Uncertainty in Clinical Research

Katz J. , The Silent World of Doctor and Patient (New York: Free Press, 1984), 165–66.

Levine R.J. , Ethics and Regulation of Clinical Research, 2d ed. (Baltimore: Urban & Schwarzenberg, 1986), 187ff.

Although this is the typical form of expression of the null hypothesis, it would be more accurate to say “therapy A = therapy B in the accomplishment of objective O in population P,” where objective O is the endpoint under examination (e.g., lowering of blood pressure) and population P is a subset of those patients with disease D (e.g., essential hypertension) who have the necessary attributes (inclusion criteria and lack of exclusion criteria) to be eligible for participation in the RCT.

Levine R.J. , supra note 2, at 188–89.

Fried C. , Medical Experimentation: Personal Integrity and Social Policy (New York: American Elsevier Company, 1974), 51 ff.

Shaw L.W. and Chalmers T.C. , “Ethics in Cooperative Trials”, Annals of the New York Academy of Sciences, 169 (1970): 487–95.

Chalmers T.C. Block J.B. and Lee S. , “Controlled Studies in Clinical Cancer Research”, New England Journal of Medicine, 287 (1972): 75–78.

Levine R.J. , supra note 2, at 187–88.

Cato A.E. and Cook L. , “Clinical Research”, in Matoren G.M. , ed., The Clinical Research Process in the Pharmaceutical Industry (New York: Marcel Dekker, Inc., 1984), 217–38.

Levine R.J. , supra note 2, at 202–07.

Marquis D. and Stephens R. Siris E.S. and Kemeny M.M. and Levine R.J. . “The Doctor's Unproven Beliefs and the Subject's Informed Choice,” IRB: A Review of Human Subjects Research 10, 2 (May/June 1988): 3–5; Vanderpool H.Y. and Weiss G.B. , “False Data and Last Hopes: Enrolling Ineligible Patients in Clinical Trials”, Hastings Center Report, 17, 2, (April 1987): 16–19.

Shaw L.W. and Chalmers T.C. , supra note 6.

Friedman L. and Demets D. , “The Data Monitoring Committee: How It Operates and Why”, IRB: A Review of Human Subjects Research 3, 4, (April 1981): 6–8.

Ethics Advisory Board, Department of Health and Human Services, “The Request of the National Institutes of Health for a Limited Exemption from the Freedom of Information Act,” Report Submitted to the Secretary, DHHS, May 21, 1980.

Freedman B. , “Equipoise and the Ethics of Clinical Research”, New England Journal of Medicine, 317 (1987): 141–145.

Katz J. , supra note 1, at 189.

Chalmers T.C. , “The Ethics of Randomization as a Decision Making Technique and the Problem of Informed Consent”, in USDHEW Report of the 14th Annual Conference of Cardiovascular Training Grant Program Directors (Bethesda, MD: National Heart Institute, 1967). As cited by C. Fried, supra note 5.

Levine R.J. , supra note 2, at 194 ff.

Chalmers T.C. , “The Clinical Trial”, Milbank Memorial Fund Quarterly, 59 (1981): 324–339.

Taylor K.M. Margolese R.G. and Soskolne C.L. , “Physicians' Reasons for Not Entering Eligible Patients in a Randomized Clinical Trial of Surgery for Breast Cancer”, New England Journal of Medicine, 310 (1984): 1363–67.

A full discussion of prerandomization designs is beside the point of this article; such a discussion may be found in Levine R.J. , supra note 2, at 194–97.

Ellenberg S.S. , “Randomization Designs in Comparative Clinical Trials”, New England Journal of Medicine 310 (1984): 1404–08.

Actually, most consent forms for placebo-controlled RCTs which I have seen do not use the expression, “it is not known.” Many of them provide information based upon which prospective subjects could make either of two seemingly inconsistent inferences: 1) The consent form usually refers to preliminary evidence that the active drug is effective and labels the placebo as “an inert substance.” In presenting the risks of placebo, it may also refer to the perils of withholding active therapy. From such information the prospective subject could reasonably infer that the investigator already believes that the active drug is more likely than not to prove superior to placebo. 2) Institutional Review Boards (IRBs) generally constrain investigators from making clear statements that the investigational drug is likely to be effective, reasoning that if this were already known, it would invalidate the null hypothesis used to justify the RCT. Following this reasoning, grounded in the concept of theoretical equipoise, it is considered unethical to tell subjects that a new drug is likely to be effective until the RCT demonstrates that it is. IRBs generally require that subjects be informed that “the purpose of this study is to determine whether the drug is effective.” Since in order to do this it will be compared with placebo, the subject could infer that “it is not known whether the new drug is better or worse than placebo.”

Levine R.J. , “The Use of Placebos in Randomized Clinical Trials”, IRB: A Review of Human Subjects Research, 7, 2 (March/April 1985): 1–4.

Id.

For further discussion of such justification, see Levine R.J. , supra note 2, at 202–06.

Schafer A. , “The Ethics of the Randomized Clinical Trial”, New England Journal of Medicine, 307 (1982): 719–24.

Marquis D. , “Leaving Therapy to Chance”, Hastings Center Report, 13, 4 (August 1983): 40–47.

Meier P. , “Terminating a Trial—the Ethical Problem”, Clinical Pharmacology & Therapeutics, 25 (1979): 633–40.

Freedman B. , supra note 15.

Levine R.J. , supra note 2, at 202ff.

Fischl M. , “The Efficacy of Azidothymidine (AZT) in the Treatment of Patients with AIDS and AIDS-Related Complex”, New England Journal of Medicine, 317 (1987): 185–91.

Melton G.B. , “Community Consultation in Socially Sensitive Research: Lessons from the Clinical Trials of Treatments for AIDS”, American Psychologist (in press).

For further elaboration of this point including the specifics of what ought to be disclosed and explained, see Levine R.J. , supra note 2, at 200–01.

Committee on Policy for DNR Decisions, Yale-New Haven Hospital, “Report on Do Not Resuscitate Decisions,” Connecticut Medicine 47 (1983): 477–83.

Id.; Levine R.J. and Nolan K.A. , “Do Not Resuscitate Decisions: A Policy,” Connecticut Medicine, 47 (1983): 511–12.

Katz J. , supra note 1, at xvi.

I have discussed the leading criticisms of RCTs in Levine R.J. , supra note 2, at 207–210.

Feinstein A.R. , “An Additional Basic Science for Clinical Medicine: II. The Limitations of Randomized Trials”, Annals of Internal Medicine, 99 (1983): 544–50.

Feinstein A.R. , “An Additional Basic Science for Clinical Medicine: IV. The Development of Clinimetrics”, Annals of Internal Medicine, 99 (1983): 843–48.

Diamond G.A. and Forrester J.S. , “Clinical Trials and Statistical Verdicts: Probable Grounds for Appeal”, Annals of Internal Medicine, 98 (1983): 385–94.

A full discussion of why some statisticians prefer Bayesian methods is beyond the scope of this discussion. For a very lucid exposition of the problem in which the relevant concepts are made accessible to the relatively unsophisticated reader, see Berger J.O. and Berry D.A. , “Statistical Analysis and the Illusion of Objectivity”, American Scientist, 76 (1988): 159–65.