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

囊性纤维化是一种遗传性的缩短寿命的疾病，在英国大约有10,000人受到影响(1)。在肺部，粘稠的分泌物和慢性感染会导致健康状况的逐渐恶化。慢性纤维性心脏病患者每天接受多项治疗(即使病情良好，每天也要花费1-2个小时)，简化治疗负担被CF社区选为最优先的研究项目(2)。针对CF的潜在原因的新治疗方法现在可以显著改变CF患者的健康状况和前景，但到目前为止的临床试验已经通过将这些新药添加到现有治疗中对它们进行了评估。这可能意味着现有的一些繁重的治疗方法(如雾化疗法)不再必要。需要有效的、无负担的临床试验来为减轻治疗负担提供证据。评估这一点的一个潜在的“实用”平台涉及英国CF注册处，其中包括从超过99%的英国CF人口那里定期收集的数据(1)。2016年，它开始了第一个针对患有CF的婴儿的随机注册临床试验，证明了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年人的机会。在本奖学金中，我将开发一个临床试验注册平台，该平台可以解决与简化CF治疗负担有关的问题，作为其他慢性病的典范。将探索可能比传统方法更合适的新临床试验设计，重点是使用常规收集的与患者相关的数据和结果的试验，并将寻求对这些方法的通俗和专业观点。这将包括与知情同意和确定符合条件的试验参与者有关的考虑因素，以及在常规护理期间或需要额外数据收集期间获得的结果(例如，患者报告的治疗负担衡量标准)。结果将通知注册中心的开发工作创建模块，这些模块将‘固定’到英国CF注册中心现有的基于网络的基础设施上，以创建一个能够托管多个随机临床试验的平台。在我的研究期间，我将调查登记和电子患者记录之间的接口，涉及这些类型的临床试验的试验数据库和监管要求。在地方一级，在大奥蒙德街医院(GOSH)的信息基础设施及其数字研究环境方面进行了大量投资，这使得复杂的数据研究成为可能。GOSH CF诊所人口约200名儿童和年轻人，这将允许进一步调查注册试验如何与电子健康记录和来自多个来源的数据集成。在国家层面，我将领导两项CF注册可行性研究，以确定这项研究是否将使运行临床试验以简化治疗负担的效率、可接受性和更低成本变得高效、可接受和更低成本。这些研究将评估在NHS CF护理中心、同意程序和登记能力内运行试验的可行性，以确定患者资格、患者招募和结果数据收集(患者报告和安全性)。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和创新未来领导者研究员努力转变研究员领导的CF临床试验格局的过程中发展新的联系。大奥蒙德街儿童健康研究所内的卓越研究环境将是本次研讨会的绝佳东道主。参考：(1)英国CF注册中心2018年年度数据报告，囊性纤维化信托基金(2019年8月发布)(2)Rowbotham N等人。《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