US Food and Drug Administration regulatory reviewer disagreements and postmarket safety actions among new therapeutics

Abstract

ObjectivesTo examine the association between regulatory reviewer disagreements and postmarket safety actions among novel therapeutics approved by the US Food and Drug Administration (FDA) between 2011 and 2015. Disagreements among FDA reviewers regarding the recommendation for a novel therapeutic’s approval, its safety, the indicated patient population and/or other parameters of the drug’s approval are common. However, the implications of such disagreements—particularly with respect to postmarket safety actions—are poorly understood.DesignCross-sectional study.SettingAll novel therapeutics approved by the FDA between January 2011 and December 2015.ParticipantsNone.Main outcome measuresPostmarket safety actions defined as new label warnings/increased warning severity, FDA safety communications and safety-related therapeutic withdrawals after the original regulatory approval.ResultsAmong 174 novel therapeutics approved by the FDA between 2011 and 2015, 42 (24%) had at least one regulatory reviewer disagreement. Altogether, 156 instances of disagreement were observed. Following market approval, a total of 253 postmarket safety actions were taken by the FDA among all new therapeutics, with at least one postmarket safety action identified for 98 (56.3%) of the 174 novel therapeutic approvals. Overall, therapeutics that were the subject of disagreement during the FDA’s review had fewer safety actions following approval compared with therapeutics in which no disagreement was observed (38.1% vs 62.1%; RR 0.61, 95% CI 0.41 to 0.92; p=0.006). Therapeutic approvals containing at least one reviewer disagreement also more often carried a black box warning at the point of approval (47.7% vs 31.1%; RR 1.53, 95% CI 1.02 to 2.30; p=0.05).ConclusionsThis investigation of regulatory reviewer disagreements and postmarket safety actions among new therapeutics suggests that disagreements among regulatory reviewers may lead to important pre-emptive actions, potentially mitigating the need for postmarket safety actions to be taken.