SUMMARY

We consider sample size re-estimation in a clinical trial, in particular when there is a significant delay before the measurement of patient response. Mehta and Pocock have proposed methods in which sample size is increased when interim results fall in a “promising zone ” where it is deemed worthwhile to increase conditional power by adding more subjects. Our analysis reveals potential pitfalls in applying this approach. Mehta and Pocock use results of Chen, DeMets and Lan to identify when increasing sample size but applying a conventional level α significance test at the end of the trial does not inflate the type I error rate: we have found the greatest gains in power per additional observation are liable to lie outside the region defined by this method. Mehta and Pocock increase sample size to achieve a particular conditional power, calculated under the current estimate of treatment effect: this leads to high increases in sample size for a small range of interim outcomes, whereas we have found it more efficient to make moderate increases in sample size over a wider range of cases. If the above pitfalls are avoided, we believe the broad framework proposed by Mehta and Pocock is valuable for clinical trial design. Working in this framework, we propose sample size rules which apply explicitly the principle of adding observations when they are most beneficial. The resulting trial designs are closely related to efficient group sequential tests for a delayed response proposed by Hampson and Jennison. Key words: clinical trial; group sequential test; sample size re-estimation; adaptive design; flexible design; optimal design; promising zone.