Impact of FDA's Enforcement Discretion of Clozapine REMS Program on Clozapine Adverse Event Reporting

IntroductionIn response to the COVID-19 pandemic, the FDA announced enforcement discretion of the clozapine Risk Evaluation and Mitigation Strategy (REMS) program on March 22, 2024. The impact of these changes on rates of Clozapine related adverse-events and reporting pattern has not been examined to-date. Using the FDA Adverse Event Reporting System (FAERS) database, we examined the effect of this regulatory change on the reporting patterns of Clozapine-related adverse events. MethodsData from the FAERS database from January 2018 to June 2024 was obtained. Interrupted time-series models were employed to evaluate the total number of reported adverse events and event-specific rates for death, agranulocytosis, neutropenia, and myocarditis, with March 22, 2020, as the index date for FDA enforcement discretion. ResultsFAERS database reports were predominantly from USA (41.63%), with majority of reports submitted by physicians (37.88%) and pharmacists (37.83%). Total reported counts per month and death count per month did not show significant changes in trend. The reported death proportion and myocarditis count showed a significant downward trend (p = 0.002 and p = 0.005, respectively). No significant trend changes were seen in reporting of agranulocytosis and neutropenia (count per month and proportion). DiscussionThe FDAs enforcement discretion of clozapine REMS program during the COVID-19 pandemic was associated with a significant reduction in reporting of clozapine-induced myocarditis and death, but not of agranulocytosis or neutropenia. Whether these changes reflect true change in rates, preferential attribution of these adverse-events to COVID-19 or change in reporting patterns warrant further verification.