• Mahesh K B Parmar, Matthew R Sydes, and Tim P Morris.
• London Hub for Trials Methodology Research, MRC Clinical Trials Unit at UCL, Aviation House, 125 Kingsway, London, WC2B 6NH, UK.
• Bmc Med. 2016 Nov 25; 14 (1): 183.

AbstractHow should we approach trial design when we can get some, but not all, of the way to the numbers required for a randomised phase III trial?We present an ordered framework for designing randomised trials to address the problem when the ideal sample size is considered larger than the number of participants that can be recruited in a reasonable time frame. Staying with the frequentist approach that is well accepted and understood in large trials, we propose a framework that includes small alterations to the design parameters. These aim to increase the numbers achievable and also potentially reduce the sample size target. The first step should always be to attempt to extend collaborations, consider broadening eligibility criteria and increase the accrual time or follow-up time. The second set of ordered considerations are the choice of research arm, outcome measures, power and target effect. If the revised design is still not feasible, in the third step we propose moving from two- to one-sided significance tests, changing the type I error rate, using covariate information at the design stage, re-randomising patients and borrowing external information.We discuss the benefits of some of these possible changes and warn against others. We illustrate, with a worked example based on the Euramos-1 trial, the application of this framework in designing a trial that is feasible, while still providing a good evidence base to evaluate a research treatment.This framework would allow appropriate evaluation of treatments when large-scale phase III trials are not possible, but where the need for high-quality randomised data is as pressing as it is for common diseases.

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