Signals of Adverse Drug Reactions Communicated by Pharmacovigilance Stakeholders: A Scoping Review of the Global Literature.

INTRODUCTION AND

objectiveSignals of adverse drug reactions (ADRs) can be supported by reports of ADRs and by interventional and non-interventional studies. The evidence base and features of ADR reports that are used to support signals remain to be comprehensively described. To this end, we have undertaken a scoping review.

methodsWe searched the following databases: PubMed, EMBASE, PsycINFO, Web of Science, and Google Scholar, without language or time restrictions. We also hand searched the bibliographies of relevant studies. We included studies of any design if the results were described as signals. We assessed the levels of evidence using the Oxford Centre for Evidence-Based Medicine (OCEBM) criteria and coded features of reports of ADRs using the Bradford Hill guidelines.

resultsOverall, 1974 publications reported 2421 studies of signals; 1683/2421 were clinical assessments of anecdotal reports of ADRs, but only 225 (13%) of these included explicit judgments on which features of the ADR reports were supportive of a signal. These 225 studies yielded 228 signals; these were supported by features, which were: 'experimental evidence' (i.e., positive dechallenge or rechallenge, 154 instances [68%]), 'temporality' (i.e., time to onset, 130 [57%]), 'exclusion of competing causes' (49 [21%]), and others (40 [17%]). Positive dechallenge/rechallenge often co-occurred with temporality (77/228). OCEBM 4 (i.e., case series and case-control studies) was the most frequent level of evidence (2078 studies). Between 2013 and 2019, there was a three-fold increase in clinical assessments of reports of ADRs compared with a less than two-fold increase in studies supported by higher levels of evidence (i.e., OCEBM 1-3). We identified an increased rate between 2013 and 2019 in disproportionality analyses (about 15 studies per year), mostly from academia.

conclusionsMost signals were supported by temporality and dechallenge/rechallenge, but clear reporting of judgments on causality remains infrequent. The number of studies supported only by anecdotal reports of ADRs increased from year to year. The impact of a growing number of signals of disproportionate reporting communicated without an accompanying clinical assessment should be evaluated.