1. Statistical Topic: Ethics and Trial Design* Elizabeth Garrett-Mayer August 14, 2009 HCC Journal Club * Thanks to my colleague Steve Goodman

2. Outline Ethics in medical research Equipoise Informed consent RCT of CBC vs. CB RCT of sunitinib vs. placebo

3. Shalala Statement Bill Clinton's Secretary of Health and Human Services Protecting Research Subjects – What Must Be Done (NEJM, 9/14/2000) The Problems Informed consent is not perfect Too many researchers not adhering to good clinical practice IRBs under pressure – oversight inadequate Increasing conflicts of interests in CTs

4. Shalala Statement (cont.) The Solutions NIH/FDA aggressive effort to improve education and training Guidelines for informed consent NIH requirement for trial monitoring plans for small trials and FDA guidelines for DSMBs Clarification of conflict of interest regulations Legislation to penalize in cases of violations of “important research practices” ($250K/investigator and $1M/institution)

5. Important Message Ethical tensions pervade every aspect of design, execution, interpretation, and use of clinical research Every choice we make about a study has ethical implications, regardless of whether or not we explicitly consider them.

6. Ethical Theories Utilitariansim – We should aim for “the good” of a world with collectively great happiness Morality concerns objective assessments of states of the world and not individual acts Deontology – We should aim for “the good” of treating people properly: the golden rule of “do unto others…” Morality concerns the rightness of individual acts, regardless of the states of the world they entail

7. The tension Utilitarian One’s chance of getting the best treatment is highest if one lives in a society where treatment choices are governed by RCTs Deontologic You want your physician to give you the treatment s/he and you decide is most likely best for you

8. However…. Helsinki Declaration In medical research on human subjects, considerations related to the well-being of the human subject should take precedence over the interests of science and society

9. Most Important Principle: Equipoise Equipoise is the concept that a clinical trial (esp. an RCT) is motivated by a collective uncertainty about the superiority of one treatment versus its alternative (Piantadosi, 2005) Satisfies the requirement that study participants not be disadvantaged “At the start of the trial, there must be a state of clinical equipoise regarding the merits of the regimens to be tested, and the trial must be designed in such a way as to make it reasonable that if it is successfully conducted, clinical equipoise will be disturbed.” (Freedman, 1987)

10. Equipoise Once equipoise is “disturbed” It is no longer ethical to randomize (or otherwise assign) patients to less effective therapy If trial is done well: lack of efficacy should be clear efficacy should be clear should NOT have a situation where we are unsure! When is it disturbed? interim analysis? early stopping for safety? early stopping for efficacy or futility? end of the study?

11. Informed Consent Clinicians, PIs, Co-Is, CTOs, etc. Understand the CTs (for the most part) Understand the risks and benefits risks differ by phase phase I less likely to improve prognosis phase III is likely to provide standard of care or better We are very used to the idea of trials (RCTs and others) Patients, generally Are unfamiliar with clinical research Put trust in their doctors Assume that they will get “the best” treatment when it is known Do not understand “chance” and “randomization” Assume a trial will help (even Phase I)

12. Informed Consent: 4 criteria Is patient capable of giving consent? Protection for those with diminished capacity (children, prisoners, developmentally disabled, elderly) Recognition of patient vulnerability due to anxiety, or effects prior to treatment Is consent given freely? “Coercion” Refusal to offer certain therapies outside of study settings Change in caregiver due to refusal of consent Is patient given ALL necessary information, including alternatives? Can patient UNDERSTAND information?

13. Informed Consent 6 th -8 th grade reading level No “big” words Short sentences Short and sweet vs. long and tiresome? Conflicts: PI and caregiver? Accrual goals

14. Ethical issues in RCT of CB vs. CBC in metastatic colorectal cancer Sufficient investigation of combination a priori? synergistic/overlapping toxicities? strength of evidence of increased efficacy in phase II study (N=40)? Preliminary data and basis for study design is from a different ‘similar’ regimen Choice of endpoint: PFS death progression last follow-up (censored)

15. Ethical issues in RCT of CB vs. CBC in metastatic colorectal cancer “Unexpected interaction” between two monoclonal antibodies could this have been anticipated with sufficient preliminary data? Interaction in effects on signaling pathway “subtle interactions in intracellular signaling” biological basis for combination?

16. RCTs of new combinations Interesting contrast: for most studies of A vs. A+B patients want combination arm equipoise questionable: how can adding an active agent be worse? sometimes one-sided approach to testing often have 2:1 randomization favoring the combination

17. Adding cetuximab Major differences in QoL AND PFS QoL difference not discussed very much Overall survival not different Significant increase in grade 3&4 toxicities attributes to cetuximab

18. Adding cetuximab: potential problem with interpretation 81 (26%) and 99 (30%) of patients discontinued due to adverse events in the CB and CBC arms (respectively). But, at what time did the discontinuations occur? Time to discontinuation is likely important patients who discontinue earlier are more likely to have earlier progression current discussion does not address time to discontinuation in two arms can glean some intuition based on number of cycles and duration of treatment median duration (months): 7 CB and 6 CBC median number cycles: 10 CB and 9 CBC

19. Controversial topic in phase III trials: placebo arm Controversial when placebo is not added to some active agent Example: RCT of Sunitinib in advanced GI stromal tumor

21. Ethical issues in RCT of Sunitinib in advanced GI stromal tumor 2:1 ratio of Sutent vs. placebo Does that make us question equipoise? Is it for patient accrual? Phase I/II study showed “promising activity” Little response Significant stable disease

22. Ethical issues in RCT of Sunitinib in advanced GI stromal tumor Cross-over included (but didn’t help) Double-Blinded: maintains equipoise Interim analyses after 141 and 211 progressions Valid design Prevalent problem in “frequentist” statistics: need to wait At what point COULD we have stopped?

23. Observed Data What if they had looked at the data earlier in the study?

24. Why not single arm? What is standard of care? No 2 nd line treatments after failure of imatinib Was this ethically designed? Revised Helsinki Declaration (section 29) The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic and therapeutic methods. This does not exclude the use of placebo, or no treatment, where no proven prophylactic. diagnostic or therapeutic method exists. What design would you have felt most comfortable with? as a researcher, which is the best design? would you encourage your family member to go on this trial?