Meta-analysis of clinical trial safety data in a drug development program: Answers to frequently asked questions

Abstract

Meta-analyses of clinical trial safety data have risen in importance beyond regulatory submissions. During drug development, sponsors need to recognize safety signals early and adjust the development program accordingly, so as to facilitate the assessment of causality. Once a product is marketed, sponsors add postapproval clinical trial data to the body of information to help understand existing safety concerns or those that arise from other postapproval data sources, such as spontaneous reports. This article focuses on common questions encountered when designing and performing a meta-analysis of clinical trial safety data. Although far from an exhaustive set of questions, they touch on some basic and often misunderstood features of conducting such meta-analyses. The authors reviewed the current literature and used their combined experience with regulatory and other uses of meta-analysis to answer common questions that arise when performing meta-analyses of safety data. We addressed the following topics: choice of studies to pool, effects of the method of ascertainment, use of patient-level data compared to trial-level data, the need (or not) for multiplicity adjustments, heterogeneity of effects and sources of it, and choice of fixed effects versus random effects. The list of topics is not exhaustive and the opinions offered represent only our perspective; we recognize that there may be other valid perspectives. Meta-analysis can be a valuable tool for evaluating safety questions, but a number of methodological choices need to be made in designing and conducting any meta-analysis. This article provides advice on some of the more commonly encountered choices.