Issues in planning and interpreting active control equivalence studies.

Active control equivalence studies, with the goal of demonstrating therapeutic equivalence between a new and an active control treatment, are becoming more widespread due to current therapies that reflect previous successes in the development of new treatments. Because ethical requirements preclude the use of a placebo or no-treatment control for internal study validation, certain methodologic issues arise in active control equivalence trials that require special attention. We emphasize a special feature of this alternative study design, namely, its reliance on an implicit "historical control assumption". To conclude that a new drug is efficacious on the basis of an active control equivalence study (ACES) requires a fundamental assumption that the active control drug would have performed better than a placebo, had a placebo been used in the trial. In designing an ACES, one needs some assurance that historical estimates of the active control drug's efficacy relative to placebo are applicable to the new experimental setting. Steps that can be taken to compile such evidence and to justify the use of an active control equivalence design are described. These issues are illustrated in the context of a planned study to evaluate the efficacy of a new drug for the prevention of stroke, using aspirin as an active control.