FDA accepts historical controls for epilepsy monotherapy studies

July 20, 2010

New York University researchers revealed that data from previously completed withdrawal to monotherapy studies for antiepileptic drugs (AEDs) provide a valid control for future studies, obviating the need for placebo/pseudo-placebo trials to demonstrate the efficacy of these drugs as monotherapy. Results of this study are now available online in Epilepsia, a journal published by Wiley-Blackwell on behalf of the International League Against Epilepsy.

According to a National Institute of Neurological Disorders and Stroke workshop, monotherapy is the ultimate treatment strategy for newly-diagnosed and many long-term patients because of fewer side effects, better compliance, less risk of fetal malformations (teratogencity) and lower cost compared with polytherapy.

However, in the U.S., it is difficult to get monotherapy approval for AEDs because the FDA, in accordance with the International Conference on Harmonization (ICH), requires an internal, interpretable control group in which the shows superiority over the control. New AEDs, while offering improvements in safety and efficacy, rarely demonstrate superiority compared to standard AEDs, leaving placebo or pseudo-placebo as the only acceptable internal controls.

The pseudo-placebo withdrawal to monotherapy study model assigns treatment-resistant patients to receive a study drug or a suboptimal maintenance dose of a safe and effective active drug. Once patients are randomized and standardized to the intended dose, they undergo a withdrawal phase (when background AEDs are removed over a specified time frame) followed by a monotherapy phase. The trial continues until either all phases are completed or patients reach pre-specified endpoints.

Study leader Dr. Jacqueline French explains why this clinical trial model isn't suited for epilepsy patients. "Epilepsy is different from other conditions where placebo may be utilized (such as hypertension), since there is no way to exit a patient at a warning stage, before harm can occur. In a hypertensive patient, one can withdraw a patient on placebo if blood pressure increases, before it gets dangerously high. But with an epilepsy patient, the escape criteria consist of an increase or worsening of seizures, which by itself can be considered an adverse outcome."

The study authors proposed that a historical control, based on an evaluation of prior pseudo-placebo withdrawal to monotherapy studies, would provide a valid alternative to an actual . The team analyzed 8 separate studies of similar design and escape criteria, with randomized patients of common demographic characteristics. The primary endpoint was the same for all trials: percent of patients exiting the trial due to seizure worsening. All 8 studies had consistent outcomes, with the percentages of patients exiting their respective trials ranging from 74.9%-95.9%.

Dr. French concludes, "These trials would appear to meet the criteria set forth by ICH for use of historical control. Therefore, this group of trials might reasonably be used as historical controls for future trials of withdrawal to monotherapy using a similar design in a similar population."

The historical control design allows all patients to receive a promising AED at an effective dose, making the study more attractive to patients and to physicians. Dr. Emilio Perucca agreed with these findings, stating in this month's Epilepsia Commentary, "The New York University team should be commended for their scholarly work…in setting the stage for a new conversion-to-monotherapy design in which patients are no longer required to receive suboptimal, and therefore, potentially hazardous, treatments."

Based upon this French et al. study, the FDA has accepted the concept of historical controls in this setting, a major milestone in AED development. Several trials utilizing this design planned for regulatory submission have begun.

More information:
Article: "Historical control monotherapy design in the treatment of epilepsy." Jacqueline A. French, Steven Wang, Bob Warnock, and Nancy Temkin. Epilepsia; Published Online: June 18, 2010 (DOI: 10.1111/j.1528-1167.2010.02650.x).
Editorial: "When clinical trials make history: Demonstrating efficacy of new antiepileptic drugs as monotherapy." Emilio Perucca. Epilepsia; Published Online: May 14, 2010 (DOI: 10.1111/j.1528-1167.2010.02589.x).

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