Better comparisons of antiepileptic drugs: what measures of efficacy?

With the licensing of new antiepileptic drugs there is an obvious need for the determination of the comparative efficacy, tolerability and overall effectiveness against standard (existing) antiepileptic drugs. Such data can only be determined within the context of well-designed randomised clinical trials (RCTs). Such comparative monotherapy studies may form a part of phase III drug development programmes for a new antiepileptic drug. They may be commenced once there is satisfactory evidence for efficacy and safety derived from placebo-controlled add-on studies in more refractory populations of patients. In this manuscript definitions of outcomes such as effectiveness, efficacy, and tolerability are given. Health-related quality of life measures are presented, and it can be argued that such measures should be a primary outcome variable. However, there is little evidence that any quality of life measures have sufficient validity and sensitivity to be a useful tool in the comparison of drug treatments for epilepsy. Different populations can be studied in 'withdrawal to monotherapy' designs. In such studies patients poorly controlled on their existing therapy are randomised to receive different monotherapy regimes with withdrawal of their existing antiepileptic drugs. This clinical trial design has not been used in genuine comparisons between antiepileptic drugs and the efficiency of this approach has yet to be determined. Experience from studies comparing monotherapy would suggest that differences in efficacy between antiepileptic drugs in the target populations may be difficult to detect. Differences likely exist between the incidence and profile of adverse effects between different drugs. The main benefit of new antiepileptic drugs may be in reducing the incidence and severity of adverse reactions compared to older drugs and in doing so they may prove to be more effective.