Time-to-event estimands and loss to follow-up in oncology in light of the estimands framework

TL;DR

This paper discusses how the estimands framework impacts the design and analysis of oncology trials, especially when loss to follow-up occurs, emphasizing the importance of aligning clinical questions with study design.

Contribution

It provides practical recommendations for trial design under the estimands framework, addressing challenges of loss to follow-up and intercurrent events in oncology studies.

Findings

Guidelines for aligning clinical questions with study design.

Strategies for handling loss to follow-up in estimand definitions.

Use of sensitivity analyses to assess assumptions.

Abstract

Time-to-event estimands are central to many oncology clinical trials. The estimand framework (addendum to the ICH E9 guideline) calls for precisely defining the treatment effect of interest to align with the clinical question of interest and requires predefining the handling of intercurrent events that occur after treatment initiation and either preclude the observation of an event of interest or impact the interpretation of the treatment effect. We discuss a practical problem in clinical trial design and execution, i.e. in some clinical contexts it is not feasible to systematically follow patients to an event of interest. Loss to follow-up in the presence of intercurrent events can affect the meaning and interpretation of the study results. We provide recommendations for trial design, stressing the need for close alignment of the clinical question of interest and study design, impact on data collection and other practical implications. When patients cannot be systematically followed, compromise may be necessary to select the best available estimand that can be feasibly estimated under the circumstances. We discuss the use of sensitivity and supplementary analyses to examine assumptions of interest.