Who protects participants in non-inferiority trials when the outcome is death?

Abstract

A non-inferiority design accepts the possibility of some efficacy loss, as part of a “successful”, statistically significant result. That loss may be excessive when the non-inferiority threshold is lenient. However, even stringent significance thresholds and safety monitoring may fail to adequately protect study participants when the primary outcome is death. The OPTIMAAL trial, a large randomized clinical trial performed in high-risk patients, is discussed as an example, using the Belmont Report principles as an ethical frame of reference. OPTIMAAL compared losartan, a new drug, to captopril, a drug known to reduce the risk of death in patients with heart failure after a myocardial infarction. Serious ethical challenges occurred in that study. Firstly, subjects had to tolerate captopril to participate, meaning that participation implied the possibility of higher risk of death if randomized to the losartan arm, as compared to the standard of care. Additionally, the stopping rules had to ensure enough power to detect non-inferiority, and potentially tolerated additional participant deaths as the study went on. There may have been fifty additional deaths in the losartan arm by the end of the trial—deaths that perhaps could have been prevented if participants took captopril. Those features represent a challenge to the beneficence principle. Finally, it is unclear whether the consenting process adhered to the respect of persons principle, because consent forms were not published, and we cannot determine whether a clear description of the risk of death during participation was provided.