A proof of concept phase II non-inferiority criterion

Traditional phase III non-inferiority trials require compelling evidence that the treatment vs control effect theta is better than a pre-specified non-inferiority margin theta(NI). 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 theta(C), and (2) the type I error with regard to theta(NI) 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 theta(C), 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 (C) 2011 John Wiley & Sons, Ltd.