Non-inferiority studies: a methodological and regulatory perspective

Abstract

There is a knowledge gap in designing so-called “non-inferiority trials”, which aim to show whether the effect of a new drug is not unacceptably worse (i.e., non-inferior) than a drug already used to treat the targeted disease. This thesis focuses on issues related to a main source of this knowledge gap: the choice of the non-inferiority margin (the maximal acceptable size of the difference between the two drugs). Studies in this thesis indicate that the choice of the margin is not mentioned in more than half of the published non-inferiority trials and that there is no consensus among stakeholders about the preferred approach. We also found that different approaches used to choose the margin could lead to a different judgement of non-inferiority. Additionally, we provided an investigation of the design of these trials from a regulatory perspective and we showed how regulators (dis)agree on the margin and what the impact is on approval decisions. Finally, we investigated whether non-inferiority of a new drug that was demonstrated in a clinical trial could also be demonstrated in daily clinical practice with recommendations on how to perform such an assessment. Based on these studies, the conclusion of this thesis is that reporting of non-inferiority margins in scientific articles should improve and that stakeholders should reach consensus on the approach of choosing this margin. Further research in assessing the non-inferiority of drugs in daily clinical practice is important for optimal decision making in daily healthcare.