Review of FDA Amendments Act Section 921 Experience in Posting Data-mining Results from the FAERS Database.

Title IX, § 921 of the Food and Drug Administration (FDA) Amendments Act of 2007 requires the FDA to mine data on a regular basis, using its adverse events database, the FDA Adverse Event Reporting System, to identify potential signals of serious risks/new safety information. This review of the FDA's quarterly web-posted results is the first to document the contributions of the program to maintaining the continued safe use of approved pharmaceutical drugs/biologics and the lessons that have emerged from this rich experience. Details on proprietary prescription drugs/biologics, generic prescription drugs, and over-the-counter drugs were downloaded from the quarterly posts that begin in first quarter of 2008. Key information was tabulated, including proprietary and generic names of products or classes of products, the identified potential signals of serious risks, the labeling-decision category (updated, no action is necessary at this time, or evaluating the need for regulatory action), the labeling section (Warnings and Precautions, Adverse Reactions, Drug Safety Communications, Contraindications, or Boxed Warnings), and estimated times to updated decisions. Since the beginning of the FDAAA Section 921 posting requirement, the FDA has posted 555 potential signals of serious risk or new safety information. Of these, there have been 262 posts (47%) that resulted in decisions requiring updated product labeling, 75 posts (14%) that resulted in decisions that no action was necessary, and 218 posts (39%) indicating that the FDA was evaluating the need for regulatory action. Of the 262 posts that required updating one or more sections of a product label, there was a preponderance of Warnings and Precautions, with 172 (66%); followed by Adverse Reactions, with 114 (44%); Drug Safety Communications, 44 (18%); Contraindications, 27 (10%); and Boxed Warnings, 19 (7%). The median times to update decisions were 12 months for Warnings & Precautions, Adverse Reactions, and Boxed Warnings, and 11 months for Contraindications. Important themes from the present analysis include the following: (1) nearly 80% of posts resulted in updated product labeling; (2) 20% of decisions concerned classes of proprietary and generic drug/biologic products; (3) product-use errors, such as name confusion, continue to be important; (4) the safe use of pharmaceuticals in children is gaining attention but still has a long way to go; and (5) drug-drug interactions are of continuing concern. The FDA Amendments Act § 921 program will continue to have an important place in the future of pharmacovigilance practices.

Beninger P ，Murray M 《-》

Sources of Evidence Triggering and Supporting Safety-Related Labeling Changes: A 10-Year Longitudinal Assessment of 22 New Molecular Entities Approved in 2008 by the US Food and Drug Administration.

New safety issues concerning US FDA-approved drugs are commonly communicated through safety-related labeling changes. Therefore, to optimize and refine postmarket safety surveillance strategies, it is important to comprehensively characterize the sources of data giving rise to safety-related labeling changes. Our objective was to characterize the sources of data triggering and supporting the identification of new safety risks of FDA-approved drugs communicated through safety-related labeling changes. We conducted a retrospective study with a 10-year observation period using FDA's internal electronic data repositories for all prescription new molecular entities (NME) approved in 2008. We collected and analyzed information on new safety issues, the section of the full prescribing information updated, initiators (FDA, drug manufacturer), and triggering and supporting sources of evidence. Among 22 NMEs approved in 2008, 189 new safety issues for 18 NMEs were identified. Compared to drug manufacturer, FDA initiated safety-related labeling changes in nine of the ten changes to the Boxed Warnings, 28 of the 52 changes to the Warnings and Precautions, and 43 of the 134 changes to the Adverse Reactions sections of the full prescribing information. The most frequent triggering sources of evidence included the drug manufacturer safety database (32.3%) and FDA Adverse Event Reporting System (FAERS) safety reports (15.3%) for all relevant sections of the full prescribing information, and class-labeling changes (17.5%) for Boxed Warnings and the Warnings and Precautions sections. The most frequent triggering source of evidence was FAERS safety reports (69%) in the first year after drug approval and the drug manufacturer safety database in subsequent years. Our findings emphasize the continued importance of safety reports from FAERS and drug manufacturer safety databases and a comprehensive drug safety surveillance program throughout a drug's lifecycle.

Croteau D ，Pinnow E ，Wu E ，Muñoz M ，Bulatao I ，Dal Pan G ... -  《-》

Impact of United States Food and Drug Administration's boxed warnings on adverse drug reactions reporting rates and risk mitigation for multiple myeloma drugs.

Garg V ，Raisch DW ，McKoy JM ，Trifilio SM ，Holbrook J ，Edwards BJ ，Belknap SM ，Samaras AT ，Nardone B ，West DP ... -  《-》

Evaluation of Pre-marketing Factors to Predict Post-marketing Boxed Warnings and Safety Withdrawals.

Schick A ，Miller KL ，Lanthier M ，Dal Pan G ，Nardinelli C ... -  《-》

Assessment of the impact of scheduled postmarketing safety summary analyses on regulatory actions.

In addition to standard postmarketing drug safety monitoring, Section 915 of the Food and Drug Administration Amendments Act of 2007 (FDAAA) requires the US Food and Drug Administration (FDA) to conduct a summary analysis of adverse event reports to identify risks of a drug or biologic product 18 months after product approval, or after 10,000 patients have used the product, whichever is later. We assessed the extent to which these analyses identified new safety signals and resultant safety-related label changes. Among 458 newly approved products, 300 were the subjects of a scheduled analysis; a new safety signal that resulted in a safety-related label change was found for 11 of these products. Less than 2% of 713 safety-related label changes were based on the scheduled analyses. Our study suggests that the safety summary analyses provide only marginal value over other pharmacovigilance activities.

Sekine S ，Pinnow EE ，Wu E ，Kurtzig R ，Hall M ，Dal Pan GJ ... -  《-》