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Identifying combined design and analysis procedures in two-stage trials with a binary end point

Lookup NU author(s): Professor James WasonORCiD


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Two-stage trial designs provide the flexibility to stop early for efficacy or futility and are popular because they have a smaller sample size on average than a traditional trial has with the same type I and II error rates. This makes them financially attractive but also has the ethical benefit of reducing, in the long run, the number of patients who are given ineffective treatments. Designs that minimise the expected sample size are often referred to as 'optimal'. However, two-stage designs can impart a substantial bias into the parameter estimate at the end of the trial. In this paper, we argue that the expected performance of one's chosen estimation method should also be considered when deciding on a two-stage trial design. We review the properties of standard and bias-adjusted maximum likelihood estimators as well as mean and median unbiased estimators. We then identify optimal two-stage design and analysis procedures that balance projected sample size considerations with those of estimator performance. We make available software to implement this new methodology. © 2012 John Wiley & Sons, Ltd.

Publication metadata

Author(s): Bowden J, Wason J

Publication type: Article

Publication status: Published

Journal: Statistics in Medicine

Year: 2012

Volume: 31

Issue: 29

Pages: 3874-3884

Print publication date: 20/12/2012

Online publication date: 11/07/2012

ISSN (print): 0277-6715

ISSN (electronic): 1097-0258

Publisher: John Wiley & Sons Ltd


DOI: 10.1002/sim.5468

PubMed id: 22786815


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