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Estimation in multi-arm two-stage trials with treatment selection and time-to-event endpoint

Research output: Contribution to journalJournal article

Published
<mark>Journal publication date</mark>10/09/2017
<mark>Journal</mark>Statistics in Medicine
Issue number20
Volume36
Number of pages17
Pages (from-to)3137-3153
<mark>State</mark>Published
Early online date13/06/17
<mark>Original language</mark>English

Abstract

We consider estimation of treatment effects in two-stage adaptive multi-arm trials with a common control. The best treatment is selected at interim, and the primary endpoint is modeled via a Cox proportional hazards model. The maximum partial-likelihood estimator of the log hazard ratio of the selected treatment will overestimate the true treatment effect in this case. Several methods for reducing the selection bias have been proposed for normal endpoints, including an iterative method based on the estimated conditional selection biases and a shrinkage approach based on empirical Bayes theory. We adapt these methods to time-to-event data and compare the bias and mean squared error of all methods in an extensive simulation study and apply the proposed methods to reconstructed data from the FOCUS trial. We find that all methods tend to overcorrect the bias, and only the shrinkage methods can reduce the mean squared error.