A narrative review of estimands in drug development and regulatory evaluation: old wine in new barrels?

作者：Marian Mitroiu, Katrien Oude Rengerink, Steven Teerenstra, Frank Pétavy, Kit C. B. Roes · 发表于：Trials · 年份：2020 · DOI：10.1186/s13063-020-04546-1 · 被引用次数：32 · 研究领域：Statistical Methods in Clinical Trials、Advanced Causal Inference Techniques、Health Systems, Economic Evaluations, Quality of Life

BACKGROUND: An estimand defines the target of estimation for a clinical trial through specification of the treatment, target population, variable, population-level summary and of the strategies for intercurrent events. A carefully defined estimand aligns the clinical trial design and analysis with the scientific question of interest and adequately accounts for so-called intercurrent events. The ICH E9(R1) addendum suggests five estimand strategies. We evaluated to what extent current practice in drug development and regulatory assessment fits in the estimand framework. METHODS: We systematically evaluated what estimands, especially what strategies for intercurrent events are advised in European Medicines Agency disease guidelines, used in sponsors' trials and additionally requested by the European Medicines Agency in assessment dossiers. We selected four therapeutic areas: nervous system, oncology, cardiovascular diseases and respiratory diseases. For each, we evaluated all disease guidelines with approved drugs, the dossiers of the most recently approved drugs matching the guidelines and corresponding regulatory questions. RESULTS: Strategies for intercurrent events were present in 18 (53%) of 34 guidelines, in all 34 sponsor documentations and in 15 (44%) of 34 sets of regulatory questions. Treatment policy was advised in 13 (38%) guidelines and was applied in 9 corresponding sponsor documentations. Of these 9, it was the sole strategy in 4 cases and accompanied by another ...