From clinical trials of antiepileptic drugs to treatment

Abstract

Rational prescribing should be based on the assessment of high-quality evidence about the benefits and risks of available treatment options. Because clinical trials, particularly randomized controlled trials (RCTs), provide the best source of evidence, their design and results need to be carefully scrutinized. The majority of RCTs of antiepileptic drugs (AEDs) have been designed to address regulatory requirements, and generally they involve restrictive eligibility criteria, rigid dosing schemes, short duration of follow-up, and comparison with placebo rather than standard treatments. Although these studies have high internal validity, they are conducted in a setting that is distant from routine clinical practice and therefore their usefulness in guiding treatment decisions is limited. Information more directly applicable to clinical practice can be derived from a relatively small number of comparative effectiveness monotherapy RCTs, although the design of some of these studies was probably biased in favor of the sponsor's product. Alarmingly, there is a paucity of well-designed trials in epilepsy syndromes other than focal epilepsies, and no RCTs at all in most of the less common epileptic syndromes of infancy and childhood. In the light of these shortcomings, there is scope for re-assessing regulatory requirements to facilitate generation of data more directly applicable to the routine clinical setting. Likewise, research-funding organizations should be sensitized about the lack of adequate evidence to guide therapeutic practice in epilepsy, and the need to promote high-quality comparative effectiveness trials. Future prospective pragmatic trials may benefit from the increasingly widespread availability of electronic health records.

Keywords: Antiepileptic drugs; Clinical trials; Comparative effectiveness; Drug therapy; Epilepsy; Seizures.

Figure 1

Representative double‐blind trial design for assessing the efficacy and tolerability of investigational new antiepileptic drugs (AEDs) given as adjunctive therapy. After an initial 4‐ to 8‐week prospective evaluation to establish a baseline, patients are randomized to 3 parallel‐dose groups or placebo. Treatment generally includes a titration period of variable length and modalities, and a 12‐week maintenance period. Efficacy is evaluated by comparing changes in seizure frequency or responder rate (versus baseline) between each dose group and the placebo group. The treatment period used for efficacy assessment typically includes the titration and maintenance period combined (FDA‐preferred analysis) or the maintenance period alone (EMA‐preferred analysis). In the trial design illustrated in the figure, the maintenance phase is followed by a dose‐alignment phase during which all patients are blindly converted to a common dose in order to preserve the double‐blind. When dose alignment is completed, open‐label flexible‐dose treatment can be continued long‐term as clinically indicated. The dose alignment phase also allows patients initially exposed to placebo to receive a trial treatment with the investigational drug.