New antiepileptic drugs and clinical trial designs

Background. While several antiepileptic drugs (AEDs) have been licensed in the last 10 years, newer agents are currently in an advanced stage of investigation and appear to be promising for the treatment of epilepsy. The need for rigorous guidelines to evaluate these new drugs has been frequently stressed in the recent literature. Comparative studies involve complex ethical and methodological problems which still have to be refined. The aim of the present paper is to discuss some relevant aspects. Definition of the terms and related aspects. Monotherapy comparative studies have the advantage of avoiding pharmacokinetic and pharmacodynamic drug interactions which may take place in "add-on" investigations and may confound interpretation of the data. The results derived from these studies are especially useful for newly diagnosed, untreated patients. Comparative monotherapy studies are usually part of the phase III and phase IV development programs. They utilize a parallel-group design and can be initiated, for obvious ethical reasons, only after placebo-controlled add-on studies in patients with refractory epilepsy have yielded satisfactory evidence of efficacy and safety. Outcome measures include: efficacy (e.g., proportion of patients becoming seizure free); tolerability (incidence and severity of adverse effects); effectiveness (e.g., retention of patients on the alocated treatment, a combined measure of efficacy and tolerability). Monotherapy trials can be: explanatory, which adopt tightly defined entry and dosing criteria, and pragmatic, which mimic daily clinical practice and do not apply rigid management procedures. These two approaches can be considered complementary. Concluding remarks. The above-mentioned approaches provide an example of the complexity of clinical trial methodology for new AED development.