Introduction The Food and Drug Administration Adverse Event Reporting System (FAERS) is a database of adverse event (AE) and medication error reports for drugs and therapeutic biologics. Examining trends of reported individual case safety reports (ICSRs) provides context for evaluating safety concerns. Objective Characterize pediatric FAERS ICSRs and compare trends (1) to adult reports; (2) within pediatric subgroups. Methods This cross-sectional study examined FAERS ICSRs received between January 1, 2010, through December 31, 2020. Stratified age bands were neonates, infants, younger children, older children, adolescents, and adults. We characterized groups by patient demographic information, suspect products, AEs, and reporter type. Results From 2010 to 2020, there were 11,258,995 FAERS ICSRs; 3.1% described pediatric patients. Compared to adults, pediatric ICSRs had higher proportions of all serious outcomes except death. Within pediatric subgroups, neonates had the highest proportions of serious outcomes (96.2%) compared to infants, younger children, older children, and adolescents (79.8%, 67.9%, 59.5%, and 52.7%, respectively). Younger pediatric age groups were more likely to have weight information than older age groups but were less likely to include gender information. The most frequently reported AE was off label use for pediatrics and drug ineffective for adults. Products and AEs reported also differed among pediatric subgroups. Neonates, infants, and adolescents had entirely distinct sets of top five product-event combinations. Conclusion Pediatric ICSRs represent a minority of FAERS reports but have distinctly different attributes relative to adult ICSRs. Reporting trends also vary within pediatric subgroups, which highlights the need for unique considerations for pediatric safety surveillance.

The US Food and Drug Administration's (FDA's) routine postmarketing drug safety monitoring may lead to safety-related labeling changes for identified risks. Additionally, the Best Pharmaceuticals for Children Act (BPCA) and Pediatric Research Equity Act (PREA) require the FDA to conduct postmarket pediatric-focused safety reviews of adverse events. The purpose of these pediatric reviews is to identify risks associated with drug or biological products 18 months after the FDA approves a pediatric labeling change pursuant to studies conducted under the BPCA or PREA. These reviews are presented to the FDA Pediatric Advisory Committee (PAC) or publicly posted on FDA's website. The aim of this study was to evaluate the impact of pediatric reviews prompted by BPCA/PREA from October 1, 2013, to September 30, 2019. The impact was quantified by the number of new safety signals identified and the subsequent safety-related labeling changes resulting from pediatric reviews relative to safety-related labeling changes triggered by other data sources. Among 163 products with at least one pediatric review completed, a new safety signal that resulted in a safety-related labeling change was found for 5 of these products (representing 3 active ingredients); none described risks specific to the pediatric population. Between October 2013 and September 2021, there were 585 safety-related labeling changes implemented for products with at least one completed pediatric review. Less than 1% of 585 safety-related labeling changes were the result of a mandated pediatric review. Our study suggests that mandated pediatric reviews conducted 18 months after a pediatric labeling change provided minimal value over other postmarket safety surveillance activities.

Introduction 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. Objectives 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. Methods 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. Results 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. Conclusions 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.

The US Food and Drug Administration (FDA) receives millions of postmarket adverse event reports for drug and therapeutic biologic products every year. One of the most salient issues with these submissions is report duplication, where an adverse event experienced by one patient is reported multiple times to the FDA. Duplication has important negative implications for data analysis. We improved and optimized an existing deduplication algorithm that used both structured and free-text data, developed a web-based application to support data processing, and conducted a 6-month dedicated evaluation to assess the potential operationalization of the deduplication process in the FDA. Comparing algorithm predictions with reviewer determinations of duplicates for twenty-seven files for case series reviews (with a median size of 281 reports), the average pairwise recall and precision were equal to 0.71 (SD ± 0.32) and 0.67 (SD ± 0.34). Overall, reviewers felt confident about the algorithm and expressed their interest in using it. These findings support the operationalization of the deduplication process for case series review as a supplement to human review.

The US Food and Drug Administration Adverse Event Reporting System (FAERS) contains over 24 million individual case safety reports (ICSRs). In this research project, we evaluated a natural language processing (NLP) tool’s ability to extract four demographic variables (gender, weight, ethnicity, race) from ICSR narratives. Specificity of the NLP algorithm was over 94% for all demographics, while sensitivity varied between the demographics: 98.6% (gender), 45.5% (weight), 100% (ethnicity), and 85.3% (race). Among ICSRs missing weight, ethnicity, and race in the structured field, few cases had this information in the narrative (>95% missing); consequently, the positive predictive value (PPV) for these three demographics had wide 95% confidence intervals. After NLP implementation, the total number of ICSRs missing gender was reduced by 33% (i.e., NLP identified 472 thousand reports having a gender value in the narrative that was not in the structured field), while the total number of ICSRs missing weight, ethnicity, or race was reduced by less than 4%. This study demonstrated that the implementation of an NLP tool can provide meaningful improvements in the availability of gender information for pharmacovigilance activities conducted with FAERS data. In contrast, NLP tools targeting the extraction of weight, ethnicity, or race from free-text fields have minimal impact largely because the information was infrequently provided by the reporter. Further gains in completeness of these fields must originate from increases in provision of demographic information from the reporter rather than informatic solutions.

INTRODUCTION:Missing age presents a significant challenge when evaluating individual case safety reports (ICSRs) in the FDA Adverse Event Reporting System (FAERS). When age is missing in an ICSR's structured field, it may be in the report's free-text narrative. OBJECTIVES:This study aimed to evaluate the performance and assess the potential impact of a rule-based natural language processing (NLP) tool that utilizes a text string search to identify patients' numerical age from unstructured narratives. METHODS:Using FAERS ICSRs from 2002 to 2018, we evaluated the annual proportion of ICSRs with age missing in the structured field before and after NLP application. Reviewers manually identified patients' age from ICSR narratives (gold standard) from a random sample of 1500 ICSRs. The gold standard was compared to the NLP-identified age. RESULTS:During the study period, the percentage of ICSRs missing age in the structured field increased from 21.9 to 43.8%. The NLP tool performed well among the random sample: sensitivity 98.5%, specificity 92.9%, positive predictive value (PPV) 94.9%, and F-measure 96.7%. It also performed well for the subset of ICSRs missing age in the structured field; when applied to these cases, NLP identified age for an additional one million ICSRs (10% of the total number of ICSRs from 2002 to 2018) and decreased the percentage of ICSRs missing age to 27% overall. CONCLUSIONS:NLP has potential utility to extract patients' age from ICSR narratives. Use of this tool would enhance pharmacovigilance and research using FAERS data.

Introduction The US FDA receives more than 2 million postmarket reports each year. Safety Evaluators (SEs) review these reports, as well as external information, to identify potential safety signals. With the increasing number of reports and the size of external information, more efficient solutions for data integration and decision making are needed. Objectives The aim of this study was to develop an interactive decision support application for drug safety surveillance that integrates and visualizes information from postmarket reports, product labels, and biomedical literature. Methods We conducted multiple meetings with a group of seven SEs at the FDA to collect the requirements for the Information Visualization Platform (InfoViP). Using infographic design principles, we implemented the InfoViP prototype version as a modern web application using the integrated information collected from the FDA Adverse Event Reporting System, the DailyMed repository, and PubMed. The same group of SEs evaluated the InfoViP prototype functionalities using a simple evaluation form and provided input for potential enhancements. Results The SEs described their workflows and overall expectations around the automation of time-consuming tasks, including the access to the visualization of external information. We developed a set of wireframes, shared them with the SEs, and finalized the InfoViP design. The InfoViP prototype architecture relied on a javascript and a python-based framework, as well as an existing tool for the processing of free-text information in all sources. This natural language processing tool supported multiple functionalities, especially the construction of time plots for individual postmarket reports and groups of reports. Overall, we received positive comments from the SEs during the InfoViP prototype evaluation and addressed their suggestions in the final version. Conclusions The InfoViP system uses context-driven interactive visualizations and informatics tools to assist FDA SEs in synthesizing data from multiple sources for their case series analyses.

Introduction: Ticagrelor and high-intensity statins are recommended for secondary prevention of ASCVD events. We evaluated FDA Adverse Event Reporting System (FAERS) reports of myopathy/rhabdomyoly...

Study Objective Consumers and healthcare professionals can voluntarily report adverse experiences associated with drug products to the United States Food and Drug Administration's (FDA) Adverse Event Reporting System (FAERS). Consumers and healthcare professionals used the same general voluntary reporting form (GVR) until mid-2013, when a consumer voluntary reporting form (ConVR), written in plain language, was implemented. The objective of this study was to examine the effect of the ConVR on the quality and quantity of consumer reports submitted directly to FAERS. Design Descriptive; quasi-experimental. Data Source FAERS database. Measurements and Main Results We identified all consumer and healthcare professional reports received directly by the FDA from January 1, 2011, through December 31, 2015. Report quality was defined by the completeness of 15 individual data fields and a structured tool measuring clinical documentation. An interrupted time series design was used to evaluate the impact on the quantity of consumer reports. Consumer reports submitted on the ConVR generally included more patient, product, and event data in the structured data fields than those submitted on the GVR. Fields with the greatest absolute percentage difference after the ConVR was introduced included race/ethnicity (+77.2%), product start and stop dates (+43% and +40.3%, respectively), dechallenge and rechallenge information (+19.1% and +29.4%, respectively), and medical history (+27%). Our structured assessment also classified more reports received on the ConVR as well documented relative to the GVR consumer reports (64.9% vs 37.8%, p<0.01). The time series model demonstrated an immediate increase of 499 consumer reports in the month following the ConVR's implementation (p<0.01). Conclusion Our findings suggest that the ConVR has contributed positively to both the quality and quantity of consumer reports in FAERS.

INTRODUCTION:The most commonly reported adverse event, based on frequency of Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (PTs), in the US FDA Adverse Event Reporting System (FAERS) database is "drug ineffective" (DI). This study aimed to describe the DI reports and provide data to support recommendations on how to best evaluate these reports.METHODS:We characterized all FAERS reports coded with the MedDRA PT "drug ineffective" received between 1 September 2012 and 31 August 2016 using all other FAERS reports as a comparator. Additionally, we conducted a manual evaluation to identify informative data elements in the report narratives.RESULTS:During the study period, 247,513 (6.4% of all FAERS reports) DI reports were entered in FAERS. Compared with non-DI reports, DI reports were more likely to be reported by consumers (69.8 vs. 48.1%) and less likely to report a serious outcome (26.2 vs. 56.3%). Most DI reports (88%) were from the USA. Manual evaluation of 552 sample US reports identified 43 reports (7.8%) deemed "useful"; a higher proportion of "useful" reports provided a batch or lot number (39.5 vs. 17.2%) and were coded with additional PTs beyond "drug ineffective" (83.7 vs. 59.2%), the most frequent of which were "product quality issue" (23.3%) and "product substitution issue" (18.6%).CONCLUSIONS:DI was the most frequently reported adverse event in the FAERS database; however, the yield from these reports in terms of usefulness from a pharmacovigilance perspective was low. Efficient strategies are needed to identify which DI reports are more likely to contain useful information.

Objective: The purpose of this investigation was to identify and characterize post-marketing reports of cardiotoxicity, including torsades de pointes (TdP), associated with loperamide use.Methods: We searched the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database for post-marketing reports of serious cardiac adverse events associated with loperamide use from December 28, 1976 (U.S. drug approval date), through December 14, 2015. We also conducted a Pubmed and Google Scholar search to identify additional published reports of cardiotoxicity associated with loperamide in the medical literature through February 11, 2016.Results: Forty-eight cases of serious cardiac adverse events associated with loperamide use composed the case series. The most frequently reported cardiac adverse events were syncope (n = 24), cardiac arrest (n = 13), QT-interval prolongation (n = 13), ventricular tachycardia (n = 10), and TdP (n = 7). There were 10 cases that resulted in death. Of the 48 cases, the most commonly reported reasons for use can be characterized as drug abuse (n = 22) and diarrhea treatment (n = 17). More than one-half of the 48 cases were reported after 2010. Of the 22 drug abuse cases, the median daily dose was 250 mg (range 70 mg to 1600 mg) and events occurred as early as 6 hours after a dose and as long as 18 months after initiation of loperamide. Thirteen of the 22 cases reported using loperamide for euphoric or analgesic effects, and 9 reported use to prevent opioid withdrawal symptoms.Conclusion: The FAERS case reports provide evidence to suggest that high doses of loperamide are associated with TdP and other serious cardiac adverse events. The majority of cases in this series occurred in the setting of drug abuse for the purpose of preventing opioid withdrawal or to produce euphoric effects. It is important for both clinicians and patients to be aware of this potential risk, because prompt therapy and discontinuation of the offending agent are often essential to management and prevention of loperamide-induced cardiac arrhythmias. Published by Elsevier Inc. on behalf of the American Pharmacists Association.

We read with great interest the loperamide study of Klein et al. [(1)][1]. The U.S. Food and Drug Administration (FDA) Division of Pharmacovigilance recently reviewed 48 cases of torsades de pointes and other serious cardiac adverse events with loperamide use received through the FDA Adverse Event

Author Affiliations: 1. Department of Population Medicine, Harvard M edical School and Harvard Pilgrim Health Care Institute, Boston, MA. 2. Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA), Silver Spring, MD. 3. Office of New Drugs, CDER, FDA, Silver Spring, MD. 4. Office of Translational Sciences, CDER, FDA, Silver Spring, MD. 5. Division of Cardiology, Duke University School of Medicine, Durham, NC. 6. Office of Medical Policy, CDER, FDA, Silver Spring, MD. 7. Center for Clinical Epidemiology and B iostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA

Purpose It is critical to have pediatric post-marketing safety systems that contain enough clinical and epidemiological detail to draw regulatory, public health, and clinical conclusions. The pediatric safety surveillance workshop (PSSW), coordinated by the Food and Drug Administration (FDA), identified these pediatric systems as of 2010. This manuscript aims to update the information from the PSSW and look critically at the systems currently in use. Methods We reviewed North American pediatric post-marketing safety systems such as databases, networks, and research consortiums found in peer-reviewed journals and other online sources. We detail clinical examples from three systems that FDA used to assess pediatric medical product safety. Results Of the 59 systems reviewed for pediatric content, only nine were pediatric-focused and met the inclusion criteria. Brief descriptions are provided for these nine. The strengths and weaknesses of three systems (two of the nine pediatric-focused and one including both children and adults) are illustrated with clinical examples. Conclusions Systems reviewed in this manuscript have strengths such as clinical detail, a large enough sample size to capture rare adverse events, and/or a patient denominator internal to the database. Few systems include all of these attributes. Pediatric drug safety would be better informed by utilizing multiple systems to take advantage of their individual characteristics.