Ethical issues in clinical trials

1. Ethical issues in clinical trials Bernard Lo, M.D. February 16, 2012

2. Conflicts of interest • None

3. Issues to discuss • Use of placebo control where an effective treatment exists • Informed consent • Participants who develop adverse outcomes

4. Osteoporosis RCTs • New drug + background Ca + vit D vs. background alone • Primary end point • Vertebral Fx at 3 y • Nonvertebral Fx, breast CA at 5 years

5. Osteoporosis RCTs • Effective drugs for osteoporosis • Bisphosphonates • Estrogen • SERMs (raloxifene)

6. Does placebo raise ethical concrens if effective treatment exists?

7. Objections to placebo controlsif effective Rx • Withholding effective Rx intentionally harms participants • Unless patient fails or cannot tolerate Rx • Unless minor, self-limiting condition • Unless efficacy varies from trial to trial • Even if participant consents

8. 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

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. Is this serious and irreversible harm? Active Placebo Hip Fx 0.7% 1.2% Vertebral Fx 2.3% 7.2%

11. FDA may insist on placebo • Variable response to active drugs • Depression • Peptic ulcer disease • If active control, can’t tell if either drug superior to placebo in that trial

12. Sponsor perspective • Why use placebo controls?

13. Power • Enrolled 2500 participants • 90% power to detect 40% reduction in vertebral fractures at 3 years • What about power if active control?

14. How to minimize the risk of serious, irreversible harm? • Exclude persons at unacceptable risk • Recent vertebral Fx • T score < - 4.5 • Enroll only those who failed or cannot tolerate other Rx

15. How to minimize the risk of serious, irreversible harm? • Reduce risks during trial • Refer to treating MD if worsen • T score < - 4.5 • Osteoporotic Fx

16. How to minimize the risk of serious, irreversible harm? • Change study design • Make osteoporosis the study endpoint • Problems with surrogate endpoints • Problems with FDA approval

17. How to minimize the risk of serious, irreversible harm? • Do study where poor access to effective drugs? • Involve advocates in trial design

18. Informed consent • Problem of how to ensure participants understand what is in consent form

19. Strategies to enhance comprehension • Spend more time talking to participants • Questions and feedback • Shorter, simpler consent forms • Multimedia -- mixed evidence

20. Strategies to enhance comprehension • Test comprehension of key features of study • In designing consent process, involve • Obstetricians and general internists • Patient advocacy groups

21. Sponsor perspective • How do these suggestions impact on trial?

22. Patient advocate perspective • When participants develop adverse outcomes, concerns about referral to treating MD? • Other approaches?

23. Concerns about referral to treating MD • Poor access to care • Suboptimal management of osteoporosis

24. Other approaches • Information or support for treating MDs • Referral to independent experts in osteoporosis

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

28. Osteoporosis RCTs • Role of sponsor • Designed the protocol • Managed the data • Held the data, carried out statistical analyses requested • Scientific advisory committee planned analyses before unblinding