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Abstract

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. 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. 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with drugs approved at other times, drugs approved in the 2 months before their PDUFA deadlines were more likely to be withdrawn for safety reasons (odds ratio, 5.5; 95% confidence interval [CI], 1.3 to 27.8), more likely to carry a subsequent black-box warning (odds ratio, 4.4; 95% CI,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). 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. Copyright 2008 Massachusetts Medical Society.

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Most cited references 11

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Timing of new black box warnings and withdrawals for prescription medications.

Karen Lasser (2002)

Recently approved drugs may be more likely to have unrecognized adverse drug reactions (ADRs) than established drugs, but no recent studies have examined how frequently postmarketing surveillance identifies important ADRs. To determine the frequency and timing of discovery of new ADRs described in black box warnings or necessitating withdrawal of the drug from the market. Examination of the Physicians' Desk Reference for all new chemical entities approved by the US Food and Drug Administration between 1975 and 1999, and all drugs withdrawn from the market between 1975 and 2000 (with or without a prior black box warning). Frequency of and time to a new black box warning or drug withdrawal. A total of 548 new chemical entities were approved in 1975-1999; 56 (10.2%) acquired a new black box warning or were withdrawn. Forty-five drugs (8.2%) acquired 1 or more black box warnings and 16 (2.9%) were withdrawn from the market. In Kaplan-Meier analyses, the estimated probability of acquiring a new black box warning or being withdrawn from the market over 25 years was 20%. Eighty-one major changes to drug labeling in the Physicians' Desk Reference occurred including the addition of 1 or more black box warnings per drug, or drug withdrawal. In Kaplan-Meier analyses, half of these changes occurred within 7 years of drug introduction; half of the withdrawals occurred within 2 years. Serious ADRs commonly emerge after Food and Drug Administration approval. The safety of new agents cannot be known with certainty until a drug has been on the market for many years.