Estimand framework: Are we asking the right questions? A case study in the solid tumor setting

Abstract

Summary The estimand framework requires a precise definition of the clinical question of interest (the estimand) as different ways of accounting for “intercurrent” events post randomization may result in different scientific questions. The initiation of subsequent therapy is common in oncology clinical trials and is considered an intercurrent event if the start of such therapy occurs prior to a recurrence or progression event. Three possible ways to account for this intercurrent event in the analysis are to censor at initiation, consider recurrence or progression events (including death) that occur before and after the initiation of subsequent therapy, or consider the start of subsequent therapy as an event in and of itself. The new estimand framework clarifies that these analyses address different questions (“does the drug delay recurrence if no patient had received subsequent therapy?” vs “does the drug delay recurrence with or without subsequent therapy?” vs “does the drug delay recurrence or start of subsequent therapy?”). The framework facilitates discussions during clinical trial planning and design to ensure alignment between the key question of interest, the analysis, and interpretation. This article is a result of a cross‐industry collaboration to connect the International Council for Harmonisation E9 addendum concepts to applications. Data from previously reported randomized phase 3 studies in the renal cell carcinoma setting are used to consider common intercurrent events in solid tumor studies, and to illustrate different scientific questions and the consequences of the estimand choice for study design, data collection, analysis, and interpretation.

The Case Against Censoring of Progression-Free Survival in Cancer Clinical Trials – A Pandemic Shutdown as an Illustration

“…The oncology estimand working group, a cross-industry international collaboration, was established by the European Federation of Statisticians in the Pharmaceutical Industry as a European special-interest group for estimands in oncology, and was granted the o cial status of American Statistical Association scienti c working group. In their publications, they have argued that the clinical trial objective should relate to a world without ongoing Covid-19 pandemic, including no major disruption of healthcare systems [20]. The censoring of time-to-event endpoints at the intercurrent event was suggested as a possible way to target a hypothetical estimand, even in the context of the Covid-19 pandemic-related healthcare system disruptions in PFS analysis [25].…”

“…On the other hand, censoring of time-to-event endpoints for an intercurrent event is widely used for targeting a hypothetical estimand. This "hypothetical" approach has been suggested as a way to account for the health-caresystem disruptions related to the pandemic [20].…”

Multistate Models as a Framework for Estimand Specification in Clinical Trials of Complex Processes

“…Ways to define estimands and make treatment comparisons in the presence of intercurrent events have received a great deal of attention in recent years (Rufibach, 2019). Numerous researchers and working groups have proposed estimands and guidelines for specific settings involving competing risks (Rufibach, 2019;Stensrud et al, 2020;Young et al, 2020;Nevo and Gorfine, 2021;Poythress et al, 2020), recurrent and terminal events (Andersen et al, 2019;Schmidli et al, 2021;Wei et al, 2021), introduction of rescue therapies (Ster et al, 2020) or treatment switching (Watkins et al, 2013;Manitz et al, 2022); see also Casey et al (2021) and Stensrud and Dukes (2022).…”

The case against censoring of progression-free survival in cancer clinical trials – A pandemic shutdown as an illustration

“…On the other hand, censoring of time-to-event endpoints for an intercurrent event is widely used for targeting a hypothetical estimand. This “hypothetical” approach has been suggested as a way to account for the health-care-system disruptions related to the pandemic [ 23 ].…”