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

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

This research will primarily benefit the UK lay and professional cystic fibrosis (CF) community. It will also demonstrate to the wider clinical and scientific community the potential opportunities for pragmatic clinical trials involving disease Registries in a digital health era, in design, efficient delivery and conduct.
Simplifying treatment burden has been identified as the top priority for clinical research in CF by the lay and professional CF community (1). My research will develop and evaluate a Registry-based clinical trials infrastructure able to answer important research questions relating to simplifying the burden of treatment in CF. Hosted by my Project Partner the CF Trust, the CF Registry includes data from over 99% of people with CF in the UK.
This research will enable clinical trials aimed at reducing treatment burden to be conducted alongside routine NHS CF care and data collection, by embedding them in the CF Registry. It will provide a legacy resource for the CF community, capable of hosting multiple randomised trials. For the Project Partner, the research will also contribute to improved data quality and opportunities for automatic data entry to the CF Registry from electronic health records, in addition to the potential for researchers to conduct more efficient and un-burdensome clinical trials for the benefit of the UK CF patient community it represents. This research will be conducted with meaningful input from people with CF and relevant stakeholders at all stages of development, to maximise its relevance and impact for the CF patient community, health professionals in the NHS, and regulatory authorities.
It will allow an evidence-based approach to de-escalation of existing treatments in a rapidly evolving era of highly effective new medicines for CF, to determine which existing treatments may be able to be stopped safely. At present, people with CF typically are prescribed 10 different daily treatments taking 1-2 hours per day even when clinically stable (2). New medicines (called 'highly effective CFTR modulators') may mean that some existing treatments can stop. Evidence from future clinical trials using the trials infrastructure developed in this research may support stopping a specified medicine for a particular group of patients (e.g. according to their disease severity and combination of treatments). This will impact on the clinical care of people with CF in the UK and beyond. For example, if a particular nebulised treatment could be withdrawn without adversely affecting health, the impact for an individual may include reduced side effects, improved quality of life, and a reduction in treatment burden through time benefits associated with no longer needing to collect nebuliser prescriptions, cleaning equipment, and treatment administration. This would also result in cost savings for the NHS.
The outputs of research to understand whether designs other than the traditional randomised controlled trial, particularly for non-blinded clinical trials, are appropriate and acceptable to the CF community and their health care teams will be important for the CF community but also highly relevant to the potential to improve patient outcomes in other long term conditions. Another important impact translatable to other long term conditions will be to demonstrate progress relating to direct import of routinely collected NHS data to the Registry e.g. relating to current medications, lung function measurements or laboratory results. This research will investigate how these processes can make clinical trials more efficient and less burdensome for health professionals in the NHS in order that such trials can become integrated into the routine delivery of care. These processes are likely to be of great interest to local and national stakeholders, other researchers, and Health Data Research-UK.
1) Rowbotham NJ et al, Thorax 2018;73:388-90
2) Davies G et al, Journal of Cystic Fibrosis 2019 (in press)