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Developing a European Platform for Rare Disease Registries

Deliverable of EPIRARE WP8:

Luciano Vittozzi, Sabina Gainotti, Emanuela Mollo, Domenica Taruscio

National Centre for Rare Diseases – National Institute for Health – Rome, Italy

With contributions from: Manuel Posada, Institute of Rare Diseases Research, Institute of Health Carlos III – Madrid, Spain

Please send comments and amendments by e-mail to L.Vittozzi (cnmr.eu@iss.it)

Notice on confidentiality: This draft is sent to the recipients for a consultation aiming to collect observations and amendments on the document, and especially to improve the contents regarding the needs provisionally attributed to the stakeholders and the platform services proposed for their use. The recipients of this document are kindly requested not to distribute this document for purposes other than those indicated above.

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Contents

Acknowledgements ............................................................................................. 4

Executive Summary .............................................................................................. 6

Background ......................................................................................................... 8

Methodological note ............................................................................................ 9

I. The current context: the relevance of a rare disease registry platform .......... 10

A. EU Public Health policies .................................................................................................................... 10

1. The EU Recommendation for an action in the field of rare diseases (RD) and the Cross-Border Health Care Directive.............................................................................................................................. 10

2. Orphan Medicinal Products (OMP) policy ...................................................................................... 11

3. EU Health strategy .......................................................................................................................... 11

4. The regional dimension of the health policies ................................................................................ 11

B. Other relevant EU policies .................................................................................................................. 12

1. e-Health policy ................................................................................................................................ 12

2. Research policy and Industrial policy .............................................................................................. 12

3. The Revision of the Personal Data Protection Directive ................................................................. 12

C. Current Activities in Research and Public Health ................................................................................ 13

II. EU rare disease registry platform: stakeholders, their needs and their support role .................................................................................................................... 17

A. Stakeholders’ needs and supporting role ........................................................................................... 18

III. The proposal for a Platform .......................................................................... 20

A. The possible scenarios ........................................................................................................................ 20

B. The EPIRARE platform scope .............................................................................................................. 21

C. The EPIRARE platform model ............................................................................................................. 22

D. The data repository function .............................................................................................................. 24

E. The pre-defined outputs and services ................................................................................................ 25

F. Financial and other circuits ................................................................................................................. 34

G. Governance mechanisms ................................................................................................................... 37

H. The EU Platform implementation process .......................................................................................... 35

1. Policy work: .................................................................................................................................... 35

2. Expert work: ................................................................................................................................... 36

3. Quality assurance system development and implementation........................................................ 37

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4. ICT work: ......................................................................................................................................... 37

5. Temporary Platform management ................................................................................................. 37

APPENDIX A – European Technology Platforms ................................................... 39

I. Extracts from the EURAB (2004) Report on European Technology Platforms .................................... 39

J. Extracts from Idea Consult (2008) - Evaluation of the European Technology Platforms (ETPs)) ........ 40

1. Main objectives .............................................................................................................................. 40

2. Main priorities and deliverables ..................................................................................................... 40

3. Main stakeholders of the ETPs ....................................................................................................... 41

4. Some key operational principles of the ETPs .................................................................................. 41

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Acknowledgements

The authors are gratefully indebted with the following experts, who read the manuscript and provided their precious comments. Since the Authors had to interpret their input at some extent, the contents of this document might not fully reflect their suggestions. We apologize for any partial or incorrect consideration of their observations.

Faisal Ahmed School of Medicine, University of Glasgow – Glasgow,

UK

Stein Are Aksnes Rehabilitation and Rare Disorders Department,

Directorate of Health – Oslo, Norway

Ingeborg Barisic Department of Paediatrics, Children's University

Hospital, University of Zagreb – Zagreb, Croatia

Wolfgang Bödeker BKK Bundesverband, Abteilung Statistik & Analysen -

Essen, Germany

Francesc Cardellach Hospital Clínic, University of Barcelona – Barcellona,

Spain

Nona Chiriac Center for Health Services Research and Evaluation,

National School of Public Health, Management and

Professional Development – Bucharest, Romania

Laura Deroma Centre for Rare Diseases, University Hospital "Santa

Maria della Misericordia" - Udine, Italy

Johan den Dunnen Leiden Muscular Dystrophy pages, Human and Clinical

Genetics, Leiden University Medical Center – Leiden,

The Netherlands

Jean DONADIEU Service d'Hémato-Oncologie Pédiatrique

Hopital Trousseau – Paris, France

Pietro Folino Gallo European Assessment Office, Italian Medicine Agency –

Roma, Italy

Juan Carlos Garcia-Pagán Hepatic Hemodynamic Laboratory, Liver Unit, Hospital

Clinic – Barcelona, Spain

Ester Garne Paediatric Department, Hospital Lillebaelt – Kolding, DENMARK

Alexandra Halbach Bundesministerium für Gesundheit, Referat 313 -

Molekulare Medizin, Bioethik - Berlin, Germany

Panos Kanavos LSE Health, London School of Economics, London, UK

Alastair Kent Genetic Alliance UK

Member of European Genetic Alliances' Network –

London, UK

Maurizio Luisetti University of Pavia, Pneumology Section, Fondazione

IRCCS Policlinico San Matteo – Pavia, Italy

Milan Macek Department of the Health Services, Ministry of Health – Prague, Czech Republic

Vitaliy Matyushenko Kharkiv Charitable Foundation “Children with Spinal

Muscular Atrophy” (CSMA) - Kharkiv, Ukraine

Maria Judit Molnar Institute of Genomic Medicine and Rare Disorders

Semmelweis University- Budapest, Hungary

Elena M. Nicod LSE Health, London School of Economics, London, UK

Karaman Pagava Child & Adolescent Medicine, Tbilisi State Medical

University – Tbilisi, Georgia

Samantha PARKER External Affairs and Rare Disease Partnerships, Orphan

Europe – Paris, France

Pilar Soler Crespo Dirección General de Salud Pública, Calidad e

Innovación, Ministerio de Sanidad, Servicios Sociales e

Igualdad - Madrid, Spain

Christiane Steinmüller Project Management Agency, Part of the German

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Aerospace Center, Health Research – Bonn, Germany

Peter Taschner Department of Human Genetics, Center for Human and

Clinical Genetics, Leiden University Medical Center –

Leiden, The Netherlands

Marieke Verschuuren National Institute for Public Health and the Environment

(RIVM) - Bilthoven, the Netherland

EUPHA section Public Health Monitoring and Reporting

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Executive Summary

Developing a European Platform for Rare Disease Registries and Databases

The general objective of the EPIRARE project is to build consensus and synergies to address legal, ethical and technical issues associated with the registration of RD patients and to elaborate a proposal for a EU web-based multi-disease platform which, by sharing information and resources, can increase the sustainability of registries, promotes the use of registry quality procedures and provides an effective way of dissemination of the results.

The objective of this document is to develop a proposal for the scope, services and outputs of an EU platform for rare disease registries, based on an analysis of the elements that have been defined as particularly relevant for the platform feasibility. In line with the guiding principles and the main common features of technological platforms as outlined in the EURAB Report1 this analysis addresses issues pertinent to the strategic relevance and complexity of the rare disease field, the variety and dimension of the stakeholders involved, their expected needs and support, the use of the platform for research on diseases and development of Orphan Medicinal Products as well as for purposes regarding public health and social service operation.

Within the framework of the EUCERD Recommendations on RD Patient Registration and Data Collection, the model which is proposed by EPIRARE (Fig. 1) to fulfil the above mentioned prerequisites is a web-based platform providing a number of functions:

a data repository function, including a separate section for ad hoc collaborative projects;

production of predefined outputs for the funding organizations and the public;

production of tools and resources of use to registries;

communication to the public, promotion of registration and networking among patients.

Data quality and output reliability are key for fund-raising; therefore the platform sets quality targets and maintains an External Quality Assurance System (EQAS).

Participation in the platform is granted to registries and databases complying with data quality criteria. The registries and databases participating in the platform communicate data of specified sets of common data elements (SCE) to the platform data repository, have conditional access to it and get tools and resources for their operation and sustainability.

It is necessary that the existing expertise is called to collaborate and play key roles in the management of scientific issues within the platform and the participating registries, in this way also ensuring the management continuity of existing registries. Expert Committees made of disease specialists, including the registry management boards should be set up and supported by the platform, for the management of scientific and specialist issues of a disease or registry.

The platform data repository is devised to provide a number of outputs, which can hardly be provided by individual registries and which serve a range of purposes: epidemiological features of diagnosed RD; monitoring public health actions and RD-dedicated services for improved planning; assessment of treatment alternatives; support for patient recruitment; patient care benchmarks. The data repository is organized as a registry data hub with the data necessary for the predefined platform outputs. Other registry data will be referenced in the metadata repository. The registry data to be communicated to the platform are organized in “modules” serving different aims and predefined outputs: one mandatory

1 EURAB 2004 Report on European Technology Platforms (EURAB 04.010-final)

http://ec.europa.eu/research/eurab/pdf/recommendations9.pdf (accesssed on 9 June 2012)

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“Minimum Set of Common Data Elements”; a number of “Purpose-Specific Sets of Common Data Elements”, of which at least one is adopted by participating registries; Disease-Specific Sets of Data Elements, if key disease features are agreed and their centralized collection is found useful; finally the platform can support ad hoc collaborative studies, collecting Project-Specific Sets of Data Elements agreed by the study participants. A proposal of predefined outputs with the necessary data elements, as well as of tools and services for use of registries participating in the platform, and for the better use and communication of platform data and services is presented in the document.

The document is completed by a prospect of the agreements to be achieved at policy and expert levels, and of the ICT activities to be undertaken to prepare the implementation of the platform.

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Developing a European Platform for Rare Disease Registries

Background

The general objective of the EPIRARE project is to build consensus and synergies to address legal, ethical and technical issues associated with the registration of RD patients and to elaborate a proposal for a EU web-based multi-disease platform which, by sharing information and resources, can increase the sustainability of registries, promotes the use of registry quality procedures and provides an effective way of dissemination of the results. In order to improve the use of data collected by registries and attract the interest of different stakeholders, the platform is devised to provide a number of outputs, which can hardly be provided by individual registries and which serve a range of purposes: epidemiological features of diagnosed RD; monitoring public health actions and RD-dedicated services for improved planning; assessment of treatment alternatives; support for patient recruitment; patient care benchmarks. The aspects that the EPIRARE project takes into consideration and that will be the subject of dedicated documents, are: the legal requirements for the data processing within the platform; the governance mechanism of the platform; identification of the stakeholders and definition of their needs; the services and added value outputs to be delivered by the platform; the minimum data set and other common data elements that should be communicated by the participating registries to the platform data repository; a system of External Quality Assurance monitoring registry data quality and providing registries with assistance on the implementation of quality assurance guidelines and governance criteria.

The main targets of the different deliverables of the EPIRARE project are, in primis, the European Commission and the EU Member States. The European Commission, indeed, funded this project and, with its subsidiary function, is in the position to fund initiatives at EU level and to promote coordinated activities of EU Member States, which move away from the current situation of fostering public health and clinical research on rare diseases by funding individual registries and networks. The EU Member States may undertake individually the development of national registries, which very likely will have a multi-disease scope and will support public health and clinical research. It is hoped that the competent EU and national institutions may find useful the analysis of the information collected by the project with the input of the many stakeholders consulted, the proposals elaborated and the conclusions achieved.

At the same time, the contents of the EPIRARE documents can also be of interest to researchers and clinicians who already manage a registry or wish to establish a register and are going to take into consideration the scenarios which will develop in the next future regarding data collection and data exchange for international cooperation in RD research and health care. Referring to the registry targets of these documents, it is important to clarify that the platform is intended, in line with the current draft EUCERD Recommendations2, to be a tool addressed to different types of data sources, from well established, multicentre and quality registries to small locally-held data collections. With such a wide range of targets, the approach of the platform has to be flexible, although preserving data quality. Actually, for it to be very effective, the platform should aim not only at data collection and sharing from quality registries, but, rather, it should also aim at spreading quality registration.

The objective of this document is to develop a proposal for the scope, services and outputs of an EU platform for rare disease registries, based on an analysis of the elements that have been defined as particularly relevant for the platform feasibility. In line with the guiding principles and the main common

2 EUCERD Draft Recommendations on RD Patient Registration and Data Collection: “Patient registries are collections of

computerised data. It is usual to distinguish between population-based registries, which refer to a geographically defined population and aim to register all cases in that population, and registries based on clinical centres or other criteria (members of a patient organization, participants registered via an ERN or other disease specific registry etc.) where the population coverage may not be comprehensive. These types of registry have different uses but both are useful provided they serve identified target aims and both types of registry are the targets of these recommendations.

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features of technological platforms as outlined in the EURAB Report3 this analysis addresses issues pertinent to the strategic relevance and complexity of the rare disease field, the variety and dimension of the stakeholders involved, their expected needs and support, the use of the platform for research on diseases and development of Orphan Medicinal Products as well as for purposes regarding public health and social service operation.

Methodological note

Consistently with its general objective, the EPIRARE project has carried out extensive consultations of the potential stakeholders of the platform. In preparation of this work, an informal EPIRARE Network of additional collaborating partners was established, open to all interested persons interested to be informed and to provide input on the EPIRARE activities and documents. It is currently made of 34 individuals from private organizations, patients associations and public institutions from 15 Countries. Moreover, an extensive mailing list of registries was compiled from ........ . Registry holders and patients were consulted, altogether in three surveys by means of on-line questionnaires. Experts from different stakeholder groups, including the EUCERD members, experts from EMA, projects dealing with RD platforms, registry holders involved in the surveys, EUNetHTA, relevant scientific societies, European Patients associations, selected EUPHA Working Groups, the EBE-EuropaBio Joint Task Force on Rare Diseases and Orphan Drugs, national experts from countries planning to develop national registries of rare diseases, the German Federal Association of Company Health Insurance Funds, US ORDR, and the informal EPIRARE Network, were requested to comment informally on this document. Although provided informally, some replies were the result of group consultations.

3 EURAB 2004 Report on European Technology Platforms (EURAB 04.010-final)

http://ec.europa.eu/research/eurab/pdf/recommendations9.pdf (accesssed on 9 June 2012)

Commento [L1]: To be completed with precise data

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I. The current context: the relevance of a rare disease registry platform

Luciano Vittozzi1, Sabina Gainotti1, Emanuela Mollo1, Manuel Posada2, Domenica Taruscio1 1: National Centre for Rare Diseases – National Institute for Health – Rome, Italy 2: Institute of Rare Diseases Research, Instituto de Salud Carlos III – Madrid, Spain

A. EU Public Health policies

1. The EU Recommendation for an action in the field of rare diseases (RD) and the Cross-Border Health Care Directive

The public health policies in the field of rare diseases in EU are essentially resulting from the EU Recommendation for an action in the field of rare diseases (2009/C 151/02), that triggered all EU Member States to develop national plans for RD, and recommending, among other actions, the promotion of databases and registries. The operative indications have been given in the EC Communication “Rare Diseases: A Europe’s Challenge” (2008)4. Actions to develop European Cooperation and to improve access to high-quality healthcare for rare diseases refer to:

Development of national/regional Centres of Expertise and establishing EU Reference Networks

Access to specialised social services

Access to Orphan Medicinal Products

Compassionate Use programmes

Medical devices

Incentives for Orphan Drug development

e-Health

Screening practices

Quality management of diagnostic laboratories

Primary prevention

Registries and databases

Research and Development

The Directive 2011/24/EU of the European Parliament and of the Council of 9 March 2011 on Cross-Border Health Care that acknowledges a special priority to the establishment of European Reference Networks of designated Centres of Expertise for rare diseases, will necessarily result in a change in the way the patient information is stored and made available across different national health systems. The need to access patient health information and data from different places will result in a strong boost of the use of electronic data processing within the health system. As a consequence, the implementation of technological solutions allowing both to collect and exchange patient data within registry networks will be facilitated.

A platform for rare disease registries, not only fulfils one of the indications of the EU recommendation on rare diseases, but could also support in several ways the development of the new EU system of rare disease care as depicted by the EU Directive on Cross-Border Health Care. Indeed, the core function of a technological service platform, supporting collection and sharing of patient data within networks of

professionals dedicated to specific diseases, will result in the promotion of clinical research on rare diseases

4 http://ec.europa.eu/health/ph_threats/non_com/docs/rare_com_en.pdf

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and in networking among EU countries and possibly beyond. Moreover, if appropriately planned and governed, it may support: the enlargement of the registered patient population with disseminating a culture of registration among patients; the assessment and the improved planning of health care and social services, while monitoring and benchmarking critical points of rare disease care, including time to diagnosis and patient migration for diagnosis and treatment; monitoring and assessing the appropriateness and

effectiveness of treatments and their costs, especially if prescription registration were connected with reimbursement; improvement of data quality; web-based training courses for the operators of registries;

improvement of epidemiological research if patient data became representative of a well-defined catchment area or a well-defined population, e.g. with a mechanism of integration with the Centres of Expertise or the European Reference Networks.

2. Orphan Medicinal Products (OMP) policy5

The specific features of OMP and the small population of patients for whom they are developed, make the extensive collection of clinical data difficult before the marketing authorization. For these medicinal products, therefore, the acquisition of safety, effectiveness and appropriateness data after the marketing authorization is of special value compared to that of other drugs.

3. EU Health strategy

The current Programme of Community Action in the field of Public Health, ending in 2013, will be superseded by the third Health Programme (Health for Growth) for the period 2014-20206, as part of the EU health strategy within the overall “Europe 2020” Strategy. This programme is at present under discussion at the European Parliament.

Among the four specific objectives proposed in the current draft of the Programme, two appear particularly relevant for the EU rare disease registry platform:

To develop common tools and mechanisms at EU level to address shortages of resources, both human and financial, and to facilitate up-take of innovation in healthcare in order to contribute to innovative and sustainable health systems.

To increase access to medical expertise and information for specific conditions also beyond national borders, and to develop shared solutions and guidelines to improve healthcare quality and patient safety in order to increase access to better and safer healthcare for EU citizens.

This platform will enable synergies between isolated registries and avoid duplication of efforts. The impact the platform can have on the costs of running separate registries have not been evaluated but is generally supposed to be beneficial. Moreover, it may provide a tool facilitating access to medical expertise from distant sites where this is not available, and may extend its scope beyond the EU. The adoption of robust data quality criteria, required by participation in the platform, as well as the professional relationships growing among the platform users, will facilitate building consensus and knowledge and the achievement of shared solutions or guidelines.

4. The regional dimension of the health policies

Among the principles of the EU health policies is the reduction of inequalities. Addressing the regional dimension of inequalities has particular importance for rare diseases, since the expertise for the diagnosis and care of rare diseases is scattered and the quality of services is heterogeneous across the EU.

5 The Orphan Medicinal Product Regulation (Regulation (EC) No 141/2000 of the European Parliament and of the

Council of 16 December 1999 on orphan medicinal products). 6 Proposal for a REGULATION OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL on establishing a Health for

Growth Programme, the third multi-annual programme of EU action in the field of health for the period 2014-2020 (COM(2011) 709 final) of 9/11/2011 (http://ec.europa.eu/health/programme/docs/prop_prog2014_en.pdf)

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The platform fulfils this cross-cutting need for reducing inequalities in health among EU regions. Indeed, the participation of stakeholders from different regions will enable the benchmarking of standard of care across countries and can provide a positive contribution to reducing the inequalities among EU regions and support neighbouring countries.

B. Other relevant EU policies

1. e-Health policy

The EU e-Health policies are changing dramatically the ways of operation of the national health systems, with the development of powerful communication technology applications and infrastructures. Electronic health records, electronic prescriptions, patient’s card, diagnosis networks are being used more and more widely in EU member states. Such transition shows a perspective in which the health service organization will exploit more and more communication technologies and electronic records, thus facilitating, from a technological standpoint, patient data collection and exchange within the European Reference Networks (see above) and reducing the burden of data entry for the purpose of registry feeding.

The platform for rare disease registries will therefore synergize with the e-health and cross-border health care actions, producing its positive effects on registration activities other than data entry. Indeed, the platform will reduce the burden of the organizational aspects of establishing and holding a registry, by providing resources supporting common registry activities, such as applications for data sharing and elaboration; staff training; data quality guidelines; recommended ethical procedures, and ensuring visibility and use of the results obtained.

2. Research policy and Industrial policy

Innovation has been placed at the heart of the Europe 2020 strategy. With over thirty action points, the Innovation Union (one of the Europe 2020 branches) aims to improve conditions and access to finance for research and innovation in Europe, to ensure that innovative ideas can be turned into products and services that create growth and jobs.

The EU industrial policy actively encourages the participation of Small and Medium Enterprises (SME), given their role as indispensable partners of the larger industrial players and their importance as developers of leading edge technologies and drivers of innovation. In connection with rare diseases, it should be observed that Orphan Medicinal Products (OMP) are often developed by small pharmaceutical companies, following the advances in the research on the etiology and pathophysiology of rare diseases.

Therefore, a platform for rare disease registries, which is able to perform the identification of patient cohorts for clinical trials and the timely collection of related data, will support the activities of SME developing OMP, thus contributing to the EU industrial policy.

Moreover, since it directly supports the cooperation among EU national health systems, the platform contributes to the implementation of commitment 29 (Pooling forces to achieve breakthroughs: European Innovation Partnerships) within the Innovation Union policy, due to its relevance for developing clinical research on rare diseases, whose advancements can be of use also for other more common diseases.

3. The Revision of the Personal Data Protection Directive

The current Directive has been implemented in the EU Member States and represents a major barrier to systematic registration of patients’ health data and, also due to differences in national transpositions, to their international collection. The text of the current Directive is available at: http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CELEX:31995L0046:en:NOT). Since then, technological progress and globalisation have profoundly changed the way our data is collected, accessed and used. In addition, the 27 EU Member States have implemented the 1995 rules differently, resulting in divergent national regulations. These divergences have made it difficult to share health data for medical research and public health purposes. The European Commission has proposed a comprehensive reform of the EU's 1995

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data protection rules to strengthen the online privacy rights and to boost Europe's digital economy. The proposed text is available at: http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CELEX:52012PC0010:en:NOT.

The revision of the Personal Data Protection Directive and the on-going debate at the European Parliament represent an opportunity to raise attention to the specific needs of rare disease care. A platform will be a timely initiative to promote registration, especially whether the EU legislation will contain specific provisions for the collection, sharing and processing of rare disease patients’ health data.

C. Current Activities in Research and Public Health

Thanks to the EU Council Recommendation on Rare Diseases (2009), we are assisting to an unprecedented and concurrent development of the national health services for rare disease patients; the active development of National Plans for Rare Diseases witnesses the involvement of health authorities and the awareness that the conditions of rare disease patients are a health and social priority. An EU committee has been formally established (EU Committee of Experts on Rare Diseases - EUCERD), supported in its activity by the EUCERD Joint Action (EJA), funded by Directorate General for Health & Consumers (DG SANCO) to support the European Commission with the preparation and implementation of Community activities in the field of rare diseases, in cooperation and consultation with Member States and other relevant stakeholders acting in the field. Member States are aware that coordinated efforts and common instruments need to be developed to reduce costs and avoid fragmentation of initiatives. Although the actions on rare diseases have rightly deserved dedicated attention and urgent implementation, they are also a reference model for cooperation on more common diseases. Therefore, while the actions on rare diseases address a specific public health topic, they are part of the wider need of EU Member States for reliable data, rather than estimates, on their healthcare services, which will allow a more cost-effective service planning and monitoring and will represent a first important step in the implementation of the Cross Border Health Care Directive.

The EU Committee of Experts on Rare Diseases (EUCERD), as well as the Cross-Border Health Care Expert Group, are developing recommendations on the establishment of European Reference Networks (ERN) of Centres of Expertise, which comply with selection criteria. Within ERN, potential for networking has been identified in areas such as databases and registries, newborn screening, biobanks, tele-expertise tools, guidelines, information packages, quality assurance schemes and training tools covering the medical dimensions of diseases.

EUCERD is also developing a position paper on “EUCERD Recommendations on RD Patient Registration and Data Collection”; this will become an important reference document, since it is being developed with the agreement of the many different stakeholders participating in EUCERD. The proposal developed by EPIRARE for the EU Platform for rare disease registries is developed fully in line with the current draft of the EUCERD Document.

The European Medicine Agency coordinates the European Network of Centres for Pharmaco-epidemiology and Pharmacovigilance (ENCePP), which has been developed in collaboration with European experts in the fields of pharmaco-epidemiology and pharmaco-vigilance. The goal of ENCePP is to further strengthen the post-authorisation monitoring of medicinal products in Europe by facilitating the conduct of multi-centre, independent, post-authorisation studies focusing on safety and on benefit:risk, using available expertise and research experience across Europe. This network comprises relevant research centres, medical-care centres, healthcare databases, electronic registries and existing European networks covering certain rare diseases, therapeutic fields and adverse drug events of interest.

A multi-stakeholder group within the EJA and in collaboration with the EMA is discussing possible registry models to avoid the fragmentation of data in industry led post marketing surveillance studies. Any new

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model will need to take into account the new pharmacovigilance regulation which is reinforcing the companies obligation to provide safety and effectiveness follow up of their drug.

DG Health and Consumers has been financing, during the last years, 11 networks of researchers and

clinicians on a single disease or on a group of related rare diseases7. The 6th and 7th Framework

programmes, managed by EC DG Research, have funded 188 and 27 projects9 for rare disease research, respectively. Among these projects, E-RARE established a European Research Area for rare diseases among 13 EU and non-EU countries, which is aiming at reducing the fragmentation in rare disease research and co-funded 13 international projects in 201110. A preliminary analysis of many networks has been performed by EJA11. No selection of these projects will be mentioned here; however, many of these projects have been remarkably successful in developing registries and interesting applications from them.

More recently the EU Commission published a page stating that the creation of a European Platform for Rare Disease Registries is a strategic objective for their action in this field12. Moreover, the EU Commission is concluding a contract agreement for the development of the platform infrastructure for rare disease registries with the EU Joint Research Centre (Ispra, Italy) as part of the Work Plan 2013 of the Programme of Community Action on Health, with a budget of 2 million Euro. The activities in ISPRA should start expectedly by the end of 2013.

BURQOL (Social economic burden and health-related quality of life in Patients with Rare Diseases in Europe) is a 3-year project that began in March 2010 funded by the 2nd Programme of Community Action in the Field of Public Health, promoted by EC DG Health and Consumers. It is coordinated by the Canary Foundation of Investigation and Health, and includes 21 associated and collaborating partners. The primary objective of BURQOL is to generate a methodological framework to quantify the socio-economic burden and impact on health-related quality of life (HRQOL) of both patients and carers, for ten rare diseases in eight different European countries. Planned outcomes include an integrated and harmonised set of instruments to assess and monitor socio-economic burden and HRQOL of patient affected by rare diseases and their caregivers, and a detailed analysis of the services (health and social care) received by people with specific rare diseases in different EU countries, including the identification of formal and informal care. The results and deliverables that emerge from this project will stimulate the future comparability and monitoring of rare diseases in Europe as well as anticipate future information needs, which will also be relevant to include into the EPIRARE EU platform for rare disease registries.

The Cross Border PAtient Registries iNiTiative (PARENT Joint Action), a project funded by DG SANCO, started in 2012 and aims to assist in the establishment of registries to enable the analysis of secondary data

for public health and research purposes in fields where this need has been identified13

, with a special

reference to the implementation of the Directive on Cross Border Health Care, which, in its Article 12 (“European Reference Networks”) requests the European Commission to support the development of ERN, particularly in the area of rare diseases.

The European Partnership for Action Against Cancer (EPAAC Joint Action) brings together the efforts of different stakeholders into a joint response to prevent and control cancer. The EPAAC Joint Action

7 http://ec.europa.eu/health/rare_diseases/projects/networks/index_en.htm (accessed on 29/06/2012)

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http://www.healthcompetence.eu/converis/publicweb/area/1353?show=PROJECT&page=1&sortBy=start_date&sortAsc=false&items=10&fsearchkey=&ftypename=0&fsequence=0&fyear=0&forganisation=&fperson=&fkeyword=&farea=1377&fcountry= 9 http://ec.europa.eu/research/health/medical-research/rare-diseases/projectsfp7_en.html

10 http://e-rare.eu (accessed on 29/06/2012)

11 Preliminary analysis of pilot European Reference Networks for Rare Diseases, May 2011

12 http://ec.europa.eu/health/rare_diseases/policy/registries/index_en.htm (accessed on 5 December 2012)

13 http://www.patientregistries.eu/2012/03/about-parent-joint-action.html (accessed on 29/06/2012)

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encompasses 36 associated partners from across Europe and over 90 collaborating partners. Among the activities of this consortium, one aims at the establishment of a European comprehensive information system networking different stakeholders and including cancer registries with the aim of developing best approaches to care and dissemination of good practice. Similarly, the EUROCOURSE project funded by DG Research, is addressing the optimisation of the use of registries for scientific excellence in research.

The EU Biobanking and Biomolecular Resources Research Infrastructure (BBMRI) and the FP7 Gene2Phen project (gene-specific and genomic variant databases including phenotypic information) aim at developing platforms to network the pertinent centres and have developed standards concerning data formats and exchange for this type of information. Although these are resources dedicated to foster highly specialized research, a connection between them and a platform of rare disease registries may be highly beneficial for both sides. The development of the RD registries platform should consider attentively to ensure smooth communications with these platforms.

ORPHANET is a portal of information for professionals and patients interested in rare diseases. In 2009, ORPHANET published a list of rare disease registries active in Europe14. This list included initially 402 registries with national, regional, European and global dimension, and a more recent list reported over 600 registries. These registries, together with other registries not reported in these lists were included in the mailing list of the EPIRARE surveys. However, many of these registries did not reply or the e-mail addresses seemed no more valid. The reasons for these results may be varied and should be investigated further. Termination of the registry, either due to lack of sustainability or because of the successful achievement of the registry objectives would suggest that the opportunity has been missed for a better exploitation of the data collected and of the resources used for the registry establishment. Lack of interest or of time for the registry staff to reply would also suggest that a platform providing appropriate tools and resources for registration may improve data sharing and use in a wider context.

The International Rare Disease Research Consortium (IRDiRC) was launched in April 2011 as a bilateral EU-USA initiative dedicated to foster international collaboration in rare diseases research. The European Commission and the US National Institutes of Health initiated the discussions, and several other stakeholders, including other funding agencies (Canada and Australia), have also joined the consortium since then. IRDiRC will team up researchers and organisations investing in rare diseases research in order to achieve two main objectives, namely to deliver 200 new therapies for rare diseases and means to diagnose most rare diseases by the year 2020. IRDiRC gathers organisations that share common goals and principles and have agreed to work in a coordinated and collaborative manner within a multinational consortium. RD registries are one of the main topics of this international consortium because they provide information about the natural history of diseases as well as promote all types of research.

Within IRDiRC, the RD-Connect project, funded by the Directorate-General for Research & Innovation of the European Commission (DG Research; start date November, 1st 2012), is also aiming at establishing an integrated platform connecting databases, registries, biobanks and clinical bioinformatics for rare disease research. It will deploy its activities with a global partnership ensuring links with the main initiatives in EU and beyond, including the EPIRARE project and the EUCERD.

Among European patients Associations, EURORDIS is very active and organizes every other year the European Conference on Rare Diseases & Orphan Products, a unique forum across all rare diseases and across all European countries. It brings together all stakeholders - academics, health care professionals, industry, policy makers, and patients’ representatives. It provides the state-of-the-art of the rare disease environment, monitoring and benchmarking initiatives. It covers research, development of new treatments, health care, social care, information, public health and support at European, national and regional levels. Also, every year EURORDIS organises its Membership Meeting in a different European city. This is an occasion for patient representatives to gather and learn from each other.

14

http://www.orpha.net/orphacom/cahiers/docs/GB/Registries.pdf

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EURORDIS, together with NORD and CORD has prepared a Joint Declaration of Rare Disease Patient Registries, where 10 Key Principles have been proposed:

1. Patient Registries should be recognized as a global priority in the field of Rare Diseases. 2. Rare Disease Patient Registries should encompass the widest geographic scope possible. 3. Rare Disease Patient Registries should be centred on a disease or group of diseases rather than a

therapeutic intervention. 4. Interoperability and harmonization between Rare Disease Patient Registries should be consistently

pursued. 5. A minimum set of Common Data Elements should be consistently used in all Rare Disease Patient

Registries. 6. Rare Disease Patient Registries data should be linked with corresponding biobank data. 7. Rare Disease Patient Registries should include data directly reported by patients along with data

reported by healthcare professionals 8. Public-Private Partnerships should be encouraged to ensure sustainability of Rare Disease Patient

Registries. 9. Patients should be equally involved with other stakeholders in the governance of Rare Disease Patient

Registries. 10. Rare Disease Patient Registries should serve as key instruments for building and empowering patient

communities These principles clearly reflect the interest of patient organizations in the development of RD registries and also their capacity to contribute to registry development. These principles represent the framework within which this proposal for an EU platform for rare disease registries has been developed.

In the USA, two US initiatives provide important counterparts for building bridges between Europe and USA common strategies in the field of RD patient registries.

The Global Rare Diseases Registry and Data repository (GRDR) has been established by the NIH Office of Rare Disease Research. It is connected with RD-HUB platform addressed to RD biobanks. The GRDR provides the rare disease community a resource of standardized aggregated de-identified patient information to accelerate research and advance therapeutic development. This initiative includes all type of patient registries and rare diseases. They have to achieve good quality standards and use common data elements definitions. All patients are registered anonymously with a Global Unique Identifier (GUID) which avoids duplicate patient records.

In parallel to this rare disease repository, the US Agency for Healthcare Research and Quality (AHRQ) has recently launched the Registry of Patient Registries (RoPR) strategy, which is not primarily addressed to rare diseases but it offers good criteria for building a rare disease registry platform based on metadata and not on individual’s data. This platform is complementary to the very well-known website named cinicaltrials.gov. Both websites provide important clues for whatever other kind of rare disease registry platforms to be created.

Finally, the number of private companies offering software platforms for web-based registries15

and

patient management is rapidly increasing.

In conclusion, both the EU policies for the next years and the on-going activities at global, EU and Member State levels indicates a clear transition to new modes of cooperation operated by international networking and exchange of information addressed to scientific and economic development and to reduce inequalities.

15

For example: PatientsLikeMe (http://partners.patientslikeme.com/products-and-services/research/patient-registry/); PC PAL (http://www.pcpal.eu/media/patient-registries.pdf); Wellcentive (http://www.wellcentive.com/); Parexel (http://www.parexel.com/services-and-capabilities/late-phase/registries/);

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Within this context, the EU platform for RD registries, by sharing core data and providing an External Quality Assurance System based on agreed quality standards will participate to reduce certain central costs of registries, to provide quality measures and, ultimately, to effectively support the economic, scientific and health care development. European Reference Networks of Centres of Expertise, by participating with the platform and providing data will result in strong synergies among public health services, translational research on RD and OMP development.

II. EU rare disease registry platform: stakeholders, their needs and their support role

Sabina Gainotti1, Emanuela Mollo1, Luciano Vittozzi1, Domenica Taruscio1 1: National Centre for Rare Diseases – National Institute for Health – Rome, Italy

From the analysis of the context of on-going activities and policies, it is possible to identify the following groups that may have a potential interest in the development of an EU platform on rare disease registries:

A) Rare Disease Registry holders (Researchers and clinicians); B) Rare Disease Patients and their Associations; C) National public health authorities, public health agencies/institutions, including HTA-competent

bodies and Social Health Insurances. D) Pharmaceutical Industry; E) European Medicine Agency; F) EU Commission, in particular the Directorates General for Research (DG RES), for Public Health (DG

SANCO) and for Industry (DG ENTR); G) Other temporary stakeholders can be anticipated, such as Health Organizations and Statistical

Services)

The identified stakeholders are similar to those supporting other European Technological Platforms: an extended academic and clinical community with their institutes16, an active civil society with widespread associations17, EU and national public authorities, and the industry. This ensures a widespread interest in the operation of the platform and confirms that the platform is the appropriate tool of cooperation. However, the success of the EU rare disease registry platform depends on its added value, compared to the current situation, for the operation of strategic activities planned in the EU (e.g.: the European Reference Networks) or involving the EU, the implementation of national and EU current and future policies, and on the financial and political support it can trigger by fulfilling the needs of all stakeholders.

16 The number of respondents to the EPIRARE survey (220 different registries in different EU Countries), as well as information from other sources, indicate that there is a wealth of registration activities in EU and outside, which are

interested in improving their sustainability and are aware of the importance to join forces and to network. 17 Many national rare disease patients associations exist in each country. European-level Associations federate most of them, with different focus on various aspects of rare diseases. For example, the Patients Network for Medical Research and Health (EGAN) has a special interest in genetics, genomics and biotechnology, encompassing not only genetic disorders. The Central & Eastern European Genetic Network focuses on genetic and congenital conditions and their care in Central and Eastern Europe. The European Organisation for Rare Diseases (EURORDIS) is a non-governmental patient-driven alliance of patient organisations representing more than 528 rare diseases patient organisations in 48 countries. It addresses all rare diseases and all aspects of their care.

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A. Stakeholders’ needs and supporting role

A preliminary analysis of the needs and role of these stakeholders is presented in Table 1. The analysis of needs is based on the results of two EPIRARE surveys, one carried out among researchers and clinicians holding a registry18 and the other among rare disease patients (results from 1565 completely filled questionnaire obtained up to 8 October 2012); moreover, experts belonging to the other stakeholder groups have been consulted during the process of finalization of this document. The indications on the expected role of the stakeholders have been subject to consultation during the finalization of the document.

Table 1 –Needs and supporting role of identified stakeholders’ groups.

Stakeholders and their needs Role expected from stakeholders

Researchers and Clinicians

Services improving patient management: benchmarks for scientific/biomedical/care patient outcomes; practical tools for patient management;

Services reducing collateral workload of a registry: end-user registry interface, technological and technical solutions avoiding duplication of data entry, allowing use of current registry application; Staff education and training.

Assistance to start and run a registry: software applications; secure servers; quality procedures; data collection and processing protocols; scientific, legal and ethical advice.

Funding: Seed money; Sustainability plans (reduction of running costs, assured long term funding

Motivation of professionals providing data: Networking with other registries; building relationships between researchers and clinicians; Integration with other initiatives (such as ERN, biobanks networks); Easy access to useful and sound data sources; Publication, institutional communication and institutional use of the data; Visibility of the scientific activity, data contribution, and expertise.

Provision of patient’s data

Provision of biomedical and clinical expertise

Scientific development

Definition of disease-specific data sets

Ensure data validity and quality by complying with the quality criteria established by the platform

Ensure continuity of their registry, eg: by setting up an effective governance structure

Comply with the Minimum Set of Common Data Elements and other sets of Data Elements, as applicable

Patients

18

Report on the results of the EPIRARE survey on rare disease registries. Reference:……….

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Improved care for RD patients: improved health and social services planning; accelerated OMP (treatment) development; participation in clinical trials; improved scientific knowledge and accelerated research on RD;

Information: efficacy/safety of a treatment; natural history of the disease; quality of life; disability; epidemiology of the disease

Social inclusion: Contact for expert and individual counselling; exchange of information and experiences with other patients;

Active role in governance (aims, type of data collected, ethical and legal issues, access to data)

Stimulate and motivate data provision by clinicians and other data providers

Direct input of selected data, e.g., quality of life and disability

Spread the registration culture among the patient community

Demand the establishment of quality registries, and the registration of their data in registries applying appropriate data protection safeguards.

National Health Authorities/Institutions including HTA-competent bodies and social health insurances

Increased health system efficiency: monitoring the operation of the RD healthcare service; improved RD health service organization and planning; Integration with the public health and social care service, including European Reference Networks and Centres of Expertise; improved cost-effectiveness of registries.

Health Technology Assessment: Costs of disease (medical products, hospitalization, social support, disability and quality of life, productivity losses, intangible costs); OMP use appropriateness, effectiveness, added value; Outcomes of interventions and treatments; Types and severity of side effects of treatments; Services used. Social Health insurances (payers): relative effectiveness of OMP; treatment paths and outcomes

Support the establishing anf operation of registries participating in the platform

Co-fund national data providers and registry activities at national level

Protect the patient security regarding the data confidentiality

Recognize the studies carried out within the platform quality assurance system as suitable for HTA

Pharmaceutical Industry (requests to the platform, as distinct from requests to disease-specific

registries)

One stop shop for accessing information on diseases

System for obtaining information on a disease in defined areas: prevalence, incidence, by country, centre etc.

Finding a disease specific registry in order to look at a potential partnership for natural history data, PMS etc.

Recruitment of patients for Clinical trials

Funding registries supporting specific projects of interest.

Fund platform support for specific projects of interest(e.g.: research studies) or ad hoc analyses of data in the platform.

Fund provision of predefined outputs and services, such as support for patient recruitment, and tracing registries with data of interest.

EMA

Monitoring implementation and effectiveness of Co-fund platform development and maintenance

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actions on OMP

OMP clinical added value, drug effectiveness and use appropriateness

regarding OMP-related monitoring programs andpre-defined outputs.

Recognize the studies carried out within the platform quality assurance system as suitable for HTA

EU Commission

Coherence with and implementation of EU policies

and common values and principles19: Public Health; Research; e-Health; Cross-Border Health Care; Europe 2020 strategy; Orphan Medicinal Products; Industry; Protection of Personal Data; reduction of health inequalities.

Improved planning and implementation of RD actions at EU and national level (EU added value): Monitoring effectiveness of EU actions on RD; Monitoring the condition of RD patients and services in the EU; Provision of healthcare benchmarks to EU member states; production of clinical guidelines and other documents pooling expertise to analyse platform and registry data.

Assist the platform governance, development and maintenance

Co-fund platform development, management and maintenance

Protect the patient security regarding the data confidentiality

Other temporary stakeholders (Health Organizations; Statistical Services)

Quality, efficient, flexible system, able to respond quickly to new requests

Ability to quickly start projects and provide dedicated data elaborations on demand

Targeted funding for platform resources development and/or specific outputs

III. The proposal for a Platform

Luciano Vittozzi1, Sabina Gainotti1, Emanuela Mollo1, Domenica Taruscio1 1: National Centre for Rare Diseases – National Institute for Health – Rome, Italy

A. The possible scenarios

The reference scenario of the EPIRARE project assumes that the existing registries and databases are mainly spontaneous and addressing specific research goals (as resulting from the EPIRARE survey) and that the platform is not backed by any regulatory measure; therefore, it cannot force new or existing registries to modify their operation to comply with centrally defined rules and data elements. This scenario corresponds to the present situation.

A number of strategic changes in health research and healthcare may be foreseen. For example, European Reference Networks are expected for the next future, as a consequence of the implementation of the

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Cross-Border Healthcare Directive. The ERNs will be likely developed to link the Centres of Expertise in different Countries with a system of communication tools especially devoted to high quality clinical care, among which may be a registry of clinical data based on Electronic Health Records. Progresses towards this scenario will be underpinned by the extended use of Electronic Health Records and of Electronic Prescriptions and other technologies developed within the e-health initiatives. The development of international collaboration in clinical and research activities will trigger a process of extensive data standardization and interoperability.

A further change is related to the development of national multi-disease, multi-purpose rare disease registries. These national registries may have dramatic impact on the operation of the current registries and databases, since in both cases it is expected that the national health authorities will regulate their operation. This National Registries are being developed by individual decisions of some member states, likely triggered by the developments consequent to the EU Recommendation on Rare Diseases and the EU Directive on Cross-Border Health Care. The independent development of national registries, which is noted at present, may reduce the scope of the platform and will impact on the possibility of international data sharing and data interoperability. On the other hand, national registries which are developed in coordination among member states and, possibly, with the EU platform, may result in a data flow which can optimize the interaction with the national health systems and ensures the commitment of national authorities.

All these developments may be strongly affected by the final provisions of the General Data Protection Regulation, which is under discussion at the EU Parliament. Main concerns refer to the proposed deletion of special provisions for research and statistical reasons and the lack of derogations to consent with the use of alternative safeguards, which will hinder the possibility of data use for unforeseen but compatible research purposes and the use of secondary data sources. EPIRARE is carrying out any possible action to brief the Members of the European Parliament and the competent national authorities of the EU member states on the special needs of rare disease research and healthcare in order to avoid this prejudicial outcome.

Since it is very likely that these different initiatives will become effective at different times and will characterize different stages of a single future scenario, the platform model should be flexible enough to accommodate itself to these different features and possibly should minimize their impact.

B. The EPIRARE platform scope

Devising the EU Platform for Rare Disease Registries, should have the main scope of making possible the pulling and analysis of rare disease patient data, in the fastest and most efficient way, in full respect and protection of patient rights and needs. To this aim, the platform should tackle the technical and non-technical barriers to data sharing and data processing. It should take care of promoting data collection by facilitating the establishment of new networks and the integration of existing networks of data sources, as well as by employing the most advanced technologies. Moreover, it should ensure the use of the resulting knowledge to provide outputs that fulfil the needs of all involved stakeholders. Last, but not least, it should contribute to spreading the most advanced expertise across EU and to non-EU countries.

The prerequisites which have been set out for the EPIRARE platform are:

The platform should assist new registries in setting up their structure, procedures and tools for data collection, sharing, analysis and quality assurance.

The platform should improve the exploitation of currently existing data with minimum impact on existing registries and databases. Any adaptation that is requested to existing registries or databases

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for them to provide data should consider a trade off with improved knowledge and with platform tools and resources facilitating registry operation and sustainability.

The platform should be inclusive and supportive also towards small registries and databases. However, the platform quality standards should be met without exceptions. Quality assurance interventions can be planned and monitored before data are accepted from registries and databases interested to join the platform.

The data collected by the platform are the basis for elaborating outputs of interest to those organizations which fund the platform and the underlying registries and databases. Since the identified stakeholders, which can fund the platform (e.g: the European Commission, the national health authorities, the pharmaceutical industry), have different information needs, the platform should attempt to provide, as far as feasible, multiple outputs fulfilling the interests of different stakeholders.

The adaptations requested by the platform to the registries or databases cannot involve changes in their aims, scientific competence and studied population. Therefore, the platform should be sufficiently flexible to receive and elaborate data from registries and databases, each of which covers only partially the purposes, populations and diseases which are in the scope of the platform.

Ownership of the scientific and organizational achievements of the registries should be acknowledged.

The platform should be ultimately focused on patient care, so that the results it produces can be used not only for general public health statistics, but can provide the benchmark against which appropriateness of care is assessed for each patient.

The platform should be based, as far as possible, on multiple data sources not only to avoid duplication of activities and improve economies, but rather to ensure that the sampled population of the platform is not biased and to allow estimates of underreporting and its correction.

However, it is also necessary to consider the following additional elements, which are essential for the stability of the platform and may impact on the stakeholders’ participation:

Definition of a governance model ensuring transparency, a balanced representation of the stakeholders’ views and a swift management of approval of new registry participation, and new study projects. Rules for data access by the participating registries and by third parties are also to be defined with agreements acknowledging the source registries. Governance should also take into consideration any feasible integration, in terms of functional organization and devolved responsibilities, with the national health systems. This aspect will be dealt with by EPIRARE in a separate but coordinated document.

Definition of the financial mechanism for the platform long-term sustainability. This aspect will not be dealt with by the EPIRARE project beyond the indications on expected roles of the stakeholders, which have been given in the previous chapter.

Establishment of a forum in which stakeholders can contribute to the formulation and implementation of coherent and effective RD policies and action plans, and can debate on the strategies for the platform development.

Establishment of a training program to improve the human skills and standardized procedures in the registry operations, where necessary.

Establishment of a communication and awareness-raising plan on the platform activities.

C. The EPIRARE platform model

The model which is proposed by EPIRARE (Fig. 1) to fulfil the above mentioned prerequisites is a web-based platform providing a number of functions:

a data repository function, including a separate section for ad hoc collaborative projects;

production of predefined outputs for the funding organizations and the public;

production of tools and resources of use to registries;

communication to the public, promotion of registration and networking among patients.

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Data quality and output reliability are key for fund-raising; therefore the platform sets quality targets and maintains an External Quality Assurance System (EQAS).

Participation in the platform is granted to registries and databases complying with data quality criteria. The registries and databases participating in the platform communicate data of specified sets of common data elements (SCE) to the platform data repository, have conditional access to it and get tools and resources for their operation and sustainability.

It is not necessary to say that the platform and its core staff cannot pretend to become the reference for registry and disease-specialist activity, nor to fulfil the needs of the registry maintenance and development just with the provision of technological tools and general managerial skills. The expertise matured in years of activity in contact with patients and of dedication to registry improvement cannot be replaced by a new and complex system like the platform. Therefore it is necessary that the existing expertise is called to collaborate and play key roles in the management of scientific issues within the platform and the participating registries, in this way also ensuring the management continuity of existing registries. Expert Committees made of disease specialists, including the registry management boards should be set up and supported by the platform, for the management of scientific and specialist issues of a disease or registry.

Figure 1 – The EPIRARE platform model

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D. The data repository function

The flexibility necessary to balance the need for the provision of predefined outputs and the range of specific registry aims is achieved with the definition of different sets of a limited number of (common) data elements, each of which serves specified platform functions or outputs. For these data elements, the platform acts as a registry data hub.

The registries keep their data and remain free to record any other variable for the research study aims in which they are interested. However, the platform can collect information on the registries and the variables they collect (metadata repository) in order to facilitate retrieval and access to registry specific data.

This solution has its value in the ability of exploiting the devotion of researchers and clinicians currently holding a registry or interested in the many rare diseases not yet considered by registration initiatives, thus ensuring professional competence and active case registration within a quality assurance environment. Registration of further rare diseases may be achieved with specific incentives by the EU institutions or national health authorities.

The Registry Data Hub

A list of candidate Common Data Elements (CDE) has been defined from the analysis of the data needed to produce the pre-defined outputs of the platform (see chapter E below in this section). However, the detailed description and the feasibility of different sets of CDE (and consequently of the related outputs) will be presented in a different document analysing the results of a survey among rare disease registries existing in Europe. Here we anticipate that, to ensure the platform flexibility at the “interface” with the registries, while performing data merging and standard outputs, it is proposed that the sets of data elements, contained in the platform data hub, are as follows:

One Minimum Set of Common Data Elements (Minimum SCE): a set of CEs which allows basic functions of the data repository: data aggregation and data source tracing. All registries participating in the platform adopt the Minimum SCE.

A number of Purpose-Specific Sets of Common Data Elements (Purpose-SSCE): a set of CEs, other than the Minimum SCE, which is considered necessary for the platform to achieve a pre-defined purpose-related output or a group of outputs. These outputs should allow, wherever applicable, different criteria and levels of aggregation, e.g. by disease; treatment; patient city, region and country of residence; diagnosis centre city, region and country. The registries participating in the platform adopt at least one of the Purpose-SSCE.

Disease-Specific Sets of Data Elements (Disease-SSDE): a number of disease-specific data elements can be agreed by the Expert Committee managing the scientific aspects of the registered disease, because they are worth of attention, e.g., with regard to their ascertained key role in the disease, to test current hypotheses, prepare for expected developments in research, or just because their collection according to common rules can be agreed widely and easily. The involved registries adapt their data collection to access the resulting information. The data so collected in the platform, where available, may be used, with the necessary agreements on data access and use, to improve the information contents of the platform outputs and particularly the patient management benchmarks.

The data repository section for ad hoc collaborative projects

The data repository component should also include a separate section to support ad hoc collaborative projects, which have a time limited duration, fulfil specific knowledge needs and are agreed upon by some of the registries participating in the platform. This section needs to be separate from the main data repository not only because of the use of different and study specific data elements which are agreed by the collaborating centresand are relevant to the study objective , but rather because it should implement appropriate safeguards to protect intellectual property and commercial interests. Indeed, ad hoc studies may include, for example, clinical research studies, post-marketing drug monitoring and, ideally, even

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treatment effectiveness assessments and clinical trials, all of which require a range of confidentiality measures. For the best exploitation of this section, it should be desirable that the results of studies carried out with the support of the platform and of its Quality Assurance System are recognized as suitable for inclusion in technical dossiers of regulatory assessments. This section is connected to the platform general data repository by means of the Minimum Set of Common Data Elements.

Typical data in this section are based on Project-Specific Sets of Data Elements (Project-SSDE): sets of data elements, which are considered necessary to achieve a specific aim of a time-limited study project20. It may include disease-specific data elements and the definitions are agreed among the registries and databases collaborating in the study. Access to the data so collected in the platform will be limited to the project participants until the end of the study and, if it is the case and with the necessary agreements, can be made available to other platform users.

The name, definition, representation terms and the set, range and/or format of values of the project-specific data elements, agreed by the study participants, are stored in the platform data dictionary for possible reference in future studies. In this way the platform will support dynamically collaborative research projects among registries and will progressively improve the standardization of data definitions and quality. Where appropriate, some of these project-specific data elements can become part of the sets of Common Data Elements if they add informative content for the pre-defined outputs.

The data flow structure

The data flow from the registries to the platform should rely as much as possible on already active national data flows and should avoid duplicated notifications. National registries, if based on CDEs compatible with those in the platform, could be a kind of national nodes cooperating with the European platform on quality assurance and data analysis. A data flow structure based on national nodes will facilitate the adaptation of the platform to the future developments of the EU healthcare scenario and could be appropriate with reference to the national prerogatives in the delivery of care and the organization of information and healthcare services; it might also provide some advantages with regard to data protection rules. However, while in some cases, focus on different levels (sub-national, national, European) and on different geographic cohorts may improve the data analysis and its interpretation, it is important that access to and analysis of the whole platform database is not restricted depending on geographical competence. Unless the platform will be endowed with functions (which are not foreseen in this document) requiring particularly rapid action related to data entry, a periodic batch communication of case data is recommended, to improve data security and to make the daily work of clinicians smoother and less dependent from external conditions of the web.

Registries are assessed and data are validated according to the platform quality assurance rules, which are described in a separate document.

E. The pre-defined outputs and services

A rather clear picture of the services and predefined outputs that are to be provided by the platform can be drawn on the basis of the analysis of the information and resource needs of the stakeholders as resulting from the surveys and consultations carried out by this project (see the Methodological Note).

A working proposal of possible pre-defined outputs that can be delivered by the platform to fulfil the information needs of the stakeholders is given in Table 2. These outputs are made possible by the data

20

Project-SDES may be of use, e.g., in studies related to clinical trials or to the assessment of a pilot newborn screening program, or to test a scientific hypothesis by a number of collaborating interested research centres. The platform provides resources and procedures for data protection, controlled access, quality data and reliable outputs.

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present in data repository; the data elements which are associated to these outputs and, therefore, should be available to the platform either as a result of the overall flow of data from the participating registries or from other data sources are also indicated in Table 2. It is remarkable that the data needed to produce the pre-defined outputs are not related to clinical disease-specific data, except for the diagnosis and for the occasional use of clinical indicators, which, although improving the specificity of the information, are not necessary for the production of the output. On the other hand, the desirable use of selected clinical parameters, to be agreed by experts, represents a stimulus for a more general application of definitions agreed for data elements used in specific purpose projects. Another important observation is that some outputs can be provided also with a single-point observation at the time of diagnosis. The possibility to collect data prospectively, however, can extend dramatically the information produced by the analysis of the platform data.

The platform should also provide a number of tools and services, for the needs of the registries and the scientists feeding data to them. These tools and services are exemplified in Table 3. Start up support tools and services have been mentioned repeatedly by the experts consulted during the preparation of this document as a very important assistance to new registries and therefore it is necessary to highlight the need for particular care in developing and providing these services and tools. Beside assistance in developing tailored measures for data protection and provision of other common resources, the platform may develop, on-request, disease or registry-tailored specific database structure and data entry mask, expanding the core mask and structure based on the Minimum and Purpose-Specific Sets of Common Data Elements. Another very important service, which may result in a dramatically reduces costs is the assistance in development of the internal quality assurance system and the supervision by a platform External Quality Assurance System.

The software application is also an important instrument that should fully fulfill the needs of the registry users, rather than being just a data collection tool. The development of this application may give the opportunity to promote participation of existing registries by acknowledging their ownership in the development of successful and original applications for their registries. Several examples of interesting and successful original application developments were presented in the 1st International Workshop on Rare Disease and Orphan Drug Registries, organized by EPIRARE (Rome, 8-9 October 2012). Dynamic data selection and plot for clinical use; solutions for patient empowerment; integration in hospital patient management activities; data accuracy control procedures; distant learning material; guidance to patients on data interpretation; tools for networking with GPs and Pediatricians and continuity of care; extensive dictionaries were among the solutions presented.

Finally, the platform should care that appropriate dissemination of information is carried out to extend registration activities and ensure the effective use of its products (Table 4). To this aim, a number of actions for communication, registration promotion and use of information should be carried out. Moreover, the platform, which manages continually scientific activities, disposes of most updated data, and in fact promotes cooperation and dialogue among RD experts, can be in a particularly suitable condition to manage the provision of expert advice to EU and national health institutions by convening periodic fora on matters identified by the stakeholders or by convening Expert Committees to discuss priority issues on request of EU bodies.

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TABLE 2 – Pre-defined platform outputs, the needed registry data and possible alternative data sources

Area of Interest Pre-defined Outputs

Data associated with patient, from RD registries in bold: longitudinal observations required

Alternative sources of data associated with patient

RD epidemiology: RD features

Life span; life expectancy; mean patient survival time

Date of birth; date of diagnosis; date of treatment (intervention); Date of death;

causes of death registries: date of death

Age of onset Date of birth; date of onset Patients

Disability, QoL Disability indicators; QoL indicators; Patients: disability and QoL indicators

Genetics of disease Relevant genetic variations confirmatory diagnostic tests; genomic databases

Incidence diagnosis; date of diagnosis; Population catchment

Inventory of diseases actually diagnosed in a time period

Diagnosis; date of diagnosis

Prevalence 1) Incidence; date of death; 2) treated patients?; causes of death registries: date of death

RD epidemiology: Monitoring effectiveness of RD actions

Registration promotion/impact of the platform on registration (EU and national level)

Number of registries participating in the platform; Number of centres participating in RD registries; number of cases in the platform

OMP use (EU and national level) OMP prescribed; OMP consumption (Electronic) Prescriptions records

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RD epidemiology: Monitoring and planning public health activities on RD

Number of centres of diagnosis and treatment

name of Centre which made diagnosis; name of Treating Centre

Workload of diagnostic and treatment centres

Centre which made diagnosis; Date of Diagnosis; Treating Centre;

Accessibility of services to patients (including intra-country and Cross-border patient migration)

Diagnosis centre city; Treating centre city; patient residence city

Time to diagnosis Date of first contact with the NHS for the disease diagnosed; Date of onset; date of diagnosis

Patients: date of first contact with NHS for the disease diagnosed; date of onset

Monitoring quality of care in RD services time to diagnosis; Treating Centre name; Disability indicators; QoL indicators; disease-specific key clinical indicators (if agreed)

Patients: disability and QoL indicators; Rehabilitation Centres?: patient rehabilitation data?; prescription of supportive devices?

Assessing effectiveness of neonatal screening programs (EU and national relevance)

Screen positive (confirmed) Patient Neonatal screening laboratories: Screened patient; screen positive case; Screening laboratory

Social and economic Burden of Disease Disability indicators; QoL indicators; informal care; productivity loss; intangible costs; costs of treatment paths

Patients

Health Technology Assessment: Monitoring and Assessing treatments use, appropriateness, safety

comorbidity other diseases observed

OMP treatment (relative) effectiveness OMP prescribed; Disability indicators; QoL indicators; disease-specific key clinical indicators (if agreed)

Patients: disability and QoL indicators; ENCEPP/PASS

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OMP treatments safety OMP prescribed; type of side effects; severity of side effects; comorbidity

ENCEPP/PASS

Other treatments (incl. interventions and supportive devices) effectiveness

Other treatment received; Disability indicators; QoL indicators; disease-specific key clinical indicators (if agreed)

Patients: disability and QoL indicators

other treament (incl. interventions and supportive devices) safety

Other treatment received; type of side effects; severity of side effects; comorbidity

EHR (through National Patient Identifier)

Resource use Hospitalization; home care; rehabilitation; transportation costs; social service support

EHR (through National Patient Identifier): hospitalization; home care Rehabilitation Centres?: patient rehabilitation data?; prescription of supportive devices?

Treatment paths and outcomes

OMP prescribed; Other treatment received; Hospitalization; home care; rehabilitation; transportation costs; social service support; type of side effects; severity of side effects; comorbidity; Disability indicators; QoL indicators; disease-specific key clinical indicators (if agreed)

Health Technology Assessment: Monitoring and Assessing treatments costs

OMP treatment costs OMP prescribed; OMP consumption (Electronic) Prescriptions records

Socio-economic costs of disease and treatment paths

costs of treatment paths and outcomes; informal care; productivity loss; intangible costs

Payers: Information on costs? Patients: informal care; productivity loss; intangible costs

Research: Patient recruitment

Data on patient patient's willingness to participate; patient contact information

Data relevant for patient inclusion/exclusion genetic variations; disease-specific key clinical indicators (if agreed); other relevant disease indicators;

confirmatory diagnostic tests; genomic databases

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comorbidity

Other useful information Biomaterial donation data; genomics database data; clinical trial enrollment data; National Patient Identifier (NPI);

Biobanks; Genomics databases; EMA: EU Clinical Trials Register; EHR data (through NPI)

Research: patient benchmarks

Natural history of disease Date of birth; date of onset; suspect diagnosis; diagnosis; genetic data; disease-specific key clinical indicators (if agreed); Disability indicators; QoL indicators; date of death

Patients: disability and QoL indicators; Rehabilitation Centres?: patient rehabilitation data?; prescription of supportive devices?

Quality and effectiveness of OMP and other treatments (incl. interventions)

OMP treatment (relative) effectiveness; OMP treatments safety ; Other treatments (incl. interventions) effectiveness; Other treatments (incl. interventions) safety

comorbidity other diseases observed

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TABLE 3 – Non exhaustive list of services and tools

Type of services and tools Examples

start up support

Provide advice on data protection, ethics and ethical approval, quality control

Distant learning and distant training of registry operators on harmonized procedures, data validation, data quality, disease coding, ...

Collect and make available common resources from most succesful registries (Patient information form, informed consent procedures; data access policies); collect information on ethical approval requirements in different countries; develop documents suitable for the international use of data through the platform.

Develop and make available software applications for secure collection of all registry data and data sharing among the registry centres; protected servers for secure data storage; development of registry-tailored specific database structure and data entry mask, e.g.: expanding a common core database structure and mask based on the Minimum and Purpose-Specific Sets of Common Data Elements; tools for data communication between registries and the platform; develop software application "interfacing" with existing local applications of patients registration and patient management; develop toolkits (e.g.: standard data elaborations or statistical analysis packages) for integration in the platform software applications

Provide guidance for the establishment of new registries

Set out data quality management criteria and model procedures

operational support

Integrate, in the platform software, applications developed by existing registries to carry out successful advanced registry functions.

Access to useful external resources and information

Link with other useful initiatives (e.g.: quality assessment networks, certified genetic laboratories)

Networking among experts and centres; promote collaboration between researchers and healthcare professionals

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Collect and make available reports; case studies; articles; clinical protocols developed in various countries; Best practice and Guidelines for clinical management of patients

Technological support

ICT technical advice and IT platform operation maintenance

Protected servers for data storage, communication and sharing

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TABLE 4 – Platform activities for communication, networking and registration promotion

Type of Activities Examples

Communication and registration promotion area

Public campaigns on reliability, safety and quality of data processing in platform registries

Promoting registry visibility and use of platform registry data

Annual Reports and periodic updates on scientific and organization achievements of platform registries to identified targets, including policy makers, patients’ associations, the European Reference Networks and Centres of Expertise (in collaboration with ORPHANET?)

Promotion and information support to Mutual Help Networks

Providing protected social networking tools to support patient social networking

Retrieval of relevant news from newspapers, scientific journals, etc and feeding to registries (in collaboration with ORPHANET (ORPHANEWS?) or other EU projects?)

Editing of a scientific Journal dedicated to Rare Disease Clinical and Public Health research

Setting and updating directories of experts and centres participating in the platform registries to support direct counselling and registry centre visibility (in collaboration with ORPHANET?).

Advice-to-policy area

Disease-specific expert fora and Committees

Platform Management Committee connected with EU Policy Advisory Committees

Quality of life and disability forum

Stakeholders’ Advisory Forum

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F. Financial and other circuits

Although an economic analysis of the platform is out of the scope of this project, some considerations can be developed regarding the mechanisms that can support the platform on the basis of the stakeholders interests and the platform outputs.

As shown in Fig. 2, the system made of the platform, participating registries and their data sources, has to be supported mainly by the EU Commission and member states, which are the target users of the platform pre-defined outputs and have major responsibilities in the financial support of research projects and national health service planning and delivery. The financial support of the EU and the member states will be very effective if accompanied by appropriate regulatory measures to embed patient registration in the routine activities of the national health system, improving synergies, eg. with other statistical data flows, avoiding duplication of tasks and exploiting technological developments. The EU can prominently fund the platform overall operation and the coordination activities of the participating registries. It can also care for the framework regulation. The member states can fund registry centers in their territory and regulate national registration activities. It is expected that, at current conditions, the national funds allocated to registries should not increase. At the same time, the information collected and delivered to the EU and national authorities can improve the efficient allocation of funds to the RD dedicated public health service and a more informed planning, which can result in improved economies.

A second important circuit is activated by the provision of tools, resources and information from the platform to the participating registries and their data sources. In this case, the workload of patient data registration and of quality assurance can be balanced, on the economic side, by an easier and less costly registry development and routine activities, sustained and more secure funding; and by the visibility of the expertise and activities of the clinician/centre acting as data source, and by the return of information to benchmark their own performances, eg.: treatment effectiveness or disease course of the cohort of patients cared by the clinician/centre. This type of information, if appropriately managed, may be the basis for improved scientific knowledge, experience and healthcare capacity of the centre. Due to the wide range of registry dimensions, different tradeoffs can be expected. From successful registries, a negotiation may be appropriate to identify the win-win conditions for the exchange of data, tools and achievements of the platform and of the registries; with quality registries the platform will share data and offer tools and services; with other data collections, the platform has to activate a process of “assistance” to improve the quality and the long term sustainability before data are collected.

A third important circuit is made with the participation of the patients. Indeed, the platform, if governed with public control, appropriate involvement of patients and appropriate data protection, can increase the confidence of patients in the registration activities, reducing their diffidence towards possible misuse of their data. Higher confidence in the platform activities can also be increased by the provision of social network applications which are really safe and do not record stealthily data from communications among patients. Higher trust, together with the provision, by the platform, of appropriate information regarding their condition, is expected to result in increased numbers of registered patients. The information, which can be uniquely provided by the platform, regards the comparison of the condition of the single patient in comparison with cohorts of similar patients, which appears to be one of the most popular information items that patients would like to know. Other types of information are also of interest, and appropriate cooperation with already existing platform, like ORPHANET, should by assured. Patients may be also the source of outcomes information. The entry of data directly by patients is a controversial issue. However, while it is necessary to assure that data entered are reliable and accurate, it should not be forgotten that this additional data source provides a possible way to spot patients that are not met by the network of clinical centres feeding the platform and to allow an estimate of the underreporting using dedicated statistical methods.

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A fourth circuit refers to the performance of ad hoc studies. As already described, ad hoc studies may aim at specific research goals, health technology assessment and, possibly, even for clinical trials. The platform may attract especially studies designed and carried by researchers or small centres with providing advice and a system ready to start, with all necessary facilities for safe data transfer and storage, and assuring an external quality assurance system to allow the study acceptance for assessment purposes. This type of users is not that rare in the area of genetic research and may contribute to support start ups. This use of the platform will be funded ad hoc, depending on the dimension of the study and the possible public participation in the use of the results.

Inputs and outputs

Registries

Regular Funders (EU; PH authorities and

institutions; Industry; HTA; Social insurances)

Patients and Patients’ Associations

Ad hoc funders; Industry

Platform

Pre-defined outputs

Improved Care; Sound information;Networking

centre

clinicianclinician

tools, resources,EQAS

Patient managementbenchmarks;

visibility

Statistical data flow,Supporting Legislation,Funds

Ad hocoutputs

Ad hoc studies,Ad hoc funds

Patients for registration

Patients’ outcomes

centre

Exp

ert

ad

vice

,dat

a,

too

ls

Figure 2 – Inputs and outputs contributing to the platform and registries sustainability

G. The EU Platform implementation process

An effective platform implementation requires that a number of preparatory action are coordinated and carried out timely. An outline of specific objectives to be addressed within different “environments” in the initial phase of the platform implementation is presented here below.

1. Policy work:

It is recommended that this work is carried out within EUCERD.

Coordinated action on legal issues related to the legislation ruling Personal Data Protection.

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Lobbying activity is to be carried out to influence the outcomes of the EU Parliamentary discussion of the General Data Protection Regulation, in a way that the initiatives, particularly on registration, of the EU and Member States to improve care of RD patients are not voided. In particular, derogations to consent, with use of alternative reasonable safeguards, should be possible to allow unforeseen but compatible processing of patient health data already collected; given the peculiarities of rare diseases, research and registries are to be considered essential elements of the provision of quality care; pseudonymization should be possible to avoid duplication of data records from the same patient and to contact patients in cases of necessity; integration of selected data sources and use of secondary data sources should be possible to ensure data completeness and reliability. Rare disease patient registration should be subject to rules which protect privacy but do not impact on health research.

Agreement with MS on registry cooperation schemes. Major elements are the compatibility among national registries core data sets and EU platform sets of common data elements; data flows (outbound) and output flows (inbound); common mechanism for encryption of identifiers, possibly compatible with the Global Unique Identifier (GUID)21.

Agreement with stakeholders on the EU platform governance: This activity has to address the agreed definition of the platform mission and definition of outputs; roles and responsibilities of the stakeholders participating in the undertaking; if applicable, designation of participating institutions, registries and their centres; rules for data access and other key points of the platform governance.

Definition of a first group of Expert Committees and their initial mandate It is important that quality expertise is called from the most advanced registries and scientific/professional Societies, to set out the overall framework of elements relevant to the scientific quality of disease-specific data collections; this activity should include pilot exercises to test the data validation rules on a limited number of registries of different dimension and addressing priority diseases.

Integration of sources and preparatory work at national level In the preparatory phase it is also important that other useful data sources are identified and that related agreements, at national - and possibly EU - level are pursued so that the platform data repository structure and quality can be assured. A system accommodating to the progressive implementation of varied national sources is to be foreseen also in view of the implementation of e-health initiatives (cause of death registries; prescription records; (institutional) social insurances data bases; biobanks data, etc.)

2. Expert work:

This work is carried out most suitably by Expert Committees made of selected registry holders and other knowledgeable experts on the related diseases. This work will refer mostly to disease-specific aspects and to the platform data repository sets of Data Elements. Some work on cross-cutting aspects may also be necessary.

Definition of quality assurance standards for disease-specific data collection related to the different set of data elements to be communicated to the platform

Adoption of Common Dictionaries

21

S B Johnson, G Whitney, M McAuliffe, H Wang, E McCreedy, L Rozenblit, C C Evans (2010): Using global unique identifiers to link autism collections. J Am Med Inform Assoc 2010;17:689-695. Available on line at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3000750/pdf/amiajnl2063.pdf (accessed on 9 August, 2012)

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Final adoption of Platform Common Data Elements and Disease-Specific Data Elements, formats, permissible values and procedures.

Adoption of a Common Coding system. The Coding system of Rare Diseases should be adopted in view of the future ICD11: ORPHACODES should be supported as far as possible and, if necessary, combined with OMIM in view of a global interoperability of the EU platform. Other reference coding systems should be identified for other data elements, such as common diseases, interventions, supportive devices, disability, quality of life.

3. Quality assurance system development and implementation

This work should address the quality assurance system for the registries, the platform data repository and for the other activities of the platform. It should be completed by a dedicated and specialized team before the beginning of the platform operation.

4. ICT work:

This work is to be carried out by an ICT specialist team to implement the platform according to the indications of the EPIRARE deliverables, as confirmed and detailed by the additional operative indications resulting from the Policy and Expert work.

Data repository development: o Developing a new IT infrastructure for new registries; o Developing solutions for existing registries o Developing solutions for the export of selected data among those collected with local (hospital)

applications; o data elaboration toolkits for pre-defined outputs; o development of easy to use interface for data entry, data selection and data access control; o Establishing connections with other data sources following cooperation agreements

Tools to motivate patients and clinicians: protected patient’s social networks; Tools for consultation and data exchange among professionals;

Tools for assistance (distant training modules; advice on data protection, ethics...): ..........

communication with basic additional sources

5. Temporary Platform management

A small team should be tasked of the executive management of the platform during the implementation period. This team executes decisions made by the bodies tasked with the policy and expert work, including provision of suitable indications for the ICT work and the development of the quality assurance system. This team monitors also the platform implementation progress in order to identify steps requiring acceleration or other corrective measures to assure timely completion of the platform. After the initial phase of platform implementation, this team could start, with the assistance of experts, the assessment of further candidate registries and subsequent identification of registries ready to join the platform or definition of “contingency plans” for those registries requiring quality improvements. This activity is undertaken with the aim of populating as rapidly as possible the platform with quality data.

IV. Governance mechanisms

Anna Kole1, Luciano Vittozzi2, Monica Ensini1, …… 1: EURORDIS 2: National Centre for Rare Diseases – National Institute for Health – Rome, Italy

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The outcomes of the platform can be affected very strongly by the way in which its services and outputs are delivered. The mechanisms governing the platform operation (management, access policies, etc) are therefore of utmost importance for its effective use.

Transparent and trustworthy operation is key for the success of the platform: representatives of public health authorities, HTA organizations, patients, professionals and the industry should be represented in the governing bodies of the platform and the Quality Assurance Unit.

The governance mechanism should aim at a distribution of responsibilities and tasks between the platform level and the registry level, so that it can assure the achievement of the platform aims (data quality, registry data interoperability, promotion of registration, predetermined platform outputs and sustainability) while maintaining flexibility of registry aims, reduction of costs for registry establishment and maintenance, research freedom, registry ownership and acknowledgement of intellectual property and of contribution to registry data. Finally, it is necessary that the approval process for running a registry within the platform is transparent, not too time consuming and bureaucratic, to avoid creation of further barriers to the establishment of registries.

A detailed proposal for the platform governance within different scenarios will be developed by EPIRARE Work Package 5 in a separate, but coordinated, document.

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APPENDIX A – European Technology Platforms

European Technology Platforms were first established in EU following the Commission Communication “Investing in research: an action plan for Europe” (2003)22.

A. Extracts from the EURAB (2004) Report on European Technology Platforms23

A European Technology Platform is actually a European Innovation Initiative which is mission-oriented to solve a major European challenge / need / problem. It draws together the main stakeholders – industrialists, governments, legislators, politicians as well as researchers - from across Europe – even globally – who, working together, can provide the solutions.

According to the European Research Advisory Board (EURAB) (2004), the following guiding principles have to be taken into account when judging upon the relevance of a European Technology Platform (ETP):

A Response to major European challenges: platforms are mission-oriented and address major European economic-environmental-technical-social challenges. They are not short-term, problem-solving devices.

A strategic European initiative: platforms should be set up only when there is a well defined, European strategic need for such an instrument, and European added value can be clearly justified.

Politically highly visible: to affect change across national, industrial and technological boundaries, platforms must create strong political support and be highly visible at a European and even at a global level.

Industry-led: to be effective, platforms must be driven by actors from the applications / problem end of the innovation process.

Well-planned and executed: there must be a road map with a longer-term vision, a sound strategy for achieving this vision, and a detailed action-plan for carrying out the necessary activities.

The EURAB definition and guiding principles, therefore, clearly indicate that ETPs represent an innovative approach which can be used not only in research and technology development, but also in other fields, provided that they are applied to strategic matters of specific complexity and wide participation. Interestingly enough, to exemplify the use of EU platforms in the research context, the EURAB Document begins with an example on health care to show that curing effectively a ill person is not only a question of scientific research and development of a drug.

In spite that ETPs address widely different aims, they share many similarities in their grounds, as well as in their approach and characteristics. Common features are their scale, complexity and strategic importance and the pan-European nature of the response they provide to addressing the fields concerned. An active and committed involvement of all stakeholders (including industry, public authorities, the research community, financial institutions, civil society and consumers) is vital to the success and credibility of each platform. There is a need for coherence between the predominant platform role towards knowledge development and the downstream business framework in which the outcomes will subsequently be brought to the market and to the society. Platforms should assess the cost/efficiency and market potential of the activities they envisage to focus on. They also need to give close attention to financial engineering aspects. Therefore, in parallel with the preparation of a strategic research agenda, it is important to identify all the potential funding sources and mechanisms which will enable its subsequent implementation. The setting up of a specific working group for this purpose is envisaged in many cases.

22

http://ec.europa.eu/invest-in-research/pdf/226/en.pdf 23

EURAB 2004 Report on European Technology Platforms (EURAB 04.010-final) http://ec.europa.eu/research/eurab/pdf/recommendations9.pdf (accesssed on 9 June 2012)

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Moreover, in order to increase public awareness, understanding programmes and acceptance of the activities concerned and the research policy choices necessary to maximise the benefits for all stakeholders, platforms should give priority to dissemination and communication of their objectives, activities and progress. Another similarity in the cases which have emerged so far is that they are in no way starting from scratch. On the contrary, they have tended to arise through the clustering of existing initiatives and through actively seeking to bring together all the relevant European, national, regional and local projects, programs, networks and initiatives, as well as privately-funded industrial research and technology development activities. Such a wide participation is a prerequisite to alleviate the currently fragmented RTD effort in Europe. The active involvement of Member States, for example through the setting up of a Member States Mirror Group, is also essential, especially in the context of their readiness to co-ordinate national research activities in the field concerned around the platform’s overall objectives.

B. Extracts from Idea Consult (2008) - Evaluation of the European Technology Platforms (ETPs)24)

1. Main objectives

The primary objective of the European Technology Platforms (ETPs) is to “define a coherent and unified approach to tackle major economic, technological or societal challenges of vital importance for Europe’s future competitiveness and economic growth”25 . In particular, the ETPs provide a framework to define research and development priorities and action plans for each technology domain concerned. As such, the ETPs are designed to provide a strategic vision and research agenda for leading technologies at European level and therefore contribute significantly to the realization of the objectives of the European Research Area. In this framework, the involvement of public authorities as well as all other relevant stakeholders is vital for the fulfillment of the mission of ETPs. The policy objectives of the ETPs can be summarized as follows:

Support the development and deployment of those key technologies in Europe that are vital to address major economic and societal challenges.

Define a European vision and a strategic agenda for the development and deployment of these technologies.

Support the objective of increasing European private research investment by bringing research closer to industry and improving markets for innovative products.

2. Main priorities and deliverables

As of December 2007, there were 34 ETPs representing a wide range of technological fields. Their activities focus on the production of the following deliverables (see reference 25):

A Strategic Research Agenda (SRA) which sets out RTD priorities for the medium to long-term, including measures for enhancing networking and clustering of the RTD capacity in Europe26. This SRA is

24 Idea Consult (2008): Evaluation of the European Technology Platforms (ETPs) - Final Report. Request Services in the context of the DG BUDG. Framework Service Contracts on Evaluation and Evaluation-related Services. Ref. nr.: BUDG06/PO/01/Lot 3 (ftp://ftp.cordis.europa.eu/pub/technology-platforms/docs/evaluation-etps.pdf) accessed July 2012

25 European Commission (2004), ‘Technology Platforms: from definition to implementation of a Common Research

Agenda’ 26

Where the ETPs fit with objectives of the European research policy, the Strategic Research Agendas developed by ETPs have been taken into account in the development of FP7, in particular the ten Themes of the "Cooperation" Specific Programme and their respective work programmes for 2008.

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supposed to take account of the technological framework (including regulatory issues, intellectual property rights etc.) and the business environment for future market penetration. In harness with the Strategic Research Agenda therefore, a Deployment Strategy should also be formulated.

Mechanisms to mobilize the private and public investments required for the implementation of the research and development strategies. Potential funding sources include the EU Framework Programmes, the programming documents of the Structural Funds, national, regional and private research funding, the European Investment Bank (EIB), and the intergovernmental EUREKA Initiative27. Technology platforms should explore with the financial community and European and national public authorities ways to enhance the use of guarantee mechanisms in attracting both debt and equity financing for implementing RTD activities.

Identifying challenges and actions related to education and training opportunities with a view to maintaining and enhancing a high-skilled work force which can ensure an effective future implementation of the technologies concerned in the medium to long term.

Establishment and implementation of a communication plan that aims to raise public awareness and enhance dialogue on the justification for concentration of efforts at a European level in the technological field concerned.

3. Main stakeholders of the ETPs

The effective operation of the ETPs necessitates a wide range of stakeholders to be involved in the formulation and prioritization of research activities by means of vision development and the formulation of the Strategic Research Agenda (SRA). The various categories of stakeholder are as follows:

Regulatory bodies at EU, national or local levels.

Industry, representing large, medium, small companies and the whole production and supply chain. In addition to research actors, actors involved in technology transfer and commercial deployment of technologies also participate.

Public authorities, covering policy makers, funding agencies and also promoters and consumers of technologies. Some platforms have introduced Member State “mirror groups” in order to provide an interface between the developments at the Technology Platform level and complementary activities at the national level.

Research institutes and the academic community, encouraging participation of the academic/ industrial interface.

Financiers, covering private banks (including EIB), the European Investment Fund (EIF), the European Bank for Reconstruction and Development (EBRD), venture capital funds, business incubators, etc.

Civil society, including NGOs, consumer associations and other representatives of users of the technology.

4. Some key operational principles of the ETPs

The ETPs are designed to operate according to the following ‘horizontal’ operational principles, which also constitute horizontal objectives, as they apply to all ETPs28.

Openness and transparency: every ETP must ensure that it is open to all interest groups and that it is not dominated by narrow interest groupings or lobbies. In December 2004 a voluntary code of conduct was

formulated to ensure the openness and transparency of ETPs29. In this context, actions taken cover:

Rotating membership of Advisory Council

Regular stakeholder meetings

27

EUREKA is a pan-European network for market-oriented, industrial R&D. Created as an intergovernmental Initiative in 1985, EUREKA aims to enhance European competitiveness through its support to businesses, research centres and universities who carry out pan-European projects to develop innovative products, processes and services. 28

http://cordis.europa.eu/technology-platforms/further_en.html 29

ftp://ftp.cordis.europa.eu/pub/technology-platforms/docs/etp_web_061114_en.pdf

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Openness to the participation of new stakeholders (esp. SMEs)

Setting up of a platform website

SMEs have been identified as a particular group that should be encouraged to be involved in ETPs. In some cases, in order to support the involvement of SMEs in ETP and to facilitate the dissemination of information towards them, national technology platforms have been set up.

Awareness-raising: the objectives and activities of the ETPs should be disseminated to all stakeholders involving a wide range of actors such as policy makers, regulators, the business sector; but also consumers and end users as ETPs focus also on the identification of future market needs and developments. Initiatives taken to increase the ‘reach’ of the ETPs include:

Regular meetings of the ETP leaders with the European Commissioner for Science and Research.

The Austrian EU Presidency Conference has been organized in order to inform a broad audience about

the activities of ETPs and to raise awareness with respect to the role of the ETPs30.

Since 2004 several meetings and other events have been organized with EU authorities, individual Member States, regional authorities, and international organizations.

A Commission website has been developed including detailed information about the ETPs31.

Financial Engineering: although funding schemes for collaborative research can be used to finance the activities of ETPs, other funding sources have to be sought as well. The ETPs are therefore expected to identify additional financial sources, e.g. national and regional programmes, financial institutions such as the EIB, etc. - Especially for high-risk projects, the EC and the EIB have developed the ‘Risk-Sharing facility’ which finances large R&D projects at the EU level32. - The Structural Funds are another potential source of funding for the implementation of the Strategic Research Agendas.

Internationalization: the involvement of non-EU countries is considered as beneficial, especially for particular platforms in which interaction and collaboration with countries outside EU is vital, e.g. in topics such as health or water sanitation.

30 http://cordis.europa.eu/technology-platforms/seminarvienna_en.html

31 http://cordis.europa.eu/technology-platforms

32

http://www.eib.org/products/loans/special/rsff/index.htm