Informative censoring in externally controlled clinical trials: a potential source of bias.

Abstract

Background: Cancer researchers frequently consider the use of single-arm and randomized controlled clinical trial designs that leverage external data. The literature has reported extensively on how the use of external data can introduce bias through a variety of distortion mechanisms. In this article, we focus on a distortion mechanism that is often overlooked: informative censoring. Informative censoring arises when there is statistical dependence between patients' censoring times and survival times.

Materials and methods: We used simulations to investigate how informative censoring of external controls (ECs) can influence the results of cancer clinical trials. Our simulations included the following: (i) model-based replicates of clinical trials and in silico glioblastoma trials obtained by resampling patients from completed phase III trials; (ii) single-arm and randomized controlled cancer clinical trial designs; and (iii) different types of informative censoring, with positive or negative associations between censoring times and survival times.

Results: Our simulations showed that informative censoring of EC data can bias cancer clinical trial results. The direction of the bias depends on the censoring mechanism. Similarly, informative censoring can inflate or reduce type I error and power.

Conclusions: Selection of EC data and the decision to leverage these data in the analysis of clinical trials should account for the risk of bias due to informative censoring. Analyses to detect informative censoring are recommended when the clinical trial design involves external data.