Drug-review deadlines and safety problems

N Engl J Med. 2008 Mar 27;358(13):1354-61. doi: 10.1056/NEJMsa0706341.


Background: The Prescription Drug User Fee Act (PDUFA) imposes deadlines for the completion of drug reviews by the Food and Drug Administration (FDA). Critics have suggested that these deadlines may result in rushed approvals and the emergence of unanticipated safety problems once a product is in clinical use.

Methods: We assessed the association between the PDUFA deadlines and the timing of FDA drug approval by constructing dynamic Cox proportional-hazards models of review times for all new molecular entities approved between 1950 and 2005. To determine whether the deadlines were associated with postmarketing safety problems, we focused on drugs submitted since January 1993, when the deadlines were first imposed. We used exact logistic regression to determine whether drugs approved immediately before the deadlines were associated with a higher rate of postmarketing safety problems (e.g., withdrawals and black-box warnings) than drugs approved at other times.

Results: Initiation of the PDUFA requirements concentrated the number of approval decisions made in the weeks immediately preceding the deadlines. As compared with drugs approved at other times, drugs approved in the 2 months before their PDUFA deadlines were more likely to be withdrawn for safety reasons (odds ratio, 5.5; 95% confidence interval [CI], 1.3 to 27.8), more likely to carry a subsequent black-box warning (odds ratio, 4.4; 95% CI, 1.2 to 20.5), and more likely to have one or more dosage forms voluntarily discontinued by the manufacturer (odds ratio, 3.3; 95% CI, 1.5 to 7.5).

Conclusions: PDUFA deadlines have appreciably changed the approval decisions of the FDA. Once medications are in clinical use, the discovery of safety problems is more likely for drugs approved immediately before a deadline than for those approved at other times.

Publication types

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

MeSH terms

  • Drug Approval / legislation & jurisprudence*
  • Drug Approval / methods
  • Drug Industry / economics
  • Drug Industry / legislation & jurisprudence
  • Drug Labeling
  • Drug and Narcotic Control / statistics & numerical data*
  • Drug-Related Side Effects and Adverse Reactions*
  • Government Regulation*
  • Product Surveillance, Postmarketing
  • Time Factors
  • United States
  • United States Food and Drug Administration / legislation & jurisprudence*