Adjusting for Time-Varying Treatment Switches in Randomized Clinical Trials: The Danger of Extrapolation and How to Address It

Abstract

When choosing estimands and estimators in randomized clinical trials, caution is warranted, as intercurrent events, such as, due to patients who switch treatment after disease progression, are often strongly associated with patients’ time-varying prognostic factors. Consequently, for patients who did experience intercurrent events, there are typically no comparable patients who did not. Statistical analyses may then easily lure one into making large implicit extrapolations, which often go unnoticed. We will illustrate this problem of implicit extrapolations using a real oncology case study, with a right-censored time-to-event endpoint, in which patients can cross over from the control to the experimental treatment after disease progression, for ethical reasons. We address this by developing an estimator for the survival risk ratio contrasting the survival probabilities at each time t if all patients would take experimental treatment with the survival probabilities at those times t if all patients would take control treatment up to time t, using randomization as an instrumental variable to avoid reliance on no unmeasured confounders assumptions. This doubly robust estimator can handle time-varying treatment switches and right-censored survival times. Insight into the rationale behind the estimator is provided and the approach is demonstrated by reanalyzing the oncology trial.

KEYWORDS:

• Causal inference
• Estimand
• Hypothetical estimand
• Instrumental variable
• Treatment switching

Supplementary Materials

The supplementary materials contain additional information and proofs of the proposed estimators and estimands, as well as additional results on the data analysis.

Acknowledgments

The authors would like to thank Mouna Akacha, Jonathan Bartlett, Oliver Dukes, Cristina Sotto and Kelly Van Lancker for encouragement, discussions and insightful comments.

Disclosure Statement

The authors report that there are no competing interests to declare.

Additional information

Funding

This project has received funding form VLAIO (Flemish Innovation and Entrepreneurship) under Baekeland grant agreement HBC.2019.2155.