The fifty-second revision of the Declaration of Helsinki included a statement that proscribed, on an ethical basis, the use of placebo in clinical research when treatment is available. Scientific methods suggest that this determination could affect the validity of research in conditions that show placebo response. Researchers became concerned about the impact that this could have on the quality of drug development. Although the clarification to the Declaration of Helsinki reversed this position, the situation called for revisions to the ethical implications of the use of placebo. Most authors agree that placebo is unacceptable in life-threatening diseases or when there is a risk of irreversible damage, but other instances require evaluation on a case-to-case basis. Institutional review boards (IRBs) have to consider the principles of research ethics when deciding whether to approve or reject placebo-controlled studies. Some algorithms to review placebo-controlled studies on ethical grounds have been published Based on these efforts and the ethical and methodological considerations derived from our own IRB experiences, the authors of this paper have designed a checklist to assist IRBs in the evaluation of placebo-controlled studies. The checklist was tested in IRB meetings and modified to better reflect the needs expressed in the discussions. It has been useful in guiding deliberations and obtaining consistency in the evaluation of placebo-controlled studies.
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World Medical Association. 52nd Revision of the Declaration of Helsinki. General Assembly. Edinburgh, Scotland; October 2000.
World Medical Association. Newsletter, October 2001. Declaration of Helsinki: Note of Clarification on placebo-controlled trials. Available at: www.wma.net/e/home.html. (Accessed October 16, 2001).
US Code of Federal Regulations. Food and Drug Administration; 21 CFR Parts 50 and 56.
US Code of Federal Regulation. National Institutes of Health; 45 CFR Part 46.
Baruch AB. When are placebo-controlled trials no longer appropriate? Control Clin Trials. 1997;18:602–612.
Cleophas TJM, Meulen J, Kalmansohn RB. Clinical trials: specific problems associated with the use of a placebo control group. Br J Clin Pharmacol. 1997;43:219–221.
Simon R. Are placebo-controlled clinical trials ethical or needed when alternative treatment exists? Ann Intern Med. 2000;133:474–475.
Ezequiel E. The ethics of placebo-controlled trials—a middle ground. N Engl J Med. 2001;64: 915–919.
Bostrom H. Placebo—the forgotten drug. Scand J Work Environ Health. 1997;64 Suppl 3:53–57.
Ilnyckyj A, Shanahan F, Anton PA, Cheang M, Bernstein CN. Quantification of the placebo response in ulcerative colitis. Gastroenterology. 1997;113:2021–2022.
Villani P, Bouvenot G. Assessment of the placebo effect of symptomatic slow acting anti-arthritics. Presse Med. 1998;27:211–214.
Preston RA, Materson BJ, Reda DJ, Williams DW. Placebo-associated blood pressure response and adverse effects in the treatment of hypertension: observation from a Department of Veterans Affairs Cooperative Study. Arch Intern Med. 2000;160:1449–1454.
Brody H. The lie that heals: the ethics of giving placebos. Ann Intern Med. 1982;97:112–118.
Biller N. The placebo effect: mocking or mirroring medicine? Perspectives Biol Med. 1999;42:398–401.
Hrobjartsson A, Gotzsche PC. Early intervention in HIV infection: where are we? AIDS Res Hum Retroviruses. 1994;10:893–899.
Swartzman LC, Burkell J. Expectations and the placebo effect in clinical drug trials: Why we should not turn a blind eye to unwinding, and other cautionary notes. Clin Pharmacol Ther. 1998;64.
Chassany O, Duracinsky M. Ethics and clinical trials. Fundam Clin Pharmacol. 1999;13:437–444.
Quitkin FM. Placebos, drug effects, and study design: a clinician’s guide. Am J Psychiatry. 1999;156:829–836.
Rossner S. Sibutramine—antidepressive agent tested against obesity. Lakartidningen. 2001;64:98.
Chouinard G, Annable L, Bradwejn J. An early phase II clinical trial of tomoxetine (LY139603) in the treatment of newly admitted depressed patients. Psychopharmacology. 1984;83:126–128.
US Food and Drug Administration. FDA talk paper T97-57. FDA Approved Sibutramine to Treat Obesity. Rockville, MD: US Department of Health and Human Services, US Food and Drug Administration; Nov 24, 1997.
Spencer T, Biederman J, Heiligenstein J, Wilens T, Faries D, Prince J, Faraone SV, Witcher J, Zervas S. An open label, dose ranging study of atomoxetine in children with attention deficit hyperactivity disorder. J Child Adolesc Psychopharmacol. 2001;11:251–265.
Weiner M, Weiner G. The kinetics and dynamics of responses to placebo. Clin Pharmacol Ther. 1996;60:247–254.
Temple R, Ellenberg S. 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.
Mavissakalina M. The placebo effect in agoraphobia II. J Nerv Ment Dis. 1988;176:446–448.
Weijer C. Placebo-controlled trials in schizophrenia: are they ethical? Are they necessary? Schizophr Res. 1999;35:211–218,227–236.
Ellenberg S, Temple R. Placebo-controlled trials and active-control trials in the evaluation of new treatments. Part 2: Practical Issues and Specific Cases. Ann Intern Med. 2000;133:464–470.
Fabre LF, Putman HP 3rd. A fixed-dose clinical trial of fluoxetine in outpatients with major depression. J Clin Psychiatry. 1987;48:406–408.
Hasselblad V, King DF. Statistical methods for comparison to placebo in active-control trials. Drug Inf J. 2001;35:435–449.
Belmont Report. Ethical Principles and Guidelines for the Protection of Human Subjects of Research. Federal Register, Document 79-12065.
Beauchamp TL, Childress JF. Principles of Biomedical Ethics. 5th Edition. New York, NY: Oxford University Press; 2001:9–23.
De Abajo FJ, Gracia DM. Ethics of the use of placebo in clinical research. Investigation Sci. November 1997:90–99.
Rothman KJ, Michels KB. The continuing unethical use of placebo controls. N Engl J Med. 1994;331:394–398.
De Deyn PP, D’Hooge R. Placebos in clinical practice and research. J Med Ethics. 1996;22:140–146.
Gelmon K, Weller IV. Randomized placebo controlled trials in HIV infection: to be or not to be? Genitourin Med. 1989;65:143–145.
Aldhous P. AIDS drug tests: placebo or no placebo? Nature. 1990;64:95.
Somberkoff MS, Hartigan PM, Hamilton JD. Ethical dilemma in continuing a zidovidune-placebo trial in symptomatic human immunodeficiency virus infection. Trans Assoc Am Physicians. 1991;104:92–96.
Collier AC. Early intervention in HIV infection: where are we? AIDS Res Hum Retroviruses. 1994;10:893–899.
Social Sciences and Humanities Research Council of Canada Policies. Ethical conduct for research involving human subjects, Article 7.4. Ottawa, Canada: Social Sciences and Humanities Research Council; September 17, 1998.
Draft ICH Consensus Guideline E10—Parts 2 and 3. Choice of control group in clinical trials. Good Clinical Practice J. 1999;6:38–45.
Funding for this project was provided by Western Institutional Review Board.
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Cavazos, N., Forster, D. & Bowen, A.J. Ethical Concerns in Placebo-Controlled Studies: An Analytical Approach. Ther Innov Regul Sci 36, 249–259 (2002). https://doi.org/10.1177/009286150203600203
- Ethical review
- Declaration of Helsinki