Evaluation of antiepileptic drug efficacy. A review of clinical trial design.

Up to 30% of patients with epilepsy are not adequately treated with currently available antiepileptic drugs. Despite a need for new agents, few were developed after valproic acid (sodium valproate), which appeared in the 1970s. This picture has changed recently. A number of new antiepileptic drugs have been approved for marketing, and additional approvals are expected soon. The evidence in the form of adequate and well controlled studies supporting the efficacy of each of these new drugs has included (and in some cases been wholly composed of) placebo-controlled add-on trials, showing the viability of that design. Add-on trials, which compare a new drug with placebo in the presence of a stable regimen of antiepileptic drug therapy, can be conducted as parallel or cross-over designs. These designs have been considered insensitive because they are conducted in patients refractory to available antiepileptic drugs, but add-on trials have proved able to identify effective new drugs. They also permit long term evaluation and provide information, including drug interaction data, in one of the major clinical contexts where a new antiepileptic drug may be used. New designs now allow the evaluation of antiepileptic effectiveness in other clinical contexts, including monotherapy, and provide alternatives when drug interactions obscure add-on trial interpretation. The key feature of this class of monotherapy designs is basing patients' trial duration on their seizure activity rather than on a fixed time period. This is accomplished by defining 'therapeutic failure' criteria which serve to assess efficacy of the test agent while protecting patient safety.(ABSTRACT TRUNCATED AT 250 WORDS)