Oਉਇਉਁ Aਔਉਃਅ The European standards of Haemophilia Centres Paul Giangrande1,2, Gabriele Calizzani2,3, Ivana Menichini2,4, Fabio Candura2,3, Pier Mannuccio Mannucci5, Michael Makris6 Oxford University Hospitals NHS Trust, Oxford, United Kingdom; 2European Haemophilia Consortium, Bruxelles, Belgium; 3National Blood Centre, National Institute of Health, Rome, Italy; 4Necstep Studio Associato, Modena, Italy; 5Scientific Direction, IRCCS Ca’ Granda Maggiore Policlinico Hospital Foundation, Milan, Italy; 6Department of Cardiovascular Science, University of Sheffield, Sheffield, United Kingdom 1
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Introduction. The European haemophilia community of professionals and patients has agreed on the principles of haemophilia care to address comprehensive optimal delivery of care which is nowadays scattered throughout Europe. Many of the health facilities call themselves Haemophilia Centres despite their variation in size, expertise and services provided. Only a small number of countries have Haemophilia Centre accreditation systems in place. Methods. In the framework of the European Haemophilia Network project, following an inclusive process of stakeholder involvement, the European Guidelines for the certification of haemophilia centres have been developed in order to set quality standards for European Haemophilia Centres and criteria for their certification. Results. The Guidelines define the standards and criteria for the designation of two levels of care delivery: European Haemophilia Treatment Centres, providing local routine care, and European Haemophilia Comprehensive Care Centres, providing specialised and multi-disciplinary care and functioning as tertiary referral centres. Additionally, they define standards about general requirements, patient care, provision of an advisory service and establishment of network of clinical and specialised services. Conclusions. The implementation of the European Guidelines for the certification of Haemophilia Centres will contribute to the reduction of health inequalities through the standardisation of quality of care in European Union Member States and could represent a model to be taken into consideration for other rare disease groups.
Introduction
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Keywords: standards and criteria, certification system, haemophilia care, EUHANET.
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Inherited bleeding disorders (IBDs) are caused by deficiencies of plasma proteins involved in haemostasis. The most common are von Willebrand disease (vWD), haemophilia A and haemophilia B. Inherited coagulation disorders are considered rare diseases, with a prevalence estimated at 1 in 5,000 males for haemophilia A1, 1 in 30,000 for haemophilia B2, and 1-3 in 1,000,000 for the most severe form of vWD (type 3)3. The clinical phenotype of haemophilia is related to the baseline level of the relevant coagulation factor, which may be used to classify the severity. Patients with haemophilia may be classified as severe, moderate or mild. Severe haemophilia is defined by a baseline level of factor VIII (or IX) below 1 IU/dL (%). These patients typically experience repeated and spontaneous bleeding into joints such as the knees, elbows and ankles and require regular treatment. Subjects with a factor VIII (or IX) level between 1 and 5 IU/dL are defined
as having moderate haemophilia and experience less frequent bleeding. Patients with levels above 5 IU/dL are classified as having mild disease and usually experience bleeding only after injury or trauma4. In the context of great disparities among (and within) European Union Member States (EU MS) in terms of facilities available for treatment, types of products used, amount of factor VIII and IX concentrates used, number of patients treated in individual centres, conditions of access and quality of care5, 409 facilities in Europe, of widely varying in size and expertise, call themselves "Haemophilia Centres" (HCs)6. Only a small number of countries have accreditation or certification systems in place based on shared standards of care for HCs. In the framework of the Second Health Programme 2008-2013, the European Commission through the Executive Agency for Health and Consumers (EAHC) funded the European Haemophilia Network (EUHANET) project with the main objective of ensuring
Blood Transfus 2014; 12 Suppl 3: s525-30 DOI 10.2450/2014.0056-14s © SIMTI Servizi Srl
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Certification vs accreditation Different meanings could be given to the word "standard". Its origin was used to denote "an emblem or flag of an army, raised on a pole to indicate the rallying point in battle", as a unit of measurement and evaluation for the movement of the armies in the battlefield. From this, as an extension of the meaning, it derived the meaning of "an acknowledged measure of comparison for quantitative or qualitative values" for which it is commonly used nowadays, especially referring to "something, such as a practice or a product that is widely recognised or employed, particularly because of its excellence"9. While the accreditation is a formal procedure that finds its legal framework within the Regulation 765/2008 and it is coordinated at European level by the European co-operation for Accreditation, the certification10, as a process for standardisation, is a voluntary procedure attesting the fulfilment of a set of technical/organisational specifications which are developed on the basis of consensus among all interested parties. It is carried out by independent standards bodies, acting at national, European and international level11. The European Union has, since the mid-1980s, made an increasing use of standards in support of its policies and legislation. Furthermore, European standardisation supports European policies in the areas of competitiveness, information and communication technologies, innovation, interoperability, environment, transport, energy, public health, health care delivery, consumer protection, etc.12.
involved European stakeholders. The first consultation process was launched in Prague during the European Haemophilia Consortium (EHC) Conference 18 in October 2012 and aimed to share principles and criteria as preliminary requirements to define the scope, approaches and rules for the production of a common set of EU standards on Haemophilia Centres for European countries. On the basis of the consensus reached and on the literature review, Work Package 4 Team members, in charge of developing the Guidelines, started the production of standards. With the agreement of the EUHANET Steering Committee, these standards were subject to a further round of consultation addressed to EU and non-EU MS stakeholders including clinicians, institutions and patient organisations and the EUHANET project partnership. This second consultation process was launched at the 6th Annual Congress of the European Association for Haemophilia and Allied Disorders held in Warsaw in February 201319. The Guidelines have been modified according to the revisions and comments received and finally launched during the international meeting Haemophilia Centre Certification Systems across Europe held in Rome in July 201320 and at the round table Haemophilia Centres of Expertise in Europe at the European Parliament on 17th October 201321.
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equity of haemophilia treatment and care throughout Europe7. In order to set quality standards for European HCs and criteria for their certification, a group of experts drafted the European Guidelines for the Certification of Haemophilia Centres (hereinafter called as Guidelines)8, as one of the outputs of EUHANET project. Finally, the main objective of this manuscript is to describe the structure and the contents of the Guidelines.
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Materials and methods The development of standards and criteria for the certification of HCs is based on the review and analysis of key reference documents including: three recommendations on rare diseases drafted by the European Union Committee of Experts on Rare Diseases (EUCERD)13-15, the European principles of haemophilia care launched at the European Parliament in January 200916, and information on the existing certification systems in use in EU MS. As described elsewhere 17 , the Guidelines are the result of two consultation processes that widely
The European Guidelines for the Certification of Haemophilia Centres The Guidelines refer to the management of patients with IBDs, covering haemophilia A and B (including female carriers), the rarer congenital deficiencies of other coagulation factors (such as fibrinogen and factors II, V, VII, X, XI and XIII), vWD and inherited platelet defects and applies to both adult and paediatric patients. All patients should have access to a comprehensive care programme. The document sets the standards for an optimal delivery of haemophilia care and for the designation of two levels of European HCs: i) European Haemophilia Treatment Centres (EHTCs), providing local routine care, and ii) European Haemophilia Comprehensive Care Centres (EHCCCs), providing specialised and multi-disciplinary care and functioning as tertiary referral centres. The delivery of a comprehensive care programme may be provided by a EHCCC or by a EHTC which has established a formal relationship with one or more EHCCCs. Requirements for the two levels of Haemophilia Centres The HCs would be distinguished according to functions and activities they carry out. Functions and activities have been identified and listed for both EHTCs and EHCCCs
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European standards for Haemophilia Centres
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from sample collection to result reporting) that could be taken as discerning criterion also. The list of coagulation tests is reported in Table I. The TAT for laboratory tests carried out must be agreed in writing between the clinical and laboratory services and be subject to monitoring. The laboratories that perform the above-mentioned tests must participate in an accredited external quality assurance scheme in haemostasis. The last discernible functions and activities among EHTC and EHCCC are based on the integrated approach to patient multidisciplinary comprehensive care. While EHTC must have access to multidisciplinary support, locally or in conjunction with EHCCCs (i.e. physiotherapy and orthopaedics, surgery, dental care, hepatology, infectious diseases, obstetrics and gynaecology, paediatric facilities if children are treated, genetics, clinical psychology and social worker), EHCCC must carry out and have access to the additional following functions and activities: i) orthopaedic and/ or rheumatology service with provision of surgery, ii) physiotherapy service, iii) specialised obstetric and gynaecological service for the management of haemophilia carriers and women with vWD and other hereditary bleeding disorders, iv) paediatric facilities if children are treated, v) genetic diagnosis service providing also carrier detection and antenatal diagnosis, vi) dental service and vii) hepatology and infectious diseases service for patients with HIV and/or viral hepatitis. The above-mentioned functions and activities are outlined in Table II. Other requirements In the Guidelines, other requirements are grouped in four main areas. General requirements include those activities/functions that a EHTC/EHCCC must attain in
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and can be summarised in four groups, as follows: 1. minimum number of severe haemophilia patients for the designation as EHTC or EHCCC; 2. expert haemophilia medical cover; 3. coagulation tests and related "turn around time" of the laboratories; 4. integrated approach to patient multidisciplinary comprehensive care. Referring to the first function, the EHTCs should normally care for at least 10 people with severe haemophilia A or B or vWD type 3, while EHCCC should normally care for at least 40 people with severe haemophilia. Another discerning point is the provision of expert haemophilia medical cover in the event of an emergency or in case treatment is needed outside normal working hours. EHTC must provide a 24-hour emergency treatment service, also by formalised arrangements with other departments and/or designated EHCCCs; additionally a EHCCC must provide a 24-hour advisory service for patients, families, hospital doctors, general practitioners and affiliated EHTCs health care professionals as well as a 24-hour laboratory service for clotting factor assays and inhibitors screens. In terms of coagulation tests performed, the EHTCs must provide basic diagnostic and monitoring laboratory support during normal working hours for the more common IBDs and offer specific treatment for patients with inhibitors and immune tolerance in collaboration with a EHCCC which offers a diagnostic and reference laboratory service with a full repertoire of tests for the diagnosis and monitoring of inherited disorders of haemostasis. EHTCs/EHCCCs have both access to a laboratory, which may be either internal or external to the centres, which provides at least an agreed set of coagulation tests in a defined "turn around time" (TAT: completion time
Table I - List of coagulation tests provided by both European Haemophilia Treatment Centres and European Haemophilia Comprehensive Care Centres and their related "turn around time". Tests
E-HCCC
E-HTC 24 hr service
24 hr service
PT, APTT, thrombin time and mixing studies
Yes TAT: within 3 hours
Yes
Yes TAT: within 3 hours
-
Factor VIII and IX assays
Yes TAT: within 6 hours
Yes
Yes
-
Inhibitor screen
Yes TAT: within 12 hours
Yes
Yes
-
Fibrinogen, vWF and factor II, V, VII, X, XI activity assays
Yes TAT: within 12 hours
Yes
Yes
-
Platelet aggregation
Yes
-
-
-
vWF antigen and multimers
Yes
-
-
-
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Table II - Functions and activities for the European Haemophilia Treatment Centres and the European Haemophilia Comprehensive Care Centres. Main functions and activities for the EHCCC
Should normally care for at least 10 people with severe haemophilia A or B or vWD type 3.
Should normally care for at least 40 people with severe haemophilia.
•
Carries out the following additional functions and activities: • Co-ordinates the delivery of haemophilia services - both in hospital and in the community including liaison with affiliated EHTCs. • Provides a 24-hour advisory service for patients, families, hospital doctors, general practitioners and affiliated EHTCs health care professionals. • Provides specialist care for patients with inhibitors, including surgery. • Provides a diagnostic and reference laboratory service with a full repertoire of tests for the diagnosis and monitoring of inherited disorders of haemostasis. • Provides a 24-hour laboratory service for clotting factor assays and inhibitors screens. • Has access to orthopaedic and/or rheumatology. service with provision of surgery. • Has access to physiotherapy service. • Has access to a specialised obstetric and gynaecological service for the management of haemophilia carriers and women with vWD and other hereditary bleeding disorders. • Has access to paediatric facilities if children are treated. • Has access to a genetic diagnosis service providing also carrier detection and antenatal diagnosis. • Has access to dental service. • Has access to hepatology and infectious diseases service for patients with HIV and/or viral hepatitis. • Offers professional psychological support. • Has access to social worker and welfare advice. • Collates data (e.g. product usage, patient demographics). • Participates in research, including clinical trials.
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Provides care for patients, including diagnosis, treatment, followup and rehabilitation. Provides patients with safe and effective treatment products. Provides a 24-hour emergency treatment service. Provides basic diagnostic and monitoring laboratory support during normal working hours for the more common inherited bleeding disorders. Has access to multidisciplinary support, locally or in conjunction with EHCCC (physiotherapy and orthopaedics, surgery, dental care, hepatology, infectious diseases, obstetrics and gynaecology, paediatric facilities if children are treated, genetics, clinical psychology and social worker). Offers specific treatment for patients with inhibitors and immune tolerance in collaboration with a EHCCC. Provides advisory service, including genetic counselling, to patients and healthcare professionals. Promotes information and training programs on inherited bleeding disorders to patients and healthcare professionals.
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Main functions and activities for the EHTC
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order to preserve the role of health care facility for rare diseases. They include among others the record-keeping and data collection (patient register; medical records; data management) and the participation in registers on IBDs at regional/national levels, as well as the supply and management of therapeutic products, reagents and medical devices. Standard requirements describe also the activities addressed to patient care: from the activities of information and education to patients and their families to those pertaining to diagnosis and therapy of haemophilia and other related IBDs (including all forms of acquired haemophilia). Periodic clinical and multi-disciplinary review yearly based as well as genetic services are not excluded within this group of standard requirements. Not last, a core set of outcome indicators should be provided and be subjected of monitoring activities. Indicators should include: units of coagulation factor concentrate used by each patient per year; number of new bleeding episodes (including breakthrough bleeds in the case of patients on prophylaxis); adverse events possibly related to treatment (inhibitors, viral infections, poor efficacy of treatment, etc.); mortality and causes of death. Additionally, a specific call on the social-health impact of IBDs should be also taken into consideration measuring, for example, the quality of life of the patients along with the number of days missed from school or work due to bleeds.
Advisory service is provided as a continuous emergency medical cover by the EHCCC but generally both levels provides this service to patients and their families, and to other professionals and caregivers who treat the patients during normal working hours. The last group of standard requirements concerns networking activities of EHTCs/EHCCCs. Many small EHTCs play a critical role in providing effective emergency care at a local level for patients with haemophilia and other IBDs. However, patients may need to attend a EHCCC for more comprehensive elements of care (e.g. elective surgery in patients with inhibitors). The level of collaboration will depend upon the degree of expertise available in the EHTC. In particular, in order to guarantee integrated approach to patient multidisciplinary comprehensive care, the relationships and agreements of a EHTC with one or more EHCCCs must be formally established as well as those with structures providing specialist services and with laboratories (see above).
Conclusions The delivery of haemophilia and other related IBDs care is scattered throughout Europe. Many of the health facilities call themselves "Haemophilia Centres" despite considerable variation in size, expertise and services provided . Although a small number of countries have
Blood Transfus 2014; 12 Suppl 3: s525-30 DOI 10.2450/2014.0056-14s s528 All rights reserved - For personal use only No other uses without permission
European standards for Haemophilia Centres
website: http://www.euhanet.org/MappedCentres. aspx). Once implemented across EU MS, the European Guidelines for the certification of Haemophilia Centres will contribute to the reduction of health inequalities through the standardisation of quality of care. The standards are not intended to establish best practices or include all procedures and practices that centres or individuals should implement; on the contrary, are designed to provide minimum Guidelines especially for those EU MS where haemophilia care is not definite deeply affecting equity of access and, more generally, rights of citizenship. Finally, the process of stakeholders engagement, the document itself and the emerging network of treatment centres will represent a model for European networks of reference to be established for other rare diseases groups.
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The EUHANET project is funded by the European Commission Health Programme through the Executive Agency for Health and Consumers (EAHC) (Project number 2011207) with co-financing from 12 pharmaceutical manufacturers.
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accreditation systems in place, the majority do not. Delivery of care is challenging because of the rarity and costs of treatment of this group of diseases. As well as other rare disease groups, IBDs are characterised by treatment specificities and peculiarities. In order to deal with the heterogeneity of EU MS health systems as well as to their different regulatory frameworks, the Guidelines have been discussed, evaluated and ameliorated by a sound number of EU and non-EU stakeholders in different inclusive consultation processes that brought a highly qualified added value to the document. Thus, the Guidelines evolved taking into consideration all relevant comments received. Among them it is worthwhile mentioning the concerns for the thresholds applied, as a mandatory standard, to the number of patients treated by the HCs in order to define the level of care provided. These concerns resulted more evident in view of small population countries. While the long-debated threshold for the designation of a EHCCC might be considered as flexible (a EHCCC should normally care for at least 40 people with severe haemophilia) where all other mandatory standards are satisfied, the lower threshold of 10 people with severe haemophilia treated to designate a EHTC has been defined after the proposals received. Relationships and collaborations in patients' health care management between EHTCs and one or more EHCCCs are currently established in some EU MS. It is unusual that these agreements are defined under a formalised framework of protocols. In order to ensure an integrated approach to patient multidisciplinary comprehensive care as recommended within the European principles of haemophilia care16, procedures, rules for collaboration between EHTCs and EHCCCs must be written, shared and made available to the public. The implementation of these Guidelines and the application process on voluntary basis to the European certification system are to be considered as the first stage for shaping the upcoming European haemophilia network. Certification is issued after the examination of the information provided by the HCs (e.g. number of patients registered, facilities offered) to EUHANET. Non confidential information will be available on a public website. Nevertheless, an evaluation framework within a prospective and more structured system of external auditing is wished for and expressively claimed by the national and international patient organisations. Networks of reference of centres of expertise for rare diseases are crucial for EU health policy as stated within the cross-border directive (article 12)22. Thus, all European HCs will be invited to apply for certification (the European Guidelines for the Certification of Haemophilia Centres and the application form for certification are available at the EUHANET project
Author contributions
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Paul Giangrande and Gabriele Calizzani are equally first authors of this manuscript. Paul Giangrande contributed to the study implementation and manuscript draft. Gabriele Calizzani contributed to the study design, study implementation and manuscript draft. Ivana Menichini contributed to the study design, study implementation, manuscript revision and manuscript approval. Fabio Candura contributed to the study design, study implementation, manuscript draft, manuscript revision and manuscript approval. Pier Mannuccio Mannucci contributed to the study design, manuscript revision and manuscript approval. Michael Makris contributed to the study design, manuscript revision and manuscript approval.
Conflicts of interest The Authors declare that the pharmaceutical companies co-financing this project are Baxter, Bayer, Biotest, BPL, CSL Behring, Grifols, Kedrion, LFB, NovoNordisk, Octapharma, Pfizer, SOBI/Biogen Idec. Pier Mannuccio Mannucci declares that he received honoraria for participating as speaker at educational meetings organised by Biotest, Bayer, Grifols, Kedrion Biopharma and Novo Nordisk. The other Authors declare no conflicts of interest.
References 1)
Stonebraker JS, Bolton-Maggs PH, Soucie JM, et al. A study of variation in the reported haemophilia A prevalence around the world. Haemophilia 2010; 16: 20-32.
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and Member States on improving informed decisions based on the Clinical Added Value of Orphan Medicinal Products (COVAMP) information flow (September 2012). Available at: http://www.eucerd.eu/?post_type=document&p=1446. Accessed on 15/01/2014. Colvin BT, Astermark J, Fischer K, Gringeri A, Lassila R, Schramm W, A. Thomas A and Ingerslev J for the inter disciplinary working group. European principles of Haemophilia Care. Haemophilia 2008; 14: 361-74. Candura F, Menichini I, Calizzani G, et al. The methodology for defining the European Standards for the designation of Haemophilia Centres in Europe. Blood Transfus 2014; 12 (Suppl 3): s519-24. European Haemophilia Consortium 2012 Conference. European Haemophilia Consortium. Available at: http:// www.ehc.eu/nc/en/ehc-conference/current-ehc-conference/ former-conferences/ehc-conference2012.html?sword_ list%5B%5D=prague. Accessed on 29/12/2013. European Association for Haemophilia and Allied Disorders 2013 Congress. European Association for Haemophilia and Allied Disorders. Available at: http://www.eahad2013.pl/. Accessed on 29/12/2013. International meeting on Haemophilia Centre Certification Systems across Europe. Centro Nazionale Sangue (Italian National Blood Centre). Available at: http://www. centronazionalesangue.it/newsbox/seminario-malattieemorragiche-congenite-mec. Accessed on 15/01/2014. The 20th European Haemophilia Consortium Round Table of Stakeholders on "Haemophilia Centres of Expertise in Europe". Available at http://www.ehc.eu/en/round-table-ofstake-holders/last-round-table/archive-of-round-table/201310-17-round-table.html. Accessed on 15/02/2014. Official Journal of the European Union L 88/45. Directive 2011/24/EU of the European Parliament and of the Council of 9 March 2011 on the application of patients' rights in crossborder healthcare.
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Stonebraker JS, Bolton-Maggs PH, Soucie JM, et al. A study of variations in the reported haemophilia B prevalence around the world. Haemophilia 2012; 18: e91-94. Mannucci PM. Treatment of von Willebrand's disease. N Engl J Med 2004; 351: 683-94. White GC 2nd, Rosendaal F, Aledort LM, et al. Definition in hemophilia. Recommendation of scientific subcommittee on factor VIII and factor IX of scientific and standardization committee of the International Society of Thrombosis and Haemostasis. Thromb Haemost 2001; 85: 560. O'Mahony B, Noone D, Giangrande PL, Prihodova L. Haemophilia care in Europe - a survey of 35 countries. Haemophilia 2013; 19: e239-247. Geographic distribution of Haemophilia Centres in Europe. http://www.euhanet.org/MappedCentres.aspx. Accessed on 15/01/2014. Makris M, Calizzani G, Fischer K, et al. For the EUHANET project Steering Committee The European Haemophilia Network (EUHANET). Blood Transfus 2014; 12 (Suppl 3): s515-8. European Guidelines for the Certification of Haemophilia Centres. European Haemophilia Network. Available at: http:// www.euhanet.org/docs/Euhanet-European_Guidelines_ for_the_certification_of_Haemophilia_Centres_2013.pdf. Accessed on 09/01/2014. Meaning of the word 'standard' from English Oxford Dictionary. http://www.oxforddictionaries.com/. Accessed on 15/001/2014. L 218/30 Official Journal of the European Union 13.8.2008 Regulation (EC) No765/2008 of the European Parliament and of the Council of 9 July 2008 setting out the requirements for accreditation and market surveillance relating to the marketing of products and repealing Regulation (EEC) No 339/93. Available at: http://eur-lex.europa.eu/LexUriServ/ LexUriServ.do?uri=OJ:L:2008:218:0030:0047:en:PDF. Accessed on 15/01/2014. European standards. Available at: http://ec.europa.eu/ enterprise/policies/european-standards/index_en.htm. Accessed on 15/01/2014. European standardisation policy. Available at: http:// ec.europa.eu/enterprise/policies/european-standards/ standardisation-policy/index_en.htm. Accessed on 12/01/2014. EUCERD Recommendations on rare disease European reference networks (RD ERNS) (31 January 2013). Available at: http://www.eucerd.eu/?post_type=document&p=2207. Accessed on 03/01/2014. EUCERD Recommendations on Quality Criteria for Centres of Expertise for Rare Diseases in Member States (24 October 2011). Available at: http://www.eucerd.eu/upload/file/ EUCERDRecommendationCE.pdf. Accessed on 08/01/2014. EUCERD Recommendation to the European Commission
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Correspondence: Gabriele Calizzani National Blood Centre, National Institute of Health Via Giano della Bella 27 00162 Rome, Italy e-mail: [email protected]
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Introduction. The European haemophilia community of professionals and patients has agreed on the principles of haemophilia care to address comprehensive optimal delivery of care which is nowadays scattered throughout Europe. Many of the health facilities call themselves Haemophilia Centres despite their variation in size, expertise and services provided. Only a small number of countries have Haemophilia Centre accreditation systems in place. Methods. In the framework of the European Haemophilia Network project, following an inclusive process of stakeholder involvement, the European Guidelines for the certification of haemophilia centres have been developed in order to set quality standards for European Haemophilia Centres and criteria for their certification. Results. The Guidelines define the standards and criteria for the designation of two levels of care delivery: European Haemophilia Treatment Centres, providing local routine care, and European Haemophilia Comprehensive Care Centres, providing specialised and multi-disciplinary care and functioning as tertiary referral centres. Additionally, they define standards about general requirements, patient care, provision of an advisory service and establishment of network of clinical and specialised services. Conclusions. The implementation of the European Guidelines for the certification of Haemophilia Centres will contribute to the reduction of health inequalities through the standardisation of quality of care in European Union Member States and could represent a model to be taken into consideration for other rare disease groups.
Introduction
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Keywords: standards and criteria, certification system, haemophilia care, EUHANET.
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Inherited bleeding disorders (IBDs) are caused by deficiencies of plasma proteins involved in haemostasis. The most common are von Willebrand disease (vWD), haemophilia A and haemophilia B. Inherited coagulation disorders are considered rare diseases, with a prevalence estimated at 1 in 5,000 males for haemophilia A1, 1 in 30,000 for haemophilia B2, and 1-3 in 1,000,000 for the most severe form of vWD (type 3)3. The clinical phenotype of haemophilia is related to the baseline level of the relevant coagulation factor, which may be used to classify the severity. Patients with haemophilia may be classified as severe, moderate or mild. Severe haemophilia is defined by a baseline level of factor VIII (or IX) below 1 IU/dL (%). These patients typically experience repeated and spontaneous bleeding into joints such as the knees, elbows and ankles and require regular treatment. Subjects with a factor VIII (or IX) level between 1 and 5 IU/dL are defined
as having moderate haemophilia and experience less frequent bleeding. Patients with levels above 5 IU/dL are classified as having mild disease and usually experience bleeding only after injury or trauma4. In the context of great disparities among (and within) European Union Member States (EU MS) in terms of facilities available for treatment, types of products used, amount of factor VIII and IX concentrates used, number of patients treated in individual centres, conditions of access and quality of care5, 409 facilities in Europe, of widely varying in size and expertise, call themselves "Haemophilia Centres" (HCs)6. Only a small number of countries have accreditation or certification systems in place based on shared standards of care for HCs. In the framework of the Second Health Programme 2008-2013, the European Commission through the Executive Agency for Health and Consumers (EAHC) funded the European Haemophilia Network (EUHANET) project with the main objective of ensuring
Blood Transfus 2014; 12 Suppl 3: s525-30 DOI 10.2450/2014.0056-14s © SIMTI Servizi Srl
s525 All rights reserved - For personal use only No other uses without permission
Giangrande P et al
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Certification vs accreditation Different meanings could be given to the word "standard". Its origin was used to denote "an emblem or flag of an army, raised on a pole to indicate the rallying point in battle", as a unit of measurement and evaluation for the movement of the armies in the battlefield. From this, as an extension of the meaning, it derived the meaning of "an acknowledged measure of comparison for quantitative or qualitative values" for which it is commonly used nowadays, especially referring to "something, such as a practice or a product that is widely recognised or employed, particularly because of its excellence"9. While the accreditation is a formal procedure that finds its legal framework within the Regulation 765/2008 and it is coordinated at European level by the European co-operation for Accreditation, the certification10, as a process for standardisation, is a voluntary procedure attesting the fulfilment of a set of technical/organisational specifications which are developed on the basis of consensus among all interested parties. It is carried out by independent standards bodies, acting at national, European and international level11. The European Union has, since the mid-1980s, made an increasing use of standards in support of its policies and legislation. Furthermore, European standardisation supports European policies in the areas of competitiveness, information and communication technologies, innovation, interoperability, environment, transport, energy, public health, health care delivery, consumer protection, etc.12.
involved European stakeholders. The first consultation process was launched in Prague during the European Haemophilia Consortium (EHC) Conference 18 in October 2012 and aimed to share principles and criteria as preliminary requirements to define the scope, approaches and rules for the production of a common set of EU standards on Haemophilia Centres for European countries. On the basis of the consensus reached and on the literature review, Work Package 4 Team members, in charge of developing the Guidelines, started the production of standards. With the agreement of the EUHANET Steering Committee, these standards were subject to a further round of consultation addressed to EU and non-EU MS stakeholders including clinicians, institutions and patient organisations and the EUHANET project partnership. This second consultation process was launched at the 6th Annual Congress of the European Association for Haemophilia and Allied Disorders held in Warsaw in February 201319. The Guidelines have been modified according to the revisions and comments received and finally launched during the international meeting Haemophilia Centre Certification Systems across Europe held in Rome in July 201320 and at the round table Haemophilia Centres of Expertise in Europe at the European Parliament on 17th October 201321.
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equity of haemophilia treatment and care throughout Europe7. In order to set quality standards for European HCs and criteria for their certification, a group of experts drafted the European Guidelines for the Certification of Haemophilia Centres (hereinafter called as Guidelines)8, as one of the outputs of EUHANET project. Finally, the main objective of this manuscript is to describe the structure and the contents of the Guidelines.
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Materials and methods The development of standards and criteria for the certification of HCs is based on the review and analysis of key reference documents including: three recommendations on rare diseases drafted by the European Union Committee of Experts on Rare Diseases (EUCERD)13-15, the European principles of haemophilia care launched at the European Parliament in January 200916, and information on the existing certification systems in use in EU MS. As described elsewhere 17 , the Guidelines are the result of two consultation processes that widely
The European Guidelines for the Certification of Haemophilia Centres The Guidelines refer to the management of patients with IBDs, covering haemophilia A and B (including female carriers), the rarer congenital deficiencies of other coagulation factors (such as fibrinogen and factors II, V, VII, X, XI and XIII), vWD and inherited platelet defects and applies to both adult and paediatric patients. All patients should have access to a comprehensive care programme. The document sets the standards for an optimal delivery of haemophilia care and for the designation of two levels of European HCs: i) European Haemophilia Treatment Centres (EHTCs), providing local routine care, and ii) European Haemophilia Comprehensive Care Centres (EHCCCs), providing specialised and multi-disciplinary care and functioning as tertiary referral centres. The delivery of a comprehensive care programme may be provided by a EHCCC or by a EHTC which has established a formal relationship with one or more EHCCCs. Requirements for the two levels of Haemophilia Centres The HCs would be distinguished according to functions and activities they carry out. Functions and activities have been identified and listed for both EHTCs and EHCCCs
Blood Transfus 2014; 12 Suppl 3: s525-30 DOI 10.2450/2014.0056-14s s526 All rights reserved - For personal use only No other uses without permission
European standards for Haemophilia Centres
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from sample collection to result reporting) that could be taken as discerning criterion also. The list of coagulation tests is reported in Table I. The TAT for laboratory tests carried out must be agreed in writing between the clinical and laboratory services and be subject to monitoring. The laboratories that perform the above-mentioned tests must participate in an accredited external quality assurance scheme in haemostasis. The last discernible functions and activities among EHTC and EHCCC are based on the integrated approach to patient multidisciplinary comprehensive care. While EHTC must have access to multidisciplinary support, locally or in conjunction with EHCCCs (i.e. physiotherapy and orthopaedics, surgery, dental care, hepatology, infectious diseases, obstetrics and gynaecology, paediatric facilities if children are treated, genetics, clinical psychology and social worker), EHCCC must carry out and have access to the additional following functions and activities: i) orthopaedic and/ or rheumatology service with provision of surgery, ii) physiotherapy service, iii) specialised obstetric and gynaecological service for the management of haemophilia carriers and women with vWD and other hereditary bleeding disorders, iv) paediatric facilities if children are treated, v) genetic diagnosis service providing also carrier detection and antenatal diagnosis, vi) dental service and vii) hepatology and infectious diseases service for patients with HIV and/or viral hepatitis. The above-mentioned functions and activities are outlined in Table II. Other requirements In the Guidelines, other requirements are grouped in four main areas. General requirements include those activities/functions that a EHTC/EHCCC must attain in
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and can be summarised in four groups, as follows: 1. minimum number of severe haemophilia patients for the designation as EHTC or EHCCC; 2. expert haemophilia medical cover; 3. coagulation tests and related "turn around time" of the laboratories; 4. integrated approach to patient multidisciplinary comprehensive care. Referring to the first function, the EHTCs should normally care for at least 10 people with severe haemophilia A or B or vWD type 3, while EHCCC should normally care for at least 40 people with severe haemophilia. Another discerning point is the provision of expert haemophilia medical cover in the event of an emergency or in case treatment is needed outside normal working hours. EHTC must provide a 24-hour emergency treatment service, also by formalised arrangements with other departments and/or designated EHCCCs; additionally a EHCCC must provide a 24-hour advisory service for patients, families, hospital doctors, general practitioners and affiliated EHTCs health care professionals as well as a 24-hour laboratory service for clotting factor assays and inhibitors screens. In terms of coagulation tests performed, the EHTCs must provide basic diagnostic and monitoring laboratory support during normal working hours for the more common IBDs and offer specific treatment for patients with inhibitors and immune tolerance in collaboration with a EHCCC which offers a diagnostic and reference laboratory service with a full repertoire of tests for the diagnosis and monitoring of inherited disorders of haemostasis. EHTCs/EHCCCs have both access to a laboratory, which may be either internal or external to the centres, which provides at least an agreed set of coagulation tests in a defined "turn around time" (TAT: completion time
Table I - List of coagulation tests provided by both European Haemophilia Treatment Centres and European Haemophilia Comprehensive Care Centres and their related "turn around time". Tests
E-HCCC
E-HTC 24 hr service
24 hr service
PT, APTT, thrombin time and mixing studies
Yes TAT: within 3 hours
Yes
Yes TAT: within 3 hours
-
Factor VIII and IX assays
Yes TAT: within 6 hours
Yes
Yes
-
Inhibitor screen
Yes TAT: within 12 hours
Yes
Yes
-
Fibrinogen, vWF and factor II, V, VII, X, XI activity assays
Yes TAT: within 12 hours
Yes
Yes
-
Platelet aggregation
Yes
-
-
-
vWF antigen and multimers
Yes
-
-
-
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Giangrande P et al
Table II - Functions and activities for the European Haemophilia Treatment Centres and the European Haemophilia Comprehensive Care Centres. Main functions and activities for the EHCCC
Should normally care for at least 10 people with severe haemophilia A or B or vWD type 3.
Should normally care for at least 40 people with severe haemophilia.
•
Carries out the following additional functions and activities: • Co-ordinates the delivery of haemophilia services - both in hospital and in the community including liaison with affiliated EHTCs. • Provides a 24-hour advisory service for patients, families, hospital doctors, general practitioners and affiliated EHTCs health care professionals. • Provides specialist care for patients with inhibitors, including surgery. • Provides a diagnostic and reference laboratory service with a full repertoire of tests for the diagnosis and monitoring of inherited disorders of haemostasis. • Provides a 24-hour laboratory service for clotting factor assays and inhibitors screens. • Has access to orthopaedic and/or rheumatology. service with provision of surgery. • Has access to physiotherapy service. • Has access to a specialised obstetric and gynaecological service for the management of haemophilia carriers and women with vWD and other hereditary bleeding disorders. • Has access to paediatric facilities if children are treated. • Has access to a genetic diagnosis service providing also carrier detection and antenatal diagnosis. • Has access to dental service. • Has access to hepatology and infectious diseases service for patients with HIV and/or viral hepatitis. • Offers professional psychological support. • Has access to social worker and welfare advice. • Collates data (e.g. product usage, patient demographics). • Participates in research, including clinical trials.
• • • •
• •
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Provides care for patients, including diagnosis, treatment, followup and rehabilitation. Provides patients with safe and effective treatment products. Provides a 24-hour emergency treatment service. Provides basic diagnostic and monitoring laboratory support during normal working hours for the more common inherited bleeding disorders. Has access to multidisciplinary support, locally or in conjunction with EHCCC (physiotherapy and orthopaedics, surgery, dental care, hepatology, infectious diseases, obstetrics and gynaecology, paediatric facilities if children are treated, genetics, clinical psychology and social worker). Offers specific treatment for patients with inhibitors and immune tolerance in collaboration with a EHCCC. Provides advisory service, including genetic counselling, to patients and healthcare professionals. Promotes information and training programs on inherited bleeding disorders to patients and healthcare professionals.
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Main functions and activities for the EHTC
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order to preserve the role of health care facility for rare diseases. They include among others the record-keeping and data collection (patient register; medical records; data management) and the participation in registers on IBDs at regional/national levels, as well as the supply and management of therapeutic products, reagents and medical devices. Standard requirements describe also the activities addressed to patient care: from the activities of information and education to patients and their families to those pertaining to diagnosis and therapy of haemophilia and other related IBDs (including all forms of acquired haemophilia). Periodic clinical and multi-disciplinary review yearly based as well as genetic services are not excluded within this group of standard requirements. Not last, a core set of outcome indicators should be provided and be subjected of monitoring activities. Indicators should include: units of coagulation factor concentrate used by each patient per year; number of new bleeding episodes (including breakthrough bleeds in the case of patients on prophylaxis); adverse events possibly related to treatment (inhibitors, viral infections, poor efficacy of treatment, etc.); mortality and causes of death. Additionally, a specific call on the social-health impact of IBDs should be also taken into consideration measuring, for example, the quality of life of the patients along with the number of days missed from school or work due to bleeds.
Advisory service is provided as a continuous emergency medical cover by the EHCCC but generally both levels provides this service to patients and their families, and to other professionals and caregivers who treat the patients during normal working hours. The last group of standard requirements concerns networking activities of EHTCs/EHCCCs. Many small EHTCs play a critical role in providing effective emergency care at a local level for patients with haemophilia and other IBDs. However, patients may need to attend a EHCCC for more comprehensive elements of care (e.g. elective surgery in patients with inhibitors). The level of collaboration will depend upon the degree of expertise available in the EHTC. In particular, in order to guarantee integrated approach to patient multidisciplinary comprehensive care, the relationships and agreements of a EHTC with one or more EHCCCs must be formally established as well as those with structures providing specialist services and with laboratories (see above).
Conclusions The delivery of haemophilia and other related IBDs care is scattered throughout Europe. Many of the health facilities call themselves "Haemophilia Centres" despite considerable variation in size, expertise and services provided . Although a small number of countries have
Blood Transfus 2014; 12 Suppl 3: s525-30 DOI 10.2450/2014.0056-14s s528 All rights reserved - For personal use only No other uses without permission
European standards for Haemophilia Centres
website: http://www.euhanet.org/MappedCentres. aspx). Once implemented across EU MS, the European Guidelines for the certification of Haemophilia Centres will contribute to the reduction of health inequalities through the standardisation of quality of care. The standards are not intended to establish best practices or include all procedures and practices that centres or individuals should implement; on the contrary, are designed to provide minimum Guidelines especially for those EU MS where haemophilia care is not definite deeply affecting equity of access and, more generally, rights of citizenship. Finally, the process of stakeholders engagement, the document itself and the emerging network of treatment centres will represent a model for European networks of reference to be established for other rare diseases groups.
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The EUHANET project is funded by the European Commission Health Programme through the Executive Agency for Health and Consumers (EAHC) (Project number 2011207) with co-financing from 12 pharmaceutical manufacturers.
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accreditation systems in place, the majority do not. Delivery of care is challenging because of the rarity and costs of treatment of this group of diseases. As well as other rare disease groups, IBDs are characterised by treatment specificities and peculiarities. In order to deal with the heterogeneity of EU MS health systems as well as to their different regulatory frameworks, the Guidelines have been discussed, evaluated and ameliorated by a sound number of EU and non-EU stakeholders in different inclusive consultation processes that brought a highly qualified added value to the document. Thus, the Guidelines evolved taking into consideration all relevant comments received. Among them it is worthwhile mentioning the concerns for the thresholds applied, as a mandatory standard, to the number of patients treated by the HCs in order to define the level of care provided. These concerns resulted more evident in view of small population countries. While the long-debated threshold for the designation of a EHCCC might be considered as flexible (a EHCCC should normally care for at least 40 people with severe haemophilia) where all other mandatory standards are satisfied, the lower threshold of 10 people with severe haemophilia treated to designate a EHTC has been defined after the proposals received. Relationships and collaborations in patients' health care management between EHTCs and one or more EHCCCs are currently established in some EU MS. It is unusual that these agreements are defined under a formalised framework of protocols. In order to ensure an integrated approach to patient multidisciplinary comprehensive care as recommended within the European principles of haemophilia care16, procedures, rules for collaboration between EHTCs and EHCCCs must be written, shared and made available to the public. The implementation of these Guidelines and the application process on voluntary basis to the European certification system are to be considered as the first stage for shaping the upcoming European haemophilia network. Certification is issued after the examination of the information provided by the HCs (e.g. number of patients registered, facilities offered) to EUHANET. Non confidential information will be available on a public website. Nevertheless, an evaluation framework within a prospective and more structured system of external auditing is wished for and expressively claimed by the national and international patient organisations. Networks of reference of centres of expertise for rare diseases are crucial for EU health policy as stated within the cross-border directive (article 12)22. Thus, all European HCs will be invited to apply for certification (the European Guidelines for the Certification of Haemophilia Centres and the application form for certification are available at the EUHANET project
Author contributions
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Paul Giangrande and Gabriele Calizzani are equally first authors of this manuscript. Paul Giangrande contributed to the study implementation and manuscript draft. Gabriele Calizzani contributed to the study design, study implementation and manuscript draft. Ivana Menichini contributed to the study design, study implementation, manuscript revision and manuscript approval. Fabio Candura contributed to the study design, study implementation, manuscript draft, manuscript revision and manuscript approval. Pier Mannuccio Mannucci contributed to the study design, manuscript revision and manuscript approval. Michael Makris contributed to the study design, manuscript revision and manuscript approval.
Conflicts of interest The Authors declare that the pharmaceutical companies co-financing this project are Baxter, Bayer, Biotest, BPL, CSL Behring, Grifols, Kedrion, LFB, NovoNordisk, Octapharma, Pfizer, SOBI/Biogen Idec. Pier Mannuccio Mannucci declares that he received honoraria for participating as speaker at educational meetings organised by Biotest, Bayer, Grifols, Kedrion Biopharma and Novo Nordisk. The other Authors declare no conflicts of interest.
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Correspondence: Gabriele Calizzani National Blood Centre, National Institute of Health Via Giano della Bella 27 00162 Rome, Italy e-mail: [email protected]
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