Randomization in survival studies: An evaluation method that takes into account selection and chronological bias.

Abstract

The random allocation of patients to treatments is a crucial step in the design and conduct of a randomized controlled trial. For this purpose, a variety of randomization procedures is available. In the case of imperfect blinding, the extent to which a randomization procedure forces balanced group sizes throughout the allocation process affects the predictability of allocations. As a result, some randomization procedures perform superior with respect to selection bias, whereas others are less susceptible to chronological bias. The choice of a suitable randomization procedure therefore depends on the expected risk for selection and chronological bias within the particular study in question. To enable a sound comparison of different randomization procedures, we introduce a model for the combined effect of selection and chronological bias in randomized studies with a survival outcome. We present an evaluation method to quantify the influence of bias on the test decision of the log-rank test in a randomized parallel group trial with a survival outcome. The effect of selection and chronological bias and the dependence on the study setting are illustrated in a sensitivity analysis. We conclude with a case study to showcase the application of our model for comparing different randomization procedures in consideration of the expected type I error probability.