Novel trial designs for monotherapy.

Unlike many other areas of therapeutics, specific regulatory trial programmes are required to be undertaken in newly diagnosed epilepsy to support the licensing of novel antiepileptic drugs for use in drug-naïve patients. To complicate matters further, American and European regulators have taken markedly different approaches to this issue, with the FDA requiring withdrawal to monotherapy data comparing more than one dose of newer agents with historical controls, whereas the EMA recommends undertaking randomised head-to-head studies versus an established comparator. The former studies are designed to show superiority compared to previously published data, whereas the latter will accept a non-inferiority (equivalence) outcome. This paper discusses the positive and negative aspects of both designs and explores novel alternative options. Particular focus has been placed on placebo-controlled studies following a single seizure with supportive electroencephalographic and/or brain imaging evidence, in the hope of identifying a realistic design that will satisfy licensing authorities on both sides of the Atlantic Ocean.