Causal inference methods to assess safety upper bounds in randomized trials with noncompliance

Clinical Trials : Journal of the Society for Clinical Trials
Yiting WangMarsha A Wilcox

Abstract

Premature discontinuation and other forms of noncompliance with treatment assignment can complicate causal inference of treatment effects in randomized trials. The intent-to-treat analysis gives unbiased estimates for causal effects of treatment assignment on outcome, but may understate potential benefit or harm of actual treatment. The corresponding upper confidence limit can also be underestimated. To compare estimates of the hazard ratio and upper bound of the two-sided 95% confidence interval from causal inference methods that account for noncompliance with those from the intent-to-treat analysis. We used simulations with parameters chosen to reflect cardiovascular safety trials of diabetes drugs, with a focus on upper bound estimates relative to 1.3, based on regulatory guidelines. A total of 1000 simulations were run under each parameter combination for a hypothetical trial of 10,000 total subjects randomly assigned to active treatment or control at 1:1 ratio. Noncompliance was considered in the form of treatment discontinuation and cross-over at specified proportions, with an assumed true hazard ratio of 0.9, 1, and 1.3, respectively. Various levels of risk associated with being a non-complier (independent of treatment s...Continue Reading

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