Background: Natural history (NH) studies, using observational methods, are common in rare and orphan diseases (80% of which have a genetic component). There is profound interest in identifying genetic mutations driving these diseases in these studies to support the formulation of targeted precision medicines. The global regulatory classification of NH studies with novel molecular biomarker collection has not been clearly delineated, presenting researchers with the challenge of determining how these studies are classified and regulated across multiple geographies. Objective: The aim of this investigation was to conduct a review of regulations related to NH studies and genetic testing to elucidate regulatory pathways to inform clinical researchers in the field. Methods: Regulatory provisions for NH studies and genetic testing were obtained from Pharmaceutical Product Development (PPD)’s propriety regulatory intelligence database and by surveying the company’s country-specific regulatory experts. A literature search was conducted in the Google Scholar search engine and PubMed for supplementary information. Results: Nineteen countries were evaluated; 37% classified NH studies with biomarker collection as noninterventional and 26% required regulatory approval (increasing to 47% when molecular biomarker testing was introduced). No regulatory provisions for genetic testing could be identified in 32% of countries, and 58% did not have binding requirements for genetic counseling. Conclusion: Lack of harmonization of regulations governing NH studies with molecular biomarker collection contributes to the operational complexity of conducting multinational studies in orphan and rare diseases. A set of harmonized international guidelines for these studies would improve efficiency, and this may be on the horizon with the recent adaption of International Conference on Harmonisation (ICH) guideline E18.
Public Health Genomics

中文翻译：

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自然历史研究中的基因检测：监管和法律环境回顾


背景：使用观察方法的自然史 (NH) 研究在罕见疾病和孤儿疾病（其中 80% 具有遗传成分）中很常见。在这些研究中，人们对识别导致这些疾病的基因突变有浓厚的兴趣，以支持靶向精准药物的制定。具有新型分子生物标志物收集的 NH 研究的全球监管分类尚未明确界定，这给研究人员带来了确定如何在多个地区对这些研究进行分类和监管的挑战。目的：本次调查的目的是对 NH 研究和基因检测相关法规进行审查，以阐明监管途径，为该领域的临床研究人员提供信息。方法： NH 研究和基因检测的监管规定是通过药品开发 (PPD) 的专有监管情报数据库以及对该公司特定国家监管专家的调查获得的。在 Google Scholar 搜索引擎和 PubMed 中进行文献检索以获取补充信息。结果：对 19 个国家进行了评估； 37% 将收集生物标志物的 NH 研究归类为非干预性研究，26% 需要监管部门批准（引入分子生物标志物测试后，这一比例增加至 47%）。 32% 的国家没有针对基因检测的监管规定，58% 的国家没有对遗传咨询提出约束性要求。 结论： NH 研究与分子生物标志物收集的监管法规缺乏统一，导致孤儿和罕见疾病跨国研究的操作复杂性。为这些研究制定一套统一的国际指南将提高效率，随着国际协调会议 (ICH) 指南 E18 最近的调整，这可能即将到来。
 公共卫生基因组学