The Impact of Variability in Patient Exposure During Premarket Clinical Development on Postmarket Safety Outcomes.

We characterized the size of the premarket safety population for 278 small-molecule new molecular entities (NMEs) and 61 new therapeutic biologics (NTBs) approved by the US Food and Drug Administration (FDA) between October 1, 2002, and December 31, 2014, evaluating the relationship of premarket safety population size to regulatory characteristics and postmarket safety outcomes. The median size of the safety population was 1,044, and was lower for NTBs than NMEs (median: 920 vs. 1,138, P = 0.04), orphan products than nonorphan products (393 vs. 1,606, P < 0.001), and for products with fast-track designation (617 vs. 1,455, P < 0.001), priority review (630 vs. 1,735, P < 0.001), and accelerated approval (475 vs. 1,164, P < 0.001), than products without that designation. The median number of postmarket safety label updates and issues added to the label were higher with larger premarket exposure among nonorphan products, but not among orphan products. Products with accelerated approval using a surrogate end point had a higher median number of safety issues added to the label than those with full approval, but this did not vary with the size of the safety population; fast-track and priority review were not associated with the number of safety issues added to the label. A smaller safety population size was associated with a longer time to first safety outcome for nonorphan products but not orphan products. For orphan and nonorphan products combined, smaller premarket safety population size is not associated with the number or timing of postmarket safety outcomes, regardless of expedited program participation.

Postmarketing Safety-Related Regulatory Actions for New Therapeutic Biologics Approved in the United States 2002-2014: Similarities and Differences With New Molecular Entities.

We examined the relationship of regulatory and review characteristics to postmarketing safety-related regulatory actions for 61 new therapeutic biologics (NTBs) approved between October 1, 2002 and December 31, 2014. We also compared NTBs with small-molecule new molecular entities (NMEs) on these measures. Postmarketing safety-related regulatory actions were defined as a safety-related withdrawal or a safety-related update to a safety section of the label through June 30, 2018. Four NTBs were withdrawn, two for safety reasons. At least one safety-related update was added to the labels of 54 (88.5%) NTBs. Label updates occurred throughout the follow-up period. Time to the first safety-related regulatory action was shorter for NTBs approved under accelerated approval. The occurrence of safety events was more likely to occur with NTBs than with NMEs. This may be explained in part by the higher proportion of NTBs in the anatomical therapeutic chemical classification categories with higher frequency of safety-related updates. NTBs also had shorter time to safety events than NMEs. These findings underscore the importance of continued development of the life cycle safety surveillance system for both drugs and biologics with consideration for product type and its characteristics, including pharmacologic action.