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 incidence and causes of mortality in patients with epilepsy participating in clinical trials of antiepileptic drugs (AEDs); and to examine the incidence of and risk factors for sudden unexplained death in such patients.


METHODS
Exposure data and death narratives were obtained from the NDAs of five recently reviewed AEDs. Deaths were classified as sudden unexplained, accidental, or other cause using the 1993 Burroughs-Wellcome expert panel criteria, and mortality rates were calculated for each category. Add-on trials were analyzed separately from monotherapy initiation trials.


RESULTS
Among 9,144 patients in the add-on trial database, the all-cause and sudden unexplained mortality rates were 9.1 and 3.8 deaths per 1,000 person-years (124 and 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-cause 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).


CONCLUSIONS
A large proportion of the deaths in the add-on cohort was attributable to epilepsy-related causes. Mortality due to sudden death in the add-on cohort falls into the high end of the reported range for patients with epilepsy. The difference in mortality due to sudden death between the add-on and monotherapy initiation cohorts suggests that disease severity is the primary determining factor for risk of sudden unexplained death.
Division of Neuropharmacological Drug Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Rockville, MD 20857, USA. racoosinj@cder.fda.gov
J A
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Racoosin
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Feeney
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Burkhart
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Boehm
D000293:Adolescent; D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000009:adverse effects* / Q000627:therapeutic use; D002423:Cause of Death; D002648:Child; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D004345:Drug Industry; D004827:Epilepsy / Q000188:drug therapy / Q000401:mortality*; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D012307:Risk Factors
D000927:Anticonvulsants