Application of Time-to-Event Methods in the Assessment of Safety in Clinical Trials

TL;DRAbstract

Safety analysis in randomized controlled trials (RCTs) involves estimation of the treatment effect on the numerous adverse events (AEs) that are collected in the study. RCTs are typically designed and powered for efficacy rather than safety. Even when assessment of AEs is a major objective of study, the trial size is generally not increased to improve likelihood of detecting AEs [1]. As a result, power is an important concern in the analysis of the effect of treatment on AEs in RCTs [2]. Typically in an RCT, crude incidences of each AE are reported at some fixed endpoint such as the end of study [3-5]. These crude estimates often ignore missing observations that frequently occur in RCTs due to early patient withdrawals [6]. A review of published RCTs in major medical journals found that the censored data are often inadequately accounted for in their statistical analyses [7]. A crude estimator that ignores censoring can be highly biased when the proportion of dropouts differs between trea

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