Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
Department of Neurosciences, University of California, La Jolla, CA, USA.
Nat Commun. 2024 Nov 12;15(1):9802. doi: 10.1038/s41467-024-54077-5.
Individualized genetic therapies-medicines that precisely target a genetic variant that may only be found in a small number of individuals, as few as only one-offer promise for addressing unmet needs in genetic disease, but present unique challenges for trial design. By nature these new individualized medicines require testing in individualized N-of-1 trials. Here, we provide a framework for maintaining scientific rigor in N-of-1 trials. Building upon best practices from traditional clinical trial design, recent guidance from the United States Food and Drug Administration, and our own clinical research experience, we suggest key considerations including comprehensive baseline natural history, selection of appropriate clinical outcome assessments (COAs) individualized to the patient genotype-phenotype for safety and efficacy assessment over time, and specific statistical considerations. Standardization of N-of-1 trial designs in this fashion will maximize efficient learning from this next generation of targeted individualized therapeutics.
个体化基因治疗——针对可能仅存在于少数个体中的特定基因突变的精准药物，仅为一个体提供了满足遗传疾病未满足需求的可能，但是为试验设计带来了独特的挑战。这些新型个体化药物本质上需要在个体化的 N-of-1 试验中进行测试。在这里，我们提供了一个在 N-of-1 试验中保持科学严谨性的框架。在借鉴传统临床试验设计最佳实践、美国食品和药物管理局（FDA）最近的指导意见以及我们自己的临床研究经验的基础上，我们提出了一些关键的考虑因素，包括全面的基线自然病史、选择针对患者基因型-表型的适当临床结局评估（COAs），以进行安全性和有效性评估，以及特定的统计学考虑因素。以这种方式标准化 N-of-1 试验设计，将最大限度地从下一代靶向个体化治疗中获得高效的学习。
