The sine qua non of an RCT is that there be a control or comparison group, with an appropriate sample of patients randomly assigned to the treatment and control groups, with blinded assessment of outcome, and with analysis by intention to treat. A reasonable analogy of conducting an RCT is that it is like juggling many balls, trying to keep them all in the air at the same time: choice of control group, randomization, blinding, sampling, treatment protocol, measurement protocol, and fidelity to the protocols during the study, analysis, and interpretation of results, etc. The more research questions that are to be addressed in a particular RCT, and the more complex each research question is, the more balls are being juggled and the more slippery they are. Moreover, as soon as one ball drops, the others are likely also to follow. Any mistake in sampling, for example, is likely to have repercussions in analysis and interpretation of results. Poor measurement (e.g., use of a binary primary outcome) will have an effect on design (sample size). Improved design (e.g., repeated measures of the primary outcome) will have an effect on analysis and interpretation of results. For this reason, the best studies result when there is a focus on the primary research question, when all research decisions are made to protect the integrity of and amplify the answers to that primary research question. When the effort is made to answer as many questions as possible in one study, e.g., addressing multiple outcomes, or controlling or adjusting for multiple variables, RCTs tend not to answer any research questions well at all.

The choice of an appropriate control group is context specific but should take into consideration ethical and clinical as well as scientific issues. On the issue of using placebo control groups, we distinguished RCTs to establish the efficacy or effectiveness of a drug from studies done for the purpose of gaining FDA approval of a drug versus randomized medical experiments to explicate basic science questions, which are often performed with subjects who are not patients and for purposes that have little or nothing to do with efficacy or effectiveness of treatments.

We have discussed in detail when it is best and least controversial to use a placebo control group (i.e., when there is no better alternative to placebo) and when it may be more appropriate to use a TAU control group or a standard-of-care control group, particularly in cases where withholding treatment, as would be done with placebo control subjects, raises ethical questions as well as logistical questions.

Using placebo control groups as a foil to understand differences not seen between two active treatments is often based on a misinterpretation of statistical significance. Moreover, use of placebo control groups as an aid in establishing equivalence or noninferiority is questionable, because what may appear to be equivalence is often related to poor study execution rather than to actual equivalence between treatments. Also, it is not clear why equivalence is important to clinical decision making.

In short, in some circumstances using a placebo control group is the only choice, and in others using a placebo control group is the best choice. There are also circumstances in which ethical, clinical, and scientific interests are best served by using other types of control groups. Finally, there have been circumstances in which inclusion of placebo control groups has misled thinking about the effects of other drugs.

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