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Abstract:
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Since the release of the ICH E9(R1) document in 2019, the estimand framework has become a fundamental part of clinical trial protocols. In parallel, complex innovative designs have gained increased popularity in drug development. It is currently unclear, however, to which degree the estimand framework applies to these novel designs. For example, should a different estimand be specified for each sub-population (defined, for example, by cancer site) in a basket trial? Or can a single estimand focusing on the general population (defined, for example, by the positivity to a certain biomarker) be used? In the case of platform trials, should a different estimand be proposed for each drug investigated? We discuss relevant estimand considerations pertaining to different types of complex innovative designs. We consider trials that allow adding or selecting experimental treatment arms, modifying the control arm, and selecting or pooling populations. We also address the potentially data-driven, adaptive selection of estimands in an ongoing trial and disentangle certain statistical issues that pertain to estimation rather than to estimands, such as the borrowing of non-concurrent information.
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