Originally published as JCO Early Release 10.1200/JCO.2007.13.5335 on January 28 2008

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Ethical, Scientific, and Regulatory Perspectives Regarding the Use of Placebos in Cancer Clinical Trials

Christopher K. Daugherty, Mark J. Ratain, Ezekiel J. Emanuel, Ann T. Farrell, Richard L. Schilsky

From the University of Chicago, Pritzker School of Medicine, Chicago, IL; Clinical Center, National Institutes of Health, Bethesda; United States Food and Drug Administration, Rockville, MD

Corresponding author: Richard L. Schilsky, MD, University of Chicago, Pritzker School of Medicine, 5841 South Maryland Ave, MC 2115, Chicago, IL 60637-1463; e-mail: rschilsk{at}medicine.bsd.uchicago.edu

Purpose: To examine the ethical, scientific, and regulatory issues in the design and conduct of placebo-controlled cancer clinical trials.

Methods: Several content experts contributed to this article.

Results: Specific criteria can be applied to determine the appropriate use of placebos in oncology drug development. Placebo controls may be justified to prove efficacy of a new treatment in diseases with high placebo response rates; in conditions that wax and wane in severity, have spontaneous remissions, or have an uncertain and unpredictable course; when existing therapies are minimally effective or have serious adverse effects; or in the absence of effective therapy. Use of placebos may also be justified to assure blinding of physicians and patients regarding treatment assignment so as to minimize bias in assessment of study end points. If a trial meets these methodologic criteria, it must then fulfill additional criteria to be considered ethical. These criteria include full disclosure to patients and an assurance that participants randomly assigned to placebo are not substantially more likely than those in active treatment group(s) to die; suffer irreversible morbidity, disability, or other substantial harms; suffer reversible but serious harm; or suffer severe discomfort.

Conclusion: We conclude that placebo-controlled oncology trials are scientifically feasible, ethically justifiable, and may be necessary or desirable to meet regulatory standards for drug approval. Using cross-over or randomized withdrawal trial designs, requiring inclusion of state-of-the-art palliative care, and developing valid and acceptable surrogates for survival are critical strategies to address some of the ethical dilemmas associated with placebo-controlled trials.

published online ahead of print at www.jco.org on January 28, 2008.

Reviewed and approved by the American Society of Clinical Oncology Board of Directors, July 12, 2007.

Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA.

The views expressed in this article are the result of independent work and do not necessarily represent the views and findings of the United States Food and Drug Administration.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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