Non-Inferiority Trials

The objective of non-inferiority trials is to compare a novel treatment to an active treatment with a view of demonstrating that it is not clinically worse with regards to a specified endpoint. It is assumed that the comparator treatment has been established to have a significant clinical effect (against placebo). These trials are frequently used in situations where use of a superiority trial against a placebo control may be considered unethical.

Non-inferiority is most easily assessed using a confidence interval (CI) approach.

Firstly we specify a non-inferiority margin, d. This is the maximum difference we are prepared to tolerate in a given direction if the new treatment is not to be considered (clinically) inferior.

If a 95% confidence interval for the difference between treatment means lies above or below this boundary value (in a favourable direction) then non-inferiority is deemed to have been established.


  • Suppose a test treatment, T, is considered inferior if it produces a measurement of 3 points or more below some control treatment, C, on average.
  • If a 95% CI for the difference between means, T – C, lies above d = -3 then the test treatment is deemed not inferior to control.
  • The diagram below illustrates possible outcomes:

The choice of inferiority margin, d, affects the sample size calculation and the conclusion of the study. A general rule of thumb is that this quantity must be considerably smaller (1/2 or 1/3) than the minimal clinical difference we might use to calculate sample size in a superiority trial.

Some web links and articles: