PISC Expert Team White Paper: Toward a Consistent Standard of Evidence When Evaluating the Efficacy of an Experimental Treatment From a Randomized, Active-Controlled Trial

The double-blind placebo-controlled trial is the established standard for determining the efficacy of an experimental treatment. However, there are circumstances where the use of a placebo is unethical or impractical, and active-controlled trials are a common alternative. In an active-controlled trial, the objective is typically to show that the effect of the experimental treatment is within some prespecified margin of the control effect. The margin is often chosen specifically to guarantee 50% or 75% preservation of the control effect over placebo. An implicit assumption is that a higher standard of efficacy is required when a new treatment is evaluated in an active-controlled trial. In this article, we argue that standards based on margins and/or percent preservation are inherently arbitrary and lacking in objective clinical or scientific justification. The use of these ad hoc standards introduces logical inconsistencies for regulatory evaluation such that safe and effective treatments may be denied reg...