Paradoxical interpretations of noninferiority studies: violating the excluded middle

Abstract

Background: The noninferiority of a novel therapy compared with a standard of care is customarily defined by a noninferiority margin derived from an assessment of what would constitute a clinically relevant decrement in efficacy while preserving some of the treatment effect over placebo. Conundrum: If the one-sided 97.5% CI around the difference in the point estimates of efficacy between the two treatments (investigational drug minus comparator drug) does not extend below the prespecified threshold, noninferiority of the new agent to the comparator is typically concluded. In some cases, the corresponding two-sided 95% CI will fall entirely between zero and the noninferiority delta, technically implying inferiority and noninferiority concurrently. Solution: Stipulating that the upper bound of the two-sided confidence interval reach or exceed zero (as well as fall entirely above the noninferiority limit) to establish statistical noninferiority versus the comparator would avoid paradoxical interpretations.