"Fortunate are those who take the first steps"? The psychosocial impact of novel drug development.

Novel drug development offers people with cystic fibrosis exciting opportunities but is not without challenges. Currently, there is an understandable emphasis on protecting patients' physical health when developing treatments. However, there appears to be little consideration of how novel drug development impacts on psychosocial wellbeing, or the downstream consequences of this. Using an illustrative case and reviewing the literature we explore themes regarding the psychosocial impact of trial participation and novel drug development and identify areas requiring further research. Through this, we hope to prepare healthcare professionals to better understand the needs of their patients in this rapidly evolving landscape.

Disease-modifying drug therapy in cystic fibrosis.

Whilst substantial progress has been made in the treatment of cystic fibrosis, the disease still carries a significant burden in terms of symptoms, requirement for treatment and early mortality. The last decade has witnessed a new era in the development of small molecule drugs targeting the CFTR protein, which for the first time may provide a truly disease-modifying approach to treatment. This article reviews progress and highlights some of the current and future challenges in CFTR modulator therapies.

A discrete choice experiment to quantify the influence of trial features on the decision to participate in cystic fibrosis trials.

BACKGROUND: Patient-centred trial design optimises recruitment and retention, reduces trial failure rates and increases the diversity of trial cohorts. This allows safe and effective treatments to reach clinic more quickly. To achieve this, patients' views must be incorporated into trial design. METHODS: A discrete choice experiment was used to quantify preferences of pwCF for trials features; medicine type, trial location, stipend, washout, drug access on trial completion and trial design. Respondents were presented pairs of hypothetical trial scenarios with different level combinations assigned through experimental design. Respondents were asked to pick their preferred option or decline both. The cross-sectional data were explored using a Random Parameters Logit model. RESULTS: We received 207 eligible responses between Oct2020-Jan2021. The strongest influence on the decision to participate was trial location; pwCF favour participation at their usual clinical centre. Greater travel distances made respondents less willing to participate. Post-trial drug access ranked second. pwCF would rather participate in modulator trials than trials of other drugs. In general, pwCF did not favour a washout period, but were more prepared to washout non-modulators than modulators. Stipend provision was not ranked highly, but higher stipends increased intention to participate. Trial design (placebo vs open-label) had minimal influence on the decision to participate. There are complex interactions between placebos and washouts. CONCLUSIONS: We used quantitative methods to systematically elicit preferences of pwCF for clinical trials' features. We explore the relevance of our findings to trial design and delivery in the current CF trials landscape.

How representative are clinical trial cohorts of the general CF population? Implications for trial planning.

Understanding the number of patients eligible to participate in research is important to design protocols and define research priorities. We reviewed the records of all patients with CF, age 12+, who receive care at our centre. We assessed their eligibility for trial participation based on common trial inclusion/exclusion criteria. 643 patients were included in the analysis, 31 were modulator ineligible(MI). Only 198(31 %) of the total cohort and 7(23 %) of the MI cohort were eligible for participation based on the hypothetical criteria. The most common reason for ineligibility was ppFEV1 ≥90 % followed by clinical instability, complex comorbidity and anticipated inability to adhere to the protocol. We suggest this would be a useful exercise for centres planning to either participate in, or refer subjects into, upcoming trials to undertake for their own cohort. We also make suggestions for protocol designs that optimise the number of patients who are eligible to participate.

Levelling the playing field through the London Network of the UK clinical trials accelerator platform.

Cystic fibrosis (CF) is a multisystem, genetic disease with a significantly reduced life expectancy. Despite substantial progress in therapies in the last 10-15 years, there is still no cure. There are dozens of drugs in the development pipeline and multiple clinical trials are being conducted across the globe. The UK Cystic Fibrosis Trust's (CFT) Clinical Trials Accelerator Platform (CTAP) is a national initiative bringing together 25 UK based CF centres to support the CF community in accessing and participating in CF clinical trials. CTAP enables more CF centres to run a broader portfolio of trials and increases the range of CF studies available for UK patients. There are four large specialist CF centres based in London, all within a small geographical region as well as two smaller centres which deliver CF care. At the launch of CTAP, these centres formed a sub-network in a consortium-style collaboration. The purpose of the network was to ensure equity of access to trials for patients across the UK's capital, and to share experience and knowledge. Four years into the programme we have reviewed our practices through working group meetings and an online survey. We sought to identify strengths and areas for improvement. We share our findings here, as we believe they are relevant to others delivering research in regions outside of London and in other chronic diseases.

A systematic review to identify and collate factors influencing patient journeys through clinical trials.

Patient-centred trial design and delivery; improves recruitment and retention; increases participant satisfaction; encourages participation by a more representative cohort; and allows researchers to better meet participants' needs. Research in this area mostly focusses on narrow facets of trial participation. We aimed to systematically identify the breadth of patient-centred factors influencing participation and engagement in trials, and collate them into a framework. Through this we hoped to assist researchers to identify factors that could improve patient-centred trial design and delivery. Robust qualitative and mixed methods systematic reviews are becoming increasingly common in health research. The protocol for this review was prospectively registered on PROSPERO, CRD42020184886. We used the SPIDER (Sample, Phenomenon of Interest, Design, Evaluation, Research Type) framework as a standardised systematic search strategy tool. 3 databases were searched as well as references checking, and thematic synthesis was conducted. Screening agreement was performed and code and theme checking were conducted by 2 independent researchers. Data were drawn from 285 peer-reviewed articles. 300 discrete factors were identified, and sorted into 13 themes and subthemes. The full catalogue of factors is included in the Supplementary Material. A summary framework is included in the body of the article. This paper focusses on outlining common ground that themes share, highlighting critical features, and exploring interesting points from the data. Through this, we hope researchers from multiple specialities may be better able to meet patients' needs, protect patients' psychosocial wellbeing, and optimise trial recruitment and retention, with direct positive impact on research time and cost efficiency.

Going the Extra Mile: Why Clinical Research in Cystic Fibrosis Must Include Children.

This is an exciting time for research and novel drug development in cystic fibrosis. However, rarely has the adage, "Children are not just little adults" been more relevant. This article is divided into two main sections. In the first, we explore why it is important to involve children in research. We discuss the potential benefits of understanding a disease and its treatment in children, and we highlight that children have the same legal and ethical right to evidence-based therapy as adults. Additionally, we discuss why extrapolation from adults may be inappropriate, for example, medication pharmacokinetics may be different in children, and there may be unpredictable adverse effects. In the second part, we discuss how to involve children and their families in research. We outline the importance and the complexities of selecting appropriate outcome measures, and we discuss the role co-design may have in improving the involvement of children. We highlight the importance of appropriate staffing and resourcing, and we outline some of the common challenges and possible solutions, including practical tips on obtaining consent/assent in children and adolescents. We conclude that it is unethical to simply rely on extrapolation from adult studies because research in young children is challenging and that research should be seen as a normal part of the paediatric therapeutic journey.

Discrete choice experiment (DCE) to quantify the influence of trial features on the decision to participate in cystic fibrosis (CF) clinical trials.

INTRODUCTION: Engaging people with cystic fibrosis (CF) in clinical trials is critical to improving outcomes for this fatal disease. Following extensive exploration of engagement in CF trials we believe six key concepts require a quantitative understanding of their influence in the current CF trials landscape including how controversial issues like placebos, washouts, stipend provision and location of trial visits are viewed by the CF community and how these might be modified depending on the type of medicine being investigated and the mechanism of access to the drug on trial completion. METHODS AND ANALYSIS: We have designed and will administer an online discrete choice experiment to elicit and quantify preferences of people with CF for these trials' attributes and estimate the relative importance of an attribute when choosing to participate in a trial. The cross-sectional data generated will be explored using conditional multinomial logit model. Mixed logit models such as the random-parameters logit and a latent class models will be used to explore preference heterogeneity. To determine the relative importance of an attribute, the difference between the attribute level with the highest preference weight and the level with the lowest preference weight will be calculated. ETHICS AND DISSEMINATION: Imperial College London Joint Research Compliance Office has granted ethical approval for this study. Patient consent will be sought following full explanation. No identifying information will be collected. Dissemination will be via international conferences, peer-review publication and patient accessible forums. Major CF trials networks have agreed to incorporate our findings into their review process, meaning our results can realistically influence and optimise CF trial delivery. PROSPERO REGISTRATION NUMBER: CRD42020184886.

Entering the era of highly effective modulator therapies.

Since the discovery of the gene responsible for cystic fibrosis (CF) in 1989, hopes have been pinned on a future with novel therapies tackling the basis of the disease rather than its symptoms. These have become a reality over the last decade with the development through to the clinic of CF transmembrane conductance regulator (CFTR) modulators. These are oral drugs which improve CFTR protein function through either increasing the time the channel pore is open (potentiators) or facilitating its trafficking through the cell to its location on the cell membrane (correctors). The first potentiator, ivacaftor, is now licensed and available clinically in many parts of the world. It is highly effective with impressive clinical impact in the lungs and gastrointestinal tract; longer-term data from patient registries show fewer exacerbations, a slower rate of lung function loss and reduced need for transplantation in patients receiving ivacaftor. However, as a single drug, it is suitable for only a small minority of patients. The commonest CFTR mutation, F508del, requires both correction and potentiation for clinical efficacy. Two dual-agent drugs (lumacaftor/ivacaftor and tezacaftor/ivacaftor) have progressed through to licensing, although their short term impact is more modest than that of ivacaftor; this is likely due to only partial correction of protein misfolding and trafficking. Most recently, triple compounds have been developed: two different corrector molecules (elexacaftor and tezacaftor) which, by addressing different regions in the misfolded F508del protein, more effectively improve trafficking. In addition to large improvements in clinical outcomes in people with two copies of F508del, the combination is sufficiently effective that it works in patients with only one copy of F508del and a second, nonmodulator responsive mutation. For the first time, we thus have a drug suitable for around 85% of people with CF. Even more gains are likely to be possible when these drugs can be used in younger children, although more sensitive outcome measures are needed for this age group. Special consideration is needed for people with very rare mutations; those with nonmodulatable mutation combinations will likely require gene or messenger RNA-based therapeutic approaches, many of which are being explored. Although this progress is hugely to be celebrated, we still have more work to do. The international collaboration between trials networks, pharma, patient organizations, registries, and people with CF is something we are all rightly proud of, but innovative trial design and implementation will be needed if we are to continue to build on this progress and further develop drugs for people with CF.