Applying the estimand framework to clinical pharmacology trials with a case study in bioequivalence

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use has published an addendum on estimands and sensitivity analysis in clinical trials along with related training materials. These define an estimand as a precise description of the treatment effect that reflects the scientific question of interest. In December 2022, the US Food and Drug Administration released draft guidance recommending estimands of interest be specified in bioequivalence trial protocols. However, experience in implementing estimands in clinical pharmacology trials is limited and so we introduce estimands and provide step-by-step considerations about the estimand thinking process in this setting. We also describe a particular case study, a bioequivalence trial, illustrating how the estimand framework can provide transparency and alignment throughout the design, conduct and analysis of the trial. This involves discussion of how to identify and handle intercurrent events, which are events that can affect interpretation of the drug or metabolite endpoints. Furthermore, we discuss the broader applicability of the estimand framework to other clinical pharmacology trials. Finally, we encourage further discussion between industry, academia, regulators and the International Council for Harmonisation on whether the estimand framework should be considered in all clinical pharmacology regulatory guidance documents.