Ethical issues in clinical trials

1. Ethical issues in clinical trials Bernard Lo, M.D. February 7, 2008

2. Outline of talk • Do we need clinical trials? • When is randomization justified? • May negative findings be withheld? • What are responsibilities of investigators in trials?

4. Treating patients with hESC • Testimonials on Internet • Charge $50,000 • Scant publication in journals • Independent follow up: no “functional benefit”

5. Treating patients with hESC • India Board for Medical Research rejected grant application • Not explain how obtain or purify cells

6. Regulatory issue • May innovative treatments be introduced in clinical practice without evidence of safety and efficacy?

7. Ethical issue • Do physician-investigators have ethical duty to determine whether new interventions are effective and safe?

8. Experimental interventions ineffective or unsafe • Autologous bone marrow transplantation in breast cancer • Torcetrapib raises HDL, lowers LDL but increases mortality

10. CHOIR • Target Hgb 13.5 vs. target Hgb 11.3 • 1432 patients with CKD, no dialysis • Time to composite endpoint death, MI, CVA, hospitalization for CHF NEJM 206; 355: 2085

11. Literature review • RCT target Hct 42 vs Hct 30 in patients with heart disease on dialysis • More MIs in high Hct group, but not significant. • Trial halted (1998)

12. Literature review • Meta-analysis of dialysis patients (2004) • Hb <12 had lower mortality than Hb >13 • RR = .04 (0.71 to 1.0)

13. Randomization • Most rigorous design • In clinical care, MD recommends what is best for individual patient • Requires ethical justification

14. Clinical equipoise justifies randomization • Experts find current evidence inconclusive or conflicting • If experts disagree or uncertain, no harm to participants • Clinicians willing to enroll patients

15. Clinical equipoise justifies randomization • Participant agrees to be randomized • Should be told results of pertinent other trials

16. Outcomes at 16 months Hgb 13.5 Hgb 11.3 N=715 N=717 Endpoint 125 97 17.5% 13.5% Hazard ratio 1.34, 95% CI = 1.03-1.74

17. Outcomes at 16 months Hgb 13.5 Hgb 11.3 N=715 N=717 Death 52 (7.3%) 35 (5.0%) CHF 64 (9.0%) 47 (6.6%)

19. Vitorin • Combination ezetimibe + simvastatin • Prescribed to 800,000 patients, cost $4 billion

20. ENHANCE trial • Compare progression of carotid plaques in ezetimibe + simvistatin vs. simvistatin alone • Finished 3/ 2006 • Press reports 12/07 that results not released

21. ENHANCE trial • Press release Jan 2008 • No benefit on plaque progression

22. Ethical concerns raised by Vitorin trial • Withholding of negative findings? • Harm future patients • Protect trade secrets? • Role of academic PI of study?

23. American Heart Association • “Study was not large enough or long enough to determine whether the combination drug is more or less effective than the single drug in reducing heart attacks or deaths” • Check with doctor

24. American Heart Association • Not mention that AHA receives $2 million annually from manufacturer of Vitorin • AHA site has direct link to manufacturer webpage

28. 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.”

29. Conflicts of interest • Primary mission of clinical trial investigator is to generate valid knowledge • Different than drug marketing or sales

30. Responses to conflicts of interest in clinical trials • Disclose • To institution, IRB, participants • Doesn’t prevent bias

31. Responses to conflicts of interest • Manage • Review by institutional committees • But no one looks at science+ethics+conflict of interest • Registry of clinical trials • But results might not be disseminated

32. Responses to conflicts of interest • Forbid certain actions or situations • Authors must have • Access to data • Control over data analysis • Freedom to publish

34. VIGOR (11/04) • Fewer GI side effects on rofecoxib than naproxen (2.1 vs. 4.5) • Rofecoxib sales over $2.5 billion annually

35. VIGOR adverse effects • More MIs on refecoxib (0.4 vs 0.1) • Attributed to protective effect of naproxen

36. VIGOR adverse effects • 3 additional MIs on refecoxib before publication • Reported to FDA before publication • Known to 2 employee / authors

37. What should authors do about inaccurate findings?

38. What should authors do? • Report to academic authors • Report to NEJM

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

40. Selection of endpoint in APPROVe • Count only events while on Rx or up to 14 days after stopping • Count AEs over entire follow-up • Methodology concerns? • What kind of bias might be introduced?

41. Selection of endpoint in APPROVe • Academic authors said they were just following the protocol from sponsor

42. APPROVe problems • Presented all events to FDA 5/06 • Curves diverge at 4 months, not 18 • Was choice of endpoint based on sound science or litigation concerns? • Defend lawsuits against patients on drug for short time

43. 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.”

44. Concerns raised by rofecoxib trials • Invalid and biased presentation of results • Defenses against bias ineffective • Academic investigators

45. Take home message • Give trial a catchy NAME • Ethical issues are inherent in clinical trials • Investigators, referring clinicians, reviewers, readers need to be aware of ethical issues and how to resolve them