situations • Sponsor may not restrict author’s • Access to data • Control over data analysis • Freedom to publish

  27. Take home message • Ethical issues are inherent in human participants research • Investigators, referring clinicians, readers need to be aware of ethical issues and how to resolve them

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