Historical control monotherapy design in the treatment of epilepsy

Abstract

Summary Purpose: Monotherapy approvals have been difficult to obtain from the U.S. Food and Drug Administration (FDA), and have almost all been achieved using a trial design entitled “withdrawal to monotherapy” in treatment‐resistant patients, which employs a so‐called “pseudo‐placebo” as a comparator arm. The authors submitted a white paper to the FDA advocating use of a virtual placebo historical control as an alternative to pseudo‐placebo. Such an approach reduces patient risk that would result from exposure to pseudo‐placebo. In this article, we present the data submitted to the FDA to justify a historical control. Methods: We analyzed individual patient data from eight previously completed withdrawal to monotherapy studies, which we determined had similar design. All studies employed percent meeting predetermined exit criteria (denoting worsening of seizure control) as the outcome measure. Kaplan‐Meier estimates of the percent exiting were calculated at 112 days. Results: The percent meeting exit criteria were uniformly high, ranging from 74.9–95.9%. The eight studies appear to meet the criteria set forth for use of historical control. The estimate of the combined percent exit based on the noniterative mixed‐effects model is 85.1%, with a lower bound of the 95% prediction interval of 65.3%, and 72.2% for an 80% prediction interval. Conclusion: There is justification for proposing that these data can serve as a historical control for future monotherapy studies, obviating the need for a placebo/pseudo‐placebo arm in trials intended to demonstrate the efficacy of approved drugs as monotherapy in treatment‐resistant patients.

Lamotrigine XR Conversion to Monotherapy: First Study Using a Historical Control Group

“…The 8 trials contributing to the historical control dataset were conducted in the mid-1990s and compared a test medication to a pseudoplacebo that was either low-dose valproate or a low dose of the test medication. Similarities among the 8 studies in patient population, design, conduct, and endpoints allowed aggregation and use of the data as a historical control [7].…”

“…The main efficacy analysis compared the upper 95% confidence limit of the proportion of patients in the LTG XR (300 mg/day) group who met escape criteria with the lower 95% prediction interval of the historical pseudoplacebo control data (65.3% [7]). The proportion of patients who prematurely withdrew from the study for any reason was also evaluated.…”

“…Such use of a pseudoplacebo raises ethical concerns as it appears not to fully comply with the principle of the Helsinki Declaration that patients in clinical studies should receive the best proven therapy [6]. In fact, in the pseudoplacebocontrolled withdrawal to monotherapy studies performed to date, 74.9% to 95.9% of patients worsened, as defined by predetermined exit criteria, with half of the studies having an estimated percent exiting of between 77.2 and 87.5% [7]. An alternative approach that avoids these ethical concerns is the use of a historical control, in which metaanalysis of multiple placebo-controlled or pseudoplacebocontrolled studies is performed to "model" the behavior of a placebo or pseudoplacebo in a randomized trial [7,8].…”

“…Moreover, this approach has recently been accepted by the FDA as a pathway to monotherapy approval of new AEDs with the condition that any study using the historical control as a comparator be similar, as much as possible, in design, patient population, and endpoint analysis to the studies that comprise the historical control. Such a historical control was recently compiled [7] and showed a consistently high escape rate (the primary outcome measure), thereby allowing it to be used as an alternate to a concurrent placebo comparison. The study described herein, evaluating the efficacy of LTG XR as conversionto-monotherapy for the treatment of partial seizures, used this novel historical control comparator, consisting of data from the pseudoplacebo arms of 8 similarly designed and conducted conversion-to-monotherapy studies [7,9], and it is the first such study to complete enrollment.…”

“…Such a historical control was recently compiled [7] and showed a consistently high escape rate (the primary outcome measure), thereby allowing it to be used as an alternate to a concurrent placebo comparison. The study described herein, evaluating the efficacy of LTG XR as conversionto-monotherapy for the treatment of partial seizures, used this novel historical control comparator, consisting of data from the pseudoplacebo arms of 8 similarly designed and conducted conversion-to-monotherapy studies [7,9], and it is the first such study to complete enrollment. This study exemplifies the issues and difficulties of using this approach.…”