Little or no argument about the choice of placebo as the control group in an RCT occurs when the usual treatment by clinicians in the community is no treatment at all. Then, using a placebo in the control group mimics clinicians' recommendations exactly in providing no treatment that can influence the disorder.
In such cases, patients may be better off volunteering for participation in an RCT, where they have at least a chance of being assigned to receive an effective treatment. Patients might actually respond better to a placebo in an RCT than to absence of treatment in the community because of one of the artifactual responses that the control group controls for. For example, the attention, care, and scrutiny provided to patients in an RCT are usually far beyond those provided in usual clinical practice, and that may benefit patients. For all these reasons, when usual care in the community is no treatment, patients have strong inducement to volunteer to participate in a placebo-controlled RCT.
Moreover, in this situation patients have little inducement to drop out of the RCT, for nothing is available as an alternative in the community that can be better than what is offered in the placebo control group, and what is offered in the T group may improve their condition. Thus, when usual treatment in the community is no treatment, placebo control groups are the only choice, and an excellent choice at that.
Even when there are treatments thought to be effective in the community for a disorder (often other drug companies' products), drug companies generally prefer placebo control groups in studies directed to the FDA for drug approval.
The FDA requires that the drug company provide "proof that a drug has a therapeutic effect in at least some patients," and "no requirements are imposed regarding the 'representativeness'" of a study sample vis-à-vis the population of patients from which it is drawn" (Leber and Davis 1998, p. 179).
Moreover, the FDA does not set any criteria for a clinically significant effect, although it generally—as noted above in the "Indications" section—requires demonstration in more than one RCT of a statistically significant effect. Thus, drug companies prefer to use a control group in which response is minimized to that associated with unavoidable artifacts of participating in an RCT, because having such a control group maximizes the chance of finding a statistically significant effect. Given that the sample size necessary to demonstrate a statistically significant effect is smallest when the effect size is largest, the easiest way to achieve drug approval is to use very stringent inclusion/exclusion criteria that favor recruitment into the RCT of only those most likely to respond well to the drug (an efficacy trial) and a placebo control group that minimizes the benefit in the control group. Pharmaceutical companies are then doing exactly what they need to do to satisfy FDA requirements to market their drugs.
What the FDA requires or accepts depends on how it interprets the mandate from the U.S. Congress, under which it operates, and what drug companies do is determined by what the FDA requires and accepts. For these reasons, issues related to the use of placebo control groups in RCTs that are performed to establish the efficacy or effectiveness of treatments in clinical populations might well be considered separately from issues related to FDA requirements for drug approval and drug companies' efforts to satisfy those requirements.
However, as described above, the results of studies funded by drug companies to gain FDA approval of an agent may not generalize to the type of patients clinicians are treating. Even within the limited populations actually studied in some such studies, the clinical benefits of the drug may well be statistically significantly better, but not clinically significantly better, than the effects of withholding treatment (i.e., as in placebo control groups), or the drug's effects may be both statistically and clinically worse than the effects of whatever treatments clinicians are already using for their patients.
Such considerations relate closely to present-day concerns about conflict-of-interest issues when academic researchers are associated with studies funded by drug companies and explain the requirements of many research journals and professional organizations that such conflicts of interests be reported when presenting results of such studies.
Another situation is a medical experiment that is not a clinical trial. Basic researchers in pharmacology, for example, might be interested in the pharmacokinetics of a particular drug in human subjects, not in the efficacy or effectiveness of that drug in any patient population. To test their hypotheses, a control group, randomization, and blinding may also be necessary. However, in many cases, the individuals recruited into such a study are not patients with a disorder but simply volunteers, and the outcomes are focused not on the clinical benefits or harm to patients but rather on aspects of the drug, such as rates of drug absorption and elimination. In many such situations, a placebo control group is the only scientifically valid choice to test hypotheses. Because the focus here is not on establishing the efficacy or effectiveness of a treatment, this is a medical experiment but is not that specific type of medical experiment called the clinical trial. Such medical experiments are fundamental to progress in basic science and translational research.
The issues about the use of human subjects in medical experiments, including that of using placebo control subjects, are specific to the particular research question being addressed in a study and are generally different from those in an RCT. These are issues that institutional review boards must assess for each individual research project. Informed consent forms for such studies should not describe the study as an RCT and should spell out clearly that the focus of the study is to further biochemical or pharmacological knowledge about the drug, not (at least not in the near future) to improve treatment for any patients with a disorder.
In many cases, an RCT is performed to test whether a new treatment that is used as a supplement to an established treatment is more effective or efficacious than the standard treatment alone. This is a case in which there are few, if any, reservations to the use of a placebo to control the artifactual effects of offering two treatments rather than one. All patients would receive the standard treatment and then be randomly assigned to supplementation with either the new treatment or a placebo. If researchers find a statistically and clinically significant difference between the two groups, it would represent not an effect of the new treatment but rather an additive or interactive effect of the old and new treatments together. Here few people would have ethical or scientific concerns about the use of a placebo control group.
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