T3 + 3: 3 + 3 Design With Delayed Outcomes.

IF 1.3 4区 医学 Q4 PHARMACOLOGY & PHARMACY Pharmaceutical Statistics Pub Date : 2024-06-25 DOI:10.1002/pst.2414
Jiaying Guo, Mengyi Lu, Isabella Wan, Yumin Wang, Leng Han, Yong Zang
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Abstract

Delayed outcome is common in phase I oncology clinical trials. It causes logistic difficulty, wastes resources, and prolongs the trial duration. This article investigates this issue and proposes the time-to-event 3 + 3 (T3 + 3) design, which utilizes the actual follow-up time for at-risk patients with pending toxicity outcomes. The T3 + 3 design allows continuous accrual without unnecessary trial suspension and is costless and implementable with pretabulated dose decision rules. Besides, the T3 + 3 design uses the isotonic regression to estimate the toxicity rates across dose levels and therefore can accommodate for any targeted toxicity rate for maximum tolerated dose (MTD). It dramatically facilitates the trial preparation and conduct without intensive computation and statistical consultation. The extension to other algorithm-based phase I dose-finding designs (e.g., i3 + 3 design) is also studied. Comprehensive computer simulation studies are conducted to investigate the performance of the T3 + 3 design under various dose-toxicity scenarios. The results confirm that the T3 + 3 design substantially shortens the trial duration compared with the conventional 3 + 3 design and yields much higher accuracy in MTD identification than the rolling six design. In summary, the T3 + 3 design addresses the delayed outcome issue while keeping the desirable features of the 3 + 3 design, such as simplicity, transparency, and costless implementation. It has great potential to accelerate early-phase drug development.

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T3 + 3:延迟结果的 3 + 3 设计。
延迟结果在肿瘤学一期临床试验中很常见。它给后勤工作带来困难,浪费资源,延长试验时间。本文对这一问题进行了研究,并提出了从时间到事件的 3 + 3(T3 + 3)设计,即利用实际随访时间对毒性结果待定的高危患者进行随访。T3 + 3 设计允许持续累积,而无需不必要地暂停试验,而且成本低廉,可通过预先制定的剂量决策规则来实施。此外,T3 + 3 设计使用等张回归法来估算各剂量水平的毒性率,因此可以适应最大耐受剂量(MTD)的任何目标毒性率。这极大地方便了试验的准备和实施,无需大量计算和统计咨询。此外,还研究了将该方法推广到其他基于算法的 I 期剂量寻找设计(如 i3 + 3 设计)的可能性。还进行了全面的计算机模拟研究,以调查 T3 + 3 设计在各种剂量-毒性情况下的表现。结果证实,与传统的 3 + 3 设计相比,T3 + 3 设计大大缩短了试验持续时间,而且与滚动 6 设计相比,T3 + 3 设计的 MTD 识别准确率要高得多。总之,T3 + 3 设计既解决了延迟结果问题,又保留了 3 + 3 设计的理想特性,如简单、透明和实施成本低。它在加速早期药物开发方面具有巨大潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Pharmaceutical Statistics
Pharmaceutical Statistics 医学-统计学与概率论
CiteScore
2.70
自引率
6.70%
发文量
90
审稿时长
6-12 weeks
期刊介绍: Pharmaceutical Statistics is an industry-led initiative, tackling real problems in statistical applications. The Journal publishes papers that share experiences in the practical application of statistics within the pharmaceutical industry. It covers all aspects of pharmaceutical statistical applications from discovery, through pre-clinical development, clinical development, post-marketing surveillance, consumer health, production, epidemiology, and health economics. The Journal is both international and multidisciplinary. It includes high quality practical papers, case studies and review papers.
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