Ethical Obligations and the Use of Placebo Controls

Can J Psychiatry 2008;53(7):428-429 The double-blind, randomized, placebo-controlled clinical trial is considered the best method for collecting evidence about diagnostic, therapeutic, or preventive interventions. Well-conducted placebo-controlled trials have high internal validity. However, when established effective therapy exists, various issues-clinical, methodological, even legal-converge to raise ethical concerns about when one may ethically withhold such therapy in a clinical trial. Clinical Relevance The clinical relevance of research is important consideration. There has been agreement since Nuremberg that research should be designed to yield fruitful results for the good of society.1 In considering whether a placebo control would be ethically permissible, Sir A Bradford Hill, who introduced the modern era of clinical trials, suggested that when there is already available an orthodox treatment of proved or accepted value.. .the question hardly arises, for the doctor will wish to know whether a new treatment is more, or less, effective than the old, not that it is more effective than nothing.2 One can question the clinical utility of knowing absolute efficacy (for example, the drug is better than no treatment), compared with comparative efficacy (the drug is as good as-or better than-others available to the clinician). Hill's statement reflects the same concern asserted in requiring that a study must begin with honest null hypothesis: genuine medical uncertainty concerning the relative merits of the various treatment arms included in a trial's design.3 Wasting resources or putting participants at risk without the possibility of acquiring valuable knowledge raises serious ethical concerns. Scientific Validity Some argue that placebo and not active controls are necessary to determine whether unproven treatment has assay sensitivity, that it is in fact effective.4 However, in practice, there are obstacles to the assurance of assay sensitivity, even with active controls. One serious difficulty with placebocontrolled trials is inattention to the importance of blinding. Any argument relying on the superiority of having a placebo arm requires that neither those running the trial nor the participants can tell who is on active control and who is receiving a placebo. However, many trials provide no commentary on blinding in their published results.5 Further, arguments supporting the necessity of placebo controls for scientific rigour lead inescapably to the conclusion that active controlled trials in such areas as infection control or oncology, which frequently use placebo as add-on, may result in the approval of inferior therapies because of the inability to use a placebo control. These issues seriously undermine the arguments that trials require a placebo control for scientific or methodological rigour. While potentially raising feasibility issues, many of the scientific validity problems cited in the literature can be overcome by designing larger trials, as opposed to leaving participants untreated. Ethical Issues Even if placebo controls were required for methodological rigour, this would not in itself make such trials ethical. Scientific validity is a necessary but insufficient requirement for ethical trials. Research must also respect the participant's interests. Codes of medical ethics are clear that the patient's well-being is the physician's primary concern. Some argue otherwise. They make appeals to liberty, arguing patient autonomy to choose trial participation. They distinguish research from clinical care by their different objectives. The former, they state, is designed to answer a research question, while the latter is intended to provide care in the patient's interest. The result is a claim that the ethics of the traditional physician-patient relationship do not apply to research because a clinical trial is not a form of therapy. Consequently, they allege, the investigator's obligation is only one of not exploiting research participants by exposing them to excessive risk, as opposed to acting in their best interests. …

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