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Timing of New Black Box Warnings and Withdrawals for Prescription Medications

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Timing of New Black Box Warnings and Withdrawals for Prescription Medications ORIGINAL CONTRIBUTION Timing of New Black Box Warnings and Withdrawals for Prescription Medications Karen E. Lasser, MD, MPH Context Recently approved drugs may be more likely to have unrecognized ad- Paul D. Allen, MD, MPH verse drug reactions (ADRs) than established drugs, but no recent studies have examined how frequently postmarketing surveillance identifies important ADRs. Steffie J. Woolhandler, MD, MPH Objective To determine the frequency and timing of discovery of new ADRs de- David U. Himmelstein, MD scribed in black box warnings or necessitating withdrawal of the drug from the market. Sidney M. Wolfe, MD Design and Setting Examination of the Physicians’ Desk Reference for all new chemi- David H. Bor, MD cal entities approved by the US Food and Drug Administration between 1975 and 1999, and all drugs withdrawn from the market between 1975 and 2000 (with or without a DVERSE DRUG REACTIONS prior black box warning). (ADRs) are believed to be a Main Outcome Measures Frequency of and time to a new black box warning or leading cause of death in the drug withdrawal. 1 United States. Prior to ap- Results A total of 548 new chemical entities were approved in 1975-1999; 56 (10.2%) Aproval, drugs are studied in selected acquired a new black box warning or were withdrawn. Forty-five drugs (8.2%) ac- populations2,3 for limited periods, pos- quired 1 or more black box warnings and 16 (2.9%) were withdrawn from the mar- sibly contributing to an increased risk ket. In Kaplan-Meier analyses, the estimated probability of acquiring a new black box of ADRs after approval. Pharmaceuti- warning or being withdrawn from the market over 25 years was 20%. Eighty-one ma- cal companies frequently market new jor changes to drug labeling in the Physicians’ Desk Reference occurred including the drugs heavily to both patients and cli- 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; nicians before the full range of ADRs half of the withdrawals occurred within 2 years. is ascertained. Inadequate clinician re- porting may delay detection of post- 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 marketing ADRs; less than 10% of all been on the market for many years. ADRs are estimated to be reported to JAMA. 2002;287:2215-2220 www.jama.com MEDWATCH,4 the Food and Drug Ad- ministration’s (FDA’s) voluntary post- marketing reporting system. esophageal reflux in adults. After its ence from 1975 to 2000, a marker of the Patient exposure to new drugs with introduction, many pediatricians pre- most serious ADRs, and used survival unknown toxic effects may be exten- scribed the drug to infants with gastric analyses to determine the course of their sive. Nearly 20 million patients in the reflux, 24 of whom were reported to discovery. We also calculated the fre- United States took at least 1 of the have died.6 quency and timing of drug withdraw- 5 drugs withdrawn from the market Should clinicians hesitate to pre- als over this period. between September 1997 and Sep- scribe newly approved drugs? Few data tember 1998.5 Three of these 5 drugs are available on how frequently seri- METHODS were new, having been on the market ous ADRs are discovered after drug in- Data Sources and Definitions for less than 2 years. Seven drugs troduction. Previous studies examin- We chose the study period 1975-2000 approved since 1993 and subsequently ing drug labeling changes have found because it corresponds with the FDA’s withdrawn from the market have been high rates of undetected postapproval reported as possibly contributing to risks7 with low rates of subsequent drug Author Affiliations: Department of Medicine, Cam- 6 8,9 1002 deaths. For example, cisapride withdrawal. However, no study has bridge Hospital and Harvard Medical School, Cam- was approved for the treatment of a analyzed changes in the Physicians’ Desk bridge, Mass (Drs Lasser, Allen, Woolhandler, Him- 10-35 melstein, and Bor); and Public Citizen Health Research benign condition, nocturnal gastro- Reference, the most commonly used Group, Washington, DC (Dr Wolfe). source of labeling information.36 We Corresponding Author and Reprints: Karen E. Lasser, analyzed the incidence of new black box MD, MPH, Macht 4th Floor, Cambridge Hospital, 1493 For editorial comment see p 2273. Cambridge St, Cambridge, MA 02139 (e-mail: klasser warnings in the Physicians’ Desk Refer- @challiance.org). ©2002 American Medical Association. All rights reserved. (Reprinted) JAMA, May 1, 2002—Vol 287, No. 17 2215 Downloaded From: https://jamanetwork.com/ on 09/29/2021 BLACK BOX WARNINGS FOR DRUGS compendium of the FDA-approved pro- counted 2 separate events in the analy- Figure. Kaplan-Meier Estimate of New Drug Survival Without a New Black Box Warning fessional product labeling for selected sis of Physicians’ Desk Reference changes, or Withdrawal (Physicians’ Desk Reference drugs, is released in November of the year and counted only the withdrawal date in Changes) before its cover date. Black box warn- the analysis of time until withdrawal. We ings are prominently displayed in the calculated the time that elapsed before 1.0 Physicians’ Desk Reference to alert prac- 50% of eventual drug withdrawals took 0.8 titioners to serious risks.46 According to place, and the time that elapsed before 0.6 the Federal Register, 50% of all Physicians’ Desk Reference Special problems, particularly those that changes were made. We also analyzed the 0.4 may lead to death or serious injury, may be content of the black box warnings and 0.2 required by the Food and Drug Adminis- the reasons for withdrawal according to Warning or WithdrawalWarning tration to be placed in a prominently dis- Probability of No Black Box Probability the type of toxicity. 0 played box. The boxed warning ordinarily shall be based on clinical data, but serious 0 5 10 15 20 25 Statistical Methods Years After New Drug Approval animal toxicity may also be the basis of a boxed warning in the absence of clinical We used the SAS statistical package data.47 (Version 8; SAS Institute, Cary, NC) for modern era of drug surveillance.37,38 We We excluded black box warnings that frequency analysis, and the Lifetest pro- obtained a list of drugs approved from were present when a drug first ap- cedure to calculate Kaplan-Meier sur- 1975-1999 from the Tufts Center for the peared in the Physicians’ Desk Refer- vival curves for censored failure-time Study of Drug Development.39 (Drugs ap- ence. We also excluded black box warn- data. We used Kaplan-Meier survival proved in 2000 were excluded because ings that a drug should be administered curves to estimate a drug’s “survival” none appear in the other data source for by a qualified physician, as this warn- (without reaching the end point of a new the study, the year 2000 Physicians’ Desk ing may not indicate a new ADR. We black box warning and/or withdrawal Reference,34 which was released in No- defined a Physicians’ Desk Reference from the market) over the study pe- vember 1999.) We used the drug ap- change as either the addition of 1 or riod, taking into account the fact that proval date to approximate the date the more black box warnings per drug or drugs are on the market for varying pe- drug was first marketed. We compiled the withdrawal of a drug. riods (some briefly). We censored those a list of drugs withdrawn for safety rea- drugs that had not reached the end point sons from a Federal Register notice40 pub- Analysis in question at the time of the analysis. lished in 1998 and from information on For drugs that had a black box warn- the FDA Web site about drug withdraw- ing in the 2000 Physicians’ Desk Refer- RESULTS als between 1998 and 2000.41-43 We de- ence, we examined earlier editions of the Five hundred forty-eight new chemical fined a drug as “withdrawn for safety rea- Physicians’ Desk Reference to determine entities were approved from 1975- sons” if the drug removal was initiated when the black box warning first ap- 1999. Of these, 56 (10.2%) drugs ac- by the FDA for safety reasons or if the peared. If a drug did not have a black box quired a new black box warning or were manufacturer voluntarily withdrew it warning in the Physicians’ Desk Refer- withdrawn from the market. In Kaplan- from the market following the identifi- ence in which it first appeared, we mea- Meier analyses, the estimated probabil- cation of life-threatening ADRs. sured the time (rounded to the nearest ity of a new drug acquiring black box We included all drugs that the FDA month) that elapsed between the ap- warnings or being withdrawn from the defined as new molecular entities (ie, proval date and the year of the first Phy- market over 25 years was 20% (FIGURE). an active ingredient that had never been sicians’ Desk Reference in which a black Forty-five drugs (8.2%) acquired 1 or marketed in the United States).44 We ex- box warning appeared. We approxi- more black box warnings that were not cluded over-the-counter medications, mated the exact date of the Physicians’ present when the drug was approved diagnostic agents, and biologics (de- Desk Reference year as January 1 of its (TABLE 1). Sixteen drugs (2.9%) ap- fined as any drug approved through the cover year. We similarly measured the proved between 1975 and 2000 were FDA’s Center for Biologics Evaluation time from approval to withdrawal for withdrawn from the market between and Research45).
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