Retrieval of adverse event reports based on coded drug–event co-occurrence enables large-scale pharmacovigilance analyses but yields candidate reports rather than clinically adjudicated cases. Without explicit case identification, heterogeneous reports may be combined within the same case series and misinterpreted in downstream analyses. The aim of the study was to develop a structured framework for distinguishing clinically meaningful cases from candidate reports retrieved through coded drug–event co-occurrence, and to illustrate its application across information-rich and routine-review conditions. We conducted a sequential framework-development study using two case studies. Drug-induced impulsivity was used to iteratively develop and refine the framework under information-rich conditions. Drug-induced suicidality was used to examine its application under routine-review conditions with variable information availability and explicit classification of nonassessability. In case 1, nonrelevant reports were more frequent for drugs with uncertain or no established evidence ( 20–40
In the absence of a gold standard for assessing the completeness of spontaneous adverse drug reaction (ADR) reports, most studies have relied on assessing the proportion of reports containing information on predefined categories. The same principle applies to the Vigi4Eudra-score, which can be used to analyse the completeness of ADR reports from EudraVigilance. Moreover, ADR reports with a high level of information provided may be more useful in pharmacovigilance practice. The first aim of our study was to further develop the already existing Vigi4Eudra-score by modifying its penalties and by adding additional relevant categories (= EudraScore). The second aim was to assess whether the EudraScore performed better than the Vigi4Eudra-score to identify reports with at least a possible causal relationship as “well documented”. An expert panel was established comprising assessors from the pharmacovigilance and the research department of the German Federal Institute for Drugs and Medical Devices, with many years of experience in the assessment of ADR reports. Based on expert consensus, the Vigi4Eudra-score was modified by adapting existing categories and incorporating additional causality-relevant criteria, resulting in the EudraScore. A use case was conducted to compare the values calculated using the EudraScore with those obtained from the Vigi4Eudra-score. The performance of both scores in identifying reports with an “at least possible” causal relationship as “well documented” was evaluated by calculating sensitivity and specificity. Compared to the Vigi4Eudra-score, some penalties were adjusted for the EudraScore, with reduced penalties for missing country of origin and drug dose (from 10 to 5
The spontaneous reporting system is the cornerstone of pharmacovigilance but is limited by substantial underreporting, which may delay safety signal detection. The aim of this study was to evaluate the electronic health record-adverse event search method for identifying and reporting additional potential adverse drug reactions in electronic health records to strengthen routine signal detection. Between August 2022 and August 2025, targeted searches for adverse drug reactions were conducted in approximately 2,750,000 electronic health records from two Dutch hospitals using a data collection text-mining tool. Search criteria were derived from information in spontaneous reports of specific drug–adverse event associations. Structured (e.g. laboratory results, medication prescriptions) and unstructured (e.g. clinical notes, hospital discharge letters) data were used to identify potential adverse drug reactions. Identified cases were manually verified and, when relevant, reported to the Netherlands Pharmacovigilance Centre Lareb and analysed alongside spontaneous reports for signal detection. A total of 147 electronic health record-derived cases were reported for 41 drug–adverse event associations. These contributed to 34 signal detection analyses, supporting the assessment of seven safety signals. In 75
Fezolinetant, the first neurokinin-3 receptor (NK3R) antagonist licensed for moderate-to-severe vasomotor symptoms associated with menopause, carries an unresolved neoplasm signal. An imbalance in neoplasm events across the SKYLIGHT phase III programme, raised in 2023, has been set aside by regulators as a chance finding lacking a plausible mechanism. We reassess that inference on three grounds. First, exposure-adjusted incidence of non-benign neoplasms rises across placebo, 30 mg and 45 mg, at 0.2, 0.7 and 1.2 per 100 subject-years, giving a relative risk at the licensed dose of 6.6 (95
Ranitidine, a histamine-2 receptor antagonist, was withdrawn globally in 2020 following the detection of N-nitrosodimethylamine (NMDA), a probable human carcinogen. We aimed to assess advanced pharmacovigilance bias-mitigation approaches by evaluating ranitidine-associated cancer signals in the FDA Adverse Event Reporting System (FAERS) and Japanese Adverse Drug Event Report (JADER) databases alongside a systematic review of comparative safety studies. A retrospective disproportionality analysis was conducted using the FAERS and the JADER databases. Signal detection was performed using four complementary algorithms (proportional reporting ratio (PRR), reporting odds ratio, information component, and empirical Bayes geometric mean), with an active comparator (famotidine) and time-restricted (pre- and post-recall) analyses, and a systematic review of comparative safety studies was also conducted. A pronounced surge in cancer reporting was observed for ranitidine, with 140,985 reports recorded in FAERS during 2020–21, accounting for more than two thirds of all reported cancer cases. Most reports were consumer submitted and geographically clustered in regions affected by regulatory actions and litigation. Unrestricted analyses of the full FAERS database identified high-magnitude signals for multiple cancers, particularly gastrointestinal and genitourinary cancers. However, these signals were markedly attenuated or absent in active-comparator and time-restricted analyses, with convergence observed in the reporting profiles of ranitidine and famotidine. In the JADER analysis, a significant ranitidine–cancer signal among suspected drug reports (PRR = 3.54) disappeared completely when all involvement types were analyzed (PRR = 0.92), indicating that the observed association likely reflects protopathic bias, rather than a true carcinogenic effect. The systematic review revealed heterogeneous findings, with most large cohort studies demonstrating no increased risk of overall or site-specific cancers. The observed cancer signals for ranitidine in spontaneous reporting systems were predominantly attributable to the NMDA related regulatory alerts rather than intrinsic carcinogenicity. Active-comparator and time-restricted analyses, together with systematic reviews of comparative safety studies, are essential to avoid misleading inferences in pharmacovigilance assessments.
