Designing and enabling pragmatic clinical trials in cystic fibrosis to simplify the burden of treatment

囊性纤维化（CF）是一种遗传性、缩短寿命的疾病，在英国约有1万人受到影响(1)。在肺部，粘稠的分泌物和慢性感染导致健康状况逐渐恶化。CF患者每天接受多种治疗（即使“健康”，每天也要接受1-2小时的治疗），简化治疗负担被CF社区评为最高的研究优先事项(2)。针对CF的潜在病因的新治疗方法现在可以显着改变CF患者的健康状况和前景，但迄今为止的临床试验通过将这些新药添加到现有治疗中来评估这些新药。这可能意味着一些现有的繁重治疗（如雾化治疗）不再必要。需要有效的无负担的临床试验来提供证据以减轻治疗负担。评估这一点的一个潜在的“务实”平台涉及英国CF登记处，其中包括从99%以上的英国CF人群中常规收集的数据(1)。2016年，该公司启动了首个CF婴儿随机注册临床试验，证明CF注册试验是可行的，但尚未评估年龄较大的儿童和患有既定疾病的成人的机会。在这项研究中，我将开发一个临床试验注册平台，可以解决与简化CF治疗负担有关的问题，作为其他慢性疾病的范例。将探索可能比传统方法更合适的新的临床试验设计，重点是使用常规收集的数据和与患者相关的结果的试验，并将寻求这些方法的外行和专业观点。这将包括与知情同意和确定合格试验参与者有关的考虑，以及在常规护理期间捕获的结果或需要额外捕获的数据（例如，患者报告的治疗负担措施）。结果将告知注册中心的开发工作，以创建模块，这些模块将“连接”到英国CF注册中心现有的基于网络的基础设施上，以创建一个能够承载多个随机临床试验的平台。在我的奖学金期间，我将调查登记处和电子病历之间的接口，涉及试验数据库和这些类型的临床试验的监管要求。在地方一级，对大奥蒙德街医院（GOSH）的信息基础设施及其数字研究环境进行了大量投资，以便进行复杂的数据研究。GOSH CF诊所约有200名儿童和年轻人，将允许进一步调查注册试验如何与来自多个来源的电子健康记录和数据整合相互作用。在国家层面上，我将领导两项CF Registry可行性研究，以确定该研究是否能够有效、可接受且成本更低地进行临床试验，以简化治疗负担，并根据上述产出进行设计。这些研究将评估在NHS CF护理中心进行试验的可行性、同意程序和注册中心识别患者资格、患者招募和结果数据收集（患者报告和安全性）的能力。这些结果将有助于为英国CF社区计划大型随机对照试验。我期待着与现有的国内和国际合作者合作，并在我作为英国研究与创新未来领袖研究员努力改变研究者主导的CF临床试验格局的过程中建立新的联系。大奥蒙德街儿童健康研究所的卓越研究环境将是这项研究金的绝佳东道主。参考文献：(1)英国CF登记处2018年年度数据报告，囊性纤维化信托基金（2019年8月出版）(2)Rowbotham N等。胸腔2018;73:388-9

Cystic fibrosis (CF) is an inherited, life-shortening disease affecting around 10,000 people in the UK (1). In the lungs, thick sticky secretions and chronic infection lead to a progressive deterioration in health. People with CF take multiple treatments on a daily basis (taking a total of 1-2 hours per day even when 'well') and simplifying the treatment burden was voted the highest research priority by the CF community (2). New treatments for CF which target the underlying cause of the disease can now significantly change the health profile and outlook for people with CF, but clinical trials to date have evaluated these new drugs by adding them to existing treatments. This may mean that some existing burdensome treatments (such as nebulised therapies) are no longer necessary. Efficient non-burdensome clinical trials are needed to provide evidence to reduce treatment burden. A potential 'pragmatic' platform to evaluate this involves the UK CF Registry, which includes routinely collected data from over 99% of the UK CF population (1). In 2016 it embarked on the first randomised Registry clinical trial in infants with CF, demonstrating that a CF Registry trial is feasible but opportunities in older children and adults with established disease have not been evaluated.In this Fellowship I will develop a Registry platform for clinical trials that can address questions relating to simplifying treatment burden in CF, as an exemplar for other chronic diseases. New clinical trial designs will be explored that may be more appropriate than traditional approaches, with an emphasis on trials that use routinely collected data and outcomes relevant to patients, and lay and professional perspectives on these approaches will be sought. This will include considerations relating to informed consent and identification of eligible trial participants, as well as outcomes captured during routine care or requiring additional data capture (e.g. patient reported measures of treatment burden). Results will inform Registry development work to create modules that will 'bolt on' to the existing web-based infrastructure of the UK CF Registry, to create a platform capable of hosting multiple randomised clinical trials. During my Fellowship I will investigate the interfaces between Registries and electronic patient records in relation to trial databases and regulatory requirements for these types of clinical trials. At a local level, there has been a significant investment in the informatics infrastructure at Great Ormond Street Hospital (GOSH) and its Digital Research Environment, which allow sophisticated data research. A GOSH CF clinic population of around 200 children and young people will allow further investigation of how Registry trials may interact with electronic health records and data integration from multiple sources.At a national level, I will lead two CF Registry feasibility studies to determine whether this research would make it efficient, acceptable and less costly to run clinical trials to simplify treatment burden, designed according to outputs from the above. These studies will assess the feasibility of running the trials within NHS CF centres of care, consent processes, and Registry capability for identifying patient eligibility, patient recruitment, and outcome data collection (patient reported and safety). These results will help plan large randomised controlled trials, for the UK CF community. I look forward to working with existing national and international collaborators, and to developing new links as I work towards transforming the investigator-led CF clinical trials landscape as a UK Research and Innovation Future Leaders Fellow. The research excellence environment within the Great Ormond Street Institute of Child Health will be an excellent host for this Fellowship.References:(1) UK CF Registry Annual Data Report 2018, Cystic Fibrosis Trust (published Aug 2019)(2) Rowbotham N et al. Thorax 2018;73:388-9