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

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.

A Comparison of Signals of Designated Medical Events and Non-designated Medical Events: Results from a Scoping Review

“…We should stress that completeness of reports is accounted for in methods for signal detection, such as vigiRank [ 19 ], which increase the rate of detected signals compared with disproportionality analysis [ 20 ], but does not necessarily have a bearing on the timeliness of signal detection from disproportionality analyses [ 21 ]. Rather, completeness of reports has been regarded as useful in performing clinical reviews [ 14 ], which also constitute the main type of evidence underpinning signals [ 5 ]. We reiterate that although the difference in median completeness score between DME and non-DME signals was statistically significant, the effect size was small and we did not record a difference in TTC for DME and non-DME signals supported by well-documented reports.…”

“…We used the dataset from our published scoping review of the evidence underpinning signals [ 5 ], which included studies of signals/SDRs communicated by stakeholders in pharmacovigilance between 1986 and 2020. Each study in the dataset had had a level of evidence attributed according to the Oxford Centre for Evidence-Based Medicine (OCEBM) classification tool; study designs were thus ranked from 1 (available evidence of the highest quality for decision-making) to 4 (lowest quality), following the row “What are the rare harms?”.…”

“…In a previously published scoping review of signals of ADRs and signals of disproportionate reporting (SDRs), we identified over 10,000 signals/SDRs. The median time interval between the first report in VigiBase, the WHO’s global database of reports of suspected ADRs, and the year in which a signal was communicated was 9 years [ 5 ].…”

Supporting Pharmacovigilance Signal Validation and Prioritization with Analyses of Routinely Collected Health Data: Lessons Learned from an EHDEN Network Study

“…The detection, analysis and communication of signals that indicate a possible causal relationship between a medicine and an adverse event are key pharmacovigilance priorities. Signal management relies extensively on adverse event reports submitted by health care professionals, patients and pharmaceutical manufacturers [ 1 , 2 ]. Their analysis informs most regulatory decisions related to safety signals for marketed medicinal products [ 3 , 4 ].…”

Mapping Strategies to Assess and Increase the Validity of Published Disproportionality Signals: A Meta-Research Study

“…Spontaneous reporting systems play a key role in monitoring the safety of drugs after they have been approved for the market, complementing drugs’ safety profile obtained from clinical trials [ 1 ]. Disproportionality analyses [ 2 ] are the most common statistical approach to analyze these reports and identify potential adverse drug reactions. They are used by health agencies, research centers, and pharmaceutical companies [ 3 ], for both signal detection (generating new hypotheses about potential adverse drug reactions) and signal refinement (characterizing unknown features of expected adverse drug reactions).…”