Survival analysis for AdVerse events with VarYing follow-up times (SAVVY) -- comparison of adverse event risks in randomized controlled trials.

Analyses of adverse events (AEs) are an important aspect of benefit-risk and health-technology assessments of therapies. The SAVVY project aims to improve the analyses of AE data in clinical trials through the use of survival techniques appropriately dealing with varying follow-up times and competing events (CEs). In an empirical study including randomized clinical trials (RCT) from several sponsor organisations the effect of varying follow-up times and CEs on comparisons of two treatment arms with respect to AE risks is investigated. CEs definition does not only include death before AE but also end of follow-up for AEs due to events possibly related to the disease course or safety of the treatment. The comparisons of relative risks (RRs) of standard probability-based estimators to the gold-standard Aalen-Johansen estimator (AJE) or hazard-based estimators to an estimated hazard ratio (HR) from Cox regression are done descriptively, with graphical displays, and using a random effects meta-analysis. The influence of different factors on the size of the bias is investigated in a meta-regression. Ten sponsors provided 17 RCTs including 186 types of AEs. We confirm for estimation of the RR concerns regarding incidence densities: the probability transform incidence density ignoring CEs performed worst. However, accounting for CEs in an analysis that parametrically mimicked the non-parametric AJE performed better than both one minus Kaplan-Meier and AJE that only considered death as a CE. The analysis based on hazards revealed that the incidence density underestimates the HR of AE and CE of death hazard compared to the gold-standard Cox regression. Both the choice of the estimator of the AE probability and a careful definition of CEs are crucial in estimation of RRs. For RRs based on hazards, the HR based on Cox regression has better properties than the ratio of incidence densities.