Non-inferiority and superiority trials

Non-Inferiority and Superiority 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 the trial investigators specify a non-inferiority margin, delta. This is the maximum difference that they 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.

Logic of Non-Inferiority studies

• If a standard S is consistently superior to placebo, then
• to show that a test treatment T is superior to placebo
  • it suffices to show that the test treatment is as good as (not inferior) to the standard

Setting the non-inferiority margin

• subjective - often contentious
• if too large:
  • inferior treatments may be called non-inferior
  • if too small: huge sample sizes are required
• usually a fraction of the historical difference between control and placebo

Interpreting a noninferiority trial as a superiority trial

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Reference:

• Hahn S. Understanding noninferiority trials. Korean J Pediatr. 2012;55(11):403-407. doi:10.3345/kjp.2012.55.11.403