Sample size re-estimation: recent developments and practical considerations.

Abstract

Interim findings of a clinical trial often will be useful for increasing the sample size if necessary to provide the required power against the null hypothesis when the alternative hypothesis is true. Strategies for carrying out the interim examination that have been described over the past several years include "internal pilot studies", blinded interim sample size adjustment and conditional power. Simulation studies show that the alternative methods generally control the type I error rate satisfactorily, although the power properties are more variable. The important issues associated with sample size re-estimation are strategic, not numeric. Clearly expressed regulatory preferences suggest that methods not requiring unblinding the data before completion of the trial would be most appropriate. Extending a trial has its risks. The investigators/patients enrolled later in the course of a trial are not necessarily the same as those recruited/entered early. Re-activating the enrollment process may be sufficiently complicated and expensive to justify enrolling more investigators/patients at the outset. Since sample size re-estimation adjusts the sample size on the basis of variability while efficacy interim analysis adjusts the sample size based on the basis of estimated effect size, both principles can be used in the same trial. Sample size re-estimation may not be advisable for trials involving extended follow-up of individual patients or, more generally, when the follow-up time is long relative to the recruitment time. In such cases, it may be better to estimate the sample size conservatively and introduce an interim efficacy evaluation.