Clinical trial design for new antiepileptic drugs: Determination of dose and titration schedules

The development of drugs for the treatment of epilepsy is challenging. The issues involved with the successful development of these drugs have been we ll documented, and many guidelines have been issued by regulatory authoriti es and academic institutions. At least six new antiepileptic drugs (AEDs) h ave been licensed for use since the late 1980s, each with its own particula r profile of efficacy and tolerability. Much has been written recently abou t clinical trial methodology in the area of epilepsy: the regulatory requir ements of various countries, the technical and logistic difficulties and th e ethical constraints are well documented. In reviewing retrospectively the results of the development programmes for these newer AEDs, what issues ha ve proven most problematic! Various issues have been reviewed extensively e lsewhere. It is apparent from the current usage of these drugs that the dos es used in current clinical practice are not identical to those used in cli nical trials, raising the question of how dose and titration schedules are selected in early development. This has been an issue particularly relevant for topiramate. This review considers a sample of clinical trials performe d on some of the new AEDs to illustrate the problems of trial methodology i n this rapidly evolving area. With a specific focus on dose selection and t itration, the issue is considered of how particular trials may have influen ced the development of some of these drugs.