Confounding adjustment in the analysis of augmented randomized controlled trial with hybrid control arm.

The augmented randomized controlled trial (RCT) with hybrid control arm includes a randomized treatment group (RT), a smaller randomized control group (RC), and a large synthetic control (SC) group from real-world data. This kind of trial is useful when there is logistics and ethics hurdle to conduct a fully powered RCT with equal allocation, or when it is necessary to increase the power of the RCT by incorporating real-world data. A difficulty in the analysis of augmented RCT is that the SC and RC may be systematically different in the distribution of observed and unmeasured confounding factors, causing bias when the two control groups are analyzed together as hybrid controls. We propose to use propensity score (PS) analysis to balance the observed confounders between SC and RC. The possible bias caused by unmeasured confounders can be estimated and tested by analyzing propensity score adjusted outcomes from SC and RC. We also propose a partial bias correction (PBC) procedure to reduce bias from unmeasured confounding. Extensive simulation studies show that the proposed PS + PBC procedures can improve the efficiency and statistical power by effectively incorporating the SC into the RCT data analysis, while still control the estimation bias and Type I error inflation that might arise from unmeasured confounding. We illustrate the proposed statistical procedures with data from an augmented RCT in oncology.