The FDA Drug Safety Surveillance Program: Adverse Event Reporting Trends FREE

The Adverse Event Reporting System (AERS) of the US Food and Drug Association (FDA) is the largest repository of passively reported adverse drug events in the world.¹ Approximately one-half million reports are received by the FDA annually. Designed as a safety net, allowing the FDA to monitor all marketed drugs and quickly detect serious safety problems, AERS reports have served as the basis for numerous regulatory actions.² In an 8-year period (1998-2005), the number of serious event reports increased 2.6-fold and reports of deaths increased 2.7-fold.³ Given the dramatic increase in adverse event reporting following the last major revision of the AERS database in 1997, we sought to characterize current reporting patterns.

Adverse event reports received by the FDA from January 1, 2000, through December 31, 2009, were identified in the public release of AERS. Each report is classified by report type. Reports that come through the product sponsors are either expedited (serious and unexpected or unlabeled events), which must be reported within 15 days of learning of the event, or periodic (all other serious events). The frequency of submitting periodic summary reports to the FDA and the need to supply individual event reports varies by the time since approval and the existence of a report waiver.⁴ Direct reports come to the FDA from health care professionals and the public through their MedWatch program.

The absolute minimum information that constitutes a report is an identifiable reporter, a unique patient, an adverse event, and a drug that is suspected by the reporter to have caused or contributed to the event. Adverse events are classified using the Medical Dictionary for Regulatory Activities (MedDRA).⁵ Possible outcomes include death; life-threatening condition; hospitalization (initial or prolonged); required intervention to prevent harm, disability, or permanent damage; and congenital anomaly.

We used QSCAN-FDA (DrugLogic, Reston, Virginia) to identify the cohort from the publically released AERS data and conduct analyses. Original and follow-up reports of the same event were consolidated. Rates of reporting were calculated by dividing the total reports received annually by the FDA⁶ by the estimated number of visits to physician offices during which drugs were prescribed, ordered, or provided (drug visits) in the United States from the National Ambulatory Medical Care Survey.^7- 8

One-half (2.2 million [54.8%]) of the reports in the AERS database, from its inception in 1969 through the end of 2009, were received in just the past 10 years. This represents a 1.65-fold increase from the prior decade. Report volume increased from 2000 to 2010 at a mean annual rate of 11.3%. Report rates, as a proportion of drug visits at physician offices, increased from 4.90 reports per 10 000 visits in 2000 to 6.83 reports per 10 000 visits in 2005.

There was a slight preponderance of adverse event reports for women (55.3%), which is consistent with the distribution of drug visits by sex (58.5% female in 2005). In AERS, one-third (32.8%) of reports were among adults aged 30 to 64 years, and an even higher percentage (37.4%) were missing age. Just 4.4% of reports were among patients younger than 18 years and 20.1% among patients 65 years and older. Among 1 635 014 reports in which an outcome was reported, patients were hospitalized in 687 442 (42.0%), and in 247 171 reports (15.1%) the patient died. There remain significant limitations in the completeness and quality of reports. Reports missing data on age (37.4%) and sex (7.5%) have implications in the interpretation of studies limited to a particular subset and these key variables in the identification of duplicate reports. While not technically considered missing, the outcome of “other” was checked in 48% of reports.

Recombinant DNA products predominated among the most frequently reported suspect brand name drugs. The tumor necrosis factor (TNF) blockers Enbrel (etanercept; Immunex Corp, Seattle, Washington; approved November 1998), Humira (adalimumab; Abbott Laboratories, Abbott Park, Illinois; approved December 2002), and Remicade (infliximab; Centocor Ortho Biotech Inc, Horsham, Pennsylvania; approved November 1999) were first, third, and fourth most frequently reported suspect drugs, respectively. Because these drugs suppress the immune system, they carry the risk of opportunistic infections. In 2005 the FDA required the manufacturers of all TNF blockers to add a warning about lymphomas, followed by a safety alert issued in September 2008 and strengthened warnings about the risk of invasive fungal infections on the product label for these and another TNF blocker, Cimzia (certolizumab pegol; UCB, Brussels, Belgium). The reporting curves for Enbrel, Humira, and Vioxx (rofecoxib; Merck & Co Inc, Whitehouse Station, New Jersey) are bimodal (Figure). All begin with a typical Weber effect reporting curve, where the reports increased over the first 2 years of follow-up and then began to go down, until the safety alerts spurred a second larger peak. Remicade was the subject of a safety alert in 2001 regarding increased mortality among patients with congestive heart failure and saw only a slight dip in reporting 5 years after approval.

Two oral medications were among the top 10 suspect drug list: the analgesic Vioxx (rofecoxib) and the antipsychotic Seroquel (quetiapine fumarate; AstraZeneca Pharmaceuticals LP, Wilmington, Delaware). Rofecoxib (approved in 1999) was voluntarily withdrawn from the market in 2004 because of an increased risk of serious cardiovascular events. Other agents among the top 10 suspect agents included injectables for diabetes (Byetta, exenatide; Amylin Pharmaceuticals Inc, San Diego, California) and osteoporosis (Forteo, teriparatide; Eli Lilly and Company, Indianapolis, Indiana), a biological agent indicated for multiple sclerosis (Avonex, interferon beta 1a; Biogen Idec, Weston, Massachusetts) and 2 birth control products, a transdermal patch (Ortho Evra, norelgestromin and ethinyl estradiol transdermal; Ortho-McNeil-Janssen Pharmaceuticals, Raritan, New Jersey) and an intrauterine device (Mirena, levonorgestrel-releasing intrauterine system; Bayer HealthCare Pharmaceuticals Inc, Wayne, New Jersey).

Reporting of adverse events to the FDA has increased dramatically, such that the majority of reports in the 40-year-old database were received just in the past decade. Reporting was clearly stimulated by the release of new safety information, with the 10 most commonly reported suspect drugs accounting for almost one-half million reports, and may be of limited value for signal discovery. What proportion of the increase in reports can be attributed to a real increase in adverse events—possibly driven by more patients using drugs, an increase in polypharmacy, and growth in populations such as the elderly who may be more susceptible to certain adverse events—and how much represents increased reporting of suspected adverse events is unknown.

Correspondence: Dr Weiss-Smith, Pharmaceutical Health Services Research, University of Maryland, School of Pharmacy, 220 Arch St, 12th Floor, Baltimore, MD 21201 (sweiss@rx.umaryland.edu).

Author Contributions:Study concept and design: Weiss-Smith and Gogolak. Acquisition of data: Chung and Gogolak. Analysis and interpretation of data: Weiss-Smith, Deshpande, and Gogolak. Drafting of the manuscript: Weiss-Smith and Deshpande. Critical revision of the manuscript for important intellectual content: Smith, Chung, and Gogolak. Statistical analysis: Deshpande and Gogolak. Obtained funding: Weiss-Smith. Administrative, technical, and material support: Chung. Study supervision: Weiss-Smith and Gogolak.

Financial Disclosure: None reported.