Blood Transfus 2014; 12 Suppl 3
Official journal of
Blood Transfusion - Trimestrale spedizione in abbonamento postale 70% - Poste Italiane SpA LO/MI
Società Italiana di Medicina Trasfusionale e Immunoematologia - SIMTI
Associazione Italiana dei Centri Emofilia - AICE
Hrvatsko društvo za hematologiju i transfuzijsku medicinu - HDHTM
Sociedad Española de Transfusión Sanguínea y Terapia Celular - SETS
Haemophilia Centre Accreditation Systems and Networks of Centres
of Expertise for Rare Diseases in Europe and North America
PROCEEDINGS
"Haemophilia Centre certification systems across Europe"
Rome (Italy), July 11th 2013
GUEST EDITORS: Gabriele Calizzani, Giuliano Grazzini, Pier Mannuccio Mannucci
Blood Transfus 12, Supplement no. 3, April 2014 - ISSN 1723-2007
w w w. b l o o d t r a n s f u s i o n . i t
Edizioni SIMTI
Blood Transfus DOI 10.2450/2012.00??????
© SIMTI Servizi Srl
1
ISSN 1723-2007
Edizioni SIMTI
© SIMTI Servizi Srl
Official journal of:
Società Italiana di Medicina Trasfusionale e Immunoematologia, SIMTI
Associazione Italiana dei Centri Emofilia, AICE
Hrvatsko društvo za hematologiju i transfuzijsku medicinu, HDHTM
Sociedad Española de Transfusión Sanguinea y Terapia Celular, SETS
Affiliated Societies of the journal:
Associação Portuguesa de Imuno-Hemoterapia, APIH - Hellenic Society of Blood Transfusion, HSBT
Editor-in-Chief
Claudio Velati
claudio.velati@simti.it
Associate Editors
Giovanni Di Minno
Massimo Franchini
Joan Ramon Grifols
Irena Jukić
Giancarlo M Liumbruno
Pier Mannuccio Mannucci
Daniele Prati
Roberto Reverberi
Luisa Romanò
Giuseppe Tagariello
Tomislav Vuk
Alberto Zanella
Affiliated Society Editors
Maria Helena Gonçalves, APIH
Alice Maniatis, HSBT
Massimo Morfini, AICE
Eduardo Muñiz-Diaz, SETS
Ana Planinc Peraica, HDHTM
Executive Director
Stefano Antoncecchi
Founder
Lorenzo Lapponi
Past Editors-in-Chief
Lorenzo Lapponi, 1956-1964
Carlo Alberto Lang, 1965-1966
Roberto Venturelli, 1967-1968
Rosalino Sacchi, 1969-1978
Giorgio Reali, 1979-2006
Editorial Office
Luisa Stea and Francesca Fermi
Via Desiderio, 21 - 20131 Milano
Website
www.bloodtransfusion.it
Printing
Grafica Briantea Srl
Via per Vimercate, 25/27 - 20040 Usmate (MI)
International Editorial Board
Jean-Pierre Allain, United Kingdom
Giuseppe Aprili, Italy
John Barbara, United Kingdom
Lydia Blanco, Spain
Ines Bojanić, Croatia
Pietro Bonomo, Italy
Dialina Brilhante, Portugal
Maria Domenica Cappellini, Italy
Jean-Pierre Cartron, France
Giancarlo Castaman, Italy
Francine Décary, Canada
Josè António Duran, Portugal
Willy A Flegel, United States of America
Gilles Folléa, The Netherlands
Zulmira Fonseca, Portugal
Gabriella Girelli, Italy
Giuliano Grazzini, Italy
Ana Hećimović, Croatia
Giancarlo Icardi, Italy
Syria Laperche, France
Luis Larrea, Spain
Franco Locatelli, Italy
Aurelio Maggio, Italy
Michael Makris, United Kingdom
Ivanka Mihaljević, Croatia
Manuel Muñoz, Spain
Mario Muon, Portugal
Alessandro Nanni Costa, Italy
Salvador Oyonarte, Spain
Arturo Pereira, Spain
Flora Peyvandi, Italy
Paolo Rebulla, Italy
Angiola Rocino, Italy
Elena Santagostino, Italy
Dorotea Šarlija, Croatia
Erhard Seifried, Germany
Paul FW Strengers, The Netherlands
Cees L van der Poel, The Netherlands
Jonathan H Waters, United States of America
Alessandro Zanetti, Italy
Tribunale di Milano
Authorisation n° 380, 16th June 2003
This number is published in 700 copies.
Printed in April 2014
The journal is indexed in PubMed-MEDLINE,
Google Scholar, Embase and Scopus and PubMed Central
Blood Transfusion articles are indexed in Journal of Citation Reports
(JCR) for Impact Factor determination.
Impact Factor 2012: 1,858.
Associated with USPI
Unione Stampa Periodica Italiana
CONTENTS
PREFACE
s491
Claudio Velati
EDITORIAL
Haemophilia Centre Certification Systems: optional or optimal choice for healthcare systems?
Gabriele Calizzani, Michael Makris, Pier Mannuccio Mannucci, Domenica Taruscio, Giuliano Grazzini,
Fabrizio Oleari
s492
HAEMOPHILIA CENTRES CERTIFICATION SYSTEMS ACROSS EUROPE AND NORTH AMERICA
Haemophilia Centre certification system across Europe: the Belgian experience
Cedric Hermans
Quality of haemophilia care in the Netherlands: new standards for optimal care
Frank W.G. Leebeek, Kathelijn Fischer
A certification/accreditation model for Haemophilia Centres in Italy
Pier Mannuccio Mannucci, Ivana Menichini
The Italian institutional accreditation model for Haemophilia Centres
Gabriele Calizzani, Fabio Candura, Ivana Menichini, Romano Arcieri, Giancarlo Castaman,
Alessandro Lamanna, Maria R. Tamburrini, Antonio Fortino, Monica Lanzoni, Samantha Profili,
Simonetta Pupella, Giancarlo M. Liumbruno, Giuliano Grazzini
The European Haemophilia Network (EUHANET)
Michael Makris, Gabriele Calizzani, Kathelijn Fischer, Alexander Gatt, Estelle Gilman, Robert Hollingsworth,
Thierry Lambert, Riitta Lassila, Pier Mannuccio Mannucci, Flora Peyvandi, Jerzy Windyga
The methodology for defining the European Standards for the certification of Haemophilia Centres in Europe
Fabio Candura, Ivana Menichini, Gabriele Calizzani, Paul Giangrande, Pier Mannuccio Mannucci, Michael Makris
The European standards of Haemophilia Centres
Paul Giangrande, Gabriele Calizzani, Ivana Menichini, Fabio Candura, Pier Mannuccio Mannucci, Michael Makris
The haemophilia certification system in Canada
Davide Matino, Jerry Teitel, David Page, Arun Keepanasseril, Alfonso Iorio, Irwin Walker
The National Haemophilia Program Standards, Evaluation and Oversight Systems
in the United States of America
Mark W. Skinner, J. Michael Soucie, Kathryn McLaughlin
s497
s501
s505
s510
s515
s519
s525
s531
s542
THE MODEL FOR THE PREVENTION AND REDUCTION OF HEALTH AND SOCIAL IMPACTS
OF INHERITED BLEEDING DISORDERS IN ITALY
Institutional accreditation of Health Services in Italy: the long road to quality
Antonio Fortino, Francesco Di Stanislao
Current and evolving features in the clinical management of haemophilia
Antonio Coppola, Massimo Morfini, Ernesto Cimino, Antonella Tufano, Anna M. Cerbone, Giovanni Di Minno
Uncovered needs in the management of inherited bleeding disorders in Italy
Romano Arcieri, Angelo C. Molinari, Stefania Farace, Giuseppe Mazza, Alberto Garnero, Gabriele Calizzani,
Paola Giordano, Emily Oliovecchio, Lorenzo Mantovani, Lamberto Manzoli, Paul Giangrande
The social burden and quality of life of patients with haemophilia in Italy
Yllka Kodra, Marianna Cavazza, Arrigo Schieppati, Marta De Santis, Patrizio Armeni, Romano Arcieri,
Gabriele Calizzani, Giovanni Fattore, Lamberto Manzoli, Lorenzo Mantovani, Domenica Taruscio
Current status of Italian Registries on inherited bleeding disorders
Hamisa Jane Hassan, Massimo Morfini, Domenica Taruscio, Francesca Abbonizio, Adele Giampaolo,
Yllka Kodra, Emily Oliovecchio, Luciano Vittozzi
Blood Transfus 2014; 12, Suppl 3
© SIMTI Servizi Srl
s551
s554
s563
s567
s576
Definition of an organisational model for the prevention and reduction of health
and social impacts of inherited bleeding disorders
Gabriele Calizzani, Ivana Menichini, Fabio Candura, Monica Lanzoni, Samantha Profili, Maria Rita Tamburrini,
Antonio Fortino, Stefania Vaglio, Giuseppe Marano, Giuseppina Facco, Emily Oliovecchio, Massimo Franchini,
Antonio Coppola, Romano Arcieri, Cinzia Bon, Marco Saia, Sabina Nuti, Massimo Morfini, Giancarlo M. Liumbruno,
Giovanni Di Minno, Giuliano Grazzini
s582
REGIONAL, NATIONAL AND EUROPEAN ACTIONS IN THE FIELD OF RARE DISEASES
The Italian National Centre for Rare Diseases: where research and public health translate into action
Domenica Taruscio, Linda Agresta, Annalisa Amato, Giuseppe Bernardo, Luana Bernardo, Francesca Braguti,
Pietro Carbone, Claudio Carta, Marina Ceccarini, Federica Censi, Simona Coppola, Patrizia Crialese,
Marta De Santis, Stefano Diemoz, Carlo Donati, Sabina Gainotti, Gianluca Ferrari, Giovanna Floridia,
Claudio Frank, Rosa Giuseppa Frazzica, Amalia E. Gentile, Orietta Granata, Yllka Kodra, Manuela Latrofa,
Paola Laricchiuta, Armando Magrelli, Cristina Morciano, Agata Polizzi, Stefania Razeto, Marco Salvatore,
Antonella Sanseverino, Daniele Savini, Paola Torreri, Fabrizio Tosto, Flavia Villani, Giorgio Vincenti,
Luciano Vittozzi
The Italian National Rare Diseases Registry
Domenica Taruscio, Yllka Kodra, Gianluca Ferrari, Luciano Vittozzi
and the National Rare Diseases Registry Collaborating Group
The Italian National Plan on rare diseases
Maria Elena Congiu
Piedmont and Aosta Valley inter-regional network in the context
of the Italian National Network for rare diseases
Simone Baldovino, Elisa Menegatti, Vittorio Modena, Maria Maspoli, Flavia Avanzi, Dario Roccatello
Centres of Expertise and European Reference Networks: key issues in the field of rare diseases. The EUCERD
Recommendations
Domenica Taruscio, Amalia E. Gentile, Teresinha Evangelista, Rosa G. Frazzica,
Kate Bushby, Antoni Moliner Montserrat
European Reference Networks for rare diseases: the vision of patients
Terkel Andersen, Yann Le Cam, Ariane Weinman
s591
ACKNOWLEDGEMEMETS
S628
s606
s614
s617
s621
s626
Citation of the manuscripts published in this volume should be as follows
Author(s). Title. Journal year; Volume (Suppl 4): page number.
E.g.: Taruscio D, Kodra Y, Ferrari G et al. The Italian National Rare Diseases Registry. Blood Transfus 2014; 12 (Suppl 3): s606-13.
PREFACE
Preface
Claudio Velati
Editor-in-Chief of Blood Transfusion
Haemophilia and other inherited bleeding disorders
are life-threatening or chronically debilitating diseases
whose prevalence is less than 5 over 10,000 persons in
the European Union. Inherited bleeding disorders could
be regarded as a case study in the field of health services
research on rare disorders (RDs).
In the light of the principles contained in the
Cross-border Healthcare European Directive, the
Italian National Blood Centre, as a part of the Italian
National Institute of Health, has recently organised in
Rome an international meeting on Haemophilia Centre
Certification Systems across Europe.
The meeting provided the opportunity for an
official presentation of the European Guidelines for the
certification of Haemophilia Centres.
The meeting stimulated a fruitful discussion among
scientific societies, international, national and regional
institutions and experts on how to guarantee patients
suffering from RDs to benefit of Network of Centres of
Expertise and specific clinical pathways.
This resulted in a number of manuscripts of
remarkable scientific and organisational importance
that I consider a valuable contribution to the scientific
community as well as to healthcare systems in Europe
and North America.
Blood Transfusion has the pleasure to publish a
Special Issue on this challenging event and on the several
related contributions provided by other experts.
I would like to give my hearty thanks to Gabriele
Calizzani, Giuliano Grazzini and Pier Mannuccio
Mannucci for having kindly accepted to be the Guest
Editors.
Blood Transfus 2014; 12 Suppl 3: s491 DOI 10.2450/2014.0100-14s
© SIMTI Servizi Srl
s491
EDITORIAL
Haemophilia Centre Certification Systems: optional or optimal choice
for healthcare systems?
Gabriele Calizzani1, Michael Makris2, Pier Mannuccio Mannucci3, Domenica Taruscio4, Giuliano
Grazzini1, Fabrizio Oleari5
1
National Blood Centre, National Institute of Health, Rome, Italy; 2Department of Cardiovascular Science, University of
Sheffield, United Kingdom; 3Scientific Direction, IRCCS Ca' Granda Maggiore Policlinico Hospital Foundation, Milan,
Italy; 4National Centre for Rare Diseases, National Institute of Health, Rome, Italy; 5National Institute of Health, Rome, Italy
On July 11th 2013, an international meeting on
Haemophilia Centre Certification Systems across
Europe was held at the National Institute of Health in
Rome1 with the goal of evaluating the possibility of
transposing the principles contained in the Directive
2011/24/EU2, usually referred to as the Cross-border
Healthcare Directive, into the reality of the current health
systems of Member States (MSs). In fact, haemophilia
and other inherited bleeding disorders (IBDs) meet
the definition of rare diseases (RDs) provided by the
European Commission as they are life-threatening or
chronically debilitating diseases whose prevalence is
less than 5 in 10,000 persons in the EU3.
The Cross-border Healthcare Directive aims to
ensure access to healthcare meeting defined quality
and safety criteria, as well as patient mobility within
the European Union (EU) MSs through mutual
assistance and cooperation2. Moreover, it encourages
the development of Centres of Expertise (CoE) and
European Reference Networks in the field of RDs.
The provision of an optimal level of healthcare to
IBD patients requires the availability of multidisciplinary
teams at specialised Haemophilia Centres (HCs)4,5.
However, many of the health facilities calling themselves
HCs worldwide vary in size, expertise and services
provided. In order to assure equitable access and quality
of care across their health systems, many Countries are
in the process of developing and implementing standards
and certification/accreditation systems for HCs.
In Belgium, quality and efficiency of haemophilia
care are negatively influenced by the lack of an official
recognition, certification and an auditing programme
and specific funding for HCs by the Belgian Ministry of
Health6. In the Netherlands, since 2009, a formal process
to draft new quality standards for HCs has been carried
out and the text was formally approved by the Central
body of Experts on quality standards in clinical care and
the Ministry of Health in 20137. HCs have to apply for
certification after an audit performed by a team composed
of trained haemophilia clinicians, nurses and an officer
from a specialised auditing company. The certificate is
reviewed annually and audits are scheduled every three
years. In Italy, since 2008, a professional accreditation
programme proved to be successful in improving good
clinical practice and developing benchmark activities
among peers 8,9. In parallel, a complementary HCs
institutional accreditation system was developed9,10.
The defined requirements for HC healthcare delivery
are considered necessary and appropriate in order to
provide services such as basic levels of healthcare under
the aegis of the National Health Service.
These experiences, along with those from the
United Kingdom11, provided the inspiration for and led
to the development and production of the European
Guidelines for the certification of HCs in the context of
the European Haemophilia Network project (EUHANET,
www.euhanet.org)12, in which the National Institute of
Health, through the National Blood Centre, participated
as collaborating partner. The European Guidelines have
been discussed and reviewed by a large number of EU and
non-EU stakeholders in different inclusive consultation
processes that brought a highly qualified added value
to the document13,14. All European HCs will be invited
to apply for certification. The implementation of these
European Guidelines and the application process on
a voluntary basis to the European certification system
should be considered as the first stage in order to shape the
upcoming European Haemophilia Network, as a part of
the wider Network of reference of CoE for RDs envisaged
by the Cross-border Healthcare Directive (article 12)2.
Similar developments have been taking place in
Canada and the United States of America (USA). In
Canada, an accountable system of haemophilia care has
been developed based on a set of uniform and national
standards. It is aimed at being needs-based, data-driven
and supported by evidence of effectiveness. A full audit
process, modelled on the Irish and UK experience, has
been planned and carried out through interviews and
patient questionnaires15. At present, there is no formal
HCs accreditation system in the USA. Nevertheless,
a number of programmes and systems are in place to
promote and to assess the level of adherence to best
practices, monitor patient outcomes and encourage
continuous operational improvement16.
Blood Transfus 2014; 12 Suppl 3: s492-4 DOI 10.2450/2014.0076-14s
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© SIMTI Servizi Srl
Haemophilia Centre Certification Systems
In Europe, alongside the establishment of a CoE
network, the organisation of healthcare pathways through
the contribution of relevant experts and the exchange of
professional expertise has been identified by the European
Union Committee of Experts on Rare Diseases (EUCERD)
as a key policy in the management of patients suffering
from RDs17. An example is provided by the project,
funded in 2010 by the Italian Ministry of Health, on the
Definition of a model of disease management of patient with
congenital bleeding disorders aimed at the prevention and
reduction of both health and social impact of the disease
and its complications. Alongside unsolved challenges in
clinical management of haemophilia, patients and their
treaters are now facing new challenges arising from
age-related co-morbidities (e.g. cardiovascular diseases,
malignancies)18. As a consequence, in order to define the
most appropriate diagnostic and therapeutic strategies
for identifying, preventing and treating age-related comorbidities, a closer cooperation among specialists would
be required. However, in Italy a wide variation within and
between Regions in terms of volume of activity and of
organisational models of haemophilia care was observed19.
This could at least partially explain the reason why patients
must still travel long distances to attend a HC. On the basis
of the emerging needs of haemophilia patients5,20, a disease
management model for IBDs improving the quality, safety
and efficiency in the delivery of basic/essential levels of
healthcare by the National Health Service was developed
after a highly inclusive process21. With the Agreement
between the Government and the Regions of March 13th,
201322, a formal commitment was taken by the Regions to
adopt healthcare pathways and an institutional accreditation
system for IBDs on the basis of the recommendations
established at national level for planning healthcare
delivery23, and for identifying organisational requirements
and standards for HCs8,10. Notwithstanding this, it is still
necessary to improve the process of data collection, in order
to support performance of benchmarking and outcome
measurement to inform any future strategies19,24.
The demand for clotting factor concentrates represents
the main driver of total direct costs of haemophilia care25.
However, in order to assess the sustainability of the
haemophilia model of care, further studies focusing also
on the social burden of the disease are required. According
to the findings of the project Social and Economic Burden
and Health-Related Quality of Life in Patients with RD in
Europe (BURQOL RD, www.burqol-rd.com) carried out
on a sample of Italian haemophilia patients26, an improved
quality of life associated with the current regimen of care
has a direct impact on the patient's life as well as on the
healthcare and non-healthcare resources consumed and
related to the disease (e.g. informal care, productivity loss),
and on the patient's capacity to contribute positively to the
social-economic system.
The improvement of diagnosis, accessible and costefficient quality healthcare assistance is an important
objective, especially in the field of RDs in which the
Italian National Institute of Health has been engaged
for several years27. In RDs, one of the main issues is to
collect epidemiological data on the prevalence28. However,
where expertise is rare, the need to gather skills, share and
disseminate information and knowledge (e.g. international
and multicentre clinical trials) is also envisaged with
economically efficient use of resources, considering the
current economic and financial context.
As pointed out by Taruscio et al.29 and Andersen and
co-workers30, quality criteria and standards for the delivery
of services by CoE, whether considered for groups of
RDs or a single RD, are set on the basis of European
recommendations shared with patient organisations.
All MSs are called on to establish such CoE within their
national plans or strategies for RDs. Examples are provided
by the inspiring principles driving the development of the
Italian national plan for RDs31, as well as by the regional
plan of Piedmont and Aosta Valley Regions32.
As a common element, in all experiences of certification
for HCs, there is a strong participation and involvement of
patient organisations in the process, either as a promoter
(Italian Institutional model, Canada, EUHANET) or as a
component of the inspection team (Canada, UK, Ireland).
A difference is the voluntary vs mandatory adherence to
the accreditation models that is a characteristic of the
Dutch and the Italian institutional models. Whereas the
evaluation procedures are based on self-assessment and
peer-review procedures in the Italian professional model,
the Dutch, Canadian and Italian Institutional models are
based on external evaluation carried out by third party
and independent auditors. All models aim to achieve a
standardisation of haemophilia care and recognition by
Health Authorities.
Certification/accreditation systems of CoE for
groups of RDs or a single RD are an on-going process
throughout all Europe. The experience acquired in
haemophilia and other IBDs can be regarded as a pilot
model in the field of accreditation and designation of
CoE for RDs. It is the result of policy development
following a vertical scheme/flow (top-down adoption
from European, national to regional level and
bottom-up pressure from patient organisations to health
policy makers) and at the horizontal level through the
involvement and consultation of key stakeholders such
as health professionals and patient bodies, RD experts,
policy and decision makers.
In conclusion, the international meeting Haemophilia
Centre Certification Systems across Europe contributed
to providing a wide-angle snapshot of the on-going HCs
certification / accreditation systems which are an addedvalue choice to enhancing national models of public
Blood Transfus 2014; 12 Suppl 3: s492-4 DOI 10.2450/2014.0076-14s
493
Calizzani G et al
healthcare and can play a key role in promoting the
development of international reference networks for RDs.
Conflict of interest
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.
17)
18)
19)
20)
References
1)
2)
3)
4)
5)
6)
7)
8)
9)
10)
11)
12)
13)
14)
15)
16)
International Meeting "Haemophilia Centre Certification
Systems across Europe". Centro Nazionale Sangue. Available
at http://www.centronazionalesangue.it/newsbox/seminariomalattie-emorragiche-congenite-mec. Accessed on 05/03/2014.
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
cross-border healthcare. Availablt ae http://eur-lex.europa.eu/
LexUriServ/LexUriServ.do?uri=OJ:L:2011:088:0045:0065:e
n:PDF. Accessed on 15/01/2014.
European Parliament and Council. Regulation (EC)
141/2000 of the European Parliament and of the
Council of 16 December 1999 on orphan medicinal
products. Official Journal 2000; L 18:1-5. Available
at http://eurlex.europa.eu/LexUriServ/LexUriServ.do?uri=
OJ:L:2000:018:0001:0005:en:PDF. Accessed on 15/01/2014.
Colvin BT, Astermark J, Fischer K, et al. European principles
of haemophilia care. Haemophilia 2008; 14: 361-374.
Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al.
Guidelines for the management of haemophilia. Haemophilia
2013; 19: e1-47.
Hermans C. Haemophilia Centre certification system across
Europe: the Belgian experience. Blood Transfus 2014; 12
(Suppl 3): s497-500.
Leebeek FWG, Fischer K. Quality of haemophilia care in the
Netherlands: new standards for optimal care. Blood Transfus
2014; 12 (Suppl 3): s501-4.
Calizzani G, Vaglio S, Arcieri R, et al. Models for institutional
and professional accreditation of haemophilia centres in Italy.
Haemophilia 2013; 19: e248-55
Mannucci PM, Menichini I. A certification/accreditation
model for Haemophilia Centres in Italy. Blood Transfus 2014;
12 (Suppl 3): s505-9.
Calizzani G, Candura F, Menichini I, et al. The Italian
institutional accreditation model for the Haemophilia Centres.
Blood Transfus 2014; 12 (Suppl 3): s510-4.
Haemophilia Alliance. A National Service Specification for
Haemophilia and other Inherited Bleeding Disorders, 2nd edn.
London. The Haemophilia Alliance, 2006. Available at: http://
www.ukhcdo.org/docs/HaemAlliance-NatSvsSpec2006.pdf.
Accessed on 15/01/2014.
Makris M, Calizzani G, Fischer K, et al. The European
Haemophilia Network (EUHANET). Blood Transfus 2014;
12 (Suppl 3): s515-8.
Giangrande P, Calizzani G, Menichini I, et al. The European
standards of Haemophilia Centres. Blood Transfus 2014; 12
(Suppl 3): s525-30.
Candura F, Menichini I, Calizzani G, et al. The methodology
for defining the European Standards for the certification of
Haemophilia Centres in Europe. Blood Transfus 2014; 12
(Suppl 3): s519-24.
Martino D, Teitel J, Page D, et al. The haemophilia certification
system in Canada. Blood Transfus 2014; 12 (Suppl 3): s53141.
Skinner MW, Soucie JM, McLaughlin K. The National
Haemophilia Program Standards, Evaluation and Oversight
21)
22)
23)
24)
25)
26)
27)
28)
29)
30)
31)
32)
Systems in the United States of America. Blood Transfus 2014;
12 (Suppl 3): s542-8.
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/EUCERD
RecommendationCE.pdf. Accessed on 05/03/2014
Coppola A, Morfini M, Cimino E, et al. Current and evolving
features in the clinical management of haemophilia. Blood
Transfus 2014; 12 (Suppl 3): s554-62.
Nuti S. La sostenibilità del modello di cura. Available at http://
www.centronazionalesangue.it/sites/default/files/nuti_la_
sostenibilita_del_modello_di_cura.pdf. Accessed on 23/02/2014
Arcieri R, Molinari AC, Farace S. Uncovered needs in the
management of inherited bleeding disorders in Italy. Blood
Transfus 2014; 12 (Suppl 3): s563-6.
Calizzani G, Menichini I, Candura F, et al. Definition of an
organisational model for the prevention and reduction of health
and social impacts of inherited bleeding disorders. Blood
Transfus 2014; 12 (Suppl 3): s582-8.
Official Journal of Italian Republic no. 107 May 9th, 2013.
Accordo, ai sensi dell'articolo 4 del decreto legislativo
28 agosto 1997, n.281, tra il Governo, le Regioni e le
Province autonome di Trento e Bolzano sulla definizione
dei percorsi regionali o interregionali di assistenza per le
persone affette da Malattie Emorragiche Congenite (MEC).
Available at http://www.centronazionalesangue.it/sites/
default/files/accordo_csr_13.03.2013_gu_n._107_09.05.2013_
assistenza_mec.pdf. Accessed on 16/02/2014.
Fortino A, Di Stanislao F. Institutional accreditation of Health
Services in Italy: the long road to quality. Blood Transfus 2014;
12 (Suppl 3): s551-3.
Hassan HJ, Morfini M, Taruscio D, et al. Current status of Italian
Registries on inherited bleeding disorders. Blood Transfus 2014;
12 (Suppl 3): s576-81.
Lanzoni M, Candura F, Calizzani G, et al. Public expenditure
for plasma-derived and recombinant medicinal products in Italy.
Blood Transfus 2013; 11 (Suppl 4): s110-7.
Kodra Y, Cavazza M, Schieppati A, et al. The social burden
and quality of life of patients with haemophilia in Italy. Blood
Transfus 2014; 12 (Suppl 3): s567-75
Taruscio D, Agresta L, Amato A, et al. The Italian National
Centre for Rare Diseases: where research and public health
translate into action. Blood Transfus 2014; 12 (Suppl 3):
s591-605.
Taruscio D, Kodra Y, Ferrari G, et al. The Italian National Rare
Diseases Registry. Blood Transfus 2014; 12 (Suppl 3): s606-13.
Taruscio D, Gentile AE, Evangelista T, et al. Centres of Expertise
and European Reference Networks: key issues in the field of rare
diseases. The EUCERD Recommendations. Blood Transfus
2014; 12 (Suppl 3): s621-5.
Andersen T, Le Cam Y, Weinman A. European Reference
Networks for rare diseases: the vision of patients. Blood Transfus
2014; 12 (Suppl 3): s626-7.
Congiu ME. The Italian National Plan for Rare Diseases. Blood
Transfus 2014; 12 (Suppl 3): s614-6.
Baldovino S. Menegatti E, Modena V, et al. Piedmont and
Aosta Valley inter-regional network in the context of the Italian
National Network for Rare Diseases. Blood Transfus 2014; 12
(Suppl 3): s617-20.
Correspondence: Gabriele Calizzani
Italian National Blood Centre
Via Giano della Bella 27
00162 Rome, Italy
e-mail address: areaplasma.cns@iss.it
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HAEMOPHILIA CENTRE CERTIFICATION SYSTEMS ACROSS EUROPE AND NORTH AMERICA
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REVIEW
Haemophilia Centre certification system across Europe:
the Belgian experience
Cedric Hermans
Haemostasis and Thrombosis Unit, Division of Haematology, Haemophilia Clinic, Saint-Luc University Hospital,
Bruxelles, Belgium
Introduction
Haemophilia is characterised by recurrent bleeding,
especially into the joints, which eventually results in
chronic crippling arthropathy. Since the early 1960s,
replacement therapy using intravenous clotting factors
has become available1. Clotting factor concentrates can
be administered as on-demand therapy in the event of
bleeding episodes, or at regular time intervals, often three
times a week, as prophylaxis-therapy to prevent bleeding.
Regardless of the strategy chosen, haemophilia care
requires intensive life-long treatment. By definition,
patient management is multidisciplinary, involving
nurses, physiotherapists and social workers, as well as
haemophilia physicians or haematologists, surgeons,
specialists in rehabilitation and other relevant medical
personnel. Delivering high-quality haemophilia care
requires skill and experience, from first diagnosis and
continuing throughout patients' life.
Several initiatives have recently been launched in order
to review and assess current trends in haemophilia treatment
across Europe, with the ultimate goal of standardising
patient care and promoting the best medical practices
across the board. This paper outlines the current state
of haemophilia care in Belgium and reports on ongoing
national and European initiatives aimed at certifying
specialised Haemophilia Treatment Centres (HTCs).
Haemophilia care in Belgium
Approximately 1,150 patients with a deficiency in
coagulation factor VIII (FVIII) or factor IX (FIX), including
haemophilia carriers with clotting factor deficiency, are
currently included in the Belgian patient Haemophilia
Association (AHVH) registry. Given the lack of official
national independent registry, this represents the most valid
demographic estimation currently available. In 2011, the
total cost of haemophilia care related to using FVIII and FIX
concentrates, as well as by-passing agents, was estimated
by the Belgian National Institute of Health (INAMI) at
approximately 81 million euro (Table I). As is the case for
most countries, in Belgium the cost of replacement therapy
has been steadily increasing over the last 10 years.
The Belgian paradox and ambiguity of
haemophilia care
Haemophilia patients, along with the health
professionals involved in their care, benefit from
excellent access to replacement therapy. Plasma-derived
and recombinant FVIII or FIX concentrates are available
with no restrictions or limitations of use. This allows for
prophylaxis to be given to all ages, invasive procedures to
be successfully conducted, and coagulation factor inhibitors
to be eradicated using high-dose immune tolerance, where
appropriate. Concentrates can easily be obtained from
most hospitals, even from private pharmacists, and selfand home-treatment is widely available. The cost of each
FVIII unit, excluding subsequent post-procurement taxes
and cost-reduction measures implemented by national
government, as well as that of service and support costs,
is among the highest in Europe, ranging from 0.81-0.98
euro per unit. This renders the Belgian haemophilia market
particularly attractive to the pharmaceutical industry. The
exceptions to this rule are by-passing agents, such as Factor
Eight Inhibitor Bypassing Activity (FEIBA), and FIX
concentrates, with the former priced at one of the lowest
Table I - Cost of replacement therapy for haemophilia in Belgium (in euros).
Factor VIII (plasma-derived and recombinant)
Factor IX (plasma-derived)
Factor IX (recombinant)
FEIBA
Novo Seven
Total Belgian population
2006
2007
2008
2009
2010
2011
53,901,207
56,035,135
61,902,053
61,662,285
64,127,153
65,624,411
552,223
462,114
510,704
676,431
642,646
662,424
3,666,620
3,994,425
4,863,122
5,207,261
6,357,121
6,597,562
578,834
772,044
1,166,180
729,312
1,545,327
1,525,654
2,039,854
4,241,009
2,563,050
2,584,382
2,849,959
6,692,361
10,511,382
10,584,534
10,666,866
10,753,080
10,839,905
11,000,638
FEIBA: Factor Eight Inhibitor Bypassing Activity
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Hermans C
levels in Europe and the latter sold at lower prices
compared to other countries.
In addition to coagulation factors, other treatment
elements, such as specialised consultations, laboratory
tests and specific treatments like dental care, orthopaedic
surgery and physiotherapy receive full financial support.
At present, there are 10 HTCs registered with the World
Federation of Haemophilia, spread throughout the country,
with five in Flanders, four in Bruxelles and one in Wallonia.
Access to high-quality replacement therapy and specialised
haemophilia care has been made possible and continuously
improved by the sustained initiatives, effort and input of the
AHVH, founded over 50 years ago.
Yet these positive features are not sufficient to outweigh
the numerous weaknesses inherent to haemophilia care in
Belgium. Unlike concentrates, which are fully reimbursed,
there is currently no financial support for training courses
on self- and home-therapy, systematic multidisciplinary
consultation or comprehensive care. Furthermore, none of
the existing centres are officially recognised or certified
by the Belgian Ministry of Health, nor are they audited
or specifically funded for haemophilia care. As a result,
most centres are highly dependent on external funding
provided by the pharmaceutical industry. In addition, there
is no independent national registry, rendering it difficult
to provide valid data regarding the use of resources,
incidence of inhibitor development and patient outcomes
at a national level. Given this context, implementing
a national tender process for concentrates appears
unfeasible. Factor concentrates can also be prescribed by
general practitioners, for a significant but undetermined
proportion of patients that primarily comprises those with
mild or moderate disease. This therefore means there is
no incentive to regularly attend specialised clinics. The
percentage of Belgian haemophilia patients who are not
regularly followed-up in Haemophilia Centres is thus
still unknown. For this reason, it may be assumed that
the physical health, quality of life and life expectancy of
these patients could be markedly improved if they were
regularly referred to specialised centres.
Current adherence to European haemophilia
care principles: the Belgian situation
In order to standardise practices, an expert group of
haemophilia care providers drew up the Principles of
Haemophilia Care in 2008, published by Colvin et al. in
Haemophilia2. This document summarises the essential
components of a comprehensive national haemophilia
care service in the form of 10 recommendations,
provided in Table II. They emphasise the need for service
coordination, with the first recommendation stating
that this could be best achieved by means of a national
committee involving all stakeholders, charged with
overseeing and planning all national services. The second
recommendation, almost as relevant as the first, stresses
the need for a confidential national registry of all patients
affected by the disease. Knowing the exact number of
patients with congenital bleeding disorders, along with
their disease severity, makes it possible to better plan
the care service, and particularly to precisely calculate
what therapeutic resources will be required. The third
recommendation advises that comprehensive haemophilia
care centres should be established within an appropriate
network, with patient distribution and geographic factors
likely constituting the basis of its construction. The other
recommendations relate to detailed service provision
at the centres, such as monitoring adverse therapeutic
events, home therapy and prophylaxis implementation.
The European principles of haemophilia care are now
being considered as a framework for service development
over the entire continent, especially in countries with
not as well-developed coordinated organisation. When
campaigning for improvements in haemophilia care
services, the strategy of involving national government
health departments has proven useful to advocates. To
promote adherence within the European community,
the 10 recommendation principles have been presented
to members of the European Parliament with positive
results.
Table II - The European principles of care according to
Colvin et al.2.
1.
A central haemophilia organisation with supporting local groups.
2.
National haemophilia patient registries.
3.
Comprehensive Care Centres (CCCs) and Haemophilia Treatment
Centres (HTCs).
4.
Partnership in delivery of care.
5.
Safe and effective concentrates at optimum treatment levels.
6.
Home treatment and delivery.
7.
Prophylactic (preventive) treatment.
8.
Specialist services and emergency care.
9.
Management of inhibitors.
10.
Education and research.
The service provision level within different
European countries, in comparison with the principles
of haemophilia care recommendations, has recently been
audited by two studies, one performed by physicians and
the other by patient organisations3,4. The first revealed
that the principles of haemophilia care were generally
applied throughout Europe, yet with centralised care not
being available for all patients (Table III). Moreover, a
number of features pertaining to the manner in which
national care is organised, such as using registries,
physiotherapy coverage, formal paediatric care and
laboratory services, warrant improvements. For
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Certification of haemophilia centres in Belgium
Table III - Summary of adherence to Principles 1, 2, 3 and 7 according to country3.
Country
N. of centres
Principle 1
Central
organisation
Principle 2
Patient registry
Principle 3
All patients
treated in CCC/
HTC
N. of CCC/
HTC per million
inhabitants
Principle 7
% of children on
prophylaxis
Principle 7
% of adults on
prophylaxis
Belgium
1
No
No
No
0.83
75-100
50-75
France
1
Yes
Yes
Yes
0.71
75-100
1-25
Germany
2
Yes
Yes
No
0.89
75-100
50-75
Greece
1
Yes
Yes
Yes
0.37
75-100
1-25
Italy
3
Yes
Yes
Yes
0.81
75-100
1-25
Netherlands
2
Yes
No
Yes
0.78
75-100
50-75
Norway
1
Yes
No
Yes
0.40
75-100
50-75
Poland
1
Yes
No
No
0.84
75-100
1-25
Portugal
1
No
No
No
3.77
75-100
1-25
Slovakia
1
Yes
Yes
Yes
7.78
75-100
1-25
Spain
3
No
Yes
Yes
0.91
75-100
1-25
Sweden
1
Yes
No
Yes
0.32
75-100
75-100
Switzerland
1
Yes
Yes
No
1.27
75-100
1-25
United Kingdom
2
Yes
Yes
Yes
1.06
75-100
50-75
Total 21
79% Yes
57% Yes
64% Yes
Median 0.84
IQR0.62-1.11
100% (75-100)
57% (1-25)
36% (50-75)
7% (75-100)
Summary
CCC: Comprehensive Care Centre; HTC: Haemophilia Treatment Centre; IQR: Interquartile range
Belgium, the survey highlighted the absence of both
a national registry and designated comprehensive
Haemophilia care Centres.
National initiative to improve haemophilia care
organisation
In 2007, a new model for haemophilia organisation
in Belgium was proposed, though it has not yet been
implemented5. According to this new model, there
should be a single national coordinating centre in charge
of overseeing over 150 patients with severe FVIII or
FIX deficiency. This centre should be characterised by
significant scientific production, estimated on the basis
of a cumulative impact factor >100 of peer-reviewed
publications over the past 5 years, along with recognised
expertise in haemophilia care. In addition to this, there
should be several smaller HTCs, the exact number of
which still needs to be defined. These centres should
follow up at least 10 severe haemophilia A or B adults
or children, be spread out across the country and provide
access to care and concentrates. This recommended
number of patients per centre is much lower than that
suggested by several established organisations (i.e. the
World Federation of Haemophilia and United Kingdom
Haemophilia Centre Doctors' Organisation, UKHCDO),
and is incompatible with the level of expertise currently
required by haemophilia care. The prescription of
clotting factor concentrates should be restricted to
"haemophilia specialists", the exact qualification and
experience of whom still need to be defined for Belgium.
Since 2007, applications for hosting a comprehensive
Haemophilia care Centre have been submitted by several
hospitals. At the beginning of 2014, the Belgian health
authorities announced that this new plan for haemophilia
care would soon be implemented and granted funding.
In addition to this disease's rarity and complexity,
there are several obstacles to improving haemophilia
care organisation in Belgium. Patient centralisation
in a limited number of specialised centres appears, in
fact, to be negatively impacted by several factors. These
include competition between hospitals, high variability
of patient number between centres and political factors,
with the latter proving particularly significant in a small
but complexly governed country like Belgium.
European initiative of Haemophilia Centre
certification
The European Commission (EC) has asked all
member states to support the creation of European
Reference Networks for all rare diseases. Given this
context, the EC has pledged its support to the European
Haemophilia Network (EUHANET) project, one of its
aims being to create a certification scheme for European
Haemophilia Centres. Following extensive study of the
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Hermans C
scientific literature and communication with all European
countries, a document entitled European Guidelines for the
certification of Haemophilia Centres has been produced.
After several rounds of extensive consultation, the initial
document was modified, and the final version distributed
at an international meeting in Rome in July 2013 and at
the European Parliament in October 2013.
The standard document, consultable at www.euhanet.
org, defines two levels of Haemophilia Centre: European
Haemophilia Treatment Centre (EHTC) and European
Haemophilia Comprehensive Care Centre (EHCCC).
EHCCCs will likely be in charge of over 40 severe
haemophilia patients and offer round-the-clock care, with
high-quality coagulation laboratory back-up and a full
range of facilities. Any centre in Europe can apply for
certification, with applications reviewed by a committee
of medical, nursing and patient representatives. The
application form is available on the EUHANET website.
By January 2014, 44 centres had applied for certification,
including 3 in Belgium. It is worth noting that these Belgian
centres will be certified at the European level prior to
national recognition and funding.
Reference
1)
2)
3)
4)
5)
Nilsson IM, Berntorp E, Lofqvist T et al. Twenty-five years'
experience of prophylactic treatment in severe haemophilia
A and B. J Intern Med. 1992; 232: 25-32.
Colvin BT, Astermark J, Fischer K et al. European principles
of haemophilia care. Haemophilia. 2008; 14: 361-74.
Fischer K, Hermans C. The European Principles of
Haemophilia Care: a pilot investigation of adherence to the
principles in Europe. Haemophilia. 2013; 19:35-43.
O'Mahony B, Noone D, Giangrande PL, Prihodova L.
Haemophilia care in Europe - a survey of 35 countries.
Haemophilia. 2013; 19: e239-47.
Institut National d'Assurance Maladie Invalidité (INAMI).
Comprehensive care pour hémophiles - Maladies
hémorragiques héréditaires chroniques [in French]. Note
CCMC 2007/5.
Conclusions
Belgian haemophilia patients benefit from
unrestricted access to a wide range of plasma-derived or
recombinant clotting factor concentrates and by-passing
agents. Patient care quality and efficiency is, however,
negatively impacted by the absence of a national
haemophilia registry and specific funding, as well as
by the lack of official recognition and certification for
specialised haemophilia centres. In the framework of
the Belgian plan for rare diseases, ongoing national
and European initiatives should soon contribute to
a more efficient organisation of haemophilia care in
Belgium. These include the creation of a national funded
network and, at the European level, official EUHANET
certification of European haemophilia treatment centres.
Keywords: haemophilia, comprehensive care,
certification.
Conflicts of interest
Cedric Hermans has received honoraria for his role
as consultant for and active participation on advisory
boards organised by Baxter, Bayer, Pfizer, CAF-DCF,
SOBI, Ipsen, LFB, CSL-Behring, Novo Nordisk and
Octapharma. He has received research grants or lecture
chair positions from Baxter, Bayer, Pfizer, CAF-DCF,
CSL-Behring, Novo Nordisk, Octapharma and Ipsen.
Correspondence: Cedric Hermans
Haemostasis and Thrombosis Unit
Division of Haematology
Haemophilia Clinic
St-Luc University Hospital
Avenue Hippocrate 10
1150 Bruxelles, Belgium
e-mail: cedric.hermans@uclouvain.be
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ORIGINAL ARTICLE
Quality of haemophilia care in the Netherlands: new standards for optimal
care
Frank W.G. Leebeek1, Kathelijn Fischer2,3
1
Erasmus University Medical Centre, Rotterdam; 2Van Creveldkliniek, University Medical Centre Utrecht, Utrecht,
Julius Center for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht, the Netherlands
3
Background. In the Netherlands, the first formal haemophilia comprehensive care centre was
established in 1964, and Dutch haemophilia doctors have been organised since 1972. Although
several steps were taken to centralise haemophilia care and maintain quality of care, treatment was
still delivered in many hospitals, and formal criteria for haemophilia treatment centres as well as a
national haemophilia registry were lacking.
Material and methods. In collaboration with patients and other stakeholders, Dutch haemophilia
doctors have undertaken a formal process to draft new quality standards for the haemophilia treatment
centres. First a project group including doctors, nurses, patients and the institute for harmonisation of
quality standards undertook a literature study on quality standards and performed explorative visits to
several haemophilia treatment centres in the Netherlands. Afterwards concept standards were defined
and validated in two treatment centres. Next, the concept standards were evaluated by haemophilia
doctors, patients, health insurance representatives and regulators. Finally, the final version of the
standards of care was approved by Central body of Experts on quality standards in clinical care and
the Dutch Ministry of Health.
Results. A team of expert auditors have been trained and, together with an independent auditor,
will perform audits in haemophilia centres applying for formal certification. Concomitantly, a national
registry for haemophilia and allied disorders is being set up.
Discussion. It is expected that these processes will lead to further concentration and improved
quality of haemophilia care in the Netherlands.
Keywords: standards, quality, audit, registry, haemophilia.
Introduction
Haemophilia in the Netherlands
The Netherlands is a densely populated country in
Western Europe and has a population of 16.5 million
inhabitants, who are living on an area of 33,883 Km2,
with a population density of 487 per km2.
Although a formal haemophilia registry is still
lacking, the estimated number of patients with
haemophilia is 1,600 to 1,800, including around 800 with
severe haemophilia (< 0.01 U/mL of coagulation factor
[F]VIII/IX). Simon van Creveld (1894-1971), professor
of paediatrics at the University of Amsterdam since
1938, was the Dutch pioneer regarding the organisation
of haemophilia care.
Historical organisation of Dutch Haemophilia care
1950-1998
Haemophilia care has always been well organised
in our country. Already in 1950, Simon van Creveld
founded a specialized clinic for children with chronic
diseases, including a specialised centre for children
with haemophilia. In 1964, the first haemophilia clinic
in the world was officially opened by the Dutch Queen
Juliana. This haemophilia clinic was an example for
many other clinics in the world, and was recognised
by the World Federation of Haemophilia. In 1971,
Professor van Creveld died and the clinic was named
Van Creveldkliniek. In the late 1960s prophylactic
replacement therapy was introduced1, followed by
home treatment in 1974 and low dose immune tolerance
in 19812. Meanwhile, treatment with cryoprecipitate
infusions was applied in many hospitals in the
Netherlands.
The Dutch Haemophilia Centres Doctors Organisation
(NVHB) was established in 1972 and this organisation
is still active. The doctors from the NVHB meet every
three months. These meetings are also attended by a
representative of the manufacturers of coagulation factor
concentrates, the Haemophilia Patients Organisation
(NVHP) and the haemophilia nurses. Clinical problems
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Leebeek FWG, Fischer K
and management issues are discussed, as well as side
effects of treatment.
In 1981 the Van Creveldkliniek was the national
haemophilia treatment centre and eight hospitals
were recognised as regional treatment centres, but
21 other hospitals also treated haemophilia patients.
This situation remained till 1999, without any quality
control. The number of patients treated in these hospitals
centre varied from 8 to 600 patients, which resulted in a
variability in expertise and quality of care.
1999-2002
In 1999, The Ministry of Health in collaboration
with the doctors from the NVHB and the Dutch
Haemophilia Patient Society (NVHP), wrote a
haemophilia management policy stating that care for
patients with haemophilia should be centralised in
haemophilia treatment centres to ensure quality of care
by concentrating expertise. No distinction was made
between national and regional centres, nor between
treatment centres and comprehensive care centres at that
time. This resulted in 16 haemophilia treatment centres
geographically distributed over the country, ensuring
treatment in hospitals nearby for all patients, most of
these centres treated adults only.
2002-today
In 2002 and 2003 the 1999-haemophilia management
policy was evaluated and it turned out only 6/16
centres complied with the standards of care. It was
advised to further centralise haemophilia care, but
this advice was not followed due to opposition of the
patient organisation, which was strongly in favour of
treatment in hospitals nearby for all. Until 2013 still 13
hospitals were treating haemophilia patients, with patient
numbers ranging from under 20 to over 500 per centre.
A consensus treatment guideline was drafted by doctors
of the NVHB and published in 20093.
Complications of haemophilia and of treatment have
been registered every three months in a national system
(KWARK) since 2002. In addition three treatment
centres report their complications to the European
Haemophilia Safety Surveillance (EUHASS) database,
www.EUHASS.org.
Material and methods
New quality system for haemophilia in the Netherlands
Life-long treatment of haemophilia includes many
medical disciplines and requires experience and
coordination for optimum results. It has been established
that centralised haemophilia care improves patient
outcome in different settings4-6. Although the European
principles of haemophilia care were formally established
in 20087, adherence to these principles is not yet perfect8.
In 2009 the NVHB took the initiative to start for a new
quality system for haemophilia care in the Netherlands.
With financial support of the Ministry of Health a formal
development process was undertaken from 2009 to 2011.
First, a project group consisting of doctors from larger
and smaller haemophilia treatment centres, nurses, and
patient representatives in collaboration with the institute
for harmonisation of quality standards in clinical care
(Stichting HKZ) undertook a study of available literature
on quality standards and performed explorative visits
to two Dutch haemophilia treatment centres. Secondly,
concept standards were defined, which were validated
in two treatment centres to test their use in clinical
practice. Next, the concept standards were evaluated
by haemophilia doctors (NVHB), patients, health
insurance representatives and regulators. Finally, the
final version of the standards of care was approved by
Central body of Experts on quality standards in clinical
care (CCvD-Z/W) and submitted to the regulatory body
at the Dutch Ministry of Health. Approval was obtained
in March 2013.
Results
Standards for delivery of haemophilia care
The most important quality standards for delivery
of haemophilia care are shown in Table I. These quality
standards are considered mandatory for certification
as a haemophilia treatment centre. Each centre should
at least treat 40 patients with severe haemophilia, of
which at least ten children. This quality norm has been
implemented because we felt that in centres with fewer
patients expertise cannot be guaranteed, not only by the
haemophilia doctors and nurses, but also of other members
of the multidisciplinary team involved. One of the new
regulations was that a treatment centre should treat both
children and adults. This will lead to a better transition
of care from the children's hospital to adult care. Also
this will result in optimal genetic counselling and care for
pregnant carriers of haemophilia and women with other
bleeding disorders can be achieved during pregnancy
and at delivery. In the team an internist/haematologist,
as well as a paediatrician/haematologist should be
available. These haemophilia doctors are primarily
responsible for the care of these patients with respect
to treatment of bleeding and coordinate prophylaxis to
prevent bleeding. In addition they coordinate care before
and after surgical procedures or other interventions.
The team also consists of at least one specialised
haemophilia nurse. Nurses are responsible for infusion of
coagulation factor concentrates as well as for instructing
and teaching patients, both children and adults, how to
infuse coagulation factor concentrates and supporting
patients on home treatment. They also are involved in
teaching other nurses in the hospital. In addition, every
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Dutch standards for quality of haemophilia care
centre should have a multidisciplinary team including a
physical therapist, orthopaedic surgeon, rehabilitation
doctor, clinical genetic specialist and social worker or
psychologist. There has to be direct collaboration with
haepatologists or specialist in infectious diseases and
with gynaecologists to take care of pregnant carriers of
haemophilia or women with other bleeding disorders,
including von Willebrand disease. There is a need for a
dedicated dentist or surgeon for dental care in patients
with bleeding disorders. The multidisciplinary team
meets with minimum intervals (Table I). In addition every
haemophilia treatment centre has dedicated laboratory
facilities which offers measurements of coagulation
factor analysis, including FVIII, FIX, von Willebrand
factor and other individual coagulation factors at
all hours. Routine molecular diagnostic analysis of
mutations in FVIII or FIX is performed and centralised
in four treatment centres. All centres have adequate
supply of coagulation factor concentrates for all bleeding
disorders available at all times.
Patients with haemophilia and allied bleeding
disorders who are treated with coagulation factor
concentrates are seen at least once a year in the
haemophilia treatment centre. Patients with severe
haemophilia are seen more often, at least 2 to 4 times
a year. Surgery should always be performed in one of
the haemophilia treatment centres. For every patient
an individual treatment plan is made and available in
the electronic patient files. In this treatment plan, the
diagnosis, treatment in case of acute bleeding or surgery,
and co-morbidity are specified. Carriers of haemophilia,
especially women with reduced FVIII of FIX (<40%),
should be registered in one of the Haemophilia
Treatment Centres (HTCs) in order to receive adequate
treatment for bleeding, pregnancies and delivery, and
obtain genetic counseling.
Certification and auditing of Treatment Centres
After approval of the regulations in March 2013,
candidate treatment centres have to apply for certification
as a Haemophilia Treatment Centre (HTC). This includes
a 1-2 day audit of each candidate centre. For this purpose
a limited number of haemophilia doctors and nurses
received training to act as haemophilia experts-auditors.
Centres will be visited by a team of a doctor, a nurse and
one auditor of an official specialised auditing company
(Det Norske Veritas, Barendrecht, the Netherlands).
The certificate will be evaluated yearly and audits
will be performed every three years. Based on the new
standards that have been set up, four HTCs have decided
to stop their function as haemophilia treatment centre and
two centres have been founded by merging four former
HTCs. Other centres who were previously separated
into a paediatric and adult centre in the same city are
Table I -
Most important quality standards for Haemophilia
Treatment Centres in the Netherlands.
Index
Crucial standards
Note
Number of patients
with severe
haemophilia
Minimum 40 of which at least 10
children
Including both
children and
adults
Multidisciplinary
haemophilia team
Internist-haematologist for adults
Paediatrician-haematologist for
children
Haemophilia nurse/specialised
nurse
Physical therapist
Social worker/psychologist
Dedicated
protocols for
Diagnostics
Treatment of bleeding
Prophylaxis
Peri-operative period
Emergency department
Treatment in case of inhibitors
Treatment of inhibitors
Treatment and prevention of viral
infections
Methods of infusion of
coagulation factors
Guidance of haemophilia carriers
Education for home treatment
Registration of
patients in national
registry
NA
Complication
registration
NA
Regular meetings
of different
disciplines
Adult and paediatric haemophilia
doctors
Every month
Orthopaedic surgeons/physical
therapists and rehabilitation
experts
Every 2
months
Haemophilia
expert available
for 24 hours a day
7 days a week
NA
Every patient
has an individual
treatment plan
NA
For every
bleeding disorder
adequate supply
of coagulation
factor concentrate
available
NA
NA: not applicable.
intensifying collaboration to provide more continuity
of care and operate as a single centre. Currently, there
are in seven candidate HTCs in the Netherlands:
Haemophilia Treatment Centre south-west Netherlands
(Leiden University Medical Centre, Leiden & HAGA
Hospital, The Hague), Haemophilia Treatment Centre
south (Maxima Medical Centre Eindhoven & Maastricht
University Medical Centre), Academic Medical Centre
Amsterdam, University Medical Centre Groningen,
Radboud University Medical Centre Nijmegen,
University Medical Centre Utrecht (van Creveldkliniek),
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Leebeek FWG, Fischer K
and Erasmus University Medical Centre Rotterdam. The
further centralisation of haemophilia care will lead to
larger travel distances for patients, but considering the
presumed benefit and the relatively small distances in
the Netherlands the patients organisation have decided
that quality is more important that proximity.
Registration of patients and coagulation factor
concentrates
Although the Netherlands has a registry of blood
products transfused since April 1999 and a registry
of mortality, viral infections, and side effects of
haemophilia treatment since 2002 (KWARK), there is no
formal registry of Dutch haemophilia patients. Despite
this, participation in a national haemophilia registry is
part of the principles of haemophilia care7 and the Dutch
quality regulations. At the same time of starting the
certification process, additional funding from The Dutch
Organisation for Health Research and Development
(ZONMW) was obtained to initiate a registry of Dutch
patients with haemophilia and allied bleeding disorders.
The registry will use a web-based platform, starting with
a database of all patients with their diagnosis, and links
to electronic diaries and hospital databases in the second
phase of development. The aim of this registry is to
provide exact data on the number of patients according to
diagnosis, the use of various clotting factor concentrates,
safety data and data on outcomes.
The registry will serve several purposes. For
evaluating treatment and side effects, data across
treatment centres can be compared. For decision
makers, the registry will provide an overview of the total
number of patients according to diagnosis, including
data on clotting factor consumption. For research,
the registry will serve as a base for the haemophilia
in the Netherlands (Haemophilia HIN) projects9. It
will identify nationwide sub cohorts (e.g. ex-inhibitor
patients, or HIV infected patients) eligible for specific
studies. Outcome data can be compared with other full
cohorts (e.g. with data collected by United Kingdom
Haemophilia Centre Doctors' Organisation in the United
Kingdom). Data on side effects can be used for postmarketing surveillance of new clotting factors, which
will be registered from 2014 onwards. In addition,
data on side effects are entered in EUHASS (European
Haemophilia Safety Surveillance System) and used in
comparison with those from other countries.
Reimbursement
In the Netherlands, health insurance is mandatory and
up to 2012 all costs for clotting factor concentrates were
covered without restriction. Since 2012, hospital budgets,
including budget for clotting factor concentrates, are
fixed at the level of 2010, with a maximum annual
growth of 2.5%. As consumption shows a yearly
increase of around 5 %, these budgets are insufficient.
Individual centers have negotiated with health insurance
companies to increase the budget and at the same time
with manufacturers of coagulation factor concentrates to
reduce the price of concentrates, e.g. by using only one
FVIII product. It is expected that future reimbursement
of haemophilia care will be conditional on certification
of the HTCs.
Conclusion
In an effort to improve the quality of haemophilia
care in the Netherlands the NVHB, in collaboration
with patients and other stakeholders, have undertaken
a formal process to draft new quality standards for the
HTCs. The quality standards were approved by the
regulatory agencies and will be enforced by a formal
auditing process initiated in 2014. Concomitantly, a
national registry for haemophilia and allied disorders
is being set up. It is expected that these processes will
lead to further centralisation and improved quality of
haemophilia care in the Netherlands.
The Authors declare no conflicts of interest.
References
1)
2)
3)
4)
5)
6)
7)
8)
9)
van Creveld S. Prophylaxis of joint hemorrhages in
hemophilia. Acta Haematol 1969; 41: 206-14.
Mauser-Bunschoten EP, Nieuwenhuis HK, Roosendaal G,
Van den Berg HM. Low-dose immune tolerance induction in
hemophilia A patients with inhibitors. Blood 1995; 86: 983-8.
Nederlandse Vereniging voor Hemofiliebehandelaars
(NVHB). Richtlijn Diagnostiek en behandeling van hemofilie
en aanverwante hemostasestoornissen. Leebeek, F.W.G.
and Mauser-Bunschoten, E.P. 1. 2009. Utrecht, Van Zuiden
Communications BV.
Soucie JM, Nuss R, Evatt B et al. Mortality among males
with hemophilia: relations with source of medical care. Blood
2000; 96: 437-42.
Baker JR, Crudder SO, Riske B, et al. A model for a regional
system of care to promote the health and well-being of people
with rare chronic genetic disorders. Am J Public Health 2005;
95: 1910-6.
Evatt BL, Robillard L. Establishing haemophilia care in
developing countries: using data to overcome the barrier of
pessimism. Haemophilia 2000; 6: 131-4.
Colvin BT, Astermark J, Fischer K et al. European principles
of haemophilia care. Haemophilia 2008; 14: 361-74.
Fischer K, Hermans C. The European Principles of
Haemophilia Care: a pilot investigation of adherence to the
principles in Europe. Haemophilia 2013; 19: 35-43.
Plug I, Van der Bom JG, Peters M et al. Thirty years of
hemophilia treatment in the Netherlands, 1972-2001. Blood
2004; 104: 3494-500.
Correspondence: Kathelijn Fischer
Van Creveldkliniek
Room C 01.425
PO Box 85500
3508 GA Utrecht The Netherlands
e-mail: k.fischer@umcutrecht.nl
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ORIGINAL ARTICLE
A certification/accreditation model for Haemophilia Centres in Italy
Pier Mannuccio Mannucci1, Ivana Menichini2
1
Scientific Direction, IRCCS Ca' Granda Maggiore Policlinico Hospital Foundation, Milan; 2Necstep Studio
Associato, Modena, Italy
Background. The Italian Association of Haemophilia Centres has developed a voluntary
programme of professional accreditation of Haemophilia Centres, run by its members. Participation
in the programme, which aims to foster staff involvement in clinical governance, includes both
medical personnel and nurses.
Materials and methods. Accreditation is awarded provided the candidate Haemophilia Centre
is able to adhere to a pre-established set of quality standards and meet a number of clinical and
organisational requirements, previously defined on the basis of evidence-based medicine. Selfevaluation is the first step in the programme, followed by a site visit by a team of peer professionals
experienced in quality auditing.
Results. The programme has so far involved 21 Italian Haemophilia Centres. The comparison
between self- and peer-evaluation revealed less discrepancies for disease-related than for organisational
requirements, the latter being met to a lesser degree by most Haemophilia Centres.
Discussion. This programme of professional accreditation developed by the Italian Association of
Haemophilia Centres has the potential to describe, monitor and improve clinical and organisational
performances in the management of patients with haemophilia and allied inherited coagulation
disorders. It should also be seen as a contribution to the implementation of the strategy for improving
professional governance in Haemophilia Centres.
Keywords: professional accreditation, quality of care, standards.
Introduction
Improvement in the quality of health care delivery
is a primary goal for the medical profession1-5. In the
past few years, the attainment of this goal has been
attempted by means of several different institutional
approaches, local and international, which in general
focused on organisational and procedural aspects of
health care delivery. These programmes pay relatively
little attention to quality aspects of clinical management
and, most importantly, do not succeed in involving in
the process such key players as the medical and nursing
professionals. As a consequence, they often fail to
truly promote and implement clinical governance6,7.
For instance, the ISO 9000 family of standards, which
was devised originally by the industry, is effective
as a guideline, but its promotion as a standard "helps
to mislead companies into thinking that certification
means better quality, … [undermining] the need for
each organization to set its own quality standards''8. On
the other hand, Joint Commission International (JCI)
evaluates organisational processes of hospitals as a
whole, being less focused on professional aspects of
clinical governance9. Accordingly, the staff involved
in clinical management feel that these activities are
imposed from above, and sometimes they see them as
quite foreign to their medical practice.
In order to overcome these limitations, the Italian
Association of Haemophilia Centres (AICE) convened
a working group with the aim of developing a quality
ascertainment programme focused on those clinical
and organisational activities that are most appropriate
for Haemophilia Centres (HCs), based on the direct
involvement of the staff and on site visits by a team of
professional peers. The ultimate goal of this programme
was to award a certificate of accreditation by a learned
professional association to those HCs which had
reached a pre-established performance threshold.
To attain this goal, the HCs had to demonstrate that
they were able first to meet a number of clinical and
organisational requirements, and then to focus on
deficient aspects and so develop a suitable plan aimed to
improve unsatisfactory performance. The early results
of the accreditation programme at 21 Italian HCs are
presented here, with special emphasis on the comparison
between self-evaluation and the subsequent independent
evaluation by an external team of professional peers.
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Mannucci PM, Menichini I
Materials and methods
The process of professional accreditation
developed and implemented by AICE followed these
steps: self-evaluation was first carried out by each HC,
based on adherence to a panel of standards previously
defined by the an ad-hoc panel comprising clinicians
and patients. Requirements were set on the basis of
the best available clinical evidence and management
guidelines 10 . After self-evaluation results were
obtained, peer-evaluation was carried out by a team
of professionals previously trained in the auditing
process by external experts in the quality control of
health care systems. Peer-evaluation was conducted
by means of direct interviews with the staff during
site visits conducted at the applicant HC, analysis of a
random sample of at least 15 medical records and onsite auditing of the operating procedures. Adherence
to each standard was evaluated by means of scores
attributed to each requirement. The scores employed
to express the degree of adherence to standards were 3
for full compliance (when all aspects of the standards
were met); 2, for almost full compliance (when most
aspects of the standard were met); 1, for partial
compliance (when only some aspects of the standards
were met); 0, for non-compliance (when no aspects
of the standards were met) and NA for not applicable.
This report is based upon an evaluation of 21
Centres (Appendix 1) conducted by a team of 5
professionals (Appendix 2). Evaluation took into
account requirements set for awareness, information
and education of patients and their families (3
requirements); patient care (119 requirements);
laboratory practice (33 requirements) and organisational
aspects dealing with the daily activities of the HCs (32
requirements). All these criteria are consultable for
Italian HCs on a web site10.
Results
Figure 1 summarises the overall results for the 21
HCs, obtained by comparing self- with peer-evaluation
expressed in percentage of the maximal total score
attainable for the whole panel of requirements. On
average, self-evaluation gave slightly higher results than
peer-evaluation (86 vs 82% of the maximal possible
score), self-evaluation being lower in 3 HCs only.
Analysis of adherence to each requirement did reveal
varied results, of which a few representative examples
are reported here. For instance, the requirements related
to participation of HCs in national and/or regional
registries of inherited and acquired bleeding disorders
showed good concordance between self- and peerevaluation (score 3: 86 vs 81%). On the other hand, for
the criterion on the regular organisation, in collaboration
with patient associations, of events for the education
and training of patients and their families (including
home therapy/self-infusion), the score assigned by
peer-evaluation was higher than that assigned by selfevaluation.
Highly relevant requirements for the management of
inherited coagulation disorders, such as the prescription
of coagulation tests according to professional guidelines,
was satisfactorily met by a large percentage of HCs, with
a good agreement between self- and peer-evaluation.
There was also a good degree of adherence related to
the production of a written report on diagnosis within
one month of the initial visit.
Other requirements were less frequently met.
For instance, not all HCs provided 24-hour expert
haemophilia medical cover and, for this criterion,
there was a clear overestimation of performance in
self-evaluation (Figure 2). On the contrary, for some
requirements the score assigned by peer-evaluation was
even higher than that assigned by self-evaluation: for
instance, for the determination of the level of antibody
titre in patients who developed inhibitors (score 3: 76
vs 81%) (Figure 3).
Figure 1 - Comparison of self-evaluation (closed bars) with
peer-evaluation (open bars) for 21 HCs (identified
by capital letters).
Values are expressed as percentages of the maximal
total score that could be obtained for the whole set of
standards.
Figure 2 - Percent distribution of HCs providing 24-h expert
medical cover for hemophilia patients.
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A certification/accreditation model for Haemophilia Centres in Italy
Discussion
Figure 3 - As for Figure 2, according to the capacity to provide
the actual titre of the antibody in patients who
develop inhibitors.
Under the heading of requirements related to
periodical clinical and multi-disciplinary check-up,
there was a good concordance between self- and peerevaluation for the requirement for the organisation
of patient check-ups at least once a year (score 3:
90 vs 81%). For the organisation of specific visits
for patients characterised by particularly frequent
bleeding episodes or complications such as inhibitors,
arthropathy or chronic viral infections (score 3: 76 vs
71%) and for drafting a letter for the patients after each
visit, with information about current clinical problems,
recommended treatment regimens, results of relevant
laboratory data and other tests such as imaging, there
was also good concordance (score 3: 76 vs 71%).
On the other hand, less concordance was found
between self- and peer-evaluation with regard to the
network of clinical and specialised services needed
to collaborate with the haemophilia team. Only a
few HCs have in place specific formal agreements
that regulate relationships with structures providing
specialist services, and peer-evaluation revealed that
standards were much less adhered to than declared
on self-evaluation, especially in relation to formal
agreements with clinicians expert in hepatology (score
3: 67 vs 29%), infectious diseases (score 3: 67 vs 29%)
and physiotherapy/orthopaedics (score 3: 67 vs 24%).
For the 11 HCs with an internal laboratory, there was a
high degree of adherence to the provision of all coagulation
tests recommended by the standards: PT; APTT; thrombin
time; search of lupus anticoagulant; factor VIII and factor
IX assays; inhibitor screen; VWF antigen and ristocetin
cofactor activity; fibrinogen and factor II, V, VII, X, XI,
XII, XIII assays; platelet aggregation induced by ADP,
collagen, adrenaline and ristocetin: (score 3: 91% both in
self- and peer-evaluation). For the 10 HCs centres that have
no internal laboratory and that rely on external laboratories
to provide them with tests through formal agreements that
regulate the relationship, self-evaluation was too optimistic
with respect to the satisfaction of standards (score 3: 55%
vs 0; score 2: 36% in both self- and peer-evaluation).
The first consideration that stems from this
programme of accreditation of Italian HCs by peer
professionals is that, in comparison with other models
of certification or accreditation, the medical teams
under evaluation shared with peer evaluators a common
language and attitude for tackling clinical problems,
which greatly facilitated the auditing process. Peer
involvement also helped to make mutually acceptable
the final judgement made by the accreditation team
concerning the performance of the HCs. Finally, the
voluntary nature of this programme emphasises the
direct involvement of participating physicians in the
resilient affirmation of their role in the professional
governance of their own HCs.
In general, self-evaluation shows a tendency to
overrate the quality of performance in this study, in
agreement with previous observations, even if the opposite
pattern of results was also observed in some cases. For
example, the radiological Pettersson score and the
magnetic resonance score were not always performed for
all children in the periodic clinical and multi-disciplinary
check-ups, at variance with the statement made by some
HCs. On the other hand, the prescription of some unusual
tests of kidney function rather peculiar for patients with
haemophilia B undergoing immune tolerance for FIX
inhibitors (serum creatinine, proteinuria) was identified
more frequently by the peer-evaluation board than actually
declared in self-evaluation.
Special attention was paid in the accreditation
programme not only to the preparation and updating
of patient clinical records but also to the provision
of written information addressed to patients' family
physicians, pediatricians and other specialists, in order
to assure and optimise health care continuity. On these
topics, peer-evaluation indicated that adherence to
standards was often overestimated by the HCs. The
discrepancies between self- and peer-evaluations might
reflect some lack of documentation of the activity rather
than lack of performing the activity. However, we
believe that adequate and accurate documentation of
daily professional activities does indeed reflect the best
professional knowledge and practice, particularly in the
context of team work. The critical aspects documented
during on-site visits by peers were incorporated by the
HCs, which were encouraged to develop a plan aimed
to improve the quality of care, to be monitored regularly
at least on a yearly basis.
The AICE professional accreditation programme
proved to be flexible, so that it could be easily adopted
in the different realities of Italian HCs. The programme
also proved to be practically feasible, because auditing
visits by peers could be concluded and completed within
one working day. Like all the models of accreditation
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Mannucci PM, Menichini I
and certification, this programme is obviously not
static and foresees, as mentioned above, updating of
the set of requirements at regular intervals, in line with
the progress of medical knowledge and corresponding
practice guidelines.
In conclusion, the professional accreditation
programme of AICE is proposing a methodology
effective for promoting good clinical practice to identify
critical aspects of medical processes and to provide
an opportunity for the improvement of professional
performance through the effect of peer pressure.
Moreover, as an initiative started by professionals and not
by external authorities and/or hospital administrators, it
fosters the direct and resilient involvement of clinicians
in the clinical governance of their HCs. Focusing on
the professional aspects peculiar to haemophilia care is
not an alternative but rather a complementary strategy
to other models and programmes of certification and
accreditation widely implemented in Europe, which
mainly consider organisational and procedural aspects
of health care delivery.
Conflict of interest
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.
Ivana Menichini declares no conflicts of interest.
References
1)
Donabedian A. Explorations in quality assessment and
monitoring: The definition of quality and approaches to its
assessment. Ann Arbor, USA; 1980.
2) Berwick DM. Heal thyself or heal thy system: can doctors
help to improve medical care? Qual Health Care 1992; 1
(Suppl): S2-8.
3) Moss F. Achieving quality in hospital practice. Qual Health
Care 1992; 1 (Suppl): S17-9.
4) Berwick DM. Disseminating innovations in health care. JAMA
2003; 289: 1969-75.
5) Werner RM, Bradlow ET, Asch DA. Does hospital performance
on process measures directly measure high quality care or is it a
marker of unmeasured care? Health Serv Res 2008; 43: 1464-84.
6) UNI EN ISO 9001:2008. Available at: http://www.iso.org/iso/
iso_9000_essentials. Accessed on 30/11/2013.
7) Werner RM, McNutt R. A new strategy to improve quality.
Rewarding actions rather than measures. JAMA 2009; 301: 1375-7.
8) Wade J. Is ISO 9000 really a standard? ISO management
systems; May-June, 1-20; 2002.
9) Joint Commission International. Available at: http://www.
jointcommissin international.org. Accessed on 30/11/2013.
10) World Federation of Hemophilia. Guidelines for the management
of Hemophilia. Available at: http://www.hematologija.org/dl/
uploads/Gudelines%20Hemophilia.pdf. http://eimwebserver01.
eim.it/necstep/. Accessed on 30/11/2013.
Correspondence: Pier Mannuccio Mannucci
Scientific Direction
IRCCS Ca' Granda Maggiore Policlinico Hospital Foundation
Via Pace 9
20122 Milano, Italy
e-mail: piermannuccio.mannucci@policlinico.mi.it
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A certification/accreditation model for Haemophilia Centres in Italy
Appendix 1
Haemophilia Centres participating in the AICE programme of professional accreditation
- Centro Emofilia e Trombosi Angelo Bianchi Bonomi, Fondazione IRCSS Ca' Granda, Ospedale Maggiore
Policlinico, Milano, Chief: Pier Mannuccio Mannucci.
- Centro per l'Emofilia e Coagulopatie Congenite, IRCCS Fondazione Policlinico San Matteo, Università di
Pavia, Chief: Gabriella Gamba.
- Centro Malattie Emorragiche e Trombotiche, AOU S. Maria della Misericordia, Udine, Chief: Giovanni Barillari.
- Centro Emofilia, U.O. Angiologia e Malattie della Coagulazione "Marino Golinelli", AOU Policlinico S.
Orsola-Malpighi Bologna, Chief: Lelia Valdrè.
- Centro Emofilia, SSCVD Malattie Trombotiche Emorragiche, Città della Salute e della Scienza, Torino, Chief:
Piercarla Schinco.
- Centro Emofilia, Emostasi e Trombosi, Ospedale Pugliese Ciaccio, Catanzaro, Chief: Rita Santoro.
- Centro di Riferimento Regionale per le Malattie Emorragiche e Trombotiche Ereditarie in età pediatrica, A.O.U
Città della Salute e della Scienza, Torino, Chief: Maria Messina.
- Centro Regionale Malattie Emorragiche e Trombotiche, Ospedale San Bortolo, ULSS 6 Vicenza, Chief: Giancarlo
Castaman.
- Centro Regionale per le malattie del sangue - Struttura di riferimento per le malattie rare, ULSS 8 Veneto,
Ospedale Civile, Castelfranco Veneto, Chief: Giuseppe Tagariello.
- Agenzia per l'Emofilia, AOU Careggi, Firenze, Chief: Massimo Morfini.
- Servizio Malattie Emorragiche e Trombotiche, Università Cattolica S. Cuore - Policlinico Universitario A.
Gemelli, Roma, Chief: Raimondo De Cristofaro.
- Centro Emofilia, U.O. Oncoematologia Pediatrica, Ospedale dei Bambini, Spedali Riuniti di Brescia, Chief:
Lucia Dora Notarangelo.
- U.O.S. Interdipartimentale di Emostasi, U.O. Ematologia con trapianto, AOU Policlinico P. Giaccone, Palermo,
Chief: Sergio Siragusa.
- Centro Emofilia e Malattie della Coagulazione, Arcispedale Santa Maria Nuova, Reggio Emilia, Chief: Ido
Iori.
- Centro Coagulopatie Emorragiche Congenite - Trombofilia, ASUR Area Vasta n° 3, Macerata, Chief: Isabella
Cantori.
- Centro Emostasi e Trombosi, AO SS. Antonio e Biagio e Cesare Arrigo, Alessandria, Chief: Laura Contino.
- U.O.S.D. Centro Emofilia, Malattie Emorragiche e Trombotiche Congenite, ASL Pescara, Chief: Alfredo
Dragani.
- U.O.S. Gestione e Organizzazione Funzione HUB Emofilia, AOU di Parma, Chief: Anna Rita Tagliaferri.
- Centro Emofilia, AOU di Padova, Chief: Ezio Zanon.
- Centro Emofilia, ASLTO4, Ivrea, Chief: Grazia Delios.
- Centro di Riferimento Regionale per le Malattie Emorragiche, IRCCS G. Gaslini, Genova, Chief: Angelo
Claudio Molinari.
Appendix 2
Peer professionals involved in the evaluation process of the AICE programme of professional
accreditation
- Francesco Baudo, physician, expert in bleeding disorders
- Elio Boeri, physician, expert in bleeding disorders
- Cesare Manotti, physician, expert in bleeding disorders
- Vincenzo Trapani Lombardo, physician, expert in bleeding disorders
- Ivana Menichini, senior quality systems consultant
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ORIGINAL ARTICLE
The Italian institutional accreditation model for Haemophilia Centres
Gabriele Calizzani1, Fabio Candura1, Ivana Menichini2,3, Romano Arcieri2, Giancarlo Castaman4,
Alessandro Lamanna5, Maria R. Tamburrini6, Antonio Fortino7, Monica Lanzoni1,8, Samantha
Profili1, Simonetta Pupella1, Giancarlo M. Liumbruno1, Giuliano Grazzini1
1
National Blood Centre, National Institute of Health, Rome; 2Italian Federation of Haemophilia Societies (FedEmo),
Rome; 3Necstep Studio Associato, Modena; 4Department of Haematology and Haemophilia and Thrombosis Centre,
San Bortolo Hospital, Vicenza; 5National Agency for the Regional Healthcare Systems, Rome; 6Blood and Transplant
Unit, Ministry of Health, Rome; 7National Institute for Health, Migration and Poverty, Rome; 8IRCCS Ca' Granda
Foundation Maggiore Policlinico Hospital, Milan, Italy
Background. In Italy, basic health needs of patients with inherited bleeding disorders are met by
a network of 50 haemophilia centres belonging to the Italian Association of Haemophilia Centres.
Further emerging needs, due to the increased life expectancy of this patient group, require a multiprofessional clinical management of the disease and provide a challenge to the organisation of centres.
In order to achieve harmonised quality standards of haemophilia care across Italian Regions, an
institutional accreditation model for haemophilia centres has been developed.
Material and methods. To develop an accreditation scheme for haemophilia centres, a panel
of experts representing medical and patient bodies, the Ministry of Health and Regional Health
Authorities has been appointed by the National Blood Centre. Following a public consultation, a
technical proposal in the form of recommendations for Regional Health Authorities has been formally
submitted to the Ministry of Health and has formed the basis for a proposal of Agreement between
the Government and the Regions.
Results. The institutional accreditation model for Haemophilia Centres was approved as an
Agreement between the Government and the Regions in March 2013. It identified 23 organisational
requirements for haemophilia centres covering different areas and activities.
Discussion. The Italian institutional accreditation model aims to achieve harmonised quality
standards across Regions and to implement continuous improvement efforts, certified by regional
inspection systems. The identified requirements are considered as necessary and appropriate in order
to provide haemophilia services as "basic healthcare levels" under the umbrella of the National Health
Service. This model provides Regions with a flexible institutional accreditation scheme that can be
potentially extended to other rare diseases.
Keywords: standards and criteria, accreditation system, haemophilia care.
Introduction
Among the inherited bleeding disorders (IBDs),
haemophilia A and B are the most known forms affecting
worldwide around 1 in 6,000 and 1 in 30,000 males,
respectively1,2. According to the Italian Association of
Haemophilia Centres (AICE), there are 50 Haemophilia
Treatment Centres (HCs) across Italy, meeting the basic
needs for diagnosis, treatment, emergency management,
home treatment and care of patients with haemophilia
and other IBDs.
In 2008, AICE launched a voluntary professional
accreditation project entitled Improve AICE3. According
to the results of 21 HC audits, the AICE professional
accreditation programme proved to be effective for
promoting good clinical practice4. However, as HCs
differ widely in term of size, expertise and services
provided, the availability and quality of haemophilia care
delivery across Italian Regions is not homogeneous; this
finding is confirmed by the results of surveys carried out
by patient organisations5,6.
The emerging needs of patients with IBDs require a
multi-professional clinical management of haemophilia
patients and provide a challenge to HC organisation7.
In order to achieve harmonised quality standards of
haemophilia care across Italian Regions, an institutional
accreditation model for HCs has been developed, driven
by each Regional Authority (RA), through which public
and private facilities are authorised to provide services in
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Institutional Accreditation Model for Haemophilia Centres
the name, and on behalf of the National Health Service
(NHS)8,9. General accreditation criteria specify the
structural, technological and organisational requirements
of health providers whose compliance is periodically
verified by regional inspection systems10.
Haemophilia and other IBDs meet the definition
of rare disease provided by the European Commission
as they are life-threatening or chronically debilitating
diseases whose prevalence is less than 5 over 10,000
persons in the European Union11. In Italy, the field of
rare diseases (RDs) is regulated by a specific legislative
framework and policies. A RDs network was established
with the Ministerial Decree (MD) 279/2001, and
reasserted by the Agreement between the Government
and the Regions of 10th of May 2007, in order to support
the prevention, surveillance, diagnosis and treatment
of RDs patients 12,13. The RDs network comprises
hospital-based Centres of Reference (CoR)14, designed
by each RA; this network has not been included in any
institutional accreditation process to date.
In Italy, haemophilia knowledge and health care
has a very long history15 and comprehensive treatment
centres as well as home-treatment programmes have
been in place since 197016-18. Therefore, a long-standing
HC network was already in place when the MD 279/01
(National network of rare diseases) was adopted and
many of the 50 HCs now belong to the RDs network.
This paper aims to provide a description of the Italian
institutional accreditation model for HCs approved with
the Agreement between the Government and the Regions
no. 66 in March 201319. An outline of the complex
process required and the role of multiple actors involved
for its development is also provided.
Materials and methods
With the aim of promoting higher and harmonised
standards of haemophilia care across Regions, the Italian
Federation of Haemophilia Societies (FedEmo, www.
fedemo.it) proposed the development of an institutional
accreditation scheme for HCs to the Health Commission
of the Permanent Conference for relations among the
Government and the Regions (HCCGR). HCCGR
appointed the Italian National Blood Centre (NBC,
www.centronazionalesangue.it) to investigate the matter
and to develop a technical proposal. In order to meet
this commitment, the NBC convened a panel of experts
belonging to medical (AICE) and patient (FedEmo)
bodies, the Ministry of Health (MoH, www.salute.gov.
it) and Regional Health Authorities (RHAs). The panel
conducted a literature review from institutional sources in
order to collect all the available scientific and regulatory
references related to requirements, recommendations, as
well as general and specific certification/accreditation
systems. An analysis was conducted on critical issues
specifically related to HC organisation and service
management, that were not included in the general
accreditation process carried out by Regions for
health care centres. Particular concern was given to
organisational requirements of HCs, since structural and
technological standards were already considered and
assessed in the institutional and voluntary/professional
accreditation processes, respectively. After a public
consultation, held in April 2011, a technical proposal
in form of recommendations for RHAs was produced
by the NBC and formally submitted to the MoH in
February 2012. The MoH launched a further technical
consultation process involving internal actors such as the
Department of Health Care Planning (RDs Unit), and
other institutions such as the National Medicines Agency
(AIFA, www.agenziafarmaco.gov.it) and the National
Institute of Health (ISS, www.iss.it). The proposal was
reviewed after a careful evaluation of the legal nature of
the document to be adopted (recommendations or more
binding requirements) and of the current legislation
and policies on RDs, and taking into account clinical
disease-specific pathways to be adopted by RHAs as
Basic Levels of Care. The document became the basis
for a proposal of an Agreement between the Government
and the Regions. The Agreement was approved in March
2013 and the Italian Regions had six months to transpose
it into their legislation19.
Results
The panel of experts convened by the NBC identified
two levels of organisational requirements related to
different functions assigned to HCs: one level for HCs
providing basic haemophilia services and the other
for HCs offering a more integrated and specialised
multi-professional approach to patients. However,
while 23 organisational requirements for basic HCs
were substantially confirmed in the final document, 4
additional requirements for the Comprehensive HCs
were amended since the Regions decided about the
opportunity to recognise only one level of HCs and to
adopt an unique accreditation system for it.
The organisational requirements for basic HCs cover
different areas and activities, such as record-keeping,
patient awareness and safety, treatment programme,
periodical check-up, home treatment plan, access
to laboratories, information, training and quality
management.
In particular, they include the following activities:
1- preparation and updating of patient records;
2- formalisation of the diagnosis of coagulopathy,
detailing a specific set of information;
3- drawing up of the certificate of diagnosis of rare
disease, according to the procedures defined by
the Regions, valid nationally, in order to release
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Calizzani G et al
the certificate of exemption from co-payments of
healthcare services provision by the Local Health
Authority;
4- production of a detailed report in line with specific
requirements while formalising the diagnosis of
coagulopathy;
5- issuing of a treatment plan containing the personalised
prescription of clotting factor concentrate to be used,
with dosage and any other prescription the clinician
deems appropriate;
6- issuing for each patien, of a sheet containing
summary information about the therapeutic product
to be used including the recommended dosages and
procedures to be considered in the event of minor
and major bleeding episodes, and practical references
about services, patient rights and how to access them;
7- adoption of specific protocols that define the criteria
to be used for research, titration and possible followup of inhibitor;
8- adoption of appropriate protocols in collaboration
with the network of genetics laboratories aimed
at ensuring the diagnosis of the patient's family
members, including genetic counseling and pre-and
postnatal genetic diagnosis;
9- for each patient, definition and regular updating of
a specific treatment programme (including product,
dosage, treatment regimen, the reasons for the choice
of treatment and eventual home therapy modality
in collaboration with the local health services) with
informed consent from the patient;
10-provision of patients with written instructions and
instruments for the recording of the infusions of
therapeutic products in home therapy;
11- evaluation of the suitability of each patient regarding
the self-infusion practice;
12-systematic registration of data regarding the home
therapy of each patient infusion of therapeutic
products carried out in home therapy, at the HCs or
in other health facilities involved in the therapeutic
pathway;
13-planning and organisation of periodical check-ups;
14-adoption of protocols for the multidisciplinary
assessment of patients with complications associated
with IBDs (inhibitor, arthropathy, chronic liver
disease, HIV infection);
15-adoption of procedures for the procurement of
therapeutic products, in order to ensure continuity of
care and timely treatment of bleeding episodes and
emergencies, in cooperation with the pharmacies;
16-delivering of multi-disciplinary treatment
programmes based on written protocols, planned
with specialised services;
17-access to laboratories performing a predetermined
set of coagulation tests: Prothrombin time (PT);
activated Partial Thromboplastin Time (aPTT);
fibrinogen dosage; thrombin time (TT); mixing
tests (PT, aPTT, TT; test for the research of lupus
anticoagulant; factor VIII/IX dosage; research of
FVIII/IX inhibitor; von Willebrand Factor Antigen
(VWF:Ag); von Willebrand Factor Ristocetin
Cofactor (VWF:RCo); Coagulation factors dosage:
II, V, VII, X, XI, XII, XIII; study of platelet function
through platelet aggregation induced by ADP,
collagen, epinephrine, arachidonic acid, ristocetin;
18-access to laboratories for coagulation tests that
guarantee the availability of results and reports in
a timeframe compatible with the urgency of the
request;
19-availability to patients and their families of
appropriate updated information related to the
characteristics of haemophilia and other IBDs, as
well as issues related to the daily life of patients with
haemophilia (PWH);
20-organisation of periodical events for informing and
training the patients with IBDs and their families,
including courses for home therapy, in collaboration
with other HCs and local patient associations;
21-organisation of periodical training addressed to
personnel of specialised services (emergency
service, general practitioners and paediatricians,
pharmaceutical services, etc.);
22-participation in registries related to IBDs, in
compliance with current legislation regarding the
protection of personal data;
23-conduct of systematic clinical and quality audits
aimed at assessing compliance with established
policies and procedures, and planning of specific
quality improvement objectives related to clinical
and organisational processes, also through the
involvement of patients and their associations.
Therefore, in the first version of the document, 2
levels of haemophilia care delivery were originally
developed by the panel of experts convened by NBC
and inspired by the Hub and Spoke organisational model
of haemophilia care20. In this context, the "Hub" centre
performs high resource and competence demanding
activities and is linked to a network of "Spoke" centres
providing basic services close to where the patient lives.
This model would offer the opportunity to balance access
to health care and sustainability. In addition, it would
allow Hub centres to deal with a minimum number of
patients necessary to maintain the multi-disciplinary
and specialised expertise required for haemophilia
patient management. Thus, four additional requirements/
activities were identified for Comprehensive HCs
(Hubs): coordination of a network of hospital facilities
providing comprehensive care, 24-hours availability
of a physician with experience in the treatment of
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Institutional Accreditation Model for Haemophilia Centres
coagulation disorders, 24-hours access to a laboratory
providing a set of specific tests within agreed turn around
times; 24-hours availability of an advisory service to
patients and their families, as well as other professionals
and caregivers. However, after the consultation process,
according to the Agreement between the Government
and the Regions, RAs decided, in order to achieve greater
autonomy in the organisation of health services, that
these functions should be ensured through addressing
indications provided in the context of current health
planning procedures.
Discussion
In Italy, a designation process of CoR based on a
disease-specific accreditation scheme had not been
developed previously. The process that led to the final
improvement of the Italian HC accreditation model
proved to be complex and time consuming. Different
opinions had to be compared and addressed, in particular
on the feasibility of developing a specific process of
accreditation for RDs. Other challenges are related to the
large numbers of actors involved in the process and to
the specific features of the relationship between Central
State and Regions, influenced by political forces and
characterised by a continuous negotiation effort.
The experience developed in Italy in the accreditation
of HCs -both institutional and professional- provided
the inspiration and drove the development of European
standards21 in the context of the European Haemophilia
Network project (EUHANET, www.euhanet.org)22. The
two above-mentioned accreditation models comprised
the main reference documents for the production of
the European Guidelines for the certification of HCs,
supplemented by other European national experiences
and models23,24 (e.g. Belgium, the Netherlands, United
Kingdom) and the European principles of haemophilia
care20.
The development of European reference networks in
the MS is one of the core provisions of the cross-border
health care directive25. In particular, article 12 of this
directive describes the general aims and objectives, as
well as peculiarities, that reference networks should meet.
The European Union Committee of Experts on Rare
Diseases (EUCERD)26, which supports the European
Commission with the preparation and implementation
of Community activities in the field of RDs, has issued,
among others, specific recommendations on centres of
expertise27 (CoE) and European Reference Networks28.
In particular, such centres should be compliant with
the EUCERD recommendations for quality criteria
for CoE in RDs and Directive 2011/24/EU, mentioned
above. Each MS should establish a procedure to define
and approve designation criteria along with transparent
designation and evaluation processes.
The institutional HC accreditation model could be
regarded as a "pilot study" in the field of accreditation
and designation of CoR for RDs. This experience has
shown that an earlier involvement in the process of RD
experts and policy makers would have facilitated the
process and provided the accreditation model with better
flexibility and acceptability. Indeed, it is the opinion of
the authors that the specificities linked to haemophilia
and other IBDs (number of patients, clinical history of
the disease, pre-existing network of HCs, treatments
costs, etc.) permit the development of a specific
accreditation system for this group of diseases. However,
it is necessary to introduce a continuous process of data
collection on the model implementation to support
decision making processes. It cannot be excluded
that in the future, based on the evidence collected, the
system of accreditation of HCs might be considered
within a broader dedicated system of accreditation for
all RDs with consideration of a set of common generic
requirements for all CoR for RDs, and a set of specific
requirements for each disease or group of RDs.
Conclusions
The Italian institutional accreditation system aims to
achieve harmonised quality standards across Regions and
to implement continuous improvement efforts, certified
by rigorous and objective regional inspection systems.
The identified requirements are considered as necessary
and appropriate in order to provide haemophilia services
as "basic/essential healthcare levels" under the aegis
of the NHS. This system is the outcome of a long and
complex consultation process involving experts from
RAs and national institutions (NBC, MoH, ISS, AIFA,
etc.), with the participation of representatives of patient
associations (FedEmo) and learned scientific societies
(AICE). All types of facilities providing haemophilia
services are eligible to be involved in the accreditation
model, regardless of the level, intensity and type of
services provided.
It is the authors' opinion that this model could provide
Regions with a flexible institutional accreditation
scheme for HCs which can be potentially extended to
other RDs. Regions, in fact, could adapt the requirements
to their specific context and develop further more
stringent requirements, for instance by taking into
account EUHANET recommendations on the minimum
number of severe patients followed by HCs. To date, 4
RAs out of 21 (Emilia-Romagna, Liguria, Autonomous
Provinces of Trento and Bolzano) have already formally
adopted it. A wider implementation will provide useful
information in order to adapt and improve the model.
The Authors declare no conflicts of interest.
Blood Transfus 2014; 12 Suppl 3: s510-4 DOI 10.2450/2014.0058-14s
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Calizzani G et al
References
1)
2)
3)
4)
5)
6)
7)
8)
9)
10)
11)
12)
13)
14)
15)
Stonebraker JS, Bolton-Maggs PHB, Michael Soucie J et al. A
study of variations in the reported haemophilia A prevalence
around the world. Haemophilia 2010; 16: 20-32.
Stonebraker JS, Bolton-Maggs PHB, Michael Soucie J et al. A
study of variations in the reported haemophilia B prevalence
around the world. Haemophilia 2012; 18: e91-4.
Calizzani G, Vaglio S, Arcieri R et al. Models for institutional
and professional accreditation of haemophilia centres in Italy.
Haemophilia 2013; 19: e248-55.
Mannucci PM, Menichini I. A certification/accreditation
model for Haemophilia Centres in Italy. Blood Transfus 2014;
12 (Suppl 3): s505-9.
Arcieri R, Molinari AC, Farace S et al. Present and future
challenges in the treatment of haemophilia: the patient's
perspective. Blood Transfus 2013; 11 Suppl 4: s82-5.
Arcieri R, Molinari AC, Farace S. Uncovered needs in the
management of inherited bleeding disorders' in Italy. Blood
Transfus 2014; 12 (Suppl 3): s553-6.
Coppola A, Santoro C, Franchini M et al. Emerging issues on
comprehensive hemophilia care: preventing, identifying, and
monitoring age-related comorbidities. Semin Thromb Hemost.
2013; 39: 794-802.
Decreto del Presidente della Repubblica 14 gennaio 1997:
"Approvazione dell'atto di indirizzo e coordinamento alle
regioni e alle province autonome di Trento e di Bolzano, in
materia di requisiti strutturali, tecnologici ed organizzativi
minimi per l'esercizio delle attività 8 sanitarie da parte delle
strutture pubbliche e private".
Di Stanislao F, Liva C, editors. L'Accreditamento dei Servizi
Sanitari in Italia. Turin, Italy: Centro Scientifico Editore; 1998.
Fortino A, Di Stanislao F. Institutional accreditation of Health
Services in Italy: the long road to quality. Blood Transfus
2014; 12 (Suppl 3): s551-3.
European Parliament and Council. Regulation (EC)
141/2000 of the European Parliament and of the Council
of 16 December 1999 on orphan medicinal products.
Official Journal 2000; L 18:1-5. Available at http://
e u r l e x . e u r o p a . e u / L e x U r i S e r v / L e x U r i S e r v. d o ? u r i =
OJ:L:2000:018:0001:0005:en:PDF. Accessed on 15/01/2014.
Decreto Ministeriale 18 Maggio 2001, n. 279. Regolamento
di istituzione della rete nazionale delle malattie rare e
di esenzione dalla partecipazione al costo delle relative
prestazioni sanitarie, ai sensi dell'articolo 5, comma 1, lettera
b), del decreto legislativo 29 aprile 1998, n. 124. Gazzetta
Ufficiale n. 160, 12/07/2001. Suppl. Ordinario n.180/L.
Accordo, ai sensi dell'articolo 4 del decreto legislativo 28
agosto 1997, n. 281, tra il Governo, le Regioni e le Province
autonome di Trento e Bolzano sul riconoscimento di Centri
di coordinamento regionali e/o interregionali, di Presidi
assistenziali sovraregionali per patologie a bassa prevalenza
e sull'attivazione dei registri regionali ed interregionali delle
malattie rare. Rep. n. 103/CSR del 10 maggio 2007. Available
at: http://www.centronazionalesangue.it/sites/default/files/
accordo_csr_13.03.2013_gu_n._107_09.05.2013_assistenza_
mec.pdf. Accessed on 15/01/2014.
Taruscio D, Agresta L, Amato A, et al. The Italian National
Centre for Rare Diseases: where research and public health
translate into action. Blood Transfus 2014; 12 (Suppl 3):
s591-605.
Mannucci PM, Ruggeri ZM. Hemophilia care in Italy. Thromb
Haemost. 1976; 35: 531-6.
16) Franchini M. The modern treatment of haemophilia: a narrative
review. Blood Transfus 2013; 11: 178-82.
17) Franchini M, Mannucci PM. Past, present and future of
hemophilia: a narrative review. Orphanet J Rare Dis 2012;
7: 24.
18) Franchini M, Mannucci PM. Present and future challanges in
the treatment of haemophilia: a clinician's perspective. Blood
Transfus 2013; 11 (Suppl 4): s77-81
19) Official Journal of Italian Republic no. 107 May 9th, 2013.
Accordo, ai sensi dell'articolo 4 del decreto legislativo
28 agosto 1997, n.281, tra il Governo, le Regioni e le
Province autonome di Trento e Bolzano sulla definizione
dei percorsi regionali o interregionali di assistenza per le
persone affette da Malattie Emorragiche Congenite (MEC).
Rep Atti n 66/CSR del 13 marzo 2013) Available at http://
www.centronazionalesangue.it/sites/default/files/accordo_
csr_13.03.2013_gu_n._107_09.05.2013_assistenza_mec.pdf.
Accessed on 16/02/2014.
20) Colvin BT, Astermark J, Fischer K et al. European Principles
of Haemophilia Care. Haemophilia 2008; 14, 361-74.
21) Giangrande P, Calizzani G, Menichini I et al. The European
standards of Haemophilia Centres. Blood Transfus 2014; 12
(Suppl 3): s525-30.
22) Makris M, Calizzani G, Fischer K et al. The European
Haemophilia Network (EUHANET). Blood Transfus 2014;
12 (Suppl 3): s515-8.
23) Hermans C. Haemophilia Centre certification system across
Europe: the Belgian experience. Blood Transfus 2014; 12
(Suppl 3): s497-500.
24) Leebeek FWG, Fischer KQuality of haemophilia care in the
Netherlands: new standards for optimal care. Blood Transfus
2014; 12 (Suppl 3): s501-4.
25) Directive 2011/24/EU of the European Parliament and of the
Council of 9 March 2011 on the application of patients' rights
in cross-border healthcare. Available at: http://eur-lex.europa.
eu/LexUriServ/LexUriServ.do?uri=OJ:L:2011:088:0045:006
5:en:PDF. Accessed on 15/01/2014.
26) European Union Committee of Experts on Rare Diseases
(EUCERD). Available at: http://www.eucerd.eu/ Accessed on
18/02/2014. Accessed on: 15/01/2014.
27) European Union Committee of Experts on Rare Diseases
(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 18/02/2014.
28) European Union Committee of Experts on Rare Diseases
(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 18/02/2014.
Correspondence: Gabriele Calizzani
National Blood Centre, National Institute of Health
Via Giano della Bella 27
00162, Rome, Italy
e-mail: areaplasma.cns@iss.it
Blood Transfus 2014; 12 Suppl 3: s510-4 DOI 10.2450/2014.0058-14s
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REVIEW
The European Haemophilia Network (EUHANET)
Michael Makris1,2, Gabriele Calizzani3, Kathelijn Fischer4, Alexander Gatt5, Estelle Gilman1, Robert
Hollingsworth6, Thierry Lambert7, Riitta Lassila8, Pier Mannuccio Mannucci9, Flora Peyvandi10, Jerzy
Windyga11
1
Department of Cardiovascular Science, University of Sheffield, Sheffield, United Kingdom; 2Sheffield Haemophilia
and Thrombosis Centre, Sheffield, United Kingdom; 3National Blood Centre, National Institute of Health,
Rome, Italy; 4Van Creveldkliniek and Julius Centre for Health Sciences and Primary Care, University Medical
Centre Utrecht, The Netherlands; 5Mater Dei Hospital, Msida, Malta; 6Medical Data Solutions and Services
Ltd, Manchester, United Kingdom; 7Treatment Centre of Haemophilia, Bicêtre AP-HP Hospital, Paris, France;
8
Helsinki University Hospital, Helsinki, Finland; 9Scientific Direction, Fondazione IRCCS Ca' Granda, Ospedale
Maggiore Policlinico, Milan, Italy; 10Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Angelo
Bianchi Bonomi Haemophilia and Thrombosis Centre, Milan, Italy; 11Institute of Haematology and Transfusion
Medicine, Warsaw, Poland
Introduction
Haemophilia A and B are rare inherited bleeding
disorders due to reduced factor VIII (FVIII) or factor
IX (FIX) activity, occurring in 1 in 10,000 and 1 in
50,000 of the population respectively1,2. Several other
bleeding disorders such as deficiencies of factors I, II, V,
VII, X, XI and XIII are even rarer. When the deficiency
is severe these disorders present with spontaneous
bleeding whilst for milder disorders traumatic bleeding
is observed3. When bleeding occurs patients are treated
with clotting factor concentrates which can be plasma
derived or recombinant. Individuals with inherited
bleeding disorders are cared for in Haemophilia
Centres. There is major disparity in patient access to
Haemophilia Centres throughout Europe4, although it
must be appreciated that this publication was based on
data from the individual country patient organisations
and was not based on national registries. There is a need
for harmonisation of the data available in care centres,
national data sources and patient organisations and these
activities are planned to be improved by the European
Haemophilia Network (EUHANET) project. There is
also variation in the number of Haemophilia Centres
within European countries and whilst in some there are
over 80 Haemophilia Centres in others there is only a
single centre.
The use of clotting factor concentrates has been
associated with major adverse effects. Patients
treated with plasma derived clotting concentrates
prior to 1985 had an almost 100% risk of being
infected with hepatitis C (HCV) and a 30-60% risk
of Human Immunodeficiency Virus (HIV) infection5.
Although the HCV/HIV viruses were eliminated
following the introduction of viral inactivation,
improvements in diagnostic tools used for the
biological qualification of blood donations and the
use of recombinant concentrates, other adverse events
such as alloantibodies to FVIII or FIX remain6. The
rarity of these disorders makes it difficult to determine
the precise frequency of the adverse events because
large numbers of patients are required which are not
available in single centres. To overcome this problem,
the European Haemophilia Safety Surveillance
(EUHASS) system was set up in 2008 7. This was
a collaboration of over 70 European Haemophilia
Centres in 26 countries which agreed to prospectively
report adverse events occurring in their patients. The
project was funded by the European Commission with
pharmaceutical industry support. The EUHASS project
demonstrated the willingness of these Haemophilia
Centres to work together so the EUHANET was set
up. This is a collaboration in four separate areas, the
certification of Haemophilia Centres, the set up of a
haemophilia website, the expansion of the EUHASS
system and the establishment of a prospective project
on afibrinogenemia and FXIII deficiency.
Organisation of the project
The lead partner of the EUHANET project is the
University of Sheffield in the United Kingdom. The
other main partners are the European Haemophilia
and Allied Disorders organisation, the European
Haemophilia Consortium, the University Medical Centre
Utrecht, Fondazione IRCCS Ca' Granda in Milan and
Medical Data Solutions and Services Ltd in Manchester.
In addition there are 84 collaborating partners in
26 European countries. The project has eight work
packages and is overseen by a steering committee with
a representative from each of the main partners as well
as four representatives from the collaborating partners.
EUHANET is funded by the European Commission
Health Programme through the Executive Agency for
Health and Consumers (EAHC) with co-financing from
12 pharmaceutical manufacturers.
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Certification of Haemophilia Centres
There is wide variation in the availability of
Haemophilia Centres in different countries as well as
in the range of services provided by individual centres.
Many names are used by centres such as Haemophilia
Centre, comprehensive care centre, Haemophilia
Treatment Centre, Haemophilia Reference Centre,
national haemophilia centre, etc. There is no agreed
definition of what constitutes a haemophilia centre and
whilst some centres care for more than 350 patients with
severe haemophilia, others have less than 5 patients.
Furthermore the laboratory support of haemophilia
centres varies enormously.
Patients with inherited bleeding disorders have no
way of knowing how comprehensive the care provided
by a particular haemophilia centre is. This knowledge
is important both for patients within a geographical
region where several haemophilia centres are located,
as well as for patients from other countries or areas
who are travelling and are looking for emergency care.
As a haemophilia community we have been looking at
standardising the labelling of European Haemophilia
Centres and categorising them. At the same time the
European Commission has provided guidance for
countries to develop centres for rare diseases8. Therefore
a part of the EUHANET project is the standardisation of
the labelling of Haemophilia Centres in Europe.
The certification work package undertook the
development of this work and the process is described
in the other manuscripts in this supplement of the Blood
Transfusion journal. Briefly, the current regulations and
processes within all European countries were reviewed
and a document of standards of haemophilia care was
prepared. Extensive consultation during several stages of
the process led to modification of the document. The final
standards document was approved in May 2013 and it was
launched at a meeting in Rome in July 20139. Two types
of Haemophilia Centres are recognised by the standards
document, the European Haemophilia Treatment Centre
(EHTC) and the European Haemophilia Comprehensive
Care Centre (EHCCC).
Because of the length of the standards document, a
pro-forma of the key areas was developed for centres
to use when applying for certification. This asks for
the number of patients registered, the services offered,
the emergency care facilities as well as the laboratory
backup. Both the standards document and the application
pro-forma are available on the EUHANET project
website (www.euhanet.org).
The application process was launched in December
2013 and any Haemophilia Centre in Europe can apply
for certification into EHTC or EHCCC. Although the
standards for the two types are different, there are certain
minimum requirements that have to be satisfied before
one of these two titles are awarded to a centre. Once an
application is made, it is reviewed by a five member
committee which has representatives from medical and
nursing staff as well as patients.
The certification process is based on data supplied
by the centres and there are no site visits to check the
accuracy of the data. Because of this, several parts of
the application form will be made publically available.
This is a first step and it is anticipated that in future audit
visits will be incorporated into the process, although
political, geographical and language differences have
to be addressed to achieve this.
Haemophilia Central website
Although there is a lot of information about
inherited bleeding disorders on the web, it is spread
over many sites and its accuracy is often unclear. In
the EUHANET project we set out to develop a website
with all the information in a single place. The site is
called Haemophilia Central and can be found at www.
haemophiliacentral.org. Several components will
be developed during the project but those currently
publically available are:
1. News - this is produced in collaboration with Dr
Uwe Schlenkrich. The site is regularly updated with
haemophilia and other bleeding disorder related
news;
2. Guidelines - here readers can select guidelines by
subject and language. For most guidelines the reader
is redirected to the site of the original publication;
3. Clinical trials - this is a search engine for any trials
registered on www.clinicaltrials.gov in the field of
acquired or inherited bleeding disorders;
4. Concentrate directory - this section contains details
of all the available clotting factor concentrates in
Europe. Once a concentrate is selected, the details
of the manufacturer, production and characteristics
of the product as well as publications relating to the
products are provided;
5. Database of centres and organisations. A fully
functional database assists the user in locating
Haemophilia Centres and patient, doctor, nurses and
physiotherapy organisations based in Europe;
6. Frequently asked questions section for queries
relating to the EUHANET project as well as to
bleeding disorders more specifically;
7. Links - contains links to the journals Blood,
Haemophilia and Journal of Thrombosis and
Haemostasis, and to an information site for very rare
coagulation disorders.
Haemophilia Centre Locator (www.hclocator.org)
The EUHANET project has developed a search
engine that can be accessed by all devices including
Blood Transfus 2014; 12 Suppl 3: s515-8 DOI 10.2450/2014.0008-14s
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The European Haemophilia Network
personal computers, tablets and mobile phones using
any software. Once a user accesses www.hclocator.
org they can enter any address or choose their current
location. The site generates a map with the nearest
five Haemophilia Centres. Clicking on the name of
any of these centres will give information on location
and phone numbers about how to get emergency care
from the centre during normal working hours or in an
emergency. Currently the system works only for Europe
but it is intended to expand it so it covers Haemophilia
Centres worldwide.
European Haemophilia Safety Surveillance
(EUHASS)
The EUHASS project began on 1st October 2008
and currently 84 European Haemophilia Centres from
26 countries are participating. A report on the initial
experience has been published7. The original EUHASS
project has been extended and incorporated into the
EUHANET in 2012. Prior to participation all centres
have to obtain clearance from the Ethics Committee
(Institutional Review Board) of their organisation. All
adverse events are reported anonymously online either
when they occur or within a maximum of three months.
Every three months all centres have to actively sign
off the quarter even if no events have occurred in their
centre. The patients included in the surveillance are those
with inherited deficiency of factors I, II, V, VII, VIII,
IX, X, XI, XIII, von Willebrand disease, Glanzmann
thrombasthenia, Bernard Soulier syndrome, platelet
storage pool disease, acquired haemophilia and acquired
von Willebrand disease.
The events reported are:
1. acute or allergic events;
2. transfusion transmitted infections;
3. inhibitors;
4. thromboses;
5. malignancies;
6. deaths;
7. unexpected poor efficacy;
8. any other possible adverse event.
For each of the above events limited details regarding
the event such as the timing of the last clotting factor
exposure and exposure days are also collected.
Annually the participating centres report the total
number of patients registered at their centre, how many
of these have severe disease and how many were treated
with concentrate over the previous year. Furthermore the
centres report how many patients received each specific
concentrate and how many of these patients had severe
disease. This information allows the determination of
the rates of adverse events per 1,000 treatment years.
The rates of inhibitors in previously untreated
patients is traditionally calculated by following a cohort
of severely affected patients from first treatment to their
50th exposure day, but such studies take a long time to
complete. EUHASS determines the inhibitor rate in
previously untreated patients using a novel method
which is based on number of patients reaching the 50th
exposure day during a specific year10.
Prospective rare diseases database
The evidence base for the bleeding disorders other than
the haemophilias is weak due to the rarity of the disorders
and the fact that most patients are to be found in countries
without a strong background in research. A significant
advance has been the collaboration of several Haemophilia
Centres in the previously funded EAHC project led by
Professor Flora Peyvandi to set up the Rare Bleeding
Disorders Database (EN-RBD)11. This database obtained
retrospective information on the non-haemophilic RBD.
Data was collected on demographics, phenotype, genotype,
bleeding manifestations, treatment and their complications.
Personal identification data were not entered.
A problem with retrospectively collected data is bias
and it would be desirable to collect prospective data. As
part of the EUHANET project the EN-RBD database,
now applied on a global scale (RBDD) has been revised
to create the prospective RBDD (Pro-RBDD, http://
eu.rbdd.org), so that prospective information can be
collected. Initially this database is collecting data on
patients with deficiencies of fibrinogen and factor XIII.
Over the three years of the EUHANET project there
will be 6 data entry points per patient. Subsequently,
prospective data will be collected for all RBD and the
data will be used to design clinical trials of treatment
modalities. Central laboratory testing for clotting factor
levels and genotyping as well as an external laboratory
quality control is provided.
Acknowledgement
This publication arises from the project EUHANET
which has received funding from the European Union,
in the framework of the Health Programme.
Keywords: haemophilia, EUHANET, reference
networks, European, certification.
Funding and conflict of interest
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.
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.
Blood Transfus 2014; 12 Suppl 3: s515-8 DOI 10.2450/2014.0008-14s
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Makris M et al
9)
References
1)
2)
3)
4)
5)
6)
7)
8)
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.
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: e91-4.
Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al.
Guidelines for the management of hemophilia. Haemophilia
2013; 19: e1-47.
O'Mahony B, Noone D, Giangrande PL, Prihodova L.
Haemophilia care in Europe - a survey of 35 countries.
Haemophilia 2013; 19: e239-47.
Makris M, Preston FE, Rosendaal FR, et al. The natural history
of chronic hepatitis C in haemophiliacs. British Journal of
Haematology 1996; 94: 746-52.
Weinstein M, Makris M, Ludlam CA. Biovigilance and
pharmacovigilance for haemophilia. Haemophilia 2010; 16
(Suppl 5): 17-21.
Makris M, Calizzani G, Fischer K, et al. EUHASS:
The European Haemophilia Safety Surveillance system.
Thrombosis Research 2011; 127 (Suppl 2): S22-5.
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/
EUCERDRecommenda-tionCE.pdf. Accessed on 09/01/2014.
International Meeting "Haemophilia Centre Certification
Systems across Europe". Centro Nazionale Sangue.
Available at: http://www.centronazionalesangue.it/newsbox/
seminario-malattie-emorragiche-congenite-mec. Accessed
on 09/01/2014.
10) Fischer K, Lewandowski D, Van den Berg MH, Janssen MP.
Validity of assessing inhibitor development in haemophilia
PUPs using registry data. Haemophilia 2012; 18: e241-6.
11) Peyvandi F, Palla R, Menegatti M, et al. Coagulation factor
activity and clinical bleeding severity in rare bleeding
disorders: results from the European Network of Rare Bleeding
Disorders. Journal of Thrombosis and Haemostasis 2012; 10:
615-21.
Correspondence: Michael Makris
Sheffield Haemophilia and Thrombosis Centre,
Royal Hallamshire Hospital
Glossop Road
Sheffield, S10 2JF, United Kingdom
e-mail: m.makris@sheffield.ac.uk
Blood Transfus 2014; 12 Suppl 3: s515-8 DOI 10.2450/2014.0008-14s
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ORIGINAL ARTICLE
The methodology for defining the European Standards for the certification
of Haemophilia Centres in Europe
Fabio Candura1,2, Ivana Menichini1,3, Gabriele Calizzani1,2, Paul Giangrande1,4, Pier Mannuccio
Mannucci5, Michael Makris6
1
European Haemophilia Consortium, Brussels, Belgium; 2National Blood Centre, National Institute of Health,
Rome, Italy; 3Necstep Studio Associato, Modena, Italy; 4Oxford University Hospitals NHS Trust, United Kingdom;
5
Scientific Direction, IRCCS Ca' Granda Maggiore Policlinico Hospital Foundation, Milan, Italy; 6Department
of Cardiovascular Science, University of Sheffield, Sheffield, United Kingdom
Introduction. Work Package 4 Development of the standardisation criteria of the European
Haemophilia Network project has the main objective of implementing a common and shared European
strategy for a certification system for two levels of Haemophilia Centres: European Haemophilia
Treatment Centres and European Haemophilia Comprehensive Care Centres in the Member States
of the European Union.
Materials and methods. An inclusive and participatory process for developing shared standards
and criteria for the management of patients with inherited bleeding disorders has been carried out.
The process has been implemented through four different consultation events involving the entire
European community of stakeholders that significantly contributed in the drafting of the European
Guidelines for the certification of Haemophilia Centres.
Results. The Guidelines set the standards for the designation of centres that provide specialised
and multidisciplinary care (Haemophilia Comprehensive Care Centres) as well as local routine care
(Haemophilia Treatment Centres). Standards cover several issues such as: general requirements;
patient care; advisory services; laboratory; networking of clinical and specialised services.
Conclusions. The drafting of the European Guidelines for the certification of Haemophilia
Centres was performed adopting a rigorous methodological approach. In order to build the widest
possible consensus to the quality standards, the main institutional and scientific stakeholders have
been involved. The resulting document will significantly contribute in promoting standardisation in
the quality of diagnosis and treatment in European Haemophilia Centres.
Keywords: standards, criteria, certification system, haemophilia care, EUHANET.
Introduction
One of the work streams of the European Haemophilia
Network (EUHANET) project is the promotion of
standardisation of the quality of diagnosis and treatment
in European Haemophilia Centres. EUHANET is a
project funded by the Executive Agency for Health and
Consumers (EAHC) of the European Commission1.
Within the EUHANET project, Work Package number
4 (WP4) Development of the standardisation criteria
has the main objective of implementing a common and
shared European strategy for a certification system for
two levels of Haemophilia Centres (HCs): European
Haemophilia Treatment Centres (EHTCs) and European
Haemophilia Comprehensive Care Centres (EHCCCs)
in the Member States of the European Union (EU MS).
The resulting output was the European Guidelines
for the certification of Haemophilia Centres2.
The main objective of this article is to describe the
methodology adopted for an inclusive and participatory
process of developing shared standards and criteria for
the management of patients with inherited bleeding
disorders as a model to be considered for implementation
by other groups of rare diseases.
Materials and methods
Operational steps for the development of the
European Guidelines for the certification of
Haemophilia Centres
The different drafts of the European Guidelines for
the certification of Haemophilia Centres (henceforth
referred to as Guidelines) have been widely discussed
with different European stakeholders (National Health
Authorities, Health Professionals, Patient Organisations,
EUHANET Project Partnership) at the time of several
events and followed a very inclusive methodology of
consultation using a bottom-up approach.
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Candura F et al
The activities of WP4 have been implemented
through five steps:
1) review of literature on certification systems of HCs
available in EU MS;
2) definition and sharing of principles and criteria to
be considered for the development of requirement
standards with EUHANET and other collaborating
partners;
3) drawing up of a draft of the guiding document for
consultation;
4) finalisation of the guiding document incorporating
feedback received from the consultation process;
5) proposal of an evaluation system framework for EU
HCs.
Review of literature on certification systems of HCs
available in EU MS
The specific objective of step 1 was to conduct a
survey of available standards and certification systems in
EU MS. To reach this goal, and in particular to gather and
validate information from official sources that may not
be available through common search methods (published
materials in official languages, grey literature, etc.), the
WP4 team disseminated a preliminary questionnaire to
27 EU MS country stakeholders. 7 out of 17 returned
questionnaires contained information about certification
systems currently in place in the corresponding 7 countries.
Definition and sharing of principles and criteria to be
considered for the development of requirement standards
with EUHANET and other collaborating partners
In step 2, a cross-match analysis has been performed
using all available materials, such as current national
standards and certification systems as well as European
key reference documents, including the European
Haemophilia Principles of Care 3 and EUCERD
recommendations4,5, with the aim of identifying common
principles and criteria (i.e. scopes, approaches and rules)
to be used as a basis for the draft of the Guidelines.
The WP4 team selected 7 criteria such as types of
structures involved, types of diseases to be considered,
etc. and disseminated a Questionnaire for evaluating the
level of agreement on each of them. Table I shows the
list of proposed criteria.
The Principles and Criteria Questionnaire was
launched during the European Haemophilia Consortium
Annual Conference held in Prague on the 28 th of
October 2012. Thus, WP4 collected 56 questionnaires
from 26 EU and non-EU countries. The analysis of
free text comments and answers showed a very high
Table I - List of criteria proposed.
Criteria
WP4 proposals
1
Types of structures involved
Standards for two levels of HCs, in relation to different functions assigned: Comprehensive Care Centres (CCC - providing
specialised and multidisciplinary care and functioning as tertiary referral Centres) and HTC (providing local routine care).
2
Types of diseases
Haemophilia and allied inherited bleeding disorders, and acquired bleeding disorders
3
Age groups of patients
Adults and paediatric patients.
4
Reference sources
Standards developed on the basis of main European and national scientific evidence and recommendations.
5
Types of standards
a) Only "organisational" standards.
Standards do not aim to take the place of scientific guidelines. HCs are requested to develop clinical protocols in adherence
to available national and European scientific references, and to provide evidence of their correct and systematic application
and supervision.
b) General standards for quality system management (according to EUCERD recommendations).
c) Quality indicators to be monitored and evaluated by the HCs to confirm that the clinical outcome reaches the requested standards
(according to EUCERD recommendations) and related targets.
6
Assessment
Only standards that could objectively be assessed by objective evidence collected during audits.
7
Issues to be analysed
and developed
a) General organisational requirements
- Quality of the facility
- Information about the Centre
- Organisation and staffing
- Policies and procedures
- Record-keeping and data collection
- Personnel appraisal and continuing education
- Equipment
- Supply and management of therapeutic products, reagents and medical devices
- Quality planning, evaluation and improvement
- Participation in institutional registries/databases related to inherited and acquired bleeding disorders
- Participation in clinical research
b) Patient care
- Awareness, information and education of patients and their families
- Diagnosis and therapy of haemophilia and allied inherited bleeding disorders, and all the forms of acquired haemophilia
- Periodic clinical and multi-disciplinary review
- Genetic services
c) Laboratory
d) Network of clinical and specialised services acting in conjunction with the haemophilia team (physiotherapy, orthopaedic,
psychological, dental care, social, infectious diseases, etc.)
e) Formal agreements between the CCC and HTC and between the HTC and third parties whose services impact patient management.
f) Recommended quality indicators (patient care) that should be routinely measured and evaluated by the HCs.
Blood Transfus 2014; 12 Suppl 3: s519-24 DOI 10.2450/2014.0046-14s
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Methodology for European Standards for Haemophilia Centres
level of agreement on each of the criteria proposed.
This agreement ranged from a minimum of 70% to a
maximum of 90% on the total of the questionnaires
received (Figure 1).
Drawing up of a draft of the guiding document for
consultation
Once validated, the above-mentioned criteria were
used in Step 3 in order to draw up the core draft of the
Guidelines document through the following actions: i)
definition of standards index and framework, ii) cross
reference of EU MS standards, where available, and iii)
development of standards.
An example of the resulting table of cross reference of
EU MS standards is shown in the excerpt below (Table II).
From the set of standards developed, 11 key
standards were selected for further consultation through
the Questionnaire on key points for the production of
standards for HCs and for the development of a related
evaluation system, that was presented in Warsaw during
the Annual Congress of the European Association
for Haemophilia and Allied Disorders (EAHAD). In
particular, the issues that were brought to the attention of
the European community of stakeholders were related to:
1) proposal for the names of the European Haemophilia
Centres: European Haemophilia Treatment Centres
(EHTCs) and European Haemophilia Comprehensive
Care Centres (EHCCCs);
2) criteria for the designation of a HC as an EHCCC or
an EHTC - number of patients/severity:
i) forty severe haemophilia patients for EHCCCs;
ii) exclusion of patients with moderate and
mild haemophilia, as well as those with von
Willebrand disease and rare disorders, in the
number of patients taken into consideration for
EHCCC designation;
iii) no minimum number of patients required for
designation of EHTCs;
3) procedures for the designation of EHCCCs/EHTCs:
i) validity of the certification (3 years);
ii) designation of EHCCCs/EHTCs based upon selfassessment;
4) requirement standards:
i) Provision of 24-h expert haemophilia medical
cover for EHCCCs;
ii) Provision of 24-h medical cover by formalised
arrangements with other departments and/or
designated EHCCCs for EHTCs;
iii) Establishment of a formal relationship between
EHTCs and EHCCCs;
Figure 1 - Percentage distribution of answers for each of the seven principles/criteria proposed by the EUropean HAemophilia
NETwork project - Work Package 4.
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Candura F et al
Table II - Example of cross-match analysis of some of the relevant documents used as a basis for the drafting of the European
guidelines for the certification of Haemophilia Centres6-8.
EU principles of
haemophilia care
EU MS 1
EU MS 2
EU MS 3
EU MS 4
NA
The cornerstone of the treatment of
haemophilia is comprehensive care
delivered by a multi-disciplinary and
specialised team on a 24 hour basis.
In practice this involves a core team
consisting of the following personnel:
- Haemophilia centre medical
staff, who carry out routine and
emergency treatment, …
- Haemophilia nursing staff who
co-ordinate much of the day to day
treatment, …
Art. 6
The organisation of treatment centre
staff always includes the following
functions performed by one or more
persons meeting the conditions laid
down in Artic. 7:
1) Physician coordinator.
2) Physician specialist in internal
medicine.
3) Physician specialist in paediatrics.
4) Physician specialist in clinical
biology.
5) ………………………….
NA
0.2.1 The Executive
Management of the Centre
defines and formalises
responsibilities, mandates
and assigns functions
within the organisation…
EU MS n
Standard WP4 (proposal)
The cornerstone of the treatment of haemophilia and other related bleeding disorders is comprehensive care delivered by a multi-disciplinary and specialised team.
1.4.1 The core team members of an EHTC/EHCCC consist of the following personnel:
- medical staff, who carry out routine and emergency treatment and follow-up clinical reviews;
- nursing staff, who co-ordinate much of the day to day treatment and supplies of coagulation factor concentrates;
- laboratory staff, who provide a diagnostic and factor replacement monitoring service.
- ……………………………………………………………………..
NA: not available
iv) Guarantee of an integrated approach to patient
multidisciplinary comprehensive care, also
through a formal relationship between EHTCs
and EHCCCs;
v) For both EHCCCs and EHTCs, access to a
laboratory that provides a minimum set of
coagulation tests (Prothrombin time; activated
Partial Thromboplastin Time; Thrombin time
and mixing studies; Factor VIII and IX assays;
Inhibitor screen; Fibrinogen and factor II, V,
VII, X and XI assays; platelet aggregation;
von Willebrand Factor multimers) and related
monitoring, on the basis of formal agreements
between the clinical and laboratory services;
5) availability of information related to EHTCs/EHCCCs
on a public website.
More than two hundred European stakeholders
participated in the survey. Agreement on each
key point was shown in the great majority of the
questionnaires received, with the exception of key
point no. 2 (Figure 2). On this point, although there was
agreement in over 50% of the questionnaires received,
the comments received pointed out that in small
population countries this threshold could represent
a discouraging limitation for EHCCC designation.
Moreover, the vast majority of respondents agreed
to establish a minimum threshold number of patients
(10) for the designation of an EHTC.
Finalisation of the Guiding document incorporating
feedback received from the consultation process
In Step 4, the Guidelines document was revised in
light of the results of the consultation process taking into
account all relevant comments received. A new version
of the Guidelines was then made available for further,
final consultation. The final release of the document was
approved on the 7th of June 2013 and launched in Rome
at the Italian National Institute of Health on the 11th of
July 2013 during the International Meeting Haemophilia
Centre Certification Systems across Europe9 and the
round table Haemophilia Centres of Expertise in Europe
at the European Parliament on 17th October 201310.
Proposal of an evaluation system framework for EU HCs
Finally, in Step 5 the WP4 team outlined the proposal
of a framework for the evaluation of applications to be
received by European HCs during WP5 activities.
All the entire methodology about consensus building
and consultation processes developed in EUHANET
WP4 is represented in Figure 3.
Results
The European Guidelines for the certification
of Haemophilia Centres set the standards for the
designation of two levels of European HCs: European
Haemophilia Comprehensive Care Centres, that provide
specialised and multidisciplinary care and function as
tertiary referral Centres, and European Haemophilia
Treatment Centres, that provide local routine care. The
standards apply to both adults and paediatric patients.
Their focus is on organisational issues and covers:
1) general requirements (facility; general policy and
objectives; information about the HCs; organisation
and staffing; policies and procedures; record-keeping
and data collection; personnel appraisal and continuing
education; supply and management of therapeutic
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Methodology for European Standards for Haemophilia Centres
Figure 2 - Percentage distribution of answers for each of the key points proposed in the EUropean HAemophilia NETwork
project - Work Package 4.
2)
3)
4)
5)
products, reagents and medical devices; quality
planning, evaluation and improvement; participation
in registries; participation in clinical research);
patient care (awareness, information and education of
patients and their families; diagnosis and therapy of
haemophilia and other related bleeding disorders and
all forms of acquired haemophilia; periodic clinical
and multi-disciplinary review; genetic services;
outcome indicators);
advisory services;
laboratory;
networking of clinical and specialised services.
Conclusions
Figure 3 - Flowchart of the consultation processes developed
in the EUropean HAemophilia NETwork project Work Package 4.
The drafting of the European guidelines for the
certification of haemophilia centres was performed adopting
a rigorous methodological approach. The document came
into being as a result of a synthesis of the experience
accumulated by the EU MS on HC quality management and
certification systems and European key reference documents
(European Haemophilia Principles of Care, EUCERD
recommendations). The drawing up of the Guidelines
involved the main institutional and scientific stakeholders
(EAHAD, EHC, EUHASS, EUHANET, EU and non-EU
countries) in all the key steps of the project, in order to build
Blood Transfus 2014; 12 Suppl 3: s519-24 DOI 10.2450/2014.0046-14s
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Candura F et al
the widest possible consensus to the quality standards to be
implemented in European Haemophilia Centres.
Acknowledgements
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.
Funding and conflict 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 has 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)
2)
3)
4)
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 .
Giangrande P, Calizzani G, Menichini I et al. The European
Standards of Haemophilia Centres. Blood Transfus 2014; 12
(Suppl 3): s525-30.
Colvin BT, Astermark J, Fischer K, et al. for the Inter
Disciplinary Working Group. European principles of
haemophilia care. Haemophilia 2008; 14: 361-74.
Recommendations on Quality Criteria for Centres of
Expertise for Rare Diseases in Member States, 24 October
2011. European Committee of Experts on Rare Diseases EUCERD. Available at: http://www.EUCERD.eu/upload/file/
EUCERDRecommendationCE.pdf. Accessed on 15/12/2013.
5)
Recommendations to the European Commission and the
Member States on European Reference Networks for Rare
Diseases, 31 January 2013. European Committee of Experts
on Rare Diseases - EUCERD. Available at: http://www.eucerd.
eu/?post_type=document&p=2207. Accessed on 15/12/2013.
6) Haemophilia Alliance. A National Service Specification for
Haemophilia and other Inherited Bleeding Disorders, 2nd edn.
London. The Haemophilia Alliance, 2006. Available at: http://
www.ukhcdo.org/docs/HaemAlliance-NatSvsSpec2006.pdf.
Accessed on 15/01/2014.
7) Conseil scientifique des maladie chroniques. «Comprehensive
Care» pour Hémophiles. Bruxelles, Belgium: Rijksinstituut
voor Ziekte- en Invaliditeitsverzekering (RIZIV) = Institut
National Maladie Invalidité (INAMI); 2007.
8) Associazione Italiana Centri Emofilia. Programma di
accreditamento professionale AICE, 2nd edn. 2010. Available
at: www.aiceonline.it. Accessed on 15/12/2013.
9) I n t e r n a t i o n a l m e e t i n g o n H a e m o p h i l i a C e n t re
C e r t i f i c a t i o n S y s t e m s a c ro s s E u ro p e . C e n t r o
Nazionale Sangue (Italian National Blood Centre).
Available at: http://www.centronazionalesangue.it/
newsbox/seminario-malattie-emorragiche-congenite-mec.
Accessed on 15/01/2014.
10) 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.
Correspondence: Fabio Candura
Italian National Blood Centre
National Institute of Health
Via Giano della Bella 27
00162 Rome, Italy
e-mail: fabio.candura@iss.it
Blood Transfus 2014; 12 Suppl 3: s519-24 DOI 10.2450/2014.0046-14s
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ORIGINAL ARTICLE
The European standards of Haemophilia Centres
Paul Giangrande1,2, Gabriele Calizzani2,3, Ivana Menichini2,4, Fabio Candura2,3, Pier Mannuccio
Mannucci5, Michael Makris6
1
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
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.
Keywords: standards and criteria, certification system, haemophilia care, EUHANET.
Introduction
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
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Giangrande P et al
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.
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.
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
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.
Results
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
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European standards for Haemophilia Centres
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
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
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 EHTC
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.
•
•
•
•
•
•
•
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.
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
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European standards for Haemophilia Centres
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
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.
Acknowledgements
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.
Author contributions
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.
Blood Transfus 2014; 12 Suppl 3: s525-30 DOI 10.2450/2014.0056-14s
s529
Giangrande P et al
2)
3)
4)
5)
6)
7)
8)
9)
10)
11)
12)
13)
14)
15)
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
16)
17)
18)
19)
20)
21)
22)
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.
Correspondence: Gabriele Calizzani
National Blood Centre, National Institute of Health
Via Giano della Bella 27
00162 Rome, Italy
e-mail: areaplasma.cns@iss.it
Blood Transfus 2014; 12 Suppl 3: s525-30 DOI 10.2450/2014.0056-14s
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REVIEW
The haemophilia certification system in Canada
Davide Matino1, Jerry Teitel2, David Page3, Arun Keepanasseril1, Alfonso Iorio1,4, Irwin Walker4
1
Health Information Research Unit, Department of Clinical Epidemiology and Biostatics, McMaster University,
Hamilton; 2St. Michaels Hospital, Toronto; 3Canadian Haemophilia Society, Montreal; 4Division of Hematology,
Department of Medicine, Hamilton, Canada
Introduction
Inherited bleeding disorders are caused by the
deficiency or dysfunction of plasma proteins required for
the development of a physiological hemostatic process1,2.
Von Willebrand disease (vWD), haemophilia A and
haemophilia B are the most common inherited disorders
of hemostasis. In their severe forms, these disorders
are life-threatening. However advanced treatment
modalities have enabled even severely affected patients
to reach the same life expectancy of the general male
population at least in high-income countries3,4 . Indeed,
after the dramatic events of widespread blood-borne
virus transmission in the 1970s-1980s in haemophilic
patients, leading to a 35-to-40-year reduction in life
expectancy in Canadian patients5, there has been a strong
drive towards continuous improvement, primarily in the
safety of replacement therapy6 .There is now a very high
degree of safety from risk of blood borne transmission
of pathogens as evidenced by the absence of reported
transmission of blood-borne viruses in persons with
haemophilia since the late 1980s to date7. The safety of
current replacement therapies was recently confirmed by
a prospective surveillance program ongoing since 2008
and based on regular monitoring of 22,242 European
patients (European Haemophilia Safety Surveillance
System; www.euhass.org). Regular factor prophylaxis
as a therapeutic regimen has been proven effective in
preventing haemophilic arthropathy8. Even in the presence
of neutralizing antibodies (inhibitors) directed against
the deficient clotting factor, particularly in haemophilia
A, bleeding can usually be treated successfully using
activated variants of coagulation factors9. Moreover,
immune tolerance induction (ITI), based on the long-term
intravenous infusion of large doses of FVIII, eradicates
inhibitors in as many as two-thirds of patients10. Therefore,
improving quality of life has become the primary objective
of care in developed countries; thus multiple modalities
(psychosocial support, physiotherapy, integration into
community life, etc), not just the infusion of the deficient
factor, are made available to the patient and his family, to
allow them to fully experience good health.
The haemophilia care in Canada
Canada is a very large country geographically. With
a total of 9.98 million square kilometres, Canada is the
world's second-largest country by total area consisting
of 10 provinces and 3 territories. Provinces have a great
deal of power relative to the federal government, with
jurisdiction over many public goods such as health
care (but also education, welfare, and intra-provincial
transportation). Current Canada's total population
estimate (http://www.statcan.gc.ca/) is 35,295,770.
The Canadian Hemophilia Registry identified a total
of 2,966 haemophilia A patients, 690 haemophilia B
patients, 3,963 patients affected by vWD and 1,740
patients with other bleeding disorders, including rare
platelet disorders (http://fhs.mcmaster.ca/chr/data.
html). Factors usage from 2007 to 2012 is reported in
Table I. In 2012 a total of 190,189,628 FVIII IU were
used and the mean per capita FVIII usage was 5.39 IU
while a total of 45,772,681 FIX IU consumption was
registered with a mean per capita FIX usage of 1.29 IU.
Some patients live many hundreds of kilometers from
the nearest Haemophilia Treatment Centre (HTC). A
number of strategies are used to provide care to them.
Home infusion is encouraged where feasible. Specialists
in the HTC create links with local practitioners to
coordinate care in distant locations. Telemedicine is
used to communicate with patients and their caregivers.
Nurse coordinators connect extensively with patients by
telephone. Some centre teams conduct outreach clinics to
smaller centers where a concentration of patients reside.
Programs funded by government or the local chapter
of the CHS provide financial support for families to
travel to the HTC for annual assessments. Electronic
infusion reporting systems are used to report product use.
Distribution of the 24 Haemophilia Treatment Centers
(HTCs) in Canada is shown in Figure 1.
The standard of care for haemophilia in Canada
A functional, efficient, and accountable system of
haemophilia care has been developed in Canada mostly at
the initiative of the comprehensive care centers, without
acting official mandates. However, several Canadian
provinces have since designated provincial haemophilia
programs in specific centres (e.g. British Columbia,
Saskatchewan, Manitoba and Quebec). The existing
system is thus an eloquent testimony to the goodwill
and constructive collaboration among patients and their
families, health care providers and funders. The idea that
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Table I - Reported use of factor concentrates in Canada from 2007 to 2012.
Product
Factor Eight Inhibitor Bypassing
Activity
2012-2013
2011-2012
2010-2011
2009-2010
2008-2009
2007-2008
Unit
Quantity
Quantity
Quantity
Quantity
Quantity
Quantity
IU
14.059.865
14.059.865
12.139.931
11.406.109
9.492.307
7.096.409
Compl.prot.total Octaplex
IU
3.360.500
3.360.500
9.942.500
920.000
12.600
0
Factor IX
IU
42.975.510
42.975.510
43.612.325
39.861.108
37.136.322
33.569.155
Factor VIIa
IU
1.463.400
1.463.400
1.248.000
1.107.000
1.227.000
978.600
Factor VIIa rec. NiaStase®
mg
25.483
25.483
30.502
30.686
34.124
33.740
Porcine FVIII
IU
-
-
0
0
0
249.340
Recombinant Factor VIII
IU
178.234.199
178.234.199
178.792.631
164.791.696
155.487.497
144.129.307
Factor VIII/VWF
IU
28.730.716
28.730.716
26.711.363
24.364.514
20.701.440
18.620.052
Factor XI
IU
35.890
35.890
51.275
74.455
64.575
85.705
Factor XIII
IU
559.000
559.000
533.000
471.750
522.000
444.250
Fibrinogen
g
542
542
933
390
1.188
901
Figure 1 - Distribution of Haemophilia Treatment Centers across Canada
a national standard of care for haemophilia be developed
for Canada was first promulgated in the conference
"Comprehensive Care for the Canadian Haemophiliac",
Winnipeg, May 1978, organised by the Canadian
Haemophilia Society (CHS) in close collaboration with its
own multi-disciplinary Medical and Scientific Advisory
Committee (MSAC).
To analyze the scope of the initiative, we will refer
to the definition given in 1998 in the Standards for
comprehensive care of haemophilia in Canada, agreed
upon during a "second" Winnipeg conference, on April
30 - May 1, 1998.
The Association of Haemophilia Clinic Directors
of Canada (AHCDC) and the CHS felt that national
standards of care for haemophilia should be developed
for the following reasons:
1. to preserve the integrity of the network of Haemophilia
Comprehensive Care Programs;
2. to assure equal access and equal standards of care;
3. to establish a reference for discussion of future
advances and needs;
4. to be a reference point and unifying force for staff
of various organizations that are geographically
dispersed and serve a small population;
5. to promote discussion and research regarding optimal
ways to deliver care; and
6. to provide the basis for the design of clinics, for
accreditation, and for audit and evaluation.
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At its Annual General Meeting in Edmonton, the
AHCDC appointed a working group on standards of care
with two of us (Irwin Walker and Jerome Teitel) as cochairs. The working group was later expanded to become
a multidisciplinary one.
With the aim of developing national standards,
a national multidisciplinary committee, including
members of the CHS, the Canadian Association of
Nurses in Haemophilia Care (CANHC), Canadian
Association of Physiotherapists in Haemophilia
Care (CAPHC), and the Canadian Social Workers in
Haemophilia Care (CSWHC) was initiated to further
the initiatives of the AHCDC. The National Standards
Committee for Haemophilia Treatment Centres
conducted a first conference on April 20, 2005. It was
attended by the representatives from the CHS and the
AHCDC. An important recommendation from the
meeting was that Haemophilia Comprehensive Care
should be delivered according to a set of uniform
national standards and wherever possible these standards
should be needs-based, data-driven and supported by
evidence of effectiveness. The meeting also held that
generic national standards be developed, but as they
would be implemented locally the system must be
flexible and adaptable, with the emphasis being the
delivery of a uniformly high quality of care.
The meeting also formalised the constitution of
a multidisciplinary standards of care working group
to develop comprehensive standards of care for
haemophilia, led by the AHCDC. All four health care
provider groups and CHS were represented in the
working group.
Simultaneously, the Ontario clinics were working
on provincial standards of care, and they published their
document which later became the template for the national
standards. This work was spearheaded by the Provincial
Haemophilia Coordinator at the time, Julia Sek, and
the co-chairs of that group were Jerome Teitel and John
Plater. After a series of meetings and deliberations, the
first edition of the Canadian Haemophilia Standard of
Care was published in 2007 (Canadian Comprehensive
Care Standards for Haemophilia and Other Inherited
Bleeding Disorders, http://www.haemophilia.ca/en)
for use by Haemophilia Treatment Centres, hospital
administrations, and provincial Ministries of Health. It has
to be acknowledged that this national document was largely
based on the Ontario Provincial standards.
The premises of the Canadian comprehensive care
standards for haemophilia and other inherited bleeding
disorders are that:
- improved quality of life is the ultimate goal of care,
with an emphasis on measurable outcomes and
independent living;
- inherited bleeding disorders are rare and therefore
-
-
-
-
collaboration among HTCs and networks needs to be
encouraged;
bleeding disorders and their treatments are associated
with a number of complications - medical, psychological
and social-that may affect quality of life of affected
individuals and so care needs to be comprehensive;
evaluation and documentation of clinical outcomes are
essential components of a comprehensive program;
standards of care are measures that HTCs can adhere to
and which can be used for auditing. Key indicators are
signals that demonstrate whether a standard has been
attained. They provide a way in which to measure and
communicate the impact or result of the standard, as
well as the process.
accountability for utilization of factor replacement
product is necessary due to its potential to cause adverse
events and its high cost; this is equally true for products
used in centres and at home in supervised home therapy
programmes;
HTCs have a responsibility to participate in research,
education and innovation to the degree that they are
capable. Regional differences within the province or
region must be acknowledged in the provision of care
for people with bleeding disorders.
Future perspective and conclusions
The vision is to provide comprehensive care to all
individuals with inherited bleeding disorders, guided
by clear standards, facilitated by engagement with
stakeholders, and driven by needs and best practice,
resulting in best outcomes. The focus of these standards
is on the structural and resource requirements necessary
for a HTC to effectively provide care, and on its
functions and responsibilities.
In 2009 in response to a request from the AHCDC
executive, the Standards group initiated a self assessment
survey among Canadian Haemophilia Treatment Centers
according to the specific standards (Table II, III, IV) and
key indicators (see appendix 1) proposed. Standards of
care are measures that Haemophilia Treatment Centres
can adhere to and which can be used for self-evaluation
and auditing. Key indicators are signals that demonstrate
whether a standard has been attained. They provide a
way in which to measure and communicate the impact or
result of the standard, as well as the process. The goal was
to validate the Canadian clinic standards by assessing
acceptability and adherence. The average adherence by
all clinics to all standards was 92% (standards being
adhered to by an average of 22 of 24 HTCs). Adherence
levels below 83% (20 of 24 HTC) were observed for
only 4 standards; for two of these standards the low
adherence was due to a lack of core team members,
particularly social workers and physiotherapists and
possibly administrative staff as well. As indicated by
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Table II - Standards - 1. Scope of care
The HTC will:
1.
Establish correct diagnoses.
2.
Establish and maintain a full complement of core team members
3.
Develop visibility in the bleeding disorder and medical community.
4.
Strive to enrol all members of the target population in its region.
5.
Establish a collaborative relationship among core team members
6.
Establish a routine for patient access to regular and emergency care.
7.
Establish a process for referring patients to services not provided within the programme.
8.
Register patients in CHARMS (Canadian Haemophilia Assessment and Resource Management System) and CHR (Canadian Haemophilia Registry) databases.
9.
Provide the patient with documentation that identifies his/her bleeding disorder and recommended treatment.
10. Provide education to affected individuals, family members, health care givers and others as necessary.
11. Have a home infusion program, in which patients and families are instructed in home therapy, including prevention and recognition of bleeds and
correct practices.
12. Provide primary and secondary prophylaxis regimens as appropriate (all pediatric patients with severe haemophilia should be considered).
13. Provide early intervention and follow-up care to reduce long-term complications.
14. Network with outside agencies creating formal linkages to provide efficient access to their services.
15. Encourage and facilitate eligible members to participate in activities of AHCDC, CANHC, CPHC, CSWHC and other relevant HTC working groups.
Table III - Standards - 2. Quality Measures1
The HTC will:
1.
Maintain health records according to legislation, which must include:
- history and physical examination;
- diagnosis and treatment recommendations;
- operative/special procedure notes and records;
- interdisciplinary progress notes;
- medication records;
- consent forms;
- adverse events/allergies;
- records of home therapy program (teaching, home visit to initiate program, and annual certification);
- records of telephone communications.
2.
Participate in data collection and submission to CHARMS including:
- i. patient demographics;
4.
- ii. factor utilization.
Submit anonymous data to the Centre Point module of CHARMS and to the CHR, as required by AHCDC. AHCDC will pool and collate factor
concentrate utilization data and make it available to the operators of the blood system to plan purchases, flag inconsistencies, outliers and adverse events
and to conduct efficient recalls and advisories as necessary. AHCDC will also use data for research planning, and various administrative and political
purposes.
Adhere to provincial health information privacy protection acts.
5.
Be supported by its host hospital and the provincial Ministry of Health.
6.
Accept accountability for the appropriate use of all factor concentrates distributed within its catchment area to registered patients with inherited
bleeding disorders. This excludes cryoprecipitate and fresh frozen plasma, but includes all plasma derived and recombinant concentrated clotting
factors distributed by Canadian Blood Services and Héma-Québec.
7.
Participate in a formal accreditation and evaluation process once it is established.
8.
Mentor, where possible, students and trainees in the health professions.
9.
Establish mechanisms to acknowledge and review compliments, complaints and special requests. These compliments and complaints are documented
and reviewed periodically.
3.
1
This section describes expected activities of an HTC that contribute to the quality of both the individual centre and the Canadian HTC network.
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Table IV - Standards - 3.Therapeutic Services1
The HTC will:
1.
Provide the appropriate professional care for their patients, recognizing the need for pediatric and adult medical expertise as appropriate.
2.
Provide a comprehensive evaluation (including laboratory testing) at least annually for adult patients and semi-annually for children. This frequency
is recommended for those with higher bleeding risk; for those with a lower bleeding risk a less frequent schedule will be appropriate. The evaluation
will include updating wallet cards (treatment recommendations).
3.
Provide assessments from each core team member at least annually. Patients will have additional access to core team members as required.
4.
Provide emergency departments and family physicians with diagnosis and treatment recommendations for registered patients, consistent with the PHIPA
and the hospital’s health records policy. The HTC will arrange for qualified 24-hour medical coverage and consultative services for the target population.
5.
Educate patients and families on the best way to advocate for and to access emergency care and other services.
6.
Utilize, as appropriate, clinical practice guidelines published by AHCDC and other expert bodies for the management of bleeding episodes, inhibitors
and special or surgical procedures.
7.
Establish formal links to provide access to special hemostasis testing, genetic testing, and treatment for haemophilia and its complications.
8.
Work in collaboration with patients and their families to promote health and to enhance ability to cope with a chronic health condition.
9.
Provide education and recommendations to other community professionals who provide services to patients with inherited bleeding disorders.
10.
Provide prophylaxis (primary and secondary) to patients in accordance with AHCDC recommendations and best practice.
11.
Provide a home therapy program to all appropriate patients and monitor its effectiveness for each individual. The home therapy program will include
comprehensive training in intravenous technique and procedures for both care givers and patients themselves, as appropriate, safe and responsible
handling and storage of factor concentrates and safe disposal of used equipment and supplies.
12.
Maintenance of home therapy records will be encouraged and routinely reviewed, to help in making treatment recommendations.
13.
Provide injection equipment and other supplies to patients.
14.
Provide management for patients with inhibitors with reference to guidelines issued by the AHCDC and other expert bodies.
15.
Be located in a facility that should be readily accessible to people with disabilities.
16.
Be located within an Ambulatory Clinic area to facilitate prompt assessment and treatment of acute bleeding episodes.
17.
Be located in a facility that has or is linked with an Emergency Department where patients can obtain treatment outside of regular hours.
1
This section describes the actions required of an HTC in the direct delivery of therapeutic services.
statements from the World Federation of Haemophilia
and by the Canadian standards, a lack of any of these
team members is particularly serious considering their
importance. Lack of complete adherence to other
standards was due to a variety of reasons, in most cases
either easily explainable or spurious.
No correlation was found between the level of
adherence to the standards and any one of a variety of
HTC descriptors. The general level of acceptability of the
standards was high; most clinics (20 of 24, 83%) thought
the standards were useful and 22 of 24 clinics (92%)
expressed their willingness to participate in evaluation
and accreditation processes once these are established.
To fulfill the proposed standards of care a full audit
process, modeled on the Ireland and UK experience,
has been planned by the AHCHC-led Canadian
Haemophilia Standards Group, but has been slowed
down by unexpected privacy issues encountered early
in the process.
Complementarily to this process, and in order to gather
information that can be used to advocate for adequate
resources in clinics, a CHS task force led by PastPresident, Pam Wilton, has developed a Haemophilia/
Bleeding Disorder Clinic evaluation process to be led
by CHS to roll out in 2013. The proposed process,
which is supported by the Executive Committee of the
AHCDC, consists of an assessment of the services and
resources in Haemophilia/Bleeding Disorder Clinics
through interviews with clinic personnel and a patient
questionnaire. This survey is evaluating the adequacy of
the physical, material and human resources in Canada's
24 HTC. The overall goal is to identify any gaps in
resources that may prevent Haemophilia/Bleeding
Disorder Clinics from delivering care and treatment
according to the Canadian Comprehensive Care Standards
for Haemophilia and Other Inherited Bleeding Disorders
and that may lead to sub-optimal patient outcomes (see
Table I, II, III).
The primary objectives are:
- to conduct a thorough assessment of the services and
resources in Haemophilia/Bleeding Disorder Clinics
in each province;
- to prepare a detailed report and recommendations
for hospital administrators and/or Ministry of Health
officials in each province;
- to identify and meet key decision-makers in each
province with the goal of maintaining and improving
the care for people with inherited bleeding disorders;
- to follow up support implementation of
recommendations.
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Interviews with clinic personnel and patient
questionnaires (see appendix 2, 3) are used in the
evaluation.
The process is based on a successful initiative by
the Quebec Chapter of the CHS. Study interviewers
met all 37 clinic personnel across Quebec in half-hour
meetings. These face-to-face interviews are preferred
to a written survey to allow dialogue and clarification
of responses. The resulting report is validated by the
clinic directors and recommendations are made to the
Ministry of Health. The same approach will be applied
to all clinics across Canada.
To promote a consistent approach, the interviews
are conducted by David Page, CHS National Executive
Director, and Michel Long, CHS National Program
Manager and, in Ontario, Sarah Crymble, Haemophilia
Provincial Coordinator. The patient questionnaire was
originally developed for the Irish and U.K. HTC audits,
and has been modified by the group preparing the
Canadian audit.
The observations, based on the clinic interviews
and patient questionnaires, will be assembled in a draft
report by the CHS National Office for each clinic and
then shared first with the clinic director. Once vetted
and approved by the clinic director a final report will be
shared with the local chapter Board of Directors. Then, if
necessary, a strategy will be developed to approach the
appropriate health authorities - hospital administration,
regional health authority of Ministry of Health - with a
proposal to better meet the standards of care. Up to now,
most of the Ontario assessments have been concluded
and the visits in Western Canada have been scheduled
for winter 2014. We expect that by the end of April 2014
the visits will be completed. Patient questionnaires are
actively being distributed by Centres and responses are
being received.
In summary, the process of haemophilia centre
accreditation in Canada was born with the cooperation
of patients and doctors. It will serve as the model to
standardize and, where necessary, to improve the care
of Canadian haemophilia patients. There is no "end" to
such a process. In our opinion, many important results
have been achieved, and several important lessons can
be learned. As well, we are sure that interesting and
actionable results will stem from the ongoing process.
2)
Lillicrap D. vonWillebrand disease: advances in pathogenetic
understanding, diagnosis, and therapy. Blood 2013; 122:
3735-40.
3) Darby SC, Kan SW, Spooner RJ et al. Mortality rates, life
expectancy, and causes of death in people with haemophilia
A or B in the United Kingdom who were not infected with
HIV. Blood 2007; 110: 815-25.
4) Tagliaferri A, Rivolta GF, Iorio A et al. Mortality and causes
of death in Italian persons with haemophilia, 1990-2007.
Haemophilia 2010; 16: 437-46.
5) Walker IR, Julian JA. and Association of Haemophilia Clinic
Directors of Canada. Causes of death in Canadians with
haemophilia, 1980-1995. Haemophilia 1998; 4: 714-20.
6) Mannucci PM. Treatment of haemophilia: building on strength
in the third millennium. Haemophilia 2011; 17 (Suppl 3): 1-24.
7) Blood safety monitoring among persons with bleeding
disorders-United States, May 1998-June 2002. MMWR Morb
Mortal Wkly Rep. 2003; 51: 1152-4.
8) Iorio A, Marchesini E, Marcucci M, Stobart K, Chan AK.
Clotting factor concentrates given to prevent bleeding and
bleeding-related complications in people with haemophilia
A or B. Cochrane Database Syst Rev. 2011 Sep 7; (9):
CD003429.
9) Iorio A, Matino D, D'Amico R, Makris M. Recombinant
Factor VIIa concentrate versus plasma derived concentrates
for the treatment of acute bleeding episodes in people with
haemophilia and inhibitors. Cochrane Database Syst Rev. 2010
Aug 4;(8): CD004449.
10) Hay CR, Di Michele DM. The principal results of the
International Immune Tolerance Study: a randomized dose
comparison. Blood. 2012; 119: 1335-44.
Keywords: haemophilia, comprehensive care, audit,
accreditation, certification.
The Authors declare no conflicts of interest.
References
1)
Kumar R, Carcao M. Inherited abnormalities of coagulation:
haemophilia, von Willebrand disease, and beyond. Pediatr
Clin North Am 2013; 60: 1419-41.
Correspondence: Alfonso Iorio
HIRU CRL-140
Clinical Epidemiology and Biostatistis
McMaster University
1280 Main St. West
L8S4L8 Hamilton, Ontario, Canada
e-mail: iorioa@mcmaster.ca
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Appendix 1
Key Indicators - 1. Scope of Care*
1-1
1-2
1-3a
1-3b
1-3c
1-4
1-5a
1-5b
1-6a
1-6b
1-6c
1-7a
1-7b
1-7c
1-8a
1-8b
1-8c
1-9
1-10a
1-10b
1-11a
1-11b
1-11c
1-12a
1-12b
1-13a
1-13b
1-14
1-15a
1-15b
Patients’ factor levels are documented in their clinic records.
The HTC has a complete complement of core team members as listed in the standards.
The HTC has regular communications with the local chapter or region of the Canadian Hemophilia Society.
The HTC has a process in which to communicate to outside agencies about current events/workshops and conferences.
Outside agencies are able to contact team members for information.
The HTC is aware of the pattern of factor concentrate utilization in the region
There is evidence of collaboration among all members.
Core team members contribute to the development of policies, procedures and standards.
Registered patients can access care and follow-up care for acute bleeds.
Non life-threatening bleeds in non inhibitor patients are managed in the ambulatory care setting, so that there is a low
hospitalization rate for bleeding episodes.
Policies & procedures are available for the treatment of non-urgent, urgent and emergency bleeding episodes.
The HTC has a referral list for secondary team members and utilizes their services routinely.
Secondary team members are extended invitations to team educational workshops and activities.
The core team is aware of referral procedures to secondary team members.
CHARMS software is available in the HTC.
All core team members have access to the CHARMS program.
Clerical work for data entry is kept current.
Wallet cards or FactorFirst cards are issued to registered patients and updated as needed.
Policies and procedures for education of newly diagnosed patients are available.
A variety of educational resources are available to distribute to patients, families and community.
Policies & procedures are available on how to administer the home therapy program.
There are patients registered in the home therapy program and the list of participants is available.
There is documentation in the patient health record about participation in home therapy programme (including date of
certification)
Prophylaxis therapy is made available to the appropriate patients.
A current list of patients on prophylaxis is available.
The HTC has access to a special hemostasis laboratory, transfusion medicine department, and diagnostic imaging
department.
The HTC has a procedure for assigning priority for new patient referrals.
Contact information for the HTC is current in listings with the Canadian Hemophilia Society, the World Federation of
Hemophilia and parent hospital.
Core team members are members of relevant organizations and / or working groups within the bleeding disorder
community and communicate regularly with these organizations.
Core team members, when able, serve on appropriate committees within the organization (AHCDC, CANHC, CPHC,
and hospital).
Key Indicators - 2. Quality Measures*
2-1a
2-1b
2-2a
2-2b
2-2c
2-3a
2-3b
2-4
2-5a
Hospital records contain current HTC documentation that may include assessments by core team members stating
patient goals, team recommendations, patient issues, and patient progress.
Hospital records and clinic charts include documentation of telephone calls for patient advice and follow-up.
Data is routinely exported from CHARMS to Centre Point.
Factor utilization reports are available from the local CHARMS program.
The HTC has the ability to monitor expiry dates of factor concentrates within its jurisdiction via the CHARMS program.
Data is routinely exported from CHARMS to Centre Point.
Registered patients are assigned a CHR number.
If the HTC has clinic charts, the charts are stored appropriately to maintain privacy and confidentiality, and are accessible
to appropriate team members.
The HTC participates in hospital or peer evaluation and responds to critical appraisal.
2-5b There is a process to request adjustment in resources and to monitor services available to the patient
population.
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2-6
2-7
2-8
2-9
Data is routinely exported from CHARMS to Centre Point.
Centre volunteers to undergo accreditation process or responds to requests to do so.
HTCs located in academic healthcare institutions provide professional educational opportunities.
Patients and families have a mechanism in which to communicate concerns and compliments.
Key Indicators - 3. Therapeutic Services*
3-1
3-2a
3-2b
3-3
3-4a
3-4b
3-5a
3-5b
3-5c
3-6
The members of the HTC have the appropriate training and qualifications to provide care to the patient population.
The number of assessment clinics offered is sufficient to meet the standard of annual and semi-annual patient evaluation.
The HTC provides a mechanism for team members to share knowledge with each other to promote best patient outcomes.
Core team members are available for assessment clinics and urgent care.
The HTC has resources available to ER departments regarding treatment and complications.
HTC provides treatment recommendations to emergency departments and family physicians.
Educational information is offered to patients and family on current issues/events related to bleeding disorders.
Each core team member provides education and support to patients and families.
Team members ensure that patients have sufficient information to make informed decisions.
There are reference materials available to team members and students (i.e. AHCDC Clinical Practice Guidelines, journal
articles and texts).
3-7
There are formal links to specialised laboratories and Canadian Blood Services
3-8a When participating in research or clinical trials, team members ensure the safety and well-being of the patient above
all other objectives.
3-8b The HTC has contact information available (e.g. business cards).
3-9a When a patient moves to a location served by another HTC, the two centres will ensure that a formal transfer takes
place promptly, including the forwarding of all relevant medical records, with patient consent.
3-9b Educational information is offered within the community as requested or needed (i.e. school, daycare).
3-10 There are reference materials available to team members and students (i.e. AHCDC Clinical Practice Guidelines, journal
articles and texts).
3-11 The team has a mechanism to evaluate the home therapy program outcomes with participants.
3-12 Patients receive injection equipment and supplies free of charge
3-13 There are reference materials available to team members and students (i.e. AHCDC Clinical Practice Guidelines, journal
articles and texts).
3-14 Physical clinic space is appropriate for people with disabilities or mobility aids.
3-15a There is private clinic space available for acute assessments and treatment.
3-15b The HTC ensures an adequate stock of factor concentrates is maintained within its institution.
3-16 The Emergency Department affiliated with the HTC has recommended treatment guidelines for registered patients.
*Numbering of Key Indicators refers to the corresponding Standards
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Appendix 2
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Appendix 3
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REVIEW
The National Haemophilia Program Standards, Evaluation and Oversight
Systems in the United States of America
Mark W. Skinner1, J. Michael Soucie2, Kathryn McLaughlin3
1
National Hemophilia Foundation, Washington, DC; 2Division of Blood Disorders, National Center on Birth
Defects and Developmental Disabilities, Centers for Disease Control and Prevention, US Department of Health
and Human Services, Atlanta, GA; 3Genetic Services Branch, Division of Children with Special Health Care Needs,
Maternal and Child Health Bureau, Health Resources and Services Administration, US Department of Health and
Human Services, Washington, DC, United States of America
Introduction
The US National Hemophilia Program (NHP) is a
collaborative relationship between the Maternal and
Child Health Bureau (MCHB) of the Health Resources
and Services Administration (HRSA), the Centers
for Disease Control and Prevention (CDC) and the
Medical and Scientific Advisory Council (MASAC)
of the National Hemophilia Foundation (NHF). This
article is written in three parts outlining the roles,
collaborative and integrated working relationships of
the three core entities (MCHB, CDC, NHF). We will
discuss the birth and evolution of the modern day NHP
and haemophilia treatment center (HTC) network, the
evolution and role of surveillance programs, treatment
guideline and standard setting, the impact of health care
reform on access to comprehensive care and on-going
initiatives to improve health outcomes for those living
with haemophilia and related bleeding disorders.
Although there is, at present, no formal HTC
accreditation system in the US, we will describe a
number of programs and systems that are already in place
to promote and measure adherence to best practices,
monitor patient outcomes and encourage continual
operational and clinical improvement according to
established standards. Finally, we will describe various
initiatives that are underway to further develop evidencebased guidelines, which may lay the foundation for
a future, formalised HTC self-audit evaluation or
accreditation system.
Discussion
History of the evolution of HTCs in the US
Legislative Authority
Providing federal support to facilitate Federal-State
partnerships on public health issues for women and
children, specifically those in rural areas and with
special health care needs, has been longstanding at
HRSA, beginning with the passage of Title V of the
Social Security Act in 19351. Title V funding to States
helped support the development of an infrastructure to
treat patients with haemophilia in the US since 19752.
Title V funding has undergone many revisions since its
passage in 1935: the most significant change relating
to haemophilia occurred in 1981 with passage of the
Omnibus Budget Reconciliation Act (OBRA '81), which
converted the Title V program into a Maternal and Child
Health (MCH) Block Grant program.
In addition, with OBRA'81, 15 percent of the Title V
appropriation for each fiscal year was set aside to support
Special Projects of Regional and National Significance
(SPRANS) as part of the MCH Block Grant3. Funding
for federal haemophilia diagnostic and treatment centers
(now known as the National Hemophilia Program)
was included in the fifteen percent of the MCH Block
Grant funds set aside for SPRANS programs; this
appropriation remains to this day.
Evolution of HRSA's National Hemophilia Program
(NHP)
The MCHB SPRANS funding for the NHP
is administered through the Division of Children
with Special Health Care Needs (DCSHN) by the
Genetic Services Branch (GSB). The NHP has two
distinct programmatic parts: the Regional Hemophilia
Network (RHN) and the National Hemophilia Program
Coordinating Center (NHPCC). The RHN comprises
the HTCs that receive the grant funding directly from
MCHB. The NHPCC provides technical assistance to
the RHN on care delivery and program evaluation to
support participating HTCs in complying with NHP
roles and responsibilities as discussed below.
The main purpose of the RHN is to establish
integrated and collaborative regional networks to
promote the comprehensive care of individuals with
haemophilia and related bleeding disorders or clotting
disorders such as thrombophilia. The primary goal of
the RHN grant program is to ensure that individuals
with haemophilia and other bleeding disorders and their
families have access to appropriate, quality care and
other medical expertise and information in the context
of a medical home model that provides family-centered,
comprehensive, and culturally effective care4. Providing
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US Haemophilia Treatment Center framework and evaluation
comprehensive care through a core team of specialists
is integral to being considered a federally qualified
HTC and all HTCs within the network are required to
comply with the NHF MASAC Recommendation 132
- Standards and Criteria for Persons with Congenital
Bleeding Disorders, in order to qualify for federal
funding as discussed below5,6.
Since OBRA '81, MCHB has awarded funding
for haemophilia through a regional approach using
grants. In 2012, HRSA adjusted the regional structure
from 12 historical regions to 8 regions, along with the
development and implementation of the NHPCC. This
organizational change was made to move from a regional
to a national focus in terms of data collection and
evaluation, as well as to better align program resources
with patient needs.
The RHN is currently comprised of 132 HTCs
including 8 regional core centers. The regional core
centers are funded as grants, however, the NHPCC
was awarded as a cooperative agreement which allows
the MCHB Program Officer to adjust work plans and
timelines to better suit successful completion of goals
and objectives. The core centers distribute available
funding to their subrecipient HTCs within their regions
and the number of HTCs is variable, depending on
the geographic size of the region. The core centers are
responsible for ensuring that their subrecipient HTCs
comply with the roles and responsibilities laid out in the
funding opportunity announcement published by HRSA.
Advent of the NHPCC and its objectives
During the discussions on how to organizationally
restructure the NHP in 2011-2012, MCHB looked to
other successful regional grant programs. Critical to the
success of these other programs was the presence of a
national coordinating center to compile and disseminate
regional best practices; therefore, the decision was made
to develop a similar funding opportunity for a NHPCC.
The purpose of the NHPCC is to facilitate, coordinate,
and evaluate (in terms of assisting in the development
of regional and national evaluation plans) the activities
carried out by the RHNs. Working collaboratively with
the RHNs to develop a best practices model and establish
a standard of care model will also be important activities.
The American Thrombosis and Hemostasis Network
(ATHN)
ATHN was awarded funding as the NHPCC
in June 2012. ATHN, as the NHPCC, is not an
oversight or punitive organization, but one that
provides technical assistance to the RHN on program
evaluation, recruitment and retention of staff, as well
as incorporation of genetics and public health into the
NHP7. The genesis of ATHN dates back to the early
2000s, when specialists and clinicians who provide care
to those living with haemophilia and others with rare
bleeding disorders within the NHP acknowledged unmet
needs within their community regarding collecting data
and evaluating care for their patient populations with
small numbers in the existing electronic medical record
systems. During 2005 and early 2006, a broad range
of key haemophilia stakeholders (e.g., haemophilia
organizations, institutions, clinical disciplines, and
experts in related fıelds of expertise) formed multiple
clinical and operational working groups to assess the
information needs of the community and develop a
consensus approach to address them. The outcome of
these deliberations led to the development of ATHN.
ATHN's mission is "(…) to provide stewardship of
a secure national database infrastructure to support
standardised data collection, clinical outcomes analysis,
research, advocacy, and public health reporting for the
bleeding and clotting disorders community"8.
Growth of the surveillance and data collection aspects
CDC's Role
CDC began its partnership with the US HTCs in
the 1980s as part of public health efforts to prevent the
spread of HIV infection resulting from use of treatment
products made before the virus was identified. In 1991,
in response to requests from constituents, Congress
authorised CDC to expand its public health prevention
activities with the aim of reducing the complications of
bleeding disorders.
Public health surveillance is the ongoing systematic
collection, analysis, and interpretation of health data
for purposes of improving health and safety9. In order
to assess the public health needs of the haemophilia
community, surveillance was conducted in six US
states in 1993-1998. Data from this surveillance were
used to assess the burden of haemophilia in the country
and to identify sources of care and treatment practices.
Data were also collected to measure rates and severity
not only of infectious disease complications including
hepatitis and HIV but also those of chronic joint
disease, intracranial hemorrhage and other bleeding
complications as well as mortality.
Analyses of these population-based surveillance
data revealed an estimated US haemophilia population
of about 17,000, nearly 70% of which had received
care in HTCs10. Although most of those not receiving
care in HTCs had mild haemophilia, 34% of those
with moderate and 14% of those with severe disease
received care outside of the HTC network. When
outcomes were compared, males with haemophilia
who had received care from HTCs had lower mortality
rates 11 and fewer hospitalizations for bleeding
complications12.
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This population-based surveillance system was
replaced in 1998 with the Universal Data Collection
(UDC) surveillance system established in the HTC
network in order to collect the more detailed data
needed to inform and evaluate public health prevention
programs13. For example, analyses of UDC data on height
and weight and joint range of motion measurements
lead to the recognition that increased body mass index
(a measure of body adiposity) was associated with
decreased joint mobility regardless of haemophilia
severity14. Based on these findings it became clear that
overweight and obesity, at epidemic levels in the general
US population, was not only just as common among boys
and men with haemophilia but also was contributing to
preventable joint disease. Public health messages about
the need to maintain a healthy weight to protect joints are
part of the prevention strategies implemented because
of these findings. Continued surveillance will be used
to evaluate these prevention efforts.
The UDC also included annual blood sample
collection with infectious disease testing performed at
CDC in order to assess the safety of treatment products.
Results of this surveillance have provided evidence
for the safety of these products as well as the need for
continued vigilance15,16.
UDC surveillance data have also been used to
examine patterns of care within the HTC network.
For example, the administration of treatment product
on a regular basis to prevent bleeding episodes, called
prophylaxis therapy, has been shown to prevent joint
disease in young boys with haemophilia17. However, in
an analysis of UDC data there was a full spectrum of
variation from 0% to 100% of youth in individual HTCs
who were receiving prophylaxis therapy18. These kinds
of analyses can be useful both to monitor the adoption of
standards of care as well as to gain an understanding of
facilitators and barriers to the practices by studying the
characteristics of HTCs with high and low adoption rates.
Another example of using surveillance data is in
the identification of an inhibitor, which is currently the
most serious complication of haemophilia treatment.
An inhibitor is an antibody to treatment product that
develops in up to one-third of people with haemophilia
and renders it ineffective in preventing or stopping
bleeding episodes. People with an inhibitor are more
likely to be hospitalised for a bleeding complication
and treatment costs are far greater than those without
an inhibitor19-21. A blood test is necessary for diagnosing
an inhibitor. Earlier identification of inhibitors,
accomplished through regular screening, leads to higher
inhibitor eradication success22.
From 2006-2010, only 46% of patients with severe
haemophilia (those at highest risk of an inhibitor) had
a screening test performed (unpublished CDC data).
Furthermore, similar to the rates of primary prophylaxis,
inhibitor testing varied from 0% to 100% among the
HTCs. Based on discussions with experts, a substantial
barrier to regular inhibitor screening was the lack of
capacity of most local laboratories to accurately perform
the necessary testing in the presence of infused factor
VIII, especially among patients who were receiving
prophylactic therapy (unpublished CDC data).
To address this barrier, the CDC Division of Blood
Disorder's laboratory has developed and validated a
modified testing method that can be used to screen for
an inhibitor regardless of treatment status23. This method
is being disseminated to local laboratories and its use
for regular screening for inhibitors should become part
of the standard of care for HTCs. The UDC has recently
been updated (now called Community Counts) to include
national monitoring of inhibitors through the use of both
local and CDC testing of blood specimens collected as
part of the surveillance. Using data from Community
Counts will allow CDC to monitor the adoption of this
important testing as a new standard of care.
Current Status of the National Hemophilia Program
and long term objectives
CDC's Public Health Surveillance for the prevention
of complications of bleeding and clotting disorders
cooperative agreement is the funding mechanism
through which its surveillance and prevention programs
are funded. In 2011, the RHN applied for the CDC
funding through ATHN. As part of the new cooperative
agreement, the data elements collected through the
new surveillance system were revised based on
recommendations from an expert panel through a
collaborative process between CDC scientists and a
scientific committee comprised of clinicians organised
and supported by ATHN. Community Counts, the new
surveillance system has three components: 1) the HTC
Population Profile; 2) Mortality Reporting; and 3) the
Registry for Bleeding Disorders Surveillance. The first
component collects a minimum set of demographic and
clinical information on all of the patients with bleeding
and clotting disorders who are receiving care within the
RHN. The second component collects limited data about
causes of death. The third component will be a more
in-depth data collection project that will collect more
complex data elements on health and complications,
including collecting biologic samples for infectious
disease and inhibitor surveillance.
This collaboration marks an exciting new prospect
for the haemophilia community as some data elements
from the CDC's project will be utilised by the RHN and
NHPCC to report as the national data source for several
developmental Healthy People 2020 performance
measures within the blood disorders and blood safety
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US Haemophilia Treatment Center framework and evaluation
topic objective24. Healthy People is a national effort
by the US Department of Health and Human Services
to develop measures and benchmarks to track national
progress, in 10-year cycles, on government efforts to
improve the public health of the country25.
With the new regional organization and the
development of ATHN as the national coordinating
center, the NHP is well placed to accomplish goals and
activities that have not previously been possible given
the lack of focus on working on a national level. Since
June 2012, the RHN and the NHPCC has completed
the first ever technical assistance needs assessment for
HTC Staff, currently under analysis, which will provide
insight to HRSA on the help needed by HTC staff both
in the management of patient care and in navigating the
federal grant process as well as informing HRSA how
the NHPCC can begin to provide needed services.
The program is also currently analyzing the results
of the first national HTC patient needs assessment that
was a requirement for both the RHNs and the NHPCC
to accomplish, so that the haemophilia community can
use the results to set national priorities for the program to
help with the development of a national evaluation plan to
track the improvement of the care received in the coming
years. A third party evaluation consultant has been
contracted by both the NHPCC and the regions to analyze
the results of the needs assessment, on both a regional and
national level. The results of the analysis will be utilised
to set national priorities for the NHP through a multistakeholder process involving the regions, the NHPCC,
consumer advocacy groups, and our federal partners. The
national priorities, once determined, will form the basis
of a national evaluation plan to track patient outcomes
for those who receive care through the NHP.
Results of the patient needs assessment will be widely
disseminated within the federal program and haemophilia
consumer advocacy groups and other stakeholders within
the bleeding community. Finally, these major projects and
increased requirements for data collection and evaluation
plans will inform the development of standards of care
and methods for dissemination of best practices, which
will require the assistance and expertise of the National
Hemophilia Foundation's MASAC, whose efforts are
described below.
The role of the NHF MASAC in standard setting
Impact of the Affordable Care Act
Federal enactment of the Patient Protection and
Affordable Care Act26 on March 23, 2010 came with
a promise to provide quality affordable health care for
all Americans. Since then, the US health care system
has been undergoing a major overhaul impacting
both insurance availability and the delivery of care.
The Affordable Care Act contains many long sought
improvements for those living with high cost diseases
or having pre-existing conditions such as haemophilia.
The substantial growth in managed care plans and the
many changes to private and public insurance programs
made by the Affordable Care Act are having direct and
indirect consequences for the bleeding disorders community.
The Affordable Care Act provides for the establishment of
essential health benefits that must be offered by new plans
available in the insurance market. However, the choice
of health care providers available to an insured within a
plan is left to the insurance plan provider, subject to rules
requiring access to a minimum percentage of the essential
community providers in the plan service area27. These rules
encourage, but do not require, insurers to include access to
a federally funded HTC within their provider networks. To
reduce reliance on expensive drugs and incentivize patients
to choose lower-cost generic alternatives, if available,
some plans are requiring higher cost-sharing (co-payments
and coinsurance) for medications such as clotting factor
concentrates. While the Affordable Care Act has the
potential to increase patient access to needed treatments and
services, it is too early to evaluate how this translates into
outcomes for people with bleeding disorders.
The Affordable Care Act also contained provisions
placing a greater emphasis on evidence-based medicine and
performance outcomes measures. Thus, establishing and
bolstering evidence-based standards and recommendations
to support haemophilia care and its delivery through a
recognised HTC has taken on an increased importance.
Over many years, the NHF and its MASAC have
led the development of a range of standards and
recommendations addressing clinical management,
treatment safety, and care delivery for those living with a
bleeding disorder. Issued in the form of recommendations,
MASAC guidelines set the standard of care and are
frequently referred to by an international array of
physicians, medical schools, pharmacists, emergency
room personnel, insurance companies, patients and
others. MASAC is comprised of scientists, physicians,
allied health professionals, patients and government
liaisons from the relevant federal agencies within the
US Department of Health and Human Services (CDC,
Food and Drug Administration, MCHB and the National
Institutes of Health). The full list of recommendations are
available on the NHF website28. Adherence to MASAC
recommendations is widely promoted, however, outside
of the specific requirements with the NHP compliance
with other MASAC recommendations is voluntary.
Two MASAC recommendations are of particular
note with regard to the oversight and management of
US HTCs:
1) MASAC Recommendation 132 - Standards and
Criteria for Persons with Congenital Bleeding
Disorders29.
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Last revised in 2002, MASAC Recommendation
132 outlines comprehensive standards of care and
lists services that should be provided by HTCs. The
recommendation includes an extensive discussion
of the delivery of integrated, multi-disciplinary,
comprehensive care. The recommendation places
an emphasis on early diagnosis and intervention to
prevent disease complications.
The composition, general and specific functions,
availability and training of the Comprehensive
C a r e Te a m d e p e n d o n p a t i e n t c e n s u s a n d
individual circumstance. The staff and services
required for proper HIV care for men and women,
haepatitis-related services, care for women
with bleeding disorders, the need for culturally
sensitive outreach programs, and access to clinical
research protocols are also addressed.
Within the NHP, all HTCs are required and expected
to comply with and follow the guidelines for
elements and core services of the HTC-based model
of care delineated in Recommendation 132.
2) MASAC Recommendation 188 - Standards of
Service for Pharmacy Providers of Clotting Factor
Concentrates for Home Use to Patients with Bleeding
Disorders30.
A varied range of pharmacy providers supply clotting
factor concentrates to patients for treatment at home.
The pharmacy providers are principally specialty
pharmacies or factor programs administered through
the HTC. When patients do not receive optimal
service from these providers, there is potential for
adverse health events that lead to poor outcomes and/
or increased costs30.
Given challenges in achieving optimal service,
MASAC adopted standards of service for pharmacy
providers. MASAC acknowledged the necessity of
cost efficiency in the provision of health care, yet
emphasised that cost efficiency should not occur at
the expense of quality patient care. The purpose of the
recommendation is to establish minimum standards
of service for pharmacy providers to meet the
specific needs of individuals with bleeding disorders.
The standards address pharmacy provider staff
knowledge, availability of clotting factor concentrates
and ancillary supplies, processing of prescription
orders, hours of operation, access to pharmacy staff,
delivery, recordkeeping, billing and product recall.
Over 30 national specialty pharmacies and most US
HTCs have voluntarily self-reported they have met
or exceeded the standards of Recommendation 188.
At the state level, various legislative and regulatory
initiatives have been implemented to promote optimal
access to home care services to further reinforce the
importance of pharmacy standards. The most prominent and
widely cited examples of best practice of model legislation
are New Jersey and more recently Missouri31-33. As this
article was written, a number of states are considering
adoption of similar statutory or regulatory provisions.
The National Association of Boards of Pharmacy recently
featured a news article profiling the NHF model standards
of service and is working with NHF to achieve uniformity
in the regulation of this specialty area34.
In 1997, New Jersey included language in state
Health Maintenance Organization (HMO) regulations
securing access to and reimbursement for care at HTCs.
In 2000, legislation was enacted requiring HMO and
managed care insurers to comply with standards in the
provision of benefits to patients with haemophilia31.
Insurance carriers offering managed care health
benefit plans in New Jersey must contract with
designated health care providers for the delivery of
services for the home treatment of bleeding episodes
associated with haemophilia, including the purchase of
blood products and blood infusion equipment. The State
maintains an on-line registry of designated haemophilia
home care providers meeting statutory requirements32.
Building on the New Jersey precedent, in 2011,
Missouri enacted legislation33 creating standards of care
for pharmacies dispensing blood-clotting therapies. The
Missouri HealthNet Division (which oversees Medicaid)
previously covered blood clotting products and services.
The law specifically adds blood clotting equipment,
supplies, and assessments in the home to the list of
Missouri HealthNet benefits.
Development of evidence-based clinical practice
guidelines for Comprehensive Care
NHF is acutely aware of the major ongoing changes
in health care occurring in the US. In 2012, the NHF
held a strategic summit to develop a plan for haemophilia
care within the evolving US health care environment.
The Summit report addressed the implications of the
Affordable Care Act and provided a series of strategic
recommendations35. Among these was a call for NHF to
sponsor the production and maintenance of evidence-based
clinical practice guidelines (CPGs).
Health plans are taking note of the geographic variations
in practice and standards of practice (e.g. prophylaxis
regimens) and clinical behavior (e.g. use of comprehensive
care services). Such variations suggest insufficient evidence
to support practice or a lack of clinician concurrence about,
or adherence to, evidence-based practice.
Recognizing the value of establishing, promoting,
and adhering to CPGs and associated standards
of practice, the NHF and its MASAC leadership
launched an initiative to develop a comprehensive set
of evidence-based CPGs to support patient-centered
clinical decision-making and optimize care.
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US Haemophilia Treatment Center framework and evaluation
The initial phase of the CPG initiative addresses the
comprehensive care model for haemophilia. In addition
to recognizing the importance of a range of coordinated
services to most patients with haemophilia, addressing
the comprehensive care model as the first evidence-based
CPG will establish a foundation upon which more specific
CPGs addressing other aspects of care may be developed.
The comprehensive care CPG will:
- define comprehensive care as it relates to the
haemophilia patient;
- specify the coordinated set of diagnostic, therapeutic,
and certain auxiliary and supplemental services that
are most important for haemophilia patients across
the U.S.;
- identify the range of clinical and non-clinical
members of a haemophilia comprehensive care team
(including, e.g., social workers, dentists);
- identify best-practices and evidence-based standards
of comprehensive/coordinated care for haemophilia
treatment centers (HTCs) and individual clinical
practices.
NHF foresees that the development of the
comprehensive care CPG will provide a catalyst to
promote harmonization of care delivery and reduce
practice variations among the US HTC system. An agreed
evidence-based benchmark would allow for both internal
and external evaluation of adherence to best practices and
benchmark available services with an HTC. Ultimately, it
will serve as an important starting point for establishment
of a US HTC self-audit or accreditation system.
Keywords: Haemophilia Treatment Center, Program
evaluation, Child Health Bureau (MCHB), Centers
for Disease Control and Prevention (CDC), National
Hemophilia Foundation (NHF).
Acknowledgments and disclosures
Mark Skinner serves as a consultant to the National
Hemophilia Foundation. CDC Disclaimer: The findings
and conclusions in this report are those of the authors
and do not necessarily represent the official position of
the Centers for Disease Control and Prevention.
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The Authors declare no conflicts of interest.
References
1)
2)
Katherine B. Oettinger. Title V of the Social Security Act:
What it has meant for children. Social Security Bulletin.
V23; No8, pgs 39-50, August, 1960. Available at: http://www.
ssa.gov/policy/docs/ssb/v23n8/v23n8p39.pdf. Accessed on
19/01/2014.
Understanding Title V of the Social Security Act: A Guide to
the Provisions of the Federal Maternal and Child Health Block
Grant. Maternal and Child Health Bureau, Health Resources
and Services Administration. Available at: http://www.amchp.
org/AboutTitleV/Documents/UnderstandingTitleV.pdf.
Accessed on 18/01/2014.
15)
16)
17)
Understanding Title V of the Social Security Act: A Guide to
the Provisions of the Federal Maternal and Child Health Block
Grant. Maternal and Child Health Bureau, Health Resources
and Services Administration., Available at: http://www.
amchp.org/AboutTitleV/Documents/UnderstandingTitleV.
pdf. Accessed on 18/01/2014.
Funding Opportunity Announcement: Regional Hemophilia
Network. Announcement No. HRSA-12-133, CFDA# 93.110,
FY 2012. Release Date: 11/16/2011; Due Date: 01/10/2012.
Available at: https://grants3.hrsa.gov/2010/Web2External/
Platform/Interface/DisplayAttachment.aspx?dm_rtc=16&dm_
attid=89e6028e-37f2-4411-8334-acd06b02d5db&dm_
attinst=0. Accessed on 18/01/2014.
NHF MASAC Recommendation 132 - Standards and Criteria
for the care of Persons with Congenital Bleeding Disorders.
National Hemophilia Foundation. Available at: http://www.
hemophilia.org/NHFWeb/Resource/StaticPages/menu0/
menu5/menu57/masac132.pdf. Accessed on 20/01/2014.
Funding Opportunity Announcement: Regional Hemophilia
Network. Announcement No. HRSA-12-133, CFDA# 93.110,
FY 2012. Release Date: 11/16/2011; Due Date: 01/10/2012.
Available at: https://grants3.hrsa.gov/2010/Web2External/
Platform/Interface/DisplayAttachment.aspx?dm_rtc=16&dm_
attid=89e6028e-37f2-4411-8334-acd06b02d5db&dm_
attinst=0. Accessed on 18/01/2014.
Funding Opportunity Announcement: National Hemophilia
Program Coordinating Center. Announcement No. HRSA-12135, CFDA# 93.110, FY 2012. Release Date: 11/16/2011; Due
Date: 12/30/2011. Available at: https://grants3.hrsa.gov/2010/
Web2External/Interface/FundingCycle/ExternalView.
aspx?&fCycleID=EDA323E3-02AC-483A-ABE6-92474D2
335EF&txtAction=View+Details&submitAction=Go&View
Mode=EU. Accessed on 18/01/14.
Aschman DJ, Abshire TC, Shapiro AD, et al. A CommunityBased Partnership to Promote Information Infrastructure for
Bleeding Disorders. Am J Prev Med 2011; 41 (6S4): S332-7.
Available at: http://www.ajpmonline.org/article/S07493797%2811%2900680-5/fulltext. Accessed on 20/01/2014.
Thacker SB, Berkelman RL. Public health surveillance in the
United States. Epidemiol Rev 1988; 10: 164-90.
Soucie JM, Jackson D, Evatt B. The occurrence of hemophilia
in the United States. Am J Hematol 1998; 59: 288-94.
Soucie JM, Nuss R, Evatt B, et al and the Hemophilia
Surveillance System Project Investigators. Mortality among
males with hemophilia: relations with source of medical care.
Blood 2000; 96: 437-42.
Soucie JM, Symons J, Evatt B, et al and the Hemophilia
Surveillance System Project Investigators. Home-based factor
infusion therapy and hospitalization for bleeding complications
among males with hemophilia. Haemophilia 2001; 7:198-206.
Soucie JM, McAlister S, McClellan A, et al. The universal data
collection surveillance system for rare bleeding disorders. Am
J Prev Med 2010; 38 (4 Suppl): S475-81.
Soucie JM, Cianfrini C, Janco RL, et al. Joint range of motion
limitations among young males with hemophilia: Prevalence
and risk factors. Blood 2004; 103: 2467-73.
Centers for Disease Control and Prevention. Blood safety
monitoring among persons with bleeding disorders - United
States, May 1998-June 2002. MMWR Morb Mortal Wkly
Rep 2003; 51: 1152-4.
Soucie JM, De Staercke C, Monahan PE, et al. Evidence for
the Transmission of Parvovirus B19 in Patients with Bleeding
Disorders Treated with Plasma-derived Factor Concentrates
in the Era of Nucleic Acid Test (NAT) Screening. Transfusion
2013; 53: 1217-25.
Manco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis
versus episodic treatment to prevent joint disease in boys with
severe hemophilia. N Engl J Med 2007; 357: 535-44.
Blood Transfus 2014; 12 Suppl 3: s542-8 DOI 10.2450/2014.0019-14s
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Skinner MW et al
18) Soucie JM, McAlister S, McClellan A, et al. The universal data
collection surveillance system for rare bleeding disorders. Am
J Prev Med 2010; 38 (4 Suppl): S475-81.
19) Soucie JM, Symons J, Evatt B, et al and the Hemophilia
Surveillance System Project Investigators. Home-based
factor infusion therapy and hospitalization for bleeding
complications among males with hemophilia. Haemophilia
2001; 7: 198-206.
20) Guh S, Grosse SD, McAlister S, et al. Healthcare expenditures
for males with haemophilia and employer-sponsored insurance
in the United States, 2008. Haemophilia 2012; 18: 268-75.
21) Guh S, Grosse SD, McAlister S, et al. Health care expenditures
for Medicaid-covered males with haemophilia in the United
States, 2008. Haemophilia. 2012; 18: 276-83.
22) DiMichele DM. Immune tolerance in haemophilia: the long
journey to the fork in the road. Brit J Haematol 2012; 159:
123-34.
23) Miller CH, Rice AS, Boylan B, et al, the Hemophilia Inhibitor
Research Study Investigators. Comparison of clot-based,
chromogenic, and fluorescence assays for measurement
of factor VIII inhibitors in the U.S. Hemophilia Inhibitor
Research Study (HIRS). J Thromb Haemost 2013: 11; 1300-9.
24) Healthy People 2020. Blood Disorders and Blood Safety Topic
Objectives. Available at: http://www.healthypeople.gov/2020/
topicsobjectives2020/overview.aspx?topicid=4. Accessed on
20/01/2014.
25) HHS News Press Release: HHS announces the nation's new
health promotion and disease prevention agenda. OASH
Press Office. Released December 2, 2010. Available at: http://
www.healthypeople.gov/2020/about/DefaultPressRelease.pdf.
Accessed on 20/03/2014.
26) Pub L. 111-148, 111th United States Congress. Washington,
DC. March 23, 2010.
27) HHS Centers for Medicare and Medicaid Services. Letter to
Issuers in the Federally-facilitated Marketplace. March 14,
2014. Available at: http://www.cms.gov/CCIIO/Resources/
Regulations-and-Guidance/Downloads/2015-final-issuerletter-3-14-2014.pdf. Accessed on 26/03/2014.
28) NHF MASAC Recommendations. National Hemophilia
Foundation. Available at: http://www.hemophilia.org/NHFWeb/
MainPgs/MainNHF.aspx?menuid=157&contentid=347.
Accessed on 20/03/2014.
29) NHF MASAC Recommendation 132 - Standards and Criteria
for the care of Persons with Congenital Bleeding Disorders.
National Hemophilia Foundation. Available at: http://www.
hemophilia.org/NHFWeb/Resource/StaticPages/menu0/
menu5/menu57/masac132.pdf. Accessed on 20/03/2014.
30) NHF MASAC Recommendation 188 - Standards of Service
for Pharmacy Providers of Clotting Factor Concentrates for
Home Use to Patients with Bleeding Disorders. National
Hemophilia Foundation. Available at: http://www.hemophilia.
org/NHFWeb/Resource/StaticPages/menu0/menu5/menu57/
masac188.pdf. Accessed on 20/03/2014.
31) New Jersey Statues Annotated. Section 1 of L. 2001, c. 121,
codified at N.J.S.A. 26:2S-10.1, and sections 3 through 10 of
L. 2001, c. 121, variously codified throughout Titles 17, 17B
and 26. Available at: http://njlaw.rutgers.edu/cgi-bin/njstats/
showsect.cgi?title=26&chapter=2S&section=10.1&actn=get
sect. Accessed on 20/03/2014.
32) New Jersey Designated Hemophilia Providers. Available at:
http://www.state.nj.us/dobi/division_insurance/managedcare/
mchemoprov.htm. Accessed on 20/03/2014.
33) Missouri Revised Statues. RSMo 338.400. Available at: http://
www.moga.mo.gov/statutes/C300-399/3380000400.HTM.
Accessed on 20/03/2014.
34) States Look at Standards of Service for Pharmacies Serving
Hemophilia Patients. NABP Newsletter. 2013; June-July: 12830. Available at: http://www.nabp.net/system/redactor_assets/
documents/618/Final_June-July_2013_Newsletter.pdf.
Accessed on 20/03/2014.
35) National Hemophilia Foundation: Strategic Summit Report.
October 2012. National Hemophilia Foundation. Available
at: http://www.hemophilia.org/NHFWeb/MainPgs/MainNHF.
aspx?menuid=119&contentid=2120. Accessed on 20/03/2014.
Correspondence: Mark W. Skinner
National Hemophilia Foundation
1155 23rd Street NW #3A
Washington, DC 20037, USA
e-mail: mskinnerdc@gmail.com
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DEFINITION OF AN ORGANISATIONAL MODEL FOR THE PREVENTION AND REDUCTION
OF HEALTH AND SOCIAL IMPACTS OF INHERITED BLEEDING DISORDERS IN ITALY
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Institutional accreditation of Health Services in Italy:
the long road to quality
Antonio Fortino¹, Francesco Di Stanislao2
¹National Institute for Health, Migration and Poverty (INMP), Rome; 2Marche Polytechnic University and National
Agency for Regional Health Care Services (Age.Na.S.), Rome, Italy
Introduction
The term "accreditation" was introduced in Italian
health legislation in the early '90s, with the adoption
of decrees 502/1992 e 517/19931. The concept added
a new element to the authorisation system defined in
Law n. 833, that had established the Italian National
Health Service (SSN) in 1978. It has developed over
time into an institutional recognition, issued by the
Public Authority, that is a statutory requirement for
any entity providing services as part of the SSN. It
aims to achieve a high level of guarantee of service
quality and of the selection of service providers, public
and private, that work as part of, or on behalf of, the
SSN. Specifically, the National Health Plan 1998-2000
identified the accreditation as one of instruments for
ensuring quality of healthcare in that it "responds to
the need for a process of provider selection that applies
healthcare quality criteria", thus clearly identifying their
essential aims and characteristics. The implementation
of this policy was slow and difficult, not only because
of the strength of economic interests associated with
healthcare activity and the birth of federalism in
healthcare provision, but also because of a widespread
culture that tends to give more importance to the work of
the individual healthcare professional than to achieving
a well-integrated and co-ordinated system as a whole,
with attention to, and demonstration of, transparency
in terms of inputs (resources) and outputs (processes,
results and outcomes).
Regulatory development between national and
regional level
In order to achieve a smooth transition from the
previous contracting system to the new accreditation
system, Law 724/1994 introduced the concept
of "Temporary Accreditation" for those entities
already contracted on January 1st 1993, subject to
the acceptance of the fixed price system for services
provided. Unfortunately that transitional period,
that was intended to apply only during 1995 and
1996, was prolonged in most Italian regions and was
finally revoked only in 2008. During the same period,
in response to legal appeals by some regions, the
Constitutional Court was deliberating on the subject of
accreditation, providing clarifications on the meaning
and specifying that "accreditation" was distinct from
"authorisation" and that it constituted a second step in
the process. As a consequence, it was impossible for
the implementation to proceed without the enactment
of the government decree establishing the minimal
requirements for authorisation (licensure). This was
due for adoption in 1993 but was not, in fact, published
until 4 years later, in 19972.
No instruction was provided to the regional
Authorities regarding the terms "accreditation", or
"control and quality improvement"; their definition
remained at the level of technical and academic
discussion3. In 1999, the so-called "Third Reform of
the National Health Service"4 elaborated and defined
the entire subject of authorisation and institutional
accreditation in the following terms:
- authorisation for construction is the administrative
measure that permits the construction of new health
and social health buildings on the basis of real need
with regard to regional planning;
- authorisation for practice is the administrative
measure (licensure) that permits the practice of
health or social health activities by public or
private subjects. This authorisation is released on
the basis of the demonstration of compliance with
minimal structural, technological and organisational
requirements;
- institutional accreditation is the administrative
measure through which a region authorises an entity
to provide services in the name and on behalf of
the SSN. It is released subject to verification of
compliance with a further series of requirements.
Through the accreditation process, each regional
Authority constructs its own list of service
providers, specifically qualified.
In the latter case, contractual agreements can be
established in which the regional Authorities and local
health service organisations define, together with public
and private accredited entities, the type and the quantity
of services to be provided to the regional health service,
the health objectives and the means of integration, as well
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Fortino A, Di Stanislao F
as the associated prices to be paid by the public service.
Since 1999, there have not been substantial
modifications to the legislative framework established
by Law 229/99. However, the basis of the institutional
relationships between the State and the regions has
changed considerably following the reform of Part V
of the Italian Constitution (Constitutional Law n. 3
of 2001), which increased the powers of the regional
Authorities, enlarging their competence for the
organisation of health services.
As a result, 21 models for regional accreditation
developed in the subsequent decade. These had some
characteristics in common but there were significant
differences too; the models were summarised in a
study by the National Agency for Regional Health
Care Services (Agenzia Nazionale per i Servizi
Sanitari Regionali - Age.Na.S.) published in 20095. The
quality criteria most frequently found in the regional
provisions are: patient satisfaction, service access,
communication, continuous quality improvement,
presence of guidelines and protocols, information
and data management, technology assessment,
appropriateness and continuity of service provision.
Age.Na.S. revisited the topic in 2013, updating and
exploring it in more depth, summarising the entire
picture of regional planning for authorisation accreditation and focusing on the more recent measures
and, in particular, on those adopted to finally overcome
temporary accreditation6.
In more recent years, there has been a move
towards ever greater harmonisation and sharing of
approaches between the regional Authorities, a process
that has been reinforced by challenges from Europe.
Two agreements between the State and the regional
Authorities on December 16 th 2010 addressed the
quality, safety and appropriateness of the maternity
care pathway and blood activities and transfusion
medicine7. The agreement prioritised the adoption of
uniform health and accreditation policies (including
a requirement for a minimum of 1,000 births per
year). Two important measures were adopted on July
25th 2012 that promoted national standardisation in a
more detailed manner. One was the "Agreement" on
guidelines for the accreditation of blood Establishment
and blood collection Units and the other was the
"Understanding" on standards for the accreditation of
hospices and for palliative care and pain therapy units.
Lastly, the Agreement of March 13th 2013 on the
definition of regional or inter-regional care pathways
for patients with congenital haemorrhagic disorders
defines general instructions and 23 specific "activities"
that organisations accredited for the management of these
patients must accomplish8.
At the end of this long journey, the destination is
also a point of departure: the "Understanding" between
the State and the regions of December 20th 2012 defines
8 macro criteria, 28 macro requirements and 123
specific elements of evidence, on the basis of which
the regional Authorities are reformulating and updating
their own measures for institutional accreditation:
operation of a comprehensive management system with
identification of roles and responsibilities, description
of the range of services provided, suitability of the
facilities and equipment, specific competencies of the
personnel, communication between professionals and
with patients, appropriate clinical practice and risk
management, process improvement and innovation
and humanisation9.
Conclusions
Institutional statutory accreditation is in a phase
of renewal in the SSN, with a movement toward ever
greater convergence between the regional models, in
the interest of greater standardisation, uniformity and
quality of the health services delivered to citisens10. We
look forward to a new phase of intense co-operation
between the State and the regional Authorities, the
professionals and the Health Service organisations.
Keywords: accreditation system, quality, requirements,
health service.
The Authors declare no conflicts of interest.
References
1)
2)
3)
4)
5)
6)
Decreto Legislativo 30 dicembre 1992, n. 502: Riordino della
disciplina in materia sanitaria, come modificato dal Decreto
Legislativo 7 dicembre 1993, n. 517 "Modificazioni al
decreto legislativo 30 dicembre 1992, n. 502, recante riordino
della disciplina in materia sanitaria, a norma dell'articolo 1
della legge 23 ottobre 1992, n. 421".
Decreto del Presidente della Repubblica 14 gennaio 1997:
Approvazione dell'atto di indirizzo e coordinamento alle
regioni e alle province autonome di Trento e di Bolzano, in
materia di requisiti strutturali, tecnologici ed organizzativi
minimi per l'esercizio delle attività sanitarie da parte delle
strutture pubbliche e private.
Di Stanislao F, Liva C. L'Accreditamento dei Servizi Sanitari
in Italia. Centro Scientifico Editore, Torino, 1998.
Decreto legislativo 19 giugno 1999, n. 229: Norme per la
razionalizzazione del Servizio sanitario nazionale, a norma
dell'articolo 1 della legge 30 novembre 1998, n. 419
Age.Na.S. - Agenzia Nazionale per i Servizi Sanitari
Regionali: Analisi delle dimensioni della qualità presenti
nei programmi di accreditamento istituzionale delle regioni
italiane. Rapporto agosto 2009.
Age.Na.S - Agenzia Nazionale per i Servizi Sanitari Regionali:
Ricognizione delle norme regionali sull'accreditamento
istituzionale. Available at: www.agenas.it/accreditamento.
html. Accessed on 29/11/2013.
Blood Transfus 2014; 12 Suppl 3: s551-3 DOI 10.2450/2014.0014-14s
s552
Institutional accreditation of health services in Italy
7)
8)
9)
Accordo Stato regioni su: Requisiti strutturali, tecnologici
e organizzativi minimi per l'esercizio delle attività sanitarie
dei servizi trasfusionali e delle unità di raccolta del sangue e
degli emocomponenti e sul modello per le visite di verifica.
(Rep. Atti n. 242/CSR del 16 dicembre 2010).
Accordo Stato Regioni su: Definizione dei percorsi regionali
o interregionali di assistenza per le persone affette da Malattie
Emorragiche Congenite (MEC). (Rep. Atti n. 66/CSR del
13 marzo 2013).
Intesa Stato Regioni su: Disciplinare per la revisione della
normativa dell'accreditamento, in attuazione dell'articolo 7,
comma 1, del nuovo Patto per la salute per gli anni 20102012. (Rep. Atti n. 259/CSR del 20 dicembre 2012).
10) Di Stanislao F, Bellentani D, Gangale A, et al. L'accreditamento
nella legislazione italiana e le sue differenze regionali. Revue
Sociologie Santé - Sociologia della Salute 2010; 32: 109-30.
Correspondence: Antonio Fortino
Istituto Nazionale Malattie Migrazione e Povertà (INMP)
Via di San Gallicano, 25
00153 Rome, Italy
e-mail: fortino@inmp.it
Blood Transfus 2014; 12 Suppl 3: s551-3 DOI 10.2450/2014.0014-14s
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REVIEW
Current and evolving features in the clinical management of haemophilia
Antonio Coppola1, Massimo Morfini2,, Ernesto Cimino1, Antonella Tufano1, Anna M. Cerbone1, Giovanni
Di Minno1
1
Regional Reference Centre for Bleeding Disorders, Federico II University Hospital, Naples; 2Italian Association
of Haemophilia Centres (AICE), Florence, Italy
Introduction
After the devastating consequences of acquired
immunodeficiency syndrome (AIDS) and viral hepatitis
epidemics due to the transmission of the human
immunodeficiency (HIV) and hepatitis C (HCV) viruses
through contaminated coagulation factor concentrates,
leading to death of thousands of patients in the 1980s and
1990s, over the past three decades dramatic advances in
the treatment and the overall management of haemophilia
were achieved1. These improvements of care, at least
in high-income countries, presently warrant persons
with haemophilia a highly satisfactory quality of life
and a progressive increase in life expectancy, now
approaching that of the general male population2. Such
advances rely upon the continuous improvement of factor
concentrate safety and availability, from viral-inactivated
plasmaderived products to the different generations
of recombinant concentrates1,3,4. Indeed, thanks to
the implementation of techniques for inactivating or
eliminating possible contaminating viruses from
plasmaderived factor concentrates, together with rigorous
criteria for selection of donors and the adoption of nucleic
acid testing (NAT) of donations and plasma pools, no cases
of blood-borne transmission of known virus from plasma
products have been reported over the last 25 years1. In
parallel, rapid progresses in DNA recombinant technology
led to the availability of products removing any trace
of human or animal protein from the final formulation,
and then from the culture medium and the whole
purification process5. The availability of larger amounts
of safe products, together with increasing evidence
from literature of cost-effectiveness, made possible the
diffusion of prophylaxis (i.e. regular infusion regimens of
factor concentrates with the aim to prevent bleeding and
bleeding-related complications), currently the standard of
care in children with severe haemophilia, i.e. those with
virtually absent residual factor (F) VIII/IX activity1,6, but
increasingly adopted even later in life with favourable
clinical outcomes7,8. These advances were significantly
promoted thanks to the recognition, implementation
and continuous improvement of a multidisciplinary
approach in the delivery of care at specialised haemophilia
treatment centres (HTCs)9. Indeed, comprehensive
haemophilia care is multidisciplinary by nature, in order to
face adequately the variable patients' clinical needs from
diagnosis onwards throughout life, including treatment
of bleeding, education to home treatment, prevention
and treatment of haemophilia- and treatment-related
complications, as well of other co-morbidities. These
clinical and organisational needs are presently even
more complex in the light of the evolving scenario
of ageing haemophilia patients10. Multi-centre and
multi-national efforts in addressing unsolved clinical
issues and improving the level of evidence for
treatment recommendations have been strongly
pursued, together with the development of documents
setting basic elements of haemophilia care provision
to make available or assisting healthcare providers in
implementing care programs and encouraging practice
harmonization around the world9,11-16.
Although relevant challenges remain, in particular
concerning venous access and patients with inhibitors17,
and awaiting for further improvements by new factor
concentrates with extended half-life on clinical trials18 and
by developments in gene therapy overcoming previously
disappointing findings19, the comprehensive management
of haemophilia, well beyond the treatment of bleeding,
may presently focus on warranting the best possible
quality of life for patients and their families, tailoring
treatment choices and regimens according to specific
needs. In the following paragraphs, these aspects and
open issues of modern management of haemophilia will
be briefly reviewed.
Prophylaxis for all: between evidence and
personalised treatment
In the third millennium two randomised clinical trials
([RCTs] the US Joint Outcome Study12 and the Italian
ESPRIT20) unequivocally showed the superiority of
prophylaxis over on-demand treatment in the management
of children with severe haemophilia, in terms of lower
bleeding rates and better joint outcomes and quality of
life12,20. These methodologically rigorous trials confirmed
what had been long achieved over more than 40 years of
clinical experience started in Northern Europe, reported in
retrospective cohort studies6,21,22 and in a large prospective
international study, the Orthopedic Outcome Study23,
and recommended by the World Health Organization
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Current evolving management of haemophilia
(WHO) and the World Federation of Hemophilia (WFH)
since 199424. The role of prophylaxis in promoting health
and social well-being of haemophiliacs, and reducing
the burden of their condition, was stated among the
European principles of haemophilia care by the European
Association for Haemophilia and Associated Disorders
(EAHAD) in 20099. Thanks to the results from the RCTs,
a grade 1A recommendation was assigned to the choice
of prophylaxis in children with severe hemophilia in the
first specific guideline published by the United Kingdom
Hemophilia Centre Doctors' Organization (UKHCDO)25.
Both RCTs evaluated high-dose regimens, i.e. 25 IU/
Kg e.o.d.12 and 25 IU/Kg thrice weekly20, respectively,
started as "primary" or early "secondary prophylaxis", i.e.
in children without any clinical evidence of joint damage16.
However, benefits of prophylaxis have been shown with
a variety of dose regimens and even when started later in
life7. Indeed, the lack of formal studies comparing clinical
outcomes does not enable to define the optimal prophylaxis
regimen6,26. A series of studies report the feasibility and good
clinical results with regimens individualised according to
the bleeding tendency, including the lower dose in Dutch
approach (FVIII 20-40 IU/Kg twice or thrice weekly or
FIX 30-40 IU/kg once or twice weekly)22 or the Canadian
escalating-dose regimen27, or, more recently, according to the
pharmacokinetics (PK)26,28. However, few data concerning
long-term outcomes of such personalised approaches,
including prevention of arthropathy, and no comparisons with
full-dose prophylaxis are presently available26.
Individualised regimens may also facilitate the
implementation of prophylaxis and adherence of families
to treatment in small children, as well as reduce the impact
of venous access problems, tailoring the frequency (and
the dose) of concentrate infusions6,27. Along this line,
lower dose and individualised regimens are enabling
the introduction of secondary29 and even primary30
prophylaxis in some developing countries, in which
resources for factor concentrates are limited.
As regards the age at start of prophylaxis, increasing
data are showing that prophylaxis is able to significantly
reduce joint bleeding rates, and in parallel, improve
health-related quality of life, even when started in
adolescent or adult patients15,28,31,32. In this respect,
the definition of "tertiary prophylaxis", i.e. started
in patients with established joint damage, has been
proposed16. Rigorous and long-term data on possible
benefits on joint outcomes in such patients are still
lacking, however a 5-year prospective study has been
recently completed33 and a 3-year randomised study is
presently ongoing15. Therefore, data from these studies
concerning the possibility of delaying the progression of
arthropathy are eagerly awaited, being crucial for clearly
assessing cost-effectiveness and cost-utility of such a
highly expensive regimen in adolescents and adults and
supporting clinical recommendations of prophylaxis
"for all"34. Optimal regimens of prophylaxis are even
more uncertain in this setting, being extrapolated from
those used in children, in whom PK, physical and social
needs are largely different7,32. On the other hand, whether
generations of patients, presently in the adulthood with
absent or minimal joint disease thanks to primary or
early secondary prophylaxis, may safely discontinue
such regimens or switch to less intensive modalities of
treatment is presently unknown35. A recent survey in 6
countries with different attitudes to the use of prophylaxis
showed consistently higher quality of life in individuals
on long-term prophylaxis when compared with those
treated on-demand or on intermittent prophylaxis, with
benefits continuing into adulthood36. Available evidence
supporting the different types of prophylaxis, according
to the start of treatment and the clinical objectives of
preventing or limiting the development and progression
of hemophilic arthropathy, as recently revised by the
WFH guidelines16, is summarised in Table I. Although
clinical objectives are clearly different, the choice and
the personalization of prophylaxis regimens are crucial
for achieving and maintaining the best patient outcomes
and, in particular, improvements of quality of life,
irrespective of age. In the clinical practice, prophylaxis
regimens are implemented and often adjusted by dose
and/or frequency based on the observed bleeding pattern
and, importantly, on other patient-specific factors,
including times of expected physical activity, the status
of musculoskeletal system and patient or family needs6,27.
On the whole, these clinical choices highly contribute
to the effectiveness of prophylaxis, that results
from a multi-dimensional assessment of outcomes,
particularly in the long-term, including bleeding rates,
muscle-skeletal status, laboratory parameters and, not
last, health-related quality of life. Larger collection
of data are needed for clarifying the clinical impact
of less intensive (and less expensive) prophylaxis
regimens, useful for overcoming the barrier of costs
of treatment in low-income countries. However, only
comprehensive evaluations in a lifetime perspective
enable to highlight the actual cost-effectiveness and
cost-utility of the huge investments for prophylaxis37.
Comprehensive care and the evolving scenario
of ageing haemophilic patients
The WHO and the WFH recommendations, as well the
European principles of care, clearly recognize the need
for multidisciplinary teams at specialised HTCs, in order
to deliver an optimal haemophilia care9,16. According to
the available clinical facilities and local organisation, the
core group composed of haemophilia physicians, nurses,
psychologists, social workers and laboratory specialists,
also involves orthopaedic surgeons, physiotherapists and
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Coppola A et al
Table I - Prophylaxis in haemophilia, clinical objectives and available evidence.
Type of
prophylaxis
Definition^
Main clinical objective°
Evidence
Primary
prophylaxis
Regular continuous* treatment started in the
absence of documented osteochondral joint
disease, determined by physical examination
and/or imaging studies, and started before the
second clinically evident large joint** bleed
and age 3 years.
To prevent or minimize the incidence of
hemophilic arthropathy, with its impact on
psycho-physical development of children
and quality of life
RCTs (JOS12, ESPRIT20)
Prospective study (Canada27)
Retrospective cohorts (Sweden21, Germany ,
the Netherlands22, US, UK) and comparisons
(France vs. the Netherlands and Sweden;
Norway vs. Sweden)#
Secondary
prophylaxis
Regular continuous* treatment started after 2
or more bleeds into large joints** and before
the onset of joint disease, documented by
physical examination and imaging studies.
To reduce the frequency of bleeding, the
development of target joints and hemophilic
arthropathy, maintaining satisfactory levels
of quality of life
Early: RCT (ESPRIT20)
Prospective controlled study (Orthopedic
Outcome Study23)
Retrospective cohorts (Sweden, the
Netherlands, Germany, US, UK) and
comparison (France vs. the Netherlands
and Sweden)#
Tertiary
prophylaxis
Regular continuous* treatment started after
the onset of joint disease documented by
physical examination and plain radiographs
of the affected joints.
To reduce the frequency of bleeding and
stop or delay the progression of hemophilic
arthropathy, improving quality of life; to
prevent bleeding risk due to co-morbidities
Retrospective cohorts (UK, Italy31)#
Prospective studies, short term28,32
Prospective study, long term (POTTER33)
RCT (SPINART15)
^according to the WFH guidelines, 2013 (ref. 16); °In all cases, to prevent life-threatening bleeding episodes; *With the intent of treating for 52 weeks
per year and receiving a minimum of an a priori defined frequency of infusions for at least 45 weeks (85%); **Large joints: ankles, knees, hips, elbows
and shoulders; #For reviews of these studies see references 6 and 7.
specialists in rehabilitation, hepatologists and infectious
disease specialists, and other relevant medical personnel,
in the frame of highly specialised comprehensive care
centres (CCCs). This approach enables to achieve better
clinical outcomes, including patients' life expectancy, as
shown in the developing world but even in high-income
countries38,39. Achieving or maintaining such an optimal
standard of care is the main objective of national and
international organisations and healthcare programs9,16,40.
From a clinical point of view, as a consequence of
their increased life expectancy, haemophilic patients
and their treaters are now facing the new challenges
arising from the age-related co-morbidities41. Indeed,
together with joint disease and infectious complications
(HIV infection and chronic hepatitis C), routinely
managed over the last decades at HTCs and CCCs,
ageing haemophilic patients develop the typical
diseases of the elderly, previously only rarely seen,
such as cardiovascular diseases, malignancies, renal
diseases, prostatic hypertrophy, sexual dysfunction
and neurologic problems. Few literature data presently
support the management of such co-morbidities,
that may significantly increase the bleeding risk due
to organic lesions or the need for pharmacological
interventions or invasive procedures42. The paradigm of
these challenges is the management of ischemic heart
disease in persons with haemophilia. In these cases, the
use of antithrombotic drugs, often in combination in the
acute phase, particularly when percutaneous coronary
interventions are carried out, or for long-term secondary
prevention should be balanced by specific prophylactic
regimens to prevent excessive bleeding42,43. Similarly,
haemophilic patients with malignancies undergoing
diagnostic or therapeutic invasive procedures or
chemotherapy should receive adequate replacement
treatment in order to minimise the bleeding risk44. In this
perspective, the multidisciplinary, comprehensive care
for adult and ageing haemophiliacs should be updated
and revisited. Haemophilia specialists are now learning
to search for the close cooperation of other specialists
(i.e., cardiologists, oncologists, neurologists, urologists)
to define the most appropriate diagnostic and therapeutic
strategies for identifying, preventing and treating agerelated comorbidities10,42. In the lack (and probably
unfeasibility) of rigorous studies providing evidencebased approaches, international cooperation is crucial for
improving our knowledge and expertise in this setting.
Nevertheless, even "typical" haemophilia-related comorbidities or complications should be confronted in the
evolving perspective of the prolonged life expectancy of
patients10. As regards the management of haemophilic
arthropathy, increasing numbers of patients will need
orthopedic surgeries, appropriate treatment for chronic
pain, and prosthesis revision operations42. Similarly,
addressing liver transplantation will be more frequently
considered in patients with advanced HCV-related
chronic hepatitis45. Late-onset inhibitors represent
another poorly investigated issue in elderly haemophilic
patients, as recently highlighted by United Kingdom data
demonstrating a second peak of incidence in patients
aged ≥60 years46.
Unsolved challenges in clinical management of
haemophilia
The need for intravenous, frequent administration of
factor concentrates and for an early start of prophylactic
regimens in order to optimise clinical outcomes arises
the crucial issue of venous access in haemophilic
Blood Transfus 2014; 12 Suppl 3: s554-62 DOI 10.2450/2014.0043-14s
s556
Current evolving management of haemophilia
children. Indeed, the peripheral vein access is often
unfeasible and, although individualization of dose and
frequency of infusions enables to reach full-dose regimens
later in life when children may have better peripheral
accesses6,26, central venous access devices (CVAD)
are needed in relevant proportion of children starting
prophylaxis12,20,26. The placement of external or fully
implantable central venous catheters, providing a stable
and long-lasting venous access greatly facilitate home
treatment and regular prophylaxis47. However, an accurate
specific training for caregivers is needed and CVAD
complications (infections, occlusions) remain a major
concern in the management of haemophilic children47-48.
A newer and possibly safer approach, i.e the arteriovenous
fistula (AVF), has been proposed, with encouraging low
rate of complications49. However, AVF creation may
be difficult in very small children (<2-year-old) and its
maturation requires approximately 8 weeks. On the whole,
this approach is practiced in few specialised centres and
so far only one published relevant clinical experience
about it49. Peripherally inserted central venous catheters
(PICC) are also being introduced in the management of
haemophilic children. These devices, simply inserted
(via US guide) and employed in many chronic diseases
requiring long-term venous access, are associated with
very low rates of complications (infection, occlusion,
dislodgement, phlebitis) requiring their removal50.
In the era of safe factor concentrates and of the
diffusion of prophylaxis to prevent or reduce the impact of
arthropathy, the most serious complication of hemophilia
treatment remains the development of inhibitory
alloantibodies in 25-30% of severe haemophilia A patients
and in 3-5% of those with haemophilia B51. Inhibitors
render the safe standard replacement therapy ineffective
and, particularly, preclude prophylaxis feasibility,
exposing children to higher morbidity and poorer quality
of life, with a striking increase of economic burden of
patient management52.
Intensive research has been devoted to unravel
mechanisms of such an unfavorable immune response,
in which a variety of genetic and environmental factors
interplay, only in part presently elucidated (Table II)53.
Genetic predisposition relies upon F8/F9 causative
mutations, family history, and ethnicity54, but is being
revealed more complex than previously thought, an
increasing number of genes of immune response and
intracellular signalling being identified, potentially
relevant and requiring further specific evaluation55.
In this genetic background, the presentation of the
exogenous, non-self, therapeutic protein may be not
sufficient for triggering an immune response but,
according to the "danger model", the immune system
is activated by alarm signals arising from the injured
tissues to a greater extent than by the recognition of
non-self56. Consistent with this, an increased inhibitor
risk in patients receiving intensive treatments at first
exposure days (longer than 5 consecutive exposure
days and/or FVIII doses higher than 35 IU/Kg) has been
reported57-59. On the other hand, the regular exposure
to low doses of the antigen in the absence of danger
signals by early prophylaxis might exert protective
effects, inducing the tolerance of the foreign protein,
as supported by some studies57,60,61. However, the recent
large prospective Research Of Determinants of INhibitor
development (RODIN) study59 showed that prophylaxis
was only associated with decreased inhibitor incidence
after 20 exposure days and that this association was
more pronounced in patients with low-risk F8 genotypes
than in those with high-risk F8 genotypes. Therefore,
patients with "genetic" increased risk are likely to be
less susceptible to protective effects of prophylaxis59.
On the whole, while the risk associated with the source
of FVIII product (i.e. plasma-derived vs. recombinant
concentrates) remains keenly debated, with conflicting
results from cohort studies57,62-64 and meta-analyses65,66
and a randomised trial still ongoing13, the recognition
of genetic and non-genetic (thus potentially modifiable)
risk factors (Table II) is suggesting prediction models
for identifying subjects at higher risk67 and clinical
approaches aimed to reduce the risk of inhibitor
development68, although presently far to be validated.
Even as regards the only available strategy to
attempt inhibitor eradication, induction of immune
tolerance (ITI), many questions are still unsolved69-71.
There is substantial agreement in recommending ITI
in all children with persistent inhibitors interfering
with standard FVIII replacement, as soon as possible
after inhibitor diagnosis, in order to minimize the
inhibitor-related morbidity burden, in particular on joint
health16,69-72. However, the optimal ITI regimen is still
debated, high success rates (60-80%) being reported with
heterogeneous protocols, in terms of dose and type of
FVIII concentrate, interval of infusions and association
of immunomodulating agents. According to the findings
from a recent RCT in "good-prognosis" children (i.e.
those aged <8 years, with a historical inhibitor peak titer
lower than 200 BU/mL and starting ITI when inhibitor
titer is lower than 10 BU/mL, within 24 months from
inhibitor detection), in spite of similar success rates with
a high-dose (the "Bonn" regimen, 200 IU/Kg daily) and
a low-dose (50 IU/Kg thrice weekly) FVIII regimen,
higher rates of bleeding episodes in patients on the
low-dose arm raise concerns for choosing such regimen
in this setting73. Therefore, high-dose or intermediatedose (100 IU/Kg) but daily regimens are suggested in
"good-prognosis" children72, with the possibility of
increasing FVIII dose in the case of intercurrent bleeding
or detection of high inhibitor peaks, a putative negative
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Coppola A et al
predictor of ITI success73,74. In this respect, in order to
reduce the bleeding risk and possible negative effects on
joint status in children attempting inhibitor eradication,
prophylaxis regimens with bypassing agents, have been
proposed while awaiting for ITI start and during ITI,
until FVIII recovery is achieved70,71. The administration
of activated prothrombin complex concentrate (aPCC,
100 IU/Kg every 12 hours) was included in the original
Bonn protocol, however more recently heterogeneous
regimens with both aPCC and recombinant activated
factor VII (rFVIIa) have been used, with the latter
generally preferred in children and before ITI start, due
to potential risk of anamnesis from FVIII traces in the
aPCC70. Avoiding immunologic "danger signals" from
bleeding-related tissue damage through prophylaxis
has been hypothesised to affect favorably ITI outcome,
however in this respect no evidence is so far available71.
Even more debated is the optimal ITI regimen
in "poor-risk" patients, in particular in those with
long-standing inhibitors, in whom higher success
rates are reported with high-dose regimens70,71, as
well the choice for the type of FVIII concentrate, in
the lack of prospective/controlled studies comparing
plasmaderived and recombinant concentrates. Presently,
the same product associated with inhibitor development
is usually adopted for attempting ITI69-71. Also in the
setting of inhibitor eradication, a better knowledge
of predictors of ITI outcome (Table II) is becoming
useful for optimizing the selection of candidates and
regimens of treatment. Also in this case, improving
pathophysiologic knowledge and clinical management
may result in significant impact on cost-effectiveness of
treatment and resource allocation, taking into account the
highest costs of care for inhibitor patients75. However,
only some patient-related factors, including low inhibitor
titer at ITI start - <10 BU/mL - and historical peak
inhibitor titer < 200 BU/mL are consistently reported as
predictors of ITI success70-72, whereas other immunologic
or genetic factors (including F8 mutations)74 have been
proposed but currently poorly investigated70,71.
Consistent with the search for improving clinical
outcomes and quality of life even in patients with
inhibitors, growing experience with prophylactic
regimens with both bypassing agents even in patients
who are not candidate to ITI is extending the excellent
results of prophylaxis in non-inhibitor patients in
this setting76-79. These clinical outcomes have been
documented by rigorous studies, providing evidence
of significant reductions in total, joint and target joint
bleeding rates and of improved quality of life, although
over short-term follow-up (3-12 months)76,77. Due to
such a limited observation period, these studies were
not able to document effects in preventing or delaying
joint deterioration and conflicting data are reported in
retrospective case series17,78,79. Therefore, prophylaxis is
presently used by many physicians in inhibitor patients,
although concerns about cost-effectiveness and the need
for longer term assessment of efficacy (in particular
with respect to joint outcomes) and safety are clearly
highlighted80.
Table II - Patient- and treatment-related factors associated with inhibitor development and eradication through immune
tolerance induction in haemophilia A^.
Inhibitor development
Inhibitor eradication (ITI)
Patient-related factors
F8 mutations
Ethnicity
Family history
F8 polymorphisms
HLA-class II and immunogenotype
Inhibitor titer at ITI start
Historical peak inhibitor titer
Inhibitor peak titer during ITI
Treatment-related factors
Periods of intensive treatment
Surgical procedures
Dose of FVIII
Prophylaxis*
Dose of FVIII
Unlikely
Age at first exposure
Type of FVIII product (plasma-derived vs. recombinant)
Switching between products
Breastfeeding
Age at ITI start
Time between inhibitor diagnosis and ITI start
Need for further data
Type of FVIII recombinant product
Mode of infusion (bolus vs. continuous infusion)
Extravasation of products
Vaccinations
Infections
Amniocentesis, villocentesis
F8 mutations
Ethnicity
Type of FVIII product (plasma-derived vs. recombinant)
Interruptions of treatment
Infections and other immunologic challenges
^in italics factors not consistently recognised; for reviews of these issues see references 53, 54, 70 and 71; *as a protective factor.
Blood Transfus 2014; 12 Suppl 3: s554-62 DOI 10.2450/2014.0043-14s
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Current evolving management of haemophilia
The search for safety and overcoming current
challenges
The need for safer and safer factor concentrates
was the key for research and development of both
plasmaderived and recombinant products over the last three
decades1. Current achievements rely upon plasmaderived
concentrates, manufactured with rigorous policies for
plasma collection, NAT screening and application of
viral inactivation and elimination techniques (often in
combination), and a variety of recombinant products,
including new generation protein-free concentrates,
i.e. without any addition of human or animal protein
throughout the production process5. In spite of the
high-level of safety of plasma-derived concentrates,
documented by the lack of transmission of HCV, HIV
or other clinically relevant infections over the last 25
years1, many physicians continue to prefer recombinant
products (particularly in children), thought to be safer
with respect to known and, particularly, emerging or
unknown pathogens80,81. This attitude is also consistent
with the search for the best possible treatment,
although present economic constraints tend to influence
therapeutic choices even in high-income countries80,82.
On the other hand, the ongoing and future development
of replacement products is wholly based on recombinant
technology. This search is devoted to overcome current
treatment challenges thanks to factor concentrates with
improved properties, in particular longer half-life products
to obviate frequent administration and venous access
problems, and/or reduced antigenicity/immunogenicity
products to minimise inhibitor development1,18. As
recently reviewed in detail, some modified FVIII and FIX
molecules with longer half-life are in advanced phase
of clinical trials18,83. The availability of such products
will represent a relevant progress for countries that can
afford costs of primary prophylaxis, being venous access
problems the main barrier to its widespread adoption and
adherence. These benefits will be associated ultimately
with further improvements of quality of life of persons
with hemophilia. A positive impact on the overall factor
requirements (and hopefully on costs of treatment) might
be obtained through the reduced dosage frequency and
truly personalised regimens of prophylaxis with such
products, although costs of longer half-life products are
presently not predictable83,84.
More advanced clinical development and encouraging
results with modified FIX than FVIII concentrates18,83
highlight the need for specific studies devoted to
patients with haemophilia B. Indeed, due to the lower
prevalence of hemophilia B, few patients have been
included in clinical studies and the general practice is
transferring results obtained in patients with haemophilia
A. This is true for prophylaxis regimens but even more
scarce information is available concerning inhibitor
development and management, which are complicated
by the additional morbidity of allergic reactions and
unfavorable ITI outcome85. Personalised management
in haemophilia B might also be supported by several
studies suggesting the different severity of the two forms
of haemophilia, with less severe bleeding phenotype in
haemophilia B than in haemophilia A86.
Conclusions
In spite of significant persistent challenges, like the
need for intravenous administration of replacement
products and inhibitor development in approximately
30% of previously unexposed children, persons
with haemophilia presently enjoy a highly effective
and safe treatment80, delivered through specialised
centres, comprehensively addressing their demanding
management. This results, at least in high-income
countries, in an excellent quality of life for children
born in the era of primary prophylaxis and their
families, and in improved clinical outcomes in patients
of all ages who predominantly receive long-term
prophylaxis as replacement regimen. Thanks to these
achievements, haemophilia in the third millennium can
remove its historical hallmark of a crippling inherited
bleeding disorder1,6. Prophylaxis is the milestone of this
pathway of continuous advances in the management
of haemophilic patients, driven by the achievement of
the best possible long-term quality of life and always
requiring shared decisions between physicians, patients
and their families80. After the recognition of prophylaxis
as the evidence-based treatment of choice in children,
studies are being devoted to support its adoption in
adolescents and adults and to validate individualised
regimens, useful for facilitating long-term adherence and
overcoming barriers to its diffusion, in particular venous
access and costs. Indeed, in the present era of healthcare
budget constraints, these regimens may improve costeffectiveness of treatment and reduce the apparently
insurmountable problem of costs. Along this line, in the
near future extended half-life concentrates will provide
further, possibly cost-effective, strategies for tailored
treatment. Improving clinical outcomes and quality of life
are key objectives even in the challenging management
of inhibitor patients (searching for the optimal ITI or
prophylaxis regimens) and of co-morbidities in elderly
haemophiliacs. Again, personalised treatments represent
the strategy for overcoming the limitations of unsolved
issues and lack of evidence.
Keywords: bleeding, comprehensive care, haemophilia,
prophylaxis, treatment.
The Authors declare no conflicts of interest.
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Coppola A et al
References
1)
2)
3)
4)
5)
6)
7)
8)
9)
10)
11)
12)
13)
14)
15)
16)
17)
18)
19)
20)
21)
Franchini M, Mannucci PM. Past, present and future of
hemophilia: a narrative review. Orphanet J Rare Dis 2012; 7:24.
Tagliaferri A, Rivolta GF, Iorio A, et al. Mortality and causes
of death in Italian persons with haemophilia, 1990-2007.
Haemophilia 2010; 16: 437-46.
Franchini M, Coppola A, Molinari AC, et al. Forum on: the role
of recombinant factor VIII in children with severe haemophilia
A. Haemophilia 2009; 15: 578-86.
Ofosu FA, Freedman J, Semple JW. Plasma-derived biological
medicines used to promote haemostasis. Thromb Haemost
2008; 99: 851-62.
Franchini M, Lippi G. Recombinant factor VIII concentrates.
Semin Thromb Hemost 2010; 36: 493-7.
Coppola A, Tagliaferri A, Di Capua M, Franchini M.
Prophylaxis in children with hemophilia: evidence-based
achievements, old and new challenges. Semin Thromb Hemost
2012; 38: 79-94.
Coppola A, Franchini M, Tagliaferri A. Prophylaxis in people
with hemophilia. Thromb Haemost 2009; 101: 674-81.
Gringeri A, Lambert T, Street A, Aledort L. Adolescent/
Adult Prophylaxis Expert Working Group of the International
Prophylaxis Study Group. Tertiary prophylaxis in adults: is
there a rationale? Haemophilia 2012; 18: 722-8.
Colvin BT, Astermark J, Fischer K, et al. European principles
of haemophilia care. Haemophilia 2008, 14: 361-74.
Coppola A, Santoro C, Franchini M, et al. Emerging issues on
comprehensive hemophilia care: preventing, identifying and
monitoring age-related comorbidities. Semin Thromb Hemost
2013; 39: 794-802.
Donadel-Claeyssens S. Current co-ordinated activities of the
PEDNET (European Paediatric Network for Haemophilia
Management). Haemophilia 2006; 12: 124-7.
Manco-Johnson MJ, Abshire TC, Shapiro AD, et al.
Prophylaxis vs episodic treatment to prevent joint disease in
boys with severe hemophilia. N Engl J Med 2007; 357: 535-44.
Mannucci PM, Gringeri A, Peyvandi F, Santagostino E. Factor
VIII products and inhibitor development: the SIPPET study
(survey of inhibitors in plasma-product exposed toddlers).
Haemophilia 2007; 13 (Suppl 5): 65-8.
Hay CR, DiMichele DM; International Immune Tolerance
Study. The principal results of the International Immune
Tolerance Study: a randomized dose comparison. Blood 2012;
119: 1335-44.
Manco-Johnson MJ, Kempton CL, Reding MT, et al.
Randomized, controlled, parallel-group trial of routine
prophylaxis vs on-demand treatment with rFVIII-FS in adults
with severe hemophilia A (SPINART). J Thromb Haemost
2013; 11: 1119-27.
Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al;
Treatment Guidelines Working Group on Behalf of The World
Federation Of Hemophilia. Guidelines for the management
of haemophilia. HaemophiliaHaemophilia 2013; 19: e1-47.
Forsyth AL, Giangrande P, Hay CRM et al. Difficult clinical
challenges in haemophilia: international experiential
perspective. Haemophilia 2012; 18(Suppl. 5): 39-45.
Peyvandi F, Garagiola I, Seregni S. Future of factor
replacement treatment. J Thromb Haeamost 2013; 11: 84-98.
Chuah MK, Nair N, van den Driessche T. Recent progress
in gene therapy for hemophilia. Hum Gene Ther 2012; 23:
557-65.
Gringeri A, , Lundin B, Mackensen SV, et al. A randomized
clinical trial of prophylaxis in children with hemophilia A (the
ESPRIT Study). J Thromb Haemost 2011; 9: 700-10.
Nilsson IM, Berntorp E, Löfqvist T, Pettersson H: Twentyfive years experience of prophylactic treatment in severe
haemophilia A and B. J Intern Med 1992; 232: 25-32.
22) Fischer K, van der Bom JG, Mauser-Bunschoten EP, et al.
The effects of postponing prophylactic treatment on long-term
outcome in patients with severe hemophilia. Blood 2002; 99:
2337-41.
23) Aledort L, Haschmeyer RH, Pettersson H. A longitudinal
study of orthopaedic outcomes for severe factor-VIII-deficient
haemophiliacs. The Orthopaedic Outcome Study Group. J
Intern Med 1994; 236: 391-9.
24) Berntorp E, Boulyjenkov V, Brettler D, et al. Modern treatment
of haemophilia. Bull World Health Organ 1995; 73: 691-701.
25) Richards M, Williams M, Chalmers E, et al. Paediatric
Working Party of the United Kingdom Haemophilia Doctors'
Organisation. A United Kingdom Haemophilia Centre Doctors'
Organization guideline approved by the British Committee
for Standards in Haematology. Guideline on the use of
prophylactic factor VIII concentrate in children and adults
with severe haemophilia A. Br J Haematol 2010; 149: 498-507.
26) Santoro C, Baldacci E, Mercanti C, Mazzucconi MG. Tailored
vs. standard dose prophylaxis in children with haemophilia A.
Semin Thromb Hemost 2013; 39: 711-22.
27) Feldman BM, Pai M, Rivard GE, et al. Association of
Hemophilia Clinic Directors of Canada Prophylaxis Study
Group. Tailored prophylaxis in severe hemophilia A: interim
results from the first 5 years of the Canadian Hemophilia
Primary Prophylaxis Study. J Thromb Haemost 2006; 4:
1228-36.
28) Valentino LA, Mamonov V, Hellmann A, et al. Prophylaxis
Study Group: Prophylaxis Study Group. A randomized
comparison of two prophylaxis regimens and a paired
comparison of on-demand and prophylaxis treatments in
hemophilia A management. J Thromb Haemost 2012; 10:
359-67.
29) Wu R, Luke KH, Poon MC, et al. Low dose secondary
prophylaxis reduces joint bleeding in severe and moderate
haemophilic children: a pilot study in China. Haemophilia
2011, 17:70-4.
30) Celkan T, Özdemir N. Reduced early prophylaxis of
children with haemophilia in a developing country, Turkey.
Haemophilia 2011; 17: e840-e841.
31) Tagliaferri A, Franchini M, Coppola A, et al. Effects of
secondary prophylaxis started in young-adult hemophiliacs.
Haemophilia 2008; 14: 945-51.
32) Collins P, Faradji A, Morfini M, et al. Efficacy and safety of
secondary prophylactic vs. on-demand sucrose-formulated
recombinant factor VIII treatment in adults with severe
hemophilia A: results from a 13-month crossover study. J
Thromb Haemost 2010; 8: 83-9.
33) Tagliaferri A, Rivolta GF, Coppola A, et al. Prophylaxis vs
on-demand therapy through economic report (POTTER)
study: Preliminary data from the final five-year analysis.
Haemophilia 2012; 18 (Suppl. 3):160 (abstract).
34) National Hemophilia Foundation. MASAC Recommendations
concerning prophylaxis (regular administration of clotting
factor concentrate to prevent bleeding). Document 179.
Available at: http://www.hemophilia.org/NHFWeb/MainPgs/
MainNHF.aspx?menuid=57&contentid=1007. Accessed on
13/02/2014.
35) van Dijk K, Fischer K, van der Bom JG, et al. Can long term
prophylaxis for severe haemophilia be stopped in adulthood?
Results from Denmark and the Netherlands. Br J Haematol
2005; 130: 107-12.
36) Noon D, O'Mahony B, van Dijv JP, Prihodova L. A survey of
the outcome of prophylaxis, on-demand treatment or combined
treatment in 18-35-year old men with severe haemophilia in
six countries. Haemophilia 2013; 19: 44-50.
37) Farrugia A, Cassar J, Kimber MC, et al. Treatment for life for
severe haemophilia A - A cost-utility model for prophylaxis
vs. on-demand treatment. Haemophilia 2013; 19: e228-38.
Blood Transfus 2014; 12 Suppl 3: s554-62 DOI 10.2450/2014.0043-14s
s560
Current evolving management of haemophilia
38) Soucie JM, Nuss R, Evatt B, et al. Mortality among males
with hemophilia: relations with source of medical care. Blood
2000; 96: 437-42.
39) Baker JR, Crudder So, Riske B, et al. A model for a regional
system of care to promote the health and well-being of people
with rare chronic genetic disorders. Am J Public Health 2005;
95: 1910-6.
40) Fischer K, Hermans C, on behalf of the European Haemophilia
Therapy Standardisation Board (EHTSB). The European
Principles of Haemophilia Care: a pilot investigation of
adherence to the principles in Europe. Haemophilia 2013;
19: 35-43.
41) Mauser-Bunschoten EP, van de Putte DEF, Schutgens REG.
Co-morbidity in the ageing haemophilia patient: the down side
of increased life expectancy. Haemophilia 2009; 15: 853-63.
42) Mannucci PM, Schutgens RE, Santagostino E, MauserBunschoten EP. How I treat age-related morbidities in elderly
persons with hemophilia. Blood 2009; 114: 5256-63.
43) Coppola A, Tagliaferri A, Franchini M. The management of
cardiovascular diseases in patients with hemophilia. Semin
Thromb Hemost 2010; 36: 91-102.
44) Tagliaferri A, Di Perna C, Santoro C, et al. Cancers in patients
with hemophilia: a retrospective study from the Italian
Association of Hemophilia Centres. J Thromb Haemost 2012;
10: 90-5.
45) Lambing A, Kachalsky E, Kuriakose P. Liver transplantation in
the haemophilia patient. Haemophilia 2012; 18: 300-3.
46) Hay CR, Palmer B, Chalmers E, et al. Incidence of factor VIII
inhibitors throughout life in severe hemophilia A in the United
Kingdom. Blood 2011; 117: 6367-70.
47) Valentino LA, Ewenstein B, Navickis RJ, Wilkes MM: Central
venous devices in haemophilia. Haemophilia 2004, 10:134-46.
48) Ljung R. The risk associated with indwelling catheters in
children with haemophilia. Br J Haematol 2007; 138: 580-6.
49) Mancuso M, Berardinelli L, Beretta C, et al. Improved
treatment feasibility in children with hemophilia using
arteriovenous fistulae: the results after seven years of followup. Haematologica 2009; 94: 687-92.
50) Bui S, Babre F, Hauchecorne S, et al. Intravenous peripherallyinserted central catheters for antibiotic therapy in children with
cystic fibrosis. J Cyst Fibros 2009; 8: 326-31.
51) Franchini M, Mannucci PM. Inhibithors of propagation of
coagulation (factors VIII, IX and XI): a review of current
therapeutic practice. Br J Clin Pharmacol 2011; 72: 553-62.
52) Gringeri A, Mantovani LG, Scalone L, Mannucci PM. Cost of
care and quality of life for patients with hemophilia complicated
by inhibitors: the COCIS Study Group. Blood 2003; 102:
2358-63.
53) Coppola A, Santoro C, Franchini M, Tagliaferri A, Di Minno
G. Understanding inhibitor development in haemophilia
A: towards clinical prediction and prevention strategies.
Haemophilia 2010; 16: 13-9.
54) Astermark J. Inhibitor development: patient-determined risk
factors. Haemophilia 2010; 16: 66-70.
55) Astermark J, Donfield SM, Gomperts ED, et al. The
polygenic nature of inhibitors in hemophilia A: results from
the Hemophilia Inhibitor Genetics Study (HIGS) Combined
Cohort. Blood 2013; 121: 1446-54.
56) Matzinger P. The danger model: a renewed sense of self.
Science 2002; 8: 76-82.
57) Gouw SC, van der Bom JG, van den Berg HM. Treatmentrelated risk factors of inhibitor development in previously
untreated patients with hemophilia A: the CANAL cohort study.
Blood 2007; 109: 4648-54.
58) Maclean PS, Richards M, Williams M, Collins P, Liesner
R, Keeling DM, Yee T, Will AM, Young D, Chalmers EA.
Treatment related factors and inhibitor development in children
with severe haemophilia A. Haemophilia 2011; 17: 282-7.
59) Gouw SC, van den Berg HM, Fischer K, et al. Intensity of
factor VIII treatment and inhibitor development in children
with severe hemophilia A: the RODIN study. Blood 2013;
121: 4046-55.
60) Santagostino E, Mancuso ME, Rocino A, et al. Environmental
risk factors for inhibitor development in children with
haemophilia A: a case-control study. Br J Haematol 2005;
130: 422-7.
61) Auerswald G, Bidlingmaier C, Kurnik K. Early prophylaxis/
FVIII tolerization regimen that avoids immunological
danger signals is still effective in minimizing FVIII inhibitor
developments in previously untreated patients-long-term
follow-up and continuing experience. Haemophilia 2012;
18: e18-e20.
62) Goudemand J, Rothschild C, Demiguel V, et al. Influence of
the type of factor VIII concentrate on the incidence of factor
VIII inhibitors in previously untreated patients with severe
hemophilia A. Blood 2006; 107: 46-51.
63) Mancuso ME, Mannucci PM, Rocino A, et al. Source and
purity of factor VIII products as risk factors for inhibitor
development in patients with hemophilia A. J Thromb
Haemost 2012; 10: 781-90.
64) Gouw SC, van der Bom JG, Ljung R, et al; PedNet and RODIN
Study Group. Factor VIII products and inhibitor development
in severe hemophilia A. N Engl J Med 2013; 368: 231-9.
65) Iorio A, Halimeh S, Holzhauer S, et al. Rate of inhibitor
development in previously-untreated hemophilia a patients
treated with plasma-derived or recombinant factor VIII
concentrates. A systematic review. J Thromb Haemost 2010;
8: 1256-65.
66) Franchini M, Coppola A, Rocino A, et al. Systematic review
of the role of FVIII concentrates in inhibitor development in
previously untreated patients with severe hemophilia A: a 2013
update. Semin Thromb Hemost 2013; 39: 752-66.
67) Ter Avest P, Fischer K, Mancuso ME, et al. Risk stratification
for inhibitor development at first treatment for severe
haemophilia A patients: a tool for clinical practice. J Thromb
Haemost 2008; 6: 2048-54.
68) Auerswald G, Bidlingmaier C, Kurnik K. Early prophylaxis/
FVIII tolerization regimen that avoids immunological
danger signals is still effective in minimizing FVIII inhibitor
developments in previously untreated patients--long-term
follow-up and continuing experience. Haemophilia 2012;
18: e18-e20.
69) Astermark J, Morado M, Rocino A, et al. Current European
practice in immune tolerance induction therapy in patients with
haemophilia and inhibitors. Haemophilia 2006;12:363-71.
70) DiMichele D, Hoots WK, Pipe SW, et al. International
workshop on immune tolerance induction: consensus
recommendations. Haemophilia 2007; 13: 1-22
71) Coppola A, Di Minno MN, Santagostino E. Optimizing
management of immune tolerance induction in patients with
severe haemophilia A and inhibitors: towards evidence-based
approaches. Br J Haematol 2010; 150: 515-28.
72) Collins PW, Chalmers E, Hart DP, et al. Diagnosis and
treatment of factor VIII and IX inhibitors in congenital
haemophilia: (4th edition). UK Haemophilia Centre Doctors
Organization. Br J Haematol 2013; 160: 153-170.
73) Hay CR, DiMichele DM; International Immune Tolerance
Study: The principal results of the International Immune
Tolerance Study: a randomized dose comparison. Blood 2012;
119: 1335-44.
74) Coppola A, Margaglione M, Santagostino E, et al. Factor
VIII gene (F8) mutations as predictors of outcome in immune
tolerance induction of hemophilia A patients with highresponding inhibitors. J Thromb Haemost 2009; 7: 1809-15.
75) Di Minno MND, Di Minno G, Di Capua M, et al. Cost of care of
haemophilia with inhibitors. Haemophilia 2010, 16: e190-e201.
Blood Transfus 2014; 12 Suppl 3: s554-62 DOI 10.2450/2014.0043-14s
s561
Coppola A et al
76) Konkle BA, Ebbesen LS, Erhardtsen E, et al. Randomized,
prospective clinical trial of recombinant factor VIIa for
secondary prophylaxis in hemophilia patients with inhibitors.
J Thromb Haemost 2007; 5: 1904-13.
77) Leissinger C, Gringeri A, Antmen B, et al. Anti-inhibitor
coagulant complex prophylaxis in hemophilia with inhibitors.
N Engl J Med 2011; 365: 1684-92.
78) Young G, Auerswald G, Jimenez-Yuste V, et al. PRO-PACT:
retrospective observational study on the prophylactic use of
recombinant factor VIIa in hemophilia patients with inhibitors.
Thromb Res 2012; 130: 864-70.
79) Gringeri A, Leissinger C, Cortesi PA, et al. Health-related
quality of life in patients with haemophilia and inhibitors on
prophylaxis with anti-inhibitor complex concentrate: results
from the Pro-FEIBA study. Haemophilia 2013; 19: 736-43.
80) Franchini M, Coppola A, Rocino A, et al. Perceived challenges
and attitudes to regimen and product selection from Italian
haemophilia treaters. The 2013 AICE survey. Haemophilia
2014; 20: e128-35.
81) Di Minno G, Canaro M, Ironside JW, et al. Pathogen safety of
long-term treatments for bleeding disorders: (un)predictable risks
and evolving threats. Semin Thromb Hemost 2013; 39: 779-93.
82) Tarantino MD, Ye X, Bergstrom F, Skorija K, Luo MP. The
impact of the economic downturn and health care reform on
treatment decisions for haemophilia A: patient, caregiver and
health care provider perspectives. Haemophilia 2013; 19: 51-8.
83) Kaufman RJ, Powell JS. Molecular approaches for improved
clotting factors for hemophilia. Blood 2013; 122: 3568-74.
84) Hart DP. Prophylaxis in the era of long-acting products.
Haemophilia 2014; 20(Suppl 2): 7 SP008 (abstract).
85) DiMichele DM. Inhibitors in haemophilia B: An orphan disease
in need of attention. Br J Haematol 2007; 138: 305-15.
86) Santagostino E, Fasulo MR. Hemophilia A and hemophilia B:
different types of diseases? Semin Thromb Hemost 2013; 39:
697-701.
Correspondence: Antonio Coppola
Regional Reference Centre for Bleeding Disorders
Federico II University Hospital,
Via S. Pansini, 5
80131 Naples, Italy
e-mail: antocopp@unina.it
Blood Transfus 2014; 12 Suppl 3: s554-62 DOI 10.2450/2014.0043-14s
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REVIEW
Uncovered needs in the management of inherited bleeding disorders in Italy
Romano Arcieri1, Angelo C. Molinari2,3, Stefania Farace1, Giuseppe Mazza1, Alberto Garnero1, Gabriele
Calizzani1,4, Paola Giordano2,5, Emily Oliovecchio6, Lorenzo Mantovani2,7, Lamberto Manzoli2,8, Paul
Giangrande2,9
1
Italian Federation of Haemophilia Societies (FedEmo), Rome, Italy; 2FedEmo Scientific Commettee, Rome, Italy;
Thrombosis and Hemostasis Unit, Giannina Gaslini Children's Hospital, Genoa, Italy; 4National Blood Centre,
National Institute of Health, Rome; 5Department of Biomedical Sciences and Human Oncology, Pediatric Unit,
University of Bari, Bari, Italy; 6Department of Internal Medicine, University of Perugia, Perugia, Italy; 7Department
of Clinical Medicine and Surgery Federico II University of Naples, Naples, Italy; 8Department of Medicine and Aging
Sciences, University of Chieti, Chieti, Italy; 9Oxford Haemophilia and Thrombosis Centre, Oxford, United Kingdom
3
Introduction
Haemophilia is an X-linked bleeding disorder1 and
is characterised by repeated bleeding, especially in
joints. The current management of haemophilia is based
on the replacement therapy with intravenous clotting
factor and includes plasma-derived and recombinant
factor concentrates2. The early treatment in pediatrics
age has been recognised as an important determinant
of better physical development3, and several studies
have demonstrated that primary prophylaxis has a
positive and significant impact on the quality of life
and the prevention of arthropathy in haemophiliac
children4,5. Also, home treatment has shown to improve
both life expectancy and quality of life of patients with
haemophilia6.
The global treatment of haemophilia, however,
requires a multidisciplinary team including
haematologists, physicians, surgeons, orthopaedics and
other specialists in several medical areas7. This level of
clinical assistance is or can be guaranteed only in some
countries, and this influences the life expectancy of
haemophiliacs8.
To ensure a high quality of haemophilia care, an
appropriate health organisation and economic resources
are necessary.
The European Principles of Haemophilia Care
(EPHC) were published in 20089. These Principles
detail the standard of haemophilia care that should be
achieved for an appropriate global care of persons with
haemophilia (PWH).
The aim of this review is to highlight uncovered
needs of Italian haemophilia community, relative to the
implementation of each of the EPHC.
A central haemophilia organisation supporting
local groups
Patient and medical bodies, represented in Italy
by the Italian Federation of Haemophilia Societies
(FedEmo, www.fedemo.it) and the Italian Association of
Haemophilia Centres (AICE), are national organisations
that have addressed the problems of PWH since 1996.
Because the Italian National Healthcare Service
gives to the 21 Regions political, administrative and
financial responsibility regarding the provision of
health care, each Region may develop its peculiar
healthcare organisational model10. In the majority of
the largest Regions (i.e. Emilia-Romagna, Latium,
Lombardy, Campania), the network of hospital
care is most frequently organised following a "Hub
and Spoke" model. For improving the organisation
of hemophilia care and the access to services, in
2009 FedEmo asked the Health Commission of the
Conference between the Italian State and Regions
for the development of an accreditation system for
Haemophilia Centres (HCs)11. Following this request, in
2010 the Ministry of Health funded a project aimed at
developing a model of disease management to prevent
haemophilia complications. Given this background,
FedEmo, AICE, the Italian National Blood Center
(NBC, www.centronazionalesangue.it), Italian Regional
Health Authorities and Ministry of Health proposed
an institutional accreditation scheme for HCs, that
was approved by a formal State-Regions Agreement
in March 201311,12 (hereafter referred as the March
2013 Agreement). This provides an organisational
framework for Italian Regional Health Authorities
to optimise and standardise haemophilia care on the
basis of the latest scientific evidence and international
recommendations9,13.
National Haemophilia Patient Registries
In Italy, the epidemiological data on inherited
bleeding disorders derive from the Italian National
Registry for Rare Diseases (NRRDs), the National
Registry of Congenital Coagulopathies (NRCC) and the
Italian Registry of Haemophilia and Allied Disorders
of the AICE14.
NRRDs is a population-based and multi-diseases
register established by law since 2001, that supports
national planning of interventions for patients affected by
Blood Transfus 2014; 12 Suppl 3: s563-6 DOI 10.2450/2014.0036-14s
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Arcieri R et al
rare diseases (RDs) and implements the epidemiological
national surveillance of RDs.
NRCC was activated in 1999 by the AICE and
the National Institute of Health (Istituto Superiore di
Sanità, ISS, www.iss.it). The main objectives of the
National registry of congenital bleeding disorders is
to: i) estimate the prevalence of different congenital
bleeding disorders, ii) evaluate therapy complications
with particular attention to infection diseases (HIV,
HCV, prioni), iii) monitor the appearance of inhibitor
antibodies, iv) monitor the appropriateness of
treatment15.
In 2003, AICE also created a new pathology registry:
the Italian Registry of Haemophilia and Allied Disorders
(www.aiceonline.it). A subset of data is shared between
the two registries. The main objective of this registry is
to collect data on current clinical practice and provide
data for clinical studies16.
The registries differ in terms of organisation,
purpose and data collection process. They provide
epidemiological data on inherited bleeding disorders but
at this stage do not fully support benchmarking activities
of HC performance.
Comprehensive Care Centres (CCCs) and
Haemophilia Treatment Centres (HCs)
The current management of haemophilia should
improve the health and quality of life for PWH. This
issue could be achieved with the following two actions.
Firstly, establishing a team of specialists in CCCs
and HCs, providing a continuous comprehensive care
based on three main goals: i) prevention of bleeding,
ii) management of joint and muscle damage, iii)
management of treatment complications (inhibitor
antibodies and viral infections).
Secondly, offering an equal access to CCCs and HCs
on all the national territory.
In Italy, the availability and quality of care vary
widely within the country, so that 52% of patients must
still travel long distances (101-500 km), 22% of those
living in Southern regions and islands travel more than
500 km, and 40% of patients had to change living place
to attend a HC with an optimal level of care17.
Nowadays, there is a wide difference in the
organisation and efficacy of the HCs in Italy. However,
commitments endorsed by Regions within the March
2013 Agreement provide the ground for an improvement
and standardisation of haemophilia care across the
Country. So far, three Regions (Autonomous Province
of Trent, Emilia-Romagna and Liguria) over 21
have accepted the March 2013 Agreement into their
legislation. Uncertainty remains about the way HCs
regional network should be funded.
Partnership in delivery of care
The 4 th Principle of EPHC declares that the
etablishment of an Haemophilia Co-ordination Group
is desirable. This group should be represented by
physicians, national haemophilia patient organisations
and national health authorities. Unfortunately, so far an
Italian national haemophilia Co-ordination Group has
been missing but a local haemophilia Co-ordination
Group is active in a few regions.
Some aspects related to the comprehensive care
such as pharmacological treatment, organisation and
access to specialist services have to be included in the
national program.
Allocation of economical and structural resources
is of primary importance and, to such aim, an effective
partnership between different stakeholders has to be
defined to draw up the priorities and define national
clinical and organisational recommendations.
Safe and effective concentrates at optimum
treatment levels
Actually, the treatment for haemophilia has reached
a high degree of effectiveness and safety2. In 2011, even
if with a wide variability across Regions, a standardised
national consumption of factor VIII and factor IX
respectively of 6.5 and 0.9 international units (I.U.)
per capita has been achieved18. In Italy, guidelines
for diagnosis and treatment of patients affected by
coagulation disorders have been produced by AICE
in the past years19,20. Very recently, a revised version
has been approved and will be shortly published. This
document carefully considers all the available products
and the different mainstay of the treatment (home
treatment, prophylaxis, ITI).
A scientific and economical debate on products type,
such as recombinant vs plasma-derived, is ongoing21-24
basing on the difference between the two classes of
products and mainly on the costs.
As we believe that the quality of life of patients
represents one of the more desirable outcome of care,
we would recommend instead evaluating individual
treatment taking into consideration pharmacokinetic
response, efficacy, side effects, outcomes, patient's
inhibitor history, preference and compliance25,26.
Home treatment and delivery
Home treatment has shown to improve both
life expectancy and quality of life of patients with
haemophilia and other inherited coagulation disorders,
with a reduction of musculoskeletal damage6,7.
In Italy, home treatment is a common practice, but
a specific regulation on self infusion has been adopted
in only 60% of Italian Regions (Calabria, Campania,
Emilia-Romagna, Latium, Liguria, Lombardy, Piedmont,
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Global care of bleeding disorders in Italy
Apulia, Sardinia, Tuscany, Autonomous Province of
Trent and Veneto).
No financial constrain is affecting the inhibitors
management until now.
Prophylactic (preventive) treatment
Education and research
In Italy, prophylactic treatment is now available in
all Regions without financial constrains and regular
concentrate availability. The SPINART study (Trial
to Evaluate the Effect of Secondary Prophylaxis with
Recombinant FVIII Therapy in Severe Hemophilia Adult
subjects compared to That of Episodic Treatment)27 and
the POTTER study (Prophylaxis vs On-demand Therapy
Through Economic Report)28 are eagerly awaited as they
could lead to redefine the guidelines on treatment for
haemophilia. We believe that the prophylactic treatment
should be offered to all PWH -including adults- to
maintain a high quality of life.
In Italy the number of thrombosis and haemostasis
specialist has decreased as in other countries32. It is
essential to promote specific actions in the universities,
to foster training of healthcare professional in this area
and guarantee the continuity of care.
Specialist service and emergency care
With regard to the management of haemorrhagic
emergencies, in 2011 only 36% of the Italian Regions had
set up a specific protocol, 68% had emergency units with
immediate availability and access to factor concentrates,
only 58% of HCs had a physician expert in haemostasis
available 24/24 h and 42% had 24 h access to a coagulation
laboratory able to perform inhibitor detection and titration29.
This picture represents a limitation of access to
appropriate care, and therefore the Italian haemophilia
community should develop specific plans with the
related stakeholders. Indeed, in an emergency care
setting accessibility to drugs, appropriateness and
competence are critical issues and these are the areas
needing to be improved, to avoid severe complications
and inequity. In order to improve the awareness about
this issue, FedEmo launched in 2011 an educational
project called "Safe Factor" involving the key actors
involved in emergency care like physicians of HCs,
emergency departments, pharmacist, etc. We expect
from this campaign and from the implementation of
the provisions contained in the March 2013 Agreement
a further development of regional networks for the
emergency management.
Management of inhibitors
The difference in HC organisations affects the
laboratory facilities, such as performed test and
availability of staff during working days as well as
in weekends and holidays. In Italy, immune tolerance
induction programs are regularly applied in all centers,
and bypassing agents such as recombinant activated
clotting factor VII (rFVIIa) and activated prothrombin
complex concentrate (aPCC) are regularly used 30.
However, some children have to move to the largest
HCs to receive central venous access device or have
AV fistula created31.
Conclusions
Due to the different organisational models across
the Regions, in Italy the pharmacological treatment is
accessible in all regions, but wide differences are present
for the availability of multidisciplinary services and for
the laboratory facilities.
The March 2013 Agreement application should
improve this situation, as it defines services that should
be offered and an essential list of laboratory tests that
should be available all day round.
To improve accessibility to home treatment and
emergency care at the regional level, a Co-ordination
Group should be established with the aim of identifying
and tackling the actual gaps and define the appropriate
organisation.
Following the experience of the Institutional
Accreditation Model11,12, we believe that the participation
of non-governmental organisations, such as national or
regional haemophilia patients' organisations, can bring
an added value to the policy making process, including
the product procurement process. An early involvement
of PWH representatives in the discussion of any clinical
or organisational guideline, as well as of any associated
health care program, should be systematically pursued
in line with the fourth principle of the EPHC8, as
in Emilia-Romagna Region where the structured
involvement of patient organisation for the last 13
years has contributed to produce a well established and
effective organisation of care for PWH.
Finally, we envisage the establishment of a central
organisation, involving all key stakeholders (FedEmo,
AICE, Regions and national institutions such as MoH,
NBC, National Medicines Agency, etc) with the mission
to promote the standardisation of haemophilia care
across the Country, by overseeing the implementation
of the March 2013 Agreement provisions and by
monitoring the replacement therapy supply and costs.
We also believe that the Italian national network for
HCs, in compliance with European Union Committee
of Experts on Rare Diseases (EUCERD) 33 and
European Haemophilia Network project (EUHANET)34
recommendations, should benefit of dedicated resources
in order to be put in place. Therefore, among the
tasks assigned to such central organisation, it would
Blood Transfus 2014; 12 Suppl 3: s563-6 DOI 10.2450/2014.0036-14s
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Arcieri R et al
be desirable foreseeing the commitment to advance
proposals on funding mechanism for the HCs Network.
Keywords: haemophilia, Comprehensive Care Centre,
Haemophilia Treatment Centre.
18)
19)
Acknowledgements
We are indebted to Fabio Candura and Federica
Maria Regini for the editorial assistance, and to
Francesca Gillespie for reviewing English language.
20)
21)
The Authors declare no conflicts of interest.
22)
References
1)
2)
3)
4)
5)
6)
7)
8)
9)
10)
11)
12)
13)
14)
15)
16)
17)
Mannucci PM, Tuddenham EGD. The hemophiliac - form
royal genes to gene therapy. N Engl J Med 2001; 344: 1773-9.
Mannucci PM. Back to the future: a recent history of
hemophilia treatment. Haemophilia 2008; 14 (Suppl 3): 10-8.
Fischer K, Van der Bom JG, Mauser-Bunschoten EP, et al.
Effects of postponing prophylactic treatment on long-term
outcome in patients with severe haemophilia. Blood 2002;
99: 2337-41.
Coppola A, Franchini M, Tagliaferri A. Prophylaxis in people
with haemophilia. Thromb Haemost 2009; 101: 674-81.
Gringeri A, Lundin B, von Mackensen S, et al. A randomized
clinical trial of prophylaxis in children with hemophilia A (the
ESPRIT Study). J Thromb Haemost 2011; 9: 700-10.
Tagliaferri A, Rivolta GF, Iorio A, et al. Mortality and causes
of death in Italian persons with haemophilia, 1990-2007.
Haemophilia 2010; 16: 437-46.
Coppola A, Santoro C, Franchini M, et al. Emerging issues
on comprehensive hemophilia care: preventing, identifying,
and monitoring age-related comorbidities. Semin Thromb
Hemost. 2013; 39: 794-80.
Soucie JM, Nuss R, Evatt B, et al. Mortality among males
with hemophilia: relations with source of medical care. Blood
2000; 96: 437-42.
Colvin BT, Astermak J, Fischer K, et al. European principles
of haemophilia care. Haemophilia 2008; 14: 361-74.
Maio V, Manzoli L. The Italian Health Care System: W.H.O.
ranking versus public perception. P&T, Pharmacy and
Therapeutics 2002; 27: 301-8.
Calizzani G, Vaglio S, Arcieri R, et al. Models for institutional
and professional accreditation of haemophilia centres in Italy.
Haemophilia 2013; 19: e248-55.
Calizzani G, Candura F, Menichini I, et al. The Italian
Institutional Accreditation Model for Haemophilia Centres.
Blood Transfus 2014; 12 (Suppl 3): s510-4.
Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al.
Guidelines for the management of hemophilia. Haemophilia
2013; 19: e1-47.
Hassan HJ, Morfini M, Taruscio D, et al. Current status of
Italian Registries on inherited bleeding disorders. Blood
Transfus 2014; 12 (Suppl 3): s576-81.
National registry of congenital bleeding disorders. Report
2011. Rapporti ISTISAN 12/55 (in Italian). Available at
http://www.iss.it/binary/publ/cont/12_55_web.pdf. Accessed
on 16/02/2014.
Iorio A, Oliovecchio E, Morfini M, et al. Italian Registry of
Haemophilia and Allied Disorders. Objectives, methodology
and data analysis. Haemophilia. 2008; 14: 444-53.
Federazione delle Associazioni Emofilici. Il quadro
dell'emofilia in Italia: i bisogni delle persone e le strategie
23)
24)
25)
26)
27)
28)
29)
30)
31)
32)
33)
34)
messe in campo. Rapporto ICON. Roma, 25 maggio 2005.
Available at: http://fedemo.it/cat/per-il-medico/rapporti/.
Accessed on 16/02/2014.
Calizzani G, Profili S, Candura F, et al. The demand for factor
VIII and for factor IX and the toll fractionation product surplus
management. Blood Transfus 2013; 11 (Suppl 4): s64-76.
Santagostino E, Mannucci PM, Bianchi Bonomi A. Guidelines
on replacement therapy for haemophilia and inherited
coagulation disorders. Haemophilia 2000; 6: 1-10.
Gringeri A, Mannucci PM, Italian Association of Haemophilia
Centres. Italian guidelines for the diagnosis and treatment of
patients with haemophilia and inhibitors. Haemophilia 2005;
11: 611-9.
Mannucci PM. Plasma-derived versus recombinant factor
VIII concentrates for the treatment of haemophilia A: plasmaderived is better. Blood Transfus 2010; 8: 288-91.
Franchini M. Plasma-derived versus recombinant factor VIII
concentrates for the treatment of haemophilia A: recombinant
is better. Blood Transfus 2010; 8: 292-6.
Calizzani G, Arcieri R. Clinical and organisational aspects of
haemophilia care: the patients' view. Blood Transfus 2012;
10: 110-1.
Gringeri A. Factor VIII safety: plasma-derived versus
recombinant products. Blood Transfus 2011; 9: 366-70.
Mantovani LG, Monzini M, Mannucci PM, et al. Differences
between patients', physicians' and pharmacists' preferences
for treatment products in haemophilia: a discrete choice
experiment. Haemophilia 2005; 11: 589-97.
Schramm W, Gringeri A, Ljung R, et al. Haemophilia care in
Europe: the ESCHQoL study. Haemophilia 2012; 18: 729-37.
Manco-Johnson MJ, Kempton CL, Reding MT, et al.
Randomized, controlled, parallel-group trial of routine
prophylaxis vs. on-demand treatment with sucrose-formulated
recombinant factor VIII in adults with severe hemophilia A
(SPINART). J Thromb Haemost 2013; 11: 1119-27.
Tagliaferri A. Awaiting evidence-based recommendations on
prophylaxis in adult patients. Haemophilia 2010; 16: 955-6.
Alioto A, Garnero A, Calizzani G, Arcieri R. Lo sviluppo dei
percorsi per la gestione delle emergenze emorragiche nelle
regioni italiane. Blood Transfus 2011; 9 (Suppl): 6.
Coppola C, Tagliaferri A, Calizzani G, et al. Clinical use and
the Italian demand for activated prothrombin complex and
activated recombinant factor VII concentrates. Blood Transfus
2013; 11 (Suppl 4): s101-9.
Mancuso ME, Berardinelli L, Beretta C, et al. Improved
treatment feasibility in children with hemophilia using
arteriovenous fistulae: the results after seven years of follow-up.
Haematologica 2009; 94: 687-92.
Mannucci PM, Roberts HR. Uncertain time for research on
hemophilia and allied disorders. J Throm Haemost 2005; 3: 423.
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
16/02/2014.
Makris M, Calizzani G, Fischer K, et al. The European
Haemophilia Network (EUHANET). Blood Transfus 2014;
12 (Suppl 3): s515-8.
Correspondence: Romano Arcieri
Federation of Hemophilia Associations (FedEmo)
Via Lorenzo il Magnifico 148
00162 Rome, Italy
e-mail: romano.arcieri@fedemo.it
Blood Transfus 2014; 12 Suppl 3: s563-6 DOI 10.2450/2014.0036-14s
s566
ORIGINAL ARTICLE
The social burden and quality of life of patients with haemophilia in Italy
Yllka Kodra 1, Marianna Cavazza 2, Arrigo Schieppati 3, Marta De Santis 1, Patrizio Armeni 2,
Romano Arcieri4, Gabriele Calizzani5, Giovanni Fattore2, Lamberto Manzoli6, Lorenzo Mantovani6,
Domenica Taruscio1
1
Italian National Centre for Rare Diseases, National Institute of Health, Rome; 2Centre for Research on Health
and Social Care Management (CERGAS) Bocconi University, Milan; 3Clinical Research Centre for Rare Disease,
Mario Negri Institute, Ranica and Department of Medicine, Rare Disease Unit, Papa Giovanni XXIII Hospital,
Bergamo; 4Italian Federation of Haemophilia Societies, Rome; 5National Blood Centre, National Institute of
Health, Rome; 6Italian Federation of Haemophilia Societies, Medical Council, Rome, Italy
Background. In Italy, the project on the social burden and quality of life (QoL) of patients with
haemophilia investigates costs from a society perspective and provides an overview of their quality of life.
Moreover, as life expectancy increased in recent years along with new treatment strategies implemented in
the last decades, it analyses trends of costs other than drugs simulating impacts during patient whole life.
Material and methods. We ran a web-based cross-sectional survey supported by the Italian
Federation of Haemophilia Societies in recruiting patients with haemophilia and their caregivers.
We developed a questionnaire to collect information on demographic characteristics, healthcare and
social services consumption, formal and informal care utilisation, productivity loss and quality of
life. In particular, quality of life was assessed through the EuroQoL tool. Last, we applied the illness
cost method from a society perspective.
Results. On average, quality of life is worse in adult patients compared to child and caregivers:
more than 75% of adult patients declare physical problems, 43% of adult patients and 54% of their
parents have anxiety problems. Assuming a society perspective, the estimated mean annual total
cost per patient in 2012 is 117,732 €. Drugs represent 92% of total costs. Focusing on costs other
than drugs, each additional point of EuroQoL tool implies a costs' reduction of 279 €. The impact of
age varies across age groups: each added year implies a total decrease of costs up to 46.6 years old.
Afterwards, every additional year increases costs.
Discussion. Quality of life of patients with haemophilia and their caregivers improved and it
influences positively on consumed resources and on their contribution to the social-economic system.
Costs other than drugs for patients with haemophilia follow the same trends of general population.
Keywords: quality of life, cost of illness, haemophilia.
Introduction
Haemophilias are a group of inherited bleeding
disorders caused by an X-chromosome linked deficiency
in coagulation factors VIII (FVIII) (in haemophilia A)
or IX (FIX) (in haemophilia B). The disorders are rare
affecting approximately 1 in 10,000 births1.
The prevalence in Italy, according to the most recent
report (2012) of the Italian Association of Haemophilia
Centres that operates a national registry, consists of 3,690
patients with haemophilia A and 750 with haemophilia
B2,3. The use of factor replacements has significantly
decreased the mortality and morbidity of patients with
haemophilia: life expectancy has increased from 40
years old in the 1960s to 60-70 years today4,5. Quality
of life (QoL) has become an important measure of the
health improvements in haemophilic patients brought
about by therapeutic progress in this field, although it
remains significantly poorer as compared with QoL of
general population6,7. Specifically, QoL is viewed as
a measure of the outcome of care for individuals with
haemophilia that can inform disease management and
policy decision making8. It is not known, however,
whether changes in QoL can have an impact on costs
trend in the case of haemophilia9. Last, while there are
several studies on QoL in haemophilia10-12, there have
been very few on caregivers QoL13-15.
On the other hand, the diffusion of new treatment
strategies, based not only on factor replacement
therapy, but also on a switch from the on demand to
prophylaxis treatment, has also an economic impact.
Actually, it requires a dramatic increase of economic
resources' consumption by a small portion of the
population affected by a rare condition and therefore
the third-payers interest on this disease is also increased.
Blood Transfus 2014; 12 Suppl 3: s567-75 DOI 10.2450/2014.0042-14s
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Kodra Y et al
In particular, it is an example of the socioeconomic
impact of biotechnology in rare diseases16. Hence, the
scientific literature considering economic aspects has
focused mainly on the cost-effectiveness of prophylaxis
vs on-demand treatment in patients with a severe
haemophilia17,18 or with inhibitors19. A further set of
manuscripts implements a cost of illness approach on
haemophilia in different countries and in some cases
the economic and the social burden of this disease is
included20-23. Moreover, amongst the latter ones, only
one study21 have addressed in some way the relationship
between age and QoL on one side, and costs on the other
side. This is, actually, a new perspective arisen from the
life expectancy increase in these last years.
In the early 2000s, seminal contributions concerning
the Italian context provided direct healthcare costs
evaluation for patients with haemophilia complicated by
inhibitors in the Cost of Care Inhibitors Study16 and the
first estimation of the QoL of patients without inhibitors
in the Cost of Care of Hemophilia Study24.
The Burden and Health-Related Quality of Life in
Patients with Rare Diseases - BURQoL-RD Study was
a 3 year project under the 2nd Programme of Community
Action in the Field of Public Health, that commenced in
April 2010 and was promoted by the Directorate General
Health and Consumers of European Commission. The main
aim of BURQoL-RD was to generate a model to quantify
the socio-economic costs and QoL of both patients and
caregivers, for up to 10 rare diseases (RD) in different
European countries. According to this goal, the evaluation
of the economic and social impact of haemophilias has been
one of the objects of BURQoL-RD Study.
Therefore, the BURQoL-RD Study on haemophilia
in Italy investigates costs of this disease from a society
perspective (using a cost of illness approach) for the
first time and it provides an update of this group of
patients' QoL. Moreover, considering the increase of life
expectancy occurring in these last years, it analyses the
impact of this trend on costs other than drug, simulating
the whole life cycle. Last, as the expensive switch of
treatment strategies implemented in the last decade has
provided an increased QoL, we are going to test this
improvement's impact on costs other than drugs.
Materials and methods
We conducted a web-based cross-sectional study.
The target sample were Italian patients diagnosed
with haemophilia A and B and their caregivers.
Cases were recruited from the Italian Federation of
Haemophilia Societies (Federazione delle Associazioni
Emofilici,FedEmo, www.fedemo.it). All patients and
caregivers were informed about the study objectives
and data confidentially, and were asked to indicate their
understanding of the study conditions and agreement to
participate. The survey was anonymous, as the patients
were contacted by their patient organisation and their
responses, without any identification data, were sent
directly to the researchers. The fieldwork was carried
out between March 2012 and October 2012. The
questionnaires were administrated by e-mail through
patient organisations and patients were asked to provide
information on demographic characteristics, consumed
healthcare and non healthcare resources related to the
disease and QoL information in the six months preceding
the enrolment (12 months for hospital admissions).
Costs' materials and methods
To measure the burden of haemophilia, we have
applied the cost of illness approach from a society
perspective25. Therefore, both direct and indirect costs
were included, and a bottom-up approach was used for
their calculation: we valued the average unit cost of each
set of resources consumed by enrolled patients.
Direct costs include health and non-healthcare
resources directly consumed by the surveyed Italian
patients with type A and type B haemophilia in 2012.
Direct health care costs include drugs, outpatient
and inpatient care, and all range of primary care
services. As far as their data source, we used services'
fees because Italy does not have a national healthcare
services' costs data set and we could not run specific
costs' survey. However, we applied region Lombardy's
fees as this region has updated nearly regularly its tariff
set, surveying its providers' costs26. Moreover, as far as
drugs, we have considered Italian Medicines Agency 's
drugs national formulary, reducing by 30% the price of
drugs distributed only by hospitals once they bought
them through tenders. Considering the co-payment
of drugs and outpatient care, we estimated a national
average of regional fees. Last, according to the following
strategy, we estimated the healthcare services fees out
of Italian National Health Service (INHS), paid out of
pocket by patients: we selected a small and a big town
in Northern, Centre and Southern Italy and then we ran
a pricing market analysis.
Direct non healthcare costs comprise socialhealthcare and social services managed at city-council
level: the resulting high fragmentation of these services'
provision has led us to implement again the above
described strategy to collect information on this setting
without national or regional standards. This cost's set
includes not only the formal care (i.e. provided by
contracted professionals), but also the informal care
provided by relatives and friends. We have applied the
proxy good approach to value these resources, then we
have considered if he/she did not provide these services,
he/she would need to be replaced by another person who
could provide the necessary care, applying the average
Blood Transfus 2014; 12 Suppl 3: s567-75 DOI 10.2450/2014.0042-14s
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Costs, quality of life of Italian patients with haemophilia
hour wage of contracted professionals27.
According to evidences provided by literature on
different amount of consumed resources by adults and
children, we have differentiated costs analysis between
these two populations.
Indirect costs refer to the output lost by society
because of cessation or reduction of productivity (i.e.
productivity loss) resulting from morbidity, or disability
brought on by the disease. We have collected the
following information about patients and caregivers
through the questionnaire: i. the working days and the
hours per day lost because of disease, and ii. the age
of their possible early retirement. Therefore, we have
estimated the productivity loss of both patients and
caregivers, considering both the sick leaves of both
patient and caregiver as well as the economic impact
of an early retirement. We have applied the human
capital approach28, valuing the amounts of days and
hours of sick leaves by the per hour Italian average
wage, according to 2012 Eurostat estimation. Moreover,
we have estimated the charge of early retirement by
valuing the lost gain from retirement contributions of
the working years out of the job market according to
Eurostat, and the public expenditure because of the early
pension's provision based on National Social Insurance
Agency (INPS - Istituto Nazionale della Previdenza
Sociale) data set.
QoL's materials and methods
EuroQoL (EQ-5D) was adopted to evaluate the
QoL. EQ-5D is applicable to a wide range of medical
conditions and treatment and generates a health
profile (EQ profile) consisting of 5 domains (mobility,
self-care, anxiety/depression, usual activities, and
pain/discomfort). For adult and caregivers
EQ-5D-5L with 5 levels ("no problem", "some or
moderate problems", "extreme problems/impossible to
do") was administrated. For children (under 18 years
old), the EQ-5D-Y-3L (children version) with 3 level
was used ("no problems", "some problems", "extreme
problems"). A visual analogue scale (EQ-VAS) scores
the overall QoL from 0 (the worst imaginable health
status) to 100 (the best imaginable health status).
Results from the EQ profile can be converted to utility
index, suitable for economic evaluations, by means of
an algorithm that uses population-based (social) values.
Because specific conversion values for the Italian
population are not available yet, we have converted
our EQ profile results in EQ utility index, running the
algorithm with values from Spain29.
Statistical analysis
Since it was planned to enrol all patients with
haemophilia registered in FedEmo's patients
organisations, no sample size calculation was performed.
For cost analysis we used means and central tendency
parameters, generally expressed as mean cost per patient
per year, because this parameter can be easily used for
policy maker. We reported the standard deviations as
a variability measure. Costs were stratified according
to their categories. Descriptive analyses were applied
also to define health status measurements variables and
QoL separately for adult, children and caregivers. It was
convenient to reclassify the EQ-5D-5L and EQ-5D-Y-3L
levels into 'no problems' (i.e. level 1) and "problems"
(i.e. levels 2 to 5 for EQ-5D-5L and level 2 to 3 for
EQ-5D-Y-3L). For categorical measures, statistical
significance was determined by using chi-squared test.
The one-way analysis of variance (ANOVA) was used to
determine whether there were any significant differences
between the means of two or more independent
(unrelated) groups. Intra class correlation between
ranked (ordinal) data, such as EQ-5D, was determined
by means of Spearman's correlation coefficients
(correlations >r=0.4 were considered relevant).
A multiple linear regression was ran in order to assess
the relationship between the patients' total costs without
drugs (dependent variable) and patients' age and EQ-5D.
We tested a possible non-linear (quadratic) relationship
for both independent variables and we controlled for
drugs costs and age of diagnosis. Moreover, based on
estimation results, we ran a two-way simulation analysis
to evaluate the joint impact of every pair of age and
EQ-5D on costs, all other things being equal. We let
both independent variables to range between 0 and 100
in order to capture every possible combination of the
two, also including out-of-sample values. Descriptive
analyses were performed using SPSS version 21.0
software. Regression analysis and two-way simulation
analysis were performed using Stata, release 12.
Statistical significance was set up at p<0.05 where
sample size permitted.
Results
Characteristics of the sample
A total of 134 questionnaires were collected, 45
of which were excluded because of insufficient or
inadequate provided information. The valid sample
consisted of 89 patients and 17 caregivers.
The mean age was 42.3 (SD±13.0;) years old for
adults, 8.0 (SD±4,6) for children and 40.7 (SD±16.0)
for careers. Only 3 patients more than 65 years old
were enrolled in this study. The main characteristics of
patients are shown in Table I.
The majority of patients were adults (75.3%) with
haemophilia A (79.8%). Ninety-nine per cent of adult
patients were married. 82% of patients had a mediumhigh educational level. Sixty percent of adult patients
Blood Transfus 2014; 12 Suppl 3: s567-75 DOI 10.2450/2014.0042-14s
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Kodra Y et al
were employed at the moment of the survey (Table I).
Table I - Socio-demographical sample characteristics of
patients.
Patient sample (n=89)
Value
Age, n (%)
Child (2-17 years old)
Adult (≥18 years old)
22 (24.7)
67 (75.3)
Frequency, n (%)1
Patients with Haemophilia A
Patients with Haemophilia B
71 (79.8)
15 (16.9)
Married/with a partner2
60 (90.9)
Education level
Medium-high (for adult patients)
Schooled in an ordinary centre (for children 7-17 years)
55 (82.1)
13 (100)
Need for career n (%)
21 (23.3)
Employment status (for adult patients) n (%)
1
40 (59.7)
Three values were missing; Calculation is made only for adult.
2
QoL results
On average, QoL was worse in adult patients
compared to child and career according to EQ-VAS
(ANOVA; p=0.000) (Table II).
Table II - EQ-VAS value and EQ utility index by different
study group categories.
N.
Mean EQ-VAS
(DS)
EQ utility index
(DS)
P value
Child
13
92.8 (7.5)
0.78 (0.43)
0.0000
Adult
60
68.7 (18.8)
0.69 (0.25)
Caregivers
16
83.1 (14.9)
0.95 (0.62)
Total
89
74.8 (19.2)
0.70 (0.28)
1
17 values are missing.
1
For adult patients with haemophilia, EQ-VAS score
was lower than in general population (Mean=75.8;
SD±16.6; Catalonian conversion values29). For children
patients non value sets are available for comparison.
QOL domains by adult, caregivers and child
subjects were examined at a descriptive level
(Table III). More than 75% of adult patients had
problems in the physical sphere, specifically for mobility
(75%) and pain/discomfort (76.7%). 43.3% of adult
patients and 53.9% of parents had anxiety problems.
For mobility, usual activities and pain/discomfort, the
proportions were significantly different between study
group. No differences were verified in self-care and
anxiety dimension (Table III).
Costs results
Assuming a society perspective, the estimated
average annual total cost per person in 2012 is
117,731.72 € (Table IV).
The set of direct healthcare costs is the main driver
requiring yearly in average 109,768.70 € per person:
specifically, the item drugs is the 98% of this latest
and the 92 % of the whole cost in absolute value. The
children annual average costs of drugs is higher than
adults (130,649.40 € vs 100,649.80 €). Moreover, as we
have a very high standard deviation, we have set classes
of average annual costs: in this perspective, the 55% of
children patients have a drugs cost greater than 200,000
€ vs the 38% of adult patients.
Excluding haematologic visits, adults (29% is 49 years
old over) required an average of 3.89 specialist visits in
six months while children needed 2.04 specialist visits
in the same period of time. Adults most often required
specialist visit by cardiologist, surgeon, orthopedist and
dentist. Both adults and children shared a high level of
access to physiotherapy sessions (data not shown).
Direct non healthcare costs (in average 5,223.08
€) represent the 4.4% of the total costs -in absolute
Table III - Proportion of "problem" and "no problem" by EQ dimensions and by adults, children and caregivers.
Adult
Mobility
Self-care
Usual activities
Pain/discomfort
Anxiety/depression
Child
Caregivers
p value
n.
%
n.
%
n.
%
No problems
15
25.0
10
76.9
5
38.5
Problems
45
75.0
3
23.1
8
61.5
No problems
36
60.0
12
92.3
7
53.8
Problems
24
40.0
1
7.7
6
46.2
No problems
22
36.7
12
92.3
7
53.8
Problems
38
63.3
1
7.7
6
46.2
No problems
14
23.3
11
84.6
6
46.1
Problems
46
76.7
2
15.4
7
53.9
No problems
34
56.7
11
84.6
6
46.1
Problems
26
43.3
2
15.4
7
53.9
0.000
0.1
0.001
0.000
0.3
Blood Transfus 2014; 12 Suppl 3: s567-75 DOI 10.2450/2014.0042-14s
s570
Total
880.17
€
21.32
0.00%
€
€
€
€ 114,991.78
Secondary caregivers
No healthcare transportation
Subtotal
Total direct costs (Direct
HC Costs and Direct Non
HC costs)
991.38
2,739.94
€
€
€ 117,731.72
Loss of labour productivity
carers (sick leave and early
retirement
Subtotal
Total costs
€ 98,013.37
€ 7,241.01
100%
€ 108,750.30
100%
2,320.01
31.46
2,288.55
€
€
€
2.33%
0.84%
1.49%
36.18%
0.00%
1,748.56
€
3,285.07
132.24
-
2,961.57
2,961.57
191.26
€ 106,430.31
€
€
€
€
€
4.44%
€
€ 5,904.85
4.59
59.51
587.29
786.15
995.99
61.91
€ 103,145.24
€
€
€
€
€
€
€ 100,649.80
Mean
97.67%
0.09%
0.36%
3.85%
Loss of labour productivity
patients (sick leave and early
retirement)
63.82%
100%
€ 20,815.10
€ 4,495.55
2.00%
8.14%
86.82%
231.59
€
€ 2,266.51
€ 20,153.44
94.96%
Indirect costs
5,223.08
104.43
425.16
4,534.76
€
Main caregivers
€ 22,419.95
4.21%
4,959.92
3.04%
€
535.39
Caregiver's time costs
(informal care)
€
0.13%
93.24%
0.00%
100%
0.00%
0.38%
0.05%
158.72
€ 96164.64
0.41%
0.05%
0.75%
0.51%
€
3.51
€
€ 109,768.70
Healthcare transportation
Subtotal
137.38
€ 1,510.65
€
0.80%
0.55%
0.04%
91.50%
% per
total
costs
Social services
54.46
€ 1,556.10
€ 1,582.75
0.05%
98.14%
% cost
category
Direct non healthcare costs
448.72
€
€
600.65
Devices
Primary care
Acute hospitalization
€
€
Specialistic visits
160.56
€
€
Tests
52.89
€ 95,866.80
€ 107,728.30
SD
Drugs
Direct health care costs
Mean
24.34
139.51
1,707.27
1,772.65
1,747.58
182.30
601.42
258.96
5,132.52
259.42
5,028.93
€ 96,133.36
€
€
€
€ 21,237.26
€
€
€ 21,092.40
€ 21,092.40
€
€ 103,145.24
€
€
€
€
€
€
€ 96,513.22
SD
Adult
100%
1.36%
98.64%
100%
4.03%
0.00%
90.15%
90.15%
5.82%
100%
0.00%
0.06%
0.57%
0.76%
0.97%
0.06%
97.58%
% cost
category
100%
2.13%
0.03%
2.10%
0.00%
97.87%
3.02%
0.12%
0.00%
2.72%
2.72%
0.18%
0.00%
94.85%
0.00%
0.05%
0.54%
0.72%
0.92%
0.06%
92.55%
% per
total
costs
-
38.10
-
-
505.14
23.67
53.33
11,498.54
14.40
1,801.88
9,628.92
4,099.70
4,099.70
-
€ 146,814.60
€
€
€
€ 142,714.84
€
€
€
€
€ 11,430.80
€
€ 131,216.30
€
€
€
€
€
€
€ 130,649.40
Mean
11,828.46
11,828.46
-
18,475.38
14.52
4,471.95
16,157.54
20,629.49
185.08
92,400.97
-
132.20
-
-
479.63
30.45
92,257.03
€ 100,733.90
€
€
€
€
€
€
€
€
€
€
€
€
€
€
€
€
€
SD
Children
100%
100%
0.00%
100%
0.13%
15.67%
83.74%
99.41%
0.46%
100%
0.00%
0.03%
0.00%
0.00%
0.38%
0.02%
99.57%
% cost
category
100%
2.79%
2.79%
0.00%
0.00%
97.21%
7.83%
0.01%
1.23%
6.56%
7.79%
0.04%
0.00%
89.38%
0.00%
0.03%
0.00%
0.00%
0.34%
0.02%
88.99%
% per
total
costs
Table IV - Total and percent distribution of direct health care, non health care and indirect costs per patient with haemophilia by adult and paediatric populations, in 2012,
in Italy.
Costs, quality of life of Italian patients with haemophilia
Blood Transfus 2014; 12 Suppl 3: s567-75 DOI 10.2450/2014.0042-14s
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Kodra Y et al
values- and the most relevant category is the informal
care (95%). Specifically, the 23.6% of hemophilic
patients surveyed state a need of care and -except oneall of them have an informal care: specifically, the 57%
of children require this service vs the 13% of adult
patients, moreover these latest do not need a secondary
caregiver. As not all caregivers of adult patients provided
the required data to value their time, the related results
give poor information. Therefore, we focus on children
informal care: in this case, the annual average cost of the
main caregiver is 9,628.92 € and that one of secondary
caregivers is 1,801.88 €.
As far as the other items of non healthcare costs,
these include social services and non healthcare transport
which represent respectively the 3% and the 2% of total
costs. In this case, adults are the greater consumer of
these services.
Lastly, indirect costs include the loss of productivity
by patients and caregivers because of sick leave or
early retirement. Thirty-four percent of the patients
interviewed stated that their labour productivity had
decreased in the previous six months because of the
disease: specifically, they had an average 38 days of
sick leaves a/o they worked in average two hours less
per day. Moreover, the 58% of the retired patients
did it earlier than the proper retirement age. As far as
caregivers, the average number of lost working days
was 78 in the previous six months and the average
lost working hours were daily 4. Therefore, the annual
average value of productivity loss is 2,739.94 € (2% of
total costs). This aggregated value requires also to be
differentiated between adults and children as the main
cost driver of the earliest group is the productivity loss
of patients (98%) while the main one of children is of
course the productivity loss of caregivers equal to the
annual average value of € 4,099.70.
The regression of costs without the drugs item on a
set of independent variables already described allows
us to investigate on the relationship running between
the total costs and patients' age and Qol, controlling for
drugs' costs and age of diagnosis (Table V).
The relationship between EQ-5D and costs without
drugs is linear (the quadratic term is not significant)
while the quadratic hypothesis is supported for age. In
particular, whatever the age, each additional point of
EQ-5D implies a reduction in costs of 279 €. A withinsample simulation based on this regression shows that
in our sample the 95% confidence interval of EQ-5D
is 68.39-77.55, implying a cost-variability of 2,556 €,
after controlling for age. Considering the impact of age,
whatever the level of EQ-5D, the effect varies across
age levels. Starting from an age of 0, an increase by one
year implies a cost reduction of 618 €. However this
impact is attenuated by 13.27 € every additional year
of starting. Therefore the effect of an additional year
between an age of 3 and 4 is obtainable from the first
order derivative calculated at 3 year and which is −618 €
+(3 years×13.27 €)= −578 € (where 13.27 = 2×6.64, the
coefficient of the squared term). The minimum point of
the parabola is found at the age of 46.6 years old. After
that point the impact of age becomes positive, i.e. every
additional age makes costs increase. For example, the
impact of an additional year between the ages of 55 and
56 is −618 €+(55 years×13.27 €)= +112 € (Figure 1).
Discussion
The BURQoL-RD study on haemophilia provides an
update of patients' QoL, and for the first time in Italy
offers an estimation of average total unit cost in the
society perspective. This study also shows that there is
a significant relationship between both age and QoL,
and costs other than drugs. Moreover, our results are
consistent with literature on drugs as the main cost driver
of haemophilic patients' expenses.
These results are relevant because they contribute
to further analyse two evidences highlighted by the
scientific literature: the treatment strategy's change that
occurred in these last years (i.e. the switch from ondemand to prophylaxis based treatment and the factor
replacement) and the increase of patients' QoL and life
expectancy provided by a greatly improved patient's
management.
We have used the overall costs other than drugs
because of three reasons. Firstly, the BURQoL-RD
Table V - Correlation between EQ 5D, total costs, patients' age, age of diagnosis, and total costs other than drugs:
multilinear-regression model (n=68)*.
Independent variable
Coefficient
Standard error
t
P value
95% Confidence Interval
EQ 5D
−279.4714
64.77232
−4.31
0.000
−408.9916; −149.9511
Drugs costs
.0004994
.0093903
0.05
0.958
−.0182777; .0192765
Patients' age
−618.0774
208.6071
−2.96
0.004
−1035.213; −200.9416
Squared patients'age
6.636786
2.776952
2.39
0.020
1.083927; 12.18964
Age of diagnosis
−154.6141
138.5862
−1.12
0.269
−431.7343; 122.506
*Prob>F=0.0000; Root MSE=6682.3; F(6, 61)=7.56; R-squared=0.3102
Blood Transfus 2014; 12 Suppl 3: s567-75 DOI 10.2450/2014.0042-14s
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Costs, quality of life of Italian patients with haemophilia
Figure 1 - Trend of costs other than drugs correlated to QoL and age.
project provides data on drugs consumption and their
valorisation, however information on patients' severity
and the related treatment plans are not available,
restricting the possible interpretation of drugs' data.
Secondly, the core of the treatment strategy's change
is the switch from on-demand to prophylaxis based
treatment along with new drugs' use: this substitution
may imply that the patient's consumption of drugs
does not change for long whiles, making drugs' cost no
more a fully variable cost over time. Last, even if costs
other than drugs represent a small quota of total costs,
they have been poorly investigated up to now and their
analysis allows to enlighten relevant aspects with respect
to the trends we are addressing.
The first evidence to consider is the positive
impact of new treatment's strategies on patients' QoL:
this is a consolidated evidence in both type A and B
haemophilia30,31 even if it implies a relevant increase of
costs and the debate on the related cost-effectiveness,
usually in a third-payer perspective, is still open32.
Hence, as we have in hand both direct and indirect
costs of this Italian patients' sample, we have tested the
impact of a possible QoL improvement on this set of
costs, excluding the drug ones: this is a step towards
estimating how much the new drugs' greater costs are
offset by a decrease of other costs' items33,34. The result
is that every EQ-5D point added implies a quota of
decreased total costs other than drugs: therefore, an
improved QoL has an impact not only on the patient's
life, but also on consumed healthcare and non healthcare
resources related to the disease by these patients and
on their capacity to contribute positively to the socialeconomic system where they live.
The second evidence concerns the increased life
expectancy that also Italian haemophilic population has
experienced2. Specific guidelines and clinical pathways
to manage the comorbidities, complications and
management aspects are needed now that haemophiliac
patients' are getting older35-37. However, it seems that
poor attention has been paid to the impact on costs of
this aging process. Hence, we have found a significant
relationship between age and total costs other than
drugs and moreover we have simulated the trend of
this set of costs over the patients' whole life cycle.
The main finding is that costs other than drugs for
haemophilic population follow the same trend of the
general population38 or people with diabetes39: costs are
at their highest level in the very first years of life and
then they decrease up to the age of nearly 46 years old
when they start to increase again. Moreover, we have
Blood Transfus 2014; 12 Suppl 3: s567-75 DOI 10.2450/2014.0042-14s
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Kodra Y et al
identified the main driver of costs other than drugs
according to the population age: as far as children, the
most relevant item of cost is the informal care provided
by parents and their related productivity loss that it had
never been estimated previously in Italy. In adults, the
driver is not only hospitalisation, but also specialist visits
including a significant quota of cardiology, dentist and
ophthalmologist visits, and these results are consistent
with the literature above mentioned.
Although this study provides valuable insights into
the QoL and the costs of patients with haemophilia and
their caregivers, there are some limitations that warrant
mention. Both the sample and the recruitment process
limit the external validity of the study. A limit of this study
is the costs' data source. As far as healthcare services
provided by INHS, we have valued them by tariffs
which are a costs' proxy, however we have selected the
Region Lombardy's ones as they are the most regularly
updated according to costs' surveyed at providers. A
further problem has been to identify the fees of services
provided out of INHS coverage: unfortunately, there
are not updated price lists determined by professionals
associations and then we resorted to a sort of market
survey. A similar difficulty has risen about the social
services supplied by the city councils and possibly by
Local Healthcare Units when an healthcare expertise is
required: the fragmentation level prevents to provide
any national or regional average. Therefore, we have
implemented a spot survey considering the geographical
variability and the size of the city council involved.
A further drawback of the study is that the disease
severity and treatment were not recorded, limiting
our ability for additional stratification by variables of
interest. We categorize participants only in terms of
disability level. Considering the low level of disability,
probably our sample reflects a more motivated and less
disabled patient/caregiver population.
As BURQoL-RD project comprised other RDs and
aimed to possible comparison with general population,
to measure the QoL we did not use disease specific
instruments for haemophilia.
loss of productivity of informal carers that has to be
considered. Finally, the ageing of haemophilic population
beyond previous life expectancy limits is posing new
challenges to the health care systems requiring planning
of resources and health care provisions.
Funding and resources
This deliverable arises from the project "Social
Economic Burden and Health Related Quality of
Life in Patients with Rare Diseases in Europe" which
has received funding under the 2 nd Programme of
Community Action in the Field of Public Health.
The Authors declare no conflict of interest.
References
1)
2)
3)
4)
5)
6)
7)
8)
9)
Conclusions
The BURQoL study on Italian haemophilic patients
provides the first estimation of total costs in the society's
perspective that can be of value to policy-makers. The
QoL increase in haemophilic patients implies both a life's
improvement and a decrease in the overall costs other
than drugs: even if we do not have yet evidence that the
new drugs' increased costs may be offset by the other
costs' reduction, the drugs' costs extent over the total
ones suggests that only a partial offset might be possible.
A second evidence concerns the charge's level of informal
care supplied to haemophilic children and the related
10)
11)
12)
13)
Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al.
Treatment Guidelines Working Group on Behalf of The World
Federation Of Haemophilia. Guidelines for the management
of haemophilia. Haemophilia 2013; 19: e1-47.
Abbonizio A, Giampaolo A, Arcieri R, et al. Registro
Nazionale delle Coagulopatie Congenite. Rapporto 2011.
Rapporti ISTISAN 2012; 55/12: iii, p 63.
Italian Association of Haemophilia Centres (AICE).
Individuals with Factor VIII Deficiency and Individuals with
Factor IX Deficiency. Data Summaries 2012 Dec. Available at:
http://www.aiceonline.it/emocard/summaries.htm. Accessed
on 20/01/2014.
von Mackensen S, Gringeri A, Siboni SM,et al. Health-related
quality of life and psychological well-being in elderly patients
with haemophilia. Haemophilia 2012; 18: 345-52.
Tagliaferri A, Rivolta GF, Iorio A, et al. Mortality and causes
of death in Italian persons with haemophilia, 1990-2007.
Haemophilia 2010; 16: 437-46.
Klamroth R, Pollmann H, Hermans C, et al. The relative
burden of haemophilia A and the impact of target joint
development on health-related quality of life: results from
the ADVATE Post-Authorization Safety Surveillance (PASS)
study. Haemophilia 2011; 17: 412.
Gringeri A, Mantovani LG, Scalone L, et al. for the COCIS
Study Group. Cost of care and quality of life for patients
with hemophilia complicated by inhibitors: the COCIS Study
Group. Blood 2003; 102: 2358-63.
Naraine VS, Risebrough NA, Oh P, et al. Health-related
quality-of-life treatments for severe haemophilia: utility
measurements using the Standard Gamble technique.
Haemophilia 2002; 8: 112-120.
Franchini M, Mannucci PM. Co-morbidities and quality of
life in elderly persons with haemophilia. Br J Haematol.
2010; 148: 522-33.
Gringeri A, von Mackensen S, Auerswald G, et al. Health
status and health-related quality of life of children with
haemophilia from six West European countries. Haemophilia
2004; 10 (Suppl 1): 26-33.
Pollak E, Mühlan H, von Mackensen S, et al. The Haemo-QoL
Index: developing a short measure for health-related quality of
life assessment in children and adolescents with haemophilia.
Haemophilia 2006; 12: 384-92.
Szende A, Schramm W, Flood E, et al. Health-related quality of
life assessment in adult haemophilia patients: a systematic review
and evaluation of instruments. Haemophilia 2003; 9: 678-87.
Beeton K, Neal D, Watson T, Lee CA. Parents of children
with haemophilia - a transforming experience. Haemophilia
2007; 13: 570-9.
Blood Transfus 2014; 12 Suppl 3: s567-75 DOI 10.2450/2014.0042-14s
s574
Costs, quality of life of Italian patients with haemophilia
14) Wiedebusch S, Pollmann H, Siegmund B, Muthny FA. Quality
of life, psychosocial strains and coping in parents of children
with haemophilia. Haemophilia 2008; 14: 1014-22.
15) Shaw D, Riley GA. The impact on parents of developments
in the care of children with bleeding disorders. Haemophilia
2008; 14: 65-7.
16) Gringeri A, Mantovani LG, Scalone L, et al. Cost of care
and quality of life for patients with hemophilia complicated
by inhibitors: the COCIS Study Group. Blood. 2003; 102:
2358-63.
17) Miners AH, Sabin CA, Tolley KH, et al. Cost-utility analysis
of primary prophylaxis versus treatment on-demand for
individuals with severe haemophilia. Pharmacoeconomics
2002; 20: 759-74.
18) Steen Carlsson K, Höjgård S, Glomstein A, et al. On-demand
vs. prophylactic treatment for severe haemophilia in Norway
and Sweden: differences in treatment characteristics and
outcome. Haemophilia 2003; 9: 555-66.
19) Odeyemi IAO, Guest JF. Modelling the economic impact
of recombinant activated factor VII compared and activated
prothrombin-complex concentrate in the home treatment of
a mild to moderate bleed in adults with inhibitors to clotting
factors VIII and IX at a comprehensive care centre in the UK.
Journal of Medical Economics 2002; 5: 119-33.
20) Auerswald G, Von Depka Prondzinski M, Ehlken B, et al.
Treatment patterns and cost-of-illness of severe haemophilia
in patients with inhibitors in Germany. Haemophilia 2004;
10: 499-508.
21) Globe DR, Curtis RG, Koerper MA, HUGS Steering
Committee. Utilization of care in haemophilia: a resourcebased method for cost analysis from the Haemophilia
Utilization Group Study (HUGS). Haemophilia 2004; 10
(Suppl 1): 63-70.
22) Nerich V, Tissot E, Faradji A, et al. Cost-of-illness study
of severe haemophilia A and B in five French haemophilia
treatment centres. Pharm World Sci 2008; 30: 287-92.
23) Johnson K, Zheng Yi K. Costs of Care in Hemophilia and
Possible Implications of Health Care Reform. ASH Education
Book. December 10, 2011; vol. 2011 no. 1: 413-8.
24) Scalone L, Gringeri A, Von Mackensen S, et al. Quality o of
life in haemophilic patients without inhibitors: the COCHE
Study. Value in Health 2005; 8: A14.
25) Tarricone R. Cost-of-illness analysis: What room in health
economics? Health Policy 2006; 77: 51-63.
26) Bartoli S, Cantù E. Le analisi dei costi per la determinazione
delle tariffe: esperienze regionali a confronto. In: Cantù E.
editor. Rapporto OASI 2009. L'aziendalizzazione della sanità
in Italia. Milan: Egea; 2009; 221-48.
27) Van der Berg B, Brouwe B, Koopmanschap M. Economic
valuation of informal care: an overview of methods and
application. Eur J Health Ec 2004; 5: 36-45.
28) Drummond M, Sculpher MJ, Torrance GW, et al. Methods
for economic Evaluation of Health Care Programmes 3th ed.
Oxford University Press, Oxford 2005.
29) Badia X, Roset M, Herdman M, Kind P. A comparison of
United Kingdom and Spanish general population time tradeoff values for EQ-5D health states. Med Decis Making. 2001;
21: 7-16.
30) Gringeri A, Leissinger C, Cortesi PA, et al. Health-related
quality of life in patients with haemophilia and inhibitors on
prophylaxis with anti-inhibitor complex concentrate: results
from the Pro-FEIBA study. Haemophilia 2013; 19: 736-43.
31) Windyga J, Indyga VW, Lin J, et al. Improvement in healthrelated quality of life with recombinant factor IX prophylaxis
in severe or moderately. Haemophilia 2013; 20: 1-7.
32) Farrugia A, Cassar J, Kimber K et al. Treatment for life for
severe haemophilia A. A cost-utility model for prophylaxis
vs. on-demand treatment. Haemophilia 2013; 19: e228-38.
33) Lichtenberg FR. Effects of New Drugs on Overall
Health Spending: Frank Lichtenberg responds. Health Aff
(Millwood). 2007; 26: 887-90.
34) Santerre RE. National and international tests of the new
drug cost offset theory. Southern Economic Journal 2011;
77: 1033-43.
35) Mannucci PM, Schutgens REG, Santagostino E, MauserBunschoten EP. How I treat age-related morbidities in elderly
persons with hemophilia. Blood 2009; 114: 5256-63.
36) Konkle BA. The aging patient with hemophilia. Am J Hematol.
2012; 87 (Suppl 1): S27-32.
37) Philipp C. The aging patient with hemophilia: complications,
comorbidities, and management issues. Hematology Am Soc
Hematol Educ Program. 2010; 2010: 191-6.
38) Ministry of Economy and Finance. Tendenze di medio lungo
periodo del sistema pensionistico e socio-sanitario 2013.
Ragioneria Generale dello Stato 2013 May; Rapporto n. 14.
Available at:http://www.rgs.mef.gov.it/VERSIONE-I/Attivit-i/Spesa-soci/Attivita_di_previsione_RGS/2013. Accessed
on 30/01/2014.
39) Diabetes American Association. Economic Costs of Diabetes
in the U.S. in 2012. Diabetes Care. 2013; 36: 1033-46.
Correspondence: Yllka Kodra
Italian National Centre for Rare Diseases
National Institute of Health
Via Giano della Bella 34
00162 Rome, Italy
e-mail: yllka.kodra@iss.it
Blood Transfus 2014; 12 Suppl 3: s567-75 DOI 10.2450/2014.0042-14s
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REVIEW
Current status of Italian Registries on inherited bleeding disorders
Hamisa Jane Hassan1, Massimo Morfini2, Domenica Taruscio3, Francesca Abbonizio1, Adele Giampaolo1,
Yllka Kodra3, Emily Oliovecchio2, Luciano Vittozzi3
1
Section of Transfusion Methodologies, Department of Haematology, Oncology and Molecular Medicine, Italian
National Institute of Health, Rome; 2Italian Association of Haemophilia Centres (AICE), Florence, 3National
Centre for Rare Diseases, Italian National Institute of Health, Rome, Italy
Introduction
Inherited bleeding disorders are a group of congenital
coagulopathies resulting when deficiencies of the
proteins responsible for coagulation, platelet function
or fibrinolysis occur. Haemophilia A (HA, deficiency
of factor VIII), Haemophilia B (HB, deficiency of
factor IX) and von Willebrand Disease (vWD) are the
most frequent, being >90% of all inherited bleeding
disorders with a prevalence of 0.5, 0.1 and 1-5/10,000
respectively1-3. Other rare inherited bleeding disorders
are represented by deficiencies of factor I, II, V, VII,
X, XI, XII, XIII, combined V+VIII, combined vitamin
K-dependent factors, with a general population
prevalence between 1/500,000 and 1/2,000,000 4.
Inherited bleeding disorders require wide-ranging care
and effective management within a multidisciplinary
team setting. The modern treatments of inherited
bleeding disorders are now remarkably effective,
although expensive.
In Italy the epidemiological data on inherited
bleeding disorders derive from three registries:
1) The Italian National Registry for Rare Diseases
(RNMR);
2) The National Registry of Congenital Coagulopathies
(RNCC);
3) The Haemophilia Database of the Italian Association
of Haemophilia Centres (AICE).
These registries differ in terms of organisation,
purpose and data collection process. A general description
and results for each registry is reported as follow.
Italian National Registry for Rare diseases
Organisation
The Italian National Registry for Rare Diseases
has been established by law in 2001 (Ministerial
Decree -M.D. n. 279/2001)5, and it is located at the
National Centre for Rare Diseases (NCRD) of the
Italian National Institute of Health (Istituto Superiore
di Sanità - ISS). M.D. n. 279/2001 set up a specific
Rare Disease (RD) network dedicated to the prevention,
surveillance, diagnosis and treatment of RD patients,
set out special rules for the assistance of RD patients
and ensured that health services are appropriately
delivered to RD patients. The "RD Network" is made
of formally designated Centres by each Italian region
(FDC), preferably based in hospitals and dedicated to
the management, care, training and information of RD
patients and research on RD. This network provides
data to the RNMR.
The mandate of the RNMR is to inform the national
and regional planning of RD patient care and to collect
demographic, history, clinical, laboratory determinant
data of use for medical, biomedical and epidemiological
research.
The structure of the RNMR is made of three
levels, reflecting the Italian Healthcare System:
local, regional and national level. The local level is
composed by FDC identified in each Region, which
are the primary source of data flow. Clinicians of FDC
collect demographic and clinical data and transmit
them to the regional registries. This is the intermediate
level of data flow. Each regional registry has different
organisational structure, different objectives or aims,
and as a consequence different types of information
(variables) to be collected. The use of the RNMR
central data repository and the related common data
set for the communication of mandatory data from
the regional registries to the RNMR was defined with
two Agreements among State and Regions in 2002
and in 2007. This set includes socio-demographic as
well as disease information of each case: encrypted
patient identification code, date of birth, sex, region of
residence; vital status (with decease date); diagnosis;
RD centre which made the diagnosis; date of disease
onset; date of diagnosis; orphan drug treatment. This
data set is mainly devoted to monitor RD and RD
services at national level. RNMR data are presented
and discussed annually in the national meeting of the
RNMR and regional RD registries and the production
of annual reports has started in 20116.
The RNMR monitors 495 conditions, including
individual RD and groups of RD, which are listed in
the technical annex to M.D. n. 279/2001. In particular,
the following specific conditions of inherited bleeding
disorders are under surveillance: inherited bleeding
disorders, HA, HB, vWD, inherited deficiency of
coagulation factors and platelets.
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© SIMTI Servizi Srl
Italian Registries on inherited bleeding disorders
Results
Up to 30 June 2012, a total of 11,135 notifications
on inherited bleeding disorders have been collected at
RNMR: 7,748 for inherited bleeding disorders; 1,809
for inherited disorders of platelets; 615 for HA; 503
for inherited deficiency of coagulation factors; 367 for
vWD and 93 for HB. Cases ≤18 years represent 13%.
Considerations
The RNMR is a population-based/multi-diseases
registry and consequently an important instrument
of public health, useful for health planning and
epidemiological surveillance.
The strong legal base of the RNMR and the compliance
with the national legal and ethical requirements ensures
stability to the data collection. The future directions of
RNMR are also to support the development of further
clinical registries on specific RD, in order to better
understand the natural history of RD. In fact the NCRD
participates actively in a number of collaborative efforts
with patient associations and networks of clinicians for
the collection and exchange of patient data for specific
RD registries; inherited bleeding disorders are the
subject of a collaboration with the RNCC. Moreover the
RNMR provides important indicators of accessibility
of health care and health service utilisation by patients
with RD.
The RNMR is now implemented in all the Regions
but data quality and completeness still need to be
improved. Indeed, the collaboration with different
registries has shown that case notification is far
from being complete, with considerable variation of
notification rate across the Italian territory. Moreover,
the notification of inherited bleeding disorders in RNMR
uses a non specific terminology, which should be
updated to allow sounder epidemiological observations.
The National Registry of Congenital
Coagulopathies
Organisation
In Italy, haemophilia patients and other persons with
inherited bleeding disorders are monitored by the RNCC
established at the ISS with the collaboration of AICE.
Since 1988 until 1999, at ISS was activated a
Registry aimed in particular to the surveillance of
infectious diseases in the haemophiliac population,
that, at the time, represented the most serious adverse
event in the replacement therapy of inherited bleeding
disorders7,8. After 1999 and so far, the RNCC has been
fed by AICE Database.
Since 2005 a section of the Haematology, Oncology
and Molecular Medicine Department is in charge of
the management of the RNCC: collection, validation,
elaboration and dissemination of the data. The RNCC
was resumed as a specific pathology registry, in a
stringent collaboration with AICE, the Haemophilia
Treatment Centres (HTC) and the Patient's Association
(FedEmo). The epidemiological surveillance of
population with inherited bleeding disorders, treatmentrelated complications and monitoring of needs/
consumption of products utilised in the different regimen
therapies are the main aims of the RNCC9-11.
Data collected in the RNCC are relative to all the 53
Italian Haemophilia Centres, established by Regional
laws, and distributed in the North (49%) Centre (17%)
and South and Islands (34%). They assist the Italian
patients with bleeding disorders with a coverage of
almost 100% of the severe forms. The participation of
the HTC to the RNCC data collection is on voluntary
basis. Data are provided from the local databases to the
national database anonymised and in accordance with
the Italian privacy law and standards.
Information collected in the RNCC are relative to
9,097 validated patients with HA and HB, vWD, other
rare factor deficiencies (fibrinogen and factors II, V,
VII, X, XI, XII, XIII inherited deficiencies), inherited
platelet disorders and haemophilia carriers.
Data are relative to prevalence of inherited bleeding
disorders, treatment-related complications (infectious
diseases and in particular inhibitor development),
needs/consumption of plasma-derived and recombinant
products utilised in the haemophilia replacement
therapy. These variables are available at national and
regional level, by age group and by treatment regimen
(prophylaxis/on demand/immune tolerance induction).
Haemophilia facilities, addresses, contact numbers
and referents of the Centre are indicated and described
in the appendix of the RNCC9.
Data collection is possible through a software,
now substituted by a web-based system, developed
and distributed by AICE to the HTC to assist patient
management. ISS strongly supported the AICE Database
and can access to the information sent by the HTC
being identified by AICE as the national organisation
responsible for the elaboration and diffusion of the
inherited bleeding disorders data.
Information collected are analysed and validated
through a data quality control system aimed to check
the quality of data entry and type of information. In
case of data not compliant the referent of the Centre is
asked to check the information provided for ensuring
the consistency and completeness of patient information
housed.
Since 2007, ISS has activated a specific questionnaire
realised on the basis of the therapeutic treatment plans
that represent the most reliable tool for monitoring the
consumptions12. In fact therapeutic plans establish the
products and doses to be used by patients during the year
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Hassan HJ et al
and are necessary to receive therapy free of charge by
the national public health service. Regimen and products
are defined on a case by case and after informed consent
and sharing between the specialist and the patient.
This direct data flow on treatment product
consumption with the Haemophilia Centres allows to
monitor the needs/consumptions of plasma-derived and
recombinant products necessary for the haemophilia
replacement therapy12.
Data analysed and elaborated by ISS are published in
an annual technical report (ISTISAN Report) distributed
to the National and Regional administrators and to the
HTC that contributed to data collection. RNCC is also
published on the website of the ISS (www.iss.it). Since
2006, the RNCC has been included in the National
Statistic System (SISTAN) that monitors the surveys
of public interest and it is regularly published on the
SISTAN website (www.sistan.it).
Moreover RNCC data are disseminated in the
national meetings relative to rare diseases, published on
international journals and also provided for the enquires
of the Italian Health Ministry and Parliament.
Results
Patient number/Centre, pathology severity,
age, gender, treatment regimen and annual product
consumption/patient are the main markers utilised in
the data analyses.
In 2012 the total number of validated patients
included in the RNCC was 9,097, in particular 3,696
with HA (46% with severe HA), 744 with HB (37%
with severe HB), 2,212 with vWD (4% with the severe
type 3), 1,524 with other rare deficiencies (39% factor
VII and 24% factor XI deficiencies). In 2012, the Italian
prevalence of HA and HB was 6.1/100,000 inhabitants
and 1.2/100,000 inhabitants, respectively.
The severe HA patients were 1,698 in total; 18% of
these was registered as previously or currently positive
to inhibitor. The incidence of inhibitor in severe HA
patients was about 30% in 0-2 years.
The estimated amount of factor VIII utilised in
the HA replacement therapy and factor IX for the HB
therapy was 450,000,000 of International Units (IU) and
55,000,000 of IU respectively; in both cases 80% was
represented by recombinant products.
Considerations
The Word Federation of Haemophilia (WFH)
recommends the development of national patient
registries through the collaboration between national
patient organisations, healthcare professionals, treatment
Centres and ministries of health13. The availability of a
pathology specific Registry at national level improves
the knowledge of the disease in terms of epidemiology,
correlated diseases, care requirements, resources
and new therapeutic strategies. The Italian RNCC
corresponds to the requirements of the WFH allowing
to provide reliable Italian data to international database.
There is the need to have a more efficient registration
system in order to eliminate any redundancy in patient
records and to make data collection in real time. Data
collection, in particular on home therapy, requires the
primary collaboration of the Patient's Association. The
absence of specific national regulation and funding for
the improvement of the RNCC is a limit that should be
overcome.
The Haemophilia Database of the Italian
Association of Haemophilia Centres
Organisation
The Haemophilia Database was developed within
the AICE since 2003, in accordance with the main
objectives of AICE to prompt optimal health care
delivery through the Italian HTC, basic and clinical
research and collection of epidemiological data on
inherited bleeding disorders14. It is completely doctorrun and it is characterised by a voluntary nature about
the contribution in activities of HTC directors, joined
in AICE. Data on patients with haemophilia and allied
bleeding disorders are regularly collected twice a
year. AICE is the owner of the Haemophilia Database.
Furthermore AICE has identified the ISS as the national
organisation in charge of the analysis and the diffusion
of the epidemiological data.
Management software is employed by HC directors
for the data collection of Haemophilia AICE Database.
In 2009 the software has migrated to the web, becoming
web-based (EmoWEB) to improve accessibility,
maintenance and security of users and data. EmoWeb
was also designed to support all the daily activities of
HTC and covers all the relevant fields of haemophilia
management, in order to use it as computerised medical
record.
Every 6 months each HTC director authorises patient
data extraction through an automated procedure that
anonymizes those records.
The Haemophilia AICE Database is regularly
updated with information on patient demographics,
clinical and laboratory phenotypes; after each update
an automatic procedure creates local and national hyper
textual reports. The local reports are related to patients
treated in each HTC.
The national report displays all national data collected
and discloses the Italian situation of haemophilia and
bleeding disorders. All these reports are published in
password-protected pages on the AICE website to allow
HTC directors to check and validate the local reports;
tables with summary data about Italian patients with
Blood Transfus 2014; 12 Suppl 3: s567-75 DOI 10.2450/2014.0017-14s
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Italian Registries on inherited bleeding disorders
inherited bleeding disorders are also published in a
public zone of the AICE website (http://www.aiceonline.
it/emocard/homeRN.htm).
Moreover Haemophilia Registry data are disseminated
during the AICE meeting and used for AICE research
projects. Data are also provided by the technical reports
published at the ISS.
Results
Database is filled by 53 HTC, distributed in the
country. Since 2003 a total of 11,436 patients were
collected, 10,444 after duplicate exclusion. In 2012
9,345 are living patients, 40% with HA, 8% with HB,
24% with vWD and 28% with other bleeding disorders.
The percentages of severe, moderate, and mild
HCV-infected -HA patients are 45%, 37% and 20%
respectively. The percentages of severe, moderate, and
mild HCV-infected -HB patients are 38%, 27% and 12%
respectively. The percentages of HIV infected patients
are: 10% of severe, 4% of moderate, 0.5% of mild HA
and 15% of severe, 5% of moderate, 0.6% of mild HB.
Considerations
The Haemophilia AICE Database, monitoring the
data transmission from each HTC on patients with
haemophilia and other congenital bleeding disorders,
allows to check the HTC participation to the Database
and to evaluate the homogeneity of the patient
haemophilia management at national level.
The same guidelines followed by the Centres allow
to collect harmonised data useful to address clinical
studies. Therefore, the Haemophilia AICE Database
represents a tool aimed to the implementation of
important retrospective and prospective clinical and
scientific studies on specific topics such as cancer,
quality of life and mortality of haemophilia patients15-18.
The goal of these studies is to better understand some
specific aspects on the haemophilia and bleeding
disorders management and to provide more focused
recommendations for treatment and follow-up.
Conclusions
The RNMR, the RNCC and the Haemophilia
AICE Database monitor inherited bleeding disorders
and are already well established, they have many
commonalities but many disparities at the same time
(Table I).
The primary source of data collection for the RNMR
and RNCC is different. The data sources of the RNMR
are FDC, established by regional law and dedicated to
Table I - Comparative data on the bleeding disorders data flow (2012).
National Registry for Rare
Diseases (RNMR)
Institution
National Registry of Congenital
Coagulopathies (RNCC)
Italian Association of Haemophilia
Centres (AICE) Database
By law
Voluntary
Voluntary
Governmental National Institute
Governmental National Institute
Scientific Society
Local Centres of Reference Regional Registries- National RNMR
Local Haemophilia Centres AICE Database - National RNCC
Local Haemophilia Centres - AICE
Database
Rare diseases surveillance
Inherited bleeding disorders
surveillance and drug
consumption monitoring
Clinical and scientific studies on
inherited bleeding disorders
Severe Haemophilia A
No
Yes
Yes
Moderate Haemophilia A
No
Yes
Yes
Mild Haemophilia A
No
Yes
Yes
Total Haemophilia A
Yes
Yes
Yes
Severe Haemophilia B
No
Yes
Yes
Organisation
Data flow
Purpose
Data collected
Moderate Haemophilia B
No
Yes
Yes
Mild Haemophilia B
No
Yes
Yes
Total Haemophilia B
Yes
Yes
Yes
von Willebrand Disease (type 1)
No
Yes
Yes
von Willebrand Disease (type 2)
No
Yes
Yes
von Willebrand Disease (type 3)
No
Yes
Yes
Total von Willebrand Disease
Yes
Yes
Yes
Deficiency of other coagulation factors
Yes
Yes
Yes
Inherited thrombophilic disorders
Yes
No
No
Platelet disorders
No
Yes
Yes
Inherited bleeding disorders
Yes
Yes
Yes
Drug consumption monitoring
No
Yes
No
11.135
9.097
9.345
Total inherited bleeding disorders
Blood Transfus 2014; 12 Suppl 3: s567-75 DOI 10.2450/2014.0017-14s
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Hassan HJ et al
the management of RD; data for the Haemophilia AICE
Database and the RNCC derive from the Italian HTCs,
established by regional law and assisting the Italian
patients with bleeding disorders.
The completeness of the ISS registries is different;
in particular the prevalence of HA and HB, estimated
by the RNMR, is much lower than that reported in the
RNCC. This underreporting probably depends on the
RNMR terminology, in fact the most of patients with HA
and HB are notified as patients with inherited bleeding
disorders, without specifying which bleeding disorder.
Furthermore not all FDC follow patients with bleeding
disorders and are active in sending the relative data.
The epidemiological data about patients with
bleeding disorders, collected in the Haemophilia AICE
Database and the RNCC, are more homogenous than that
collected in the RNMR because the HTC represent the
principal data source for both data collection.
The RNMR, the RNCC and the Haemophilia AICE
Database are not fully interoperable between them
because of different patient identification code and
terminology codification. Interoperability procedures
should be developed in order to obtain data sharing
through standard terminology classification and to
exchange agreed and harmonised data.
The aim of both the ISS registries is patient care and
public health oriented. The RNMR is a multi-diseases
registry, containing 495 rare diseases; every class of
pathology should be further investigated through the
institution of specific disease Registry. The RNCC,
investigating the inherited bleeding disorders, allows a
specific analysis of this group of pathologies and could
represent a model for the institution of other disease
Registries.
The European Commission Communication:
"Rare diseases: Europe's challenge", the subsequent
Council Recommendation19,20 and the WFH emphasize
the strategic importance of Patient Registries and
the development of similar specific registries can
be beneficial also for the knowledge of other rare
pathologies.
The AICE Database is managed by the scientific
association of Haemophilia Centres and is a research
oriented instrument providing data for prospective clinical
studies; epidemiological data are shared with the ISS
for the progress of the RNCC to which AICE strongly
cooperates.
Keywords: registries, rare diseases, inherited bleeding
disorders, haemophilia.
Authorship contribution
Hamisa J. Hassan, Massimo Morfini and Domenica
Taruscio contributed equally to the paper. Hamisa J.
Hassan, Massimo Morfini and Domenica Taruscio are
responsible for i) the National Registry of Congenital
Coagulopathies, ii) the Haemophilia Database and iii)
the National Registry for Rare Diseases, respectively.
Hamisa J. Hassan, Massimo Morfini and Domenica
Taruscio conceived the review.
Francesca Abbonizio, Adele Giampaolo, Yllka
Kodra, Emily Oliovecchio and Luciano Vittozzi
analysed the data and were involved in writing.
The Authors declare no conflicts of interest.
References
1)
Franchini M, Mannucci PM. Hemophilia A in the third
millennium. Blood Reviews 2013; 27: 179-84.
2) Mannucci PM. Treatment of haemophilia: building on strength
in the third millennium. Haemophilia 2011; 17: 1-24.
3) Castaman G, Goodeve A, Eikenboom J on behalf of the
European Group on von Willebrand disease (EUvWD).
Principles of care for the diagnosis and treatment of von
Willebrand disease. Haematologica 2013; 98: 667-74.
4) Mannucci PM, Duga S, Peyvandi F. Recessively inherited
coagulation disorders. Blood 2004; 104: 1243-52.
5) Decreto18 maggio 2001, n. 279. Regolamento di istituzione
della rete nazionale delle malattie rare e di esenzione dalla
partecipazione al costo delle relative prestazioni sanitarie,
ai sensi dell'articolo 5, comma 1, lettera b), del decreto
legislativo 29 aprile 1998, n. 124. (GU n. 160 del 12-7-2001Suppl. Ordinario n.180/L). Available at: http://www.iss.it/
binary/cnmr/cont/DM279-2001.1205943575.pdf. Accessed
on 15/11/2013.
6) Taruscio D. Il Registro Nazionale e i Registri Regionali/
interregionali delle Malattie Rare. Rapporto anno 2011.
(Rapporti ISTISAN 11/20). Roma: Istituto Superiore di
Sanità; 2011. Available at: http://www.iss.it/publ/index.
php?lang=1&id=2529&tipo=5. Accessed on 15/11/2013.
7) Ghirardini A, Schinaia N, Chiarotti F, et al. Registro
Nazionale delle Coagulopatie Congenite in Italia. Rapporto
1990. (Rapporti ISTISAN 91/33). Roma: Istituto Superiore
di Sanità; 1991. Available at: http://www.iss.it/publ/index.
php?lang=1&id=780&tipo=5. Accessed on 15/11/2013.
8) Ghirardini A, Puopolo M, Mannucci PM, et al. Registro
Nazionale dell'Emofilia del Gruppo Italiano Coagulopatie
Congenite (GICC): Rapporto 1993. (Rapporti ISTISAN
94/13). Roma: Istituto Superiore di Sanità; 1994. Available
at: http://www.iss.it/publ/index.php?lang=1&id=688&tipo=5.
Accessed on 15/11/2013.
9) Abbonizio F, Giampaolo A, Arcieri R, et al. Registro
Nazionale delle Coagulopatie Congenite. Rapporto 2011.
(Rapporti ISTISAN 12/55). Roma: Istituto Superiore di
Sanità; 2012. Available at: http://www.iss.it/publ/index.
php?lang=1&id=2681&tipo=5. Accessed on 15/11/2013.
10) Abbonizio F, Giampaolo A, Calizzani G, et al. Registro
Nazionale delle Coagulopatie Congenite. Rapporto 2008.
(Rapporti ISTISAN 10/31). Roma: Istituto Superiore di
Sanità; 2010. Available at: http://www.iss.it/publ/index.
php?lang=1&id=2439&tipo=5. Accessed on 15/11/2013.
11) Abbonizio F, Giampaolo A, Palmieri S, et al. Registro
Nazionale delle Coagulopatie Congenite. Rapporto
2006-2007. (Rapporti ISTISAN 08/46). Roma: Istituto
Superiore di Sanità; 2008. Available at: http://www.iss.
it/publ/index.php?lang=1&id=2269&tipo=5. Accessed
on 15/11/2013.
Blood Transfus 2014; 12 Suppl 3: s567-75 DOI 10.2450/2014.0017-14s
s580
Italian Registries on inherited bleeding disorders
12) Giampaolo A, Abbonizio F, Puopolo M, et al. Consumption
of clotting factors in severe haemophilia patients undergoing
prophylaxis and on-demand treatment in Italy. Transfus Med
2011; 21: 280-4.
13) Evatt BL, Black C, Batorova A, et al. Comprehensive care for
haemophilia around the world. Haemophilia 2004; 10: 9-13.
14) Iorio A, Oliovecchio E, Morfini M, et al. Italian Registry of
Haemophilia and Allied Disorders. Objectives, methodology
and data analysis. Haemophilia 2008, 14: 444–53.
15) Tagliaferri A, Di Perna C, Santoro C, et al. Cancers in patients
with hemophilia: a retrospective study from the Italian
Association of Hemophilia Centers. J Thromb Haemost 2012;
10: 90-5.
16) Tagliaferri A, Rivolta GF, Iorio A, et al. Mortality and causes
of death in Italian persons with haemophilia 1990-2007.
Haemophilia 2010; 16: 437-46.
17) Tagariello G, Iorio A, Santagostino E, et al. Comparison of the
rates of joint arthroplasty in patients with severe factor VIII
and IX deficiency: an index of different clinical severity of the
2 coagulation disorders. Blood 2009; 114: 779-84.
18) Rocca A, Pizzinelli S, Oliovecchio E, et al. Replacement therapy
with recombinant factor IX. A multicentre evaluation of current
dosing practices in Italy. Blood Transfusion 2010; 9: 60-9.
19) Communication from the Commission to the European
Parliament, the Council, the European economic and social
committee and the committee of the regions on rare diseases:
Europe challenges. Commission of the European Communities.
Available at http://ec.europa.eu/health/ph_threats/non_com/
docs/rare_com_en.pdf. Accessed on 15/04/2013.
20) Council Recommendation of 8 June 2009 on an action in the
field of rare diseases. The Council of the European Union.
Available on line at: http://eur-lex.europa.eu/LexUriServ/
LexUriServ.do?uri=OJ:C:2009:151:0007:0010:EN:PDF.
Accessed on 23/08/2013.
Correspondence: Hamisa J. Hassan
Department of Haematology, Oncology and Molecular Medicine
Italian National Institute of Health
Viale Regina Elena 299
00161 Rome, Italy
e-mail: jane.hassan@iss.it
Blood Transfus 2014; 12 Suppl 3: s567-75 DOI 10.2450/2014.0017-14s
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ORIGINAL ARTICLE
Definition of an organisational model for the prevention and reduction of
health and social impacts of inherited bleeding disorders
Gabriele Calizzani1, Ivana Menichini2,3, Fabio Candura1, Monica Lanzoni1,4, Samantha Profili1, Maria
Rita Tamburrini5, Antonio Fortino6, Stefania Vaglio1,7, Giuseppe Marano1, Giuseppina Facco1, Emily
Oliovecchio8,9, Massimo Franchini9,10, Antonio Coppola9,11, Romano Arcieri2, Cinzia Bon12, Marco Saia13,
Sabina Nuti14, Massimo Morfini9, Giancarlo M. Liumbruno1, Giovanni Di Minno9,11, Giuliano Grazzini1
1
National Blood Centre, National Institute of Health, Rome; 2Italian Federation of Haemophilia Societies (FedEmo),
Rome; 3Necstep Studio Associato, Modena; 4IRCCS Ca' Granda Foundation Maggiore Policlinico Hospital, Milan;
5
Blood and Transplant Unit, Ministry of Health, Rome; 6National Institute for Health, Migration and Poverty, Rome;
7
Faculty of Medicine and Psychology, Sapienza University of Rome, Rome; 8Department of Internal Medicine, University
of Perugia, Perugia; 9Italian Association of Haemophilia Centres (AICE), Florence; 10Department of Transfusion Medicine
and Hematology, Carlo Poma Hospital, Mantua; 11Regional Reference Centre for Coagulation Disorders, Federico II
University Hospital, Naples; 12Veneto Region Health Authority, Venice; 13Veneto Region Health Directorate, Venice;
14
Laboratorio Management e Sanità, Istituto di Management, Scuola Superiore Sant'Anna, Pisa, Italy
Introduction. Due to the increase in life expectancy, patients with haemophilia and other inherited
bleeding disorders are experiencing age-related comorbidities that present new challenges. In order to
meet current and emerging needs, a model for healthcare pathways was developed through a project
funded by the Italian Ministry of Health. The project aimed to prevent or reduce the social-health burden
of the disease and its complications.
Material and methods. The National Blood Centre appointed a panel of experts comprising
clinicians, patients, National and Regional Health Authority representatives. Following an analysis of the
scientific and regulatory references, the panel drafted a technical proposal containing recommendations
for Regional Health Authorities, which has been formally submitted to the Ministry of Health. Finally,
a set of indicators to monitor haemophilia care provision has been defined.
Results. In the technical document, the panel of experts proposed the adoption of health policy
recommendations summarised in areas, such as: multidisciplinary integrated approach for optimal
healthcare provision; networking and protocols for emergency care; home therapy; registries/databases;
replacement therapy supply and distribution; recruitment and training of experts in bleeding disorders.
The recommendations became the content of proposal of agreement between the Government and the
Regions. Monitoring and evaluation of haemophilia care through the set of established indicators was
partially performed due to limited available data.
Conclusions. The project provided recommendations for the clinical and organisational management
of patient with haemophilia. A particular concern was given to those areas that play a critical role in the
comorbidities and complications prevention. Recommendations are expected to harmonise healthcare
care delivery across regional networks and building the foundation for the national haemophilia network.
Keywords: haemophilia care, clinical pathway, performance indicators.
Introduction
Inherited bleeding disorders (IBDs) are rare diseases
characterised by hereditary abnormalities of proteins
necessary for blood clotting. Among IBDs, the best known
are haemophilia A, caused by a deficiency of coagulation
factor VIII (FVIII), haemophilia B, also known as
Christmas disease, caused by a deficiency of factor IX
(FIX), and von Willebrand disease (vWD), caused by a
defect or deficiency of von Willebrand factor1.
In persons with haemophilia, although the bleeding
phenotype is recognised to be heterogeneous and affected
by many genetic and environmental factors, the severity of
clinical symptoms is correlated to the residual endogenous
FVIII/FIX concentrations: on the basis of plasma factor
levels below 1 IU/dL, or between 1-5 IU/dL, or between
5-40 IU/dL haemophilia patients are classified respectively
as severe, moderate, and mild2. Thus, patients with severe
haemophilia bleed spontaneously or after trivial trauma.
The most frequently reported bleeding is haemarthrosis,
particularly into joints such as ankle, knee and elbow.
Blood Transfus 2014; 12 Suppl 3: s582-8 DOI 10.2450/2014.0087-14s
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Model for prevention and reduction of impacts of haemophilia
Recurrent episodes may lead to progressive joint morbidity
(haemophilic arthropathy) associated with chronic pain
and disability and often requiring orthopaedic surgery
and joint replacement. Muscles may be also affected.
Other less common symptoms are bleedings involving
soft tissues, mucosae and parenchyma including lifethreatening intracranial, neck-throat and gastro-intestinal
haemorrhages. Patients with moderate haemophilia
experience excessive bleeding after relatively minor
trauma while those with mild haemophilia experience
excessive bleeding in the large majority of cases only in
response to surgery, other invasive procedures or major
injuries3. Bleeding phenotype is more heterogeneous and
not easily predictable by laboratory data in vWD and,
particularly, in rarer IBDs.
Among the clinical complications of haemophilia, the
most dramatic is presently the appearance of inhibitors
against the therapeutically administered factors, which
render the replacement therapy less effective. As a
consequence, an increased bleeding-related morbidity
and a drastic reduction in the quality of life due to the
physical disability caused by hemophilic arthropathy is
reported in inhibitor patients4.
According to the Haemophilia Registry of the Italian
Association of Haemophilia Centres (AICE, Associazione
Italiana Centri Emofilia)5, the total number of patients
suffering from IBDs in Italy was 9,345 in the first semester
of 2013. Of these, 1,746 had severe haemophilia A, 293
had severe haemophilia B, and the remainder had less
severe or rarer defects.
The number of patients suffering from a severe form
of haemophilia A or B, who have an inhibitor history, are
345 and 8, respectively. Of these, 181 and 6, respectively
(10.4 and 2% of the population with a severe form of
haemophilia) have currently detectable inhibitors.
During the 1980s a number of patients were infected
with human immunodeficiency virus (HIV) and
hepatitis C virus (HCV), as a complication of treatment
using non-viral inactivated plasma derived medicinal
products. These infections and the related complications
represented the main cause of death in persons with
haemophilia (PWH) over the last three decades 6.
Currently, 278 (3.1%) HIV-positive, 1,647 (17.9%)
HCV-positive, and 239 HIV-HCV co-infected (2.6%)
living patients suffering from IBDs are registered in Italy.
Nonetheless, life expectancy for PWH has
considerably increased in recent decades as a direct
result of greater and more widespread factor availability
of efficacious and safe both plasma-derived and
recombinant factor products6. This is confirmed through
regular monitoring of more than 30,000 patients with
IBDs via the European Haemophilia Safety Surveillance
(EUHASS) system7.
In Italy, the analysis of death rate trends in the
haemophilic population in the period 1980-2007 showed
a significant reduction in mortality over time. In 2007,
life expectancy was comparable to that of the general
male population, excluding the effects on mortality
related to infection with HIV/HCV. Currently, the main
cause of death is bleeding, thanks to the reduction of the
impact of HIV/HCV-related mortality8.
Thus, as a consequence of the increased lifeexpectancy, the emerging population of middle-aged and
older PWH is experiencing age-related comorbidities
such as cardiovascular diseases, metabolic syndrome,
renal diseases, sexuality issues, malignancies, and
neurologic problems, which have rarely been seen
in this group of patients in the past. These issues
represent new challenges for physicians working in
haemophilia centres (HCs), that are adding to the
clinical complications (arthropathy, chronic infections,
psychosocial problems) routinely managed in the
comprehensive care of these patients9.
In order to satisfy emerging needs, HCs must rely on
specific, specialised clinical skills and resource planning
in order to address important organisational challenges
effectively and efficiently. Timely and effective
interventions for prevention and clinical management
of the disease can result from the definition and
implementation of disease-specific clinical pathways
for patients with IBDs. Moreover, improvements in
the efficiency and sustainability of healthcare services
provision are demanded by the progressive reduction of
the health budget witnessed in recent years.
The objective of this paper is to describe a model for
healthcare pathways for the management of patients with
IBDs; this model was developed by a group of experts
through a three-year project funded by the National
Centre for Disease Prevention and Control (CCM) of the
Italian Ministry of Health in 2010. The project aimed at
the prevention and reduction of the social-health burden
of the disease and its complications.
Materials and methods
The project, coordinated by the Italian National
Blood Centre (NBC, www.centronazionalesangue.
it), involved the Italian Association of Haemophilia
Centres (AICE, www.aiceonline.it), the Federation of
Haemophilia Patient Associations (FedEmo, www.
fedemo.it), the Veneto Region (Regional Agency of
Health - ARSS, http://www2.arssveneto.it/) representing
the Conference of the Italian Regions, and the
Laboratorio Management e Sanità, Istituto di Management,
Scuola Superiore Sant'Anna, Pisa (SSSUP, http://www.
meslab.sssup.it/en/) as partners.
Available scientific evidence was reviewed to identify
best practice in the clinical and organisational management
of haemophilia patients, including clinical pathways.
Blood Transfus 2014; 12 Suppl 3: s582-8 DOI 10.2450/2014.0087-14s
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Calizzani G et al
In addition, an analysis of the current service
provision by haemophilia services was carried out.
The analysis used the results of qualitative and
quantitative surveys carried out by FedEmo10, the pilot
study conducted by SSSUP11 and interviews of experts
from the Project Research Units and to a delegation
of Regional Health Authorities (RHA). Regulatory
frameworks in place in Italy and policies adopted for
the management of rare and chronic diseases were also
taken in consideration.
In this way, all the available scientific and
regulatory references were identified, focusing, in
particular, on organisational requirements included in
the Professional Accreditation Model developed by
AICE and described in detail by Calizzani et al. and
by Mannucci and co-workers12,13.
Finally, a set of indicators to monitor HC activities
was identified. These indicators were used for
performing regional comparisons, in terms of numbers of
patients given access and treated, complexity of diseases
treated, appropriateness of clinical practices, and timely
access of patients with IBDs to the services of a centre11.
The analysis carried out through the application of these
indicators is not the main objective of this manuscript.
Results
In order to tackle the most critical issues that have a
negative effect on patient healthcare management and
to foster the provision of optimal healthcare to PWH,
the panel of experts, through the technical document
produced, proposed the adoption of the following
policies.
a) Multidisciplinary integrated approach for optimal
healthcare provision
According to a patient survey carried out by
FedEmo10, the availability and quality of care vary
widely across Italian Regions, so that 52% of patients
must still travel long distances (101-500 km) for access
to services. In particular, among patients living in
Southern regions and islands (22%) travel more than 500
km, and 40% had to change their residence in order to
attend a HC with an optimal level of care. These data are
partially confirmed by a recent study conducted within
the framework of the CCM project by the Research
Unit SSSUP11. According to the results of the survey,
more than 15% of patients affected by a severe form of
haemophilia are treated by a HC outside the Region in
which the patient lives. At this stage, it is unclear how
much of this phenomenon can be explained by the lack
or poor quality of haemophilia services, by referrals
to more specialised centres that play a tertiary role, or
simply by the patient's choice. However, the study shows
a wide variation within and among Regions in terms of
volumes of activity and organisational models of care11.
In order to address the differences in haemophilia
services provision, an integrated approach to the
healthcare pathway of patients with IBDs should be
developed. The Regions should define an organisational
model of haemophilia healthcare capable to ensuring
integrated services and networking between HCs, both
adult and paediatric ones, and specialised units (e.g.
orthopaedics, physical and rehabilitation therapies,
emergency department, laboratory diagnostics, dentistry,
hepatology-infectious diseases, medical genetics). In
some cases, this organisation will require specific interregional agreements. In particular, Regions should adopt
the following policies.
Regions and Autonomous Provinces should ensure
different levels of complexity of healthcare functions
through IBD accredited HCs 14- 16, which provide
services directly and / or indirectly through facilities /
units functionally related to them. Standards for HCs
have been described in detail elsewhere15. Healthcare
pathways should include pre- and post-natal genetic
diagnosis and genetic counselling, in accordance with
the current legislative framework on rare diseases
(RD) management. Finally, Regions should identify
laboratories that can ensure the provision of coagulation
tests for the diagnosis, treatment, and follow-up of PWH,
as well as for 24-hour emergency services.
15
b) Networking and protocols for emergency care
Although many PWH and their families are trained
in self-administered replacement coagulation factors
therapies, they could, however, need to attend emergency
departments in cases of unexpected bleeding due to
trauma, physical effort, or even following spontaneous
bleeding, regardless of the distance to the emergency
department. Appropriate and timely triage of patients,
as well as the interaction between the emergency staff
and the expert of the HC to ensure the most appropriate
management and timely administration of coagulation
factors has been proven to be crucial in order to prevent
immediate, sometimes life-threatening, and long-term
complications17.
In order to deal with these issues, the panel of
experts proposed to the Regions to define, with the
support of inter-regional agreements, the organisation
of the HC network to ensure a 24-hour management
of haemorrhagic emergencies and the availability of
phone consultations with experts in IBDs. In addition,
Regions are prompted to share protocols between their
emergency units and their HC networks to achieve an
effective and proper emergency management of patients
within the regional territory. These protocols should
contain guidelines on the assignment of proper triage
codes and emergency treatment procedures.
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Model for prevention and reduction of impacts of haemophilia
c) Home therapy
The benefits of home therapy have been widely
proven18. Home therapy allows the administration of
clotting factor concentrates as soon as bleeding occurs,
thus decreasing the morbidity because of more rapid
recovery from bleeding episodes, and avoiding longterm complications. Home treatment also allows patients
to benefit from prophylactic treatment. Early treatment
results in the use of less factor, reduces the frequency of
accesses to HCs and provide patients and their families
with better quality of life8.
In Italy, home treatment is a common practice, but
specific regulations on self-infusion have been developed
and adopted in only 60% of Italian Regions10. Regions
should be invited to adopt policies, including legislative
provisions, based on the most recent scientific and
technological evidence and patients' needs, in order to
provide PWH with the benefits of home treatment. These
policies should include the organisation of training and
re-training of patients and their caregivers, including
nurses.
d) Registries/databases
As part of significant measures addressed to
prevention of RD, disease-specific registries or registries
for groups of rare diseases are an effective way to assess
health care needs as well as to develop research in several
areas, including epidemiology and pharmacovigilance.
In many cases, registries are the only existing source
of scientific/clinical and epidemiological information
on RD19. In particular, in Italy, three well established
registries monitoring IBDs are operating: the Italian
National Registry for RD (NRRD)20,21, the National
Registry of Congenital Coagulopathies (NRCC) at the
National Institute of Health (ISS, Istituto Superiore di
Sanità)22 and the Hemophilia Registry run by AICE23.
Although they share many features, they significantly
differ in terms of objectives, data collection methods,
data sets and last, but not least, resulting epidemiological
data24.
Therefore, interoperability among the three registries
should be promoted. Regions should strengthen IBD data
collection and surveillance activities at the regional and
inter-regional levels.
e) Replacement therapy supply and distribution
The importance of making factor concentrates
available to meet health needs is recognised by
international organisations and their strategic relevance
is confirmed by their inclusion in the WHO Essential
Medicines List25. According to the data analysed by
NBC26, in 2011 and 2012, a standardised national demand
for FVIII of 6.5 and 7.4 international units (I.U.) per capita,
respectively, was met. The comparison with European and
extra-European Countries with similar standards for the
treatment of haemophilia patients showed a per capita
national utilisation which seems to be adequate in term of
supply and in line with those internationally described27.
However, there is wide variability among Italian Regions
in the demand for clotting factors concentrates (ranging
from 2.1 in Aosta Valley to 11.5 I.U. per capita in
Calabria and Latium Regions), and consequently in the
costs sustained by the NHS. Such differences need to be
explained and addressed.
A variety of plasma-derived and recombinant
concentrates are licensed in Italy for the treatment
of haemophilia and other IBDs25. As far as FVIII is
concerned, toll fractionation products account for
around 60% of the total demand for plasma-derived
concentrates. The observed regional per capita
expenditure differs among Regions showing the
influence of both purchase volumes and mean purchase
prices per unit. Consequently, forms of centralised
purchases should be envisaged28. The evolution of the
Italian regulatory framework related in particular to the
opening of the toll fractionation market29 will certainly
introduce new elements to the Regions that could
presumably benefit from stronger competition in terms
of qualitative and quantitative supply of plasma-derived
products. These strategies are strongly needed even in
the supply of recombinant products, that are currently
used by the majority of Italian patients.
In order to ensure the continuity of care in any
treatment regimen and to ensure constant monitoring
of data related to product demand, consumption and
appropriateness, Regions should plan the supply of
medicinal products for the treatment of IBDs together
with the Regional Blood Centres.
f) Recruitment and training of experts in bleeding
disorders
The training of professionals and the development and
exchange of best practices and education are high priority
issues and are the main determinants for developing and
maintaining adequate diagnostic and therapeutic facilities
and a high quality of care. Concern has been expressed by
several authors in the past regarding the risk of a dramatic
fall off in the number of young physicians interested in a
clinical and research career in bleeding disorders30,31. In
order to address this risk, the European Association for
Haemophilia and Allied Disorders was established32, and
the European Curriculum for Thrombosis and Haemostasis
produced33. According to the European recommendation in
the field of RD34, the need for training does not refer only
to clinical expertise, but also to the ability to communicate
with patients and their families.
Despite the efforts made by professional bodies,
including AICE, the difficulties for many Italian young
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Calizzani G et al
professionals to be permanently recruited by HCs
emerged, so that some of them were forced to opt out
such career.
The formal recognition of the role of HCs in training
of professionals, through an institutional accreditation
system to be implemented by Italian Regions, should
ensure actions taken to prevent such occurrences16.
Regions should adopt any further possible measure
to ensure the availability of expertise appropriate
to the clinical management of PWH. HCs should
identify, on the other hand, and formalise the skills
and professional qualifications required for personnel
performing activities critical to quality of patient care,
also implementing plans in order to guarantee their
adequate training before they start working35.
g) Monitoring and evaluation
A set of performance indicators was defined using data
from the AICE Registry. They include: number and case-mix
of patients treated per HC, patients inflow/outflow, number of
accesses to HCs for the following possible reasons: check-up,
on demand or prophylactic treatment, emergency, volumes of
surgeries (especially orthopaedic and prosthetic operations),
monitoring timing (follow-up, emergency accesses), variation
in the clinical and pharmaceutical treatment of haemorrhagic
events (haematoma, haemarthrosis) by patients case-mix,
outcome indicators (quality of life, adverse events related to
treatment, adjusted mortality per cause)11.
However, an adequate measurement of HCs and Regional
Network outcomes and related benchmarking activities was
not carried out because of the limited data availability.
Discussion
For the model of haemophilia care delivered by the
project, a number of strengths and weaknesses can be
identified.
A key strength was the fact that the model was
the result of an inclusive process involving all key
stakeholders: patients, physicians and regional as well as
national decision makers. Therefore different expectations
were met, facilitating the implementation of the model.
The development of the model was influenced by
principles and guidance from international and national
organisations12,13,35,36 but it was also informed by an
accurate knowledge of the context, provided by the
stakeholders involved.
The project partners focused their attention on the most
critical areas of the current provision of haemophilia care,
in terms of the quality of services with ultimate impact on
patient outcomes. Some of the recommendations emerging
from the project have a direct impact, in the short term,
on the prevention and management of complications and
include the Multidisciplinary integrated approach for
optimal healthcare provision, Networking and protocols
for emergency care, and Home therapy. Others, such
as Registries/databases, Replacement therapy supply
and distribution, Recruitment and training of experts
in bleeding disorders - have an indirect impact on the
quality of healthcare delivery. However, the latter could
play a critical role in disease management, guiding service
provision in the medium to-long-term period or providing
essential information for disease surveillance.
Some weaknesses were also identified. The project
supported the development of recommendations that still
have to be implemented in many of the Italian Regions,
before being adequately assessed. In addition, some may
be considered to be too generic and might be seen more as
principles of care than organisational provisions. In fact,
the project partners were limited in their recommendations
by the current nature of relationships between central State
and Regions.The Regions have, following the devolution
process, a complete organisational autonomy in the field
of healthcare.
The authors envisage that the outputs and outcomes
of the project could have significant impacts and
consequences in terms of local health and social care and
in terms of management of PWH and other IBDs. It is
expected that a national network for HCs will be put in
place through the harmonisation of healthcare delivery
of different haemophilia regional networks. The model of
care aims to adequately meet some basic needs, such as:
- diagnosis and early treatment;
- organisational and therapeutic appropriateness;
- assistance in emergency;
- social and health care for PWH and other IBDs, also
in the context of serious co-morbidities, such as cancer
and multifactorial diseases (cardiovascular diseases,
diabetes, osteoporosis, etc.);
- prevention and reduction of the social health burden
of the disease and its complications (inhibitors, joint
damage, co-morbidity);
- provision of information and training of patients
and their families, to promote social inclusion and
home treatment, namely the model of care that is
most effective for improving the quality of life and
extending the life expectancy of PWH and other IBDs.
Despite significant limitations posed by the available
data, further studies are required in order to assess if the
observed variability can be correlated with the degree
of specialisation of network centres. The difficulty of
applying methodologies of analysis traditionally used
to measure common health interventions or procedures
to low prevalence diseases such as IBDs are evident.
However, regarding patient flows, there are still
significant margins to redefine the network in a more
integrated and homogeneous way and to improve
the efficiency and efficacy of the model of care. In
this context, it is worthwhile to underline the need to
Blood Transfus 2014; 12 Suppl 3: s582-8 DOI 10.2450/2014.0087-14s
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Model for prevention and reduction of impacts of haemophilia
strengthen the quality of data collection by existing
registers. In fact, at this time the registers and information
flows do not support reliable and consistent application
of the majority of the performance indicators identified
by the panel of experts, including outcome measures.
Moreover, these limitations hinder benchmarking
activities and comparisons between Regions and HCs.
In designing a sustainable and efficacious network
for rare disorders, such as IBDs, a continuous trade-off
between the need to provide services close to the home
of the patient and the need to provide services with a high
level of expertise and experience present an inevitable
conflict. If on the one hand, low volumes do not justify
the presence of a comprehensive HC on the territory, on
the other hand basic services are necessary to guarantee
timeliness of intervention.
5)
6)
7)
8)
9)
10)
11)
Conclusion
The CCM project defines a model for healthcare
pathways for the management of patient with IBDs
aimed at the prevention and reduction of the socialhealth burden of the disease and its complications. Such
a model provides Italian Regions with recommendations
for the arrangement of care for PWH based on the most
recent scientific evidence and current best practice.
However, the project monitoring and evaluation require
an improvement in data collected by haemophilia
registries and information matching with other health
information flows. Further evidence coming from a
wider implementation of the recommendations across
Italian Regions will show if the model is successful in
achieving the expected outcome.
12)
13)
14)
15)
16)
17)
Acknowledgements
The project Model of Disease Management of
Patient with Congenital Bleeding Disorders Aimed at the
Prevention and Reduction of both Health and Social Impact
of the Disease and its Complications is a three-year project
funded by the national Centre for Disease Prevention and
Control of the Italian Ministry of Health.
The Authors declare no conflicts of interest.
18)
19)
20)
21)
References
1)
2)
3)
4)
Mannucci PM, Tuddenham E. The Hemophilias - From Royal
Genes to Gene Therapy. N Engl J Med 2001; 344: 1773-9.
White GC, Rosendaal F, Aledort LM, et al. Definitions in
hemophilia. Recommendation of the scientific subcommittee
on factor VIII and factor IX of the scientific and standardization
committee of the International Society on Thrombosis and
Haemostasis. Thromb Haemost 2001; 85: 560.
Morfini M, Coppola A, Franchini M, Di Minno G. Clinical use
of factor VIII and factor IX concentrates. Blood Transfus 2013;
11 (Suppl 4): s55-63.
Morfini M, Haya S, Tagariello G, et al. European study on
orthopaedic status of haemophilia patients with inhibitors.
Haemophilia 2007; 13: 606-12.
22)
23)
24)
The Hemophilia Registry of the Italian Association of
Hemophilia Centres. Available at: http://www.aiceonline.it/
emocard/homeRN.htm. Accessed on 15/01/2013.
Mannucci PM, Franchini M. Present and future challenges in
the treatment of haemophilia: a clinician's perspective, Blood
Transfus 2013; 11 (Suppl 4): s77-81.
Makris M, Calizzani G, Fischer K, et al. EUHASS: The
European Haemophilia Safety Surveillance system. Thrombosis
Research 2011; 127 (Suppl 2): S22-5.
Tagliaferri A, Rivolta GF, Iorio A, et al. Mortality and causes
of death in Italian persons with haemophilia, 1990-2007.
Haemophilia. 2010 May; 16: 437-46.
Coppola A, Santoro C, Franchini M et al, Emerging issues on
comprehensive hemophilia care: preventing, identifying, and
monitoring age-related comorbidities. Semin Thromb Hemost.
2013; 39: 794-802.
Arcieri R, Molinari AC, Farace S, et al. Uncovered needs in the
management of inherited bleeding disorders'. Blood Transfus
2014; 12 (Suppl 3): s563-6.
Nuti S. La sostenibilità del modello di cura. Available at
http://www.centronazionalesangue.it/sites/default/files/
nuti_la_sostenibilita_del_modello_di_cura.pdf. Accessed on
23/02/2014.
Calizzani G, Vaglio S, Arcieri R, et al. Models for institutional
and professional accreditation of haemophilia centres in Italy.
Haemophilia 2013; 19: e248-55.
Mannucci PM, Menichini I. A certification/accreditation model
for hemophilia centers in Italy. Blood Transf
Decreto Ministeriale 18 Maggio 2001, n. 279. Regolamento di
istituzione della rete nazionale delle malattie rare e di esenzione
dalla partecipazione al costo delle relative prestazioni sanitarie,
ai sensi dell'articolo 5, comma 1, lettera b), del decreto legislativo
29 aprile 1998, n. 124. Gazzetta Ufficiale - Serie Generale n.
160, 12 luglio 2001. Suppl. Ord. n. 180/L.
Calizzani G, Candura F, Menichini I, et al. The Italian
Institutional Accreditation Model for Haemophilia Centres.
Blood Transfus 2014; 12 (Suppl 3): s510-4.
Fortino A, Di Stanislao F. Institutional accreditation of healthcare
services in Italy: the long road to quality. Blood Transfus 2014;
12 (Suppl 3): 551-3.
Fowler H, Lacey R, Keaney J, et al. Emergency and out of hours
care of patients with inherited bleeding disorders. Haemophilia
2012; 18: e126-31.
Colvin BT, Astermak J, Fischer K, et al. European principles of
haemophilia care. Haemophilia 2008; 14: 361-74.
Recommendations for the Development of National Plans
for Rare Diseases - Guidance Document. Available at: http://
www.europlanproject.eu/_newsite_986989/Resources/
docs/2008-2011_2.EuroplanRecommendations.pdf. Accessed
on 15/01/2014
Taruscio D, Kodra Y, Ferrari G, et al. The Italian National Rare
Diseases Registry. Blood Transfus 2014; 12 (Suppl 3): 606-13.
Taruscio D (Ed.). Il Registro Nazionale e i Registri Regionali/
interregionali delle malattie rare. Rapporto anno 2011. Roma:
Istituto Superiore di Sanità; 2011 (Rapporti ISTISAN 11/20).
Available at: http://www.iss.it/binary/cnmr/cont/ISTISAN_
RNMR_2011.pdf. Accessed on 15/01/2014.
Abbonizio F, Gianpaolo A, Arcieri R, Hassan HJ on behalf
of the Italian Association of Haemophilia Centres. Registro
Nazionale Coagulopatie Congenite. Rapporto 2011. Rapporti
ISTISAN 12/55.
Iorio A, Oliovecchio E, Morfini M, Mannucci PM on behalf of
the Association of Italian Hemophilia Centres Directors. Italian
Registry of Haemophilia and Allied Disorders. Objectives,
methodology and data analysis. Haemophilia 2008; 14: 444-53.
Hassan HJ, Morfini M, Taruscio D, et al. Current Status of
Italian Registries on inherited bleeding disorders. Blood
Transfus 2014; 12 (Suppl 3): s576-75.
Blood Transfus 2014; 12 Suppl 3: s582-8 DOI 10.2450/2014.0087-14s
s587
Calizzani G et al
25) WHO Model List of Essential Medicines. 18th list (April
2013). World Health Organization. Available at: http://www.
who.int/medicines/publications/essentialmedicines/18th_
EML_Final_web_8Jul13.pdf. Accessed on 15/01/2014
26) Lanzoni M, Biffoli C, Candura F, et al. Plasma-derived
medicinal products in Italy: information sources and flows.
Blood Transfus 2013; 11 (Suppl 4): s13-7
27) Calizzani G, Profili S, Candura F, et al. The demand for
factor VIII and for factor IX in Italy and the toll fractionation
product surplus management. Blood Transfus 2013; 11 (Suppl
4): s64-76.
28) Lanzoni M, Candura F, Calizzani G, et al. Public expenditure
for plasma-derived and recombinant medicinal products in
Italy. Blood Transfus 2013; 11 (Suppl 4): s110-7.
29) Decreto del Ministro della Salute 12 aprile 2012 "Modalità
per la presentazione e valutazione delle istanze volte ad
ottenere l'inserimento tra i centri e le aziende di produzione
di medicinali emoderivati autorizzati alla stipula delle
convenzioni con le Regioni e le Province Autonome per la
lavorazione del plasma raccolto sul territorio nazionale".
Available at: http://www.centronazionalesangue.it/sites/
default/files/dd.mm_._12.04.2012_plasma_gu_n._147_
del_26.06.2012_.pdf. Accessed on 15/01/2014.
30) Mannucci PM, Roberts HR. Uncertain times for research on
hemophilia and allied disorders .J Thromb Haemost 2005;
3: 423.
31) Vermylen J. More on: uncertain times for research on
hemophilia and allied disorders. J Thromb Haemost 2005;
3: 1547.
32) Ludlam CA, Mannucci PM on behalf of the Interdisciplinary
Working Group. Proposal to establish a European Association
for Hemophilia and Allied Disorders. J Thromb Haemost
2006; 4: 2270-1.
33) Astermark, J, Negrier C, Hermans C, et al. European
curriculum for thrombosis and haemostasis. Haemophilia
2009; 15: 337-44.
34) European Council. Recommendation of 8 June 2009 on
European action in the field of rare diseases. Official Journal
C151: 7-10. Available at: http://eur-lex.europa.eu/LexUriServ/
LexUriServ.do?uri=OJ:C:2009:151:0007:0010:EN:PDF.
Accessed on 21/01/2014
35) European Haemophilia Network - EUHANET. European
guidelines for the certification of Haemophilia Centres. Available
at http://www.euhanet.org/docs/Euhanet-European_guidelines
_for_the_certification_of_Haemophilia_Centres_2013.pdf.
Accessed on 15/01/2014.
36) European Union Committee of Experts on Rare Diseases
(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 18/02/2014.
Correspondence: Gabriele Calizzani
Italian National Blood Centre
Via Giano della Bella 27
00162 Rome, Italy
e-mail: areaplasma.cns@iss.it
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REGIONAL, NATIONAL AND EUROPEAN ACTIONS IN THE FIELD OF RARE DISEASES
Blood Transfus 2014; 12 Suppl 3
© SIMTI Servizi Srl
REVIEW
The Italian National Centre for Rare Diseases:
where research and public health translate into action
Domenica Taruscio, Linda Agresta, Annalisa Amato, Giuseppe Bernardo, Luana Bernardo,
Francesca Braguti, Pietro Carbone, Claudio Carta, Marina Ceccarini, Federica Censi, Simona Coppola,
Patrizia Crialese, Marta De Santis, Stefano Diemoz, Carlo Donati, Sabina Gainotti, Gianluca Ferrari,
Giovanna Floridia, Claudio Frank, Rosa Giuseppa Frazzica, Amalia E. Gentile, Orietta Granata,
Yllka Kodra, Manuela Latrofa, Paola Laricchiuta, Armando Magrelli, Cristina Morciano, Agata Polizzi,
Stefania Razeto, Marco Salvatore, Antonella Sanseverino, Daniele Savini, Paola Torreri, Fabrizio Tosto,
Flavia Villani, Giorgio Vincenti, Luciano Vittozzi
Italian National Centre for Rare Diseases, National Institute of Health, Rome, Italy
Introduction
The Italian National Centre for Rare Diseases
(CNMR) is the result of a strategic approach, which the
National Institute of Health (ISS) has been developing
for more than 10 years, to deal with the public health
challenges associated with rare diseases (RDs).
The CNMR was formally established within the
ISS in 20081. Its mission is to promote and develop
experimental research and public health actions, as well
as to provide technical expertise and information on
RDs and orphan drugs, for the prevention, treatment and
surveillance of these diseases. It is also the national focal
point for information and communication for patients
suffering from one of several thousand RDs, and for their
families, collaborating with the national organisations
of patients suffering from RDs.
The Centre employs a wide range of scientific and
technical expertise from various fields (medicine,
genetics, molecular biology, epidemiology, public
health, psychology, sociology etc.) and holds a network
of national and international collaborations, which allow
the development of a sound and integrated approach to
RDs. The CNMR provides expert advice to the Italian
Ministry of Health (MOH), to the National Health
Council, to the National Health Service (NHS), and
collaborates with the Regions, which are responsible for
the provision of health services in the Italian devolved
health system. Expert advice on RDs is also provided
at EU and at international level.
Since its establishment, the Centre has developed into
a lively and propulsive hub for experimental research,
public health, information, communication and training
on RDs in Italy, and for patient empowerment. In
addition, it has contributed to networks and scientific
boards at national, European and international level and
has implemented a number of strategic projects on RDs.
The Centre is in continuous evolution in order to follow
closely the pace of science and research, the emerging
needs of patients, the solicitations of policy makers, and
the demands of the health system.
The Italian National Centre for Rare Diseases
European and national frame of reference
Before introducing the Centre's present configuration
and its activities in detail, it is worthwhile to clarify
some general issues concerning RDs and the institutions
responsible for RD policy, programmes and actions at the
European and at the National level, which provide the
foundations for the CNMR work. The Centre maintains
relations with them as well as with other qualified
national, European and international institutions for the
realisation of its activities in the field of RDs.
General considerations on rare diseases
RDs are characterised by low prevalence (by
European Union (EU) definition less than 5/10,000 in
the general population) but represent a considerable
public health burden due to their high number and to
their complex management. According to the European
Commission2, the number of existing RDs is estimated
at between 7,000 and 8,000, affecting, altogether, 6-8%
of the general population. RDs are distinguished by
specific clinical and etiopathogenetic characteristics,
but their social and health burden share a number of
common features. Most of them set out at birth or during
infancy, while the rest appear in adulthood. RDs are
chronic, multisystem conditions often associated with
reduced life expectancy and a relevant mortality rate
in childhood, a severe disabling course, high medical
expenses and poor quality of life.
Their low prevalence rate is the main cause of a poor
awareness among health care professionals and often of
inadequate levels of care expertise. These can result in
delayed diagnosis, misdiagnosis or even un-diagnosis,
difficulties in assessing and adopting the appropriate
disease management, and in problems related to
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Taruscio D et al
the psychological and economic impact on patients
and their families. In addition, the limited market
represented by the single conditions does not make the
development of new drugs and treatments attractive to
the pharmaceutical industry. As a consequence, orphan
drugs are expensive and seldom available; furthermore,
their efficacy and safety usually cannot be thoroughly
assessed, due to the lack of a large patient population.
The Italian legislative support for rare diseases
Since 1998, RDs have been recognised as a health
priority in each of the 3-year Italian national health
plans, though a national plan/strategy for RDs has
not yet been formalised by the MOH. Meanwhile, a
coordinated and comprehensive framework of actions
was defined by Ministerial Decree (D.M.) n. 279/20013,
which established a national network of selected clinical
centres for prevention, surveillance, diagnosis and
treatment of RDs, a National Registry for RDs (RNMR),
and defined the exemptions for the costs of medical care
for a number of RDs.
Accordingly, disease related services are free for
citizens affected by a RD in the list (see Annex 1 D.M.
n. 279/2001). A major shortcoming is that not all RDs
and groups of diseases are included in the inventory and
that it is not regularly updated, although a revision is
expected in the near future.
Since 2001, Regions have established regional
registries, centres for the diagnosis and treatment of
RD patients and regional coordination centres, in order
to manage the activities, including the exchange of
information among centres and to provide expertise and
data to the regional RD registries. Regional registries
send the epidemiological data to the RNMR, established
at the CNMR in 2001, in accordance with Article 3
of the D.M. n. 279/2001. The RNMR is supported by
public funds; it is web-based, in compliance with the
legal and ethical requirements, and it is a populationbased registry, although the regional coverage is still
heterogeneous. The RNMR collects the data ("common
data set") coming from the regional registries and it is
the tool for epidemiological surveillance of RDs and
for the national and regional planning of RD measures.
The European framework for the Italian
National Centre for Rare Diseases activities
The European Union and the Council of the
European Union
The RDs gained political concern at the EU level
in the early 1990s. In fact, in November 1993, the
European Commission (EC) published the "Commission
communication on the framework for action in the field
of public health" (1993)4, defining the framework for
action by the Community and describing the role of the
Community Institutions and the Member States (MS).
After this publication, the Commission opened a
wide consultation in the Union on public health issues.
In December 1993 the Commission invited experts to
submit a proposal describing how they would seek to
formulate draft policy proposals in some of the areas
indicated in the framework document. In consultation
with the Commission, five priority areas were identified,
among them also "An EU programme for management
of rare diseases".
Subsequently, four key policy documents have been
emanated by the EU and these have paved the way to
current RDs developments in Europe; the CNMR has
aligned to it. Following are the cited documents.
a. The Orphan Medicinal Product Regulation5
This text defines the criteria for orphan designation in
the EU and described the incentives to encourage the
research, development and marketing of medicines
to treat, prevent or diagnose RDs.
b. The Commission Communication on Rare Diseases:
Europe's challenge2
This document, which was adopted on 11 November
2008, proposes an overall strategy to support MS in
diagnosing, treating and caring for RD patients in
Europe. This Communication focuses on three main
areas: i) improving recognition and visibility of RDs,
ii) supporting policies on RDs in MS for a coherent
overall strategy, and iii) developing cooperation,
coordination and regulation for RDs at EU level.
c. The Council Recommendation on an action in the
field of RDs6
This document was adopted on 8 June 2009 and
comprises twenty recommendations gathered
into seven main areas. The seven themes are:
plans and strategies in the field of RDs; adequate
definition, codification and inventorying of RDs;
research on RDs; centres of expertise and European
reference networks; gathering the expertise on
RDs at European level; empowerment of patient
organisations; sustainability.
d. Directive 2011/24/EU on the application of patients'
rights in cross-border healthcare7
This Directive was approved on 28 February 2011
and is particularly important for RD patients, because
of scarce and scattered resources for diagnosis and
care of these disorders. The Directive is meant to
facilitate the access of EU citizens to cross-border
health care and to encourage the cooperation between
EU Member States in the field of health.
The European Union Committee of Experts on Rare
Diseases
The European Union Committee of Experts on
Rare Diseases (EUCERD) was formally established by
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Italian National Centre Rare Diseases: research and public health
the European Commission Decision8 on 30 November
2009, replacing the European Commission's Rare
Diseases Task Force (RDTF). Its mission is to assist
the EC in the cooperation and consultation efforts with
the specialised bodies in the MS, the relevant European
authorities dealing with research and public health action
and other relevant stakeholders operating in the field of
RDs. Recently, the EUCERD has been replaced by the
Commission Expert Group on Rare Diseases9.
The CNMR participated regularly to the RDTF and
EUCERD meetings, and will continue to take part to the
activities of the newly established Commission Expert
Group on Rare Diseases.
The role of patient organisations in the Italian
National Centre for Rare Diseases work
National, European and international patient
organisations, representing the voice of the RDs
community, play a key role in the activities carried out
by the CNMR as highlighted in the following sections.
The Italian organisations of patients with rare
diseases
The role of patient organisations in the field of RDs
is crucial. Driven by the need to share difficulties and
problems, and by a desire to see their rights recognised,
they encourage targeted policies, research and specific
interventions for health and social care. In recent years,
much of the progress in inter-institutional relations and
between institutions and patients are attributable to the
efforts of these organisations. Their work comprises a
body of knowledge complementary to that of the doctor.
For this reason, it becomes increasingly important to
have a constructive and cooperative relationship between
patients and social and health professionals. This
collaboration allows the former to reach such a level of
empowerment that enables them to take an active part
in the decision making processes that affect them, and
the latter to make strides in research and take effective
charge of the patients, improving their quality of life.
Of the several patient organisations present in Italy,
some have chosen to carry on their battle individually,
others have opted to join umbrella organisations at
national and international level. In Italy there are
currently three major leagues:
- the Italian Federation for Rare Diseases - UNIAMO10,
connected to the European Organisation for Rare
Diseases - EURORDIS11;
- the National Council for RDs12;
- the Italian Movement for Rare Patients (MIR)13.
The European Rare Diseases Organisation
The European Rare Diseases Organisation
(EURORDIS) is a non-governmental patient-driven
alliance of patient organisations and individuals active
in the field of RDs. It was founded in 1997 for the
promotion of research on RDs and the commercial
development of orphan drugs. EURORDIS is dedicated
to improving the quality of life of all people living
with RDs in Europe. It represents more than 606 RDs
organisations in 56 different countries (of which 25 are
EU MS), covering more than 4,000 RDs11.
The CNMR works closely with EURORDIS,
particularly with regard to the implementation of the
European Project for Rare Diseases National Plans
Development (EUROPLAN) and European Platform
for Rare Disease Registries (EPIRARE) projects and
for other patient centred activities.
The International Rare Diseases Research
Consortium
The International Rare Diseases Research Consortium
(IRDiRC)14 was launched in 2011 by the European
Commission and by the US National Institutes for Health
Research to foster international collaboration in the RDs
field. The Consortium's goal is to team up researchers
and organisations investing in research to deliver 200
new therapies for RDs and to diagnose most RDs by
the year 2020.
These are some the ambitious challenges on IRDiRC
agenda to be addressed through collaborative actions:
- establish and provide access to harmonised data and
samples;
- perform the molecular and clinical characterisation
of RDs;
- boost translational, preclinical and clinical research.
The collaboration will also be required to harmonise
the policies related to research utilisation, standardisation
and dissemination. Each organisation will use its own
funding mechanism to support RDs research.
The CNMR participates in some IRDiRC research
projects and research, including the Interdisciplinary
Committee, and chairs the Working Group on Registries
and Natural History of RDs.
The frame of action of the National Centre for
Rare Diseases
The history of the CNMR dates back to the
institution of the National Registry3 for Rare Diseases
in 2001, which was the first nucleus of the Centre. In
fact, when the National Registry was instituted, the
first building stone of the CNMR was also laid. On
it, through the years, the CNMR has steadily evolved
into a dynamic and vital centre for research and action,
for prevention, diagnosis and treatment of RDs, for
patient's empowerment and public awareness, through
information and communication tools. In order to meet
old and new challenges posed by RDs, the Centre has
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developed its institutional activities along six main
pillars: 1) experimental research; 2) public health; 3)
projects; 4) information and communication; 5) training
and empowerment; 6) networks and collaborations.
1. Experimental research on Rare Diseases
The CNMR plays an important role in the coordination
and promotion of experimental research on RDs in
Italy, has participated in the Advisory Committee for
European Research and is an active Work package (WP)
leader of E-Rare project (see later). In 2003, a bilateral
Italian and US agreement between the ISS and the US
National Institutes of Health (NIH) was undersigned
with the purpose of developing and increasing research
in a number of fields, including RDs. In this respect, the
CNMR has assured the implementation of a national
programme of scientific research projects mainly based
on the study of pathogenetic mechanisms, diagnosis,
treatment and clinical management of RDs. On 16
December 2013, the agreement with the NIH was
renewed until 2016.
Within this international context, the CNMR carries
out scientific research projects on selected RDs using
advanced technologies (e.g. bioinformatic methodologies,
high resolution melting, micro-RNA platform and
CGH array). These studies are focused on a better
comprehension of the molecular mechanisms underlying
the pathogenesis of RDs, as well as the identification of
specific biological markers involved in both RDs and rare
cancers. The Centre is involved in collaborative studies
on pathological conditions related to RDs15-24.
In order to overcome the problems of the low number
of patients with RD, a transnational collaboration with
multidisciplinary approaches is highly desirable. In this
respect, the CNMR has taken part in the activities of
E-Rare, a EU funded project described in the Projects
section.
2. Public Health actions on Rare Diseases
The CNMR develops a number of public health
activities in the field of RDs, from public health research
on matters of relevance to its mission (e.g. epidemiology,
service accessibility, identification of patients' needs) to
policy. Through the coordination of the EU co-funded
EUROPLAN project, it assists European States in
defining needs and developing national plans for RDs, in
accordance with the EU Recommendations. Following
is a description of the main Public Health activities
undertaken by the Centre to deal with the RDs emerging
needs and interests.
Primary and secondary prevention
Since 2004, the Centre has coordinated the Italian
Network for folic acid promotion in the primary
prevention of congenital anomalies, which comprises
more than 200 public and private organisations, such as
local health authorities, patients organisations, scientific
societies, research institutes and communication
experts. In 2004, it developed and delivered the
"Official Recommendation for the peri-conceptional
supplementation of folic acid"25 and is currently working
for the widest application of this Recommendation26.
Subsequently, the Italian Medicines Agency (AIFA)
decided to offer 0.4 mg folic acid supplements free of
charge to all women planning a pregnancy.
In 2008, the CNMR was part of the Scientific
Cooperation Working Group (ESCO WG), established
by the European Food Safety Authority (EFSA) for
the study on the "Analysis of risks and benefits of
fortification of food with folic acid", and was co-author
of the final report published in November 200927.
The CNMR participates to the European surveillance
of congenital anomalies (EUROCAT) Joint Action
2011-2013 (see later) as coordinator of the WP on
"Primary prevention of Congenital Anomalies".
This WP has joined efforts with EUROPLAN in
order to provide the "EUROCAT-EUROPLAN
Recommendations on policies to be considered for
the primary prevention of congenital anomalies in
National Plans and Strategies on Rare Diseases"28.
The document represents the first comprehensive set
of recommendations for the primary prevention of
congenital anomalies in the EU.
The Centre played an important role in the
coordination of the EU Tender on EU New-born
Screening (NBS) Practices. The tender delivered a
report on the practices of neonatal screening for RDs
implemented in all the MS and established by the
European Network of Experts on New-born Screening
(EUNENBS). After consultation of EUNENBS
members, 70 expert opinions were finalised into an
Expert Opinion Document, to actively support the
discussion for the development of European policies
in the field of NBS of RDs29-31.
Currently, the CNMR is working on a national
project to expanded new-born screening, funded by
the National Centre for Disease Prevention and Control
(CCM) of the MOH, under their 2011 programme.
Its aim is to overcome different implementation
strategies at regional level, regarding the expanded
new-born screening, through a national model based
on principles of uniformity, coherence, effectiveness
and portability32.
The Registries
Following is the presentation of the National Registry
for Rare Diseases (RNMR) and the Disease-specific
Registries conducted by the CNMR.
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The National Registry for Rare Diseases
The RNMR was established in 2001 by Ministerial
Decree (M.D.) 279/20013 and is run by the CNMR in
collaboration with the regional registries. It collects
epidemiological information useful to determine the
dimension of the issue and the potential risk factors, to
support clinical research and to foster the definition of
diagnostic criteria.
The general objectives of the RNMR are indicated in
the Article 3 of the M.D. 279/2001; they were reasserted
in two Agreements between the State and the Regions,
in 200233 and 200734:
1 - planning and evaluating health care programmes
(services utilization, patients' mobility…);
2 - diseases surveillance (estimation of prevalence and
incidence, geographical and temporal distribution of
RDs).
The RNMR is structured into three levels, reflecting
the Italian Healthcare System: local, regional and
national level. The local level refers to clinical centres
identified in each Region, which are the primary
source of data flow. From here, patients' demographic
and clinical data are collected and transmitted to the
regional level. This is the intermediate level of data flow
and is composed by regional registries. Each regional
registry has a different organisational structure, different
objectives, and, as a consequence, different types of
information (variables) collected. Meanwhile, a common
data set to be communicated from the regional registries
to the RNMR was defined in line with the CNMR's
mandate. This set includes socio-demographic as well
as disease data for each patient: patient's identification
code, birth date and place of birth, gender, place of
residence; live-dead condition (with death date);
diagnosis; RDs clinical centre where the diagnosis has
been made; date of disease onset; date of diagnosis;
orphan drug treatment used.
The RNMR collects data on the conditions afferent to
the list of RDs (see Annex 1 M.D. n. 279/2001). In 2012,
the RNMR, in collaboration with Regional Registries,
prepared it first annual report35.
The RNMR future strategies include supporting
the development of new clinical registries on specific
RDs in order to better understand their natural
history. Furthermore, the RNMR plans to strengthen
the collaboration and networking among existing
disease specific registries at national, as well as, at
International level. For example, the RNMR is currently
collaborating with the National Registry of Congenital
Coagulopathies, established at the ISS, on Inherited
Bleeding Disorders36,37.
Meanwhile, the RNMR is working towards the
improvement of quality of data collection at national and
regional level. Accordingly, the Centre has collaborated
with the EU Task Force on RDs of the EC Health and
Consumers Protection Directorate General, whose goal
is to revise the classification and codification of RDs in
the ICD system. Its objective is to ensure that RDs are
traceable in all health information systems, including
national and international registries.
Disease specific Registries
The following Disease specific registries are
maintained by the CNMR.
Cystic Fibrosis Registry
The Italian Cystic Fibrosis Registry (ICFR) collects
demographic and epidemiological data on Cystic
Fibrosis (CF) patients from the Italian CF Regional
Centres. Anonymous data are collected using a specific
common set of variables and definitions; these data are
also forwarded to the European CF Patients Registry.
Each participating centre is identified through a specific
code. Use of data for scientific purposes is possible only
after application and approval by a scientific committee
and a representative of each regional centre. An Annual
Report is elaborated by the scientific committee and
a detailed description of CF patients (demography,
diagnosis, genetics, etc.) is published. The ICFR sends
the core data to the European Registry.
T h e I t a l i a n D a t a b a s e f o r P a ro x y s m a l N o c t u r n a l
Haemoglobinuria
The Italian Database for Paroxysmal Nocturnal
Haemoglobinuria (IDPNH) was set up in 2010 through
the cooperation of the CNMR staff, haematologists
and representatives of the patient organisation. The
database, which interfaces with the RNMR, includes all
patients with a diagnosis of PNH established according
to international criteria. The IDPNH main objective is
to enhance the knowledge of the natural history of the
disease and to obtain information on short and longterm follow-up, particularly on how patients respond
to available treatments.
A set of variables are collected: personal data, clinical
data, diagnostic tests, other laboratory data, blood
transfusion treatment, drug treatment, pregnancies and
quality of life. The IDPNH is web based and personal
data are encrypted according to national regulations on
the protection of personal data. A national expert on PNH
validates the complete data set for each individual patient.
The experience gained in the management of an
institutional/epidemiological registry that collects data
on all RDs - the RNMR - and in the management of
research oriented registries, collecting data on single
diseases (CF and PNH), has provided the CNMR
with the track record that facilitated its selection for
the coordination of the EPIRARE project and, as
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well, for the WP on RD registries of the RD-Connect
project. The two projects are aimed at building research
infrastructures for exchange of data, with a focus,
respectively, on epidemiology (EPIRARE), "omics" and
translational research (RD-Connect). Both projects are
presented in the specific Projects section.
Quality Assurance on genetic tests and external quality
assessment programmes
The CNMR participated in the Organisation for
Economic Cooperation and Development (OECD)
Panel of experts for the preparation of Guidelines for
quality assurance in molecular genetics tests and in the
EU funded project "Multi-National External Quality
Assay (EQA) programmes in Clinical Molecular
Diagnostics" 38,39. The CNMR is a member of the
European Molecular Genetics Quality Network and takes
part in the EU funded EuroGentest excellence network,
which aims at the standardisation and harmonisation of
the quality of genetic testing in the EU MS.
Since 2001, the CNMR has coordinated the National
External Quality Assessment programme for genetic
testing that covers molecular genetics (Fragile-X
syndrome, Beta-Thalassemia, FAP (APC gene) and
Cystic Fibrosis) and cytogenetics (prenatal, postnatal
and oncological diagnosis) tests40,41.
Since 2009, this activity is institutional and
laboratories pay a fee to participate in each scheme42.
Participation is voluntary and is open both to public and
private laboratories.
All submissions are assessed and reviewed
by assessors, using previously agreed marking
criteria. In molecular genetics, assessment takes into
account genotyping, interpretation and reporting. In
cytogenetics, assessment reviews banding quality,
karyotype reconstructions, completeness/accuracy of the
analysis, International System for Human Cytogenetic
Nomenclature (ISCN), written description of the result,
interpretation, completeness/accuracy of the report and
reporting times.
At the end of each round, participant laboratories
receive a report with marks and comments; a web-utility
has been developed to share documents and information
among ISS/CNMR, the assessors and the laboratories.
Up to now, nine rounds have been completed and, for
the 9th round, a category of poor performance has been
defined. In 2013, the number of participating medical
genetics centres was 94; the number of participating
cytogenetics and molecular genetics laboratories was
69 and 77 respectively. Each year the CNMR organises
the annual Meeting on "Quality assessment of genetic
testing", inviting relevant speakers, laboratories and
assessors for a joint discussion on the aggregated results
obtained.
A specific external quality control scheme for the
sweat test, a "gold standard" for the diagnosis of CF43,
has been set up and the first Italian pilot experience,
to be carried out by the CNMR, is under way. In
fact, it is of critical importance that sweat testing is
carried out accurately, with precise measurement of
relevant analytes, in order to have the most accurate
discrimination of results.
Guidelines
The CNMR is involved in developing guidelines for
the management of RDs. Guidelines are produced in
collaboration with the Italian National Guideline System
(SNLG) and with relevant stakeholders - research
organisations, governmental bodies and institutions of
the Italian National Health System.
In order to disseminate and promote the adoption
of guidelines on RDs, the CNMR selects and makes
available on its website guidelines prepared by
national and international organisations. Moreover, an
International Summer School on the development of
guidelines on RDs is organised by the CNMR yearly.
The CNMR actively participates in the international
debate on the quality of existing guidelines, on their
development and on the role of guidelines for RDs. In
2012, an international workshop with worldwide experts
was organised to stimulate the debate on these themes.
The FP7 project "RARE-Bestpractices", led by CNMR,
was conceived in the mainstream of such debate and it
is detailed in the Projects section.
Narrative Medicine
Narrative Medicine (NM) is considered a
complementary approach to classic medicine, practiced
with narrative skills of recognizing, absorbing,
interpreting and being moved by the stories of illness.
Treating by the narrative competencies, it is conducted
through the doctor's and patient's understanding of the
origin of the illness following the background of the
problems, the reason of the illness and the whole body
approach43-46.
Since 2005, NM has emerged among the activities
of the CNMR with the objective to disseminate
its application on RDs, among social and health
professionals, patients with RDs and their families, and
patient organisations. In order to achieve its objective,
a number of national and international activities were
organised by the "national laboratory of narrative
medicine" of the CNMR:
- Documentation: research, analysis, monitoring of
national and international literature in Open Source
publishing;
- Research: study of narratives relating to patients
with RDs, relatives, health professionals, patient
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organisations. Following are some examples: the
pilot study "General practitioners and rare diseases:
knowledge, skills and needs" at national level; the
first funded project "Rare diseases and Narrative
Medicine: integrations and contributions in Public
Health projects, quality of life, accessibility to
social and health services and training" (in the
NEPHIRD context), at European level and, recently,
the European project "Story Telling on Record"
(S.T.o.Re.).
- Communication and training: activities addressing
NHS workers, RD patients and their familiars.
The CNMR organised the National Congress on
"Narrative medicine and rare diseases" (2009, 2010,
2011) and the First International Congress "Narrative
medicine and rare diseases" (2012).
There are several approaches and methods in NM. In
order to clarify its definition, methodology and practical
utility (experiences and examples of application), the
CNMR promoted the Italian Consensus Conference (CC)
aimed at (a) developing recommendations (addressed to
professionals working in the medical, social and health
care sectors) for the implementation of NM at the clinical
level, with regard to rare and chronic degenerative
diseases and (b) identifying indicators useful to evaluate
their implementation. The CC celebration day will be
held in June 2014 together with the Second International
Congress on "Narrative medicine and RDs". The CC
document will be ready in Autumn 2014 and will be
addressed to health professionals working in the Italian
social and health care sectors.
A number of activities have their roots in the
NM Laboratory, such as the communication project
"Controvento - Upwind", which includes a theatre piece,
a book based on RD patients' stories and the National
Competition "The Flight of Pegasus".
The National competition "The Flight of Pegasus"
"The Flight of Pegasus" is a literary art contest,
sponsored by the CNMR. All participants are invited
to tell their own experiences through writings, poems,
drawings, photos and paintings. The main objectives
are: (a) to provide a space for expression and visibility
for people with RDs, as well as for all citizens, through
various artistic and literary channels, and (2) to promote
and disseminate the knowledge of RDs in all its aspects,
by means of targeted communication and awareness
campaigns. The results show the diverse viewpoints
with which the disease is faced: isolation and neglect,
indifference and difficulty of diagnosis and treatment,
but also strong willpower and courage, sharing and
tolerance.
After years of activity, the most important outcome
is the creation of a national network with all the
participants, providing a real exchange of ideas,
knowledge sharing and updating. The sixth award
ceremony has taken place at the ISS on 25 February
2014, close to the Rare Disease Day.
Orphan drugs
CNMR has instituted the National Register of
Orphan Drugs to collect, for a limited time period after
their marketing, data of selected drugs newly authorised
for the treatment of RDs, for the assessment of their
appropriateness and safety. From 2001 to 2009 and
from 2012-up to now, the CNMR has been the Italian
member of the Committee of Orphan Medicinal Products
(COMP) at the European Medicines Agency (EMA).
Rare Diseases and organ transplantations: a new
frontier
Organ transplantation in RDs patients represents a
new area of research for the CNMR, both for its clinical
aspects, and for potential public health implications.
Since the literature has very few data on this
topic, the CNMR is carrying out a statistical survey,
in collaboration with the Italian National Transplant
Centre, with the aim of assessing the number of cases of
RDs patients receiving organ transplantation, defining
the type of RD and the transplantation carried out,
together with the evaluation of the outcome.
According to the preliminary data, 1,306 patients
with RDs have undergone an organ transplantation
over the period 2008-2012. This figure represented
8.9% of the total of the patients undergoing a transplant
surgery in the same period (14,821 patients). The organs
transplanted were mainly kidneys, livers, hearts, or lungs
(71% of all the latter cases had RDs, mostly CF).
The data on organ survival in RDs recipients show
that, 5-6 years after the surgery, the cumulative survival
is better for the RD patients compared with patients
with other diagnoses. The reasons for this result are
currently under study. However, some hypotheses are
already being explored: are the results due to a better
selection of the cases, when the patient is not yet in a
severe condition, or to the fact that the transplantation
represents a cure for some diseases?
3. Projects
A number of national, European and international
projects on RDs are undertaken yearly by the Centre.
Following are some of the projects still under way or
recently closed.
European Platform for Rare Disease Registries
European Platform for Rare Disease Registries
(EPIRARE, www.epirare.eu)47, is a project co-funded
by the EU Commission, DG-SANCO (2011-2014). It
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is a feasibility study addressing regulatory, ethical and
technical issues, associated with the registration of RD
patients. The feasibility of a minimum data set common
to all RDs designed to inform policy-makers is also
being assessed by the project.
The project carried out two surveys among registry
and database holders and one among patients. The
first was meant to explore the conditions and needs of
existing RDs registries and to define the services and
the contents that they would expect from a European
platform.
The second survey among registry holders was
dedicated to assess the feasibility of a set of Common
Data Elements (CDEs) from the existing RDs registries,
by exploring the data elements that are currently
collected by these registries.
The survey among patients was dedicated to
understand their needs and expectations from registries
and from the implementation of a common EU
framework for the registration of RD patients.
In the framework of EPIRARE, particular interest
and concrete actions have been devoted to monitor and
influence the debate in the EU Parliament on the draft
of the Regulation on General Personal Data Protection
and an on-line petition was launched on this matter48.
The work of the EPIRARE project resulted in two
publications until now49,50.
ERA-Net for Research Programmes on Rare Diseases
ERA-Net for Research Programmes on Rare Diseases
(E-RARE: 2006-2010, 2010-2014)51 is a project funded
by FP7, dedicated to transnational coordination of
research programmes on RDs (www.e-rare.eu).
E-Rare 2, which follows the successful
implementation of E-Rare-1 (2006-2010), aims at
deepening and extending the cooperation among partners
interested in the funding mechanisms for research on
RDs. It works through the systematic exchange of
information, the yearly launching of joint calls, the
assessment of the funding strategies and the strategic
activities for the sustainable development and the
extension of the network.
In order to reach this goal, the E-Rare Consortium
has gathered 17 funding agencies/ministries from 14
European and Associated countries. Since 2007, E-Rare
has launched and completed five joint transnational
calls for research projects on RDs whereby 249 research
groups belonging to 53 research consortia have been
supported for an investment of € 37,5 million.
In particular, the CNMR coordinates the WP
dedicated to update and expand the analysis on the
state of the art of RD research funding in Europe and
in selected countries outside Europe, in order to map
the current situation in these countries. The map will
reveal the existing opportunities and the unmet needs
throughout Europe.
E-Rare-2 activities contribute to reducing the
fragmentation of research and of resources through the
coordination and the transnational funding of excellent
research projects on RDs. This project has now become
a key reference point in the landscape of European
Transnational research funding on RDs.
European Network for Surveillance of Congenital
Anomalies Joint Action
The European Network for Surveillance of Congenital
Anomalies (EUROCAT) Joint Action (JA), was funded by
the Public Health Programme 2008-2013 of the European
Commission, to take place on the period January
2011-December 2013 (www.eurocat-network.eu)52.
This JA combines funding of the EU and MS in
order to secure a sustainable, high quality and easily
accessible information system on Congenital Anomalies
(CA). Its main objectives were the improvement of
surveillance and the identification of strategies for
primary prevention of CA, involving 36 Associate and
9 Collaborating Partners, and was structured into 9 WPs.
The CNMR has coordinated the WP7, which focused
on the effectiveness of CA primary prevention. The
central aspect was the role of folic acid in the incidence
of CA but other potential risk factors have been
investigated. Risk factors studied were: use of drugs in
pregnancy, effects of maternal infection and vaccination,
chronic diseases, environmental factors, alcohol and
smoking, and other maternal lifestyle issues. These
issues were translated into the "EUROCAT-EUROPLAN
Recommendations on policies to be considered for the
primary prevention of congenital anomalies in National
Plans and Strategies on Rare Diseases" as specified
in the section on Primary and Secondary Prevention28.
European Project for Rare Diseases National Plans
Development
The European Project for Rare Diseases
National Plans Development (EUROPLAN, www.
europlanproject.eu)53-57, which comprises two phases:
EUROPLAN I (2008-2011) and EUROPLAN II
(2012-2015), is co-funded by the EU Commission
(DG-SANCO) and is coordinated by the CNMR.
Its goal is to promote and implement National
Plans or Strategies (NP/S) for RDs, and to share
relevant experiences within Countries, linking national
efforts with a common strategy at European level.
This "double-level" approach ensures that progress is
globally coherent and follows common orientations
throughout Europe. Its main objective is to establish an
international and interactive network of stakeholders
(mainly policy makers) to speed up the elaboration and
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the implementation of NP/S for RDs, through scientific
and technical assistance, workshops and the active
participation of patient organisations (EURORDIS and
National Alliances).
EUROPLAN II builds on the achievements of the
first project, whose goals was to elaborate tools and
carry out activities to help EU Countries establish and
implement NP/S in the field of RDs, coherent with the
European Council Recommendations6. One of the tools
developed during the first phase was the development
of a set of 59 Indicators, as specified in the "Report
on indicators for monitoring the implementation and
evaluating the impact of National Plans or Strategies
for rare diseases"54.
In EUROPLAN II, WP 4 of the EUCERD Joint Action,
foresees the participation of EURORDIS and Associated
e Collaborating Partners from 33 Countries. EUROPLAN
II, means to provide technical and scientific support to
Countries with various geographical/economic concerns for
the elaboration of their NP/S for RDs. This is meant to be
achieved mainly through capacity building actions, which
include training and continuing technical and scientific
support for the sustainable development of the NP/S for RDs.
In order to achieve the project's objectives, a process
has been undertaken that comprises a number of steps:
1. a survey was carried out to identify strengths and
weaknesses in the definition of NP/S in each Country
context.
2. A set of 21 Core Indicators was defined, out of the
original list, and was selected on the bases of their
usefulness and feasibility to monitor health and social
planning. The selection was the result of a Delphi
Method organised by the ISS, then easily integrated
with those selected according to the participatory
process established by EURORDIS. This work
has contributed to the elaboration of the EUCERD
"Recommendations on Core Indicators for Rare
Disease National Plans/Strategies"58.
3. Debrief sessions have been organised at the end
of each national conference on RDs, to help local
governments to focus on weak areas that need
strengthening in order to develop effective NP/S.
This is the first effective action for defining the
collaboration and the other capacity building
activities.
4. The next steps foresee the CNMR and its partners,
along with the EU, providing the necessary support
for the development of NP/S for RDs and furnishing
all that is needed to guarantee its effective and timely
sustainability.
EU Tender on EU Newborn Screening
EU Tender on EU Newborn Screening (NBS)59 was
launched by the European Commission in July 2009 in
order to (1) report on the practices of neonatal screening for
RDs implemented in all MS, including number of centres,
to estimate the number of infants screened and the number
of disorders included in the NBS, as well as the criteria
adopted for the selection of the diseases to be screened; (2)
identify the types of clinical pathways implemented in MS;
(3) establish a network of experts to analyse the results and
formulate final recommendation on the best practices, as well
as on the core panel of NBS conditions that could be included
in all MS practices, and (4) develop a decision-making
matrix that could be used by member states' programmes
to systematically expand (or contract) screening mandates.
The project, coordinated by the CNMR, was
concluded in June 2011 with a consensus conference
where the deliverables produced were approved
by the members of the EU Network of Experts in
NBS (EUNENBS), nominated by the RD competent
authorities. The documents produced by the tender are
available at: http://ec.europa.eu/health/rare_diseases/
screening/index_en.htm and have given rise to a number
of publications on scientific journals.
A platform for sharing best practices for the
management of rare diseases
A platform for sharing best practices for the
management of rare diseases (RARE-Bestpractices)60
is is a four-year project (January 2013-December
2016), funded by the Seventh Framework Programme
of the European Union (FP7/2007-2013) (www.
rarebestpractices.eu).
The overall aim of the project is to improve the care
of patients by disseminating globally best practices for
the management of persons with RDs. The CNMR acts
as coordinator of 14 partners across Europe, all with a
strong commitment in research on RDs, public health
and evidence based medicine.
The project main objectives are:
Regarding guidelines
- to provide reliable informative resources for
the RD community by creating a collection of
methodologically trustworthy and up-to-date
guidelines for the management of RDs;
- to develop a standard methodology suitable for the
development of RD guidelines;
- to set up training activities and educational tools
targeted at key stakeholders for the production of
high quality RD guidelines.
Regarding Health Technology Assessment of orphan
drugs
- to ascertain cost-effectiveness assessment methods as
well as criteria for funding decision making process
of orphan drugs across European countries.
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Other key elements of the platform will be
the identification of mechanisms to address the
limitations of the evidence, set priorities for RD
research and propose improvements in pre-approval
and post-marketing studies.
Moreover, RARE-Bestpractices is supporting
the creation of a new international open access,
online, peer-reviewed journal: "RARE DISEASES
AND ORPHAN DRUGS. An International journal of
public health" (RARE Journal). RARE Journal is a
science journal, published three times per year with no
publishing fees for readers and authors and focuses on
important aspects of public health, health policy and
clinical research on RDs. More details are provided at
the website: http://rarejournal.org/rarejournal.
An integrated platform connecting databases,
registries, biobanks and clinical bioinformatics for
rare disease research
An integrated platform connecting databases,
registries, biobanks and clinical bioinformatics for rare
disease research (RD-Connect)61 is a six-year project
funded by the EC (7FP, 2012-2016) and the CNMR
coordinates the WP on RD registries.
RD-Connect is building a global infrastructure
connecting data from RD research into a central
resource for researchers across the world. RD-Connect
is developing an integrated platform in which "omics"
data will be combined with registries, clinical phenotype
information and biomaterial availability.
As therapeutic interventions are increasingly tailored
towards the underlying genetic defects, patient registries
need to include the genetic information of individual
patients in a standardised way. Several clinical research
networks, such as the one on CF, the one on Huntington
disease and neuromuscular diseases, have concentrated
efforts on a "new generation" of gene-specific patient
databases. These include genotype data and detailed
quality-controlled phenotype data and maintain the link
with the patient within a secure ethical framework and
in close collaboration with patient organisations. These
initiatives have a much broader range of clinical utility
than either locus-specific genetic databases (which are
often anonymous and thus have no link to the patient
for trial recruitment) or registries that do not collect
genetic information and thus cannot facilitate cohort
selection for trials.
These next-generation registries have facilitated
numerous studies including clinical trials, generated
investments by commercial partners, and resulted in
better treatments. The WP2 coordinated by the CNMR
directly answers the need to harmonise and standardise
global databases and patient registries for RDs in order
to maximise their utility for "omics" and other research.
Social Economic Burden and Health-related Quality
of Life in Patients with Rare Diseases in Europe
Social Economic Burden and Health-related Quality
of Life in Patients with Rare Diseases in Europe
(BURQOL-RD;www.burqol-rd.com)62 was a 3-year
project under the 2nd Programme of Community
Action in the Field of Public Health, commenced in
April 2010 and ended in October 2013. It was funded
by DG SANCO to generate a model to quantify the
socio-economic costs and Health Related Quality of
Life (HRQOL), of both patients and caregivers, for up
to 10 RDs in different European countries.
The general objective of this project was to develop
a disease based model capable of quantifying the socioeconomic burden and the HRQOL of RD patients in
Europe and of their caregivers. The model has to be
adaptable and sufficiently sensitive to capture the
differences in the distinct Health and Social Care
Systems in the EU MS.
BURQOL-RD represents the most complete and
realistic costing of the burden of RDs performed in
European countries to date. The results of the project
show that the healthcare costs of RDs are very
substantial. However, other social costs are even higher,
such as loss of labour productivity and that of formal or
informal care, representing significant hidden costs that
should be made apparent to society.
The information generated by the BURQOL-RD
consortium will help:
- policy makers design future policies in the area of
RDs, which will ultimately have positive benefits
for EU citizens' health, both of patients and of their
caregivers;
- patient organisations and RD Federations to give
more weight to their requirements when addressing
health policy makers;
- scientific community to stimulate future research in
the field of RDs transferring the protocols established
to other RDs and to other countries.
Story Telling on Record
Story Telling on Record (S.T.o.Re. - www.
storeproject.eu) is a 2-year European partnership funded
in the Lifelong Learning Programme (Leonardo da Vinci
Multilateral Partnerships August 2013 - July 2015). The
project is coordinated by the CNMR, involves 7 partners
from 6 Countries and foresees 4 partners' meetings and
a final conference in Italy.
The objective is to design an action-research that
includes: (a) training participants, giving them the
knowledge and the skills necessary to design, test and
train people in the use of Integrated Medical Records
(IMRs), and (b) organise courses on the use of IMRs for
health care system personnel.
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The results of the project will be disseminated
through a dedicated website, scientific reports and
2 booklets (toolkits in English and in the Partners'
languages, tailored to patient organisations and to Health
institutions and professionals).
4. Information and communication
The CNMR uses different channels for information
and communication purposes.
The Institutional site
The CNMR holds a portal on RDs63 which provides
topics of interest to RD patients, to the scientific
community and to anyone interested in RDs and includes
a user friendly tool for searching disease-specific
information.
National helpline for Rare Diseases
In order to provide quality information on RDs,
a national telephone helpline for RDs (TVMR)64 was
established at the CNMR in February 2008. It is a public,
toll-free service that can be reached by composing the
phone number 800.89.69.49 or via e-mail at: tvmr@
iss.it. The service is active 5 days per week, from 9 am
to 1 pm.
A team of psychologists and medical doctors trained
and experienced in telephone counselling, public health
policies and management of RDs are involved. The main
aim of the service is to gather and provide information,
through an active and personalised listening, on several
issues regarding RDs, such as exemptions from the
costs of medical cares, clinical centres, national and
international centres of expertise, coordination of
care, clinical trials for specific conditions running in
Italy and abroad, patient organisations, how to get in
contact with other patients, access to drugs and special
services. Medical information regards rare, ultra-rare
and relatively "common" rare conditions and refers, as
a source of data, to the international scientific literature
and to the main European and international databases
on RDs. The service is addressed to any individual with
an interest in RDs: patients and their relatives, health
care professionals, clinicians, researchers, and patient
organisations. Information is accurate and up-to-date and
is meant to support and encourage patients and family
members to face and solve specific problems and needs
related to RDs.
To date, more than 17,000 enquires (most of them
phone calls) have been received and worked on. Calls are
rather equally distributed over the different geographic
areas of the country. Notably, one of the commonest
purposes of calls and complaints is about undiagnosed
diseases and/or on how to find the most appropriate
specialist for a given suspected disease.
Since 2012, TVMR is part of a European network
of email and telephone help lines for RDs coordinated
by EURORDIS.
Publications
The CNMR produces every year a number of
publications, including articles for national, European
and international journals on the activities of the Centre,
brochures, posters and other relevant material.
In order to expand its information strategy and
highlight the broad range of national and international
activities in the field of scientific research and public
health, in 2007, the CNMR has initiated the publication
of the Supplement of the ISS Bulletin on "Rare diseases
and orphan drugs".
The journal provides an overview of the CNMR
activities and, more generally, of all matters related to RDs,
from research to patient organisations. Divided into several
sections, the Bulletin is addressed to general practitioners,
to the personnel responsible for public health at regional
and national level, to patients, family members or patient
groups and to all those interested in RDs.
The publication is distributed both in paper form,
especially during scientific-informative events, and in
a digital format, published in the website of the ISS and
of the CNMR. The journal is also sent by e-mail to the
CNMR mailing list.
5. Education, training and empowerment
Every year, the CNMR organises a number of
education and training activities on RDs65,66 directed
to various stakeholders (patients and their families,
patient organisations, physicians, nurse practitioners,
paediatricians, residents of professional schools, etc.).
Training of patients and families
The CNMR is developing a programme of continuing
education in RD patient identification, referral and
management, addressed to GPs and other health
professionals. The Centre has also carried out a number
of courses, addressed to patient organisations, aiming
at empowering RD patients, as well as their families, in
the daily management of their disease.
Courses for the members of patient organisations
The CNMR has organised several training courses
dedicated to the members of patient organisations.
Among these it is worth mentioning:
1. "Implementation and evaluation of a training
programme on orphan drugs targeting patient
associations and families of patients with rare
diseases" (2008-2010), a participatory training
of trainers course on one of the major needs
expressed by patients: orphan drugs (including
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Taruscio D et al
steps and challenges related to their development
and commercialisation) and issues related to the
accessibility of treatment for RDs. The course used
Problem Based Learning (PBL) and the production
of a Project work on the elaboration of a training
and information programme on orphan drugs to be
realised in the associations to which participants
belonged.
2. The course on "Parent Training on Prader-Willi
syndrome" was to engage the parents of children
with PWS in order to improve their relationship with
the children and children's behaviour, to increase
the knowledge on PWS and to empower parents
in managing their children. The intervention was
offered to 32 parents coming from different Italian
regions. The Parent Training programme consisted
of twelve sessions of 2,3hours (from September
2008 to February 2009), and was conducted by
two moderators: a psychologist and a parent with
experience in parent training methods. Several
questionnaires have been elaborated for the
evaluation of the programme. Results from this study
have suggested that parent training is a promising
intervention for parents of children with behaviour
problems. Thus, the next steps are to disseminate this
intervention model to other RDs.
Training activities for the NHS personnel
In order to contribute to improving the quality of
health care offered to patients with RDs, the CNMR - in
collaboration with other institutions and organisations has organised, for many years, educational interventions
for health and social personnel of the NHS. One of the
most interesting training activity at the national level
was the course "Rare diseases: diagnostic suspicion
and effective communication", intended for General
Practitioners and Paediatricians. Designed originally
for the personnel of a local health organisation in the
province of Rome, the course was then replicated in
other Italian regions. It used PBL and a "one day/one
problem" approach, to make the training model flexible
and usable in a variety of contexts.
Similar initiatives, targeted at clinicians and health
professionals, also arise from the collaboration with
organisations: an example is a course on congenital
vascular malformations within the project "Promoting
the network for general practitioners and paediatricians"
(October 2013).
In addition to courses on RDs, training programmes
on specific topics such as guidelines, narrative medicine,
disease registries, helpline on RDs, have also been
carried out. Furthermore, the CNMR's researchers
offer numerous lectures on national and international
projects, oral presentations and posters, in collaboration
with institutions, scientific societies and/or patient
organisations.
Advanced national and international courses and
e-learning experience
Followig are some of the Centre's most significant
experiences regarding advanced of training.
- Summer School on Guidelines
In order to improve knowledge and adoption
of RDs guidelines, the CNMR has organised since
2012 the International Summer School on "Clinical
practices guidelines on rare diseases". The one-week
intense course means to provide participants with
the methodological basis for the development of RD
guidelines. It also gives an introduction of the commonly
used standards for the assessment of existing guidelines.
The international team of trainers facilitates an
informal and interactive learning environment, offering
useful insights for discussion and stimulating the
exchange of experiences between colleagues coming
from different countries. The official language is English.
- Summer School on Registries
The first edition of the Summer School on RDs
and orphan drug registries was in October 2013 and
the second edition is planned to take place on 15-19
September 2014. The course takes the participants
through the main concepts and practical steps that must
be undertaken in the establishment and management
of a RD registry to ensure its usefulness, soundness
and sustainability. It provides basic notions on the
methodology of observational studies, on the selection of
data elements, on quality assurance and on the technical
and legal tools that must be adopted to protect patients'
data confidentiality. The course consists of frontal
presentations followed by small group exercises. The
official language is English.
- Distance learning
The CNMR has organised, in collaboration with
the Distance Learning (FAD)67-69 working group of
the External Relation Office/ISS, a 5 modules training
course on "The prevention of congenital defects in
the peri-conceptional and peri-natal: risk factors and
protective factors for pregnancy" supported by a specific
project funded by the Italian MOH. The training used an
interactive and experiential methodology - PBL - which
is normally used in classroom training. Therefore, using
PBL in FAD, presented aspects of training innovation70.
More than 1,000 health professionals attended this
e-learning course. One year after the training, a
"Follow-up skills questionnaire" was administered to
course participants to assess their perceived impact of
the course on learning, on their professional practice,
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Italian National Centre Rare Diseases: research and public health
on opinions and attitudes towards the improvement of
the promotion of folic acid supplementation.
The data collected from the questionnaire shows
an increased awareness and an improved quality of the
participants professional practice, with more attention
paid to health promotion and primary prevention.
According to the data analysis, knowledge increased
of about 30% and about 80% of the participants
thought that the course provided a positive contribution
to change their professional activities. Overall, the
participants evaluated positively the learning experience,
appreciating the opportunity to attend an e-learning
programme with such an innovative methodology71.
- Capacity building activities
Recently, the CNMR has initiated activities of
capacity building in the framework of the EUROPLAN
project, on request of the EU. Capacity Building is a
conceptual approach to development that focuses on
understanding the obstacles that inhibit governments
from realizing their developmental goals, while
enhancing their abilities that will allow them to achieve
measurable and sustainable results.
Capacity building is a process and starts with the
definition of needs and the obstacles that hinder progress
in achieving the results. It includes all those actions that
allow the Government to accomplish specific objectives
and maintain the results over the time. Activities, tailored to
each situation, include the training of human resources but
are not limited to it. It comprises technical support and other
strengthening efforts. The experience in capacity building
that will be gained in the EUROPLAN II project will be
useful for other active sectors of the Centre's areas of interest.
6. Networks and collaborations
The CNMR base most its work on networking and
on effective collaboration at national, European and
international level. Evidence of this effort is found in
the description of the research activities, of the projects
and of the many actions related to RDs. Furthermore,
the CNMR participates, through its staff, in different
national and international committees. Among these, it
is worth mentioning the CNMR participation in:
- the Italian Clinical Trial Phase I Committee, which
is the national committee that authorises Phase I
clinical studies of new drugs;
- the Committee for Orphan Medicinal Products
(COMP), at the European Medicines Agency (EMA);
- the EU Commission Expert Group on Rare Diseases.
Discussion and final considerations
RDs have undoubtedly been on the European agenda
since the early 1990s. While a disease might be defined
as "rare", the number of persons in Europe suffering from
a RD is estimated to be between 27 and 36 million, or 6
to 8% of the European population.
Insufficient resources are dedicated to research for
RDs and these, as well as expertise in these conditions,
is fragmented across individual EU countries. Likewise,
limited resources are devoted to improve ability and
competencies in diagnosis, treatment and care of RDs
patients throughout Europe. For this purpose, a number
of documents and recommendations have been issued by
the EU advising MS to take action in addressing RDs in
their National context. In particular, a recommendation
called on all EU MS to develop plans or strategies for
RDs by 2013, in order to ensure universal access of RD
patients to high quality care.
The Italian Government has taken factual steps in
recognising the importance of RDs and has complied
with some of the main Council Recommendations.
Nevertheless, Italy has no National Plan for Rare
Diseases yet72, and this remains an open issue for
this country. Likewise, the exclusion of some/most
RDs from the list that would exempt individuals with
RDs from paying for disease-related services creates
inequities among the patients population. The low level
of investments in scientific research, the insufficient
number of specialised infrastructures and their uneven
geographical distribution, along with the lack of
knowledge of many RDs, make diagnosis and treatment
difficult, delayed and costly. Often, RD patients have
to migrate from one region to another, or even travel
abroad, in search of a diagnosis or appropriate treatment.
Without any doubt, it can be stated that RD patients,
in addition to the heavy burden of the disease, face
heavy inequalities in the access to care and services.
RDs do not only affect diagnosed people, but also their
families, friends, caregivers and society as a whole. It
is not uncommon for families of RD patients to end
up impoverishing themselves in the effort to obtain a
proper and timely diagnosis or an appropriate treatment
for their diseased relatives. These open challenges
require the utmost attention by the Government and by
all stakeholders, both at Italian and at European level.
Particularly relevant is the action of patient
organisations which, by voicing the real instances of
RD patients, can be catalyst of more positive and rapid
societal changes. Their consistent call for policies and
programmes that aim at improving the quality of life
of all people living with RDs should produce effective
results. The Italian patient organisations are proactive
and it is hopeful that their positive and determinate action
can bring about a better future for Italian RD patients
and for their families.
Since its establishment in 2008, the CNMR has
developed and carried out a wide range of activities
tackling old and new RD challenges in a comprehensive
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Taruscio D et al
and integrated manner. Innovation, enthusiasm, scientific
rigour, quality, vision and hard work are the basic
values on which the dynamic group of professionals,
that constitute the CNMR, base their daily work. Their
strategy is to gather essential elements of experimental
research, acquire the newest and most relevant public
health findings and translate both into effective and
efficient actions for the prevention, surveillance,
diagnosis and treatment of RDs in Italy. They also
participate in the on-going research and action on RDs
in Europe and at international level and thus contribute to
improving the quality of life and the care of RD patients
in Italy and elsewhere.
Keywords: rare diseases, orphan drugs, experimental
research, public health, registries.
The Authors declare no conflict of interest.
References
1)
2)
3)
4)
5)
6)
7)
8)
9)
10)
11)
12)
13)
Italia. Decreto Ministeriale 26 giugno 2008. Norme per
l'organizzazione strutturale e la disciplina del rapporto di
lavoro dei dipendenti dell'Istituto Superiore di Sanità. Centro
Nazionale delle Malattie Rare, missione: ricerca, consulenza e
documentazione sulle malattie rare e farmaci orfani finalizzata
a prevenzione, trattamento e sorveglianza. Gazzetta Ufficiale
Serie Generale n. 157, 7 luglio 2008.
Commission of the European Communities. Proposal for a
Council Recommendation on a European action in the field
of rare diseases. COM(2008); 726 final.
Italia. Decreto Ministeriale 18 Maggio 2001, n. 279.
Regolamento di istituzione della rete nazionale delle malattie
rare e di esenzione dalla partecipazione al costo delle relative
prestazioni sanitarie, ai sensi dell'articolo 5, comma 1, lettera
b), del decreto legislativo 29 aprile 1998, n. 124. Gazzetta
Ufficiale - Serie Generale n. 160, 12 luglio 2001. Suppl. Ord.
n. 180/L.
Commission of the European Communities. Communication
on the framework for action in the field of public health.
COM(1993); 559.
European Parliament and Council. Regulation (EC) 141/2000
of the European Parliament and of the Council of 16 December
1999 on orphan medicinal products. Official Journal 2000;
L 18:1-5.
European Council. Recommendation of 8 June 2009 on
European action in the field of rare diseases. Official Journal
C151:7-10.
European Parliament and Council. Directive 2011/24/EU of
the European Parliament and of the Council of 9 March 2011
on the application of patients' rights in cross-border healthcare.
Official Journal of the European Union 2011; L 88/45
Commission of the European Communities. Decision of 30
November 2009 establishing a European Union Committee
of Experts on Rare Diseases 2009; 872.
Commission of the European Communities. Decision of
30 July 2013 setting up a Commission expert group on rare
diseases and repealing Decision 2009/872/EC (2013/C 219/04)
The Italian Federation for Rare Diseases - UNIAMO. Available
at: http://www.uniamo.org. Accessed on 15/01/2014.
European Organisation for Rare Diseases - EURORDIS.
Available at: https://www.eurordis.org. Accessed on
15/01/2014.
The National Council for RDs. Available at: http://www.
cndmr-insieme.it/. Accessed on 15/01/2014
The Italian Movement for Rare Patients - MIR. Available at:
http://www.movimentorari.it/mir/. Accessed on 15/01/2014
14) International Rare Diseases Research Consortium - IRDiRC.
Available at: http://www.irdirc.org/. Accessed on 15/01/2014.
15) Taruscio D, Salvatore M, Magrelli A, Tomanin R. Predictive
medicine and biomarkers: the case of rare diseases.
Personalized Medicine 2012; 9: 143-6.
16) Taruscio D, Salvatore M, Magrelli A. The Role of microRNAs
in the Biology of Rare Diseases. Int J Mol Sci. 2011; 12 (10):
6733-42.
17) Magrelli A, Azzalin G, Salvatore M, et al. Altered microRNA
Expression Patterns in Hepatoblastoma Patients. Transl Oncol.
2009, 2: 157-63.
18) Matteucci A, Gaddini L, Macchia G, et al. Developmental
expression of dysbindin in Muller cells of rat retina.
Experimental eye research 2013; 116C: 1-8.
19) Fratini F, Macchia G, Torreri P, et al. Phosphorylation on
threonine 11 of ß-dystrobrevin alters its interaction with
kinesin heavy chain. FEBS journal 2012; 279: 4131-4.
20) Saulle E, Guerriero R, Petronelli A, et al. Autocrine role of
angiopoietins during megakaryocytic differentiation. PLoS
One. 2012; 7: e39796.
21) D'Arcangelo G, Grossi D, De Chiara G, et al. Glutamatergic
neurotransmission in a mouse model of Niemann-Pick Type
C Disease. Brain Res. 2011; 1396: 11-9.
22) Petrini S, Minnone G, Coccetti M, et al. Monocytes
and macrophages as biomarkers for the diagnosis of
megalencephalic leukoencephalopathy with subcortical cysts.
Molecular and Cellular Neuroscience 2013; 56: 307-21.
23) Villa L, Carattoli A, Nordmann P, et al. Complete sequence of
the IncT-type plasmid pT-OXA-181 carrying the blaOXA-181
carbapenemase gene from Citrobacter freundii. Antimicrob
Agents Chemother. 2013; 57: 1965-7.
24) Sassera D, Leardini I, Villa L, et al. Draft Genome Sequence
of Stenotrophomonas maltophilia Strain EPM1, Found in
Association with a Culture of the Human Parasite Giardia
duodenalis. Genome Announc. 2013; 1: e0018213.
25) Salerno P, Bianchi F, Pierini A, et al. Folic acid and congenital
malformation: scientific evidence and public health strategies.
Ann Ig. 2008; 20: 519-30.
26) Taruscio D, Carbone P, Granata O, et al. Folic acid and primary
prevention of birth defects. Biofactors. 2011, 37: 280-4.
27) ESCO Report on Analysis of Risks and Benefits of
Fortification of Food with Folic Acid. EFSA 2009.
28) EUROCAT (European Surveillance of Congenital Anomalies)
and EUROPLAN (European Project for Rare Diseases
National Plans Development) Primary prevention of
congenital anomalies. Recommendations on policies to be
considered for the primary prevention of congenital anomalies
in National Plans and Strategies on Rare Diseases. Available
at: http://www.eucerd.eu/wp-content/uploads/2013/03/
Eurocat_Reco_PrimaryPrevention.pdf. Accessed on
15/01/2014.
29) Cornel MC, Rigter T, Weinreich SS, et al. A framework to
start the debate on neonatal screening policies in the EU: an
Expert Opinion Document. Eur J Hum Genet. 2014; 22: 12-7.
30) Loeber JG, Burgard P, Cornel MC, et al. Newborn screening
programmes in Europe; arguments and efforts regarding
harmonization. Part 1. From blood spot to screening result. J
Inherit Metab Dis. 2012; 35: 603-11.
31) Burgard P, Rupp K, Lindner M, et al. Newborn screening
programmes in Europe; arguments and efforts regarding
harmonization. Part 2. From screening laboratory results to
treatment, follow-up and quality assurance. J Inherit Metab
Dis. 2012; 35: 613-25.
32) Carbone P, Sanseverino A, Granata O, et al. Expanded newborn
screening: an operative model for prevention of inborn errors
of metabolism. Not Ist Super Sanità 2013; 26 (Suppl. 1): 6-9.
33) Italia. Accordo Stato - regioni dell'11 luglio 2002 (repertorio
1485/CSR).
34) Italia. Accordo Stato - regioni del 10 maggio 2007 (repertorio
103/CSR).
35) Taruscio D (Ed). Il Registro Nazionale e i Registri Regionali/
interregionali delle malattie rare. Rapporto anno 2011. Roma:
Istituto Superiore di Sanità; 2011 (Rapporti ISTISAN 11/20).
Blood Transfus 2014; 12 Suppl 3: s591-605 DOI 10.2450/2014.0040-14s
s604
Italian National Centre Rare Diseases: research and public health
36) Abbonizio F, Giampaolo A, Arcieri R, Hassan HJ, AICE.
Registro Nazionale delle Coagulopatie Congenite. Rapporto
2011. Roma: Istituto Superiore di Sanità; 2012. (Rapporti
ISTISAN 12/55).
37) Hassan HJ, Morfini M, Taruscio D, et al. Current Status of
Italian Registries on inherited bleeding disorders. Blood
Transfus 2014; 12 (Suppl 3): s576-81.
38) Genetic Testing: A Survey of Quality Assurance and
Proficiency Standards. Available at: http://www.oecd.org/sti/
biotech/genetictestingasurveyofqualityassuranceandproficie
ncystandards.htm; Accessed on 15/01/2014.
39) Orlando C, Verderio P, Maatman R, et al. EQUAL-qual: a
European program for external quality assessment of genomic
DNA extraction and PCR amplification. Clin Chem. 2007;
53:1349-57.
40) Floridia G, Falbo V, Censi F, et al. The Italian external quality
assessment scheme in classical cytogenetics: four years of
activity. Community Genet. 2008; 11: 295-303.
41) Censi F, Tosto F, Floridia G, et al. The Italian National External
Quality Assessment programme in molecular genetic testing:
results of the VII round (2010-2011). Biomed Res Int. 2013,
doi: 10.1155/2013/739010.
42) Italia. Decreto Presidenziale. Tariffario dei servizi resi a
pagamento dall'Istituto Superiore di Sanità Gazzetta Ufficiale
Serie Generale n. 199 del7/7/2008
43) Taylor CJ, Hardcastle J, Southern KW. Physiological
measurements confirming the diagnosis of cystic fibrosis:
the sweat test and measurements of transepithelial potential
difference. Paediatr Respir Rev. 2009; 10: 220-6.
44) Charon R. Narrative medicine. A Model for Empathy,
Reflection, Profession and Trust. JAMA. 2001; 286: 1897-902.
45) Gentile AE, Taruscio D. Conclusioni. Le parole nel tempio. In
"Narrazione e disabilità intellettiva. Valorizzare le esperienze
individuali nei percorsi educativi e di cura" a cura di Ruggerini
C, Manzotti, S, Griffo G, Veglia F, in "Le Guide Erickson.
Metodologie e percorsi per la didattica, l'educazione, la
riabilitazione, il recupero e il sostegno" Collana diretta da
Dario Ianes. 2013, Edizioni Erickson, Trento.
46) Luzi I, Gentile AE, Taruscio D (Ed.). First International
Congress Narrative Medicine and Rare Diseases. Istituto
Superiore di Sanità. Rome, June 4, 2012. Proceedings. Roma:
Istituto Superiore di Sanità; 2013. (Rapporti ISTISAN 13/13).
47) European Platform for Rare Disease Registries. Available at:
http://www.epirare.eu/. Accessed on 15/01/2014
48) Vittozzi L. Don't Stop Research on Rare Diseases! Available at:
http://www.change.org/en-GB/petitions/don-t-stop-researchon-rare-diseases-2. Accessed on 15/01/2014.
49) Taruscio D, Gainotti S, Mollo E, et al. The current situation
and needs of rare disease registries in Europe. Pub. Health
Genomics 2013; 16: 288-98.
50) Vittozzi L, Gainotti S, Mollo E, et al. A Model for the European
Platform for Rare Disease Registries. Pub. Health Genomics
2013; 16: 299-304.
51) ERA-Net for Research Programmes on Rare Diseases.
Available at: http://www.e-rare.eu/. Accessed on 15/01/2014.
52) European Network for surveillance of Congenital Anomalies.
Available at: http://www.eurocat-network.eu/aboutus/
jointactioneurocat. Accessed on 15/01/2014.
53) The European Project for Rare Diseases National Plans
Development (EUROPLAN). Available at: http://www.
europlanproject.eu/. Accessed on 15/01/2014.
54) Report on EU Member States initiatives, with previous and
current experiences on rare diseases. Available at http://www.
europlanproject.eu/_newsite_986989/Resources/docs/20082011_1.EUCERDReport.pdf. Accessed on 15/01/2014.
55) Taruscio D, Gentile AE, De Santis M, et al. National Plans
on rare diseases. In Meral Özgüç (Editor) «Rare Diseases:
Integrative PPPM Approach as the Medicine of the Future»,
Series: Advances in Predictive, Preventive and Personalised
Medicine, Springer (in press).
56) Taruscio D, Gentile AE, De Santis M, et al. EUROPLAN: A
Project to Support the Development of National Plans on Rare
Diseases in Europe. Public Health Genomics 2013; 16: 278-87.
57) Taruscio D, Vittozzi L, Stefanov R. National plans and
strategies on rare diseases in Europe. Adv Exp Med Biol
2010; 686: 475-91.
58) EUCERD Recommendations on Core Indicators for RD
National Plans/Strategies (June 2013b). Available at http://
www.eucerd.eu/wp-content/uploads/2013/06/EUCERD_
Recommendations_Indicators_adopted.pdf. Accessed on
15/01/2014.
59) EU Tenders: Evaluation of population newborn screening
practices for rare disorders in Member States of the European
Union Rare diseases - New born screening. Available at: http://
ec.europa.eu/eahc/health/tenders_H09C2.html. Accessed on
15/01/2014.
60) RARE-Bestpractices A platform for sharing best practices for
the management of rare diseases. Available at: http://www.
rarebestpractices.eu/home. Accessed on 15/01/2014.
61) An integrated platform connecting databases, registries,
biobanks and clinical bioinformatics for rare disease research
-RD-Connect. Available at: http://rd-connect.eu/. Accessed
on 15/01/2014.
62) Social economic burden and health-related quality of life
in patients with rare diseases in Europe. Available at: http://
burqol-rd.com/index.html Accessed on 15/01/2014.
63) Italian National Center for Rare Diseases. Available at: http://
www.iss.it/cnmr. Accessed on 15/01/2014.
64) Taruscio D, Gentile AE. Approfondimento. Il Telefono
Verde Malattie Rare (TVMR - 800 89 69 49) dell'Istituto
Superiore di Sanità. In: Cognetti G, Il grano e il loglio: viaggio
nell'informazione sulla salute in internet per i cittadini. 2012;
8: 107.
65) Ferrelli RM, Gentile AE, De Virgilio G, Taruscio D. Training
general practitioners and paediatricians on rare disease
diagnostic suspect and effective communication [abstract].
European Conference on Rare Diseases and Orphan Products
2012 Brussels.
66) Ferrelli RM, Gentile AE, Coclite D, et al. Integrazione di
competenze tecniche e metodologiche in ISS: l'esempio della
formazione dei medici di medicina generale sulle malattie
rare. Notiziario dell'Istituto Superiore di Sanità 2011; 24: 3-6.
67) Carbone P, Granata O, Barbina D, et al. Stato delle conoscenze
degli operatori sanitari sulla prevenzione di difetti congeniti
con acido folico: le evidenze scaturite da un corso E-learning.
Network Italiano Promozione Acido Folico per la Prevenzione
Primaria di Difetti Congeniti e Coordinamento Nazionale dei
Registri delle Malformazioni Congenite, ISTISAN Congressi.
2010; 10 (C6): 15-6.
68) Granata O, Carbone P, Barbina D, et al. Il contributo della
formazione a distanza nella promozione attiva dell'acido folico
per la prevenzione di difetti congeniti: risultati di un followup sulle attitudini e i comportamenti degli operatori sanitari.
ISTISAN Congressi 2010; 10 (C6): 18-9.
69) Carbone P, Baldi F, Barbina D, et al. Realizzazione di un
percorso di formazione e-learning: La prevenzione dei difetti
congeniti nel periodo peri-concezionale e peri-natale - Fattori
di rischio e fattori protettivi per la gravidanza. ISTISAN
Congressi. 2009; 09 (C8): 32-3.
70) De Vita L, Barbina D, Bonciani M, et al. Il metodo
dell'apprendimento per problemi in un corso di formazione
a distanza sulla prevenzione delle malformazioni congenite.
ISTISAN Congressi. 2009; 09 (C8): 36-7.
71) Granata O, Carbone P, Taruscio D. Attività di formazione e
informazione per la prevenzione primaria di difetti congeniti.
Rapporti ISTISAN 2013; 13/28, 85-98.
72) Congiu ME. Italian National Plan for rare diseases. Blood
Transfus 2014; 12 (Suppl 3): s614-6.
Correspondence: Domenica Taruscio
Italian National Centre for Rare Diseases - Istituto Superiore di Sanità
Viale Regina Elena 299
00161 Rome, Italy
e-mail: domenica.taruscio@iss.it
Blood Transfus 2014; 12 Suppl 3: s591-605 DOI 10.2450/2014.0040-14s
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ORIGINAL ARTICLE
The Italian National Rare Diseases Registry
Domenica Taruscio, Yllka Kodra, Gianluca Ferrari, Luciano Vittozzi and the National Rare Diseases
Registry Collaborating Group
National Centre for Rare Diseases, Istituto Superiore di Sanità, Rome, Italy
Introduction. Rare disease registries are a priority at European level and specific actions are
being implemented by the European Commission to support their development.
In Italy, a National Registry of rare diseases has been established in 2001 as a network of regional
registries. The latter have gradually been established and the full coverage of the Italian territory was
attained during 2011.
Methods. Here we describe the basic features of the National Registry of rare diseases; the
activities carried out to promote consistent operations in the regional registries; and the overall quality
and composition of the records collected.
Results. After a validation process, including removal of duplicate records, 110,841 records of
patients with rare diseases, single and with group denominations, are stored in the National Registry
of rare diseases. They correspond to the overall diagnoses communicated to national registry by
regional registries up to 30 June 2012.
The quality of the data collected by the the National Registry of rare diseases has been assessed
with respect to completeness and consistency of procedures. Variables characterising case and
diagnosis showed a very limited number of missing values. Records reported at least one case of
485 rare conditions.
Discussion. To date, the National Registry of rare diseases is a surveillance system with the main
objective of producing epidemiologic evidence on rare diseases in Italy, and of supporting policy
making and health services planning.
Data quality still represents a limitation for any sound epidemiological estimate of rare diseases
in Italy. However, improvements of the quality of collected data and the completeness of case
notifications should be strengthened.
Keywords: Italy, rare diseases, registry, public health.
Introduction
Rare Diseases (RD) are a special challenge for the
healthcare systems, because of their limited knowledge
about their natural history, chronicity, need for long-term
follow-up and potential high demand for assistance.
Sound data on their prevalence and incidence are scantly
available1 but, since they are as many as 7-8,000, it is
estimated that, in the European Union only they affect
about 29 million people2. Thus, the term "Registry" in the
field of RD means more than a common epidemiologic
tool for collection of secondary data related to patients
with a specific RD diagnosis. Indeed, RD registries
represent an effective way to achieve a sufficient
sample size for epidemiological and clinical research3-5.
Therefore, RD registries are key instruments for the
surveillance of these diseases, with the aim of improving
patient care and health care planning6. For these reasons
registries are a priority at European level in the field of
rare diseases2,7 and specific actions are being implemented
to support the development of RD registries8.
A national institutional registry of rare disease
patients, the Registro Nazionale Malattie Rare (RNMR),
has been established in Italy in 2001 and is run by the
National Centre for Rare Diseases (Centro Nazionale
Malattie Rare, CNMR) of the Istituto Superiore di Sanità
(National Institute of Health). Since then, the national
and regional health authorities have cooperated for its
implementation and after some years necessary for the
development of the local communication networks and
of the gradual establishment of the regional registries
(RRs), the system achieved the full coverage of the
national territory during 2011.
In consideration of the expected developments
resulting from the European Union initiatives, this
paper presents the main steps of the implementation of
the RNMR and its main achievements, with the aim of
sharing the RNMR experience with scientists and policy
makers in the field of RD.
Blood Transfus 2014; 12 Suppl 3: s606-13 DOI 10.2450/2014.0064-14s
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© SIMTI Servizi Srl
The Italian RD Registry
Methods
Legal basis, integration in the health system and
scope of the RNMR
The RNMR has been established at the National
Institute of Health by Ministerial Decree (MD) in 2001
as part of the measures devoted to improve health
care for RD patients9. Indeed, it also envisaged the
establishment, at regional or interregional level, of a
network of formally designated centres (FDCs) with
recognised expertise on RD, which could carry out
the confirmatory investigations free of charge for the
suspect patient, ensure a better and more effective
patient management and ascertain the right of the patient
to RD clinical assistance and treatments. This decree
made reference to a list of 314 individual RD identified
with own codes and 52 groups and subgroups of RD
with group codes. Within these groups, 160 example
pathologies were mentioned. The RNMR mandate was
to monitor RD and inform the national and regional
planning of measures for the protection of RD patients.
The decree also explicitly mentioned the faculty for
RNMR to liaise with international registries and to
collect demographic, anamnesis, clinical, laboratory,
determinant data of use for medical, biomedical and
epidemiological research. Patient pseudonymization and
the possibility of patient tracing in case of need were
allowed in compliance with data protection legislation.
Due to the devolved organisation of the Italian health
system, which gives the Regions the responsibility for
the delivery of health services, the MD provided that the
RNMR was functionally linked to RRs, which were to
be established by regional authorities. Two agreements
between the Central Government and the Regional
Authorities, in 2002 and 2007, ensured the coordinated
implementation of the RRs, defining the set of variables
and the procedures for the data communication between
the RRs and the RNMR10,11.
Establishment of regional registries
Following the MD, to ensure the delivery of RD
special assistance, the regional authorities proceeded
to the designation of their FDCs on the basis of criteria
related to competence in the diagnosis, care and
treatment of RD and to the availability of appropriate
complementary services. Subsequently, the regional
authorities established the RRs with regional decrees
and other regulations, which ensured the necessary
infrastructures as well as the legitimacy and security
of the data flow from the FDCs to the corresponding
RRs in compliance with the personal data protection
legislation. In many cases, specific information systems
have been developed at regional level with the aim of
supporting the data collection and in some cases, the
delivery of health care services to RD patients. The RRs
may differ in aims and internal organisation: some have
mainly epidemiological and public health purposes, in
support of regional planning, while others also aim at
evaluating health services and diagnostic procedures, or
are integrated in the regional health care delivery system.
Data set and data communication
A common data set for the communication of data
from the RRs to the RNMR was defined to fulfil the
mandate of RNMR. This set is detailed in Table I. The
diagnosis was expressed according to the exemption
code attributed by the MD. The RRs sent RNMR the
data batches regarding confirmed diagnoses made by
their FDCs in each semester of the calendar year. Data
communication took place normally during January
and July. This practice is changing to an annual transfer
based on whole calendar years.
Table I - The common data set of the RNMR.
Variables
Reason
ID (encrypted code based on given
name, family name, birth date and
place, sex)
Avoid multiple registrations of the
same patient; conduct any type of
record linkage
Sex
Epidemiologic analysis
Date of birth
Age at disease onset, diagnosis, death
Place of residence
Prevalence, geographical distribution,
patient mobility
Live - dead condition
Prevalence
Date of death
Prevalence; age at death
Diagnosis of rare disease
Epidemiologic analysis
Date of diagnosis
Incidence; diagnosis delay
Centre of RD diagnosis
Patient mobility; health service
utilization
Date of disease onset
Incidence; diagnosis delay
Orphan drug used
Treatment monitoring
Training of the operators
Statisticians and computer technicians of the RNMR
have held training courses from 2002 to 2009 to the
Regions without a proprietary rare diseases registry to
introduce the operators of the RRs to the proprietary
software developed by CNMR and to standardize the
methods used to collect the data throughout the country.
Quality control procedures
Experts in each RRs were responsible for the
validation of the data of the corresponding FDCs. Some
information systems supporting registries allow quality
data control at the moment of the data entry by users.
Furthermore, quality control processes are regularly
carried out by RRs staff. In addition, at national level, the
quality control of the common data set was carried out on
the whole database in two steps by the RNMR operators.
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Taruscio D et al
The first step consisted of a control of duplicate records,
logical inconsistencies and range errors on individual
data batches sent by the RRs. In case that range errors
or logical inconsistencies were found, the records were
sent back to the RRs for a check with the regional data
sources. Inconsistencies and range errors which were not
resolved after this control were considered as missing
data. The second step was carried out on the database
resulting from the merging of the regional data batches.
In particular, this procedure checked for possible
duplicates coming from different RRs and a specific
protocol for the management of duplicate records was
followed as shown in Table II. As shown in this table,
the record management was dependent on the type of
duplication and different record extractions were carried
out depending on the scope of the analyses.
Periodic meetings and reporting
The experts responsible for the RRs convened
yearly to report on achievements and experience in the
management of their registries and to discuss common
issues. In 2012, the RNMR, in collaboration with
the RRs, prepared its first annual report12, where the
main features of the RRs and of the data quality were
described.
Compliance with personal data protection Regulations
Each regional registry collects information on patients
according to the national data protection law. When part
of the data collected by RRs are communicated to the
RNMR, an algorithm is used for the secure transfer
of information. The data transmission took place by
means of a temporary channel opened temporarily for
this purpose and the personal data were transmitted
separately from sensitive data. Personal and sensitive
data were stored in separate servers of the informatics
service of the National Institute of Health, protected with
advanced firewall and technological systems.
Results
The geographic coverage of RNMR
When the MD was put into effect, a RR of RD
patients was in operation in the Veneto region only. Since
then, RRs were progressively established and connected
to the RNMR (Figure 1). The 2007 Agreement between
Central Government and the Regions11, triggered a
significant acceleration of the process (Figure 2) and the
full coverage of the Italian territory connected with the
RNMR was achieved during 2011. The establishment
of the RRs resulted in a significant increase of the cases
communicated to the RNMR, which approximately
paralleled the increase in the nominal population
coverage calculated from the official resident population
of the regions.
Quality of the common data set
Up to 30 June 2012, 112,766 records of RD
patients were communicated to the RNMR. During
the subsequent validation process, 25 records showed
missing values for diagnosis or ID code or missing date
of birth or sex. After check with the RRs, 17 records were
discarded and 8 records were retained for subsequent
processing. The remaining set of 112,749 records
were checked for the presence of duplicate records,
i.e., multiple records of a same patient received from
different RRs and managed depending on the type of
duplication as reported in Table II, which also shows the
Table II - Description and process management of duplicate records.
Duplicate type 1
Duplicate type 2
Duplicate type 3
Description
Records with same ID, diagnosis
and diagnostic centre.
Records with same ID and diagnosis
and different diagnostic centre for
RDs.
Records with same ID and different
rare disease diagnosis.
Presumed cause
Additional notifications are made of
a case already notified.
The case was diagnosed in two
or more different centres, which
notified the case.
The case is affected by more RDs.
Record management
Aim of analysis
Analysis of the activity of
diagnosis centres
Only the record with less recent
diagnosis is considered.
The other records are discarded.
All records are considered.
No records are discarded.
All records are considered.
No records are discarded.
Analysis of cases recorded in the
RNMR
Only the record with less recent
diagnosis is considered.
The other records are discarded.
Only the record with less recent
diagnosis is considered.
No records are discarded.
Only the record with less recent
diagnosis is considered.
No records are discarded.
Analysis of RDs recorded in the
RNMR
Only the record with less recent
diagnosis is considered.
The other records are discarded.
Only the record with less recent
diagnosis is considered.
No records are discarded.
All records are considered.
No records are discarded.
Number of duplicate records
3,322
3,393
2,483
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The Italian RD Registry
results of this analysis. Discarded Type 1 records, which
represent true duplicates, were 1 908, corresponding to
1.7% of the total valid records. Therefore the cleaned
database was made of 110,841 records.
The quality of the data collected by the RNMR
has been assessed with respect to completeness and
consistency of procedures. Table III summarizes the
results of this control for each variable of the common
data set. While completeness analysis was based on the
observation of the database records, the assessment of
consistency of procedures summarizes the discrepancies
emerged during the preparation of the first RNMR
report. The variables characterizing case and diagnosis
showed a very limited number of missing values and a
remarkable improvement could be observed, during time,
in the completeness of recording of the centre making
diagnosis. It is often the case with registries, that the
date of death of patients is not collected systematically
and timely by registry data providers. Although some
records reported live cases with unrealistic age, there
was no criterion that the RNMR could use to spot all
records that did not update this information regularly.
The date of disease onset is largely and persistently
incomplete. An analysis of the records showed that
missing data were mostly associated with some RRs.
Indeed, while it is difficult to define the date of the
symptoms onset in the case of patients affected by a
rare diseases since a long time, or when the first signs or
symptoms of a rare diseases are unspecific, some RRs do
not collect this data. The completeness of data regarding
the use of orphan drugs was assessed as follows. At first,
the diseases were identified, for which an indication of
use of orphan drugs was given; then, making reference
to all the records of each of the diseases so identified, the
fraction of records with missing values was calculated.
This analysis indicated that, in the whole database,
treatments were indicated for 56 conditions and that
incomplete records (i.e. records which do not show the
indication of a drug nor the explicit indication of no drug
use) represented 14.9%. The lack of this data showed
a marked decrease with time, indicating the steady
improvement in its collection. Table 3 also summarizes
the observations regarding the accuracy of the minimum
set of data collected by RNMR.
Figure 1 - Establishment of regional RD registries in Italy.
The year indicated refers to the year of institution of the registry.
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Taruscio D et al
Figure 2 - Nominal population coverage of the RNMR and notification flow.
The year indicated refers to the institution of the regional registry. Notifications reported for the year 2012
refer to the first half of the year.
Table III - Completeness and accuracy of the common dataset.
Completeness (% missing)a
Common data set
Whole
database
Calendar years
2010-2011
Accuracy
(110,841 records)
(27,114 records)
Calendar year
2012
(6 months)
(9,913 records)
Gender
0.0
0.0
0.0
Data is collected consistently among data sources according to usual
identification procedures
Date of birth
0.0
0.0
0.0
Data is collected consistently among data sources according to usual
identification procedures
Region of residence
0.1
0.1
0.0
Data is collected consistently among data sources according to usual
identification procedures
Diagnosis
0.0
0.0
0.0
Diagnoses are controlled and validated by the RRsb and their accuracy rely
on the selection criteria for the centres to become FDC of the RD network
Date of diagnosis
1.0
--
--
Inconsistencies among regions on the identification of the relevant
diagnostic event and diagnostic centre.
Centre of RD
diagnosis
11.9
1.2
0.4
Inconsistencies among regions on the identification of the relevant
diagnostic event and diagnostic centre. A centre may change name
following reorganisation.
Vital status
ND
ND
ND c
Uncertainties in this variable depend on the fact that the data sources of
RRsb may not be fully aware of the reason why patients are lost to follow
up. In the future, date of decease will be collected from death registries:
this will result in a systematic and precise, although delayed, appraisal
of this condition.
Date of decease
ND
ND
ND
Expectedly good (when reported). In the future, date of decease will be
collected from death registries: this will result in a systematic and precise,
although delayed, appraisal of this condition.
Date of disease onset
46.4
57.1
81.4
Uncertainties in this variable depend on i) lack of patient's recollection;
ii) gradual appearance of unspecific symptoms over a long period.
Symptoms could also not set on due to effective treatment following
early diagnosis (e.g. following neonatal screening)
Orphan drug used
14.9
10.7
4.6
The name of the active substance is communicated, but no standard
catalogue or coding is used.
Data completeness is measured as the proportion (%) of records without the indication of the value of the variable; calendar years refer to the date of
diagnosis; b Regional registry; c ND = not determined
a
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Preliminary results after the start of activity with full
nominal coverage of the national territory
Altogether, the valid records which are stored at present
into RNMR are 110.841. This number corresponds to
the overall diagnoses communicated to RNMR up to 30
June 2012 by RRs which have started their collection at
different dates between 2000 and the end of 2011. The
records referred to diagnoses made in the first 6 months
of 2012, with RRs covering all the national territory, were
9,913. Although these features prevent, at present, any
sound epidemiological estimate of rare diseases in Italy,
some observations on the composition of the rare diseases
notifications communicated to RNMR, may be of interest.
Table IV shows the distribution, across the ICD 9-CM
Chapters, of the diagnoses notified to the RNMR. The RDs
under this surveillance system include conditions named
individually and with group denominations. Altogether,
the records reported at least one case of 485 conditions.
All groups and subgroups mentioned in the MD were
represented, making up 58,942 records, including 7,328
records of 137 pathologies mentioned as examples.
Besides these, 296 individual RDs were represented with
51,899 records. Of these records, about 50% were made
up by 15 most frequent diseases: achalasia, amyotrophic
lateral sclerosis, behçet disease, bullous pemphigoid,
chronic inflammatory demyelinating polyneuropathy,
down syndrome, hereditary hemorrhagic telangiectasia,
idiopathic central precocious puberty, keratoconus,
Klinefelter syndrome, Lambert-Eaton syndrome, Marfan
syndrome, mixed cryoglobulinemia, pemphigus, Turner
syndrome. Twenty-nine diseases were represented with
one record only.
Discussion
The European Commission Communication: "Rare
diseases: Europe's challenge"2 and the subsequent Council
Recommendation7 emphasize the strategic importance of
Patient Registries in the field of RD.
The national network of Centres, identified at regional
and interregional level, and of Regional/Interregional
Registries dedicated to RD, was successfully implemented
in Italy following the MD and the agreements between
the Government and the Italian regions. To date, the
Italian RNMR is a surveillance system, with the the main
objective of producing epidemiologic evidence on RD in
Italy, and of supporting policy making and HS planning.
This role of the RNMR has been confirmed by the draft
National Plan on RD, recently proposed for public
consultation by the Ministry of Health13. Considering the
complexity of building such registries in a devolved system
of responsibility for healthcare delivery, substantial efforts
were necessary in various steps of RNMR development,
especially at regional level where the supporting
infrastructures had to be established.
Table IV - Distribution, across the ICD 9-CM Chapters, of
diseases notified to RNMR up to 30 June 2012.
ICD 9-CM Chapters
Percent
records
1.
Infectious and parasitic diseases
0.1
2.
Neoplasms
5.0
3.
Endocrine, nutritional, and metabolic diseases, and
immunity disorders
17.4
4.
Diseases of the blood and blood-forming organs
16.6
6.
Diseases of the central nervous system and sense
organs
26.0
7.
Diseases of the circulatory system
4.3
9.
Diseases of the digestive system
1.3
10.
Diseases of the genitourinary system
0.6
12.
Diseases of the skin and subcutaneous tissue
3.3
13.
Diseases of the musculoskeletal system and
connective tissue
5.5
14.
Congenital anomalies
19.7
15.
Certain conditions originating in the perinatal period
0.1
16.
Symptoms, signs, and ill-defined conditions
0.0
Total
100
The strong legal base, its integration in the public health
service and its connection with the dedicated national RD
patient protection policy ensures the registry stability,
comprehensiveness and population coverage. However,
the need to cope with different levels of local resources,
the slow responsiveness and limited flexibility typical
of institutional processes as well as the need to rely on
quality and comparable data made the implementation of
the RNMR a slow and stepwise process, which is far from
being concluded. The common data set agreed among
the central and regional health authorities, is indeed the
result of a selection of data, the collection of which could
be sustainable, made comparable and be used to provide
information coherent with the national scope of the
RNMR, as distinct from the regional level responsibilities.
During the gradual establishment of the Regional
RD registries, which achieved nominal completion
during 2011, a steadily increasing flow of data on RD
patients was established from the RRs to the RNMR.
Moreover, we could observe also a continuously increasing
involvement of the operators of the RD registry system.
To achieve this result, an important role was played by
the dedicated training courses in the regions which do not
have a proprietary Rare Diseases Registry, conducted in a
systematic way by the experts of the RNMR.
The preparation of the first Report on the RNMR
activity9, in collaboration with the RRs, turned to be a
powerful tool to review the operation of this complex
system and to highlight the need for a number of critical
improvements. The collection of the vital status and death
date should be undertaken systematically. To this aim, the
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Taruscio D et al
RNMR is seeking access to the national database of death
records. Moreover, the inconsistencies in the collection
of the disease onset date and the adoption of improved
definitions of the diagnostic event relevant to determine the
date of diagnosis and the centre making diagnosis are being
discussed. Finally a more accurate list of active substances
is to be adopted. The procedures used to validate records
and to control data completeness also should be better
distributed between the RNMR and the RRs to make the
data flow a smooth process.
The actual coverage of the population depends on the
quality and functions of the information systems developed
at regional or interregional level. The different lengths of
periods of operation of the RRs (ranging from about 1 to
more than 10 years) result in different effectiveness of the
registration process and only some regions collect data
on RD patients using multiple data sources. Therefore,
with the progressive improvement of RRs operations,
the heterogeneity of the case reporting completeness will
become less and less relevant. However, this issue has to
be assessed and addressed appropriately.
At present, therefore, the data currently stored in
the RNMR represents the baseline for a continuous
improvement of the national and RRs and to start a
validation process through the comparison of the RNMR
results with studies in other population groups. For an
overall improvement of the Italian RD surveillance
system, CNMR is promoting collaborations with National
statistical services, clinicians, patient associations and
other data sources. Moreover, additional opportunities for
improvement will come from the participation of CNMR
and other experts of the Italian RD network in other
European and global initiatives, such as the European
Platform for rare disease registries (EPIRARE: www.
epirare.eu), the International Rare Disease Research
Consortium, (IRDiRC: www.irdirc.org) and the Integrated
Platform connecting databases, registries, biobanks and
clinical bioinformatics for Rare Disease research (RDConnect:www.rd-connect.eu.
G. Monasterio, Pisa, Tuscany Region) and Cecilia Berni
(Regional Coordination of Rare Diseases, Tuscany
Region), Lucia Borsellino and Salvatore Scondotto
(Department of Health and Epidemiological Observatory,
Sicily Region), Francesco Benedicenti (Provincial
Coordination Centre for Rare Diseases, Bolzano
Autonomous Province) and Paola Zuech (Provincial
Epidemiological Observatory, Bolzano Autonomous
Province), Paola Casucci and Maria Concetta Patisso
(Regional Directorate of Health and Social Cohesion,
Umbria Region), Domenico di Lallo (Public Health
Agency, Latium Region), Maria Lucia Di Nunzio
(Directorate General V, Molise Region), Annunziata
Di Palma (Provincial Coordination Centre for Rare
Diseases, Trento Autonomous Province), Matteo Volta
and Maria Vizioli (Directorate General of Health and
Social Policy, Emilia Romagna Region), Paola Facchin
and Monica Mazzucato (Coordination Rare Diseases,
Rare Diseases Registry, Veneto Region), Orazio Gabrielli
(Salesi Hospital, Clinical pediatric, Marche Region),
Roberto Della Casa ed Iris Scala (Coordination Centre
for Rare Diseases, Campania Region), Gedeone Baraldo
(Directorate General for Health, Lombardy Region) ed
Erica Daina (Coordination Centre for Rare Diseases,
Institute for Pharmacological Research "Mario Negri",
Lombardy Region), Giandomenico Palka (Department
of Biomedical Sciences, University Hospital of Chieti,
Abruzzo Region), Dario Roccatello and Vittorio Modena
(CMID, Centre of Research of Immunopathology and
Rare Diseases; ASL TO2, S. Giovanni Bosco Hospital,
Piedmont Region), Mirella Rossi (Regional Health
Agency, Liguria Region), Domenico Tripaldi and
Antonella Angione (Department of Health, Safety and
Social Solidarity, Personal Services and the Community,
Basilicata Region).
References
1)
2)
The Authors declare no conflicts of interest.
National Rare Disease Registry collaborating
group
Giuseppina Annicchiarico and Ettore Attolini
(Regional Coordination of Rare Diseases, Apulia
Region), Antonello Antonelli (Department for Hygiene
and Health and for Social Assistance of the Autonomous
Region, Directorate General of Health, Sardinia Region),
Rosalba Barone (Department of Health Protection
and Health Policies, Calabria Region), Bruno Bembi
and Laura Deroma (Regional Coordination Centre for
Rare Diseases, Friuli-Venezia Giulia Region), Fabrizio
Bianchi (Institute of Clinical Physiology CNR/Fondativo
3)
4)
5)
6)
Posada de la Paz M, Villaverde-Hueso A, Alonso V, János S,
et al. Rare Diseases Epidemiology Research Adv Exp Med
Biol 2010; 686: 17-39.
Communication from the Commission to the European
Parliament, the Council, the European economic and social
committee and the committee of the regions on rare diseases:
Europe challenges. Commision of the European Communities.
Available on line at http://ec.europa.eu/health/ph_threats/
non_com/docs/rare_com_en.pdf. Accessed on 15/01/2014.
Griggs RC, Batshaw M, Dunkle M, Gopal-Srivastava R, et al.
Rare Diseases Clinical Research Network: Clinical research
for rare disease: opportunities, challenges, and solutions. Mol
Genet Metab 2009; 96: 20-6.
Cole JA, Taylor JS, Hangartner TN, Weinreb NJ, et al.
Reducing selection bias in case-control studies from rare
disease registries. Orphanet J Rare Dis 2011; 12: 6: 61.
Luisetti M, Campo I, Scabini R, Zorzetto M, et al. The
problems of clinical trials and registries in rare diseases. Respir
Med. 2010; 104 (Suppl 1): S42-4.
Webb SM, Santos A, Valassi E. The value of a European
Blood Transfus 2014; 12 Suppl 3: s606-13 DOI 10.2450/2014.0064-14s
s612
The Italian RD Registry
registry for pituitary adenomas: the example of Cushing's
syndrome registry. Ann Endocrinol (Paris). 2012; 73: 83-9.
7) Council Recommendation of 8 June 2009 on an action in the
field of rare diseases. The Council of the European Union.
Available on line at: http://eur-lex.europa.eu/LexUriServ/
LexUriServ.do?uri=OJ:C:2009:151:0007:0010:EN:PDF.
Accessed on 23/08/2013.
8) European Commission. Supporting rare diseases registries and
providing a European Platform for rare diseases registration.
Available on line at: http://ec.europa.eu/health/rare_diseases/
policy/registries/index_en.htm. Accessed on 28/08/2013.
9) Italian Ministry of Health. Decreto 18 maggio 2001, n. 279.
Regolamento di istituzione della rete nazionale delle malattie
rare e di esenzione dalla partecipazione al costo delle relative
prestazioni sanitarie, ai sensi dell'articolo 5, comma 1, lettera
b), del decreto legislativo 29 aprile 1998, n. 124. (GU n.
160 del 12-7-2001- Suppl. Ordinario n.180/L) (in Italian).
Available at: http://www.iss.it/binary/cnmr/cont/DM2792001.1205943575.pdf. Accessed on 25/03/2014.
10) Conferenza Stato Regioni. Accordo tra il Ministro della Salute,
le Regioni e le Province Autonome di Trento e Bolzano sui criteri
di individuazione e di aggiornamento dei Centri Interregionali
di riferimento delle malattie rare. (Repertorio Atti n 1485
dell'11 luglio 2002) (in Italian). Available at: http://www.iss.
it/binary/cnmr/cont/STATOREGIONI2002.1205943700.pdf.
Accessed on 25/03/2014.
11) Conferenza Stato Regioni. Accordo, ai sensi dell'articolo 4 del
Decreto Legislativo 28 Agosto 1997, n. 281, tra il Governo,
le Regioni e le Province Autonome di Trento e Bolzano sul
riconoscimento dei Centri di coordinamento regionali e/o
interregionali, di Presidi assistenziali sovraregionali per
patologie a bassa prevalenza e sull'attivazione dei registri
regionali ed interregionali delle malattie rare. (Repertorio 103/
CSR del 10 maggio 2007) (in Italian). Available at: http://www.
iss.it/binary/cnmr/cont/STATOREGIONI2007.1205943700.
pdf . Accessed on 25/03/2014.
12) Taruscio D. Il Registro Nazionale e i Registri Regionali/
interregionali delle Malattie Rare. Rapporto anno 2011.
(Rapporti ISTISAN 11/20). Roma: Istituto Superiore di
Sanità; 2011 (in Italian). Available on line at: http://www.
iss.it/publ/index.php?lang=1&id=2529&tipo=5. Accessed
on 15/11/2013.
13) Italian Ministry of Health. Piano Nazionale Malattie Rare
2013-2016. Available on line at: http://www.salute.gov.it/
imgs/C_17_pagineAree_3296_listaFile_itemName_0_file.
pdf. Accessed on 15/01/2014.
Correspondence: Domenica Taruscio
Italian National Centre for Rare Diseases
Istituto Superiore di Sanità
Viale Regina Elena, 299
00161, Rome, Italy
e-mail: domenica.taruscio@iss.it
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The Italian National Plan for Rare Diseases
Maria Elena Congiu
Italian Ministry of Health, Rome, Italy
Introduction
Italy was one of the first Member States (MS) in
the European Union (EU) to regulate the field of rare
diseases (RD). Since 2001, many initiatives were carried
out at central and regional level. The development of a
national plan or strategy for RD stems from the necessity
to fulfill the EU Commission Recommendation to MS to
adopt national plans or strategies for RD by the end of
20131. However, the adoption of a systematic measure,
logical and coherent with planned strategies and actions
at all levels, was demanded by national stakeholders in
the field of RD.
The first version of the document was drafted by
the General Directorate of Planning at the Ministry of
Health (MoH) in collaboration with small groups of
experts. It was submitted to all the stakeholders (patient
and family organisations, healthcare professionals and
professional bodies) during a brief consultation process.
The document considered also previous requests from the
National Board of Patients with RD (http://www.cndmrinsieme.it/) and patient organisations (Federation of the
Organisations of the Italian Patients with RDs - UNIAMO
and Italian Movement of Rare Patients - MIR). These
requests had been previously presented at the final national
conference of the EUROPLAN project in 20122.
The Italian legal framework on rare diseases
Coming into force just before the approval of the
Regulation (EC) n. 141/2000 of the European Parliament
and the Council on orphan medicinal products3, the Italian
legislation in the field of RD derives from the willingness
to combine the organisation of healthcare assistance with
all aspects related to the rights of citizens affected by RD.
Specifically, the Legislative Decree n. 124/19984 introduced
the new discipline on exemption from co-payment for
health services nationwide and led to the adoption of the
Ministerial Decree (MD) n. 279/20015, which is the first
regulatory act in the field of RD. The decree identified a list
of life-threatening or chronically debilitating diseases with
both a high level of complexity of care and a prevalence
of not more than 5 in 10,000 inhabitants, in accordance
with the EU definition. The diseases included in the
above-mentioned list are formally called as "rare" and
totally exempted from the co-payment for outpatients
benefits provided by the National Health Service (NHS)
for diagnosis and treatment. When necessary for patient's
diagnosis, also genetic testing to blood relatives is
delivered without any charge. Medicinal products are not
the subject of the decree and are provided in accordance
with Italian Medicines Agency (Agenzia Italiana del
Farmaco, AIFA) classification. Moreover, the MD
279/2001 establishes a specific network for RD consisting
in both accredited health facilities identified by Regions,
which are responsible for the diagnosis and treatment
of RD and the systematic collection of data concerning
RD resulting in the National Registry of Rare Diseases
(NRRD) at the Italian National Institute of Health (Istituto
Superiore di Sanità, ISS)6.
The effectiveness of MD 279/2001 was confirmed
after the approval of the Constitutional Law n. 3/2001
that conferred to the Regions the entire responsibility
for the organisation of the healthcare assistance, the
planning and management of their own healthcare
activities, as well as the provision of healthcare services
to the population through Local Health Units. The
central State (namely the MoH) has the responsibility
to define the general principles and priorities and to
establish the national healthcare entitlements (Essential/
Basic Levels of Healthcare Assistance, LEA), which
are financed by general taxation. Moreover, the MoH is
required to ensure that LEA are provided to all citizens
and that the Regions have the appropriate financial
resources. Finally, the main guiding principles of the
NHS are those of universality, equity and solidarity
and the LEA provided to people with RD are the
same, but free, national healthcare entitlements which
are guaranteed to all citizens according to criteria of
effectiveness, appropriateness and quality, as well as
quantitative and qualitative standards and appropriate
way of delivery. On the other side, Regions are allowed
to provide further services, as far as they can cover the
costs with their own economic means. In recent years,
many Regions decided to supply "extra-LEA services"
to their population. Among the "extra-LEA services",
some Regions include free access to specific further
benefits for people suffering from a RD, such as some
medicinal products currently delivered with fee but also
healthcare assistance to further diseases not currently
included in the national list of RD.
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Italian Plan on rare diseases: role of Ministry of Health
The contents of the draft of the National Plan
for Rare Diseases
The first part of the National Plan for Rare Diseases
(NPRD) recalls the European and national legislation
and a description of the main areas of intervention: LEA;
the organisation of the system and its components (the
National network for RD, the NRRD, the Congenital
Malformations Registers (CMR), and Disease-specific
registers, the National Board of Regional Health
Authorities on RD, biobanks, coding and classification
of RDs); the healthcare and pharmaceutical pathways
for RD patients; the cross border healthcare; the role of
the patient alliances; research; training and education
of professionals, and information; prevention activities.
It is important to highlight that any social intervention
is not included in the current NPRD.
The second part of the NPRD "Objectives and
monitoring" links each of the above areas of interventions
with specific actions for the 3-year period.
The network organisation, set up with the MD
279/2001, deserves special consideration.
Despite the exclusive competence of the Regions
established by the aforementioned Constitutional Law, a
supra-regional level is recommended for very RD ensuring
follow-up activities to be performed near the patient
residence. An inter-regional organisation may allow different
but appropriate treatment of patient needs according to the
level of know-how of each health professional.
The model aims at guaranteeing both high specialised
functions and assistance to general needs, available at
the healthcare district level.
Identified units (preferably hospital units) are the
national network hubs, specifically detected among
those who can provide documentary evidence of
expertise in diagnosis and care of a specific rare
disease or groups of RD, as well as suitable equipment
and complementary services to assist in emergencies
and to perform molecular, genetic and biochemical
diagnoses. These facilities can be guaranteed also by
means of functional relations with external services,
such as genetics centres and become integral part of
the RD network. Furthermore, the identified units are
required to comply with the clinical protocols set up
in accordance with the clinical guidelines issued by
the scientific societies. In addition, all units must also
cooperate with general practitioners and local services
to provide personal, comprehensive and continuing
care to patients. Finally, the national network must
fulfill the EU requirements in order to comply with
the Council Recommendation on an action in the field
of rare diseases (2009/C 151/02)7 adopted on June 8th,
2009 along with both the EUCERD Recommendation8
concerning the quality criteria for Centers of Expertise
(CEs) in Member States and the implementation of
European Reference Networks (ERNs)9. All its identified
units, firmly included within the regional networks of
care, must be able to perform the duties expected from
European CEs.
In the assessment process of these units, Regions
can use multi-stakeholder opinions, including patient
organizations; benchmarks and indicators should cover
processes, outcomes and impacts, such as patient reported
outcomes. An appropriate governance is ensured through
the establishment of a National committee, involving the
competent Ministries, the Regions and AIFA, as well
as the National Agency for Regional Health Services
(Agenzia Nazionale per i Servizi sanitari regionali,
Age.Na.S.) and patient alliances. The Committee has
the task to both define the main strategies for diagnosis
and care, research and social promotion, adapting them
to the specific economic resources and to optimise the
most appropriate monitoring actions.
All services and national healthcare entitlements,
including those regarding RD, are currently funded by
general taxation and the NHS financial budget is yearly
distributed by the central Government to the Regions.
The specific expenditure for RDs is difficult to quantify.
However, since medicinal products are among the major
invoices of expenditure, an accurate medicinal products'
accountability may help to predict a great part of the real
expense for the NHS.
In recent years, the situation has become more
complex and more heterogeneous among Italian
Regions, due to the dramatic differences of Regional
Health Services budgets. In order to address this
scenario, the Central Government has enforced a
series of so-called Budgetary Balance Plans aimed at
solving the problems of insufficient financial coverage
for services provided in some "very critical Regions".
The Plans introduced substantial budgetary limits and
measures to contain their healthcare cost levels and
trends. As a consequence, many Regions undergoing a
Budgetary Balance Plan have been forced to cancel the
extra-LEAs services they were previously providing,
including services for people suffering from RD.
Conclusions
The MoH is aware that expectations of the main
stakeholders, in particular of patient associations,
might be excessive compared to the actions proposed
in the NPRD draft, mainly because of the limitation of
financial resources.
The possibility to further allocate dedicated funds
for RD depends on the overall evaluation of the central
Government. Indeed, the draft of the NPRD suggests
to include RD among the performances that are being
verified by the national committee for the evaluation of
the provision of LEA.
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Congiu ME
However, the draft of the NPRD specifically
considers the efficiency and the effectiveness of
the general organisation and the national network
to minimize the consequences of budgetary limits.
Moreover, it emphasises the importance of a strict
cooperation and exchange of experiences and best
practices among all the identified regional expert units
coordinated at a supra-regional level.
5)
6)
7)
8)
Keywords: Essential Levels of Assistance (LEA), extra
LEA services, national network, budgetary balance
plans.
The Author declares no conflicts of interest.
9)
Decreto ministeriale 18 maggio, n. 279 "Regolamento di
istituzione della rete nazionale delle Malattie are e di esenzioni
dalla partecipazione al costo delle relative prestazioni sanitarie,
ai sensi dell'articolo 5, comma 1, lettera b), del decreto
legislativo 29 aprile 1998, n. 124" [in Italian]. SO alla GU n.
160 del 12 luglio 2001, N. 180/L.
Taruscio D, Kodra Y, Ferrari G, et al. The Italian Registry on
Rare Diseases. Blood Transfus 2014; 12 (Suppl 3): s606-13.
Council Recommendation on an action in the field of rare
diseases. 2009/C 151/02.
Recommendations on Quality Criteria for Centres of Expertise
for Rare Diseases in Member States. European Union
Committee of Experts on Rare Diseases (EUCERD) http://
www.eucerd.eu. Accessed on 24/10/2011.
Recommendations on Rare Diseases European Reference
Networks (RD ERNS). European Union Committee of Experts
on Rare Diseases (EUCERD), 31 January 2013. Available at:
http://www.eucerd.eu/. Accessed on 18/12/2013.
References
1)
2)
3)
4)
Communication from the Commission to the European
Parliament, the Council, the European economic and social
Committee of the Regions on Rare Diseases: Europe's
challenge. Bruxelles, 11.11.2008. COM (2008), 679 final.
Conferenza Nazionale EUROPLAN in ITALIA - REPORT
FINALE [in Italian]. Available at: http://www.europlanproject.
eu/_newsite_986989/Resources/docs/EUROPLAN2010_
FINALReport_Italy.pdf. Accessed on 15/02/2014.
Regolamento del Parlamento europeo e del Consiglio
concernente i medicinali orfani [in Italian].(CE N. 141/2000) .
Decreto Legislativo 29 aprile 1998, n. 124 "Ridefinizione del
sistema di partecipazione al costo delle prestazioni sanitarie e
del regime delle esenzioni, a norma dell'articolo 59, comma
50, della L. 27 dicembre 1997, n. 449" [in Italian]. Pubblicato
nella G.U. 30 aprile 1998, n. 99
Correspondence: Maria Elena Congiu
Ministry of Health
Via Giorgio Ribotta n. 5
00144 Roma, Italy
e-mail: me.congiu@sanita.it
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REVIEW
Piedmont and Aosta Valley inter-regional network in the context of the
Italian National Network for rare diseases
Simone Baldovino 1,2, Elisa Menegatti 2, Vittorio Modena 1, Maria Maspoli 3, Flavia Avanzi 3,
Dario Roccatello1,2
1
CMID - Centre of Research of Immunopathology and Rare Diseases, Coordinating Centre of Piedmont and Aosta
Valley Network for Rare Diseases, St. G. Bosco Hospital and University of Turin, Turin; 2Department of Clinical
and Biological Sciences, University of Turin, Turin; 3Piedmont Regional Health Department, Turin, Italy
Introduction
The Italian regulatory framework on RD
In Europe rare diseases (RDs) are defined as
"diseases with a prevalence in the European Union (EU)
population of less than 5 per 10,000". This definition
includes a large group of more than 6,000 diseases,
90% of which are genetically determined and which
potentially involve all organs1. RDs are therefore a
very heterogeneous group as far as both clinical and
epidemiological aspects are concerned.
There are in fact RDs with less severe clinical
manifestations and others with important ones which
can compromise the quality of life and the life
expectancy. Furthermore, some RDs have a prevalence
approaching to the 5 per 10,000 limit and therefore
affect a significant number of patients. Indeed, from
the June 2005 to the December 2013 the Piedmont and
Aosta Valley interregional register for RDs collected
21,062, with an estimated overall prevalence of RD of
45 patients on 10,000 inhabitants. Moreover half of the
patients registered are affected by less than 20 diseases
or groups of diseases (Table I) that represent the most
important burden of care for the regional healthcare
systems. On the other hand there are several with a
much lower prevalence affecting a very small number
of patients2.
These latter often lack of timely and correct
diagnosis and adequate treatment. Moreover, the
world-wide orphan drug policies are associated with
unacceptably high costs of newly developed drugs and
inaccessibility of previously available drugs which
become unavailable over time because of limited
production by pharmaceutical industries3.
Finally, despite the low prevalence of each disorder,
the number of rare disease is fairly high. The European
Commission reports that RDs affect a total of 6-8% of
the population.
Due to all these problems, and to the fact that RDs are
often chronic and invalidating or cause early mortality,
they represent a significant public health matter of
concern in many countries.
In Europe the problem of RDs was addressed for the
first time by The Program of Community Action on rare
diseases 1999-20034.
Italy was one of the first European countries to
develop specific regulations regarding RDs5. Since 1998,
the three year National Health Plans has been issued,
intended as national-wide instructions. This document
indicated RD as a priority for National Health Service
(NHS). Moreover, in 2001, the Ministry of Health
Table I - Distribution of diseases covering 50% of reported
diseases in the Piedmont and Aosta Valley Rare
Diseases Registry.
Rare disease or group
n. of patients
%
Cumulative %
Hereditary coagulation
disorders
1,245
5.9%
5.9%
Lateral amyotrophic sclerosis
997
4.7%
10.6%
Hereditary anaemias
981
4.7%
15.3%
Progressive systemic
sclerosis
888
4.2%
19.5%
Congenital metabolic iron
disorders
745
3.5%
23.1%
Neurofibromatosis
607
2.9%
25.9%
Undifferentiated connective
tissue disease
548
2.6%
28.5%
Sarcoidosis
487
2.3%
30.9%
Chronic idiopathic
thrombocytopenic purpura
474
2.3%
33.1%
Antiphospolipids syndrome
451
2.1%
35.2%
Keratoconus
419
2.0%
37.2%
Idiopathic pulmonary
fibrosis
399
1.9%
39.1%
Genetic arrhytmias
359
1.7%
40.8%
Down syndrome
358
1.7%
42.5%
Disorders of aminoacids
metabolism and transport
356
1.7%
44.2%
Arnold-Chiari syndrome
337
1.6%
45.8%
Muscular dystrophies
332
1.6%
47.4%
Lichen sclerosus et
atrophicus
289
1.4%
48.8%
Bullous pemhigoid
271
1.3%
50.1%
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Baldovino S et al
comprehensively addressed the issue of RDs with a
specific Decree (DM 279/2001)6.
DM 279/2001 established the national network for
RDs and cost exemptions for related health service
provisions for a consistent cohort of RDs5. DM 279/2001
also established a National Registry of RDs to be kept
at the National Institute of Health7. A few months after
the publication of DM 279/2001, a Constitutional
Law (Constitutional Law 3/2001) reformed Title V of
the Italian Constitution. Several decisions on health,
including RDs, were consequently delegated to the
regional administrations. As a result the development of
networks for RDs was quite different among the various
Italian Regions.
Prior to DM 279/2001, other national laws had dealt
with specific RDs, such as cystic fibrosis and hereditary
haemorrhagic diseases. For instance, as addressed in
other papers in this issue, a network of reference centres
for haemophilia and related disorders was already
operating before 2001.
The inclusion of these previously existing network
for specific RDs was one of the problem faced by
regional administrations in implementing DM 279/2001.
and the scientific relevance of each centre. In some
regions, such as in Lombardy, the reference centres are
subject to periodic re-evaluation by a local coordinating
Centre which evaluate all the above mentioned
parameters.
Some regions have made inter-regional agreements.
Therefore there are two formally recognized interregional areas. The first one is made up of Piedmont
and Aosta Valley. The second includes Veneto, the
Autonomous Provinces of Trento and Bolzano, FriuliVenezia Giulia, Emilia-Romagna, Liguria, Puglia
and Campania13,14. The regions involved in the two
inter-regional networks share the same policy for the
accreditation of reference centres, the information
system for the management of the Registry of RDs,
treatment protocols, and standards of care.
Finally, in 2006, all the Italian Regions and
Autonomous Provinces joined in an inter-regional
network for RDs with the purpose of a joined approach
to common issues such as home administration of drugs
for metabolic diseases and telemedicine.
The regional RD networks: examples from the
current experiences
The Piedmont and Aosta Valley Inter-regional
Network for RDs was developed in 2008. It is the result
of the union between two previously separate systems,
i.e., the Piedmont regional network for RDs, founded
in 2004, and the system for RDs in the Aosta Valley
region14,15. It is a decentralised organisational model
based on the active involvement of all the professionals
operating in the public health system of the two regions.
The Piedmont Network for RDs was created to
guarantee equal opportunities of assistance throughout
the Region, develop diagnostic and treatment protocols
to be shared among physicians, provide information
on regional health organization and legislation to caregivers and patients' associations. It has also be created
to collect data for epidemiological studies through the
Regional Registry, allowing to identify both critical
problems (including delays in diagnosis and care) and
areas of possible investment of resources.
The Inter-Regional network for RDs was designed
to develop a model of healthcare assistance that would
guarantee the quality of diagnosis (including genetic
analysis) in centres with proven expertise. More
importantly, it aims to offer appropriate healthcare to
patients as close as possible to their place of living.
Thus, the Piedmont and Aosta Valley model of
decentralised network for RDs is unique among the
Italian experiences. Unlike most networks in other
Italian regions, the Piedmont and Aosta Valley network
involves all the healthcare facilities within the regions,
thus giving all the specialists the opportunity to be
The network of RDs was implemented following
different organisation systems in various Italian regions.
In some of the smaller regions with a small
population, such as Marche region, one or two reference
centres paediatric and adult patients were established8.
In other regions, such as Veneto, reference centres
for homogeneous nosological groups of diseases were
set up. Moreover, these regions have created a network
for local care in order to provide a day to day patients
take in charge9.
A similar model was applied by the Tuscany region
where a diagnostic network made up of reference centres
and a care network interact with each other to manage
the patient's healthcare needs10.
Contrarily, the Lombardy Region applied a model
based on establishing reference centres on which insist
all the aspects of the diagnosis and care of the patient11.
A final model is the "hub and spoke model" which is
implemented, for example, by Emilia Romagna. This model
bases on concentrating the more complex cases in a limited
number of centres (hubs). The clinical activity of the hub is
highly integrated through functional connections with that
of the peripheral health centres (spokes)12.
All the above models are based on establishing
reference centres which are entrusted for the diagnosis
of the disease and to supply the appropriate therapeutic
prescription. In most cases the reference centres were
established considering the number of treated patients
The Piedmont and Aosta Valley network for
RDs decentralised model
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Piedmont and Aosta Valley network of rare diseases
involved in treating patients with RDs.
A network as widespread as that of Piedmont and
Aosta Valley requires a Coordinating Centre and a
monitoring system to evaluate the appropriateness of
diagnoses and therapy. The Coordinating Centre was
established in 2004 and, since 2005, it has been supported
by a regional technical board15,16. The coordination of
clinical activities for RDs throughout the two regions
is guaranteed by Working Groups for RDs operating
in all heath institutions of the public regional systems
that act in collaboration with the Coordinating Centre.
The supply of drugs for treatment of patients suffering
from RDs is ensured by a wide network of hospital
pharmacies. These provide all the needed medicinal
products including drugs not currently available nationwide or still under investigation in selected cases, and
off-label agents. In addition, they also produce galenic
preparations which are essential for the treatment of
specific RD. The network of collaboration for the
productions of galenics among hospital pharmacies is,
to date, unique in Italy17.
Another peculiarity of the network of RDs in Piedmont
and Aosta Valley is the presence of multidisciplinary
working groups, called Consortia, dedicated to specific
RDs or to RDs with similar therapeutic or diagnostic
problems. They operate throughout the two Regions
and are composed of volunteer clinicians, other health
professionals, and patient's associations. Consortia main
goal is the development of shared protocols and clinical
pathways18,19. The Consortia deal with the most prevalent
RDs, or with the ones that are characterised by specific
issues such as the cost of treatment or the lack of reliable
data regarding treatment effectiveness and efficacy.
Twenty two Consortia were active at the end of
2013. Fourteen disease-specific or disease groupspecific clinical pathways have been implemented to
date (Table II).
In addition to developing the clinical pathways, the
Consortia also identify, if needed, Centres of Expertise.
A Centre of Expertise must have proven diagnostic
and therapeutic experience as well as availability of
appropriate support structures and complementary
services, such as laboratory and imaging facilities,
emergency department availability, etc. The main aims
of the centres of expertise are supporting the local
health authorities in the care of patients, and providing
specialised training to the health professionals. To
date, Centres of Expertise have been established for
amyotrophic lateral sclerosis, for syringomyelia, and
Arnold-Chiari syndrome.
Lastly, an important activity of the Consortia is the
production of clinical and epidemiological studies on
RDs19-24.
The Piedmont and Aosta Valley network for rare
Table II - Multidisciplinary working groups (so-called
Consortia) at December 31, 2013. In bold are
indicated the implemented clinical pathways.
Adrenogenital Syndromes
Amyloidosis
Anti-phospholipid Syndrome
Arnold Chiari Syndrome, Syringomyelia
Autoimmune peripheral neuropathies
Autoimmune Polyendocrinopathies
Bladder Pain Syndrome
Congenital Osteodystrophy
Hereditary coagulation Disorders
Hereditary retinal dystrophy
Klinefelter Syndrome
Neurofibromatosis
Lysosomal Storage Diseases
Porphyrias
Prader-Willi Syndrome
Precocious Puberty
Primary Lymphedema
Primary Pulmonary Hypertension
Systemic Sclerosis
Transition from childhood to adulthood
Undifferentiated Connective Tissue Disease
Uveitis
diseases is also involved in international collaborations, such
as the network International Conference for Rare Diseases
and Orphan Drugs, Europlan initiatives promoted by the
National Institute of Health, by the European Community,
and by Eurordis, and in the rare diseases coding promoted
by World Health Organization and by Orphanet.
Conclusion
The network of RDs in Piedmont and Aosta Valley is
a unique experience in the Italian scenario. An analysis
of 10 years of activity allows us to give a largely positive
assessment. This widespread network has improved the
clinicians' knowledge of the specific RD.
Moreover, the clinical activities of the Consortia
and of the Network of Hospital Pharmacies allowed to
provide appropriate cares to patients and to limit both
the costs and the therapeutic healthcare mobility toward
other regions.
Authorship contributions
Simone Baldovino and Elisa Menegatti participated
equally to the first draft of the paper.
Keywords: rare diseases, regional policies, Public
Health, healthcare.
The Authors declare no conflict of interest.
Blood Transfus 2014; 12 Suppl 3: s617-20 DOI 10.2450/2014.0055-14s
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Baldovino S et al
References
1)
2)
3)
4)
5)
6)
7)
8)
9)
10)
11)
12)
13)
14)
Taruscio D, Cerbo M. Rare diseases: general principles,
specific problems, and health interventions. Ann Ist Super
Sanita. 1999; 35: 237-44.
Prevalence of rare diseases: Reference data listed in order
of decreasing prevalence or number of published cases.
Available at: http://www.orpha.net/orphacom/cahiers/docs/GB/
Prevalence_of_rare_diseases_by_decreasing_prevalence_or_cases.
pdf. Accessed on 27/02/2014.
Murphy SM, Puwanant A, Griggs RC et al. Unintended effects
of orphan product designation for rare neurological diseases.
Ann Neurol 2012; 72: 481-90.
Programme of Community Action on Rare Diseases (19992003) Decision No 1295/99/EC of the European Parliament
and of the Council of 29 April 1999 (O.J. n° L 155 of
22.06.1999, p. 1) Available at: http://ec.europa.eu/health/
archive/ph_overview/previous_programme/rare_diseases/
raredis_wpgm99_en.pdf (accessed on 07/04/2014)
Taruscio D, Capozzoli F, Frank C. Rare diseases and orphan
drugs. Ann Ist Super Sanita; 2011; 47: 83-93.
Regolamento di istituzione della rete nazionale delle malattie
rare e di esenzione dalla partecipazione al costo delle relative
prestazioni sanitarie, ai sensi dell'articolo 5, comma 1, lettera
b), del decreto legislativo 29 aprile 1998, n. 124). Decreto No.
279 (18/05/2001). Available at: http://www.iss.it/binary/cnmr/
cont/DM279-2001.1234897572.pdf. Accessed on 07/04/2014.
Taruscio D, Kodra Y, Ferrari G, et al. The Italian National Rare
Disease Registry. Blood Transfus. 2014; 12 (Suppl 3): s606-13.
Individuazione del Centro regionale di riferimento per le
malattie genetiche e/o rare. Deliberazione della G.R. No. 2236
ME/SAN (25/09/2001). Available at: http://www.iss.it/binary/
ccmr/cont/20010925_DGR2236.pdf. Accessed on 07/04/2014.
Individuazione dei presidi regionali di riferimento per le
malattie rare. DGR No.204 (08/02/2002). Available at: http://
www.iss.it/binary/ccmr/cont/20020802_DGR204.pdf. Accessed
on 07/04/2014.
"Regolamento di istituzione della rete nazionale delle malattie
rare e di esenzione dalla partecipazione al costo delle relative
prestazioni sanitarie, ai sensi dell'art. 5, comma 1, lettera b
del D.Lgs. 124/98" - Individuazione presidi regionali. DGR
No. 570 (14/06/2004) - D.M. 279/2001. Available at: http://
www.iss.it/binary/ccmr/cont/20040614_DGR570.pdf Accessed
on 07/04/2014.
DGR n. 7/7328. Individuazione della Rete per la prevenzione,
la sorveglianza, la diagnosi, la terapia delle malattie rare.
Available at: http://www.iss.it/binary/ccmr/cont/20011202_
DGR7_7328.pdf. Accessed on 07/04/2014.
Hub & Spoke Emofilia Deliberazione della Giunta Regionale
No.1267 (22/07/2002). Available at: http://www.iss.it/cnmr/
ccmr/regi/cont.php?id=113&lang=1&tipo=17&regi=5. Accessed
on 07/04/2014.
Approvazione dello schema di convenzione tra la Regione
autonoma Valle d'Aosta e la Regione Piemonte per la
realizzazione di un Centro interregionale di coordinamento
per le malattie rare nonché di un Registro interregionale delle
malattie rare, nell'ambito della rete sanitaria interaziendale
ed interregionale prevista dall'accordo approvato con
deliberazione della Giunta regionale n. 1692/2002 e di
modificazione alla deliberazione della Giunta regionale n.
4054/2006. DGR No. 234 (01/02/2008). Available at: http://
www.iss.it/binary/ccmr/cont/20080201_DGR234.pdf. Accessed
on 07/04/2014.
Accordo tra Regione del Veneto, Regione Friuli Venezia
Giulia, Provincia Autonoma di Bolzano e Provincia Autonoma
di Trento per la realizzazione dell'area vasta nel campo delle
15)
16)
17)
18)
19)
20)
21)
22)
23)
24)
malattie rare. Individuazione dei Centri Interregionali di
Riferimento dell'area vasta per le Malattie Rare. DGR No.
2046 (03/07/2007). Available at: http://www.iss.it/binary/ccmr/
cont/20070703_DGR2046.pdf. Accessed on 07/04/2014.
Individuazione della rete regionale per la prevenzione, la
sorveglianza, la diagnosi, la terapia delle malattie rare e
costituzione c/o l'ASL 4 di Torino del Centro regionale di
coordinamento. DGR Deliberazione della Giunta Regionale
No. 22-11870 (02/03/2004) Available at: http://www.iss.it/
binary/ccmr/cont/20040302_DGR22_11870.pdf. Accessed
on 07/04/2014.
Regolamento di istituzione della rete nazionale delle malattie
rare e di esenzione dalla partecipazione al costo delle relative
prestazioni sanitarie, ai sensi dell'art. 5, comma 1, lettera b),
del decreto legislativo 29 aprile 1998, n. 124". Integrazione
disposizioni. DGR No. 38-15326 (12/04/2005). Available
at: http://www.malattierarepiemonte.it/15326.php. Accessed on
07/04/2014.
Crosasso P, Mosso B, Peila E et al. Percorso gestionale
standardizzato dalla prescrizione all'erogazione di galenici
magistrali per pazienti affetti da malattie rare ed allestiti presso
le farmacie ospedaliere di Piemonte e Valle d'Aosta. Giornale
Italiano Farmaci a Clinica 2012; 26: 389-397.
Ciaramitaro P, Baldovino S, Roccatello D, et al. Chiari and
Syringomyelia Consortium: a model of multidisciplinary and
sharing path for rare diseases. Neurol. Sci. 2011; 32 (Suppl
3): S271-3.
Rete regionale delle malattie rare: Linee guida per la
definizione dei Gruppi Tecnici e dei Centri Esperti. DGR
No. 36-5284 (29/01/2013). Available at: http://www.regione.
piemonte.it/governo/bollettino/abbonati/2013/08/siste/00000201.
htm. Accessed on 07/04/2014.
Bertero MT, Bazzan M, Carignola R et al. Antiphospholipid
syndrome in northwest Italy (APS Piedmont Cohort):
demographic features, risk factors, clinical and laboratory
profile. Lupus. 2012; 21: 806-9.
Sciascia S, Roccatello D, Bertero MT et al. 8-isoprostane,
prostaglandin E2, C-reactive protein and serum amyloid
A as markers of inflammation and oxidative stress in
antiphospholipid syndrome: a pilot study. Inflamm. Res.
2012; 61: 809-16.
Bazzan M, Vaccarino A, Stella S et al. Thrombotic recurrences
and bleeding events in APS vascular patients: a review from
the literature and a comparison with the APS Piedmont Cohort.
Autoimmun Rev. 2013; 12: 826-31.
Rossi D, Mansouri M, Baldovino S, et al. Nail fold
videocapillaroscopy in mixed cryoglobulinaemia. Nephrol.
Dial. Transplant. 2004; 19: 2245-9.
Mereuta OM, Baldovino S, Errichiello E, et al. Systemic
AA amyloidosis as a unique manifestation of a combined
mutation of TNFRSF1A and MEFV genes. Amyloid. 2013;
20:122-6. 10).
Correspondence: Dario Roccatello
CMID - University Centre of Immunology and Documentation
on Rare Diseases,
Coordinating Centre of Piedmont and Aosta Valley
Network for Rare Diseases
P.zza del Donatore di Sangue 3
10154 Torino, Italy
e-mail: dario.roccatello@unito.it
Blood Transfus 2014; 12 Suppl 3: s617-20 DOI 10.2450/2014.0055-14s
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ORIGINAL ARTICLE
Centres of Expertise and European Reference Networks:
key issues in the field of rare diseases. The EUCERD Recommendations.
Domenica Taruscio1, Amalia E. Gentile1, Teresinha Evangelista2, Rosa G. Frazzica1, Kate Bushby2,
Antoni Moliner Montserrat4
1
Italian National Centre for Rare Diseases, Istituto Superiore di Sanità, Rome, Italy; 2Institute of Genetic Medicine,
International Centre for Life, Newcastle upon Tyne, United Kingdom; 3Directorate of Public Health and Risk
Assessment, European Commission, Luxembourg, Luxembourg
Background. Rare diseases, because of their intrinsic characteristics - large number of disorders
and syndromes, low individual prevalence, severity, often limited information, lack of therapies - can
benefit from collaboration and sharing of expertise while maximising the limited resources available
for these conditions. Therefore, the development of Centres of Expertise (CEs) and European Reference
Networks (ERNs) in this field is crucial.
The European Union Committee of Experts on Rare Diseases (EUCERD) has been charged to assist
the European Commission with the preparation and implementation of activities in the field of rare
diseases in Europe. In particular, EUCERD has assisted the EC in drawing up the recommendations
issued in the Commission Communication and in the Council Recommendation. In this paper the
authors focus on the EUCERD Recommendations on CEs and one on ERNs.
Materials and Methods. Recommendations on CEs and ERNs are the result of two different
processes, developed through iterative reviews and discussions at workshops and EUCERD meetings,
and according to the European Union documents.
Results. EUCERD has issued two complementary Recommendations, one on CEs (2011) and a
second on ERNs (2013). Both address multiple targets (from Member States to Centres, and patient
organisations), with the objective of helping them define and organise CEs and ERNs.
Conclusions. The establishment, designation, financial support, and evaluation of CEs throughout
Europe allow RD patients and local health care providers to identify high-quality specialised services
that can simplify disease management and improve patients' care. The EUCERD Recommendations
are useful instruments to help and guide stakeholders in the development of CEs and ERNs and thus
ensure equity of access to services and care for rare diseases patients across Europe.
Keywords: rare diseases, Centres of Expertise, reference networks, public health, policy.
Introduction
Rare Diseases (RDs) are defined in Europe as those that
affect fewer than 5 in 10,000 people. They have specific
characteristics as a low prevalence in the population,
a multitude of different diseases and syndromes, the
lack of general awareness, the difficulty in diagnosing
and, for most of them, the lack of effective therapies.
These conditions make them an exceptional field for
collaboration and sharing of expertise. RDs represent
one of the best examples where European cooperation
can be a strong added value. Furthermore, only through
the strengthening of international collaboration, it will be
possible to maximise the scarce resources devoted to RDs
and, at the same time, deliver the best quality of care to
the RD patients. Therefore, the development of Centres
of Expertise (CEs) and European reference networks
(ERNs) in RDs is fundamental.
In November 1993, the European Commission (EC)
published a Communication1, defining the framework for
action in the field of public health and describing the role
of Community Institutions and of Member States (MSs).
After this publication, the EC opened a wide consultation
in the European Union (EU) on public health issues. In
December 1993, experts were invited by the EC to submit
proposals describing how they would seek to formulate
draft policy proposals in some of the areas indicated
in the framework document. In consultation with the
Commission, five priority areas were identified, among
them there was also "an EU programme for management
of rare diseases".
It is worth noting that, even at that early time,
the experts recommended "a system whereby the
Commission might seek to encourage identification of
centres of expertise on RDs and support the establishment
Blood Transfus 2014; 12 Suppl 3: s621-5 DOI 10.2450/2014.0026-14s
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Taruscio D et al
of networks for the development of research in appropriate
fields". They underlined that RD "focal points (CEs on
RD and networks with a central secretariat), should be
identified, and the existing structures concerned with
RDs within the MSs should form the backbone of the
focal points2".
More recently, the need for the development of CEs
and ERNs in the field of RDs has been highlighted
in several EU documents3-5, as a means of organising
effective care for the thousands of heterogeneous RDs
affecting patients scattered across Europe. Moreover,
the Recommendations6 of the European Project for Rare
Diseases National Plans Development (EUROPLAN www.europlanproject.eu) has reinforced the Council
Recommendations4 and has underscored the importance
of MSs to identify national or regional CEs, to define
good practices for their designation and evaluation, and
to encourage their participation in ERNs.
Between 2004 and 2013, the European Union
Committee of Experts on Rare Diseases (EUCERD7 www.eucerd.eu) - formerly the European Commission's
Rare Diseases Task Force (RDTF) - was mandated to
assist the EC with the preparation and implementation
of community activities in the RDs field. In particular,
EUCERD has assisted the EC in drawing up
Recommendations, including those concerning CEs
and ERNs for RDs, deriving them from the Commission
Communication3 and the Council Recommendation4.
EUCERD was composed of 51 members: experts
from MSs, current and former RD research project leaders,
representatives from relevant international organisations
(DG SANCO, DG Research, DG Enterprise, EuroStat,
EMA, WHO, OECD), pharmaceutical industries, and
representatives of patient organisations.
EUCERD has issued five Recommendations on the
following areas:
- Quality Criteria for CEs for RDs in MSs (October
2011)8;
- Informed decisions based on the Clinical Added
Value of Orphan Medicinal Products (CAVOMP)
(September 2012)9;
- ERNs for RDs (January 2013)10;
- RD Patient Registration and Data Collection (June
2013a)11;
- Core Indicators for RD National Plans/Strategies
(NP/S) (June 2013b)12.
Materials and methods
The elaboration of the EUCERD Recommendations
on CEs and ERNs was based upon the results of concepts
defined by the High Level Group on health care and
medical services (HLG)13, EU projects documents6,
meetings with experts and other stakeholders, several
reports investigating the state-of-the-art in the field of
RDs, and on the previous work of the RDTF/EUCERD
group14-19.
In particular, the legal aspects associated with the
Recommendations, as well as the political background,
were established by the Commission Communication3,
by the Council Recommendation4 and by the "Directive
on the application of patients' rights in cross-border
healthcare" (CBHCD)5. All draft Recommendations were
elaborated by the EUCERD Scientific Secretariat, were
sent to EUCERD members for comments, and the wording
of the recommendations was discussed in dedicated
workshops. The revised draft of the Recommendations was
then submitted to EUCERD members for final approval
prior to their meeting, where the Recommendations were
unanimously adopted by the Committee.
Results
The main results concern the publication of the
EUCERD Recommendations on CEs and ERNs, which are
complementary, as they are elucidated below. They address
numerous targets: MSs, the EC, other EC initiatives (e.g.
projects and joint actions, Cross-Border Healthcare Expert
Group, EUnetHTA, EPAAC), CEs in the field of RDs
healthcare providers, RD experts and existing RD network
co-ordinators and partners, patient organisations.
EUCERD Recommendations on CEs
The aim of these Recommendations is to help MSs
in their reflections/policy developments concerning
NP/S for RDs. Specifically, they are useful in addressing
the organisation of healthcare pathways at national
and at European level. Potentially, they are helpful
for the CBHCD application in the context of ERNs
development.
This document includes 45 Recommendations,
concerning 4 main areas:
- mission and scope of CEs: definition, coverage, patient
focus, core competencies, role in disseminating
information and education, role in research;
- criteria for designation: leadership and credibility,
multidisciplinarity and inclusiveness, capacity,
links and collaborations, mechanisms for measuring
performance/evaluation;
- process for designation: core principles of designation,
designation criteria, duration of designation;
- European dimension: sharing experience and
indicators at EU level, networking.
According to the EUCERD Recommendations, CEs
are defined as physical highly specialised structures
for the management and care of RD patients, with the
mission of providing them with the highest standards
of care and delivering timely diagnosis, appropriate
treatment and follow up, on a regional, national,
European or international level.
Blood Transfus 2014; 12 Suppl 3: s621-5 DOI 10.2450/2014.0026-14s
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CEs and ERNs: key issues in RD field. EUCERD Recommendations
Each CE specialises in a single RD or in a group of
RDs. It gathers or coordinates - within the specialised
healthcare sector - multidisciplinary competences/skills,
including paramedical skills and social services, in order
to serve the specific medical, rehabilitative, palliative
and social needs of RD patients. Multidisciplinarity
and inclusiveness were defined as the capacity to
deliver a multidisciplinary approach, integrating
medical, paramedical, psychological and social needs
and to ensure the continuity of care, from childhood
through adolescence and adulthood, as well as in
all stages of the disease. CEs should offer a wide
range of specialised services: consultations, medical
examinations, using specialised equipment, genetic
testing, counselling and social care. They should also
participate in building healthcare pathways, starting
from primary care. Furthermore, they should contribute
to research efforts through their participation in both
data collection for clinical research and in clinical trials.
They should collaborate with different stakeholders,
including RD patient organisations. The focus of these
Recommendations on CEs is on patients, so that all their
needs may be effectively met.
The criteria for the designation of CEs should be
based on leadership and credibility, multidisciplinarity
and inclusiveness, as well as on their capacity to create
links and collaborations and on the existence of an
evaluation mechanism. Moreover, MSs are responsible
for their designation and this should be done through
the adoption of transparent designation criteria, the
assurance of an on-going evaluation process and the
facilitation of access to the patients. The designation
process at MS level should ensure that the designated
CEs have the capacity and the resources to fulfil their
obligations according to the criteria and that they have
a strategy in place to meet all the criteria during a set
period of time. The CEs designation is an important step
as it provides the base for its connection to the next level
of collaboration, the ERNs level.
EUCERD Recommendations on ERNs
The general concept and the method of implementing
ERNs are defined in Article 12 of the CBHCD.
The aim of these Recommendations on ERNs is to
inform (a) the Commission's services and expert groups,
working on the criteria for the creation and designation of
ERNs on RDs specificities, in the context of the CBHCD;
(b) MSs that are developing their healthcare pathways at,
both, the national and the EU levels in the field of RDs,
particularly in the context of NP/S for RDs.
This document includes 21 Recommendations,
concerning 5 main areas:
- mission, vision and scope: providing a framework for
healthcare pathways, covering core tools and activities;
-
governance: robust and clearly defined governance,
strong leadership;
- composition of RD ERNs: different forms of
affiliation to allow inclusivity, linking CEs and
stakeholders involved in the care management of
patients;
- funding and evaluation: long-term sustainable
funding mechanisms (MS competence);
- designation of RD ERNs: development of shared
platforms across RDs, clear designation process,
stepwise-strategy, defining and implementing a
formal system for networking across all RD ERNs
and sharing expertise.
According to the EUCERD Recommendations,
an RD ERN is the physical or virtual networking of
knowledge and expertise of national CEs in more than
one European Country. The goal of an ERN is the
improvement of the overall quality and management of
care of a single RD or a group of RDs with similar health
care needs, by complementing, supporting and providing
added-value to the existing services and expertise at the
national level. In these Recommendations, it is stated
that designated CEs are the core participants, so RD
ERNs should be flexible enough to be able to work with
different national structures.
This networking activity among national CEs
promotes the sharing and mobility of expertise
rather than the movement of patients, and facilitates
the travelling of patients to cross-border CEs when
necessary.
In order to improve the delivery of care in an effective
way, while reducing its costs, the ERNs need to facilitate
the sharing of information and tools amongst CEs and
other care providers. For instance, information on disease
registries, communication of guidelines/best standards of
diagnosis and care, training and education tools, quality
assurance schemes, telemedicine, cross-border referral
mechanisms should be shared among CEs and other
interested parties.
The co-ordinating site(s) should be selected on the
basis of proven leadership and capability to coordinate
a network; it is not necessarily to be the best centre of
expertise or the one with the largest number of patients.
In the composition of RD ERNs different forms of
affiliation (association, collaboration) can be foreseen.
In small countries, where there may be a small number
of CEs or no CEs at all, other healthcare providers can
become affiliated members of an RD ERN. This allows
an RD ERN to reach out of as many MSs as possible.
RD ERNs should have clearly defined mechanisms
of governance and evaluation, and patient organisations
should play an important role in the process. Patients
in every European country can benefit from an RD
ERN, even if in their country there may not be a CE
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Taruscio D et al
that is member of an RD ERN. The objective, in the
next decade, is that RD ERNs cover all RDs grouped
by diagnostic and systemic areas, using a step-wise
approach.
of RDs offers enormous and practical potentials for
European cooperation. The specificities of these diseases the limited number of patients and the scarcity of relevant
knowledge and expertise - single them out as a prime area
for cooperation, with a very high European added-value26.
Conclusions
There are currently more than 6,000 identified
RDs20, each of which affects fewer than 5 in 10,000
people, according to the EU definition. These diseases
are thought to affect around 30 million people in the
EU countries.
For the last 10 years, RDs have become one of the
priorities of the EU health policies and the development
of CEs and ERNs in the field of RDs was encouraged in
several EC documents, as well as in EU projects, such
as EUROPLAN21.
The establishment, designation, financial support,
and evaluation of CEs throughout Europe allow RD
patients and local health care providers to identify
high-quality specialised services thus simplifying
disease management and improving patients' care.
The MSs should promote and support CEs in order to
guarantee equity of access to good quality of services
and care to their citizens affected by RDs. CEs should
reduce costs in healthcare systems by contributing to
shorter delays in diagnosis, less adverse consequences,
a reduction in misdiagnoses and subsequent unnecessary
treatments and more adequately adapted care, as pointed
out also by EURORDIS22.
The political commitment of MSs to identify and
financially support CEs is a prerequisite for the creation
of ERNs. Moreover, the establishment of ERNs also
allows health authorities to identify the best allocation
of financial resources to support the activities linked to
the effective management of RD patients.
Due to the differing health care structures, different
definitions of a CEs and differences in the diseases they
treat, each ERN, which consists of individual CEs, will
also reflect this variability. CEs should be flexible to
accommodate different stakeholders and healthcare
providers with particular emphasis being placed on
patients representatives.
Nevertheless, the establishment and the sustainability
of ERNs, as indicated in the CBHCD, is a major
opportunity for the RD community23, especially for
ultra RDs (by definition prevalence <1:2,000,00024Table I) in which expertise may be available only in a
very small number of European countries. Therefore,
ultra RD patients may need to receive care across borders.
The added-value25 of ERNs is given by the existence of
several multilateral cross border health care agreements,
by many EC funded projects, documented by the EC
HLG and by the currently funded EC pilot projects.
CEs and ERNs are a good example of how the field
Table I -
Comparison of the major characteristics of rare
and ultra-rare disorders25.
Rare Disorders
Ultra-rare disorders
Prevalence
<1:2,000
<1:2,000,000
Number of affected
newborns/disorder in
Europe
5,000 or less
5 or less
Diagnosis
Centers of expertise
(national);
E-mail consulting.
Electronic database
(international);
E-mail consulting.
Follow-up
Centers of expertise
Local healthcare
professionals;
Virtual centres of
expertise.
Provision of
information
Text books; literature;
sites (OMIM,
Orphanet, etc.)
Wiki sites
Support groups
National
International
Research
Grants difficult
Grants extremely
difficult
Acknowledgements
This paper was made possible thanks to the help of
the EUCERD Joint Action: Working for Rare Diseases,
which was funded by the EU in the framework of the
Health Programme (grant 20112201).
The Authors declare no conflicts of interest.
References
1)
2)
3)
4)
5)
6)
Commission of the European Communities, Commission
communication on the framework for action in the field of
public health.COM(93) 559. Brussels: CEC, 1993. Available
at: http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=C
OM:1997:0266:FIN:EN:PDF. Accessed on 03/01/2014.
Birt CA, Gunning-Schepers L, Hayes A, Joyce L. How should
public health policy be developed? A case study in European
public health. J Public Health Med. 1997; 19: 262-7.
Communication of the European Commission "Rare Diseases:
Europe's challenge" (COM[2008] 679 final)" (11 November
2008). Available at: http://ec.europa.eu/health/ph_threats/
non_com/docs/rare_com_en.pdf. Accessed on 03/01/2014.
Council Recommendation on an Action in the Field of Rare
Diseases (2009/C 151/02) (8 June 2009). Available at: http://
eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:C:2009:
151:0007:0010:EN:PDF. Accessed on 03/01/2014.
Directive on the application of patients' rights in cross-border
healthcare (2011/24/EU) (9 March 2011). Available at: http://
eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2011:
088:0045:0065:EN:PDF. Accessed on 03/01/2014.
EUROPLAN Recommendations for the Development of
National Plans for Rare Diseases. Guidance Document.
Available at: www.europlanproject.eu. Accessed on 03/01/2014.
Blood Transfus 2014; 12 Suppl 3: s621-5 DOI 10.2450/2014.0026-14s
s624
CEs and ERNs: key issues in RD field. EUCERD Recommendations
7)
8)
9)
10)
11)
12)
13)
14)
15)
16)
17)
18)
European Commission Decision of 30 November 2009
(2009/872/EC). Available at: http://eur-lex.europa.eu/
LexUriServ/LexUriServ.do?uri=OJ:L:2009:315:0018:0021:
EN:PDF. Accessed on 03/01/2014.
EUCERD Recommendations on Quality Criteria for Centres
of Expertise for RD in MS (October 2011). Available at: www.
eucerd.eu. Accessed on 03/01/2014.
EUCERD Recommendations on Informed decisions based
on the Clinical Added Value of Orphan Medicinal Products
(September 2012). Available at: www.eucerd.eu. Accessed
on 03/01/2014.
EUCERD Recommendations on European reference networks
for RD (January 2013). Available at: www.eucerd.eu. Accessed
on 03/01/2014.
EUCERD Recommendations on Rare Disease Patient
Registration and Data Collection (June 2013a). Available at:
www.eucerd.eu. Accessed on 03/01/2014.
EUCERD Recommendations on Core Indicators for RD
National Plans/Strategies (June 2013b). Available at: www.
eucerd.eu. Accessed on 03/01/2014.
Work of the High Level Group on Health Services and
Medical Care during 2005. Available at: http://ec.europa.
eu/health/archive/ph_overview/co_operation/mobility/docs/
highlevel_2005_013_en.pdf. Accessed on 03/01/2014.
RDTF Report: Overview of Current Centres of Reference on
rare diseases in the EU (September 2005). Available at: http://
www.eucerd.eu/upload/file/Publication/RDTFECR2005.pdf.
Accessed on 03/01/2014.
RDTF Report: Centres of Reference for Rare Diseases in
Europe – State-of-the-art in 2006 and Recommendations
of the Rare Diseases Task Force (September 2006).
Available at: http://www.eucerd.eu/upload/file/Publication/
RDTFECR2006.pdf. Accessed on 03/01/2014.
RDTF Report: European reference networks in the field
of Rare Diseases: State of the art and Future Directions
(July 2008). Available at: http://www.eucerd.eu/upload/file/
Publication/RDTFERN2008.pdf. Accessed on 03/01/2014.
EUCERD Workshop Report: Centres of expertise and
European reference networks for rare diseases (8-9 December
2010). Available at: http://www.eucerd.eu/upload/file/
WorkshopReport/EUCERDWorkshopReportCECERN.pdf.
Accessed on 03/01/2014.
EUCERD Workshop Report: National centres of expertise for
rare diseases and networking between centres of expertise for
rare diseases (21-22 March 2011). Available at: http://www.
eucerd.eu/upload/file/EUCERDReport220311.pdf. Accessed
on 03/01/2014.
19) EUCERD Report: Preliminary analysis of the experiences and
outcomes of ERNs for rare diseases (May 2011). Avalaible at:
http://www.eucerd.eu/upload/file/Reports/ERN2011Analysis.
pdf. Accessed on 03/01/2014.
20) European Parliament and Council. Regulation (EC) 141/2000
of the European Parliament and of the Council of 16 December
1999 on orphan medicinal products. Official Journal 2000;
L18: 1-5.
21) Taruscio D, Gentile AE, De Santis M, et al. EUROPLAN: A
Project to Support the Development of National Plans on Rare
Diseases in Europe. Public Health Genomics 2013; 16: 278-87.
22) 2013 EURORDIS Policy Fact Sheet - Centres of Expertise.
Available at: www.eurordis.org. Accessed on 03/01/2014.
23) 2013 EURORDIS Policy Fact Sheet - European reference
networks of Centres of Expertise. Available at: www.eurordis.
org. Accessed on 03/01/2014.
24) Bushby K. European reference networks: developing a
EUCERD opinion. Orphanet J Rare Dis 2012; 7 (Suppl 2): A6.
25) Hennekam RCM. Care for patients with ultra-rare disorders.
European Journal of Medical Genetics. Eur J Med Genet
2011; 54: 220-4.
26) Moliner Montserrat A. Creating a European Union framework
for actions in the field of rare diseases. Adv Exp Med Biol
2010; 686: 457-73.
Correspondence: Domenica Taruscio
Italian National Centre for Rare Diseases – Istituto Superiore di Sanità
Viale Regina Elena, 299
00161 Rome, Italy
e-mail: domenica.taruscio@iss.it
Blood Transfus 2014; 12 Suppl 3: s621-5 DOI 10.2450/2014.0026-14s
s625
LETTER TO THE EDITOR
European Reference Networks for rare diseases: the vision of patients
Terkel Andersen, Yann Le Cam, Ariane Weinman
European Organisation for Rare Diseases (EURORDIS), Paris, France
Dear Sir,
The European Organisation for Rare Diseases
-EURORDIS- is a non-governmental patient-driven
alliance of patient organisations and individuals active
in the field of rare diseases. EURORDIS represents
over 600 rare disease organisations in 58 countries
(including 26 EU Member States) covering more than
4,000 rare diseases. More information is available on
www.eurordis.org1.
Since 2004, EURORDIS has been involved in
different discussions at European and national levels on
shaping Centres of Expertise and European Reference
Networks (ERNs) for rare diseases with a view to
improve timely access to appropriate diagnosis and care
for people living with a rare disease.
Over almost a decade, EURORDIS has gathered
the opinions of its members on these topics through its
Annual Membership Meetings as well as through surveys
and workshops organised within the European co-funded
projects RAPSODY and POLKA2. The opinions of our
members have informed relevant EURORDIS position
papers, which thus reflect the expectations of patients
and their families regarding the organisation of care and
delivery of treatments for their diseases.
Why are ERNs important for patients with rare
diseases? Due to the low prevalence of each rare
disease, expertise is by essence scarce and scattered
throughout Europe. The best way to accelerate access
to a proper, timely diagnosis, as well as appropriate
care, is to share expertise by linking at European level
the national Centres of Expertise, healthcare providers,
diagnostic laboratories, other relevant services and
patients' organisations. ERNs are also intended to gather
a critical mass of patients and data to support rare disease
registries and clinical research.
The national Centres of Expertise are seen to
constitute the nodes of ERNs for rare diseases.
EURORDIS, through its representatives, contributed
to the Recommendation of the European Committee of
Experts on Rare Diseases (EUCERD) on the "quality
criteria for Centres of Expertise for Rare Diseases in
Member States", which was adopted on 24 October
2011. To date, the EU Member States are developing
criteria based on this Recommendation for designated
Centres of Expertise for RDs in their territory within
their national plans/strategies for rare diseases.
The European Directive 2011/24/EU 3 on the
"application of patients' rights in cross-border healthcare"
has delineated for the first time the legal framework for
European reference networks. This has been a success
in translating a concept into a real healthcare framework
with an added value for patients.
In addition, Article 13 of this Directive is specifically
dedicated to rare diseases: "The Commission shall support
Member States in cooperating in the development of
diagnosis and treatment capacity in particular by aiming
to make health professionals aware of the tools available to
them at Union level to assist them in the correct diagnosis
of rare diseases, in particular the Orphanet database, and
the European Reference Networks".
In this evolving context, EURORDIS adopted in
May 2012 a position to outline its vision and strategy
for ERNs for rare diseases; what they should comprise
and how they should function based on the patient's real
life experience.
EURORDIS rejects the logic of selecting priorities
amongst rare diseases; all patients affected with a rare
disease should be covered by at least one ERN in the
long run. As it will not be possible to fund numerous
ERNs, EURORDIS recommends that a limited number
of ERNs for RDs (20 to 30) should be created by
diagnostic and therapeutic areas in order to cover a wide
range of rare diseases. EURORDIS also emphasises that
a high-level of multi-disciplinarity and inter-operability
among ERNs are absolutely necessary. The successful
development of ERNs for RDs will rely on a step-wise
approach aimed at establishing progressively the various
activities of the ERN, such as experts' opinions, good
practice guidelines on medical care as well as social care,
training, patient registries, e-health. The ERNS should
remain flexible in order to evolve over time.
The EURORDIS representatives in the EUCERD
voiced the patients' perspectives during the consultations
on the elaboration of the Recommendation on European
Reference Networks for Rare Diseases. This EUCERD
Recommendation4 was adopted on 31 January 2013 and
integrates many elements of the rare disease patients'
position.
The new Health for Growth Programme of the
European Commission, adopted in March, shall cover a
period of seven years, from 2014 to 2020. We are aware
that there will not be enough funding for European
Blood Transfus 2014; 12 Suppl 3: s621-5 DOI 10.2450/2014.0039-14s
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© SIMTI Servizi Srl
European reference networks: the vision of patients
reference networks. Therefore, we need to be creative
and seek other sources of funding, for instance from
the Horizon 2020 programme and possibly structural
funds for health. Tonio Borg, European Commissioner
for Health, has recently emphasised that research on rare
diseases is a priority for the European Commission and
where there is an opportunity to offer a better service
to citizens, the principle of subsidiarity applies; hence
this principle applies to Cross-Border Healthcare for
Rare Diseases.
4)
European Union Committee of Experts on Rare Diseases
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 21/02/2014.
The Authors declare no conflicts of interest.
References
1)
2)
3)
Eurordis.org [Internet]. Brussels. EURORDIS Rare Diseases
Europe. Available at: www.eurordis.org.
Eurordis.org [Internet]. Brussels. POLKA: Patients' Consensus
on Preferred Policy Scenarii for Rare Disease. EURORDIS
Rare Diseases Europe. September 2008 [Page last updated:
20/07/2011]. Available at: http://www.eurordis.org/content/
polka-patients-consensus-preferred-policy-scenarii-raredisease.
Directive 2011/24/EU of the European Parliament and of the
Council of 9 March 2011 on the application of patients' rights
in cross-border healthcare. Available at: http://ec.europa.eu/
health/cross_border_care/policy/index_en.htm. Accessed on
21/02/2014.
Correspondence: Ariane Weinman
European Organisation for Rare Diseases
96, rue Didot
75014 Paris, France
e-mail: ariane.weinman@eurordis.org
Blood Transfus 2014; 12 Suppl 3: s621-5 DOI 10.2450/2014.0039-14s
s627
ACKNOWLEDGEMENTS
Our thanks to those who have helped with this special issue of Blood Transfusion and who have kindly given their
time, effort and expertise; their generosity has helped establish this publication.
Abbonizio F.
Agresta L.
Amato A.
Andersen T.
Arcieri R.
Armeni P.
Avanzi F.
Baldovino S.
Bernardo G.
Bernardo L.
Berntorp E.
Bon C.
Braguti F.
Calizzani G.
Candura F.
Carbone P.
Carta C.
Castaman G.
Cavazza M.
Ceccarini M.
Censi F.
Cerbone A.M.
Cimino E.
Congiu M.E.
Coppola A.
Coppola S.
Crialese P.
De Santis M.
Di Minno G.
Di Stanislao F.
Diemoz S.
Donati C.
Evangelista T.
Facco G.
Farace S.
Fattore G.
Ferrari G.
Fischer K.
Floridia G.
Fortino A.
Franchini M.
Frank C.
Frazzica R.G.
Gainotti S.
Garnero A.
Gatt A.
Gentile A.E.
Giampaolo A.
Giangrande P.
Gilman E.
Giordano P.
Granata O.
Grazzini G.
Hassan, H.J.
Hermans C.
Hollingsworth R.
Iorio A.
Kate Bushby K.
Keepanasseril A.
Kodra Y.
Lamanna A.
Lambert T.
Lanzoni M.
Laricchiuta P.
Lassila R.
Latrofa M.
Le Cam Y.
Leebeek, F.W.G.
Liumbruno G.M.
Magrelli A.
Makris M.
Mannucci P.M.
Mantovani L.
Manzoli L.
Marano G.
Maspoli M.
Matino D.
Mazza G.
McLaughlin K.
Menegatti E.
Menichini I.
Modena V.
Molinari A.C.
Moliner Montserrat A.
Morciano C.
Morfini M.
Nuti S.
Oleari F.
Oliovecchio E.
Page D.
Peyvandi F.
Polizzi A.
Profili S.
Pupella S.
Razeto S.
Roccatello D.
Saia M.
Salvatore M.
Sanseverino A.
Santoro C.
Savini D.
Schieppati A.
Skinner, M.W.
Soucie J.M.
Tamburrini M.R.
Taruscio D.
Teitel, J.
Torreri P.
Tosto F.
Tufano A.
Vaglio S.
Velati C.
Villani F.
Vincenti G.
Vittozzi L.
Walker I.
Weinman A.
Windyga J.
Zanon E.
Special thanks to Cannata L., Fehily D. and Gillespie F. who kindly provided the linguistic review of the manuscripts.
Blood Transfus 2014; 12 Suppl 3
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