Improving randomized controlled trial analysis via data-adaptive borrowing.

Abstract

In recent years, real-world external controls have grown in popularity as a tool to empower randomized placebo-controlled trials, particularly in rare diseases or cases where balanced randomization is unethical or impractical. However, as external controls are not always comparable to the trials, direct borrowing without scrutiny may heavily bias the treatment effect estimator. Our paper proposes a data-adaptive integrative framework capable of preventing unknown biases of the external controls. The adaptive nature is achieved by dynamically sorting out a comparable subset of external controls via bias penalization. Our proposed method can simultaneously achieve (a) the semiparametric efficiency bound when the external controls are comparable and (b) selective borrowing that mitigates the impact of the existence of incomparable external controls. Furthermore, we establish statistical guarantees, including consistency, asymptotic distribution and inference, providing Type-I error control and good power. Extensive simulations and two real-data applications show that the proposed method leads to improved performance over the trial-only estimator across various bias-generating scenarios.