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April 30, 2002 — The safety of recently approved drugs might not be known until they have been on the market for several years, according to a new study in the May 1 issue of The Journal of the American Medical Association.
Karen E. Lasser, M.D., M.P.H., of Cambridge Hospital and Harvard Medical School in Cambridge, Mass., and colleagues examined the frequency and timing of discovery of new adverse drug reactions (ADRs) described in black box warnings or necessitating withdrawal of the drug from the market. According to background information in the article, recently approved drugs may be more likely to have unrecognized ADRs than established drugs, but no recent studies have examined how frequently postmarketing surveillance identifies important ADRs.
The researchers found that serious ADRs commonly emerge after Food and Drug Administration (FDA) approval. "Clinicians should avoid using new drugs when older, similarly efficacious agents are available," the authors suggest. "Patients who must use new drugs should be informed of the drug's limited experience and safety record, and be observed for possible [serious adverse effects]."
According to other background information in the article, adverse drug reactions are believed to be a leading cause of death in the United States. "Pharmaceutical companies frequently market new drugs heavily to both patients and clinicians before the full range of ADRs is ascertained," the authors comment. "Nearly 20 million patients in the United States took at least one of the five drugs withdrawn from the market between September 1997 and September 1998. Three of these five drugs were new, having been on the market for less than two years. Seven drugs approved since 1993 and subsequently withdrawn from the market have been reported as possibly contributing to 1002 deaths," the researchers report. Another problem may be inadequate clinician reporting, which may delay detection of postmarketing ADRs: "less than 10 percent of all ADRs are estimated to be reported to MEDWATCH, the FDA's voluntary postmarketing reporting system," they write.
For this study, the researchers analyzed the incidence of new black box warnings in the Physicians' Desk Reference (PDR), the most commonly used source of drug labeling information, from 1975 to 2000. Black box warnings are prominently displayed in the PDR to alert practitioners to serious risks. The authors looked at the black box warnings as an indication of the most serious ADRs and also calculated the frequency and timing of drug withdrawals over that time period.
A total of 548 new chemical entities were approved in 1975 - 1999, according to the researchers. "Of these, 56 (10.2 percent) drugs acquired a new black box warning or were withdrawn from the market. Forty-five drugs (8.2 percent) acquired one or more black box warnings and 16 (2.9 percent) were withdrawn from the market. The authors report, "Eighty-one major changes to drug labeling in the PDR occurred including the addition of one or more black box warnings per drug, or drug withdrawal."
"Given the frequent introduction of drugs for which new serious adverse events are discovered, the FDA should consider raising its threshold for approving new drugs when safe, effective therapies already exist, or when the new drugs treat a benign condition," the authors conclude.
Editor's Note: Dr. Lasser's work was supported by a National Research Service Award grant. The work of co-authors Steffie J. Woolhandler, M.D., M.P.H., and David U. Himmelstein, M.D., was supported in part by a grant from the Open Society Institute.
Editorial: Safety Implications for Prescribing New Drugs
In an accompanying editorial, Robert J. Temple, M.D., and Martin H. Himmel, M.D., M.P.H., with the Center for Drug Evaluation and Research Policy, Food and Drug Administration in Rockville, Md., write that labeling changes are "inevitable and should be anticipated" with new drugs.
They state that Lasser's and colleagues use of the PDR in their study may not be the most accurate measure to assess time from drug approval to labeling change because of the delay between labeling changes and updated editions of the PDR. "Although the Physicians' Desk Reference is a widely used reference, important labeling changes are often communicated to physicians by 'Dear Health Care Professional' letters, and, once in labeling, the black box warning appears prominently in drug promotion materials," the authors note.
"A physician contemplating prescribing a new drug should carefully consider the reason for the choice, particularly when an equally effective alternative is available, as there is always some risk of an undiscovered ADR. But it is incorrect to describe the introduction of unsafe drugs as frequent; the analysis of drugs by Lasser et al actually demonstrates that ADRs of sufficient importance to change the role of a drug in practice are uncommon," the authors comment.
Temple and Himmel also question what steps Lasser et al believe the FDA should implement to raise the threshold for approving new drugs. "... no improvements will completely eliminate the risk of unexpected events," the authors write. "The FDA continues to rely on reporting of ADRs by physicians, other health care professionals, and others to help uncover these risks as rapidly as possible," the editorial concludes.