Consistency ensured test strategies for supportive evidence of treatment efficacy in noninferiority clinical trials

Noninferiority (NI) clinical trials are designed to demonstrate that a new treatment is not unacceptably worse than an active control on a clinically meaningful endpoint. While such an endpoint can be of any type, the focus of this manuscript is on the binary-type endpoint. Examples of this endpoint can be clinical cure endpoint for patients with bacterial diseases or based on a pre-specified virological threshold for viral diseases. However, in addition to assessing such a binary endpoint for the NI comparison, the trial may also evaluate a second clinically relevant endpoint for providing additional support to the evidence of the designated primary endpoint. Specifically, if the trial is successful in demonstrating statistical significance on the first endpoint, then observing at least a positive trend in efficacy on the second endpoint may provide additional supportive evidence of efficacy. The second endpoint can be a time-to-event type endpoint, such as time-to-symptom resolution (TSR) or time to all-cause mortality for infectious disease trials, time-to-wound closure for wound healing trials, or other endpoints. We propose two consistency ensured test strategies for the two hypotheses of a trial, one associated with the binary endpoint and the other with the second endpoint, both with the objective of drawing inference regarding the efficacy of the new treatment based on findings from testing the two hypotheses. A key feature of these test strategies is that basically it does not require multiplicity adjustment of the significance levels. We conclude with general discussion of the testing methods and possible applications to unmet medical need trials.