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. 2023 Feb;46(2):109-120.
doi: 10.1007/s40264-022-01258-0. Epub 2022 Dec 5.

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

Daniele Sartori  1   2 , Jeffrey K Aronson  3 , G Niklas Norén  4 , Igho J Onakpoya  3
Affiliations

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

Daniele Sartori et al. Drug Saf. 2023 Feb.

Abstract

Introduction and objective: Signals 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.

Methods: We 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.

Results: Overall, 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.

Conclusions: Most 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.

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Conflict of interest statement

JKA has written papers on adverse drug reactions in peer-reviewed journals and has received royalties from textbooks that he has edited or co-edited; he has often acted as an expert witness in cases involving adverse drug reactions, including opioids, most often in Coroners’ courts. DS and GNN are employed by the UMC, which manages VigiBase and holds the archives of the Signal Document used to retrieve part of the included studies. Part of the reviewed materials was published in peer-reviewed journals, drug bulletins, and abstracts or posters by researchers presently or formerly belonging to this foundation. Specifically, DS has authored signals published on drug bulletins, as abstracts or posters, some of which were included in this review, and received funding for doctoral studies from the UMC. IJO has no competing interests.

Figures

Fig. 1
Fig. 1
Preferred reporting items for systematic reviews and meta-analyses flow chart of the scoping review. 1Includes: 59 abstracts subsequently published as papers, 42 previously communicated signals, 3 duplicate publications. 2Includes: 41 non-systematic (narrative) reviews, 17 descriptive (quantitative) analyses, 9 measurements of usefulness of sources of information or biases affecting disproportionality analyses, 4 commentaries, 1 creation of an interventional program, 1 evidence mapping. 3Includes: 16 records of beneficial effects or drug repurposing, 18 of medication errors, false-positive laboratory abnormalities, or increases in plasma concentrations of a medicinal product after suspected drug–drug interactions. 4Includes: 9 not concerning medicinal products, 4 without data in humans (i.e., simulation studies), 1 withdrawn publication. 51728 from: 16 cited references in electronic records, 4 from Google Scholar, 2 from original authors, 585 from cited reference in the gray literature, 999 from websites, 122 from organizations. ADR adverse drug reaction
Fig. 2
Fig. 2
Schematic representation of 79 and 48 signals supported by at least two or three features. Each node is labeled after the features invoked in clinical assessments of adverse drug reaction reports; linked nodes indicate features that co-occurred. In brackets, count of signals per feature. Excl. excluding
Fig. 3
Fig. 3
Stacked bar graph, showing the numbers of unique studies grouped by year and by Oxford Centre for Evidence-Based Medicine (OCEBM) levels, irrespective of stakeholder, concerning 2350 studies (71 classified as N/A were omitted). In red OCEBM 1, yellow OCEBM 2, blue OCEBM 3, and dark green OCEBM 4 (excluding subtype 4, i.e., disproportionality analyses [DAs]); in light green, OCEBM subtype 4
See this image and copyright information in PMC

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