Accuracy and Safety of Novel Designs for Phase I Drug-Combination Oncology Trials.
Accuracy and Safety of Novel Designs for Phase I Drug-Combination Oncology Trials.
复制标题
肿瘤I期联合药物试验新设计的准确性和安全性。
DOI：
10.1080/19466315.2022.2081602
复制
发表时间：
2022
影响因子：
1.8
通讯作者：
Marchenko, Olga
中科院分区：
文献类型：
--
作者：
Liu, Rong;Yuan, Ying;Sen, Suman;Yang, Xin;Jiang, Qi;Li, Xiaoyun (Nicole);Lu, Chengxing (Cindy);Gonen, Mithat;Tian, Hong;Zhou, Heng;Lin, Ruitao;Marchenko, Olga
尽管已经发表了许多创新的设计用于I期药物组合剂量探索试验，但它们在真实的应用中的使用相当有限。作为美国统计协会生物制药部门的一个工作组，我们的目标是确定与药物组合相关的独特挑战，分享行业在组合试验方面的经验，并调查现有设计的利弊。为了实现这一目标，我们回顾了七种现有的设计，并根据其主要目标是找到单一最大耐受剂量（MTD）还是MTD轮廓（即，多个MTD）。基于行业指定的固定场景或随机生成的场景进行数值研究，以评估其相对准确性，安全性和易于实施。我们发现，基于算法的3+3设计的性能较差，往往无法找到MTD。基于模型的组合试验设计的性能是混合的：一些显示出较高的准确性，发现MTD，但安全性差，而另一些是安全的，但具有受损的识别准确性。相比之下，模型辅助设计，如BOIN和瀑布设计，在MTD识别的准确性和患者安全性方面具有竞争力和平衡的性能，并且易于实现，从而为设计I期药物组合试验提供了一种有吸引力的方法。通过考虑设计的操作特性，易于实施和监管，需要先进的基础设施，以及监管接受的风险，我们的论文提供了实用的指导，选择一个合适的剂量发现方法设计未来的组合试验。
Despite numerous innovative designs having been published for phase I drug-combination dose finding trials, their use in real applications is rather limited. As a working group under the American Statistical Association Biopharmaceutical Section, our goal is to identify the unique challenges associated with drug combination, share industry’s experiences with combination trials, and investigate the pros and cons of the existing designs. Toward this goal, we review seven existing designs and distinguish them based on the criterion of whether their primary objectives are to find a single maximum tolerated dose (MTD) or the MTD contour (i.e., multiple MTDs). Numerical studies, based on either industry-specified fixed scenarios or randomly generated scenarios, are performed to assess their relative accuracy, safety, and ease of implementation. We show that the algorithm-based 3+3 design has poor performance and often fails to find the MTD. The performance of model-based combination trial designs is mixed: some demonstrate high accuracy of finding the MTD but poor safety, while others are safe but with compromised identification accuracy. In comparison, the model-assisted designs, such as BOIN and waterfall designs, have competitive and balanced performance in the accuracy of MTD identification and patient safety, and are also simple to implement, thus offering an attractive approach to designing phase I drug-combination trials. By taking into consideration the design’s operating characteristics, ease of implementation and regulation, the need for advanced infrastructures, as well as the risk of regulatory acceptance, our paper offers practical guidance on the selection of a suitable dose-finding approach for designing future combination trials.
登录
查看更多内容
影响因子：
2
作者：
Mander, Adrian P.;Sweeting, Michael J.
通讯作者：
Sweeting, Michael J.
影响因子：
2.2
作者：
Pan, Haitao;Lin, Ruitao;Yuan, Ying
通讯作者：
Yuan, Ying
影响因子：
1.9
作者：
Ivanova, A
通讯作者：
Ivanova, A
影响因子：
2
作者：
Lin, Ruitao;Yin, Guosheng
通讯作者：
Yin, Guosheng
影响因子：
2.2
作者：
Quintana, Melanie;Li, Daniel H.;Connor, Jason T.
通讯作者：
Connor, Jason T.