Methods for drug safety signal detection using routinely collected observational electronic health care data: A systematic review

Abstract

Purpose: Signal detection is a crucial step in the discovery of post-marketing adverse drug reactions. There is a growing interest in using routinely collected data to complement established spontaneous report analyses. This work aims to systematically review the methods for drug safety signal detection using routinely collected healthcare data and their performance, both in general and for specific types of drugs and outcomes.Methods: We conducted a systematic review following the PRISMA guidelines, and registered a protocol in PROSPERO. MEDLINE, EMBASE, PubMed, Web of Science, Scopus, and the Cochrane Library were searched until July 13, 2021. Results:The review included 101 articles, among which there were 39 methodological works, 25 performance assessment papers, and 24 observational studies.Methods included adaptations from those used with spontaneous reports, traditional epidemiological designs, methods specific to signal detection with real-world data.More recently, implementations of machine learning have been studied in the literature. Twenty-five studies evaluated method performances, 16 of them using the area under the curve (AUC) for a range of positive and negative controls as their main measure. Despite the likelihood that performance measurement could vary by drugevent pair, only 10 studies reported performance stratified by drugs and outcomes, in a heterogeneous manner. The replicability of the performance assessment results was limited due to lack of transparency in reporting and the lack of a gold standard reference set.Conclusions: A variety of methods have been described in the literature for signal detection with routinely collected data. No method showed superior performance in all papers and across all drugs and outcomes, performance assessment and reporting were heterogeneous. However, there is limited evidence that self-controlled designs, high dimensional propensity scores, and machine learning can achieve higher performances than other methods.

Epidemiological surveillance of drug safety using cumulative sequential analysis in electronic healthcare data

“…Furthermore, they highlighted that only one of their included studies investigated the timeliness of signal detection. 7 Therefore, we investigated which of the papers included in the review by Coste et al analysed their data at multiple time points as the authors did not focus on this aspect. Additionally, on 3 March 2023, we updated the systematic search conducted by Coste et al to include papers available after 13 July 2021.…”

“…3 Recently, the list of methods for signal detection in electronic healthcare data was updated by Coste et al They further compared the performance of the methods overall and for specific types of exposures and outcomes. 7 The authors concluded that no method was superior for all drugs and outcomes and propose that more than one method may be applied for signal detection among multiple drug-outcome pairs. Furthermore, they highlighted that only one of their included studies investigated the timeliness of signal detection.…”

“…Thus, we applied the same search strategy in the same databases (Medline and Embase via OVID, PubMed, Scopus, Web of Science and the Cochrane Library). 7 We also applied the same in-and exclusion criteria screening the identified records first by title and abstract followed by a full-text screening (Supplementary Figure S1). We identified 570 new papers after 13 July 2021, after removal of duplicates.…”

“…The authors concluded that no method was superior for all drugs and outcomes and propose that more than one method may be applied for signal detection among multiple drug‐outcome pairs. Furthermore, they highlighted that only one of their included studies investigated the timeliness of signal detection 7 . Therefore, we investigated which of the papers included in the review by Coste et al analysed their data at multiple time points as the authors did not focus on this aspect.…”

“…Additionally, on 3 March 2023, we updated the systematic search conducted by Coste et al to include papers available after 13 July 2021. Thus, we applied the same search strategy in the same databases (Medline and Embase via OVID, PubMed, Scopus, Web of Science and the Cochrane Library) 7 . We also applied the same in‐ and exclusion criteria screening the identified records first by title and abstract followed by a full‐text screening (Supplementary Figure S1).…”