Cognitive and behavioural assessment in clinical trials: when should they be done?

The issue of 'timing' of behavioural assessments in clinical trials can be approached in two different ways. Firstly the 'timing' during the process of drug development. As a rule, cognitive and behavioural side effects of antiepileptic drug treatment do not become an issue until the drug is marketed. At this stage a negative result has large marketing effects and this leads to a tendency to organise 'positive studies'('no-effect results'), that can be achieved by reducing power. A second approach is the 'timing' of cognitive assessment during a trial. The first and intuitive answer to the question 'when this should be done' is to perform assessments during an untreated baseline that is then compared with an endpoint during antiepileptic drug (AED) treatment. This is the 'gold standard design' for cognitive assessments in the majority of the cognitive trials. However, in patients with epilepsy, the behavioural drug effects are not independent from the effect of the epilepsy or the seizures. Recent studies have confirmed that the effect of uncontrolled seizures are often larger than the effects of drug treatment, leading to the so-called seizure confound, that is, adverse cognitive AED effects may be masked by beneficial effects of better seizure control. In such studies endpoint scores are thus improved, hiding possible negative drug effects. Other designs may have other limitations: e.g. in using adjunctive therapy the identification of the components of a treatment most responsible for any observed effects presents a difficult problem; in normal volunteers, exposure durations which are not representative of those in epilepsy patients on chronic treatment represent a major validity issue. We therefore consider the drug withdrawal study as the optimal design for assessing behavioural drug effects. In this design subjects are tested while still on medication and after withdrawal; larger gains in the epilepsy group relative to the controls are considered evidence for a reversible impairment, attributable to AED use.