Sample size re-estimation: recent developments and practical considerations

Interim findings of a clinical trial often will be useful for increasing th e sample size if necessary to provide the required power against the null h ypothesis 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 adjustm ent and conditional power. Simulation studies show that the alternative met hods generally control the type I error rate satisfactorily, although the p ower properties are more variable. The important issues associated with sam ple size re-estimation are strategic, not numeric. Clearly expressed regula tory preferences suggest that methods not requiring unblinding the data bef ore completion of the trial would be most appropriate. Extending a trial ha s its risks. The investigators/patients enrolled later in the course of a t rial are not necessarily the same as those recruited/entered early. Re-acti vating the enrolment process may be sufficiently complicated and expensive to justify enrolling more investigators/patients at the outset. Since sampl e size re-estimation adjusts the sample size on the basis of variability wh ile efficacy interim analysis adjusts the sample size based on the basis of estimated effect size, both principles can be used in the same trial. Samp le size re-estimation may not be advisable for trials involving extended fo llow-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 t o estimate the sample size conservatively and introduce an interim efficacy evaluation. Copyright (C) 2001 John Wiley & Sons, Ltd.