A Drug Safety Rating System Based on Postmarketing Costs Associated with Adverse Events and Patient Outcomes.

BACKGROUND: Given the multiple limitations associated with relatively homogeneous preapproval clinical trials, inadequate data disclosures, slow reaction times from regulatory bodies, and deep-rooted bias against disclosing and publishing negative results, there is an acute need for the development of analytics that reflect drug safety in heterogeneous, real-world populations. OBJECTIVE: To develop a drug safety statistic that estimates downstream medical costs associated with serious adverse events (AEs) and unfavorable patient outcomes associated with the use of 706 FDA-approved drugs. METHODS: All primary suspect case reports for each drug were collected from the FDA's Adverse Event Reporting System database (FAERS) from 2010-2014. The Medical Dictionary for Regulatory Activities (MedDRA) was used to code serious AEs and outcomes, which were tallied for each case report. Medical costs associated with AEs and poor patient outcomes were derived from Agency for Healthcare Research and Quality (AHRQ) survey data, and their corresponding ICD-9-CM codes were mapped to MedDRA terms. Nonserious AEs and outcomes were not included. For each case report, either the highest AE cost or, if no eligible AE was listed, the highest outcome cost was used. All costed cases were aggregated for each drug and divided by the number of patients exposed to obtain a downstream estimated direct medical cost burden per exposure. Each drug was assigned a corresponding 1-100 point total. RESULTS: The 706 drugs showed an exponential distribution of downstream costs, and the data were transformed using the natural log to approximate a normal distribution. The minimum score was 8.29, and the maximum score was 99.25, with a mean of 44.32. Drugs with the highest individual scores tended to be kinase inhibitors, thalidomide analogs, and endothelin receptor antagonists. When scores were analyzed across Established Pharmacologic Class (EPC), the kinase inhibitor and endothelin receptor antagonist classes had the highest total. However, other EPCs with median scores of 75 and above included hepatitis C virus NS3/4A protease inhibitor, recombinant human interferon beta, vascular endothelial growth factor-directed antibody, and tumor necrosis factor blocker. When Anatomical Therapeutic Chemical classifications were analyzed, antineoplastic drugs were outliers with approximately 80% of their individual scores 60 and above, while approximately 20%-30% of blood and anti-infective drugs had scores of 60 and above. Within-drug class results served to differentiate similar drugs. For example, 6 serotonin reuptake inhibitors had a score range of 35 to 53. CONCLUSIONS: This scoring system is based on estimated direct medical costs associated with postmarketing AEs and poor patient outcomes and thereby helps fill a large information gap regarding drug safety in real-world patient populations.

Stimulated reporting: the impact of US food and drug administration-issued alerts on the adverse event reporting system (FAERS).

BACKGROUND: The US Food and Drug Administration (FDA) uses the Adverse Event Reporting System (FAERS) to support post-marketing safety surveillance programs. Currently, almost one million case reports are submitted to FAERS each year, making it a vast repository of drug safety information. Sometimes cited as a limitation of FAERS, however, is the assumption that "stimulated reporting" of adverse events (AEs) occurs in response to warnings, alerts, and label changes that are issued by the FDA. OBJECTIVE: To determine the extent of "stimulated reporting" in the modern-day FAERS database. METHODS: One hundred drugs approved by the FDA between 2001 and 2010 were included in this analysis. FDA alerts were obtained by a comprehensive search of the FDA's MedWatch and main websites. Publicly available FAERS data were used to assess the "primary suspect" AE reporting pattern for up to four quarters before, and after, the issuance of an FDA alert. RESULTS: A few drugs did demonstrate "stimulated reporting" trends. A majority of the drugs, however, showed little evidence for significant reporting changes associated with the issuance of alerts. When we compared the percentage changes in reporting after an FDA alert with those after a sham "control alert", the overall reporting trends appeared to be quite similar. Of 100 drugs analyzed for short-term reporting trends, 21 real alerts and 25 sham alerts demonstrated an increase (greater than or equal to 1 %) in reporting. The long-term analysis of 91 drugs showed that 24 real alerts and 28 sham alerts demonstrated a greater than or equal to 1 % increase. CONCLUSIONS: Our results suggest that most of modern day FAERS reporting is not significantly affected by the issuance of FDA alerts.

The Weber effect and the United States Food and Drug Administration's Adverse Event Reporting System (FAERS): analysis of sixty-two drugs approved from 2006 to 2010.

BACKGROUND: The United States Food and Drug Administration's (FDA) Adverse Event Reporting System (FAERS) consists of adverse event (AE) reports linked to approved drugs. The database is widely used to support post-marketing safety surveillance programs. Sometimes cited as a limitation to the usefulness of FAERS, however, is the 'Weber effect,' which is often summarized by stating that AE reporting peaks at the end of the second year after a regulatory authority approves a drug. Weber described this effect in 1984 based upon a single class of medications prescribed in the United Kingdom. Since that time, the FDA has made a concerted effort to improve both reporting and the database itself. Both volume and quality of AE reporting has dramatically improved since Weber's report, with an estimated 800,000 yearly reports now being logged into FAERS. OBJECTIVE: The aim of this study was to determine if current FAERS reporting follows the trend described by Weber. METHODS: Sixty-two drugs approved by the FDA between 2006 and 2010 were included in this analysis. Publicly available FAERS data were used to assess the 'primary suspect' AE reporting pattern for up to a 4-year period following each drug's approval date. RESULTS: A total of 334,984 AE reports were logged into FAERS for the 62 drugs analyzed here. While a few of the drugs demonstrated what could be considered 'Weber effect' curves, a majority of the drugs showed little evidence for the effect. In fact, the general AE reporting pattern observed in this study appears to consist simply of increasing case counts over the first three quarters after approval followed by relatively constant counts thereafter. CONCLUSIONS: Our results suggest that most of the modern adverse event reporting into FAERS does not follow the pattern described by Weber. Factors that may have contributed to this finding include large increases in the volume of AE reports since the Weber effect was described, as well as a concerted effort by the FDA to increase awareness regarding the utility of post-marketing AE reporting.