1. 1 Ethical issues in clinical trials Bernard Lo, M.D. February 10, 2010

2. 2 Case 1. PPIs in GI bleeding  IV esomprazole vs. placebo  All then received oral esomeprazole  Major upper ulcer bleed  Documented on endoscopy  Variable endoscopic treatment

3. 3 Questions 1. Would you approve study as IRB member? 2. Would you refer patients as MD? 3. Would you enroll as participant?

4. 4 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 3. Informed participant agrees to be randomized

5. Systematic reviews  H2 blockers not beneficial in DU bleeding, may be beneficial in GU (2002) 5

6. Systematic reviews  PPI reduces rebleeding and surgery in ulcer bleeding (2005)  Robust conclusions Highest quality studies Randomize after endoscopic Rx Some used H2 blocker as control 6

7. 7 Interventions for control group: Helsinki #29 (2000)  Interventions must be tested against “best current prophylactic, diagnostic, and therapeutic methods”  Rejected “highest attainable and sustainable” www.wma.net

8. 8 Interventions for control group: NBAC report (2001)  Studies must address priorities of host country  Pertinent research question may be: is a limited intervention better than current (no) care? http://bioethics.georgetown.edu/nbac/

9. 9 Interventions for control group: Helsinki (2008)  Placebo necessary to determine safety and efficacy  Compelling and scientifically sound methodological reasons  No serious and irreversible harm www.wma.net

10. Views of sponsor  Deficiencies in prior studies  Differences from prior studies  Approved by regulatory agencies  Variable response to placebo in clinical trials in PUD, depression  FDA not an ethics board 10

11. Options for IRB  Do not approve trial  Require participants to be informed  Meta-analysis results showing effectiveness  Availability off study 11

12. 12 Case 1. PPIs in GI bleeding ActiveControl p Major rebleed 72h5.9%10.3%.03 Surgery2.7% 5.4%NS Death0.8% 2.1%NS

13. 13 Use of placebo controls  Withholding effective therapy harms participants and is unethical  Unless patient fails or cannot tolerate  Unless minor, self-limiting condition  Unless great variation in efficacy from trial to trial

14. 14 Questions?

16. 16 Background  Placebo controls  Withholding negative results from clinical trials  BL experience with withdrawal and challenge studies

17. 17 Clinical trials of antidepressants  Some patients with major depression worsen on medications  How to protect participants in clinical trials?

18. 18 Opportunities to protect participants  At enrollment  During the trial  After cases are identified

19. 19 At enrollment  Exclude persons  At high risk for suicide Previous attempts  Poor support systems Require friend or relative  Poor access to psychiatric care

20. 20 During the study: If suicidality identified  Close monitoring for suicidality  Pact with patient  Monitoring by family or friend  Plan for how to respond  Train staff  Referral to psychiatric care  Count suicidality as treatment failure

21. 21 During the study: If suicidality identified  Remove participant from study  Need personal physician to treat patient off- protocol  May need more intensive therapy

22. 22 After cases are identified  Medical monitor  Are procedure to respond to suicidality appropriate?  DSMB  What increase in suicidality in one arm of trial would be clinically significant and warrant stopping the trial if statistically meaningful?

23. 23 Questions?

24. 24 Take home points  Ethical issues occur at each stage of clinical trial  Cannot rely on sponsor, FDA, IRB to assure that ethical issues addressed  Responsibility of investigator

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