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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., Competing Interests: Declaration of Competing Interest JCD has performed clinical trial leadership roles, educational and/ or advisory activities for the following: Abbvie, Algipharma AS, Bayer AG, Boehringer Ingelheim Pharma GmbH & Co. KG, Eloxx, Enterprise, Galapagos NV, Genentech, ImevaX GmbH, Ionis, LifeArc, Nivalis Therapeutics, Inc., Krystal Biotech, Novartis, PARI Medical Holding GmbH, ProQR Therapeutics III B.V., Proteostasis Therapeutics INC., Pulmocide, Raptor Pharmaceuticals Inc, Recode, Vertex Pharmaceuticals. JSE has provided consultancy and advice for Vertex, Celtaxsys, Corbus, Ionis in clinical trial design and delivery. He also holds an EU Innovative medicines Initiative grant with Novartis, Polyphor and Alaxia. MB, RD, FK and SM have no conflicts to declare., (Copyright © 2023. Published by Elsevier B.V.)

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., Competing Interests: Declaration of Competing Interest RD, SP, AJ and SM have no conflicts to declare. NJS has received fees for consultancy and speaking from Vertex, Chiesi, Gilead, Roche, Teva, Zambon, and Pulmocide. JCD has performed clinical trial leadership roles, educational and/ or advisory activities for the following: Abbvie, Algipharma AS, Bayer AG, Boehringer Ingelheim Pharma GmbH & Co. KG, Eloxx, Enterprise, Galapagos NV, Genentech, ImevaX GmbH, Ionis, LifeArc, Nivalis Therapeutics, Inc., Krystal Biotech, Novartis, PARI Medical Holding GmbH, ProQR Therapeutics III B.V., Proteostasis Therapeutics INC., Pulmocide, Raptor Pharmaceuticals Inc, Recode, Vertex Pharmaceuticals., (Copyright © 2023. Published by Elsevier B.V.)

Background: Making trials more patient-centred improves recruitment and retention, patient satisfaction and makes research accessible to a more representative population. We aimed to understand the factors that influence participation and engagement in clinical trials in cystic fibrosis (CF) trials to guide the rational design and delivery of patient-centred trials., Methods: We used a Delphi process, supported by extensive literature review and 3 workshops, to determine which factors stakeholders think exert significant influence in participation and engagement in CF trials. Panellists were recruited from across the UK and the study was administered online., Results: We had representation from 19 CF centres; 28 people with CF (pwCF), 26 parents and 30 healthcare professionals (HCPs). Panels were presented with a shortlist of 104 factors and asked which they thought influence participation and engagement in CF trials. After 3 iterations, 43 statements met consensus for pwCF, 48 for the parents and 69 for the HCPs., Conclusions: We identified many targets to make trials more patient-centred. Whilst some require an overhaul of trial delivery, many are relatively easy to implement. We outline a list of 'dos and don'ts' for sponsors and research teams including: focus on good communication; recognise that lack of time is the greatest barrier to trial participation so minimise the frequency and length of visits; help participants fit trials around busy lives; remember trial participation can be a major life-event and support participants accordingly; and don't underestimate the impact of simple strategies e.g. on-site access to Wifi and cups of tea., Competing Interests: Declaration of Competing Interest RD, LA, MB, SG, FK, SM, TP and CS have no conflicts to declare. JSE has provided consultancy and advice for Vertex, Celtaxsys, Corbus, Ionis in clinical trial design and delivery. He also holds an EU Innovative medicines Initiative grant with Novartis, Polyphor and Alaxia JCD has served on advisory boards and participated in clinical trial leadership, educational activities and grant review board activities for a number of pharma companies active in CF clinical trials: Vertex, PTI, Galapagos, AbbVie, AlgiPharma, Chiesi, Enterprise, Teva, Ionis, Eloxx, Roche, Gilead., (Copyright © 2021. Published by Elsevier B.V.)

Background: Trial participation can allow people with CF early access to CFTR modulator therapies, with high potential for clinical benefit. Therefore, the number of people wishing to participate can substantially exceed the number of slots available. We aimed to understand how the CF community thinks slots to competitive trials should be allocated across the UK and whether this should be driven by clinical need, patients' engagement/adherence or be random. For the latter, we explored site-level versus registry-based, national randomisation processes., Methods: We developed an online survey, recruiting UK-based stakeholders through social media, newsletters and personal contacts. Closed questions were analysed for frequencies and percentages of responses. Free-text questions were analysed using thematic analysis., Results: We received 203 eligible responses. Overall, 75% of stakeholders favoured allocation of slots to individual sites based on patient population size, although pharma favoured allocation based on previous metrics. Currently, few centres have defined strategies for allocating slots locally. At face-value, stakeholders believe all eligible participants should have an equal chance of getting a slot. However, further questioning reveals preference for prioritisation strategies, primarily perceived treatment adherence, although healthcare professionals were less likely to favour this strategy than other stakeholder groups. The majority of stakeholders would prefer to allocate slots and participate in trials locally but 80% said if necessary, they would engage in a system of national allocation., Conclusions: Fair allocation to highly competitive trials does not appear to have a universally acceptable solution. Therefore, transparency and empathy remain critical to negotiate this uncertain territory., Competing Interests: Declaration of Competing Interest RD, KP, LA, RB and KB have no conflicts to declare. GD reports personal fees from Chiesi Limited, outside the submitted work. SC reports personal fees from Chiesi Pharmaceuticals, personal fees and non-financial support from Vertex, personal fees from Zambon and personal fees from Insmed, outside the submitted work. NJS has participated in advisory boards for Vertex, Chiesi, Pulmocide and Roche. He has received payments for speaking engagements from Vertex, Gilead, Chiesi, Teva and Zambon. JCD has served on advisory boards and participated in clinical trial leadership, educational activities and grant review board activities for a number of pharma companies active in CF clinical trials: Vertex, PTI, Galapagos, AbbVie, AlgiPharma, Chiesi, Enterprise, Teva, Ionis, Eloxx, Roche, Gilead., (Copyright © 2021. Published by Elsevier B.V.)

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., (© 2020 The Authors. Pediatric Pulmonology Published by Wiley Periodicals LLC.)

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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Cystic fibrosis is the most common inherited condition in the Caucasian population and is associated with significantly reduced life expectancy. Recent advances in treatment have focussed on addressing the underlying cause of the condition, the defective production, expression and function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Several drugs with different modes of action have produced promising results in clinical trials, and some have been incorporated into routine clinical care for specific patients in many countries worldwide. Further trials continue to explore the safety and efficacy of these drugs in the youngest age groups and to search for more effective therapies to treat the most common disease-causing gene mutations in an ever-expanding drug pipeline. As evidence mounts for the early onset of disease in young patients, the prospect of introducing disease-modifying therapy in early life becomes more pertinent, although the cost implications of these expensive drugs are significant. In this review, we summarise these new therapy advances and review those currently being explored in clinical trials.

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., (Copyright © 2017. Published by Elsevier Ltd.)