Hi3 + 3: A model-assisted dose-finding design borrowing historical data.

Abstract Background In phase I clinical trials, historical data may be available through multi-regional programs, reformulation of the same drug, or previous trials for a drug under the same class. Statistical designs that borrow information from historical data can reduce cost, speed up drug development, and maintain safety. Purpose Based on a hybrid design that partly uses probability models and partly uses algorithmic rules for decision making, we aim to improve the efficiency of the dose-finding trials in the presence of historical data, maintain safety for patients, and achieve a level of simplicity for practical applications. Methods We propose the Hi3+3 design, in which the letter “H” represents “historical data”. We apply the idea in power prior to borrow historical data and define the effective sample size (ESS) of the prior. Dose-finding decision rules follow the idea in the i3+3 design (Liu et al., 2020 [ 1 ]) while incorporating the historical data via the power prior and ESS. The proposed Hi3+3 design pretabulates the dosing decisions before the trial starts, a desirable feature for ease of application in practice. Results In most cases we investigated, the Hi3+3 design is superior than the i3+3 design due to information borrow from historical data. Even when the historical data is incompatible with the current data, it is capable of maintaining a high level of safety for trial patients and comparable performances without sacrificing the ability to identify the correct MTD too much. Ilustration of this feature are found in the simulation results. Conclusion With the demonstrated safety, efficiency, and simplicity, the Hi3+3 design could be a desirable choice for dose-finding trials borrowing historical data.