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

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.