Historical control withdrawal to monotherapy.

The design of clinical trials can be explained in terms of selection of a control group. Two options have included (a) using an active comparator, usually a standard drug such as carbamazepine (active control) or (b) using a placebo or low-dose control. Because neither active control nor placebo/dose control appeared to be acceptable alternatives for monotherapy studies in epilepsy, a new concept has been considered: the use of "historical control". This method uses the "expected" (imputed) behavior of placebo, based on prior trials. Some trials have been performed in patients with refractory epilepsy, who are withdrawn from their previous antiepileptic drugs, and converted to monotherapy on a study drug, using a low-dose comparator, frequently called "pseudo-placebo." A meta-analysis of all pseudo-placebo arms was performed to determine whether they could serve as a historical control for future monotherapy trials. The estimate of the combined percent exit was 86.1% (CI 78.6% to 93.6%). These data may be able to serve as a historical control for future monotherapy studies, obviating the need for a placebo/pseudo placebo arm.