We conclude that the hazard ratio cannot be recommended as a general measure of the treatment effect in a randomized controlled trial, nor is it always appropriate when designing a trial. Values are compared with those from the standard approach which utilizes the logrank test. We illustrate the required sample size under proportional and non-proportional hazards, also the significance level and power of the proposed test. We support the approach through the results of simulation studies and in real examples from several cancer trials. We demonstrate the use of restricted mean survival time and a test of the difference in restricted means as an alternative measure of treatment effect. Such designs can embody proportional or non-proportional hazards of the treatment effect.

The distributions are conveniently defined as piecewise exponential distributions and can be specified through piecewise constant hazards and time-fixed or time-dependent hazard ratios. We consider the design of such trials according to a wide range of possible survival distributions in the control and research arm(s). The restricted mean is a measure of average survival from time 0 to a specified time point, and may be estimated as the area under the survival curve up to that point. Here, we describe the use of the restricted mean survival time as a possible alternative tool in the design and analysis of these trials.

However, the results of some recent trials indicate that there is no guarantee that the assumption will hold. Designs and analyses of clinical trials with a time-to-event outcome almost invariably rely on the hazard ratio to estimate the treatment effect and implicitly, therefore, on the proportional hazards assumption.

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