Timing of New Black Box Warnings and Withdrawals for Prescription Medications
Karen E. Lasser, MD, MPH; Paul D. Allen, MD, MPH; Steffie J. Woolhandler, MD, MPH; David U. Himmelstein, MD; Sidney M. Wolfe, MD; David H. Bor, MD
Context: 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.
Objective: 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.
Design and Setting: 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for all new chemical entities approved by the US Food and Drug Administration between 1975 and 1999, and all drugs withdrawn from the market between 1975 and 2000 (with or without a prior black box warning).
Main Outcome Measures: Frequency of and time to a new black box warning or drug withdrawal.
Results: A total of 548 new chemical entities were approved in 1975-1999; 56 (10.2%) acquired a new black box warning or were withdrawn. Forty-five drugs (8.2%) acquired 1 or more black box warnings and 16 (2.9%) were withdrawn from the market. In Kaplan-Meier analyses, the estimated probability of acquiring a new black box warning or being withdrawn from the market over 25 years was 20%.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.
Conclusions: 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.