Statistical methods for handling missing data to align with treatment policy strategy

Abstract

The International Council for Harmonization (ICH) E9(R1) addendum recommends choosing an appropriate estimand based on the study objectives in advance of trial design. One defining attribute of an estimand is the intercurrent event, specifically what is considered an intercurrent event and how it should be handled. The primary objective of a clinical study is usually to assess a product's effectiveness and safety based on the planned treatment regimen instead of the actual treatment received. The estimand using the treatment policy strategy, which collects and analyzes data regardless of the occurrence of intercurrent events, is usually utilized. In this article, we explain how missing data can be handled using the treatment policy strategy from the authors' viewpoint in connection with antihyperglycemic product development programs. The article discusses five statistical methods to impute missing data occurring after intercurrent events. All five methods are applied within the framework of the treatment policy strategy. The article compares the five methods via Markov Chain Monte Carlo simulations and showcases how three of these five methods have been applied to estimate the treatment effects published in the labels for three antihyperglycemic agents currently on the market.intercurrent events, missing data, retrieved dropouts, return-to-baseline, treatment policy strategy, washout method | INTRODUCTIONAn estimand is what treatment effect is to be estimated in a clinical trial. The International Council for Harmonization (ICH) E9(R1) addendum on "Estimands and Sensitivity Analysis in Clinical Trials" 1 defines an estimand as a precise description of the treatment effect aligning with a given clinical trial objective. As further explained in the addendum, an estimand features the following five attributes: treatment, target population, variable of interest (endpoint), intercurrent events, and population-level summary. An intercurrent event is defined as an event occurring after treatment initiation that affects either the interpretation or the existence of the measurements associated with the clinical question ofThe contribution was made while Dr. Susie Sinks worked at the FDA.

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“…Additional information on the imputation methods to account for missing data, including references 32 and 33 .…”