A Robust Instrumental Variable Method Accounting for Treatment Switching in Open-Label Randomized Controlled Trials

TL;DR

This paper introduces a robust instrumental variable method to accurately estimate treatment effects in open-label randomized controlled trials with treatment switching, addressing biases caused by violations of traditional IV assumptions.

Contribution

The paper proposes a new IV estimator that relaxes the exclusion restriction, with theoretical properties, simulation validation, and an R package implementation.

Findings

Estimator performs well in simulations

Provides valid inference under violations of exclusion restriction

Applied successfully to NRTI treatment effect analysis

Abstract

In a randomized controlled trial, treatment switching (also called contamination or crossover) occurs when a patient initially assigned to one treatment arm changes to another arm during the course of follow-up. Overlooking treatment switching might substantially bias the evaluation of treatment efficacy or safety. To account for treatment switching, instrumental variable (IV) methods by leveraging the initial randomized assignment as an IV serve as natural adjustment methods because they allow dependent treatment switching possibly due to underlying prognoses. However, the ``exclusion restriction'' assumption for IV methods, which requires the initial randomization to have no direct effect on the outcome, remains questionable, especially for open-label trials. We propose a robust instrumental variable estimator circumventing such a caveat. We derive large-sample properties of our proposed estimator, along with inferential tools. We conduct extensive simulations to examine the finite performance of our estimator and its associated inferential tools. An R package ``ivsacim'' implementing all proposed methods is freely available on R CRAN. We apply the estimator to evaluate the treatment effect of Nucleoside Reverse Transcriptase Inhibitors (NRTIs) on a safety outcome in the Optimized Treatment That Includes or Omits NRTIs trial.