Correspondence

The Ethics of Placebo-Controlled Trials

N Engl J Med 2002; 346:382-383January 31, 2002

Article

To the Editor:

Emanuel and Miller (Sept. 20 issue)1 characterize the current debate about placebo-controlled trials as a debate between two orthodoxies: placebo orthodoxy and active-control orthodoxy. We used the term “placebo orthodoxy” to describe the widely held but incorrect view that the use of a placebo control is always better than the use of an active control.2,3 Labeling our position “active-control orthodoxy” wrongly suggests that we believe that “if an effective therapy exists, the use of a placebo should be prohibited” in all cases.1 We do, however, represent a clinical-equipoise orthodoxy in believing that therapeutic interventions in research must be consistent with physicians' duty of care to patients.4 Mounting a trial requires genuine disagreement among expert practitioners as to the preferred treatment.4 If expert clinicians hold, as we believe they do, that not treating baldness or headaches is consistent with competent medical practice, then a placebo control is permissible. No competent clinician believes that withholding treatment from a severely depressed or schizophrenic patient is acceptable, and hence placebo-controlled trials in such cases are unethical.5

Emanuel and Miller assert, but neither argue nor prove, that the use of placebo controls and not active controls are required for scientific validity.1 They further claim that the requirement of scientific validity provides ethical justification for the use of placebo, thus leaving no room for the limitation of harm in trials. By claiming different moral standards for clinical research and clinical care, they can no longer answer the fundamental question in clinical research: When is it ethically acceptable for physicians to suggest that their patients enroll in a trial?4 This question is answered by clinical equipoise, making the protection of patients a cost of the ability to perform trials at all.

Charles Weijer, M.D., Ph.D.
Dalhousie University, Halifax, NS B3H 4H7, Canada
charles.weijer@dal.ca

Kathleen Cranley Glass, D.C.L.
McGill University, Montreal, QC H3A 1W9, Canada

5 References

1. 1

   Emanuel EJ, Miller FG. The ethics of placebo-controlled trials -- a middle ground. N Engl J Med 2001;345:915-919
   Full Text | Web of Science | Medline

2. 2

   Freedman B, Weijer C, Glass KC. Placebo orthodoxy in clinical research. I. Empirical and methodological myths. J Law Med Ethics 1996;24:243-251
   CrossRef | Web of Science | Medline

3. 3

   Freedman B, Glass KC, Weijer C. Placebo orthodoxy in clinical research. II. Ethical, legal, and regulatory myths. J Law Med Ethics 1996;24:252-259
   CrossRef | Web of Science | Medline

4. 4

   Weijer C. The ethical analysis of risk. J Law Med Ethics 2000;28:344-361
   CrossRef | Web of Science | Medline

5. 5

   Weijer C. Placebo-controlled trials in schizophrenia: are they ethical? Are they necessary? Schizophr Res 1999;35:211-218
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Central to research ethics is the distinction between clinical care and clinical research.1-3 Weijer and Glass muddle this distinction by claiming that “therapeutic interventions in research must be consistent with physicians' duty of care to patients.” The goal of all clinical research is to improve health care by testing scientific hypotheses, not by providing personalized care. The fundamental duty of clinical investigators is to avoid exploiting research participants.3,4 This is not ethically equivalent to a physician's therapeutic duty to provide optimal care to patients. Without an understanding of this difference, it would never be ethical for investigators to perform research procedures on patient volunteers, such as blood sampling, lumbar punctures, positron-emission tomographic scanning, and biopsies, which pose some risks without offering compensating personal benefits.

In our article we describe criteria for the ethical justification of placebo-controlled trials according to which they should be ruled out if research participants would be exposed to risks of substantial harm, including severe discomfort. These criteria are consistent with the responsibility to avoid exploiting research participants. Consequently, Weijer and Glass's claim that our position leaves “no room for the limitation of harm in trials” seems puzzling.

Finally, reflecting their conflation of clinical care and clinical research, Weijer and Glass assert that “the fundamental question in clinical research” is, “When is it ethically acceptable for physicians to suggest that their patients enroll in a trial?” They surely are mistaken. This is a secondary question. It presupposes a satisfactory answer to the prior question: When is it ethically justifiable to conduct a randomized clinical trial? We provide clear guidance on this question when the trial includes a placebo control.

Ezekiel J. Emanuel, M.D., Ph.D.
Franklin G. Miller, Ph.D.
National Institutes of Health, Bethesda, MD 20892-1156
fmiller@nih.gov

4 References

1. 1

   National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont report: ethical principles and guidelines for the protection of human subjects of research. Washington, D.C.: Government Printing Office, 1979.
   

2. 2

   Levine RJ. Ethics and regulation of clinical research. 2nd ed. New Haven, Conn.: Yale University Press, 1986:3-10.
   

3. 3

   Miller FG, Rosenstein DL, DeRenzo EG. Professional integrity in clinical research. JAMA 1998;280:1449-1454
   CrossRef | Web of Science | Medline

4. 4

   Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? JAMA 2000;283:2701-2711
   CrossRef | Web of Science | Medline

Citing Articles (4)

Citing Articles

1. 1

   Maurice Y. Mommaerts, Murray E. Foster, Karsten K.H. Gundlach. (2011) How to do clinical research in cranio-maxillo-facial surgery. Journal of Cranio-Maxillofacial Surgery
   CrossRef

2. 2

   Sven Ove Hansson. (2006) Uncertainty and the Ethics of Clinical Trials. Theoretical Medicine and Bioethics 27:2, 149-167
   CrossRef

3. 3

   Charles Weijer, Paul B Miller. (2004) When are research risks reasonable in relation to anticipated benefits?. Nature Medicine 10:6, 570-573
   CrossRef

4. 4

   Sven Ove hansson. (2004) Weighing Risks and Benefits. Topoi 23:2, 145-152
   CrossRef