Hierarchical nested trial design (HNTD) for demonstrating treatment efficacy of new antibacterial drugs in patient populations with emerging bacterial resistance
Hierarchical nested trial design (HNTD) for demonstrating treatment efficacy of new antibacterial drugs in patient populations with emerging bacterial resistance
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DOI：
10.1002/sim.6233
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发表时间：
2014-11-09
影响因子：
2
通讯作者：
Soon, Guoxing (Greg)
中科院分区：
文献类型：
--
作者：
Huque, Mohammad F.;Valappil, Thamban;Soon, Guoxing (Greg)
在过去十年左右的时间里，用于治疗严重细菌性疾病的新型抗菌药物领域的制药药物开发活动有所下降，同时，人们担心耐药性细菌感染的患病率增加，特别是耐药性革兰氏阴性菌感染的增加，限制了可用的治疗选择。美国疾病控制和预防中心最近的一份报告《美国的抗生素耐药性威胁》表明，抗生素耐药性是我们最严重的健康威胁之一。然而，最近有新的想法被提出来改变这种情况。在这方面提出的一个想法是进行随机临床试验，其中一些患者，根据诊断测试，可能显示存在对对照治疗耐药的细菌病原体，而其余患者将显示对对照敏感的病原体。此类试验中的对照治疗可以是标准护理或批准用于该疾病的最佳可用疗法。如果对照组中耐药病原体患者的临床体征和症状恶化，则可以选择补救治疗。此类患者人群的统计学建议是使用分层非劣效性-优效性嵌套试验设计，该设计提供信息，并允许对两个亚群进行治疗与对照比较，而不会产生任何统计学惩罚。这种设计可以在同一试验中实现双重目标：（i）根据非劣效性检验，证明新药对易感病原体患者有效，（ii）证明新药在耐药病原体患者中上级对照药物。本文讨论了实现这两个目标的统计考虑和方法，为这个设计。2014年出版。本条目属于美国政府作品，在美国属于公有领域。
In the last decade or so, pharmaceutical drug development activities in the area of new antibacterial drugs for treating serious bacterial diseases have declined, and at the same time, there are worries that the increased prevalence of antibiotic-resistant bacterial infections, especially the increase in drug-resistant Gram-negative infections, limits available treatment options . A recent CDC report, Antibiotic Resistance Threats in the United States', indicates that antimicrobial resistance is one of our most serious health threats. However, recently, new ideas have been proposed to change this situation. An idea proposed in this regard is to conduct randomized clinical trials in which some patients, on the basis of a diagnostic test, may show presence of bacterial pathogens that are resistant to the control treatment, whereas remaining patients would show pathogens that are susceptible to the control. The control treatment in such trials can be the standard of care or the best available therapy approved for the disease. Patients in the control arm with resistant pathogens can have the option for rescue therapies if their clinical signs and symptoms worsen. A statistical proposal for such patient populations is to use a hierarchical noninferiority-superiority nested trial design that is informative and allows for treatment-to-control comparisons for the two subpopulations without any statistical penalty. This design can achieve in the same trial dual objectives: (i) to show that the new drug is effective for patients with susceptible pathogens on the basis of a noninferiority test and (ii) to show that it is superior to the control in patients with resistant pathogens. This paper addresses statistical considerations and methods for achieving these two objectives for this design. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.