It is often possible to design a successful placebo-controlled trial that does not cause investigator discomfort nor raise ethical issues. Treatment periods can be kept short; early "escape" mechanisms can be built into the study so that subjects will not undergo prolonged placebo-treatment if they are not doing well. In some cases randomized placebo-controlled therapy withdrawal studies have been used to minimize exposure to placebo or unsuccessful therapy; in such studies apparent responders to a treatment in an open study are randomly assigned to continued treatment or to placebo. Subjects who fail (e.g. blood pressure rises, angina worsens) can be removed promptly, with such failure representing a study endpoint.

IRBs may face difficult issues in deciding on the acceptability of placebo-controlled and active-control trials. Placebo-controlled trials, regardless of any advantages in interpretation of results, are obviously not ethically acceptable where existing treatment is life-prolonging. A placebo-controlled study that exposes subjects to a documented serious risk is not acceptable, but it is critical to review the evidence that harm would result from denial of active treatment, because alternative study designs, especially active-control studies, may not be informative, exposing subjects to risk but without being able to collect useful information.

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