Creating a disease-agnostic scalable platform for decentralized observational and validation of digital biomarkers studies and piloting it for people with familial ALS and ultra-rare MNDs

项目摘要 生物医学科学面临的最大挑战之一是开发从根本上更好的治疗方法 治疗神经退行性疾病自然历史研究（NHS）是至关重要的，以提高我们的理解， 疾病，找到外部匹配对照，识别患有罕见和超罕见疾病的人，以及 将其纳入临床研究生态系统。 ALS和其他神经退行性疾病的异质性使疾病进展的预测复杂化 和潜在疗法的开发，使临床试验具有挑战性。预后的不确定性是 这对ALS患者及其家人来说是一个巨大的负担。实施更好的模式，以确定和征聘 患有极罕见疾病的人，如具有已知基因突变的ALS或PLS，是至关重要的。 NHS在超罕见疾病中的“传统”模式并不有效，因为参与NHS研究的网站 首先被选中，而生活在这些条件下的人可能不会去预选诊所。 虽然食品和药物管理局鼓励使用方法和技术，以尽量减少 患者的试验负担，限制前往研究中心的需要，并对探索数字化的实用性持开放态度。 生物标志物作为临床终点，实施分散的临床研究等方法， 基线时和试验期间间隔时的终点指标，在中心以标准化方式进行 测试设施、对某些访问的远程监测等没有得到广泛利用。 我们提出了一个去中心化的NHS行为模型，其中我们实施了一个疾病不可知论者- 以NeuroPRO™为中心的平台，用于招募和电子知情同意研究参与者，诊断确认，以及 基线数据采集。该平台将用于： ·利用数字生物标志物和定期的家庭或医疗服务， 最近的临床中心访问。 ·实施混合型国民保健制度，在这种制度中，以人为本的平台既可以作为平等伙伴， “传统”NHS（ALS/MND自然史研究），或作为参与者识别和招募工具， 虽然临床结果仍在临床访视期间进行测量，或者也作为优化工具， 根据招募参与者的地理分布选择参与地点（PLS Natural 历史研究）。 ·提供符合法规的环境，以快速同时验证数字生物标志物， 广泛使用的成果。 这些研究的数据将被匿名化，并与医学研究界共享。

PROJECT SUMMARY One of the greatest challenges facing biomedical sciences is the development of fundamentally better treatments for neurodegenerative diseases. Natural History studies (NHS) are critical to enhance our understanding of the disease, find external matching controls, identify people living with rare and ultra-rare forms of the diseases, and bring them into clinical research ecosystem. The heterogeneity of ALS and other neurodegenerative diseases complicates predictions of disease progression and development of potential therapies, making clinical trials challenging. Uncertainty surrounding prognosis is an enormous burden for people with ALS and their families. Implementing better models to identify and recruit people living with ultra-rare forms of diseases like ALS with known genetic mutations or PLS is essential. “Traditional” models of NHS in ultra-rare diseases are not effective, as participating in NHS research sites are being selected first, while people living with those conditions may not be attending the preselected clinics. While the Food and Drug Administration encourages the use of approaches and technologies to minimize the burden of trials on patients and limit the need for travel to study sites and is open to exploring the utility of digital biomarkers as clinical endpoints, implementation of such methods as decentralized clinical research with key endpoint measures at baseline and at intervals during the trial conducted in a standardized fashion at central testing facilities, remote monitoring for some of the visits, etc. are not utilized broadly.. We propose a decentralized model for the NHS conduct, in which we implement a disease-agnostic people- centric Platform, NeuroPRO™, for recruitment and e-consent study participants, diagnosis confirmation, and baseline data acquisition. This Platform will be used to: • Conduct a stand-alone decentralized longitudinal NHS utilizing digital biomarkers and periodic home or nearest clinical hubs visits. • Conduct a hybrid NHS, in which this people-centric platform may serve either as an equal partner to a “traditional” NHS (ALS/MND Natural History Study), or as participants identification and recruitment tool, while clinical outcomes are still being measured during clinical visits, or as also an optimization tool for participating sites selection based on geographical distribution of recruited participants (PLS Natural History Study). • Provide regulatory compliant environment for rapid simultaneous validation of digital biomarkers against widely utilized outcomes. The data from the studies will be anonymized and shared with the medical research community.