Designing clinical trials to assess antiepileptic drugs as monotherapy : difficulties and solutions.

Designing monotherapy trials in epilepsy is fraught with many hurdles, including diagnostic and classification difficulties, sparse information regarding the natural history of the disorder, and ethical objections to the use of placebo or a suboptimal comparator in a condition where the consequences of therapeutic failure can be serious. These issues are further complicated by regulatory differences between the US and the EU.In the US, the FDA considers that evidence of efficacy requires demonstration of superiority to a comparator. Because available antiepileptic drugs possess relatively high efficacy, in most settings it is unrealistic to expect that a new treatment will be superior to a standard treatment used at optimized dosages. To circumvent this problem, trial designs have been developed whereby patients in the control group are assigned to receive a suboptimal comparator and are required to exit from the trial if seizure deterioration occurs. This allows demonstration of a between-group difference in efficacy endpoints, such as time to exit or time to first seizure. Although these trials have come under increasing criticism because of ethical concerns, extensive information is now available on the outcome of patients with chronic epilepsy randomized to suboptimal treatment in similarly designed conversion to monotherapy trials. This has allowed the construction of a dataset of historical controls against which response to a fully active treatment can be compared. A number of studies using this novel approach are now in progress.In the EU, in addition to requiring data on conversion to monotherapy in refractory patients, the European Medicines Agency stipulates that a monotherapy indication in newly diagnosed epilepsy can only be granted if a candidate drug has shown at least a similar benefit/risk balance compared with an acknowledged standard at its optimal use during an assessment period of no less than 1 year. This has led to the implementation of noninferiority trials, one of which has been completed and which led to approval of the monotherapy indication for levetiracetam in the EU. Noninferiority trials provide valuable data in a setting that most closely resembles routine clinical practice, but their interpretation can be complicated by uncertainties on assay sensitivity.Major evidence gaps in the treatment of epilepsy still remain and it is hoped that these will be addressed in the near future. High quality monotherapy trials are particularly needed to assess the comparative efficacy of older and newer drugs in less common epilepsy syndromes, including most generalized epilepsies, and to investigate the different treatment options in populations homogeneous not only in terms of syndromic classification, but also in terms of underlying aetiology and associated phenotypes.