Risk for Postmarket Black Box Warnings in FDA-Approved Monoclonal Antibodies.

John B Hagan,Thanai Pongdee,Elizabeth Ender,Rohit D Divekar,Matthew A Rank

doi:10.1016/j.mayocpiqo.2021.11.009

John B Hagan, Thanai Pongdee + Show 3 more

Open Access

https://doi.org/10.1016/j.mayocpiqo.2021.11.009

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Abstract

ObjectiveTo estimate the potential risk for a future postmarket black box warning (BBW) of US Food and Drug Administration (FDA)-approved monoclonal antibodies (mAbs) because of the importance for medical clinicians to understand mAb risks and benefits, including unknown future risks, especially for recently approved mAbs.MethodsThe complete dates of the study were March 16, 2020, through May 12, 2021. We searched the FDALabel database online and reviewed the scientific literature to determine current and previous FDA-approved mAbs as of March 2020. The BBWs and initial FDA-issued safety warnings were identified. The BBWs were categorized as premarket or postmarket. For mAbs with specific postmarket BBWs, previous FDA labels were evaluated to identify the presence or absence of an initial corresponding specific FDA warning.ResultsIn March 2020, a total of 83 mAbs had FDA approval; 33 had BBWs (27 premarket and 13 postmarket BBWs). Of these 33 mAbs, 55 individual specific BBWs existed (36 premarket and 19 postmarket specific warnings). On average, the specific BBWs occurred in the postmarket period at a rate of 3.4% (19/562) per year. Most (73.7%; 14/19) specific postmarket BBWs were preceded by an FDA warning in a median time of 3.61 (interquartile range, 1.36-5.78) years. Specific postmarket BBWs not preceded by a specific FDA product label warning occurred at an average rate of 0.9% (5/562) per year.ConclusionSpecific postmarket BBWs occurred in FDA-approved mAbs at a rate of 3.4% per year. Specific postmarket BBWs not preceded by a specific FDA product label warning had a rate of 0.9% per year.

Highlights

Muromonab-CD3, daclizumab, and efalizumab were previously withdrawn from the market for safety concerns, and vedolizumab was withdrawn from the market voluntarily
Postmarket black box warning (BBW) were more likely to have occurred for Food and Drug Administration (FDA)-approved monoclonal antibody (mAb) that received approval before 2013 than mAbs approved between 2013 and March 2020 (Figure 1)
The BBWs were not associated with priority review, accelerated approval, breakthrough therapy, fast-track approval, orphan drug status, premarket BBW, or time from FDA submission to approval

Summary

Methods

Study Sample To identify all therapeutic mAbs previously approved by the FDA, we performed a search of the FDALabel database[4] for currently available lists of biological agents from the FDA’s Center for Biologics Evaluation and Research, Micromedex (IBM), and relevant literature, with a search date completion of March 27, 2020.5-9 The complete dates of the study were March 16, 2020, through May 12, 2021. Muromonab-CD3, daclizumab, and efalizumab were previously withdrawn from the market for safety concerns, and vedolizumab was withdrawn from the market voluntarily. These mAbs were not active in March 2020 and were excluded from this study. Special Regulatory Pathways The FDA has provided regulatory pathways that allow for prioritization of the assessment process.[11] The investigative team used the FDA-provided information as methodology to define various types of priority review used for mAbs. In 1992, priority review was permissible with use of the Prescription Drug User Fee Act that allowed for a 2-tier system of review times, wherein the standard 10month review could be reduced to a 6month priority review. The agency did not grant a change in trial times or an alteration of standards for drug approval or quality of evidence

Results

Discussion

Conclusion