Access to medicines for rare diseases: beating the drum for primary ciliary dyskinesia

EDITORIAL PRIMARY CILIARY DYSKINESIA Access to medicines for rare diseases: beating the drum for primary ciliary dyskinesia Suzanne Crowley 1, Inês Azevedo2,3, Mieke Boon4, Andrew Bush5, Ernst Eber6, Eric Haarman7, Bulent Karadag8, Karsten Kötz9, Margaret Leigh10, Antonio Moreno-Galdó11,12, Huda Mussaffi13, Kim G. Nielsen 14, Heymut Omran15, Jean-François Papon16, Petr Pohunek 17, Kostas Priftis18, Bernhard Rindlisbacher19, Francesca Santamaria20, Arunas Valiulis 21,22, Michal Witt23, Panayiotis Yiallouros24, Zorica Zivkovic25,26, Claudia E. Kuehni 27 and Jane S. Lucas 28for BEAT-PCD 1 Paediatric Dept for Lung and Allergic diseases, Oslo University Hospital, Oslo, Norway. 2Centro MaternoPediátrico, Centro Hospitalar Universitário de S. João, Porto, Portugal. 3Departamento de GinecologiaObstetrícia e Pediatria, Faculdade de Medicina, Universidade do Porto, Porto, Portugal. 4Dept of Paediatrics, University Hospital Gasthuisberg, Leuven, Belgium. 5Depts of Paediatrics and Paediatric Respiratory Medicine, Imperial College and Royal Brompton Hospital, London, UK. 6Division of Paediatric Pulmonology and Allergology, Dept of Paediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria. 7Dept of Pediatric Pulmonology, VU University Medical Center, Amsterdam, The Netherlands. 8Dept of Pediatric Pulmonology, Marmara University, School of Medicine, Istanbul, Turkey. 9Queen Silvias Children’s Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden. 10Dept of Pediatrics and Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 11Pediatric Pulmonology Section, Hospital Universitari Vall d’Hebron, Barcelona, Spain. 12Universitat Autònoma de Barcelona, CIBERER, Barcelona, Spain. 13Schneider Children’s Medical Center of Israel, Petach-Tikva and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. 14Danish PCD Centre, Pediatric Pulmonary Service, Dept of Pediatrics and Adolescent Medicine, Rigshospitalet (Copenhagen University Hospital), Copenhagen, Denmark. 15Dept of General Pediatrics, University Hospital, Westfalian Wilhelms-University, Muenster, Germany. 16AP-HP, Hôpital Kremlin-Bicetre, Service d’ORL et de Chirurgie Cervico-Faciale and Faculté de Médecine, Université ParisSaclay, 94070 Le Kremlin-Bicêtre, INSERM, U955 and CNRS, ERL 7240, Créteil, France. 17Paediatric Dept, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic. 183rd Dept of Paediatrics, University General Hospital Attikon, National and Kapodistrian University of Athens, Athens, Greece. 19Patient Association Kartagener Syndrom und Primäre Ciliäre Dyskinesie e.V., Steffisburg, Switzerland. 20Pediatric Pulmonology, Dept of Translational Medical Sciences, Federico II University, Azienda Ospedaliera Universitaria Federico II, Naples, Italy. 21Vilnius University Medical Faculty, Institute of Clinical Medicine, Clinic of Children’s Diseases, Vilnius, Lithuania. 22European Academy of Paediatrics (EAP/UEMSSP), Brussels, Belgium. 23Dept of Molecular and Clinical Genetics, Institute of Human Genetics Polish Academy of Sciences, Poznan, Poland. 24Medical School, University of Cyprus, Nicosia, Cyprus. 25Children’s Hospital for Lung Diseases and TB, Medical Centre “Dr Dragisa Misovic”, Belgrade, Serbia. 26Faculty of Pharmacy Novi Sad, Business Academy, Novi Sad, Serbia. 27Institute of Social and Preventive Medicine and Paediatric Respiratory Medicine, Children’s University Hospital of Bern, University of Bern, Bern, Switzerland. 28 Primary Ciliary Dyskinesia Centre, University Hospital Southampton NHS Foundation Trust and Clinical and Experimental Medicine, University of Southampton, Southampton, UK. Correspondence: Suzanne Crowley, Paediatric Dept for Lung and Allergic diseases, Oslo University Hospital, Sognvannsveien 20, 0027 Oslo, Norway. E-mail: suzanne.crowley@gmail.com @ERSpublications Primary ciliary dyskinesia, a rare disease causing bronchiectasis, lacks a sound evidence base for treatment. @beatpcd proposes 1) forming a PCD European clinical trial network to address this situation and 2) conducting n-of-1 trials to access medication. https://bit.ly/3j5blfM Cite this article as: Crowley S, Azevedo I, Boon M et al. Access to medicines for rare diseases: beating the drum for primary ciliary dyskinesia. ERJ Open Res 2020; 6: 00377-2020 [https://doi.org/ 10.1183/23120541.00377-2020]. Received: 14 June 2020 | Accepted after revision: 8 July 2020 Copyright ©ERS 2020. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0. https://doi.org/10.1183/23120541.00377-2020 ERJ Open Res 2020; 6: 00377-2020 PRIMARY CILIARY DYSKINESIA | S. CROWLEY ET AL. Rare diseases are collectively common, affecting an estimated 6.2% of the world’s population [1], but each rare disease affects fewer than 4 to 5 in 10 000 individuals in Europe or less than 200 000 individuals in the USA [2]. Patients with rare diseases are often disadvantaged by late diagnosis and off-label prescribing of medicines [3]. Primary ciliary dyskinesia (PCD) is a genetic disease of impaired motile ciliary function that does not have a unique International Classification of Diseases (ICD)-10 code or licensed treatments, although Q34.8 denoting “other specified malformations of the respiratory tract” including nasopharyngeal atresia has also been applicable to PCD since 2017. The disease is characterised by mucus stagnation leading to chronic airway infection, bronchiectasis, chronic rhinosinusitis, reduced fertility and abnormalities of organ laterality with an associated increased risk of complex congenital heart disease [4]. The estimated prevalence of PCD in Europe is around 1 in 10 000 to 1 in 20 000 [5]. The international PCD cohort (iPCD) includes over 3800 PCD patients ranging in age from under 12 months to over 80 years, from Europe, Northern and Southern America, Australia and Western Asia [6]. Under-diagnosis of PCD is due to a lack of awareness among the general public and physicians in general, as well as a lack of diagnostic expertise in some countries [7]. Tools to help physicians identify patients needing testing (e.g. PICADAR) [8] and the European Respiratory Society (ERS) guidelines for diagnostic testing [9] aim to improve this. In contrast to cystic fibrosis (CF), a monogenic disease, PCD is caused by mutations in one of at least 45 identified genes for which there is no effective mutation-specific therapy; this is likely to be a long way off for most patients [10]. Thus, treatment aims to prevent and manage disease complications. Even then, the lack of an evidence base for supportive treatment in PCD means that treatment recommendations are based on expert opinion and extrapolated from CF despite differing pathophysiology [11]. There are only two published double-blind, randomised, controlled treatment studies in PCD, each a milestone achievement given recruitment difficulties [12, 13]. Paucity of evidence means that patients are exposed to risks including inappropriate dosing [14], deleterious side-effects [15] and increased treatment burden with ineffective therapies. A further consequence has been varying reimbursement policies for medicines, restricting access to inhaled antibiotics for example, with some countries resorting to cheaper alternatives with an inferior safety profile [16] and others displaying regional policy differences [17]. This restriction of access to medicines and the difficulty in conducting clinical trials in PCD is particularly concerning in regard to children. In this editorial, we show how PCD patients are being discriminated against by inequalities of access to medications and propose two solutions. The long-term solution is conducting more randomised controlled trials (RCTs) by the formation of a clinical trials network similar to the existing European and American CF Clinical Trials Networks (ECFS-CTN, CFF-CTN, respectively). Further, the empowerment of and engagement with patient organisations is fundamental to patient recruitment for clinical trials and should be prioritised. The second solution, which can end this discrimination by being implemented immediately, is to allow the prescription of inhaled medications to PCD patients if benefit is demonstrated in an appropriate n-of-1 trial. Treatment evidence PCD lung disease is not trivial. Lung function is below 80% predicted in one-third of children at diagnosis [18] and is impaired to a similar degree in childhood compared with CF [19]. A third of paediatric and adult patients will lose more than 10 percentage points of lung function over a 10-year period [18]. Data from the American bronchiectasis registry show that adults with PCD have worse lung function, greater morbidity and are more likely to be infected with Pseudomonas aeruginosa than adults with idiopathic bronchiectasis, common variable immunodeficiency and alpha-1 antitrypsin deficiency [20]. Mobilisation of airway secretions is the cornerstone of PCD management [11]. Airway mucus in PCD and CF share similar biophysical properties [21]. The first ever prospective controlled trial of treatment in PCD, a randomised, double-blind cross-over trial of 3 months’ treatment with nebulised 7% hypertonic saline (HS) and 0.9% saline, measured quality of life (QoL) and lung function in 22 adults with PCD, finding a significant difference favouring HS only in perception of health [12]. The small number of patients, a result of recruitment difficulty, meant that the study wasn’t sufficiently powered to detect differences in the primary outcome measures. An unintended consequence of these negative findings has been the refusal of some insurance companies in the USA to fund HS and nebulisers for PCD patients (M. Leigh, personal communication); payment for HS is not reimbursed in several European countries, a situation remedied by some hospital pharmacies producing their own HS. Compared with placebo, treatment with inhaled recombinant human deoxyribonuclease (rhDNase) for longer than 6 months is associated with a decrease in pulmonary exacerbations and an improvement in lung function in CF patients [22]. There have been anecdotal reports of improved sputum expectoration and lung function after short- and longer-term treatment with rhDNase in four children with PCD who were deteriorating [23–25]. Conversely, studies of rhDNase in adults with non-CF bronchiectasis showed no clinical benefits in one study [26] and increased frequency of pulmonary exacerbations with worsened https://doi.org/10.1183/23120541.00377-2020 2 PRIMARY CILIARY DYSKINESIA | S. CROWLEY ET AL. lung function in another [15]. While rhDNase on an individual trial basis can be used when lung function is deteriorating despite maximal medical therapy [27], the prohibitive cost precludes its use in most European countries where the patient must pay. Looking to the future, a more affordable rhDNase (biosimilar JHL 1922) has undergone a phase 1 clinical trial in the Netherlands [28]; a phase 3 trial in CF patients is planned. Such clinical research initiatives represent an opportunity that should be actively pursued by the PCD community. PCD lung disease is characterised by repeated pulmonary exacerbations. The newly published, multicentre, double-blind, randomised placebo-controlled study, BESTCILIA, showed that thrice weekly maintenance treatment with azithromycin for 6 months in 90 children and adults halved the rate of respiratory exacerbations and significantly reduced the rate of sputum carriage of pathogenic bacteria compared with placebo [13]. This milestone study confirms and extends to PCD data from studies in CF and bronchiectasis, and paves the way for the development of precision medicine approaches for PCD to determine who would most benefit from this treatment [29]. Furthermore, P. aeruginosa infection in PCD is common; infection rates as high as 37% have been reported in children [30], and in 39% and 51% of adolescents and adults, respectively [31]. This compares, in the latter two age groups, with 12% and 26% for bronchiectasis and 60% and 67% for CF [31]. Data from the American adult bronchiectasis registry showed a 63.5% prevalence of at least one positive P. aeruginosa sputum culture in the previous year [20]. Chronic P. aeruginosa infection in PCD is also associated with poorer lung function, especially in women [32], while the impact on life expectancy is unknown. Prompt P. aeruginosa eradication is recommended in PCD, but with no evidence to support dosing strategies or duration of treatment [11, 27]. A survey of eradication strategies in European PCD centres showed that in some countries (Belgium, Bulgaria, Turkey and Ukraine), inhaled anti-P. aeruginosa antibiotics are not generally prescribed due to lack of reimbursement of costs [16], leaving the patient with either the risk of becoming chronically infected or having to pay, which is prohibitively expensive for most, or being falsely reclassified as having CF. Proposal CF is the only chronic suppurative lung disease for which treatment with inhaled antibiotics and rhDNase has been approved by the European Medicines Agency and the US Food and Drug Administration. The five key criteria for reimbursement of medicines in countries within Europe are demonstration of therapeutic benefit, medical necessity, safety, cost-effectiveness and budget impact [33]. Further, reimbursement may be product-specific, disease-specific, population groups-specific (e.g. children or pensioners), or consumption based. Demonstration of fulfilment of these five criteria is currently impossible for any inhaled PCD treatments. Given that a cure for PCD is unlikely in the foreseeable future, efforts also need to be directed towards establishing the efficacy in PCD of medicines shown to be effective in treating other causes of bronchiectasis. The BESTCILIA azithromycin study represents an important first step towards this goal and demonstrates the ability of the PCD community to come together to perform RCTs. A formal clinical trials network might be along the lines of the European CF Society Clinical Trial Network (ECFS-CTN) and the CF Foundation Clinical Trial Network (CFF-CTN), ideally involving every diagnosed patient. As soon as one study is completed and the results analysed, the next study should begin. This method, of including virtually every patient in a clinical study, has been adopted for decades in rare childhood cancers, where it has led to impressive improvements in long-term outcomes [34]. BEAT-PCD has recently been granted an ERS Clinical Research Collaboration to advance clinical and translational research in PCD and setting the framework for the formation of a PCD-CTN would fall within this remit. However, clinical trials take time and while they are the gold-standard, it is unreasonable that patients should be denied treatment pending the outcome of such trials. We urge regulatory authorities to fund inhaled medications if they show benefit in the individual patient in an appropriately conducted, n-of-1 trial. It is simply not good enough to refuse to fund because ”there is no evidence”. Absence of evidence should not be interpreted as absence of benefit. Even within RCTs, there is usually a wide range of individual responses, and in clinical practice, an individualised approach is taken when planning therapy. In summary, we, as a group of experts managing the care of PCD patients in Europe and the USA, wish to highlight the discrimination experienced by PCD patients, the likely detrimental effects on exacerbation frequency, future lung function, QoL and healthcare costs, and propose a solution which can be implemented now while on the road to conducting more RCTs. Conflict of interest: S. Crowley has nothing to disclose. I. Azevedo has nothing to disclose. M. Boon reports grants from Horizon 2020 MyCyFAPP and KOOR post-doctoral funding from University Hospital Leuven, outside the submitted work. A. Bush has nothing to disclose. E. Eber has nothing to disclose. E. Haarman has nothing to disclose. B. Karadag has nothing to disclose. K. Kötz has nothing to disclose. M. Leigh reports a primary ciliary dyskinesia (PCD) research grant from the National Institutes of Health and a grant for a PCD clinical trial from Parion Sciences, outside the submitted work. A. Moreno-Galdó reports support for travel to and registration for medical conferences from Actelion, Abbvie and Novartis, outside the submitted work. H. Mussaffi has nothing to disclose. K.G. Nielsen has nothing to disclose. H. Omran has nothing to disclose J-F. Papon has nothing to disclose. P. Pohunek reports grants from the https://doi.org/10.1183/23120541.00377-2020 3 PRIMARY CILIARY DYSKINESIA | S. CROWLEY ET AL. Ministry of Health, Czech Republic, during the conduct of the study. K. Priftis has nothing to disclose. B. Rindlisbacher has nothing to disclose. F. Santamaria has nothing to disclose. A. Valiulis has nothing to disclose. M. Witt has nothing to disclose. P. Yiallouros has nothing to disclose. Z. Zivkovic has nothing to disclose C.E. Kuehni reports grants from Swiss National Science Foundation during the conduct of the study. J.S. Lucas has nothing to disclose. Support statement: The authors are national representatives participating in the European Respiratory Society-sponsored clinical research collaboration (2020) and European Union-sponsored Cooperating in Science and Technology action BEAT-PCD: Better Experimental Approaches to Treat Primary Ciliary Dyskinesia (BM1407, 2014–2019). BEAT-PCD is a network of scientists and clinicians coordinating research from basic science through to clinical care with the intention of developing treatments and diagnostics that lead to improved long-term outcomes for patients. M. Boon, E. Haarman, A. Moreno-Galdó, K.G. Nielsen, H. Omran, J-F. Papon, P. Pohunek, B. Rindlisbacher, F. Santamaria, P. Yiallouros and J.S. Lucas are core members of the European Reference Network on rare lung diseases, ERN-LUNG, approved on 15 December 2016 by the European Commission’s Board of Member States. ERN-LUNG is dedicated to ensuring and promoting excellence in care and research for the benefit of patients affected by rare respiratory diseases, and is committed Europe-wide and globally to the prevention, diagnosis and treatment of rare respiratory diseases through patient care and advocacy, education and research. C.E. Kuehni receives support from the Swiss National Science Foundation (SNF 320030B_192804). M. Leigh is a MC Observer in BEAT-PCD and receives support from the Genetic Disorders of Mucociliary Clearance Consortium (US National Institutes of Health grant U54HL096458; principal investigators: S.D. Davis and T. Ferkol), a part of the NCATS Rare Diseases Clinical Research Network (RDCRN) that is funded through a collaboration between NCATS and NHLBI. K.G. 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