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

Clin Pharmacol Ther. 2021 Dec;110(6):1512-1525. doi: 10.1002/cpt.2320. Epub 2021 Jul 8.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Biological Products / administration & dosage*
  • Biological Products / standards
  • Cohort Studies
  • Drug Approval / methods*
  • Drug Development / methods*
  • Drug Development / standards
  • Humans
  • Product Surveillance, Postmarketing / methods*
  • Product Surveillance, Postmarketing / standards
  • Retrospective Studies
  • Treatment Outcome
  • United States / epidemiology
  • United States Food and Drug Administration* / standards


  • Biological Products