Scientific Publications by FDA Staff

J Biopharm Stat 2016;26(5):823-41

Bayesian methods for the design and analysis of non-inferiority trials.

Gamalo-Siebers M, Gao A, Lakshminarayanan M, Liu G, Natanegara F, Railkar R, Schmidli H, Song G

The gold standard for evaluating treatment efficacy of a medical product is a placebo-controlled trial. However, when the use of placebo is considered to be unethical or impractical, a viable alternative for evaluating treatment efficacy is through a non-inferiority (NI) study where a test treatment is compared to an active control treatment. The minimal objective of such a study is to determine whether the test treatment is superior to placebo. An assumption is made that if the active control treatment remains efficacious, as was observed when it was compared against placebo, then a test treatment that has comparable efficacy with the active control, within a certain range, must also be superior to placebo. Because of this assumption, the design, implementation and analysis of NI trials present challenges for sponsors and regulators. In designing and analyzing NI trials, substantial historical data is often required on the active control treatment and placebo. Bayesian approaches provide a natural framework for synthesizing the historical data in the form of prior distributions that can effectively be used in design and analysis of a NI clinical trial. Despite a flurry of recent research activities in the area of Bayesian approaches in medical product development, there are still substantial gaps in recognition and acceptance of Bayesian approaches in NI trial design and analysis. The Bayesian Scientific Working Group of the Drug Information Association provides a coordinated effort to target the education and implementation issues on Bayesian approaches for NI trials. In this article, we provide a review of both frequentist and Bayesian approaches in NI trials, and elaborate on the implementation for two common Bayesian methods including hierarchical prior method and meta-analytic-predictive approach. Simulations are conducted to investigate the properties of the Bayesian methods, and some real clinical trial examples are presented for illustration.