A proof of concept phase II non-inferiority criterion

• Published in: Statistics in medicine Vol. 30; no. 13; pp. 1618 - 1627
• Main Authors: Neuenschwander, Beat, Rouyrre, Nicolas, Hollaender, Norbert, Zuber, Emmanuel, Branson, Michael
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 15.06.2011; Wiley Subscription Services, Inc
• Subjects: Antineoplastic Agents - therapeutic use; Bayes Theorem; Bayesian; Bayesian analysis; Carcinoma, Renal Cell - drug therapy; Clinical trials; Clinical Trials, Phase II as Topic - methods; Comparative analysis; Confidence Intervals; Decision making; Everolimus; Humans; Indoles - therapeutic use; Kidney Neoplasms - drug therapy; level of proof; Medical treatment; Oncology; progression-free survival; proof of concept; Pyrroles - therapeutic use; Research Design; Sirolimus - analogs & derivatives; Sirolimus - therapeutic use; time-to-event
• ISSN: 0277-6715; 1097-0258
• DOI: 10.1002/sim.3997

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.