抗癌药Ⅰ期临床试验连续重评估方法解析及应用
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摘要
本文回顾性剖析了抗癌药Ⅰ期临床试验的相关概念实质,阐明传统"3+3"剂量爬坡设计的局限及连续重评估方法(Continual reassessment method,CRM)的优势,对Ⅰ期临床试验中基于单参数功效模型的CRM、贝叶斯模型平均CRM、数据增强CRM、时间-事件CRM、分数CRM及其应用分别进行了详细解析,最后就CRM的试验设计流程进行了系统性概括,旨在为我国抗癌药Ⅰ期临床试验设计的方法学提供参考。
This article briefly introduced the aim and concept of phase Ⅰ clinical trial for anti-cancer drugs.We analyzed and pointed out the disadvantages of traditional"3 + 3"design and the advantages of continual reassessment method(CRM) for dose-escalation trial.Then we introduced in detail the concept and application of CRM,including the CRM based on single skeleton,Bayesian model averaging CRM,data augmentation CRM,time-to-event CRM and fractional CRM for phase Ⅰ trial.In the end,we described the trial design process using the CRM.The information in this article we provide is aimed at clinicians and sponsors for their methodological references of phase Ⅰ trial design of anti-cancer drugs in China.
This article briefly introduced the aim and concept of phase Ⅰ clinical trial for anti-cancer drugs.We analyzed and pointed out the disadvantages of traditional"3 + 3"design and the advantages of continual reassessment method(CRM) for dose-escalation trial.Then we introduced in detail the concept and application of CRM,including the CRM based on single skeleton,Bayesian model averaging CRM,data augmentation CRM,time-to-event CRM and fractional CRM for phase Ⅰ trial.In the end,we described the trial design process using the CRM.The information in this article we provide is aimed at clinicians and sponsors for their methodological references of phase Ⅰ trial design of anti-cancer drugs in China.
引文
[1]Wheeler GM,Mander AP,Bedding A,et al.How to design a dose-finding study using the continual reassessment method[J].BMC Med Res Methodol,2019,19(1):18.
[2]Storer BE.Design and analysis of phaseⅠclinical trials[J].Biometrics,1989,45(3):925-937.
[3]O'Quigley J,Pepe M,Fisher L.Continual reassessment method:a practical design for phase 1 clinical trials in cancer[J].Biometrics,1990,46(1):33-48.
[4]Conaway MR,Petroni GR.The impact of early-phase trial design in the drug development process[J].Clin Cancer Res,2019,25(2):819-827.
[5]Zhou H,Yuan Y,Nie L.Accuracy,safety,and reliability of novel phaseⅠtrial designs[J].Clin Cancer Res,2018,24(18):4357-4364.
[6]Lee SM,Cheung YK.Calibration of prior variance in the Bayesian continual reassessment method[J].Stat Med,2011,30(17):2081-2089.
[7]Petroni GR,Wages NA,Paux G,et al.Implementation of adaptive methods in early-phase clinical trials[J].Stat Med,2017,36(2):215-224.
[8]Lee SM,Ying Kuen C.Model calibration in the continual reassessment method[J].Clin Trials,2009,6(3):227-238.
[9]O'Quigley J,Zohar S.Retrospective robustness of the continual reassessment method[J].J Biopharm Stat,2010,20(5):1013-1025.
[10]O'Quigley J,Shen LZ.Continual reassessment method:a likelihood approach[J].Biometrics,1996,52(2):673-684.
[11]Liu S,Yin G,Yuan Y.Bayesian data augmentation dose finding with continual reassessment method and delayed toxicity[J].Ann Appl Stat,2013,7(4):1837-2457.
[12]Natarajan L,O'Quigley J.Interval estimates of the probability of toxicity at the maximum tolerated dose for small samples[J].Stat Med,2003,22(11):1829-1836.
[13]Asakawa T,Hirakawa A,Hamada C.Bayesian model averaging continual reassessment method for bivariate binary efficacy and toxicity outcomes in phaseⅠoncology trials[J].J Biopharm Stat,2014,24(2):310-325.
[14]Daimon T,Zohar S,O'Quigley J.Posterior maximization and averaging for Bayesian working model choice in the continual reassessment method[J].Stat Med,2011,30(13):1563-1573.
[15]Normolle D,Lawrence T.Designing dose-escalation trials with late-onset toxicities using the time-to-event continual reassessment method[J].J Clin Oncol,2006,24(27):4426-4433.
[16]Cheung YK,Chappell R.Sequential designs for phaseⅠclinical trials with late-onset toxicities[J].Biometrics,2000,56(4):1177-1182.
[17]Yin G,Zheng S,Xu J.Fractional dose-finding methods with late-onset toxicity in phaseⅠclinical trials[J].J Biopharm Stat,2013,23(4):856-870.
[18]Yap C,Billingham LJ,Cheung YK,et al.Dose transition pathways:the missing link between complex dose-finding designs and simple decision-making[J].Clin Cancer Res,2017,23(24):7440-7447.
[19]Wages NA,Petroni GR.A web tool for designing and conducting phaseⅠtrials using the continual reassessment method[J].BMC Cancer,2018,18(1):133.
[2]Storer BE.Design and analysis of phaseⅠclinical trials[J].Biometrics,1989,45(3):925-937.
[3]O'Quigley J,Pepe M,Fisher L.Continual reassessment method:a practical design for phase 1 clinical trials in cancer[J].Biometrics,1990,46(1):33-48.
[4]Conaway MR,Petroni GR.The impact of early-phase trial design in the drug development process[J].Clin Cancer Res,2019,25(2):819-827.
[5]Zhou H,Yuan Y,Nie L.Accuracy,safety,and reliability of novel phaseⅠtrial designs[J].Clin Cancer Res,2018,24(18):4357-4364.
[6]Lee SM,Cheung YK.Calibration of prior variance in the Bayesian continual reassessment method[J].Stat Med,2011,30(17):2081-2089.
[7]Petroni GR,Wages NA,Paux G,et al.Implementation of adaptive methods in early-phase clinical trials[J].Stat Med,2017,36(2):215-224.
[8]Lee SM,Ying Kuen C.Model calibration in the continual reassessment method[J].Clin Trials,2009,6(3):227-238.
[9]O'Quigley J,Zohar S.Retrospective robustness of the continual reassessment method[J].J Biopharm Stat,2010,20(5):1013-1025.
[10]O'Quigley J,Shen LZ.Continual reassessment method:a likelihood approach[J].Biometrics,1996,52(2):673-684.
[11]Liu S,Yin G,Yuan Y.Bayesian data augmentation dose finding with continual reassessment method and delayed toxicity[J].Ann Appl Stat,2013,7(4):1837-2457.
[12]Natarajan L,O'Quigley J.Interval estimates of the probability of toxicity at the maximum tolerated dose for small samples[J].Stat Med,2003,22(11):1829-1836.
[13]Asakawa T,Hirakawa A,Hamada C.Bayesian model averaging continual reassessment method for bivariate binary efficacy and toxicity outcomes in phaseⅠoncology trials[J].J Biopharm Stat,2014,24(2):310-325.
[14]Daimon T,Zohar S,O'Quigley J.Posterior maximization and averaging for Bayesian working model choice in the continual reassessment method[J].Stat Med,2011,30(13):1563-1573.
[15]Normolle D,Lawrence T.Designing dose-escalation trials with late-onset toxicities using the time-to-event continual reassessment method[J].J Clin Oncol,2006,24(27):4426-4433.
[16]Cheung YK,Chappell R.Sequential designs for phaseⅠclinical trials with late-onset toxicities[J].Biometrics,2000,56(4):1177-1182.
[17]Yin G,Zheng S,Xu J.Fractional dose-finding methods with late-onset toxicity in phaseⅠclinical trials[J].J Biopharm Stat,2013,23(4):856-870.
[18]Yap C,Billingham LJ,Cheung YK,et al.Dose transition pathways:the missing link between complex dose-finding designs and simple decision-making[J].Clin Cancer Res,2017,23(24):7440-7447.
[19]Wages NA,Petroni GR.A web tool for designing and conducting phaseⅠtrials using the continual reassessment method[J].BMC Cancer,2018,18(1):133.