Adverse Drug Event Surveillance and Drug Withdrawals in the United States, 1969-2002 the Importance of Reporting Suspected Reactions

ORIGINAL INVESTIGATION Adverse Drug Event Surveillance and Drug Withdrawals in the United States, 1969-2002 The Importance of Reporting Suspected Reactions Diane K. Wysowski, PhD; Lynette Swartz, MEd, MBA Background: The Adverse Event Reporting System is to safety problems. In addition, 11 drugs have special re- the primary surveillance database used by the Food and quirements for prescriptions or have restricted distribu- Drug Administration for identifying postmarketing drug tion programs. Drugs withdrawn or restricted represent safety problems. a small proportion (about 1%) of marketed drugs. Methods: We analyzed all reports of suspected adverse Conclusions: The Food and Drug Administration’s Ad- drug reactions submitted to the Food and Drug Admin- verse Event Reporting System is the primary surveil- istration from the inception of the Adverse Event Re- lance database used for the identification of safety prob- porting System database in 1969 through December 2002. lems of marketed drugs. Despite the limitations of We documented drug withdrawals and restricted distri- underreporting, differential reporting, and uneven qual- bution programs based on safety concerns. ity, submitted reports often allow the identification of serious adverse events that are added to the product label- Results: During the 33-year period from 1969 when ad- ing information. In rare instances, additional regulations, verse drug event reporting was initiated through 2002, about 2.3 million case reports of adverse events for the up to and including market removal, have been re- cumulative number of approximately 6000 marketed quired. We encourage physicians, pharmacists, other drugs were entered in the database. Most reports were health care professionals, and patients to continue to re- for female patients. During this period, numerous drug port serious suspected and known adverse drug reac- reactions have been identified and added to the product tions to manufacturers and the Food and Drug Admin- labeling as boxed warnings, warnings, precautions, con- istration. traindications, and adverse reactions. More than 75 drugs/ drug products have been removed from the market due Arch Intern Med. 2005;165:1363-1369 PRIMARY MISSION OF THE A primary source of information used Center for Drug Evalua- by the FDA for identifying postmarketing tion and Research of the drug safety problems is surveillance of Food and Drug Adminis- voluntarily submitted adverse drug event tration (FDA) is the re- reports. Reports are sent by health care pro- Aview and approval for marketing of safe fessionals, consumers, drug manufactur- and effective drugs and certain biologic ers, and others to the FDA, where they are agents. Before approval, drugs are evalu- organized in a database referred to as the ated for a defined indication in clinical Adverse Event Reporting System (AERS), previously known as the Spontaneous Re- trials of relatively short duration in a porting System. Herein, we describe ad- relatively small number and in restricted verse drug event reports submitted to this categories of people. Following approval database from its inception in 1969 through and marketing, when the drug is used in December 2002 and provide information larger populations for longer durations on associated regulatory actions, includ- and for unapproved indications, previ- ing drugs removed for safety reasons. ously unidentified adverse drug events often occur. Some of these events have METHODS Author Affiliations: Office of been serious and frequent enough or have Drug Safety, Food and Drug altered the risk-benefit ratio enough to Administration, Rockville, Md. result in the drug’s removal from the The Office of Drug Safety (formerly the Office Financial Disclosure: None. market. of Post-Marketing Drug Risk Assessment) of (REPRINTED) ARCH INTERN MED/ VOL 165, JUNE 27, 2005 WWW.ARCHINTERNMED.COM 1363 ©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 and follow-up reports cannot be identified, so the numbers do 250 000 not refer to individual persons. Reports are entered continu- 225 347 ously. The data in this article refer to those accessed from June 204 654 to August 2003. 200 804 200 000 198 475 Reports with serious outcomes (death, life-threatening event, 178 542 hospitalization, disability, congenital malformation, and event 171 900 161 480 that required medical intervention) are required to be submitted by drug manufacturers to the FDA within 15 days of re- 150 000 141 102 128 610 ceipt and are priorities for analysis. A separate serious out- 123 725 come category referred to as “other” that was added in 1997 105 553 was not included in our tally of serious reports. 100 000 Previously, no more than 5 adverse events per report were No. of Case Reports 75 212 75 272 entered in the AERS, but in 1997 the system was restructured to allow entry of all adverse events mentioned in the text. Be- 50 000 cause all adverse events are entered but serious events are not identified as such, relatively nonserious events may be included in lists of events with serious outcomes. 0 We analyzed reports by year, country, sex, age, and ad- 1990 1991 1992 1993 1994 1995 19961997 1998 1999 2000 2001 2002 verse events. We identified drugs and drug products that have Year of FDA Receipt been removed from the market or have restricted distribution programs because of safety reasons—many of which were found Figure. Number of case reports entered in the Adverse Event Reporting or confirmed using the AERS database. System from 1990 through 2002. FDA indicates Food and Drug Administration. RESULTS the FDA receives reports of adverse drug events primarily from physicians and pharmacists who submit them on a stan- During the 33-year period from 1969 when adverse drug dardized form (referred to as the MedWatch form) indirectly event reporting was initiated through 2002, about 2.3 mil- through pharmaceutical companies or directly to the FDA. lion case reports of adverse events for marketed drugs Health practitioners and patients may also report adverse drug events by telephone or by accessing the MedWatch In- were entered in the AERS database. Through 1997, there ternet site. Published reports of adverse drug reactions also was a continuous increase in the annual number of re- may be submitted. ports entered. Beginning in 1998, annual changes have Each report is entered into the AERS computerized data- been inconsistent (Figure). Compared with 1999, the base using a coding thesaurus of adverse reaction terms used peak year for receipt and entry of reports, in 2002, re- for searching and retrieval purposes. Reports are entered manu- porting declined 21%. This, in part, may be because of ally; in late 1997, the system was redesigned to begin accept- the FDA’s recent procedural change to discontinue en- ing a growing number of electronic reports submitted by phar- try of reports with nonserious outcomes for drugs ap- maceutical companies. proved longer than 3 years and to allow market autho- The process for identifying adverse events and for initiat- rization holders waivers for submission of reports with ing regulatory action for drug safety problems is as follows: FDA safety staff (primarily pharmacists) receive AERS reports daily adverse events that have nonserious outcomes and that and review them for possible drug causality. After a sufficient are already mentioned in the product labeling. number of convincing reports and/or other data (including pub- About 1.8 million reports (about 80%) originated from lished studies and case reports) have accumulated implicating reporters in the United States. The second largest source the drug with a reaction, pharmacists and epidemiologists pre- was from unidentified countries. Assuming that these sent the evidence in writing to the division that reviewed and originated in this country, the proportion of US reports approved the drug. If the reviewing division agrees that the data was 87%. The country with the second largest number are compelling enough to require regulatory action (eg, a change was France (64 021 reports), followed by the United King- in the product information), it notifies the manufacturer and dom (45 864 reports) and Japan (41 053 reports). No requests the action. Disagreements between manufacturers and country besides the United States had more than 3% of the FDA may be resolved through formal dispute resolution and the use of an Advisory Committee.1 Title 21 of the Code of the total number of reports. Most reports (53%) con- Federal Regulations (eg, Sections 2.5, 7.1-7.87, 314.150, and cerned female patients, 35% referred to male patients, and 314.151) describe regulatory actions that can be taken for the 12% did not specify sex. Patient age was less well re- removal of a drug for safety reasons.2 These include recall pro- ported than sex, with 30% of reports having unspecified cedures (usually for lot specific problems), declaration of the ages. Of the reports, 5% were for patients 14 years or drug as an imminent hazard (invoked only once for phenfor- younger, 24% concerned those aged 15 to 44 years, 16% min and lactic acidosis), and notification of a judicial hear- were for those aged 45 through 59 years, and 25% re- 3 ing. In most situations after important safety problems be- ferred to those 60 years and older. Race is not a separate come evident, drugs are voluntarily withdrawn by the market field on the form. For 1969 through 2002, about 60% of authorization holder. reports were from health care professionals, 29% were The AERS data are reviewed by safety staff for duplicate and follow-up reports. Follow-up to obtain additional information from consumers, and the remainder were from study and occasionally is conducted by manufacturers and rarely by FDA literature reports, company data, and other sources. Over- staff (because of limited resources). Technology has enabled all, 29% of reports had serious outcomes.

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