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 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 -- The Hi3+3 design is superior than the i3+3 design due to information borrow from historical data. It is capable of maintaining a high level of safety for trial patients without sacrificing the ability to identify the correct MTD. Illustration 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.