INNOVATIVE MONOTHERAPY TRIAL DESIGNS FOR THE ASSESSMENT OF ANTIEPILEPTIC DRUGS - A CRITICAL-APPRAISAL

Although new antiepileptic drugs are assessed initially by adding them to pre-existing treatment, it is only through monotherapy studies tha t their therapeutic potential can be characterized in full. Since long -term treatment with a placebo alone is ethically unacceptable in epil epsy, the classical monotherapy assessment of antiepileptic drugs invo lves randomization of newly diagnosed patients to treatment with the i nvestigational drug or an established active control: followed by long term monitoring to determine seizure remission rates and potential adv erse effects. These protocols, however, are time-consuming and they ar e unlikely to demonstrate a superior efficacy), of the new agent over a comparator. In turn. a ''no-difference'' outcome in terms of seizure control does not allow one to exclude the possibility that all the tr eatments were equally ineffective: and may therefore not be regarded a s proof of efficacy by regulatory authorities. To circumvent these pro blems, innovative designs for the early monotherapy evaluation of new antiepileptic drugs have been developed in recent years. These protoco ls, often referred to as ''regulatory trials'', involve short-term stu dies in which a full dosage of the investigational agent is compared w ith a placebo or with a suboptimal dosage of an active control (possib ly the investigational agent itself). To minimize the risks associated with an ineffective treatment, provisions are made that require exit from the trial if seizures are inadequately controlled. Efficacy endpo ints are time to the n(th) seizure and patients' retention on the allo cated treatment. These studies have been conducted in patients undergo ing discontinuation of treatment for presurgical assessment, in newly diagnosed patients, and in patients whose concomitant anticonvulsants were withdrawn for trial purposes. While these trials allow statistica l demonstration of superior efficacy over a comparator, allocation of patients to ineffective or suboptimal treatments raises serious ethica l concerns. The scientific value of these studies is also doubtful, be cause dosing schedules and duration of treatment are hardly relevant t o routine clinical practice. Clinicians do not need to know whether a new drug given for a few days is better than nothing, but how that giv en for a few with established agents given in optimized dosages for lo ng periods of time. The ethical and scientific justification for regul atory trials should be reassessed, and steps are urgently needed to st imulate implementation of long-term randomized comparative trials unde r conditions that are more relevant to clinical needs.