Clinical Trials for Antiepileptic Drugs: From Add-on to Monotherapy and Dose-Related Designs

Abstract

“Add-on” parallel designs have frequently been used to demonstrate efficacy for a new antiepileptic drug in refractory patients. It might be very difficult to show effects in this patient population, which is becoming more refractory as more treatments become available. Therefore, a selection for responsive patients (“enrichment design”) might be introduced. In contrast, various “monotherapy designs” have been developed. Within the equivalence approach, standard treatment is used as the control, avoiding the use of placebo. Recent modifications (“therapeutic equivalence design”) avoid problems associated with statistical analysis for equivalence trials. Superiority of the experimental antiepileptic drug to placebo can be demonstrated in presurgical epileptic patients. A further approach represents the “therapeutic failure design.” The use of a low-dose comparator avoids placebo. Alternatively, designs might be based on the necessity to apply various dosing steps of an antiepileptic drug or to define a dose-response relationship. Overall, with the development of a number of new antiepileptic drugs, the clinical evaluation has resulted in the application of new innovative concepts for clinical trials.