Non-inferiority versus superiority drug claims: the (not so) subtle distinction

Abstract

Background: Current regulatory guidance and practice of non-inferiority trials are asymmetric in favor of the test treatment (Test) over the reference treatment (Control). These trials are designed to compare the relative efficacy of Test to Control by reference to a clinically important margin, M.

Main text: Non-inferiority trials allow for the conclusion of: (a) non-inferiority of Test to Control if Test is slightly worse than Control but by no more than M; and (b) superiority if Test is slightly better than Control even if it is by less than M. From Control's perspective, (b) should lead to a conclusion of non-inferiority of Control to Test. The logical interpretation ought to be that, while Test is statistically better, it is not clinically superior to Control (since Control should be able to claim non-inferiority to Test). This article makes a distinction between statistical and clinical significance, providing for symmetry in the interpretation of results. Statistical superiority and clinical superiority are achieved, respectively, when the null and the non-inferiority margins are exceeded. We discuss a similar modification to placebo-controlled trials.

Conclusion: Rules for interpretation should not favor one treatment over another. Claims of statistical or clinical superiority should depend on whether or not the null margin or the clinically relevant margin is exceeded.

Keywords: Confidence interval; Margin; Non-inferiority; Superiority; Trial design.

Fig. 1

Comparison of interpretation of outcomes between the FDA NI guidance document and what is proposed. FDA interpretation is provided for scenarios C and E (Figure 2 in [2]). See also Figure 6 in [4] which discusses the same example. Cel celecoxib, Nap naproxen, NI non-inferiority, sup superior