Department of Mathematics, Fudan University, China.
Center for Drug Evaluation and Research, US FDA, USA.
Contemp Clin Trials. 2021 Oct;109:106437. doi: 10.1016/j.cct.2021.106437. Epub 2021 May 18.
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.
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.
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.
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.
With the demonstrated safety, efficiency, and simplicity, the Hi3+3 design could be a desirable choice for dose-finding trials borrowing historical data.
在 I 期临床试验中，通过多区域项目、同一药物的重新配方或同一类药物的先前试验，可能会有历史数据可用。从历史数据中获取信息的统计设计可以降低成本、加快药物开发速度并保持安全性。
基于部分使用概率模型和部分使用决策算法规则的混合设计，我们旨在提高存在历史数据时剂量发现试验的效率，为患者保持安全性，并实现实际应用的简单性水平。
我们提出了 Hi3+3 设计，其中字母“H”代表“历史数据”。我们应用先验中的功效概念来借用历史数据，并定义先验的有效样本量 (ESS)。剂量发现决策规则遵循 i3+3 设计（Liu 等人，2020[1]）的思想，同时通过功效先验和 ESS 合并历史数据。所提出的 Hi3+3 设计在试验开始之前就预先制定了给药决策，这是在实践中易于应用的理想特征。
在我们研究的大多数情况下，由于从历史数据中获取信息，Hi3+3 设计优于 i3+3 设计。即使历史数据与当前数据不兼容，它也能够为试验患者保持高安全性水平，并且在不牺牲太多识别正确 MTD 的能力的情况下具有可比的性能。这一特征的说明在模拟结果中找到。
Hi3+3 设计具有已证明的安全性、效率和简单性，可成为借用历史数据进行剂量发现试验的理想选择。
