As CFTR modulator therapy transforms the landscape of cystic fibrosis (CF) care, its lack of uniform access across the globe combined with the shift towards a new standard of care creates unique challenges for the development of future CF therapies. The advancement of a full and promising CF therapeutics pipeline remains a necessary priority to ensure maximal clinical benefits for all people with CF. It is through collaboration across the global CF community that we can optimize the evaluation and approval process of new therapies. To this end, we must identify areas for which harmonization is lacking and for which efficiencies can be gained to promote ethical, feasible, and credible study designs amidst the changing CF care landscape. This article summarizes the counsel from core advisors across multiple international regions and clinical trial networks, developed during a one-day workshop in October 2019. The goal of the workshop was to identify, in consideration of the highly transitional era of CFTR modulator availability, the drug development areas for which global alignment is currently uncertain, and paths forward that will enable advancement of CF therapeutic development.

Case Western Reserve University School of Medicine Cleveland OH

Case Western Reserve University School of Medicine Cleveland OH; Rainbow Babies and Children's Hospital Cleveland OH

Centre for Experimental Medicine Queen's University Belfast Belfast Northern Ireland

Charles University Prague Czechia Motol University Hospital Prague Czechia

Children's Health Research Centre The University of Queensland Brisbane Australia

Cystic Fibrosis Center Children's Hospital University of Cologne; Faculty of Medicine and University Hospital Cologne Cologne Germany

Cystic Fibrosis Foundation Bethesda MD

Leeds Regional Paediatric Cystic Fibrosis Centre Leeds UK

Medical University of South Carolina Charleston SC

National Heart and Lung Institute Imperial College London London UK; Royal Brompton and Harefield NHS Foundation Trust London UK

National Jewish Health Denver CO

Seattle Children's Hospital Seattle WA

Université de Paris Paris France

University of British Columbia Vancouver British Columbia

University of Leuven Leuven Belgium

University of North Carolina at Chapel Hill Chapel Hill NC

University of Toronto Toronto Canada

University of Washington Seattle WA; Seattle Children's Hospital Seattle WA

Komentář v

J Cyst Fibros. 2020 Sep;19(5):669-670. doi: 10.1016/j.jcf.2020.07.019. PubMed

Zobrazit více v PubMed

Bell SC, Mall MA, Gutierrez H, Macek M, Madge S, Davies JC, Burgel PR, Tullis E, Castanos C, Castellani C, Byrnes CA, Cathcart F, Chotirmall SH, Cosgriff R, Eichler I, Fajac I, Goss CH, Drevinek P, Farrell PM, Gravelle AM, Havermans T, Mayer-Hamblett N, Kashirskaya N, Kerem E, Mathew JL, McKone EF, Naehrlich L, Nasr SZ, Oates GR, O’Neill C, Pypops U, Raraigh KS, Rowe SM, Southern KW, Sivam S, Stephenson AL, Zampoli M, Ratjen F. The future of cystic fibrosis care: a global perspective. Lancet Respir Med 2020; 8: 65–124. PubMed PMC

Davies JC, Drevinek P, Elborn JS, Kerem E, Lee T, European CFSSPTFoSuatndfCF, Amaral MD, de Boeck K, Davies JC, Drevinek P, Elborn JS, Kerem E, Lee T. Speeding up access to new drugs for CF: Considerations for clinical trial design and delivery. J Cyst Fibros 2019; 18: 677–684. PubMed

Nichols DP, Durmowicz AG, Field A, Flume PA, VanDevanter DR, Mayer-Hamblett N. Developing Inhaled Antibiotics in Cystic Fibrosis: Current Challenges and Opportunities. Ann Am Thorac Soc 2019; 16: 534–539. PubMed PMC

Mayer-Hamblett N, Boyle M, VanDevanter D. Advancing clinical development pathways for new CFTR modulators in cystic fibrosis. Thorax 2016; 71: 454–461. PubMed PMC

Mall MA, Mayer-Hamblett N, Rowe SM. Cystic Fibrosis: Emergence of Highly Effective Targeted Therapeutics and Potential Clinical Implications. Am J Respir Crit Care Med 2019. PubMed PMC

U.S. Department of Health and Human Services FDA, Center for Biologics Evaluation and Research CBER, Center for Drug Evaluation and Research CDER. Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products, Guidance for Industry; 2019.

VanDevanter DR, Mayer-Hamblett N, Boyle M. Feasibility of placebo-controlled trial designs for new CFTR modulator evaluation. J Cyst Fibros 2017; 16: 496–498. PubMed

Davies JC, Van de Steen O, van Koningsbruggen-Rietschel S, Drevinek P, Derichs N, McKone EF, Kanters D, Allamassey L, Namour F, de Kock H, Conrath K. GLPG1837, a CFTR potentiator, in p.Gly551Asp (G551D)-CF patients: An open-label, single-arm, phase 2a study (SAPHIRA1). J Cyst Fibros 2019; 18: 693–699. PubMed

Moscicki RA, Tandon PK. Drug-Development Challenges for Small Biopharmaceutical Companies. N Engl J Med 2017; 376: 469–474. PubMed

Franklin JM, Glynn RJ, Martin D, Schneeweiss S. Evaluating the Use of Nonrandomized Real-World Data Analyses for Regulatory Decision Making. Clin Pharmacol Ther 2019; 105: 867–877. PubMed

Magaret A, Warden M, Simon N, Heltshe S, Mayer-Hamblett N. Real-world evidence in cystic fibrosis modulator development: Establishing a path forward. J Cyst Fibros 2020. PubMed PMC

Durmowicz AG, Lim R, Rogers H, Rosebraugh CJ, Chowdhury BA. The U.S. Food and Drug Administration’s Experience with Ivacaftor in Cystic Fibrosis. Establishing Efficacy Using In Vitro Data in Lieu of a Clinical Trial. Ann Am Thorac Soc 2018; 15: 1–2. PubMed

Magaret AS, Mayer-Hamblett N, VanDevanter D. Expanding access to CFTR modulators for rare mutations: The utility of n-of-1 trials. J Cyst Fibros 2019. PubMed

Amaral MD, de Boeck K, CF ESPTFoSuatndf. Theranostics by testing CFTR modulators in patient-derived materials: The current status and a proposal for subjects with rare CFTR mutations. J Cyst Fibros 2019; 18: 685–692. PubMed

Clancy JP, Cotton CU, Donaldson SH, Solomon GM, VanDevanter DR, Boyle MP, Gentzsch M, Nick JA, Illek B, Wallenburg JC, Sorscher EJ, Amaral MD, Beekman JM, Naren AP, Bridges RJ, Thomas PJ, Cutting G, Rowe S, Durmowicz AG, Mense M, Boeck KD, Skach W, Penland C, Joseloff E, Bihler H, Mahoney J, Borowitz D, Tuggle KL. CFTR modulator theratyping: Current status, gaps and future directions. J Cyst Fibros 2019; 18: 22–34. PubMed PMC

Ramsey BW, Pepe MS, Quan JM, Otto KL, Montgomery AB, Williams-Warren J, Vasiljev KM, Borowitz D, Bowman CM, Marshall BC, Marshall S, Smith AL. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group. N Engl J Med 1999; 340: 23–30. PubMed

Konstan MW, Flume PA, Kappler M, Chiron R, Higgins M, Brockhaus F, Zhang J, Angyalosi G, He E, Geller DE. Safety, efficacy and convenience of tobramycin inhalation powder in cystic fibrosis patients: The EAGER trial. J Cyst Fibros 2011; 10: 54–61. PubMed PMC

McCoy KS, Quittner AL, Oermann CM, Gibson RL, Retsch-Bogart GZ, Montgomery AB. Inhaled aztreonam lysine for chronic airway Pseudomonas aeruginosa in cystic fibrosis. Am J Respir Crit Care Med 2008; 178: 921–928. PubMed PMC

Schuster A, Haliburn C, Doring G, Goldman MH, Freedom Study G. Safety, efficacy and convenience of colistimethate sodium dry powder for inhalation (Colobreathe DPI) in patients with cystic fibrosis: a randomised study. Thorax 2013; 68: 344–350. PubMed PMC

Elborn JS, Flume PA, Cohen F, Loutit J, VanDevanter DR. Safety and efficacy of prolonged levofloxacin inhalation solution (APT-1026) treatment for cystic fibrosis and chronic Pseudomonas aeruginosa airway infection. J Cyst Fibros 2016; 15: 634–640. PubMed

Mogayzel PJ Jr., Naureckas ET, Robinson KA, Brady C, Guill M, Lahiri T, Lubsch L, Matsui J, Oermann CM, Ratjen F, Rosenfeld M, Simon RH, Hazle L, Sabadosa K, Marshall BC, Cystic Fibrosis Foundation Pulmonary Clinical Practice Guidelines C. Cystic Fibrosis Foundation pulmonary guideline. pharmacologic approaches to prevention and eradication of initial Pseudomonas aeruginosa infection. Ann Am Thorac Soc 2014; 11: 1640–1650. PubMed

Heijerman H, Westerman E, Conway S, Touw D, Doring G, consensus working g. Inhaled medication and inhalation devices for lung disease in patients with cystic fibrosis: A European consensus. J Cyst Fibros 2009; 8: 295–315. PubMed

Flume PA, Clancy JP, Retsch-Bogart GZ, Tullis DE, Bresnik M, Derchak PA, Lewis SA, Ramsey BW. Continuous alternating inhaled antibiotics for chronic pseudomonal infection in cystic fibrosis. J Cyst Fibros 2016; 15: 809–815. PubMed

Abou Alaiwa MH, Launspach JL, Grogan B, Carter S, Zabner J, Stoltz DA, Singh PK, McKone EF, Welsh MJ. Ivacaftor-induced sweat chloride reductions correlate with increases in airway surface liquid pH in cystic fibrosis. JCI Insight 2018; 3. PubMed PMC

Hisert KB, Heltshe SL, Pope C, Jorth P, Wu X, Edwards RM, Radey M, Accurso FJ, Wolter DJ, Cooke G, Adam RJ, Carter S, Grogan B, Launspach JL, Donnelly SC, Gallagher CG, Bruce JE, Stoltz DA, Welsh MJ, Hoffman LR, McKone EF, Singh PK. Restoring Cystic Fibrosis Transmembrane Conductance Regulator Function Reduces Airway Bacteria and Inflammation in People with Cystic Fibrosis and Chronic Lung Infections. Am J Respir Crit Care Med 2017; 195: 1617–1628. PubMed PMC

Rowe SM, Heltshe SL, Gonska T, Donaldson SH, Borowitz D, Gelfond D, Sagel SD, Khan U, Mayer-Hamblett N, Van Dalfsen JM, Joseloff E, Ramsey BW, Network GIotCFFTD. Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis. Am J Respir Crit Care Med 2014; 190: 175–184. PubMed PMC

Harris JK, Wagner BD, Zemanick ET, Robertson CE, Stevens MJ, Heltshe SL, Rowe SM, Sagel SD, Network GIotCFFTD. Changes in Airway Microbiome and Inflammation with Ivacaftor Treatment in Patients with Cystic Fibrosis and the G551D Mutation. Ann Am Thorac Soc 2019. PubMed PMC

Middleton PG, Mall MA, Drevinek P, Lands LC, McKone EF, Polineni D, Ramsey BW, Taylor-Cousar JL, Tullis E, Vermeulen F, Marigowda G, McKee CM, Moskowitz SM, Nair N, Savage J, Simard C, Tian S, Waltz D, Xuan F, Rowe SM, Jain R, Group VXS. Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele. N Engl J Med 2019; 381: 1809–1819. PubMed PMC

Heijerman HGM, McKone EF, Downey DG, Van Braeckel E, Rowe SM, Tullis E, Mall MA, Welter JJ, Ramsey BW, McKee CM, Marigowda G, Moskowitz SM, Waltz D, Sosnay PR, Simard C, Ahluwalia N, Xuan F, Zhang Y, Taylor-Cousar JL, McCoy KS, Group VXT. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial. Lancet 2019; 394: 1940–1948. PubMed PMC

Heltshe SL, Mayer-Hamblett N, Burns JL, Khan U, Baines A, Ramsey BW, Rowe SM, Network GIotCFFTD. Pseudomonas aeruginosa in cystic fibrosis patients with G551D-CFTR treated with ivacaftor. Clin Infect Dis 2015; 60: 703–712. PubMed PMC

Gifford AH, Mayer-Hamblett N, Pearson K, Nichols DP. Answering the call to address cystic fibrosis treatment burden in the era of highly effective CFTR modulator therapy. J Cyst Fibros 2019. PubMed PMC

Rayment JH, Stanojevic S, Davis SD, Retsch-Bogart G, Ratjen F. Lung clearance index to monitor treatment response in pulmonary exacerbations in preschool children with cystic fibrosis. Thorax 2018; 73: 451–458. PubMed

Sonneveld N, Stanojevic S, Amin R, Aurora P, Davies J, Elborn JS, Horsley A, Latzin P, O’Neill K, Robinson P, Scrase E, Selvadurai H, Subbarao P, Welsh L, Yammine S, Ratjen F. Lung clearance index in cystic fibrosis subjects treated for pulmonary exacerbations. Eur Respir J 2015; 46: 1055–1064. PubMed

Gold LS, Patrick DL, Hansen RN, Goss CH, Kessler L. Correspondence between lung function and symptom measures from the Cystic Fibrosis Respiratory Symptom Diary-Chronic Respiratory Infection Symptom Score (CFRSD-CRISS). J Cyst Fibros 2019; 18: 886–893. PubMed PMC

Perrem L, Ratjen F. Anti-inflammatories and mucociliary clearance therapies in the age of CFTR modulators. Pediatr Pulmonol 2019; 54 Suppl 3: S46–S55. PubMed

Registry CFFP. Annual data report to the Center Directors, Bethesda Maryland, 2019: Cystic Fibrosis Foundation; 2018.

Konstan MW. Treatment of airway inflammation in cystic fibrosis. Curr Opin Pulm Med 1996; 2: 452–456. PubMed

Konstan MW, Byard PJ, Hoppel CL, Davis PB. Effect of high-dose ibuprofen in patients with cystic fibrosis. N Engl J Med 1995; 332: 848–854. PubMed

Lands LC, Milner R, Cantin AM, Manson D, Corey M. High-dose ibuprofen in cystic fibrosis: Canadian safety and effectiveness trial. J Pediatr 2007; 151: 249–254. PubMed

Konstan MW, VanDevanter DR, Sawicki GS, Pasta DJ, Foreman AJ, Neiman EA, Morgan WJ. Association of High-Dose Ibuprofen Use, Lung Function Decline, and Long-Term Survival in Children with Cystic Fibrosis. Ann Am Thorac Soc 2018; 15: 485–493. PubMed

Torphy TJ, Allen J, Cantin AM, Konstan MW, Accurso FJ, Joseloff E, Ratjen FA, Chmiel JF, Antiinflammatory Therapy Working G. Considerations for the Conduct of Clinical Trials with Antiinflammatory Agents in Cystic Fibrosis. A Cystic Fibrosis Foundation Workshop Report. Ann Am Thorac Soc 2015; 12: 1398–1406. PubMed

Sagel SD, Chmiel JF, Konstan MW. Sputum biomarkers of inflammation in cystic fibrosis lung disease. Proc Am Thorac Soc 2007; 4: 406–417. PubMed PMC

Ordonez CL, Henig NR, Mayer-Hamblett N, Accurso FJ, Burns JL, Chmiel JF, Daines CL, Gibson RL, McNamara S, Retsch-Bogart GZ, Zeitlin PL, Aitken ML. Inflammatory and microbiologic markers in induced sputum after intravenous antibiotics in cystic fibrosis. Am J Respir Crit Care Med 2003; 168: 1471–1475. PubMed

Mayer-Hamblett N, Aitken ML, Accurso FJ, Kronmal RA, Konstan MW, Burns JL, Sagel SD, Ramsey BW. Association between pulmonary function and sputum biomarkers in cystic fibrosis. Am J Respir Crit Care Med 2007; 175: 822–828. PubMed PMC

Sagel SD, Wagner BD, Anthony MM, Emmett P, Zemanick ET. Sputum biomarkers of inflammation and lung function decline in children with cystic fibrosis. Am J Respir Crit Care Med 2012; 186: 857–865. PubMed PMC

Sly PD, Gangell CL, Chen L, Ware RS, Ranganathan S, Mott LS, Murray CP, Stick SM, Investigators AC. Risk factors for bronchiectasis in children with cystic fibrosis. N Engl J Med 2013; 368: 1963–1970. PubMed

VanDevanter DR, Konstan MW. Outcome measures for clinical trials assessing treatment of cystic fibrosis lung disease. Clin Investig (Lond) 2012; 2: 163–175. PubMed PMC

Konstan MW, Wagener JS, Yegin A, Millar SJ, Pasta DJ, VanDevanter DR. Design and powering of cystic fibrosis clinical trials using rate of FEV(1) decline as an efficacy endpoint. J Cyst Fibros 2010; 9: 332–338. PubMed PMC

Chmiel JF, Konstan MW, Accurso FJ, Lymp J, Mayer-Hamblett N, VanDevanter DR, Rose LM, Ramsey BW, Assessment of Induced Sputum in Cystic Fibrosis Study G. Use of ibuprofen to assess inflammatory biomarkers in induced sputum: Implications for clinical trials in cystic fibrosis. J Cyst Fibros 2015; 14: 720–726. PubMed

Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Drevinek P, Griese M, McKone EF, Wainwright CE, Konstan MW, Moss R, Ratjen F, Sermet-Gaudelus I, Rowe SM, Dong Q, Rodriguez S, Yen K, Ordonez C, Elborn JS, Group VXS. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011; 365: 1663–1672. PubMed PMC

US Code of Federal Regulations. 21CFR 5051–52.

Pediatric Research Equity Act of 2007 Title IV FDA Amendments Act 2007; 2007.

US Best Pharmaceuticals for Children Act (BPCA). 2007.

Rose K, Spigarelli MG. Cystic Fibrosis Treatment: A Paradigm for New Pediatric Medicines, Globalization of Drug Development and the Role of the European Medicines Agency. Children (Basel) 2015; 2: 108–130. PubMed PMC

Group T. Study on the economic impact of the Paediatric Regulation, including its rewards and incentives. 2016. Available from: https://ec.europa.eu/health/sites/health/files/files/paediatrics/docs/paediatrics_10_years_economic_study.pdf.

Davies JC, Cunningham S, Harris WT, Lapey A, Regelmann WE, Sawicki GS, Southern KW, Robertson S, Green Y, Cooke J, Rosenfeld M, Group KS. Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2–5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study. Lancet Respir Med 2016; 4: 107–115. PubMed PMC

Rosenfeld M, Wainwright CE, Higgins M, Wang LT, McKee C, Campbell D, Tian S, Schneider J, Cunningham S, Davies JC, group As. Ivacaftor treatment of cystic fibrosis in children aged 12 to <24 months and with a CFTR gating mutation (ARRIVAL): a phase 3 single-arm study. Lancet Respir Med 2018; 6: 545–553. PubMed PMC

Saunders C, Jensen R, Robinson PD, Stanojevic S, Klingel M, Short C, Davies JC, Ratjen F. Integrating the multiple breath washout test into international multicentre trials. J Cyst Fibros 2019. PubMed

Ratjen F, Hug C, Marigowda G, Tian S, Huang X, Stanojevic S, Milla CE, Robinson PD, Waltz D, Davies JC, group VXi. Efficacy and safety of lumacaftor and ivacaftor in patients aged 6–11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled phase 3 trial. Lancet Respir Med 2017; 5: 557–567. PubMed