Choosing Estimands in Clinical Trials: Putting the ICH E9(R1) Into Practice

Bohdana Ratitch, James Bell, Craig Mallinckrodt, Jonathan W Bartlett, Niti Goel, Geert Molenberghs, Michael O'Kelly, Pritibha Singh, Ilya Lipkovich

Research output: Contribution to journalArticle

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Abstract

The National Research Council (NRC) Expert Panel Report on Prevention and Treatment of Missing Data in Clinical Trials highlighted the need for clearly defining objectives and estimands. That report sparked considerable discussion and literature on estimands and how to choose them. Importantly, consideration moved beyond missing data to include all postrandomization events that have implications for estimating quantities of interest (intercurrent events, aka ICEs). The ICH E9(R1) draft addendum builds on that research to outline key principles in choosing estimands for clinical trials, primarily with focus on confirmatory trials. This paper provides additional insights, perspectives, details, and examples to help put ICH E9(R1) into practice. Specific areas of focus include how the perspectives of different stakeholders influence the choice of estimands; the role of randomization and the intention-to-treat principle; defining the causal effects of a clearly defined treatment regimen, along with the implications this has for trial design and the generalizability of conclusions; detailed discussion of strategies for handling ICEs along with their implications and assumptions; estimands for safety objectives, time-to-event endpoints, early-phase and one-arm trials, and quality of life endpoints; and realistic examples of the thought process involved in defining estimands in specific clinical contexts.

Original languageEnglish
Pages (from-to)1-18
Number of pages18
JournalTherapeutic Innovation & Regulatory Science
Early online date4 Apr 2019
DOIs
Publication statusE-pub ahead of print - 4 Apr 2019

Cite this

Choosing Estimands in Clinical Trials: Putting the ICH E9(R1) Into Practice. / Ratitch, Bohdana; Bell, James; Mallinckrodt, Craig; Bartlett, Jonathan W; Goel, Niti; Molenberghs, Geert; O'Kelly, Michael; Singh, Pritibha; Lipkovich, Ilya.

In: Therapeutic Innovation & Regulatory Science, 04.04.2019, p. 1-18.

Research output: Contribution to journalArticle

Ratitch, B, Bell, J, Mallinckrodt, C, Bartlett, JW, Goel, N, Molenberghs, G, O'Kelly, M, Singh, P & Lipkovich, I 2019, 'Choosing Estimands in Clinical Trials: Putting the ICH E9(R1) Into Practice', Therapeutic Innovation & Regulatory Science, pp. 1-18. https://doi.org/10.1177/2168479019838827
Ratitch, Bohdana ; Bell, James ; Mallinckrodt, Craig ; Bartlett, Jonathan W ; Goel, Niti ; Molenberghs, Geert ; O'Kelly, Michael ; Singh, Pritibha ; Lipkovich, Ilya. / Choosing Estimands in Clinical Trials: Putting the ICH E9(R1) Into Practice. In: Therapeutic Innovation & Regulatory Science. 2019 ; pp. 1-18.
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