Can Estimands Support Aligned Evidence Generation for EU HTA? Reflections on Their Role in Joint Clinical Assessments, PICO Alignment, and Beyond

The primary objective is to explore how the estimand framework introduced by the ICH E9(R1) Addendum on Estimands and Sensitivity Analysis in Clinical Trials is being integrated into EU Health Technology Assessment (HTA) processes, particularly within the context of Joint Clinical Assessments (JCAs). Of interest is to assess the extent to which estimand attributes align with the PICO (Population, Intervention, Comparator, Outcome) framework and whether a common language is emerging between regulatory authorities and HTA agencies. We examined methodological and process-related guidance documents underpinning the EU JCA to evaluate how estimands are reflected. Our analysis focused on the inclusion of estimand-related content in guidance on direct and indirect comparisons, outcomes, validity of clinical studies, scoping processes, and procedural documents such as the JCA and Joint Scientific Consultation templates. We also assessed the correspondence between estimand attributes and PICO elements, as well as the consistency of interpretation and application across regulatory and HTA domains. Our analysis reveals increasing recognition of the estimand framework in HTA guidance, with some convergence between regulatory and HTA expectations. However, we identified persistent gaps in the practical integration of estimands, particularly regarding their alignment with PICOs. Inconsistencies in how treatment effects are defined and interpreted can undermine the clarity and relevance of clinical evidence for HTA purposes. While the ICH E9(R1) Addendum on Estimands and Sensitivity Analysis in Clinical Trials has enhanced regulatory clarity, further efforts are needed to support its consistent application within HTA. Stronger alignment between estimand attributes and the PICO framework could improve evidence generation across regulatory and HTA processes, ultimately supporting more coherent and transparent decision-making in the context of the EU JCA.

In Value in Health, 28(12)