A proof of concept phase II non-inferiority criterion

Stat Med. 2011 Jun 15;30(13):1618-27. doi: 10.1002/sim.3997. Epub 2011 Feb 24.


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 θ(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 θ(C), and (2) the type I error with regard to θ(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 θ(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.

Publication types

  • Comparative Study

MeSH terms

  • Antineoplastic Agents / therapeutic use
  • Bayes Theorem*
  • Carcinoma, Renal Cell / drug therapy
  • Clinical Trials, Phase II as Topic / methods*
  • Confidence Intervals*
  • Everolimus
  • Humans
  • Indoles / therapeutic use
  • Kidney Neoplasms / drug therapy
  • Pyrroles / therapeutic use
  • Research Design
  • Sirolimus / analogs & derivatives
  • Sirolimus / therapeutic use
  • Sunitinib


  • Antineoplastic Agents
  • Indoles
  • Pyrroles
  • Everolimus
  • Sunitinib
  • Sirolimus