Nonparametric Analysis of Delayed Treatment Effects using Single-Crossing Constraints
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Clinical trials involving novel immuno-oncology (IO) therapies frequently exhibit survival profiles which violate the proportional hazards assumption due to a delay in treatment effect, and in such settings, the survival curves in the two treatment arms may have a crossing before the two curves eventually separate. To flexibly model such scenarios, we describe a nonparametric approach for estimating the treatment arm-specific survival functions which constrains these two survival functions to cross at most once without making any additional assumptions about how the survival curves are related. A main advantage of our approach is that it provides an estimate of a crossing time if such a crossing exists, and moreover, our method generates interpretable measures of treatment benefit including crossing-conditional survival probabilities and crossing-conditional estimates of restricted residual mean life. We demonstrate the use and effectiveness of our approach with a large simulation study and an analysis of reconstructed outcomes from a recent combination-therapy trial.
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