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. © 2017 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

In clinical trials survival endpoints are usually compared using the log-rank test. Sequential methods for the log-rank test and the Cox proportional hazards model are largely reported in the statistical literature. When the proportional hazards assumption is violated the hazard ratio is ill-defined and the power of the log-rank test depends on the distribution of the censoring times. The average hazard ratio was proposed as an alternative effect measure, which has a meaningful interpretation in the case of non-proportional hazards, and is equal to the hazard ratio, if the hazards are indeed proportional. In the present work we prove that the average hazard ratio based sequential test statistics are asymptotically multivariate normal with the independent increments property. This allows for the calculation of group-sequential boundaries using standard methods and existing software. The finite sample characteristics of the new method are examined in a simulation study in a proportional and a non-proportional hazards setting.

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As non-proportional hazards are often met in clinical practice and the average hazard ratio tests often outperform the common logrank test, this approach should be used more routinely in applications.

Adaptive survival trials are particularly important for enrichment designs in oncology and other life-threatening diseases. Current statistical methodology for adaptive survival trials provide type I error rate control only under restrictions. For instance, if we use stage-wise P values based on increments of the log-rank test, then the information used for the interim decisions need to be restricted to the primary survival endpoint. However, it is often desirable to base interim decisions also on correlated short-term endpoints like tumor response. Alternative statistical approaches based on a patient-wise splitting of the data require unnatural restrictions on the follow-up times and do not permit to efficiently account for an early rejection of the primary null hypothesis. We therefore suggest new approaches that enable us to use discrete surrogate endpoints (like tumor response status) and also to incorporate interim rejection boundaries. The new approaches are based on weighted Kaplan-Meier estimates and thereby have additional advantages. They permit us to account for nonproportional hazards and are robust against informative censoring based on the surrogate endpoint. We will show that nonproportionality is an intrinsic and relevant issue in enrichment designs. Moreover, informative censoring based on the surrogate endpoint is likely because of withdrawals and treatment switches after insufficient treatment response. It is shown and illustrated how nonparametric tests based on weighted Kaplan-Meier estimates can be used in closed combination tests for adaptive enrichment designs, such that type I error rate control is achieved and justified asymptotically.