Adaptive sample size modification in clinical trials: start small then ask for more?

• Published in: Statistics in medicine 2015-12, Vol.34 (29), p.3793-3810
• Main Authors: Jennison, Christopher, Turnbull, Bruce W.
• Format: Article
• Language: English
• Subjects: adaptive design; Antipsychotic Agents - administration & dosage; Bias; clinical trial; Clinical trials; Clinical Trials as Topic - methods; Clinical Trials as Topic - standards; Clinical Trials as Topic - statistics & numerical data; Clinical Trials, Phase III as Topic - methods; Clinical Trials, Phase III as Topic - standards; Clinical Trials, Phase III as Topic - statistics & numerical data; group sequential test; Humans; Measurement; Medical statistics; optimal design; promising zone; Research Design - statistics & numerical data; Sample Size; sample size re-estimation; Schizophrenia - drug therapy
• ISSN: 0277-6715; 1097-0258
• DOI: 10.1002/sim.6575

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 aforementioned 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 that 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. Copyright © 2015 John Wiley & Sons, Ltd.