Abstract：
Here we present as case study how re-randomization tests were performed in two randomized, controlled clinical trials as sensitivity analyses, as recommended by the United States Food and Drug Administration in the context of adaptive randomization. This was done to confirm primary conclusions on immunological noninferiority of an investigational new fully liquid presentation of a quadrivalent cross-reacting material conjugate meningococcal vaccine (MenACWY-CRM), over its licensed lyophilized/liquid presentation. In two phase 2b studies (Study #1: NCT03652610; Study #2: NCT03433482), noninferiority of the fully liquid presentation of MenACWY-CRM to the licensed presentation was assessed and demonstrated for immune responses against meningococcal serogroup A (MenA), the only vaccine component modified from lyophilized to liquid in the new presentation. The original vaccine assignment algorithm, with a minimization procedure accounting for center or center within age strata, was used to re-randomize participants belonging to the fully liquid and licensed vaccine groups while keeping antibody responses, covariates and entry order as observed. Test statistics under re-randomization were generated according to the ANCOVA model used in the primary analysis. To confirm immunological noninferiority following re-randomization, the corresponding p-values had to be <0.025. For both studies and all primary objective evaluations, the re-randomization p-values were well below 0.025 (0.0004 for Study #1; 0.0001 for the two co-primary endpoints in Study #2). Re-randomization tests performed to comply with a regulatory request confirmed the primary conclusions of immunological noninferiority for the MenA of the fully liquid compared to the licensed vaccine presentation.
摘要：
在这里，我们作为案例研究如何在两个随机的，作为敏感性分析的对照临床试验，根据美国食品和药物管理局在适应性随机化方面的建议。这样做是为了确认有关四价交叉反应材料结合脑膜炎球菌疫苗（MenACWY-CRM）的研究性新的完全液体表现的免疫学非劣效性的主要结论，超过其许可的冻干/液体呈递。在两个2b期研究中（研究#1：NCT03652610；研究#2：NCT03433482），对MenACWY-CRM的完全液体呈递与许可呈递的非劣效性进行了评估，并证明了针对脑膜炎球菌血清群A（MenA）的免疫反应，在新的介绍中，唯一的疫苗成分从冻干变成液体。最初的疫苗分配算法，采用最小化程序，考虑年龄阶层内的中心或中心，用于重新随机化属于完全液体和许可疫苗组的参与者，同时保持抗体反应，观察到的协变量和进入顺序。根据主要分析中使用的ANCOVA模型生成再随机化下的检验统计。为了确认重新随机化后的免疫学非劣效性，相应的p值必须<0.025。对于这两项研究和所有主要的客观评价，重随机化p值远低于0.025(研究#1为0.0004;研究#2为两个共同主要终点为0.0001).为符合监管要求而进行的重新随机化测试证实了与许可的疫苗呈递相比，完全液体的MenA的免疫学非劣效性的主要结论。
