Ethical Concerns in Placebo-Controlled Studies: An Analytical Approach

  • Nora CavazosEmail author
  • D. Forster
  • A. J. Bowen


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.

Key Words

Placebo Ethical review IRB Declaration of Helsinki 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    World Medical Association. 52nd Revision of the Declaration of Helsinki. General Assembly. Edinburgh, Scotland; October 2000.Google Scholar
  2. 2.
    World Medical Association. Newsletter, October 2001. Declaration of Helsinki: Note of Clarification on placebo-controlled trials. Available at: (Accessed October 16, 2001).Google Scholar
  3. 3.
    US Code of Federal Regulations. Food and Drug Administration; 21 CFR Parts 50 and 56.Google Scholar
  4. 4.
    US Code of Federal Regulation. National Institutes of Health; 45 CFR Part 46.Google Scholar
  5. 5.
    Baruch AB. When are placebo-controlled trials no longer appropriate? Control Clin Trials. 1997;18:602–612.CrossRefGoogle Scholar
  6. 6.
    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.CrossRefGoogle Scholar
  7. 7.
    Simon R. Are placebo-controlled clinical trials ethical or needed when alternative treatment exists? Ann Intern Med. 2000;133:474–475.CrossRefGoogle Scholar
  8. 8.
    Ezequiel E. The ethics of placebo-controlled trials—a middle ground. N Engl J Med. 2001;64: 915–919.Google Scholar
  9. 9.
    Bostrom H. Placebo—the forgotten drug. Scand J Work Environ Health. 1997;64 Suppl 3:53–57.Google Scholar
  10. 10.
    Ilnyckyj A, Shanahan F, Anton PA, Cheang M, Bernstein CN. Quantification of the placebo response in ulcerative colitis. Gastroenterology. 1997;113:2021–2022.Google Scholar
  11. 11.
    Villani P, Bouvenot G. Assessment of the placebo effect of symptomatic slow acting anti-arthritics. Presse Med. 1998;27:211–214.PubMedGoogle Scholar
  12. 12.
    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.CrossRefGoogle Scholar
  13. 13.
    Brody H. The lie that heals: the ethics of giving placebos. Ann Intern Med. 1982;97:112–118.CrossRefGoogle Scholar
  14. 14.
    Biller N. The placebo effect: mocking or mirroring medicine? Perspectives Biol Med. 1999;42:398–401.CrossRefGoogle Scholar
  15. 15.
    Hrobjartsson A, Gotzsche PC. Early intervention in HIV infection: where are we? AIDS Res Hum Retroviruses. 1994;10:893–899.CrossRefGoogle Scholar
  16. 16.
    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.CrossRefGoogle Scholar
  17. 17.
    Chassany O, Duracinsky M. Ethics and clinical trials. Fundam Clin Pharmacol. 1999;13:437–444.CrossRefGoogle Scholar
  18. 18.
    Quitkin FM. Placebos, drug effects, and study design: a clinician’s guide. Am J Psychiatry. 1999;156:829–836.CrossRefGoogle Scholar
  19. 19.
    Rossner S. Sibutramine—antidepressive agent tested against obesity. Lakartidningen. 2001;64:98.Google Scholar
  20. 20.
    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.CrossRefGoogle Scholar
  21. 21.
    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.Google Scholar
  22. 22.
    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.CrossRefGoogle Scholar
  23. 23.
    Weiner M, Weiner G. The kinetics and dynamics of responses to placebo. Clin Pharmacol Ther. 1996;60:247–254.CrossRefGoogle Scholar
  24. 24.
    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.PubMedGoogle Scholar
  25. 25.
    Mavissakalina M. The placebo effect in agoraphobia II. J Nerv Ment Dis. 1988;176:446–448.CrossRefGoogle Scholar
  26. 26.
    Weijer C. Placebo-controlled trials in schizophrenia: are they ethical? Are they necessary? Schizophr Res. 1999;35:211–218,227–236.CrossRefGoogle Scholar
  27. 27.
    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.PubMedGoogle Scholar
  28. 28.
    Fabre LF, Putman HP 3rd. A fixed-dose clinical trial of fluoxetine in outpatients with major depression. J Clin Psychiatry. 1987;48:406–408.PubMedGoogle Scholar
  29. 29.
    Hasselblad V, King DF. Statistical methods for comparison to placebo in active-control trials. Drug Inf J. 2001;35:435–449.CrossRefGoogle Scholar
  30. 30.
    Belmont Report. Ethical Principles and Guidelines for the Protection of Human Subjects of Research. Federal Register, Document 79-12065.Google Scholar
  31. 31.
    Beauchamp TL, Childress JF. Principles of Biomedical Ethics. 5th Edition. New York, NY: Oxford University Press; 2001:9–23.Google Scholar
  32. 32.
    De Abajo FJ, Gracia DM. Ethics of the use of placebo in clinical research. Investigation Sci. November 1997:90–99.Google Scholar
  33. 33.
    Rothman KJ, Michels KB. The continuing unethical use of placebo controls. N Engl J Med. 1994;331:394–398.CrossRefGoogle Scholar
  34. 34.
    De Deyn PP, D’Hooge R. Placebos in clinical practice and research. J Med Ethics. 1996;22:140–146.CrossRefGoogle Scholar
  35. 35.
    Gelmon K, Weller IV. Randomized placebo controlled trials in HIV infection: to be or not to be? Genitourin Med. 1989;65:143–145.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Aldhous P. AIDS drug tests: placebo or no placebo? Nature. 1990;64:95.Google Scholar
  37. 37.
    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.Google Scholar
  38. 38.
    Collier AC. Early intervention in HIV infection: where are we? AIDS Res Hum Retroviruses. 1994;10:893–899.CrossRefGoogle Scholar
  39. 39.
    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.Google Scholar
  40. 40.
    Draft ICH Consensus Guideline E10—Parts 2 and 3. Choice of control group in clinical trials. Good Clinical Practice J. 1999;6:38–45.Google Scholar

Copyright information

© Drug Information Association, Inc 2002

Authors and Affiliations

  1. 1.Western Institutional Review BoardOlympiaUSA

Personalised recommendations