Estimands in CNS trials – A review of strategies for addressing intercurrent events

Abstract

BackgroundThe estimands framework represents a significant innovation for the design, conduct, analysis, and interpretation of clinical trials. An aim of the framework is to increase precision and transparency on the handling of intercurrent events (IEs), defined as events occurring after treatment initiation and affecting the endpoint. While the experience in constructing and reporting estimands in the published literature is limited, developers performing confirmatory studies are already making use of the new paradigm, allowing to survey the strategies proposed by applicants and endorsed by regulators. MethodsTo identify strategies for handling IEs in confirmatory central nervous system (CNS) trials, we searched scientific advice letters issued by the European Medicines Agency (EMA) between 2017 and 2022. We developed a categorisation of the IEs and classified, according to the strategies defined in the framework, the strategies proposed by the Applicants and recommended by the agency. Strategies proposed and recommended were summarised by category of IEs, and the rationale for the choices was analysed qualitatively. ResultsIn total, 170 IEs were identified in 52 confirmatory trials. A clear preference for the treatment policy strategy for treatment discontinuation and for the hypothetical strategy for pandemic-related disruptions was identified. For other categories of IEs, there are more mixed patterns. DiscussionThis study highlights the multidimensional nature of choosing a strategy for an IE. For different occurring IEs in confirmatory CNS trials different strategies are of regulatory interest, depending on the trial objective, underlying disease properties, rarity of disease, as well as frequency and timing of IEs and their relatedness to the disease.