Robert Temple, MD; Susan S. Ellenberg, PhD
In recent years, several authors have argued that placebo-controlled trials are invariably unethical when known effective therapy is available for the condition being studied, regardless of the condition or the consequences of deferring treatment. Some have also disputed the value of placebo-controlled trials in such a setting, asserting that the comparison of new treatment with old treatment is sufficient to establish efficacy and is all that should be of interest. This article considers the ethical concerns about use of placebo controls and describes the limited ability of active-control equivalence (also known as noninferiority) trials to establish efficacy of new therapies in many medical contexts. The authors conclude that placebo-controlled trials are not uniformly unethical when known effective therapies are available; rather, their acceptability is determined by whether the patient will be harmed by deferral of therapy. If patients are not harmed, such trials can ethically be carried out. Furthermore, active-control trials, although valuable, informative, and appropriate in many circumstances, often cannot provide reliable evidence of the effectiveness of a new therapy.
… a comparison between new drug and standard … is convincing only when the new remedy is superior to standard treatment. If it is inferior, or even indistinguishable from a standard remedy, the results are not readily interpretable. In the absence of placebo controls, one does not know if the “inferior” new medicine has any efficacy at all, and “equivalent” performance may reflect simply a patient population that cannot distinguish between two active treatments that differ considerably from each other, or between active drug and placebo. Certain clinical conditions, such as serious depressive states, are notoriously difficult to evaluate because of the delay in drug effects and the high rate of spontaneous improvement, and even known remedies are not readily distinguished from placebo in controlled trials.
Results of Six Trials Comparing Nomifensine, Imipramine, and Placebo
From the Center for Drug Evaluation and Research and the Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Rockville, Maryland.
Disclaimer: The views expressed in these papers are those of the authors. They are similar to the conclusions and principles published in a Food and Drug Administration draft guidance document (33) based on a guideline developed by the International Conference on Harmonization, a body representing regulators and industry from the United States, the European Union, and Japan. The inferential problems associated with use of equivalence designs to show effectiveness are reflected in regulations (15) and guidelines (41).
Requests for Single Reprints: Robert Temple, MD, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 5600 Fishers Lane, HFD-101/WOC II—6014, Rockville, MD 20857.
Current Author Addresses: Dr. Temple: Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 5600 Fishers Lane, HFD-101/WOC II—6014, Rockville, MD 20857.
Dr. Ellenberg: Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, 1401 Rockville Pike, Rockville, Maryland 20852.
Hypothetical results of five studies are shown. The result of each study is shown on the y-axis as the difference between treatments (E − E ), where represents the control and represents the test drug. A positive difference favors the standard drug. Error bars show hypothetical 95% CIs for these differences. Three possible noninferiority margins are shown (M0, M1, M2). For more explanation, see the Appendix.
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Temple R, Ellenberg SS. Placebo-Controlled Trials and Active-Control Trials in the Evaluation of New Treatments. Part 1: Ethical and Scientific Issues. Ann Intern Med. 2000;133:455–463. doi: 10.7326/0003-4819-133-6-200009190-00014
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Published: Ann Intern Med. 2000;133(6):455-463.
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