Objectives To 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.
Design Cross-sectional study.
Setting All novel therapeutics approved by the FDA between January 2011 and December 2015.
Main outcome measures Postmarket safety actions defined as new label warnings/increased warning severity, FDA safety communications and safety-related therapeutic withdrawals after the original regulatory approval.
Results Among 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).
Conclusions This 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.
- Drug-Related Side Effects and Adverse Reactions
- PUBLIC HEALTH
Data availability statement
Data are available on reasonable request. Requests for the dataset can be made to the corresponding authors at Ashley.Eadie@dal.ca or Matthew.Herder@dal.ca.
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Twitter @AshleyEadie, @JoshuaDWallach, @jsross119, @cmherder
Contributors AE and MH had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: MH, JR, JW and AE. Acquisition, analysis or interpretation: all authors. Drafting of the manuscript: AE, JW, JR and MH. Critical revision of the manuscript for important intellectual content: AE, JW, JR and MH. Statistical analysis: JW, JR and AE. Supervision: MH. Guarantor: MH.
Funding This research was supported by a grant from the Canadian Institutes of Health Research (CIHR PJT 156256).
Disclaimer The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Competing interests All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: In the past 36 months, MH reported being a member of the Patented Medicine Prices Review Board, Canada’s national drug price regulator, and receiving honoraria from the Board for his service. In the past 36 months, JW reported receiving grant support by the US Food and Drug Administration, Arnold Ventures, Johnson he reported serving as a consultant for Hagens Berman Sobol Shapiro LLP and Dugan Law Firm APLC. In the past 36 months, JR received research support through Yale University from the Laura and John Arnold Foundation for the Collaboration for Research Integrity and Transparency (CRIT) at Yale; JR currently receives research support through Yale University from Johnson and Johnson to develop methods of clinical trial data sharing, from the Medical Device Innovation Consortium as part of the National Evaluation System for Health Technology (NEST), from the Food and Drug Administration for the Yale-Mayo Clinic Center for Excellence in Regulatory Science and Innovation (CERSI) programme (U01FD005938), from the Agency for Healthcare Research and Quality (R01HS022882), from the National Heart, Lung and Blood Institute of the National Institutes of Health (NIH) (R01HS025164, R01HL144644), and from the Laura and John Arnold Foundation to establish the Good Pharma Scorecard at Bioethics International; in addition, JR is an expert witness at the request of Relator’s attorneys, the Greene Law Firm, in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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