Advertisement

Do current clinical trials in cystic fibrosis match the priorities of patients and clinicans? A systematic review

Open ArchivePublished:June 21, 2019DOI:https://doi.org/10.1016/j.jcf.2019.06.005

      Highlights

      • There is a mismatch between the CF community's research priority areas and the topics covered by clinical trials.
      • In particular, gastrointestinal problems and Non-tuberculous mycobacteria are under-represented areas.
      • There are many trials evaluating technology to enhance CF care.

      Abstract

      There are many uncertainties regarding Cystic Fibrosis (CF) treatment. Recently, the first James Lind Alliance (JLA) Priority Setting Partnership (PSP) in CF was completed, bringing clinicians, patients and carers together to identify the Top 10 research priorities. Here we investigate how well the current clinical trials landscape reflects these priorities. Trials in CF were identified through searches of research databases (Pubmed, ANZCTR, EU clinical trials register, ClinicalTrials.gov and ISRCTN). Trials meeting inclusion criteria of registered intervention studies in CF published between 01.012016 and 11.09.2017 were matched to the Top 10 priorities. We identified 259 trials, with 193 fulfilling the inclusion criteria. Only 63 (33%) of these matched one or more of the JLA priorities showing that current clinical trials poorly reflect the JLA Top 10. By increasing awareness of the Top 10 priorities, it is hoped that this will fuel future research in areas important to the CF community.

      Keywords

      Abbreviations:

      JLA (James lind alliance), PSP (Priority setting partnership)

      1. Introduction

      Knowledge of CF genetics has led to the development of many new therapies targeting CFTR dysfunction [
      • Mayer-Hamblett N.
      • Boyle M.
      • Van Devanter D.
      Advancing clinical development pathways for new CFTR modulators in cystic fibrosis.
      ], however currently the majority of treatment for CF is aimed at treating downstream consequences of the CFTR defect. There are still many uncertainties regarding symptomatic CF treatment [
      • Rowbotham N.J.
      • Smith S.
      • Prayle A.P.
      • et al.
      Gaps in the evidence for treatment decisions in cystic fibrosis: a systematic review.
      ]. Conventional therapies for persistent airways infection are still required and yet we do not have definitive evidence to guide the choice of many routine treatments (such as airway clearance). Through undertaking well-designed clinical trials, these treatment uncertainties could be answered.
      Clinical trials should focus on questions which are important to patients and clinicians; however, until now, research agendas have been determined by researchers choosing topics that are of personal interest or of interest to funders such as the Pharmaceutical Industry. The National Institute for Health Research (NIHR) in the UK supports and facilitates patient and public involvement in research [
      • Rowbotham N.J.
      • Smyth A.R.
      The patient voice in research - supporting actor or starring role?.
      ]. The NIHR James Lind Alliance (JLA) [
      • James Lind Alliance
      The James Lind Alliance guidebook version 8.
      ] brings patients, carers and clinicians together in Priority Setting Partnerships (PSP) to agree on a prioritised ‘Top 10’ list of research questions, as a stimulus to future research.
      In January 2017, the first JLA PSP in CF was completed, giving a list of Top 10 research priorities for treatment of CF [
      • Rowbotham N.J.
      • Smith S.
      • Leighton P.A.
      • et al.
      The top 10 research priorities in cystic fibrosis developed by a partnership between people with CF and healthcare providers.
      ]. During the JLA PSP process all priorities were checked to make sure we did not already know the answer using a systematic review identifying evidence gaps in treatment decisions in CF [
      • Rowbotham N.J.
      • Smith S.
      • Prayle A.P.
      • et al.
      Gaps in the evidence for treatment decisions in cystic fibrosis: a systematic review.
      ]. To investigate how well the current clinical trials landscape reflects the JLA Top 10 priorities for CF, we matched current clinical trials in CF to the JLA Top 10 priorities.

      2. Methods

      We carried out a systematic review to identify ongoing trials in CF, following a published study protocol [
      • Kalaitzis I.S.
      • Rowbotham N.J.
      • Smith S.J.
      • et al.
      A systematic review to identify how the current clinical trials landscape reflects the James Lind Alliance top 10 research priorities for cystic fibrosis.
      ]. Pubmed, Australian New Zealand Clinical Trials Registry (ANZCTR), EU clinical trials register, ClinicalTrials.gov and ISRCTN (‘International Standard Randomised Controlled Trial Number’; however, this registry now includes more than just randomised controlled trials) were searched with strategy adapted for each database, as shown in Appendix A. Other studies were identified by emailing experts in the field (Appendix B).
      Search results were collated and duplicates excluded. Inclusion criteria were completed or registered intervention studies conducted with people diagnosed with CF and published in English between January 1, 2016 to September 11, 2017. Trials that did not meet the predetermined inclusion criteria were excluded (for full inclusion criteria see Appendix C). Included studies were matched to one or more of the Top 10 priorities by first reviewer (IK) and recorded on a database then checked by second reviewer (NR) to ensure accuracy. A third reviewer (SS) was available should disagreements occur.

      3. Results

      We identified 253 trials through the database searches and an additional six studies through contact with study investigators. After removal of duplicates, this gave 252 trials for filtering of which 193 studies fulfilled the inclusion criteria and 59 were excluded. Fig. 1 shows a Prisma flow diagram of the study selection process.
      Fig. 1
      Fig. 1Prisma flow diagram of study selection process.
      Only 63 of 193 trials (33%) matched one or more of the Top 10 priorities. The number of ongoing trials matching each priority varied widely. There were only two studies addressing priority 3, treatment of lung infection due to non-tuberculous mycobacteria (NTM) – an antibiotic resistant infection which causes severe lung damage. In contrast, there were 25 studies linked to priority 6, adherence to treatment. See Table 1. Appendix D gives a full list of trial titles and the priorities they were matched to.
      Table 1The number of clinical trials matching to each of the Top 10 priorities. Priority questions are in the number order they were ranked during the JLA PSP. Some trials were matched to more than one priority.
      Priority questionNumber of trials matching
      1. What are the effective ways of simplifying the treatment burden of people with Cystic Fibrosis?10
      2. How can we relieve gastro-intestinal symptoms, such as stomach pain, bloating and nausea in people with Cystic Fibrosis?3
      3. What is the best treatment for non-tuberculous mycobacterium (NTM) in people with Cystic Fibrosis (including when to start and what medication)?2
      4. Which therapies are effective in delaying or preventing progression of lung disease in early life in people with Cystic Fibrosis?4
      5. Is there a way of preventing Cystic Fibrosis related diabetes in people with Cystic Fibrosis?7
      6. What effective ways of motivation, support and technologies help people with Cystic Fibrosis improve and sustain adherence to treatment?25
      7. Can exercise replace chest physiotherapy for people with Cystic Fibrosis?2
      8. Which antibiotic combinations and dosing plans should be used for Cystic Fibrosis exacerbations and should antibiotic combinations be rotated?6
      9. Is there a way of reducing the negative effects of antibiotics e.g., resistance risk and adverse symptoms in people with Cystic Fibrosis?3
      10. What is the best way of eradicating Pseudomonas aeruginosa in people with Cystic Fibrosis?8
      All five of the clinical trials identified through contact with study investigators matched to Priority 6 (“What effective ways of motivation, support and technologies help people with cystic fibrosis improve and sustain adherence to treatment.”)

      4. Discussion

      This study found that a very high proportion (67%) of the current trials in CF do not match any of the James Lind Top 10 priorities. This indicates a mismatch between the current clinical trials landscape and the priorities of the CF community. The James Lind top 10 priorities were derived from engagement with participants throughout the world and informed by a systematic review of existing gaps in the published research literature and so it is disappointing that ongoing research will not fill these gaps at present [
      • Rowbotham N.J.
      • Smith S.
      • Prayle A.P.
      • et al.
      Gaps in the evidence for treatment decisions in cystic fibrosis: a systematic review.
      ]. Our findings suggest a failure of the current arrangements for prioritising clinical trials. Similar studies in conditions other than CF also found a mismatch between their PSP priorities and trial landscape [
      • Crowe S.
      • Fenton M.
      • Hall M.
      • et al.
      Patients', clinicians' and the research communities' priorities for treatment research: there is an important mismatch.
      ,
      • Tinetti M.E.
      • Basch E.
      Patients' responsibility to participate in decision making and research.
      ,
      • Stiggelbout A.M.
      • Pieterse A.H.
      • De Haes J.C.
      Shared decision making: concepts, evidence, and practice.
      ]. One study [
      • Crowe S.
      • Fenton M.
      • Hall M.
      • et al.
      Patients', clinicians' and the research communities' priorities for treatment research: there is an important mismatch.
      ] identified the treatments described in prioritised research questions generated by the first 14 JLA PSPs and compared them to the treatments described in ongoing clinical trials over the same time period. The results highlighted that although the research of non-drug treatment was prioritised by the PSPs, the ongoing research mostly involved evaluations of drugs. Another study also found a mismatch between Top 10 priorities for Palliative and End of Life care and research in progress [
      • Todd Fordham F.
      • Thakrar S.
      • Shah S.
      Does current palliative and end of life care research match the priorities of patients, carers and clinicians?: NIHR..
      ].
      To date, there have been no studies that have investigated how well the current clinical trials landscape reflects the research priorities of the CF community.
      One of the most active areas of pharmaceutical research in CF is on modulators of the cystic fibrosis transmembrane conductance regulator (CFTR). Several CFTR modulators have received a marketing authorisation in recent years and many more are undergoing clinical trials. It is of interest that questions on CFTR modulators were absent from the Top 10. During discussions at the final workshop of the JLA PSP in CF, participating patients and clinicians said they believed that research regarding CFTR modulators will progress whether prioritised or not and so they did not propose them for the JLA top 10.
      The lack of ongoing trials in some JLA priority areas may be due to a lack of suitable interventions, which could be evaluated in a clinical trial (e.g. gastrointestinal problems or NTM). Increased awareness of the importance of these issues to the CF community may lead to discovery science, to understand disease mechanisms and suggest “druggable targets” or to trials of repurposed drugs.
      One strength of this study is the large number of current trials found in CF in countries worldwide, representing the current global clinical trial landscape in CF. Additional non-database searches were used to find all current and relevant trials in CF. A matching check by a second reviewer was carried out to ensure accuracy. Reproducible methods were used to systematically search, match and analyse and were described allowing for the future accurate replication. These were then matched to the JLA top 10 priorities which were derived from engagement with participants throughout the world [
      • Rowbotham N.J.
      • Smith S.
      • Leighton P.A.
      • et al.
      The top 10 research priorities in cystic fibrosis developed by a partnership between people with CF and healthcare providers.
      ].
      By identifying and highlighting the mismatches between the current clinical trials in CF and the JLA Top 10 priorities, we hope that researchers will be made aware that their agendas currently do not meet the priorities of the people who are in the greatest need of relevant research evidence. This is an important step towards “co-production” of research [
      • Rowbotham N.J.
      • Smyth A.R.
      The patient voice in research - supporting actor or starring role?.
      ]. The research landscape is starting to change in response to the Top 10 with the NIHR supporting research based on the top 10 research priorities in CF. Using the methodology described in this study, further research could explore how future clinical trials in CF match to the priorities of the clinical and patient communities and how the Top 10 priorities for CF alter the research landscape further.

      Conflict of interests statement

      NJR has given lectures at meetings sponsored by TEVA. AS has provided consultancy for Vertex and holds a current unrestricted research grant from Vertex. He has taken part in clinical trials sponsored by Vertex, Raptor and Insmed. He has given lectures at meetings sponsored by Teva and Vertex.

      Funding

      No specific funding was received for this work. NJR is an NIHR Academic Clinical Fellow.

      Authors' contributions

      All authors were involved in the study design process and contributed in preparation of the manuscript.

      Systematic review protocol

      Appendix A. Search strategies used in the systematic review

      Condition or disease: ‘cystic fibrosis’, Study Type: ‘Interventional Studies’, First posted: ‘01/01/2016’ to ‘09/11/2017’
      ISRCTN
      Condition: ‘cystic fibrosis’, Date applied ‘01/01/2016’ to ‘09/11/2017’ and Overall trial start date ‘01/01/2016’ to ‘09/11/2017’
      EU clinical trials register
      Search term ‘cystic fibrosis’, Date range ‘2016/01/01’ to ‘2017/11/09’
      Pubme
      ‘cystic fibrosis’ in title/abstract, Date- Publication ‘2016/01/01’ to ‘2017/11/09’.
      Article types: ‘Clinical trials’
      (cystic fibrosis[Title/Abstract]) AND (“2016/01/01”[Date - Publication]: “2017/11/09”[Date - Publication])
      ANZCTR
      Search term ‘cystic fibrosis’, Study type: ‘Interventional’, Trial start date ‘01/01/2016’ to ‘09/11/2017’ and registration date ‘01/01/2016’ to ‘09/11/2017’.

      Appendix B. Experts contacted

      Additional studies were found by emailing experts in the field of research in CF who were asked if they were aware of any ongoing studies of interventions which might help address any of the Top 10 priorities. Responses were received from Aliza Fink and Alexandra Quittner and both provided information on the Success with Therapies Research Consortium (STRC). Through Aliza Fink, contact was made with Cindy George who leads the STRC at CFF who gave information regarding current studies run by the STRC.

      Appendix C. Criteria for the inclusion of studies for the review

      Tabled 1
      Inclusion criteriaExclusion criteria
      Types of studyInterventional studies published in English. Studies published since 01/01/16 to present and ongoing and also registered to take place trials.Qualitative studies/observational studies
      ParticipantsParticipants diagnosed with CF (through genetic testing or sweat testing) and of any age.

      Studies including other conditions but where CF patients were analysed as a specific subgroup were included if they met the rest of the inclusion criteria.
      Patients who are screen positive for CF but with no firm diagnosis
      InterventionAny treatment intervention actively involving participants with the potential to benefit participants directly. Studies involving trials of combinations of interventions, timings and duration of intervention and stopping interventions were included.

      The interventions were expected to fall into these categories: drugs interventions (antibiotics and CFTR modulators), behavioural interventions (supportive care etc), dietary interventions (vitamin D, fiber etc), device or web based interventions (trackers, smartphone apps or virtual reality etc) and other interventions such as home monitoring and exercise for example.
      Studies covering diagnosis, newborn screening or those concerning diagnostic test accuracy as well as those concerning policy, evaluation of the training of physicians or organisation of care.

      Interventions involving miRNAs isolation from blood samples, diagnostic tests, measurement of sputum rheological properties, measure of endothelial function etc
      OutcomesAny clinically meaningful outcome measure or those that reflected patient benefit.

      The outcomes were expected to fall into the categories listed:

      * Lung Function (e.g. FEV1,FVC, Lung clearance index etc)

      * Health-related quality of life validated measures (e.g. Cystic Fibrosis Questionnaire (CFQ) 26)

      * Respiratory symptom outcomes (e.g. Respiratory and Systemic Symptoms Questionnaire RSSQ)
      Those that did not reflect patient benefit ie studies aiming to assess outcome measures such as: bioavailability or pharmacokinetics, clearance, volume of distribution, DNA methylation etc
      * Hospitalisation (e.g. number of nights inpatient)

      * School/Work attendance (e.g. number of days missed)

      * Nutrition & Growth (e.g. weight gain, height, fat)

      * Radiological (e.g. bone mineral density)

      * Sputum properties

      * Pulmonary exacerbations (measured by frequency of exacerbation or time to next exacerbation etc)

      * Antibiotic use (e.g. number of courses, combinations, delivery method)

      * Adverse effects (toxicity & allergy, microbiology, complication of delivery)

      * Exercise tolerance

      * Sweat chloride as a measure of CFTR function

      * Mucus clearance

      * Nasal symptom scores

      * Bowel symptoms (e.g. stool frequency, abdominal pain etc)

      * Treatment burden

      * Treatment adherence

      * Cost

      Appendix D. Table showing trial titles and which research priority they matched with References to clinical trials follow table

      Tabled 1
      Does the trial match any of the Top 10 research priorities?
      Trial title12345678910
      1. Integrating Supportive Care in Cystic FibrosisYESYES
      2. Evaluation of Short Antibiotic Combination Courses Followed by Aerosols in Cystic FibrosisYES
      3. Nutritional Intervention and Glycemic Improvement in Patients With Pre-diabetic Cystic Fibrosis.YES
      4. Evaluation of (R)-Roscovitine Safety and Effects in Subjects With Cystic Fibrosis, Homozygous for the F508del-CFTR MutationYES
      5. A Study of Home Monitoring in Adults With Cystic Fibrosis (HOMECF)YES
      6. Inhaled Sodium Nitrite as an Antimicrobial for Cystic FibrosisYES
      7. An Efficacy and Safety Study of Ivacaftor in Patients With Cystic Fibrosis and Two Splicing MutationsYES
      8. Study of Safety, Tolerability & Efficacy in Cystic Fibrosis Patients With Abnormal Glucose ToleranceYES
      9. A Rollover Safety Study of Lumacaftor/Ivacaftor in Subjects Aged 2 Years and Older With Cystic Fibrosis, Homozygous for the F508del-CFTR MutationYES
      10. Simplification of CF-related Diabetes Screening at HomeYESYES
      11. Does exenatide improve post prandial glycaemic control in young people with cystic fibrosis related diabetes or impaired glucose tolerance?YES
      12. The effect of low glucose load diet on glycaemic control in patients with cystic fibrosisYES
      13. The Effect of Soluble Fiber to Reduce Post-prandial Glycemic Excursion in Adults With Cystic FibrosisYES
      14. Interactive Mobile Health Information to Enhance Patient Care at a Cystic Fibrosis CenterYES
      15. The Use of Home Oral Glucose Tolerance Test Kit in Screening Cystic Fibrosis Related DiabetesYESYES
      16. Increase Tolerance for Exercise and Raise Activity Through Connectedness TrialYES
      17. Improving Therapeutic Adherence With a Co-constructed Program Involving Both Patients and Health Care ProfessionalsYES
      18. Inhaled Nitric Oxide for Cystic Fibrosis Patients With MABSCYES
      19. Saline Hypertonic in Preschoolers + CTYES
      20. Impact of Telerehabilitation Training on Pediatric Cystic Fibrosis Patients: An Exploratory StudyYES
      21. A Study of the Dosing, Efficacy, and Safety of Oral Cysteamine in Adult Patients With Cystic Fibrosis ExacerbationsYES
      22. Virtual Reality for the Reduction of Pain During Venipuncture in Children With CFYES
      23. Virtual Care in CF (VIRTUAL-CF) StudyYES
      24. A CFit Study - Acute ExerciseYES
      25. Safety and Efficacy of 2 Treatment Regimens of Aztreonam for Inhalation Solution in Children With Cystic Fibrosis and New Onset Pseudomonas Aeruginosa InfectionYES
      26. Aztreonam for Inhalation Solution (AZLI) for the Treatment of Exacerbations of Cystic FibrosisYESYES
      27. Do More, B'More, Live FitYESYES
      28. IV Colistin for Pulmonary Exacerbations: Improving Safety and EfficacyYES
      29. A Pilot Study to Evaluate the Use of Smart Adherence Technology to Measure Lumacaftor/Ivacaftor Adherence in CF Subjects Homozygous for the F508del CFTR MutationYES
      30. Standardized Treatment of Pulmonary Exacerbations IIYES
      31. Adherence to Airway Clearance. Novel Approaches to Improving AdherenceYES
      32. Project UPLIFT to Reduce Anxiety and Depression in CF PatientsYES
      33. SPI-1005 for Prevention and Treatment of Aminoglycoside Induced OtotoxicityYES
      34. The cystic fibrosis (CF) anti-staphylococcal antibiotic prophylaxis trial (CF START): A randomised registry trial to assess the safety and efficacy of flucloxacillin as a longterm prophylaxis agent for infants with CFYES
      35. Development and evaluation of an intervention to support Adherence to treatment in adults with cystic fibrosis: A feasibility study comprised of an external pilot randomised controlled trial and process evaluationYES
      36. Randomised trial of a web-based intervention for adherence in cystic fibrosisYES
      37. Effects of inhaled hypertonic saline in children with cystic fibrosisYES
      38. Aztreonam for inhalation for the treatment of acute exacerbations in cystic fibrosis. An open-label, randomised, cross-over pilot study of AZLI plus intravenous Colistin versus standard dual intravenous therapy.YES
      39. Tobramycin Inhalation Powder (TIP) Administered Once Daily Continuously Versus TIP Administered BID in 28 Day on/28 Day Off CyclesYES
      40. A Phase 3, Randomised, Open-Label, Assessor-Blind, Non-Inferiority, Active-Comparator Study Evaluating the Efficacy and Safety of Liprotamase in Subjects with Cystic Fibrosis-Related Exocrine Pancreatic InsufficiencyYES
      41. Randomised, Double-Blind, Phase 3B Trial to Evaluate the Safety and Efficacy of 2 Treatment Regimens of Aztreonam 75 mg Powder and Solvent for Nebulizer Solution/Aztreonam for Inhalation Solution (AZLI) in Pediatric Subjects with Cystic Fibrosis (CF) and New Onset Respiratory Tract Pseudomonas aeruginosa (PA) Infection/ColonizationYES
      42. An Open-Label Study Evaluating the Efficacy and Safety of Liprotamase in Subjects with Exocrine Pancreatic Insufficiency due to Cystic FibrosisYES
      43. Trial of Optimal Therapy for Pseudomonas Eradication in Cystic FibrosisYES
      44. A Phase 4, Open-label Treatment, Randomised, Multicenter, 2-arm, Parallelgroup, Pilot Study of Adherence to Lumacaftor/Ivacaftor in CF Subjects Homozygous for the F508del-CFTR MutationYES
      45. Combined Effect of CFTR Modifiers and Intensive Antibiotic TreatmentYES
      46. In adults with cystic fibrosis, what is the effect of a smartphone application used to report symptoms versus usual care on exacerbations requiring intravenous antibiotics, healthcare utilisation, lung function, quality of life, anxiety and depression, nutritional status, medication adherence and absenteeism and presenteeism.YES
      47. Exercise alone versus exercise and positive expiratory pressure as a form of airway secretion clearance in adults with mild cystic fibrosis-related respiratory disease - a feasibility studyYESYES
      48. Musculoskeletal clinical outcomes of Whole Body Vibration Training as an adjunct to physiotherapy in children with Cystic Fibrosis: a comparison of telehealth and face to face therapy deliveryYES
      49. A randomised controlled trial of a novel web-based intervention to promote physical activity participation in young people with cystic fibrosisYES
      50. CyFiT Telerehabilitation: Investigation into the efficacy of a telehealth physiotherapy intervention on quality of life and community participation for school-aged children with cystic fibrosis, a randomised controlled trialYESYES
      51. Effects of high intensity interval training on exercise capacity in people with cystic fibrosis: a randomised controlled trialYES
      52. Home Monitoring of Patients with Cystic Fibrosis to Identify and Treat Acute Pulmonary Exacerbations. eICE Study ResultsYES
      53. Effects of treadmill exercise versus Flutter® on respiratory flow and sputum properties in adults with cystic fibrosis: a randomised, controlled, cross-over trial.YES
      54. Combined Exercise Training Improves Glycemic Control in Adult with Cystic FibrosisYES
      55. Safety and Efficacy of a Novel Microbial Lipase in Patients with Exocrine Pancreatic Insufficiency due to Cystic Fibrosis: A Randomised Controlled Clinical Trial.YES
      56. Gaseous nitric oxide to treat antibiotic resistant bacterial and fungal lung infections in patients with cystic fibrosis: a phase I clinical study.YES
      57. One-year safety and efficacy of tobramycin powder for inhalation in patients with cystic fibrosis.YES
      58. Web-Based Intervention for Nutritional Management in Cystic Fibrosis: Development, Usability, and Pilot Trial.YES
      59. Standardized Measures of Barriers to Treatment AdherenceYES
      60. Design CF: Developing e-Health Systems to Improve Growth and Nutrition in CFYES
      61. Video-Based Tele-coaching to Promote Treatment AdherenceYES
      62. A Mobile Medication Planning Application, MedActionPlan® (MAP), to Encourage Self-ManagementYES
      63. Chipped eTrack Devices to Collect Objective Measures of AdherenceYES

      References

        • Mayer-Hamblett N.
        • Boyle M.
        • Van Devanter D.
        Advancing clinical development pathways for new CFTR modulators in cystic fibrosis.
        Thorax. 2016 May; 71: 454-461https://doi.org/10.1136/thoraxjnl-2015-208123
        • Rowbotham N.J.
        • Smith S.
        • Prayle A.P.
        • et al.
        Gaps in the evidence for treatment decisions in cystic fibrosis: a systematic review.
        Thorax. 2018; 74: 229-236
        https://doi.org/10.1136/thoraxjnl-2017-210858
        Date accessed: January 28, 2019
      1. Accessed date: 28 January 2019.
        • Rowbotham N.J.
        • Smyth A.R.
        The patient voice in research - supporting actor or starring role?.
        J Cyst Fibros. 2017; 16: 313-314https://doi.org/10.1016/j.jcf.2017.03.001
        • James Lind Alliance
        The James Lind Alliance guidebook version 8.
        ([updated November 2018;Date accessed 28 January 2019]. Available from:)
        • Rowbotham N.J.
        • Smith S.
        • Leighton P.A.
        • et al.
        The top 10 research priorities in cystic fibrosis developed by a partnership between people with CF and healthcare providers.
        Thorax. 2018; 73: 388-390https://doi.org/10.1136/thoraxjnl-2017-210473
        • Kalaitzis I.S.
        • Rowbotham N.J.
        • Smith S.J.
        • et al.
        A systematic review to identify how the current clinical trials landscape reflects the James Lind Alliance top 10 research priorities for cystic fibrosis.
        University of Nottingham, 2018 (4/07/18:[Available from:)
        • Crowe S.
        • Fenton M.
        • Hall M.
        • et al.
        Patients', clinicians' and the research communities' priorities for treatment research: there is an important mismatch.
        Res Involvement and Engagement. 2015 June 25; 1: 2https://doi.org/10.1186/s40900-015-0003-x
        • Tinetti M.E.
        • Basch E.
        Patients' responsibility to participate in decision making and research.
        JAMA J Am Med Assoc. 2013; 309 (Short Survey): 2331-2332
        • Stiggelbout A.M.
        • Pieterse A.H.
        • De Haes J.C.
        Shared decision making: concepts, evidence, and practice.
        Patient Educ Couns. 2015 Oct; 98: 1172-1179https://doi.org/10.1016/j.pec.2015.06.022
        • Todd Fordham F.
        • Thakrar S.
        • Shah S.
        Does current palliative and end of life care research match the priorities of patients, carers and clinicians?: NIHR..
        (Available from)