Mortality in antiepileptic drug development programs

Background: Pooled data from New Drug Applications (NDAs) submitted to the U.S. Food and Drug Administration (FDA) provide an opportunity to study the incidence of and risk factors for rare events. Objective: To examine the i ncidence and causes of mortality in patients with epilepsy participating in clinical trials of antiepileptic drugs (AEDs); and to examine the incidenc e of and risk factors for sudden unexplained death in such patients. Method s: Exposure data and death narratives were obtained from the NDAs of five r ecently reviewed AEDs. Deaths were classified as sudden unexplained, accide ntal, or other cause using the 1993 Burroughs-Wellcome expert panel criteri a, and mortality rates were calculated for each category. Add-on trials wer e analyzed separately from monotherapy initiation trials. Results: Among 9, 144 patients in the add-on trial database, the all-cause and sudden unexpla ined mortality rates were 9.1 and 3.8 deaths per 1,000 person-years (124 an d 52 deaths in 13,617.1 person-years of drug exposure). Sixty-five percent of all deaths were related to the underlying epilepsy. Of the examined risk factors, only age was associated with the incidence of sudden unexplained death. Among 1,293 patients in the monotherapy initiation trials, the all-c ause and sudden unexplained mortality rates were 7.1 and 0 deaths per 1,000 person-years (7 and 0 deaths in 982.5 person-years of drug exposure). Conc lusions: A large proportion of the deaths in the add-on cohort was attribut able to epilepsy-related causes. Mortality due to sudden death in the add-o n cohort falls into the high end of the reported range for patients with ep ilepsy. The difference in mortality due to sudden death between the add-on and monotherapy initiation cohorts suggests that disease severity is the pr imary determining factor for risk of sudden unexplained death.