Special Issue Paper
A proof of concept phase II non-inferiority criterion
Article first published online: 24 FEB 2011
Copyright © 2011 John Wiley & Sons, Ltd.
Statistics in Medicine
Special Issue: Sixth International French Society of Statistics meeting on statistical methods in biopharmacy: Recent advances and trends in statistics as applied to clinical trials
Volume 30, Issue 13, pages 1618–1627, 15 June 2011
How to Cite
Neuenschwander, B., Rouyrre, N., Hollaender, N., Zuber, E. and Branson, M. (2011), A proof of concept phase II non-inferiority criterion. Statist. Med., 30: 1618–1627. doi: 10.1002/sim.3997
- Issue published online: 19 MAY 2011
- Article first published online: 24 FEB 2011
- Manuscript Accepted: 20 MAY 2010
- Manuscript Received: 31 JAN 2010
- level of proof;
- proof of concept;
- progression-free survival;
Traditional phase III non-inferiority trials require compelling evidence that the treatment vs control effect bfθ is better than a pre-specified non-inferiority margin θNI. The standard approach compares this margin to the 95 per cent confidence interval of the effect parameter. In the phase II setting, in order to declare Proof of Concept (PoC) for non-inferiority and proceed in the development of the drug, different criteria that are specifically tailored toward company internal decision making may be more appropriate. For example, less evidence may be needed as long as the effect estimate is reasonably convincing.
We propose a non-inferiority design that addresses the specifics of the phase II setting. The requirements are that (1) the effect estimate be better than a critical threshold θC, and (2) the type I error with regard to θNI is controlled at a pre-specified level. This design is compared with the traditional design from a frequentist as well as a Bayesian perspective, where the latter relies on the Level of Proof (LoP) metric, i.e. the probability that the true effect is better than effect values of interest. Clinical input is required to establish the value θC, which makes the design transparent and improves interactions within clinical teams. The proposed design is illustrated for a non-inferiority trial for a time-to-event endpoint in oncology. Copyright © 2011 John Wiley & Sons, Ltd.