Ethical issues in clinical trials

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

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. Questions • Would you approve study as IRB member? • Would you refer patients as MD? • Would you enroll as participant?

4. 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 • Informed participant agrees to be randomized

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

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

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. 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. 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

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

12. Case 1. PPIs in GI bleeding Active Control p Major rebleed 72h 5.9% 10.3% .03 Surgery 2.7% 5.4% NS Death 0.8% 2.1% NS

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. Questions?

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

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

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

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

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. Questions?

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