Tipping Point Sensitivity Analysis for Missing Data in Time-to-Event Endpoints: Model-Based and Ad hoc Approaches

TL;DR

This paper explores methods to evaluate how sensitive treatment effect estimates are to violations of the independent censoring assumption in time-to-event trials, using model-based and ad hoc tipping point approaches.

Contribution

It introduces and compares model-based and ad hoc tipping point methods for sensitivity analysis of missing data in time-to-event endpoints.

Findings

Model-based and ad hoc approaches provide different insights into data robustness.

Application to real trial data illustrates the practical implications of each method.

Tipping point analysis helps assess the plausibility of assumptions in clinical trial conclusions.

Abstract

Treatment policy estimands are frequently favored by regulators, as they assess the effect of treatment assignment regardless of post-randomization events. Despite best efforts, missing data due to study discontinuation cannot be fully avoided and, for time-to-event endpoints, typically manifests as right censoring. Study discontinuation is often more likely following intercurrent events, particularly when it coincides with treatment discontinuation, raising concerns about violations of the independent censoring assumption. Although the independent censoring assumption is routinely adopted for the main analyses, it may be unrealistic in practice and could lead to biased estimation of the treatment effect under the treatment policy estimand. Tipping-point analyses provide a structured framework to assess the robustness of trial conclusions to departures from the independent censoring assumption. This paper describes and contrasts model-based and two ad hoc tipping point approaches, which involve "landmark" or "percentile sampling" based imputation. We illustrate their application using re-constructed examples based on real clinical trials, highlighting their underlying assumptions and implications for interpretation and clinical plausibility assessments of different tipping point approaches.