1. 1 Clinical trials with stem cells Bernard Lo, M.D. February 12, 2009

2. 2 Questions for class  Anyone know someone with Type I diabetes?

3. 3 Goal of session  Design a clinical trial of stem cell transplantation for Type I diabetes that addresses ethical concerns

4. 4 Rationale for stem cell transplantation  Type I diabetes caused by autoimmune destruction of beta cells, loss of insulin  Long term complications of Type I diabetes despite insulin therapy

5. 5 Rationale for stem cell transplantation  Shortage of donors for Islet cell transplantation  Transplant beta cells  Derived from stem cells  Direct reprogramming of pancreatic exocrine cells

7. Induced pluripotent stem cells (iPS cells)

8. 8 Ethical issues in any clinical trial 1. Risk / benefit balance  Outcomes are uncertain  Participants at risk, but not designed to benefit them  IRB must approve

9. 9 Particular concerns about risk  Pluripotent  Differentiate into unintended cells  Integrate into unintended targets  In vitro manipulation  Reprogramming may go awry

10. 10 Particular concerns about risk  Limited experience in humans  Unexpected adverse events  Long-term adverse effects in chronic illness  Hard to discontinue intervention

11. 11 Ethical issues in any clinical trial 2. Informed consent  “Therapeutic misconception”  IRB tend to require longer consent forms

12. 12 Particular barriers to consent  Strong scientific plausibility  Hope, expectations

13. 13 Question 1. Why not let everyone who wants a stem cell transplant get it? Available in some countries

14. 14 hESC transplants readily available  No information on materials, protocols  No follow-up  No control group  Conflict of interest

15. 15 Questions 2. What are risks of stem cell transplantation?

16. 16 Risks  Might not improve clinical condition  Not produce insulin  Production without regulation  Recurrence of autoimmune destruction  Adverse events  Tumors, cancer

17. 17 Questions 3. How should the consent process be improved?

18. 18 Improving the consent process  Assess comprehension of key features of trial Clinical Trials 2008; 5: 517-522

19. 19 Key features of RCT  Different than clinical care  Not sure that intervention effective or safe  May have serious side effects  May be unexpected  May not be able to reverse the intervention

20. 20 Questions 5. Who should be enrolled in Phase 1 trial?  Children?  Adults?

21. 21 Selection of participants  Children  May be more effective early in disease  Most to lose if severe adverse events  Cannot give informed consent to accept risk  Adults

22. 22 Questions 6. Who should be enrolled in pivotal Phase 3 trial?  Children?  Adults?  Someone who gave research funding?

23. 23 Questions 7. What should be design of Phase 2-3? Sham transplant? Background care in both arms?

24. 24 Questions 8. What should be duration of pivotal Phase 3 trial? 9. At close of trial should control arm be offered transplantation? 10. How assess very long-term benefits and risks?

25. 25 Recommendations for clinical trials 3. Disseminate results even if negative Limits of clinical trials databases Clinical Trials 2008; 5: 517-522

26. 26 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

27. 27