一种新型I期临床试验的模型辅助设计方法——贝叶斯最优区间(BOIN)设计

doi:10.12092/j.issn.1009-2501.2020.06.006

中国临床药理学与治疗学 ›› 2020, Vol. 25 ›› Issue (6): 640-648.doi: 10.12092/j.issn.1009-2501.2020.06.006

一种新型I期临床试验的模型辅助设计方法——贝叶斯最优区间(BOIN)设计

仲子航¹, 陈峰¹, 袁鹰², 程建成³, 于宣宣¹, 杨旻¹, 谭明敏¹, 赵杨¹, 柏建岭¹, 于浩¹

¹南京医科大学公共卫生学院生物统计学系,南京 211166,江苏;
²美国德克萨斯大学生物统计学系安德森癌症中心,休斯顿 77230,德克萨斯;
³上海复宏汉霖生物技术股份有限公司全球临床医学事务部,上海 200233

收稿日期:2020-05-14 出版日期:2020-06-26 发布日期:2020-07-09
通讯作者: 于浩,女,博士,教授,研究方向:新药临床试验中的统计学方法。E-mail: haoyu@njmu.edu.cn;柏建岭,男,博士,副教授,研究方向:新药临床试验中的统计学方法。E-mail: baijianling@njmu.edu.cn
作者简介:仲子航,女,硕士研究生,研究方向:新药临床试验中的统计学方法。Tel:18351995086 E-mail:zhzhong@njmu.edu.cn
基金资助:
国家自然科学基金(81773554);国家自然科学基金青年基金(81302512);南京医科大学公共卫生学院江苏省优势学科三期项目(创新类3-3-1)

A novel model-assisted design in phase I clinical trials: Bayesian optimal interval design

ZHONG Zihang¹, CHEN Feng¹, YUAN Ying², CHENG Jiancheng³, YU Xuanxuan¹, YANG Min¹, TAN Mingmin¹, ZHAO Yang¹, BAI Jianling¹, YU Hao¹

¹ Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, China;
² Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston77230, Texas, USA;
³ Shanghai Henlius Biotech, Inc. Global Clinical Medicine Affairs, Shanghai 200233, China

Received:2020-05-14 Online:2020-06-26 Published:2020-07-09

摘要/Abstract

摘要： 目的: 介绍一种新颖的I期临床试验模型辅助设计方法——贝叶斯最优区间设计(BOIN Design, Bayesian optimal interval design),包括其实施流程、实际应用等,并评价其表现。方法: 在贝叶斯理论框架下,BOIN设计以最小化错误决策概率为目的,推导需增减剂量时的容忍毒性边界值,并通过比较实际毒性率与该边界值决定剂量转变。以真实案例详解其实施流程。通过与现有设计方法的对比评价BOIN的表现。结果: BOIN设计具有最优化、安全、稳健、简单实用等性质。模拟实验表明,BOIN设计能够更精准地识别最大耐受剂量(maximum tolerated dose, MTD)。结论: BOIN设计具有与基于模型设计相仿的统计学表现,同时更加简练、易于实施且更易于满足特定的安全需求。BOIN设计在国外已经广泛应用于不同类型的癌症研究,是值得推广的I期临床试验剂量探索的新方法。

关键词: I期临床试验, 贝叶斯最优区间设计, “3+3”设计, 最大耐受剂量

Abstract: AIM: To introduce a novel and flexible model-assisted design for Phase I clinical trials: Bayesian optimal interval (BOIN) design, including the process of implementation, practical implementation, and evaluation of its performance. METHODS: BOIN design decides dose escalation/de-escalation by comparing the observed toxicity rate at the current dose with an escalation boundary and a de-escalation boundary that are optimized to minimize the probability of making incorrect decision of dose assignment. The application of the BOIN design is illustrated using a trial example. RESULTS: BOIN combines the advantages of the algorithm-based methods and model-based methods. It enjoys desirable statistical properties -it is optimal, safe, robust and easy to implement. Simulation study shows that the BOIN substantially outperforms the existing designs with higher accuracy to identify the maximum tolerated dose (MTD). CONCLUSION: BOIN design possesses the similar statistical performance to the much more complicated model-based designs. It is simple to implement, and easy to calibrate to meet the safety requirement mandated by regulatory agents. The BOIN design has been widely used in different types of cancers. It is a novel design that holds great potential to substantially improve phase I trials in China.

Key words: Phase I clinical trials, BION, "3+3" design, maximum tolerated dose

中图分类号:

R311

仲子航, 陈峰, 袁鹰, 程建成, 于宣宣, 杨旻, 谭明敏, 赵杨, 柏建岭, 于浩. 一种新型I期临床试验的模型辅助设计方法——贝叶斯最优区间(BOIN)设计[J]. 中国临床药理学与治疗学, 2020, 25(6): 640-648.

ZHONG Zihang, CHEN Feng, YUAN Ying, CHENG Jiancheng, YU Xuanxuan, YANG Min, TAN Mingmin, ZHAO Yang, BAI Jianling, YU Hao. A novel model-assisted design in phase I clinical trials: Bayesian optimal interval design[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2020, 25(6): 640-648.

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一种新型I期临床试验的模型辅助设计方法——贝叶斯最优区间(BOIN)设计

A novel model-assisted design in phase I clinical trials: Bayesian optimal interval design

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