. "4 Defining, Interpreting, and Applying Concepts of Risk and Benefit in Clinical Research Involving Children." The Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press, 2004.
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Ethical Conduct of Clinical Research Involving Children
and limited conditions—include a placebo-controlled trial when an effective treatment exists (see, e.g., Emanuel and Miller, 2001 and Miller and Brody, 2002; see also, Ellenberg and Temple, 2000 and Truog et al., 1999).8 One such condition is an especially meticulous informed consent process that carefully explains what a placebo is and makes clear to prospective research participants that they could be assigned to the placebo arm of the trial.
The use of placebo control groups has long been controversial (see, e.g., Ellenberg and Temple, 2000; NBAC, 2001b; and Emanuel and Miller, 2001). This controversy flared in October 2000 when the World Medical Association (WMA) revised the Declaration of Helsinki (WMA, 2002). One revision (paragraph 29) stated that any new preventive, diagnostic, or therapeutic method should be tested against the best current method and that the use of a placebo (or no treatment) control group should be limited to situations in which there is no proven alternative method. After considerable controversy over the revision, WMA qualified its opposition to state (in a footnote) that a placebo control may be ethical if a compelling scientific case supports the use of a placebo control rather than an active control or if the condition being studied is minor and the risk to the group receiving the placebo is minor (WMA, 2002).
In 2000, the International Conference on Harmonisation adopted a guideline that would allow a placebo control when there is no serious harm of withholding effective therapy (ICH, 2000a; see also FDA, 2001d). A placebo-controlled could also be ethical when the proven effective treatment has such severe toxicity that many patients would refuse treatment or when comparison with an active control treatment would not yield scientifically valid results. Similarly, the recent revision of the Guidelines of the Council of International Medical Organizations stated that placebo controls can be ethical (1) when there is no established effective intervention, (2) when withholding and established effective intervention would result in only temporary discomfort or a delay in the relief of symptoms, and (3) when an active control trial would not yield scientifically reliable results
FDA is perceived by many as conditioning the approval of drugs, in most instances, on the provision of information from placebo-controlled trials (see, e.g., Cowdry, 1997). FDA rules and guidelines do not explicitly require such trials. FDA policies require “adequate and well-controlled studies” and identify five types of studies that may be acceptable under some circumstances: placebo concurrent control, dose-comparison concurrent control (in which at least two different doses of the same drug are compared), no treatment concurrent control, active treatment concurrent control, and historical control (21 CFR 314.26(b)(2)). In responding to comments on the so-called pediatric rule (see Chapter 2), FDA stated that alternatives to placebo-controlled trials should be used if such trials can provide adequate information about the effectiveness of a therapy (FDA, 1998e).