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

2. 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. 4 Treating patients with hESC  Testimonials on Internet  Charge $50,000  Scant publication in journals  Independent follow up: no “functional benefit”

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

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

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

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

9. 9

10. 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. 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. 12 Literature review  Meta-analysis of dialysis patients (2004)  Hb 13  RR =.04 (0.71 to 1.0)

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

14. 14 Clinical equipoise justifies randomization 1. Experts find current evidence inconclusive or conflicting If experts disagree or uncertain, no harm to participants 2. Clinicians willing to enroll patients

15. 15 Clinical equipoise justifies randomization 3. Participant agrees to be randomized Should be told results of pertinent other trials

16. 16 Outcomes at 16 months Hgb 13.5Hgb 11.3 N=715N=717 Endpoint125 97 17.5%13.5% Hazard ratio 1.34, 95% CI = 1.03-1.74

17. 17 Outcomes at 16 months Hgb 13.5 Hgb 11.3 N=715N=717 Death52 (7.3%)35 (5.0%) CHF 64 (9.0%)47 (6.6%)

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

20. 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. 21 ENHANCE trial  Press release Jan 2008  No benefit on plaque progression

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

23. 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. 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. 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. 29 Conflicts of interest  Primary mission of clinical trial investigator is to generate valid knowledge  Different than drug marketing or sales

30. 30 Responses to conflicts of interest in clinical trials 1. Disclose  To institution, IRB, participants  Doesn’t prevent bias

31. 31 Responses to conflicts of interest 2. 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. 32 Responses to conflicts of interest 3. Forbid certain actions or situations  Authors must have Access to data Control over data analysis Freedom to publish

34. 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. 35 VIGOR adverse effects  More MIs on refecoxib (0.4 vs 0.1)  Attributed to protective effect of naproxen

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

37. 37 What should authors do about inaccurate findings?

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

39. 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. 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. 41 Selection of endpoint in APPROVe  Academic authors said they were just following the protocol from sponsor

42. 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. 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. 44 Concerns raised by rofecoxib trials  Invalid and biased presentation of results  Defenses against bias ineffective  Academic investigators

45. 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