Identifying Principal Stratum Causal Effects Conditional on a Post-treatment Intermediate Response

TL;DR

This paper introduces a method to estimate causal effects of treatments on survival outcomes within specific patient subgroups defined by their potential responses, addressing challenges in surrogate endpoint validation in clinical trials.

Contribution

It proposes a novel approach to estimate principal stratum causal effects using empirical data, extending to censored outcomes, which improves understanding of treatment efficacy in clinical trials.

Findings

Method successfully estimates causal effects in real clinical trial data.

Approach performs well in simulation studies under various scenarios.

Addresses challenges of censored data in causal inference.

Abstract

In neoadjuvant trials on early-stage breast cancer, patients are usually randomized into a control group and a treatment group with an additional target therapy. Early efficacy of the new regimen is assessed via the binary pathological complete response (pCR) and the eventual efficacy is assessed via long-term clinical outcomes such as survival. Although pCR is strongly associated with survival, it has not been confirmed as a surrogate endpoint. To fully understand its clinical implication, it is important to establish causal estimands such as the causal effect in survival for patients who would achieve pCR under the new regimen. Under the principal stratification framework, previous studies focus on sensitivity analyses by varying model parameters in an imposed model on counterfactual outcomes. Under mild assumptions, we propose an approach to estimate those model parameters using empirical data and subsequently the causal estimand of interest. We also extend our approach to address censored outcome data. The proposed method is applied to a recent clinical trial and its performance is evaluated via simulation studies.