Recommendations
EVENT

Leaving the non-inferiority margin fixed whatever the control event risk should not be the default standard, because of its potential impact in terms of power loss and/or interpretability of results;An alternative is to draw a SAFE non-inferiority frontier, with the goal to use certain target non-inferiority margins for certain levels of control event risk; these should be discussed with clinicians, considering how trade-offs differ for different values of control event risk. One possible approach is to:Identify which values of control event risks are plausible;Fix the desired value of non-inferiority margin at few values of control event risk (e.g. in D3 at 1% and 5% event risk); andDraw a smooth frontier (as SAFE) continuously linking the various non-inferiority margins selected.When implementing a SAFE frontier, the significance level should be reduced to a level that can control type 1 error at the nominal level; in order to maintain power, though, the significance level should only be modified when the non-inferiority margin is changed;A method based on a likelihood ratio test has optimal properties as well, but the “modify significance level if change margin” method might be easier to interpret and communicate, and is therefore recommended; andIf possible, the frontier should be implemented into the design of the trial, so that the sample size calculation reflects it.