1. Clinical equipoise and RCT design Charles Weijer, MD, PhD

2. The question “Upon what ethical grounds may the physician offer RCT enrollment to a patient?” at least two answers to this question: –uncertainty principle –clinical equipoise which is the preferred moral basis of the RCT?

3. Physician-patient relationship Fiduciary relationship when the physician becomes an investigator other ends come into play Hellman and Hellman (1991): “Consider first the initial formulation of a trial…A new agent that promises more effectiveness is the subject of study. The control group must be given either an unsatisfactory treatment or a placebo. Even though the therapeutic value of the new agent is unproved, if physicians think it has promise, are they acting in the best interests of their patients in allowing them to be randomly assigned to the control group?”

4. The uncertainty principle Peto et al. (1976): “Physicians who are convinced that one treatment is better than another for a particular patient of theirs cannot ethically choose at random which treatment to give: they must do what they think best for the particular patient. For this reason, physicians who feel they already know the answer cannot enter their patients into a trial. If they think, whether for a wise or silly reason, that they know the answer before the trial starts, they should not enter any patients…”

5. Problems Can a physician ever be said to have erred? So long as she maintains she was uncertain she cannot be said to have made an enrollment error -- a problem Peto (1998): qualification of uncertainty with “substantially” and “reasonably” As the moral locus is the individual clinician, we are left with the same problem.

6. Clinical equipoise Freedman (1987): “[t]he ethics of medical practice grants no ethical or normative meaning to a treatment preference, however powerful, that is based on a hunch or anything less than evidence publicly presented and convincing to the clinical community. Persons are licensed as physicians after they demonstrate the acquisition of this professionally validated knowledge, not after they reveal a superior capacity for guessing.”

7. Clinical equipoise Physician norms are not individual but derive from the community of practitioners treatments within a RCT may be consistent with the standard of care owed the patient Offering RCT enrollment is consistent with MD’s duty when “[t]here exists…an honest professional disagreement among expert clinicians about the preferred treatment.”

8. The preferred moral basis Equipoise arises: –evidence accrues as to the benefit of a new drug –split in practice in the clinical community* Freedman (1987): “A state of clinical equipoise is consistent with a decided treatment preference on the part of the investigators. They must simply recognize that their less favored treatment is preferred by colleagues whom they consider to be responsible and competent.” clinical equipoise is the preferred moral basis for the RCT

9. Clinical equipoise -- part II Freedman (1987): “…the trial must be designed in such a way as to make it reasonable to expect that, if it is successfully completed, clinical equipoise will be disturbed. In other words, the results of a successful trial should be convincing enough to resolve the dispute among clinicians.” ethical preconditions of clinical research are framed as an issue in medical epistemology what constitutes good treatment is defined by practice accepted by the community of expert clinicians

10. New area for moral inquiry Ethicists have labored long at the fringes of science (informed consent; limiting scope) clinical equipoise implies that aspects of RCT design are matters of ethical concern Who will be tested? What will be tested? How many will be tested? When will the study be complete? ethicists must now engage scientists in a dialogue as to the nature of good science

11. Who will be tested?

13. Explanatory RCT: narrow study pop’n Freedman (1987): :This approach purchases scientific manageability at the expense of an inability to apply the results to the ‘messy’ conditions of clinical practice…Overly [explanatory] trials, designed to resolve some theoretical question, fail to satisfy the second requirement of clinical research, since the special conditions of the trial will render it useless for influencing clinical decisions even if it is successfully completed.” clinical equipoise requires that research subjects be representative of those in the target clinical population

14. What will be tested? Rothman (1994): “The continuing unethical use of placebo controls.” Regarded by FDA as the gold standard clinical equipoise requires honest, professional disagreement as to the preferred treatment –1st generation treatments: placebo control –2nd generation treatments: active control

15. What will be tested? Freedman (1990) lists five conditions in which a placebo control may be used: there is no standard treatment; standard treatment is no better than placebo; standard treatment is placebo; the net therapeutic advantage of standard treatment has been called into question by new evidence; or effective treatment exists but is not available due to cost or short supply (additional caveats apply).

16. What will be tested? Informed consent and risk-benefit ratio are separate requirements of U.S. regulations Levine (1985): placebo in other contexts would be a non-therapeutic risk IRB must ensure risks “are minimized: (i) by using procedures which are consistent with sound research design and which do not unnecessarily expose subjects to risk.”

17. What will be tested? 1. the incentives are wrong 2. no agreed upon test for statistical significance 3. historical control assumption 4. assay sensitivity each of these propositions has been challenged (Freedman, 1996; Weijer 1999)

18. How many will be tested? Protocol section examined least by IRBs too large : subjects will be exposed unnecessarily to risk too small: unlikely to answer question deeper questions...

19. How many will be tested? Scrutinize components of sample size too type I error: probability of rejecting the null hypothesis when in fact Ho is true equipoise would have us examine the choice relative to the circumstances less conservative may be appropriate for RCT of novel treatments for rare disease

20. How many will be tested? Type II error: probability of failing to reject Ho when in fact Ha is true; power = 1- prob (type II error); typically less conservative repeatedly shown that “negative” RCTs are often “under-powered”: violates equipoise a robust RCT (power = 90% or 95%) would be likely to disturb equipoise even if the RCT result was “negative”

21. When will the study be complete? RCTs with mortality or serious morbidity as an outcome should have a DSMB researcher, clinician, biostatistician, ethicist, community RCT may be stopped early if needed

22. When will the study be complete? DSMBs employ statistical stopping guides: prevent inflation of overall type I error more stringent boundaries are set early in RCT Other crucial questions: How skeptical are clinicians? What is the quality of the data? How much data is in the “pipeline?” Do other published result shed light on the question? Pocock (1993): inevitable sacrifice of “individual ethics” for “collective ethics”

23. When will the study be complete? Clinical equipoise implies that treatments in RCT are consistent with standard of care; “individual ethics” are not compromised the RCT ought to be stopped when moral conditions for its initiation no longer obtain RCT ought to continue until sufficient evidence has been gathered to “resolve the dispute among clinicians.”

24. Conclusion Clinical equipoise is the preferred moral basis of the RCT Important implications for RCT design new moral terrain new relationship between scientists and ethicists

25. Further reading Freedman B. Equipoise and the ethics of clinical research. New England Journal of Medicine 1987: 317: 141-145. Freedman B, Shapiro S. Ethics and statistics in clinical research: towards a more comprehensive examination. Journal of Statistical Planning and Inference 1994; 42: 223-240. Fuks A, Weijer C, Freedman B, et al.. A study in contrasts: eligibility criteria in a twenty-year sample of NSABP and POG clinical trials. Journal of Clinical Epidemiology 1998; 51: 69-79. Shapiro S, Weijer C, Freedman B. Reporting who was studied in clinical trials -- Is there static on the line? Journal of Clinical Epidemiology, forthcoming. Weijer C, Crouch RA. Why should we include women and minorities in randomized controlled trials? Journal of Clinical Ethics 1999; 10: 100-106.

26. Further reading Freedman B. Placebo-controlled trials and the logic of clinical purpose. IRB: A Review of Human Subjects Research 1990; 12(6): 1-6. Freedman B, Weijer C, Glass KC. Placebo orthodoxy in clinical research I: empirical and methodological myths. Journal of Law, Medicine and Ethics 1996; 24: 243-251. Freedman B, Glass KC, Weijer C. Placebo orthodoxy in clinical research II: ethical, legal, and regulatory myths. Journal of Law, Medicine and Ethics 1996; 24: 252-259. Weijer C. Placebo-controlled trials in schizophrenia: Are they ethical? Are they necessary? Schizophrenia Research 1999; 35: 211-218. Weijer C. Thinking clearly about research risk: implications of the work of Benjamin Freedman. IRB: A Review of Human Subjects Research 1999; 21(6): 1-5.