Something Out of Nothing? The Influence of Double-Zero Studies in Meta-analysis of Adverse Events in Clinical Trials

Abstract

AbstractIn addition to clinical efficacy, safety is another important outcome to assess in randomized controlled trials. It focuses on the occurrence of adverse events, such as stroke, deaths, and other rare events. Because of the low or very low rates of observing adverse events, meta-analysis is often used to pooled together evidence from dozens or even hundreds of similar clinical trials to strengthen inference. A well-known issue in rare-event meta-analysis is that some or even majority of the available studies may observe zero events in both the treatment and control groups. The influence of these so-called double-zero studies has been researched in the literature, which nevertheless focuses on reaching a dichotomous conclusion—whether or not double-zero studies should be included in the analysis. It has not been addressed when and how they contribute to inference, especially for the odds ratio. This paper fills this gap using comparative analysis of real and simulated data sets. We find that a double-zero study contributes to the odds ratio inference through its sample sizes in the two arms. When a double-zero study has an unequal allocation of patients in its two arms, it may contain non-ignorable information. Exclusion of these studies, if taking a significant proportion of the study cohort, may result in inflated type I error, deteriorated testing power, and increased estimation bias.