title: Historical control monotherapy design in the treatment of epilepsy.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurology, New York University, New York, New York, USA. Jacqueline.french@nyumc.org
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: French
authors.forename: Steven
authors.initials: S
authors.lastname: Wang
authors.forename: Bob
authors.initials: B
authors.lastname: Warnock
authors.forename: Nancy
authors.initials: N
authors.lastname: Temkin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000008:administration & dosage / Q000627:therapeutic use*; D002648:Child; D035061:Control Groups; D018849:Controlled Clinical Trials as Topic / Q000379:methods / Q000592:standards*; D004351:Drug Resistance; D004827:Epilepsy / Q000188:drug therapy*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010919:Placebos; D016032:Randomized Controlled Trials as Topic / Q000379:methods / Q000592:standards; D012107:Research Design / Q000592:standards*; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D000927:Anticonvulsants; D010919:Placebos