Padidela et al. Orphanet Journal of Rare Diseases (2020) 15:172 https://doi.org/10.1186/s13023-020-01434-4 RESEARCH Open Access The international X-linked hypophosphataemia (XLH) registry (NCT03193476): rationale for and description of an international, observational study Raja Padidela1, Ola Nilsson2,3, Outi Makitie4, Signe Beck-Nielsen5, Gema Ariceta6, Dirk Schnabel7, Maria Luisa Brandi8, Annemieke Boot9, Elena Levtchenko10, Michael Smyth11, Ravi Jandhyala12* and Zulf Mughal1 Abstract Background: X-linked hypophosphataemia (XLH) is a rare, hereditary, progressive and lifelong phosphate wasting disorder characterised by pathological elevations in fibroblast growth factor (FGF) 23 concentration and activity; XLH has an incidence of approximately 1 in 20–25,000 individuals. Excess FGF23 activity leads to increased phosphate excretion in the kidneys – mediated by downregulation of renal tubular phosphate transporters – and reduced phosphate absorption in the intestines – due to impaired vitamin D activation. This results in impaired bone growth and mineralisation, short and disproportionate stature, leg bowing, musculoskeletal pain, spontaneous dental abscesses, rickets, and osteomalacia. The spectrum of manifestations differs between paediatric and adult patients. Those involved in the treatment of this condition face many challenges, including a lack of robust natural history and demographic data. This multicentre, international, rare-disease patient registry (XLH Registry) was established to address the paucity of data in XLH and to help inform future clinical practice. Results: The XLH Registry collects standard diagnostic and monitoring practice data, including (where applicable) diagnosis and disease progression history, treatment regimens and family history; the protocol does not mandate any interventions or clinical assessments. The XLH Registry aims to recruit 1200 paediatric and adult patients with XLH over 10 years, and several data analyses and peer-reviewed publications are expected to be generated throughout this period. A post-authorisation safety study for Bburosumab, for which the registry Sponsor is the marketing authorisation holder, will be nested as a sub-study within the XLH Registry via a subsequent protocol amendment. Conclusion: The data collected within this rare-disease patient registry will be utilised to synthesise real-world evidence to inform the management of XLH, to improve the quality of life and standard of care of patients living with this rare debilitating disease. Keywords: X-linked hypophosphataemia (XLH), Rare disease, Patient registry, Vitamin D, Disease history, Post- authorisation safety, Bburosumab, Real-world evidence, Quality of life, XLH management * Correspondence: ravi@medialis.co.uk 12 Medialis Ltd, Banbury, Oxford, UK Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Padidela et al. Orphanet Journal of Rare Diseases (2020) 15:172 Page 2 of 11 Introduction and continue to impact patients during adulthood [11]. X-linked hypophosphataemia (XLH) is a rare, hereditary, Both paediatric and adult patients, in the study by Skrinar progressive and lifelong phosphate wasting disorder et al., reported substantially worse quality of life than the characterised by pathological elevations in the serum general population [11]. Hence, findings from our study concentrations and activity of fibroblast growth factor highlight the need for a greater understanding of the nat- (FGF) 23. This increase in FGF23 is caused by inactivat- ural history and disease progression profiles of patients ing mutations in the phosphate regulating endopeptidase with XLH in order to improve the clinical management of homolog, X-linked (PHEX) gene [1]. The exact mecha- the condition. nisms linking PHEX and FGF23 remain to be fully eluci- Initially, the standard of care for patients with XLH dated. However, PHEX mutations are thought to affect was the administration of very high doses of vitamin D; expression, rather than degradation of FGF23 [2–4]. In- the adjuvant use of phosphate salts was subsequently creased FGF23 activity is responsible for downregulation published in 1964 [13, 14]. Today’s conventional treat- of the sodium-dependent phosphate co-transporters ment of XLH – popularised in the late 1970s – involves NPT2a and NPT2c in the proximal renal tubules, along- the administration of a combination of oral phosphate side diminished synthesis and increased catabolism of and active vitamin D analogue(s) [9, 10], accompanied in active vitamin D due to decreased 1α-hydroxylase and some cases by the use of adjuvant therapeutic options increased 24-hydroxylase enzyme activity. The combin- such as growth hormone [9]. None of these treatments ation of these physiological changes results in increased have undergone regulatory scrutiny and/or approval, phosphate wasting via the kidneys and reduced phos- suggesting there is no agreed posology, leading to differ- phate absorption in the intestines; these impairments in ences between treatment regimens at national – and phosphate homeostasis lead to chronic hypophosphatae- even regional – levels; an extensive consensus document mia [1]. Chronic hypophosphataemia is responsible for on the diagnosis and management of XLH has recently both defective bone mineralisation and tooth formation, been published which aims to address these issues [9]. leading to the typical skeletal and extra-skeletal manifes- While these therapeutic regimens have demonstrated tations of XLH [1]. XLH affects around 1 in 20–25,000 improvements in the clinical manifestations of many pa- individuals, meeting the European Union (EU) definition tients, they only target phosphate and active vitamin D of a rare-disease (affects < 1 in 2000 individuals) [5–8]. deficiencies and not the disease-causing excess of FGF23 Patients affected by XLH display a diverse range of [9, 10]. Conventional therapy may also lead to iatrogenic signs, symptoms and diagnoses, which differ not only be- complications, such as tertiary hyperparathyroidism, tween paediatric and adult patients but also between af- which may require additional therapeutic interventions, fected individuals. Circulating phosphate is integral for such as parathyroidectomy or cinacalcet therapy [15]. optimal growth and mineralisation of newly formed Further, there has, until recently, been a lack of consen- bones; paediatric patients are particularly affected as sus on the value of conventional treatment in adult pa- these impairments in bone growth, and mineralisation tients. Newer guidelines recommend treatment only of are often compounded during periods of rapid growth, symptomatic adult patients, i.e. those with musculoskeletal such as seen during childhood and adolescence. Chil- pain, pseudofractures, dental issues, planned orthopaedic dren with XLH typically present with symptoms such as or dental surgery, or biochemical evidence of osteomal- progressive bowing of weight-bearing extremities, de- acia; the value of treatment in non-symptomatic adults layed motor development, impaired and disproportional with XLH remains unclear [9, 10]. growth, rickets, and future dental complications. Adults Recently, a biological treatment – the fully human with XLH often display symptoms and signs of osteo- IgG1 monoclonal antibody (mAb) against FGF23, buro- malacia such as excessive pain, pseudofractures and sumab – has received regulatory approval in Europe osteoarthritis, alongside hearing deficits, increasing num- (paediatric and adolescent patients only), the Middle-East, bers of dental complications and abscesses over time, South America, Canada and the USA for the treatment of musculoskeletal deficiencies such as stiffness, impaired XLH [16, 17]. Existing evidence suggests burosumab may mobility, weakness and fatigue [9–11]. Many XLH com- be superior to conventional therapy, based on findings plications seen in adult patients are thought to stem from a Phase III clinical study in children with confirmed from sub-optimal disease management during childhood rickets that have not responded adequately to conven- [9–11]. All patients, regardless of age, tend to highlight tional therapy, with similar results observed in a Phase III that their condition has a severe negative impact on placebo-controlled study among symptomatic adults bur- their quality of life [1, 10, 12]. Evidence from a recent osumab [18, 19]. However, there currently remains a study by Skrinar et al. assessed the lifelong effects of dearth of data surrounding the long-term efficacy, safety XLH on patients, finding that many symptoms of XLH and drug usage information for burosumab in the broader which emerge in the paediatric period remain unresolved, ‘real-world’ population. Padidela et al. Orphanet Journal of Rare Diseases (2020) 15:172 Page 3 of 11 Furthermore, as with many other rare diseases, there is Any patient meeting any of the following exclusion a limited availability of large-scale data reporting on the criteria at baseline cannot be included in the XLH epidemiology of XLH, particularly in terms of incidence, Registry: prevalence, risk factors, co-morbidity, treatment modal- ities and mortality on an international level. One of the 1. Patient or their legally designated representative most effective methods of collecting all of the required does not have the cognitive capacity to provide large-scale patient data – which has been effectively used informed consent. in other rare diseases – is the use of registries [20, 21]. 2. Patients who are currently participating in an Patient registries or disease registries, can either be interventional clinical trial. prospective, retrospective or a combination of prospect- a. Patients may be approached for inclusion in the ive and retrospective observational cohort clinical stud- XLH Registry once their involvement in the ies, as no specific treatment, clinical assessment or data clinical trial (including all trial follow up collection are introduced or mandated as part of the assessments) has been completed. protocol [22]. Though patient registries can collect data b. Participating in a Compassionate Use Program, on particular treatments, they are exempt from the Pre-commercial Program (i.e. Named Patient European Commission’s (EC) Clinical Trials Regulation Sales, Nominative Temporary Use Authorisation as the protocol does not mandate any treatment or diag- (TUA)) or Investigator-Initiated Study does not nostic and monitoring practices outside of standard clin- preclude a patient from participation in the ical practice [23]. The benefits of this choice of clinical XLH Registry. study are beginning to be realised – particularly in rare diseases – not just by those involved in disease manage- Individuals who are treatment naïve, treated with con- ment but also by regulatory bodies such as the European ventional therapy alone or in combination with adjuvant Medicines Agency (EMA) [24–27]. Patient registries therapies such as growth hormone or cinacalcet, treated allow for long-term assessment of patients with much with burosumab, and those with prior XLH targeted fewer exclusion criteria than typical clinical studies and treatment histories but not currently receiving treatment provide a wealth of disease-specific information. are all eligible for inclusion in the XLH Registry. The XLH patient registry is an international, multicen- tre, non-interventional, observational cohort clinical Study design study of both paediatric and adult patients with XLH, The XLH Registry is an international, multicentre, non- collecting data retrospectively at study entry and pro- interventional clinical study. It captures treatment details spectively during follow up. Expert centres for the treat- and clinical outcome variables in patients with XLH and ment of XLH across Europe and the Middle East were patients are followed for as long as informed consent invited to participate in the XLH Registry and the data (and assent, where applicable) and regulatory permis- to be collected is intended to aid healthcare providers in sions are maintained. Only data collected during stand- the optimisation of clinical decision making, through an ard routine examinations are recorded within the XLH enhanced understanding of the variability, progression Registry, and no specific examinations/data entries are and natural history of XLH, alongside the actual burden mandated. Any drug therapy considered necessary for of disease. the patients’ welfare may be administered at the discre- tion of the treating physician; all such treatment and any changes that occur throughout participation in the XLH Methods Registry are recorded in the database. Registry identification The XLH Registry was initiated in August 2017, gained This rare-disease patient registry has been registered with its first national regulatory approval in September 2017 clinicaltrials.gov, under the identifier NCT03193476. (United Kingdom) and the first patient was enrolled on the October 42,017. The XLH Registry will run for 10 years in the first instance, at which point the Sponsor Study population may decide to continue or discontinue the registry, in To be eligible for inclusion in the XLH Registry, patients agreement with the applicable regulatory authorities. must meet all of the following criteria: Registry objectives 1. Male or female subjects of all ages at baseline. The primary objective of the XLH Registry is to collect 2. Diagnosis of XLH with clinical, radiological, data to characterise (where applicable) the treatment, biochemical and/or genetic findings consistent with burden of disease, disease progression and long-term XLH. outcomes of XLH in both paediatric and adult patients Padidela et al. Orphanet Journal of Rare Diseases (2020) 15:172 Page 4 of 11 and assess the safety of medications used to manage the of the standard diagnostic and monitoring practice at symptoms and signs of XLH in both paediatric and adult participating centres and if, in their opinion, there were patients. any items which were missing and should be included as part of the registry dataset. Following this appraisal, the Determination of sample size adjusted list was agreed upon by all members of the As this is a prospective, observational register of patients steering committee and formed the finalised list of regis- with XLH, there is no specific sample size based on stat- try data items. istical considerations. A survey conducted with XLH clinical experts across Europe provided evidence sug- Data to be collected gesting a total recruitment target of 1200 eligible XLH When patients are enrolled into the XLH Registry, both patients would be appropriate to enable robust research retrospective data [past medical history] and data avail- to be conducted on the data contained within the able at the time of consent [baseline visit] are collected. Registry. Prospective data collected post-baseline at all routine clinical visits will be added periodically (at least annu- Ethics ally) to the database. As no investigations or data cap- The XLH Registry is run following the recommendations ture outside of routine clinical practice are mandated, from the Declaration of Helsinki and has received eth- only information which is available to the treating phys- ical, regulatory and institutional approvals at national, ician within this framework is recorded within the XLH regional and site level for each participating country, as Registry. The treating physician will also be responsible required. Patient data held within the registry is kept in for collecting information about compliance with previ- accordance with the EU General Data Protection Regu- ous XLH medications and drug history. The full list of lations (GDPR) on the processing of personal data and agreed potential data fields contained within the XLH the protection of privacy in the electronic communica- Registry is presented in Table 1, alongside a summary of tion sector (2016/679/EU). the time-points at which specific data is collected All eligible patients with XLH visiting a participating (Table 2). clinic are provided with the locally approved patient or parental/caregiver information sheet to review. Age ap- Data collection tools and data management propriate information sheets have been developed for Registry data is collected in a purposely designed elec- those patients under the age of 18 (or 16) depending on tronic case record form (eCRF) and data entered into local guidelines. the registry is checked automatically using logical checks Once a patient or their legal representative have (i.e. limits set within the database program). As the XLH agreed to participate and provided informed consent, Registry does not mandate any investigations or assess- they are enrolled in the XLH Registry; minors aged ≥12 ments, participating centres can include ‘not done’ infor- years are also required to provide their assent before mation to prevent missing data queries; this function study inclusion. Patient data is link-anonymised, with also serves as an assessment of standard of care regimes physicians at the enrolling site retaining an enrolment across centres. If any confounding or missing data are log to allow patient identification. No pre-determined detected, an edit report is generated; the edit reports are follow-up requirements apply for the XLH Registry. sent electronically to the sites for clarification. However, physicians should update the registry promptly Clinical trial data collected in studies conducted by the after a patient’s visit, once new information is available Sponsor or affiliates will be used for data analysis along- or, at a minimum, on an annual basis. side the registry data, if the informed consent in these Participating centres were reimbursed for associated studies allows for the data to be used for further re- registry activities including obtaining informed consent, search purposes. The addition of previously collected pa- data entry and maintenance of regulatory folders. tient data will strengthen the ability of the registry to meet its primary objective. Data collection Determination of data and variables to collect Statistical methods A systematic assessment of all clinical trials involving All patients enrolled in the registry are included in the patients with a diagnosis of XLH was performed to iden- data analysis set. The Medical Dictionary for Regulatory tify the clinical variables which should be included Activities (MDRA) will be used to code medical history, within the registry. This initial list was then reviewed by and concomitant disease within the registry and registry members of the steering committee, sponsoring organ- internal reports will incorporate information up to and isation, and service delivery team to determine whether including the latest registry update for each patient. For the identified variables should be included, formed part regular reports on the registry data, all continuous Table 1 All data fields which are to be recorded (if collected) for each patient enrolled into the XLH patient registry. Data is grouped under headings, followed by a listing of all individual data variables collected Variable Group Variables Heading Informed Consent Date Type Assent Demographics Date of Birth Biological Ethnicity Gender XLH-Specific Dose Compliance Duration of Reason for Medication Treatment Discontinuation (All XLH-specific medications, including pain medication) Drug History Dose Compliance Duration of Reason for Treatment Discontinuation Radiography Any Type of Scanner type Analysis software and Imaging radiological assessment used Padidela et al. Orphanet Journal of Rare Diseases assessment of disease severity Physical Age Disease-specific examination examination Vital Signs Temperature Blood Pressure Pulse Rate Respiratory Rate (Sitting) (2020) 15:172 Growth Standing Sitting Height Arm Length Leg Length Weight (Kg) Body Mass Z-scores Assessments Height (metres) (metres) (metres) Index (BMI) (based on (metres) national reference) Biochemistry 1,25(OH)2D 25(OH)2D Alanine Aspartate Amylase Bilirubin Blood urea Calcium Chloride Carbon Cholesterol Creatinine Gamma- FGF23 Uric aminotransferase aminotransferase (direct and nitrogen (total) dioxide (total) glutamyl acid (ALT) (AST) total) (BUN) (CO2) transpeptidase (GGT) Biochemistry Intact Lactate Phosphorus Potassium Protein Sodium (continued) parathyroid dehydrogenase (albumin hormone and total) (iPTH Haematology Haematocrit Haemoglobin Platelet count Red blood cell Mean Mean Cell (RBC) count corpuscular Haematocrit volume (MCV) (MCH) Urine pH Specific gravity Protein Glucose Calcium Calcium/ Phosphorus Phosphorus/ TmP/GFR TRP Pregnancy test creatinine creatinine (if applicable) ratio ratio Physiotherapy Number of Use of a Use of Walking Use of Medical Home Reports Visits (since Wheelchair Aids Devices Adaptations last visit) Echocardiogram Reports Electrocardiogram Reports Audiology Assessment Page 5 of 11 Renal Ultrasound Table 1 All data fields which are to be recorded (if collected) for each patient enrolled into the XLH patient registry. Data is grouped under headings, followed by a listing of all individual data variables collected (Continued) Variable Group Variables Heading Scan Assessment Six Minute Timed Up and Bruininks- Dynamometry Tools/Outcome Walk Test Go Test (TUG) Oseretsky Test Measure Reports (6MWT) of Motor Proficiency Section Edition (BOT-2) Patient Quality Patient- Short Form Pain: Faces Pain Brief Pain Brief Fatigue Short Form Western Abbreviated Five-level EQ-5D Paediatric General Health Patient Patient of Life Reported 10 (SF-10) [for Scale-Revised Inventory - Inventory - 36 (SF-36) Ontario and XLH version of 5L Musculoskeletal Function Assessment Index Pain Questionnaires Outcomes children ≥5 (FPS-R) [for chil Short Form Short Form [for adult McMaster Resource the EuroQoL Proxy Functional Score Questionnaire Data 3 Diary or Assessment Measurement years of age] dren ≥5 years [for adult [for adult subjects) Universities Utilisation five- [for Health (GFS) (HAQ) (RAPID3) Reports (May Information of age] subjects] subjects] Osteoarthritis Survey dimensional children Questionnaire include the System Index descriptive < 5 years (PODCI-POSNA) following, but (PROMIS) [for (WOMAC) system (EQ- of age] Padidela et al. Orphanet Journal of Rare Diseases this is not an children ≥5 [for adult 5D 5 L) [for exclusive list) years of age] subjects] adult subjects] Social History Number of Work/School Dates Missed due to XLH- related Illness (2020) 15:172 since last visit. XLH-Specific Age of Onset Age at Diagnosis PHEX Mutation Family History Changes to Medical, Surgical of Symptoms Diagnosis Method(s) XLH-specific and Dental history History General Medical Pregnancy Gestational/ Incidence of Duration of Cause of Date of Cause of History and Foetal Foetal Hospitalisations Hospitalisations Hospitalisation Death Death Outcomes Exposure to Sponsor Product Page 6 of 11 Padidela et al. Orphanet Journal of Rare Diseases (2020) 15:172 Page 7 of 11 Table 2 Schedule of Assessments for Data Recording. Assessments in bold and italics are mandatory. All others are to be recorded on an if completed basis Assessments Study Visit Retrospective Baseline Prospective Site Characteristics X Informed Consent (and/or assent, as applicable) a X Xa Demographic information X XLH-specific Physical Exam X Medical history X X PHEX mutationb X Xb XLH medications X X X Concomitant Medications X Radiographs and imaging X X X Physical examination (including dental and audiological assessments) X X X Vital signs (e.g. heart rate, blood pressure) X X X Growth assessments (e.g. Height, weight, head circumference) X X X Physiotherapy X X X Echocardiogram X X X Electrocardiogram X X X Audiology X X X Renal ultrasound X X X Patient assessment tools/outcome measures X X X Exercise Tolerance Tests X Patient Quality of Life questionnairesc X X X Social Impact History X X X a Re-consent to adult registry consent when patient transitions from paediatric to adult patient b PHEX mutation to be recorded during prospective visit if not available during retrospective visit c Quality of Life questionnaires used are dependent upon local clinical practices variables are described using standard statistical mea- Electronic Case record forms (eCRF) sures (i.e. number of observations, mean, standard devi- The XLH Registry eCRF is completed and signed elec- ation, median, minimum and maximum). All categorical tronically for each included patient and is completed data is summarised in frequency tables. only by individuals qualified and trained in the comple- Patient disposition, demographic data and other base- tion and data verification of the eCRF information. The line characteristics are all treated as described above, physician should ensure the accuracy, completeness, le- while laboratory measurements and other clinical data gibility, and timeliness of the data reported in the eCRF. are tabulated. Medications and medical histories are All data requested must be recorded, and any missing coded according to the World Health Organisation Drug data must be explained. Any corrections will overwrite Dictionary, before being summarised and tabulated. the previous, initial information and an audit trail allow- Patient outcome measures and quality of life question- ing identification of any modifications will be main- naires will be summarised and listed. tained. Additional requests for confirming or modifying questioned data may be generated through the eCRF, and the investigator will be obliged to respond. Data quality assurance Monitoring and auditing procedures Management and reporting of adverse events/adverse Registry sites are remotely monitored, and essential reactions registry and site documents are requested for both qual- Details of adverse event reports associated with any ity control and storage in the registry master file. Regis- treatment for XLH submitted for an individual patient try sites are regularly contacted via telephone to assist in the previous year will be captured in the annual regis- with registry activities and through remote monitoring try entry for that patient. Adverse events will be coded for queries. with the Medical Dictionary for Regulatory Activities Padidela et al. Orphanet Journal of Rare Diseases (2020) 15:172 Page 8 of 11 system and described by organ class. Cumulative adverse XLH are unlikely to be able to recruit a sufficient num- event information will be reported in the registry’s in- ber of patients to allow for statistically robust conclu- terim and final analyses. sions to be drawn from the collected data [8]. The implementation and execution of a large, international Scientific steering committee registry-based study may overcome the potential limita- An international scientific committee consisting of ex- tions of smaller individual studies [29]. perts on XLH has been established. This committee An area of continuing uncertainty in the management consists of Sponsor representatives, European XLH phy- of XLH is the appropriateness of treatment of adult sicians and experts in rare metabolic and endocrine patients. While a recent consensus publication has pro- disorders, and European experts in patient registries. vided some clarification on current treatment recom- Governance principles have been established describing mendations in the adult XLH patient population, committee members’ responsibilities and obligations, as treatment is recommended only in symptomatic adult well as the scientific oversight of the registry’s publica- patients. A large-scale, long-term, patient registry col- tion policy; further information adapted from the full lecting treatment and outcomes data on adults may pro- registry access agreement can be found below. vide additional evidence that can be used to further Physicians entering data into the registry will have refine treatment approaches in this patient group [9]. control of their centre’s aggregated data set, and both Registry data may also provide an invaluable source of they and their patients’ will be free to withdraw their data on adolescent patients transitioning into adult care; consent for their data to be used in analyses at any time; this population is often mismanaged or lost to follow-up ownership of evidence generated from the aggregated care in many diseases, not just in XLH [30, 31]. data set will belong to the Sponsor. Access to anon- Furthermore, a multi-national XLH patient registry ymised data held within the registry is available to all can collect real-world data not only on natural history research groups following a successful application to the and patient demographics, but also on the effectiveness XLH Registry Steering Committee. The following three and safety profiles of both conventional therapy and bur- steps must be completed as part of the request before osumab. The collection of data from patients receiving access to the anonymised data is provided: conventional treatment or burosumab alongside that of patients who are not receiving treatment for XLH may 1. Submission of a current access form, providing any enable the assessment of risk-benefit profiles, informing applicable supporting documentation, future clinical practice and improving the quality of care 2. Review of submitted access form and supporting for individuals suffering with XLH. documentation by the XLH Registry Steering The XHL registry protocol was submitted for ethical Committee (six-week time limit), approval in all participating countries in August 2017, 3. Following a favourable outcome, applicants will and the first patient was recruited in October 2017 receive a signed letter from the XLH Registry (Manchester, UK). As of December 2018, 176 patients Steering Committee chair, alongside access to had been recruited into the registry out of a predicted anonymised registry data. 167 (105%); this correlates to 15% of the 1200 patient re- cruitment target (Fig. 1a). A breakdown of recruitment The results of all analyses approved by the Steering by country and region is shown in Fig. 1b. Committee will be published by the responsible researchers Further to the registry protocol described, future work named on the successful access form, with acknowledge- includes the nesting of a Post-Authorisation Safety Study ment of the Sponsor and contributing investigator sites. (PASS) for burosumab as a sub-study within the over- Registry reports are due to be written according to the arching patient registry; regulators typically require a main objectives of the registry and will be authored in PASS as part of the initial marketing authorisation of a collaboration with the XLH Registry Steering Commit- new medicinal product. The flexibility of the registry tee; all statistical analyses performed within the study re- protocol allows for protocol variations to be quickly ports must also be conducted under the supervision of processed and implemented, and a full protocol will be the Steering Committee. published shortly; not all XLH Registry sites are ex- pected to participate in the PASS sub-study as this will Discussion require the solicitation of adverse events, which may not Within the field of rare diseases, patient registries can be be within the capabilities of all participating sites. an invaluable source of natural history and epidemio- logical, clinical and medical information which may Limitation otherwise be unobtainable by traditional means [28]. A fundamental limitation of this registry study relates to Single centre – and even single country-level studies of the inconsistency between sites regarding the routine Padidela et al. Orphanet Journal of Rare Diseases (2020) 15:172 Page 9 of 11 Fig. 1 Recruitment curves for the X-Linked Hypophosphatameia Registry. a Between October 2017 and December 2018, 176 patients of a target 167 were recruited into the XLH rare-disease registry. b Recruitment numbers per country/region clinical monitoring data they collect. As the study is not a accessibility publicly available, suitably qualified individ- clinical trial, other than informed consent and baseline uals can request access to the registry for research pur- demographics, there is no mandatory data set which is re- poses. This approach meets the interoperability and quired to be collected. To mitigate this limitation, work has reuse components of the FAIR principles [32]. been conducted with the members of the Registry Steering Committee to generate an XLH-specific Disease Severity Conclusion Score (DSS) which will form the basis of a Core Dataset. This observational XLH patient registry aims to recruit This Core Dataset will help to standardise the information 1200 patients with XLH, over 10 years. It has been being collected across all sites within the Registry; the DSS designed to further the clinical understanding of this will also be freely available to those involved in researching chronic, progressive and debilitating genetic disease. It or managing XLH. also aims to categorise the demographics, natural histor- Furthermore, we consider the limited applicability of ies and treatment histories of both paediatric and adult the FAIR (findability, accessibility, interoperability, and patients suffering with XLH. The end goal of this regis- reuse of digital assets) principles [32] in its entirety to try is the synthesis, publication and dissemination of this clinical study on XLH, a potential limitation. This is real-world evidence from the collected data, which can due to existing data protection and confidentiality re- be used to improve both the understanding and clinical strictions on the utilisation and sharing of patient-level management of XLH. data. While patient-level data will not be publicly avail- able, evidence generated from aggregated data from the Abbreviations XLH Registry will be publicly available and published in XLH: X-Linked Hypophosphataemia; FGF: Fibroblast growth factor; PHEX: Phosphate regulating endopeptidase homolog, X-linked; EU: European peer-reviewed journals. In addition, as the XLH Registry Union; IgG1 mAb: Immunoglobine G1 monoclonal antibody; EC: European is registered on ClinicalTrials.gov, with full information Commission; EMA: European Medicines Agency; PASS: Pre-planned post- Padidela et al. Orphanet Journal of Rare Diseases (2020) 15:172 Page 10 of 11 authorisation safety study; TUA: Nominative Temporary Use Authorisation; Stockholm, Sweden. 3Örebro University, Örebro, Sweden. 4Children’s Hospital, GDPR: General Data Protection Regulations; EQ-5D: Euroqol 5 dimension Pediatric Research Center, University of Helsinki and Helsinki University questionnaire; SF-36: Short Form 36; eCRF: Electronic case record form; Hospital, Helsinki, Finland. 5Centre for Rare Diseases, Aarhus University DSS: Disease Severity Score; UK: United Kingdom; CRO: Clinical Research Hospital, Aarhus, Denmark. 6Hospital Vall d’Hebron, Universitat Autonoma Organisation Barcelona, Barcelona, Spain. 7Center for Chronic Sick Children, Pediatric Endocrinology, Charité, University Medicine Berlin, Berlin, Germany. 8 Acknowledgements University of Florence, Florence, Italy. 9University of Groningen, Groningen, The registry was implemented by Medialis Ltd. acting as the CRO across The Netherlands. 10University Hospitals Leuven, KULeuven, Leuven, Belgium. 11 Europe for the first year. On transitioning the XLH Registry from Medialis to a Kyowa Kirin International, Galashiels, UK. 12Medialis Ltd, Banbury, Oxford, new CRO in January 2019, the Sponsor updated the core documents to UK. make reference to the burosumab PASS as a sub-study and reassigned the role of data controller from the patient to the Sponsor. J Tonge, A Dillon and Received: 2 January 2020 Accepted: 4 June 2020 J Mac Leod, as employees of Medialis Ltd., served as study managers during the implementation of the XLH Registry. Alexander T. Hardy (Medialis Ltd) provided medical writing support for the manuscript. References Authors’ contributions 1. Beck-Nielsen SS, Mughal Z, Haffner D, Nilsson O, Levtchenko E, Ariceta G, RJ designed the XLH Registry from first principles, including the access et al. FGF23 and its role in X-linked hypophosphatemia-related morbidity. agreement and governance structure, and also created the interaction of the Orphanet J Rare Dis. 2019;14:58. https://doi.org/10.1186/s13023-019-1014-8. burosumab PASS with the XLH Registry. All the authors were involved in 2. Liu S, Guo R, Simpson LG, Xiao Z-S, Burnham CE, Quarles LD. Regulation of reviewing, revising and approving the manuscript. fibroblastic growth factor 23 expression but not degradation by PHEX. J Biol Chem. 2003;278:37419–26. https://doi.org/10.1074/jbc.M304544200. Funding 3. Benet-Pages A, Lorenz-Depiereux B, Zischka H, White KE, Econs MJ, Strom Kyowa Kirin International Plc is the Sponsor of the XLH Registry and this TM. FGF23 is processed by proprotein convertases but not by PHEX. Bone. manuscript. 2004;35:455–62. https://doi.org/10.1016/j.bone.2004.04.002. The authors were members of the Steering Committee for their respective 4. Murali SK, Andrukhova O, Clinkenbeard EL, White KE, Erben RG. Excessive countries. Osteocytic Fgf23 secretion contributes to pyrophosphate accumulation The authors did not receive payment for their contribution to the and mineralization defect in Hyp mice. PLoS Biol. 2016;14:e1002427. manuscript. https://doi.org/10.1371/journal.pbio.1002427. 5. Beck-Nielsen SS, Brock-Jacobsen B, Gram J, Brixen K, Jensen TK. Incidence Availability of data and materials and prevalence of nutritional and hereditary rickets in southern Denmark. Not applicable. Eur J Endocrinol. 2009;160:491–7. https://doi.org/10.1530/EJE-08-0818. 6. Endo I, Fukumoto S, Ozono K, Namba N, Inoue D, Okazaki R, et al. Nationwide Ethics approval and consent to participate survey of fibroblast growth factor 23 (FGF23)-related hypophosphatemic This registry is run in accordance with the recommendations from the diseases in Japan: prevalence, biochemical data and treatment. Endocr J. 2015; Declaration of Helsinki and has received ethical, regulatory and institutional 62:811–6. https://doi.org/10.1507/endocrj.EJ15-0275. approvals at national, regional and site level for each participating country, 7. Rafaelsen S, Johansson S, Ræder H, Bjerknes R. Hereditary as required. All participants or their legal representative provide informed hypophosphatemia in Norway: a retrospective population-based study of consent before their enrolment in the registry. genotypes, phenotypes, and treatment complications. Eur J Endocrinol. 2016;174:125–36. https://doi.org/10.1530/EJE-15-0515. Consent for publication 8. European Commission. Rare diseases. Public Health - Eur Comm 2016. Not applicable. https://ec.europa.eu/health/non_communicable_diseases/rare_diseases_en (Accessed 27 March 2019). Competing interests 9. Haffner D, Emma F, Eastwood DM, Duplan MB, Bacchetta J, Schnabel D, RP received research grant, honorarium as a speaker and travel grant from et al. 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