Abstract
BACKGROUND: Hybrid controlled trials with real-world data (RWD), where the control arm is composed of both trial and real-world patients, could facilitate research when the feasibility of randomized controlled trials (RCTs) is challenging and single-arm trials would provide insufficient information. METHODS: We propose a frequentist two-step borrowing method to construct hybrid control arms. We use parameters informed by a completed randomized trial in metastatic triple-negative breast cancer to simulate the operating characteristics of dynamic and static borrowing methods, highlighting key trade-offs and analytic decisions in the design of hybrid studies. RESULTS: Simulated data were generated under varying residual-bias assumptions (no bias: HR(RWD) = 1) and experimental treatment effects (target trial scenario: HR(Exp) = 0.78). Under the target scenario with no residual bias, all borrowing methods achieved the desired 88% power, an improvement over the reference model (74% power) that does not borrow information externally. The effective number of external events tended to decrease with higher bias between RWD and RCT (i.e. HR(RWD) away from 1), and with weaker experimental treatment effects (i.e. HR(Exp) closer to 1). All dynamic borrowing methods illustrated (but not the static power prior) cap the maximum Type 1 error over the residual-bias range considered. Our two-step model achieved comparable results for power, type 1 error, and effective number of external events borrowed compared to other borrowing methodologies. CONCLUSION: By pairing high-quality external data with rigorous simulations, researchers have the potential to design hybrid controlled trials that better meet the needs of patients and drug development.