Statistical methods leveraging the hierarchical structure of adverse events for signal detection in clinical trials: a scoping review of the methodological literature.

Background: In randomised controlled trials with efficacy-related primary outcomes, adverse events are collected to monitor potential intervention harms. The analysis of adverse event data is challenging, due to the complex nature of the data and the large number of unprespecified outcomes. This is compounded by a lack of guidance on best analysis approaches, resulting in widespread inadequate practices and the use of overly simplistic methods; leading to sub-optimal exploitation of these rich datasets. To address the complexities of adverse events analysis, statistical methods are proposed that leverage existing structures within the data, for instance by considering groupings of adverse events based on biological or clinical relationships.

Methods: We conducted a methodological scoping review of the literature to identify all existing methods using structures within the data to detect signals for adverse reactions in a trial. Embase, MEDLINE, Scopus and Web of Science databases were systematically searched. We reviewed the analysis approaches of each method, extracted methodological characteristics and constructed a narrative summary of the findings.

Results: We identified 18 different methods from 14 sources. These were categorised as either Bayesian approaches (n=11), which flagged events based on posterior estimates of treatment effects, or error controlling procedures (n=7), which flagged events based on adjusted p-values while controlling for some type of error rate. We identified 5 defining methodological characteristics: the type of outcomes considered (e.g. binary outcomes), the nature of the data (e.g. summary data), the timing of the analysis (e.g. final analysis), the restrictions on the events considered (e.g. rare events) and the grouping systems used.

Conclusions: We found a large number of analysis methods that use the group structures of adverse events. Continuous methodological developments in this area highlight the growing awareness that better practices are needed. The use of more adequate analysis methods could help trialists obtain a better picture of the safety-risk profile of an intervention. The results of this review can be used by statisticians to better understand the current methodological landscape and identify suitable methods for data analysis - although further research is needed to determine which methods are best suited and create adequate recommendations.