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for all new chemical entities approved by the US Food and Drug Administration between 1975 and 1999, and all drugs withdrawn from the market between 1975 and 2000 (with or without a prior black box warning).Main Outcome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A total of 548 new chemical entities were approved in 1975-1999; 56 (10.2%) acquired a new black box warning or were withdrawn. Forty-five drugs (8.2%) acquired 1 or more black box warnings and 16 (2.9%) were withdrawn from the market. In Kaplan-Meier analyses, the estimated probability of acquiring a new black box warning or being withdrawn from the market over 25 years was 20%.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.JAMA. 2002;287:2215-2220
Author/Article Information
Author Affiliations: Department of Medicine, Cambridge Hospital and Harvard Medical School, Cambridge, Mass (Drs Lasser, Allen, Woolhandler, Himmelstein, and Bor); and Public Citizen Health Research Group, Washington, DC (Dr Wolfe).
Corresponding Author and Reprints: Karen E. Lasser, MD, MPH, Macht 4th Floor, Cambridge Hospital, 1493 Cambridge St, Cambridge, MA 02139 (e-mail: klasser@challiance.org). Author Contributions: Study concept and design: Lasser, Allen, Woolhandler, Himmelstein, Wolfe, Bor.
Acquisition of data: Lasser, Allen, Woolhandler, Himmelstein, Wolfe, Bor.
Analysis and interpretation of data: Lasser, Woolhandler, Himmelstein.
Drafting of the manuscript: Lasser.
Critical revision of the manuscript for important intellectual content: Lasser, Allen, Woolhandler, Himmelstein, Wolfe, Bor.
Statistical expertise: Lasser, Woolhandler, Himmelstein, Wolfe.
Obtained funding: Bor.
Administrative, technical, or material support: Bor.
Study supervision: Woolhandler, Himmelstein, Bor.
Funding/Support: Dr Lasser's work was supported by National Research Service Award grant 5T32PE11001-12, and Drs Woolhandler and Himmelstein's work was supported in part by a grant from the Open Society Institute.
Acknowledgment: Sidney S. Atwood, BA, provided assistance in programming and data management; Peg Hewitt, research librarian, and the Tufts Center for the Study of Drug Development made their data on drugs approved in the United States available to us; John Orav, PhD, helped with statistical analyses; Larry D. Sasich, PharmD, MPH, provided us with additional information on specific drugs; and Maxim D. Shrayer, PhD, commented on earlier drafts of the manuscript.
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