Active-Control Comparative Equivalency Monotherapy Trials in Epilepsy: Are They Scientifically Valid?

Abstract

The premise of active-control comparative equivalency trials for evaluating a new therapeutic agent for the treatment of patients with epilepsy is attractive. This trial design includes one group of patients randomized to the study drug and the other to an established antiepileptic drug (AED) believed to have efficacy against the particular seizure type or epilepsy syndrome under evaluation. This design minimizes ethical concerns, as there is genuine uncertainty concerning which treatment regimen will be more efficacious. In addition, these trials compare the relative efficacy and tolerability of the new agent with a standard therapy rather than with a placebo or a pseudoplacebo. Because of these perceived advantages, active-control equivalency trials are attractive when viewed superficially. In addition, proponents of these trials have confused physicians by counteracting arguments of scientific validity with those of ethical principles and clinical relevance. Because active-control trials are being performed with increasing regularity, it is important for the epilepsy community to be fully informed of the advantages and drawbacks of such trials and to be engaged in the scientific debate regarding their validity when assessing the therapeutic efficacy of a novel AED. The objectives of this article are to provide information about the design and conduct of active-control monotherapy trials and to express serious doubts about the scientific validity of equivalence trials when evaluating therapeutic