Estimand for non-inferiority influenza vaccine immunogenicity trials.

According to recent regulatory guidance, clinical trial objectives should be translated into estimands, i.e., precise descriptions of that what is to be estimated. Hence, estimands are to be formulated for influenza vaccine immunogenicity (IVI) trials, notably for one of the most popular immunogenicity trials, the non-inferiority trial. In this paper an estimand for this trial design is proposed. An estimand should state how intercurrent events are handled. Intercurrent events are events that occur after the start of the trial and that affect the endpoint's measurement or interpretation or prevent its observation. In IVI trials the intercurrent events of interest are immunological intercurrent events (IIEs). Major IIEs are identified, i.e., protocol deviations occurring during the trial that affect immunogenicity endpoints, and the consequences for the trial data collection are discussed. In the statistical analysis endpoint values that are missing or excluded from the analysis due to IIEs are to be substituted by plausible values, by means of multiple imputing. Replacing values are based on predictors of the endpoint. A distinction is made between mandatory and non-mandatory predictors. Mandatory predictors are predictors necessary to prevent biased prediction. Non-mandatory predictors are predictors that limit the additional variance due to the imputing. The four steps of the multiple imputing are explained, and available software is listed.