Estimands and Strategies for Handling Treatment Switching As an Intercurrent Event in Evidence Synthesis of Randomized Clinical Trials in Oncology

OBJECTIVES: The ICH E9(R1) Addendum presents a structured framework to promote clear description of targeted treatment effects (estimands). Notably, it points to the need to specify events that may affect the interpretation of outcomes (i.e., intercurrent events; ICEs) and strategies to handle these events. Compared to estimands for trial planning, there is limited discussion of estimands in the context of evidence synthesis. Here, we review current practices of how treatment switching, a common ICE in oncology, is handled in evidence synthesis.

METHODS: We conducted a comprehensive review of the Cochrane Library for meta-analyses and network meta-analyses (NMAs) of immuno-, targeted, hormone, and other novel oncology therapies. Dates were restricted to 2021 and onwards to allow time for adoption of the 2019 addendum. Outcomes of interest included progression-free survival (PFS) and overall survival (OS). Information on treatment switching and analytic strategies in evidence synthesis were extracted.

RESULTS: Out of 1,180 oncology reviews published in Cochrane Library since 2021, eleven met criteria for inclusion (eight meta-analyses and three NMAs). Only five reviews acknowledged treatment switching and other ICEs outside of cross-over trials. No reviews accounted for different targeted estimands or definitions of PFS and OS in their analyses. Only one review reported the rate of treatment switching and median OS to aid the interpretation of results.

CONCLUSIONS: The ICH E9(R1) Addendum explicitly notes that integration of data from multiple trials without consideration and specification of the estimand, including the ICE handling, can be misleading. However, most meta-analyses and NMAs reviewed failed to account for important ICEs and none implemented measures to address potential bias introduced by combining findings from trials with different estimands. There is a need for evaluation of the impact of pooling different estimands in evidence synthesis and guidance on how to conduct evidence synthesis under ICH E9(R1).