Clarifying standards for using placebos.

In her article “Ethics group gives qualified nod to placebos” (News of the Week, 14 Feb., p. [995][1]), Gretchen Vogel notes that the European Group on Ethics in Science and New Technologies has judged that “placebo-controlled trials can sometimes be justified in developing countries, even when proven treatments are available in wealthy countries.” As she correctly points out, this is contrary to the Declaration of Helsinki, a declaration of the World Medical Association that gives worldwide standards for clinical research ethics, as it was revised in 2000. However, the World Medical Association issued a clarification in 2001 and, with minor revisions, incorporated this clarification into its 2002 revision of the Declaration ([1][2]). The relevant passage in this clarification states: “[A] placebo-controlled trial may be ethically acceptable, even if proven therapy is available… [w]here for compelling and scientifically sound methodological reasons its use is necessary to determine the efficacy or safety of a prophylactic, diagnostic or therapeutic method…” The statement of the European Group is not clearly incompatible with the current Declaration of Helsinki. This is because the recent clarification is not very clear. Indeed, the many critics of the 2000 version of the Declaration who protested that its position on placebo use was overly restrictive are now concerned that the clarified version may be interpreted as being overly permissive. We prefer the much clearer guidance on this matter provided in the Council of International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines for Biomedical Research Involving Human Subjects (revised version issued in 2002) ([2][3]). The relevant passage is the following: “An exception to the general rule (requiring established effective treatment as the control condition) is applicable in some studies designed to develop a therapeutic… intervention for use in a country… in which an established effective intervention is not available and unlikely in the foreseeable future to become available, usually for economic or logistic reasons. The purpose of such a study is to make available to the population of the country… an effective alternative to an established effective intervention that is locally unavailable. Accordingly, the proposed investigational intervention must be responsive to the health needs of the population from which the research subjects are recruited and there must be assurance that, if it proves to be safe and effective, it will be made reasonably available to that population. Also, the scientific and ethical review committees must be satisfied that the established effective intervention cannot be used as comparator because its use would not yield scientifically reliable results that would be relevant to the health needs of the study population. In these circumstances an ethical review committee can approve a clinical trial in which the comparator is other than an established effective intervention, such as placebo or no treatment or a local remedy.” The guidelines issued by the European Group are generally compatible with, albeit not as specific as, the CIOMS statement. Each of these ethics statements now seems to require a protocol-by-protocol judgment of the ethical issues, rather than a categorical rejection of the use of placebo where standard treatment exists. We have recently suggested guidelines for exercising such judgment when evaluating proposals to use placebo-controlled studies, using as an illustration the evaluation of treatments for schizophrenia ([3][4]). 1. 1.[↵][5]World Medical Association Declaration of Helsinki as amended by the 52nd WMA General Assembly, Edinburgh, Scotland, October 2000; Note of Clarification on Paragraph 29 added by the WMA General Assembly, Washington, DC, 2002. 2. 2.[↵][6]1. Council for international Organizations of Medical Sciences (CIOMS) , International ethical guidelines for biomedical research involving human subjects (CIOMS, Geneva, 1993). 3. 3.[↵][7]1. W. T. Carpenter, 2. P. S. Appelbaum, 3. R. J. Levine , Am. J. Psychiatry 160, 356 (2003). 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