Comments on ‘standard and reference‐based conditional mean imputation’: Regulators and trial statisticians be aware

Accurate frequentist performance of a method is desirable in confirmatory clinical trials, but is not sufficient on its own to justify the use of a missing data method. Reference‐based conditional mean imputation, with variance estimation justified solely by its frequentist performance, has the surprising and undesirable property that the estimated variance becomes smaller the greater the number of missing observations; as explained under jump‐to‐reference it effectively forces the true treatment effect to be exactly zero for patients with missing data.