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Placebo-Controlled Trials and Active-Control Trials in the Evaluation of New Treatments. Part 1: Ethical and Scientific Issues
- Robert Temple, MD; and
- Susan S. Ellenberg, PhD
- From the Center for Drug Evaluation and Research and the Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Rockville, Maryland.
Abstract
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.
- Placebos
- Clinical trials, double-blind method
- Ethics, medical
- Informed consent
- Outcome and process assessment (health care)
Article and Author Information
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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 They are similar to the conclusions and principles published in a Food and Drug Administration draft guidance document (33) based on a guideline developed by the International Conference on Harmonization, a body representing regulators and industry from the United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).
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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.
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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.
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Dr. Ellenberg: Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, 1401 Rockville Pike, Rockville, Maryland 20852.
- Copyright ©2004 by the American College of Physicians
