Historical data in the design and interpretation of trials with newly diagnosed patients.

An International League Against Epilepsy (ILAE) subcommission is exploring the possibility of utilizing historical data from treated and control (untreated or under-treated) patients who have been enrolled in monotherapy trials in newly diagnosed epilepsy. Active-control trials have not convincingly distinguished between equivalent effectiveness and equivalent ineffectiveness. Thus, there is insufficient historical evidence of sensitivity to drug effects. Noninferiority trials are based upon experience acquired with previous trials. Optimizing the exploitation of historical data obtained in newly diagnosed patients may be a way to improve the validity of future trials. A concern about use of historical controls is lack of assurance that historical populations and newly recruited populations are similar. The best approach to pooling and modeling data may be an Individual Patient Data (IPD) approach as (1) analysis of data from active-control trials, (2) demonstration that the subpopulation carrying an intermediate probability of recurrence is the most sensitive to drug effect, by comparison to similar subpopulations who received a placebo or a pseudoplacebo in historical studies. This subpopulation could become a reference for patient selection or stratification in future trials to improve assay sensitivity.