How can non-inferiority studies with mortality end points be ethically justified?

Background: Non-inferiority (NI) studies with mortality end points are increasingly frequently conducted. They aim to show that a new treatment strategy does not entail an unacceptably higher mortality than the comparator. They raise specific ethical issues related to the rationale of the study, the NI margin, certainty and informed consent. There is a need for ethical reflection.

Method: Analysis of ethical issues informed by a literature search using terms related to NI, mortality and ethics, in PubMed, CINAHL and Embase. Results are illustrated using the example of the PROFID-EHRA NI trial that the authors are involved in.

Results: Justifications for conducting an NI study instead of a superiority study are often insufficient. The NI margin is most often taken from previous studies without additional justification. There is no consensus about how patients should be involved in the design and justification of the studies and about how participants should be informed.

Discussion: We conclude that NI studies with mortality end points can be ethically justified if secondary benefits are proven and large enough for participants, and if the NI margin is acceptable to patients and ethics committees. Acceptability of the NI margin should be determined on a case-by-case basis and risks should be framed appropriately. The justification for choosing an NI rather than a superiority design should be made more explicitly. Further studies are needed on patients' views about NI trials with mortality as an end point; also, the degree of certainty and the very distinction between primary and secondary outcomes deserve systematic study.