Non-inferiority trials in cardiology: what clinicians need to know

Abstract

Clinical trials traditionally aim to show a new treatment is superior to placebo or standard treatment, that is, superiority trials. There is an increasing number of trials demonstrating a new treatment is non-inferior to standard treatment. The hypotheses, design and interpretation of non-inferiority trials are different to superiority trials. Non-inferiority trials are designed with the notion that the new treatment offers advantages over standard treatment in certain important aspects. The non-inferior margin is a predetermined margin of difference between the new and standard treatment that is considered acceptable or tolerable for the new treatment to be considered 'similar' or 'not worse'. Both relative difference and absolute difference methods can be used to define the non-inferior margin. Sequential testing for non-inferiority and superiority is often performed. Non-inferiority trials may be necessary in situations where it is no longer ethical to test any new treatment against placebo. There are inherent assumptions in non-inferiority trials which may not be correct and which are not being tested. Successive non-inferiority trials may introduce less and less effective treatments even though these treatments may have been shown to be non-inferior. Furthermore, poor quality trials favour non-inferior results. Intention-to-treat analysis, the preferred way to analyse randomised trials, may favour non-inferiority. Both intention-to-treat and per-protocol analyses should be recommended in non-inferiority trials. Clinicians should be aware of the pitfalls of non-inferiority trials and not accept non-inferiority on face value. The focus should not be on the p values but on the effect size and confidence limits.

Keywords: Biostatistics; Heart Disease; RESEARCH APPROACHES; Study design.

Figure 1

Forest plot showing hypothesis testing and possible outcomes of non-inferiority trials. The solid vertical line indicates a relative risk of 1. The dashed vertical line indicates the predefined non-inferior margin. The dotted and dashed vertical lines indicate the equivalence margins (for equivalence trials). The horizontal lines represent the 95% CIs of the possible results of non-inferiority trials. A: the 95% CI does not overlap 1 and lies entirely on the left side of 1. Therefore, the new treatment is superior to standard treatment. B: the 95% CI overlaps 1 but the upper bound of the 95% CI does not exceed the predetermined non-inferior margin. Therefore, the new treatment is not superior but is non-inferior to standard treatment. C: the 95% CI overlaps 1 and lies entirely within the equivalence margins. Therefore, the new treatment is equivalent to standard treatment. D: the 95% CI does not overlap 1 and lies entirely on the right side of 1, Therefore, the new treatment is inferior to standard treatment. However, the upper bound of the 95% CI does not exceed the predetermined non-inferior margin. Therefore, the new treatment is also non-inferior to standard treatment. This scenario is unlikely but theoretically possible. E: the 95% CI overlaps 1 and the upper bound of the 95% CI exceeds the predetermined non-inferior margin. Therefore, the new treatment is neither inferior nor non-inferior to standard treatment. F and G: the 95% CIs lie entirely to the right side of 1 and the upper bound of the 95% CIs exceed the predetermined non-inferior margin. Therefore, the new treatment is inferior to standard treatment.