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Deliverable D5

Developing a European Platform for Rare Disease Registries

Luciano Vittozzi, Sabina Gainotti, Emanuela Mollo, Domenica Taruscio

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

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Contents

Acknowledgements ............................................................................................. 3

Overview of the documents produced by EPIRARE ............................................... 5

Disclaimer ............................................................................................................ 5

ACRONYMS .......................................................................................................... 6

Executive Summary .............................................................................................. 7

I. Background .................................................................................................... 9

II. Methodological note .................................................................................... 10

III. EU rare disease registry platform: stakeholders, their needs and their support role .................................................................................................................... 11

A. Stakeholders’ needs and supporting role ........................................................................................... 11

IV. The proposal for a Platform .......................................................................... 12

A. The possible scenarios ........................................................................................................................ 12

B. The EPIRARE platform scope .............................................................................................................. 13

C. The EPIRARE platform model ............................................................................................................. 15

1. The data repository function .......................................................................................................... 16

2. The pre-defined platform outputs .................................................................................................. 19

3. The platform services ..................................................................................................................... 19

4. Quality assurance function ............................................................................................................. 20

D. Financial and other circuits ................................................................................................................. 20

E. Governance mechanisms ................................................................................................................... 22

V. The EU Platform implementation process ..................................................... 22

A. Policy work ......................................................................................................................................... 22

B. Expert work ........................................................................................................................................ 23

C. Quality assurance system development and implementation ........................................................... 24

D. ICT work .............................................................................................................................................. 24

E. Temporary Platform management ..................................................................................................... 24

VI. TABLES ......................................................................................................... 25

Table 1 –Needs and supporting role of identified stakeholders’ groups. ................................................... 26

Table 2 – Non exhaustive list of services and tools for use of the registries .............................................. 29

Table 3 – Platform activities for communication, networking and registration promotion ....................... 30

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Acknowledgements

The EPIRARE documents have been circulated to extensive networks of experts with different interests and expertise. We are gratefully indebted with all those who have kindly contributed with their observations, comments and amendments. A special thank is deserved for all experts that have replied to the surveys, which have provided the factual evidence which allowed the formulation of the concept of the platform, the definition of the common data set and the assessment of their feasibility.

In particular for this document, the Authors wish to express their gratitude to the experts reported in the table below, who read the manuscript and provided their invaluable comments. Since the Authors had to interpret at some extent the inputs received, the contents of this document might not fully reflect their suggestions. We apologize for any partial or incorrect consideration of their observations. Moreover, the authors wish to thank Victoria Hedley, who kindly and patiently made the linguistic revision of the document.

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

Stella Blackburn EMA

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

Christine Dawson European Social Insurances Platform – Brussels, Belgium

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

Persephone Doupi THL - National Institute for Health and Welfare –

Helsinki, Finland

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

Stefan Koelker University Children's Hospital, Dept of General

Pediatrics, Heidelberg, Germany

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

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Muscular Atrophy” (CSMA) - Kharkiv, Ukraine

Matic Meglic National Institute of Public Health – Ljubljana, Slovenia

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

Yaffa Rubinstein National Institutes of Health, National Center for

Advancing Translational Sciences, Bethesda (MD), USA

Birgit Schnieders Ministry of Health, Referat Molecular Medicine and

Bioethics, Berlin, Germany

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

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

Metka Zaletel National Institute of Public Health – Ljubljana, Slovenia

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Overview of the documents produced by EPIRARE

Disclaimer

The contents of this document is in the sole responsibility of the Authors; The Executive Agency for Health and Consumers is not responsible for any use that may be made of the information contained herein.

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ACRONYMS

Acronym Meaning

EUCERD EU Committee of Experts on Rare Diseases

CDE Common Data Element

ICT Information and Communication Technology

RD Rare Disease

ERN European Reference Networks

EMA European Medicines Agency

HTA Health Technology Assessment

EUPHA European Public Health Association

ESIP European Social Insurances Platform

ORDR Office of Rare Disease Research

IUPAC International Union of Pure and Applied Chemistry

ICD International Classification of Diseases

ISCN International System for Human Cytogenetic Nomenclature

HUGO Human Genome Organization

ENCePP European Network of Centres for Pharmacoepidemiology and Pharmacovigilance

EUROPLAN European Project for Rare Diseases National Plans Development

GP General practitioner

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Executive Summary

Developing a European Platform for Rare Disease Registries

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 standards and 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 rare diseases 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;

incorporation of existing and production of new tools and resources of use to registries;

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

Quality assurance function to improve the human skills and extend standardized procedures in the registry operations, where necessary.

Participation in the platform is granted to all registries and databases complying with data quality criteria. The registries and databases participating in the platform communicate data of specified sets of CDEs to the platform data repository for the platform to compute pre-determined and agreed indicators of information outputs. The registries have conditional access to the platform data repository and get tools and resources for their operation and sustainability. The registries retain full control of their data and remain free to record data of any other variables required to meet the research study aims in which they are interested. Information on these additional data can be communicated by the registries to the platform as metadata, to facilitate tracing of existing data through the platform.

It is necessary that the existing expertise is called upon to collaborate and play a key role 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 composed 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: to define better the epidemiological features of diagnosed RD; to monitor public health actions and RD-dedicated services for improved planning; to assess the value of treatment alternatives; to support patient recruitment; to support definition of patient care benchmarks. The data repository is composed of three sections: a registry data hub, a metadata repository

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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and a separate section for ad hoc collaborative studies. The registry data hub is structured to allow longitudinal case data collections and it is essentially composed of a limited number of common data elements (CDEs), each of which serves pre-determined platform outputs. Within this set of CDEs, a core set of mandatory CDEs is defined. The CDEs and the pre-determined platform outputs related to this section of the data repository have been identified and proposed in other EPIRARE Documents (EPIRARE Deliverables 9.1 and 9.3). The metadata repository collects information on the registries and the variables they collect (metadata) in order to facilitate retrieval and access to disease-specific and registry-specific data. Finally, a separate section supports ad hoc collaborative studies, collecting study-specific data elements agreed by the study participants, who only have access to the data.

Tools and services fulfilling the needs of RD registries participating in the platform, and for the better use and communication of platform data and services are also exemplified.

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

I. 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 rare disease (RD) patients and to elaborate a proposal for a EU web-based multi-disease platform which, by sharing information and resources and promoting the use of standards and registry quality procedures, can increase the sustainability of registries and can provide an effective way of improved use and 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 scarcely be provided by individual registries and which serve a range of purposes: extending the knowledge of the epidemiological features of diagnosed RD; monitoring public health actions and RD-dedicated services for improved planning; assessment of treatment alternatives; supporting patient recruitment; and providing patient care benchmarks. The aspects which the EPIRARE project takes into consideration and which will be the subject of dedicated documents, are as follows: the legal framework 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; and 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 target recipients of the various deliverables of the EPIRARE project are, in the first instance, the European Commission and the EU Member States. The European Commission, indeed, funded this project and, via its subsidiary function, is in a position to fund initiatives at EU level and to promote the coordinated activities of EU Member States. Some EU member states are currently developing national RD registries with core data sets for all RD and are aware that sharing data at a European level , possibly with a common European platform is very important to improve RD knowledge. It is hoped that the competent EU and national institutions may find useful the analysis of the information collected by the EPIRARE project, in view of 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 registry and are going to take into consideration the scenarios which will develop in the near 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 various types of data sources, from well established, multicentre and high quality registries to small locally-held data collections. With such a wide range of targets, the approach of the platform has to be flexible, whilst preserving data quality. In fact, to be most effective, the platform should aim not only at data collection and sharing from quality registries but, also at

2 EUCERD Draft Recommendations on RD Patient Registration and Data Collection: A patient registry is an organised system that uses observational study methods to collect uniform data (clinical and other) to evaluate specified outcomes for a population defined by a particular disease, condition, or exposure, and serves one or more predetermined scientific, clinical, or policy purposes. A registry database is a file (or files) derived from the registry (Gliklich RE, Dreyer NA, eds. Registries for Evaluating Patient Outcomes: A User’s Guide. 2nd ed. (AHRQ, 2010)). 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 non-population-based 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. Both types of registry are the targets of these recommendations.

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spreading quality registration. Only in this way the many existing initiatives can be sufficiently reliable to support international data sharing and the quality of their data recognized for purposes beyond their use in research.

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. Most of this analysis has been performed in other EPIRARE deliverables, addressing the variety and dimension of the stakeholders involved (Deliverable D1.1), their current situation, anticipated needs and expectations (Deliverables D1.2 and D1.3), and the possible use of the platform for research on RD as well as for purposes of public health and social services operation (Deliverables D9.1, D9.2 and D9.3).

II. Methodological note

In line with its general objective, the EPIRARE project has carried out extensive consultations with the potential stakeholders of the platform. Patients and registry holders were consulted through separate surveys based on on-line questionnaires. The methods used for the preparation of the mailing lists and for the selection of valid questionnaires are reported in the Reports dealing with these surveys (respectively EPIRARE Deliverables D1.2 and D1.3) The registries participating in the surveys are listed in the related reports (EPIRARE Deliverables D1.3).

This document was circulated, during its preparation, to the holders of active registries, whose responses were considered valid in the elaboration of results, and to experts from different stakeholder groups, including country representatives in the EU Committee of Experts on Rare Diseases (EUCERD) and experts from EMA, EU projects dealing with RD registries and genetic platforms, HTA experts, European Patients associations, selected EUPHA Working Groups, the EBE-EuropaBio Joint Task Force on Rare Diseases and Orphan Medicines, ESIP, the German Federal Association of Company Health Insurance Funds, US ORDR, and the informal EPIRARE Network. This Network is open to all interested parties wishing to be informed of and to provide input to the EPIRARE activities and documents; it is currently composed of 41 individuals from industry, patients associations and public institutions in 18 Countries.

The position of the industry summarized the position of several experts in the EBE-EuropaBio Joint Task Force on Rare Diseases and Orphan Medicines, consulted informally by Samantha Parker, an EPIRARE project partner, and benefited from the results of an independent survey carried out among industry-held product-related registries with a questionnaire similar to the one used by EPIRARE. A few members of the EUCERD replied after consultation of their national experts. A few others of the consulted experts have kindly provided general comments and/or punctual suggestions for amendments. All inputs were provided informally and do not represent the position of the experts’ organizations. The list of experts providing their comments is reported in the section “Acknowledgements”. Therefore the indications, which are attributed to the stakeholder groups, result only partially from extensive structured consultations via surveys, whereas, in other cases, they result from inputs and revisions of a very limited number of individual experts, who, however, have substantial knowledge of the specific needs of their organizations and peers.

All inputs received were taken into consideration to improve the document.

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

From the analysis of the context of on-going activities and policies3, it is possible to identify the following groups which may have a potential interest in the development of an EU platform on rare disease registries:

A) Rare Disease Registry holders and gene variant database curators (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 Medicines Agency; F) EU Commission, in particular the Directorates General for Research (DG RES), for Health and

Consumers (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 institutes4, an active civil society with widespread associations5, EU and national public authorities; and 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, in terms of 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.

A. Stakeholders’ needs and supporting role

A preliminary analysis of the needs and roles of the stakeholders is presented in Table 1. The roles expected from the stakeholders have been formulated by the Authors largely on the basis of their current roles and institutional mandates, in order to minimize the impact of the platform on the present situation. The analysis of needs is based on the results of two EPIRARE surveys, one carried out among researchers and clinicians holding a registry6 and the other among RD patients7; moreover, experts belonging to all

3 EPIRARE Deliverable D1.1 4 The number of respondents to the two EPIRARE surveys of registries (365 different registries in different EU

Countries), as well as information from other sources, indicate that there is a wealth of registration activities in the EU and beyond, which are interested in improving their sustainability and are aware of the importance of joining forces

and networking. 5 Many national rare disease patients associations exist in each country. European-level Associations federate most of these, with different focuses 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. 6 EPIRARE Deliverable D1.3 7 EPIRARE Deliverable D1.2

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stakeholder groups, including the registries responding to the questionnaires, were consulted during the process of finalization of this document and could provide inputs, amendments and comments to the indications of their needs and expected roles. As indicated in the methodological section, comments and inputs by experts from institutions and organizations represent personal positions and not the positions of their organizations. Therefore, the contents of Table 1 should be considered a first approximation of the needs and expectations of the institutional stakeholders and their formal consultation, which is not effective within the framework of a project, is necessary to confirm the EPIRARE results.

IV. The proposal for a Platform

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, stemming from the initiatives and policies characterizing the present situation8. For example, it is anticipated that European Reference Networks will be established in the next future, as a consequence of the implementation of the Cross-Border Healthcare Directive. The ERNs will likely be 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. Progress 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 for the provision of on-line health services9. 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 rare disease registries. These national registries, likely multi-disease and multi-purpose, may have a 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. These national registries are being developed through the individual decisions of certain member states, probably triggered by the developments consequent to the Council Recommendation on Rare Diseases and the EU Directive on Cross-Border Healthcare. The independent development of national registries, which is noted at present, may reduce the scope of the platform under consideration and will impact on the possibility of international data sharing and data interoperability. On the other hand, national registries which are developed via coordination between member states - and, possibly, with the EU platform - may result in a data flow which can optimize interaction with the national health systems and ensures the commitment of national authorities.

Beside the technical difficulties of merging data from different sources, the possibility of sharing individual data, even if de-identified, will be strongly affected by the final provisions of the General Data Protection Regulation, which is under discussion at the EU Parliament. The main concerns refer to the proposed deletion of special provisions for research and statistical purposes 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 undertaking all possible efforts to brief the Members of the European Parliament and the competent national authorities of the EU

8 The current Activities and policies are described extensively in the EPIRARE Deliverable 1.1. 9 See, for example, epSOS, which aims to design, build and evaluate a service infrastructure that demonstrates cross-border interoperability between electronic health record systems in Europe (http://www.epsos.eu).

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member states on the special needs of rare disease research and healthcare in order to avoid this prejudicial outcome. Since the parliamentary discussion on the General Personal Data Protection Regulation is not yet settled, it is difficult to anticipate even approximately its provisions and the possible ways to deal with them especially in case of secondary data use.

Since it is very likely that these different initiatives will take effect at different times and will characterize different stages of a single future scenario, the platform model should be flexible enough to adapt itself to these different features and possibly should minimize their impact. Making reference to the extensive impact of the General Personal Data Protection Regulation, while sufficiently precise predefined study aims and platform outputs might be made possible with appropriate collection of patient informed consent, the platform should identify aims which may be useful and sustainable even in case of a severe impact on secondary data use.

B. The EPIRARE platform scope

The vision of the platform

The EU Platform for Rare Disease Registries, should enable extraction and analysis of rare disease patient data, in the fastest and most efficient way possible, 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 promote 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. With this perspective, it should be ready to establish appropriate operative relationships with relevant initiatives in the field (such as RD-Connect, International Rare Diseases Research Consortium or other platforms) so that mutual benefits from the use of current and newly developed tools can be achieved. Moreover, it should ensure that the resulting knowledge is utilized to provide outputs which fulfil the needs of all involved stakeholders. Last, but not least, it should contribute to spreading the most advanced expertise across the EU and to non-EU countries.

The mission of the platform

The complete fulfillment of the stakeholders’ expectations requires preliminarily that the platform should be able to promote a process of adaptation and evolution of the data collected and the procedures used by the RD registries. Therefore an essential task of the platform must be the promotion of use of common tools, standards, procedures and strategies to improve quality and comparability of registered data. This function will have an essential added value regardless of the technical and legal possibilities of sharing and merging individual data. Indeed, while minimum data quality and data comparability are necessary for any data merging and data use beyond research, in case that technical or legal hurdles prevent data sharing or merging, the adoption of a number of methodological commonalities will facilitate a more effective meta-analysis of aggregated data collected in different populations and different studies.

On the other side, the platform should aim to support data collection with a longitudinal design wherever possible, such as for diseases for which registries are not yet established and where disease-specific registries are not sustainable, such as in the case of very rare diseases or diseases for which no treatment is in the development pipeline. For those diseases, for which data are already collected by registries, the added value of the platform is varied and should be assessed also in comparison with the costs of the adaptations necessary to fulfill technical, legal and ethical requirements. Here, the platform services, which facilitate the implementation of procedures assuring data quality and comparability and maximize data utilization, may play an important role. Therefore, it may be expected that the added value of the platform will be limited for those registries which have adopted sound procedures ensuring data quality and comparability and whose data are already effectively used to support the needs of all interested stakeholders.

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The prerequisites which have been set out for the EPIRARE platform to achieve its mission are as follows:

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 stimulate data comparability and interoperability; to this aim it should promote the use of a set of Common Data Elements and the use of existing international standards, nomenclature, ontologies and controlled vocabularies for the description of data (e.g. IUPAC codes, ICD-10 disease classification, gene symbols approved by the HUGO gene nomenclature committee, standard ISCN cytogenetic nomenclature, standard sequence variant nomenclature by the Human Genome Variation Society Nomenclature Committee, general recommendations by the Human Variome Project, Human Phenotype Ontology, etc.)10.

The platform should improve the exploitation of currently existing data with minimum impact on existing registries and databases. Any adaptation that is requested of existing registries or databases to enable them to provide data should be considered a trade-off against improved knowledge and the platform tools and resources facilitating registry operation and sustainability.

The platform should be inclusive and supportive 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 in joining 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, potentially envisaged to 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 stakeholders11.

The adaptations requested by the platform to the existing 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, which individually may only partially cover the purposes, populations and diseases which fall under the scope of the platform.

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

The platform should ultimately be 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.

In addition to these prerequisites, 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

10 EPIRARE studied the feasibility of Common Data Elements (CDE) in its Deliverables D9.1, D9.2 and D9.3, which also assess the difficulties of adoption of a set of CDE and the additional requirements for their use in the production of meaningful indicators and other information. 11 A selection of indicators to be computed by the platform, with the indication of the necessary data elements and additional requirements for the production of meaningful information has been carried out by EPIRARE in its deliverable 9.3

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national health systems. The platform governance is dealt with in a separate but coordinated EPIRARE document12.

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

Establishment of a forum through 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.

Definition of quality criteria and assurance of the data quality and output reliability, which are key for fund-raising and data use beyond research;

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

The stepwise development of the platform activities and its governance and sustainability are dealt with in detail in the EPIRARE Deliverable D3.

C. The EPIRARE platform model

The model which is proposed by EPIRARE (Fig. 1) to fulfil the afore mentioned prerequisites is a web-based platform providing the following 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;

incorporation of existing and production of new tools and resources of use to registries;

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

Quality assurance function to improve the human skills and extend standardized procedures in the registry operations, where necessary.

Participation in the platform is granted to all registries and databases complying with data quality criteria. The registries and databases participating in the platform communicate data of specified sets of CDEs to the platform data repository for the platform to compute pre-determined and agreed indicators of information outputs. The registries have conditional access to the platform data repository and get tools and resources for their operation and sustainability. The registries retain full control of their data and remain free to record data of any other variables required to meet the research study aims in which they are interested. Information on these additional data can be communicated by the registries to the platform as metadata, to facilitate tracing of existing data through the platform.

12 EPIRARE Deliverable D3

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Figure 1 – The EPIRARE platform model

It goes without saying that the platform and its core staff cannot pretend to become the primary reference for registry and disease-specific activity - nor would they claim to fulfil all the needs of registry maintenance and development beyond the provision of technological tools and general managerial skills. The expertise matured through years of patient-centred activity and dedication to registry improvement cannot be replaced by a new and complex system such as the platform. Therefore it is necessary that the existing expertise is called upon to collaborate and play a key role 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 composed 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.

1. The data repository function

The flexibility necessary to the platform to discharge its different functions based on registry data can be achieved with a data repository composed of three sections: a registry data hub, a metadata repository and a separate section for ad hoc collaborative studies.

The Registry Data Hub

This section is essentially a collection of CDEs-related data communicated by the participating registries for the elaboration of pre-determined and agreed platform indicators. It is structured to allow longitudinal case data collections and it is composed of a limited number of CDEs, each of which serves pre-determined platform outputs. Within this set of CDEs, a core set of mandatory CDEs is defined, whereas other CDEs, which are optional, are related to data which the registries may collect depending on their scopes. The

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Registry Data Hub contains the link to the metadata repository, in order to identify immediately the data source and to know further data collected by the source registry. Moreover, the set of CDEs contains sufficient overlap with existing data models of other resources (e.g. gene variant databases, biobanks) to support data interoperability. A set of candidate Common Data Elements (CDE) has been defined by EPIRARE from the analysis of the data currently collected by RD registries and of the indicators proposed by previous projects, which involved the consultation and/or participation of national experts (EUCERD JA and EUROPLAN)13. Updating data of patient’s willingness to participate in clinical trials and to donate biospecimens should not be overlooked, due to the importance of this information for patient recruitment in research studies according to ethical and legal procedures.

Beside the set of CDEs, which, in principle, holds for all rare diseases, experts of specific diseases (possibly, but not exclusively, the Expert Committee managing the scientific aspects of the registered diseases), can agree that a number of disease-specific data elements are worth of attention and of centralized collection, 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. Where these Disease-Specific Sets of Data Elements are available, the platform could collect them as disease-specific extensions of the CDEs. The data so collected in the platform 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. As indicated in the EPIRARE Deliverable D9.3, this achievement requires preliminary validation studies and assessment of data comparability, for it to provide reliable and sound information.

The meta-data repository

Among the data which are not in the scope of CDEs, but are collected by the registries, many are disease- and study-specific and are of extreme interest for advanced research and clinical studies. In this case, the platform can collect information on the registries and the variables they collect (metadata) in order to facilitate retrieval and access to registry-specific data. The definition of the set of metadata does not fall under the scope of the EPIRARE project. This function may show its usefulness especially in support to the analysis of data which are difficult to modify, such as existing data collections or massive data collected outside the control of registry holders, e.g. electronic health records, for which a meta-analysis approach is more suitable.

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 are of 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 study-specific data elements which are agreed by the collaborating centres and are relevant to the study objective(s), but also because the platform should implement appropriate safeguards to protect intellectual property and commercial interests. Indeed, ad hoc studies may include, for example, studies related to clinical trials or to the assessment of a pilot newborn screening programs, or to test a scientific hypothesis by a number of collaborating interested research centres, all of which require a range of confidentiality measures. This section is connected to the platform’s general data repository by means of the Minimum Set of Common Data Elements. Access to the data so collected in the platform will be limited to the project participants until the end of the study, at which time, if desirable and with the necessary agreements for the protection or acknowledgment of the intellectual property, it can be made available to other platform users. Where appropriate, the rules for communication of clinical trials results could be considered as reference.

13 The determination of the set of CDEs is the subject of the EPIRARE deliverable D9.3.

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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 between registries and will progressively improve the standardization of data definitions and quality.

For the best exploitation of this section, it should be desirable that the results of studies, which are designed according to standard protocols or with the agreement of the regulatory authorities and 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. Because of the relevance that this section may have for drug development and for post-marketing surveillance of orphan medicinal products, an important asset for this section would be the establishment of appropriate operational interactions with the EMA and ENCePP.

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 duplicate records. To this aim it is essential that the platform implements a service to elaborate an encrypted global unique ID code from personal identifiers. The encrypted ID code is connected to registry data, and communicated to the platform in association with the CDE data, while the patient identifiers, which originated the code, remain stored where they were collected. A possible model service has been described by Johnson et al14. At the current status of the debate on the General Personal Data Protection Regulation, the attribution of encrypted ID codes (pseudonymization) should be allowed. National registries, if based on CDEs compatible with those in the platform, could play the role of national nodes, communicating selected data and 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; data communication through the national nodes might also provide some advantages with regard to data protection rules. The existence of national registries/node, with their more detailed knowledge and closer focus on sub-national and national activities may improve data analysis and interpretation; however, it is important that the platform can access to and analyze the whole database and not only a selection of data elements related to indicators of EU-level relevance. Indeed, important information for health system analysis and service planning can result from the comparison of data belonging to different geographic areas.

The advantages of relying on a EU-coordinated network of national RD registries, which imply the adoption of the same set of CDE and related standards in all national registries, should be brought urgently to the attention of the national health authorities, to avoid that national registries adopt their own CDEs and standards, without any coordination with the other EU countries.

Unless the platform (or the national nodes) will be endowed with functions (which are not foreseen in this document) requiring particularly rapid response triggered by the data collected, 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 on 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.

14 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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2. The pre-defined platform outputs

Previous work, which analysed and proposed a number of indicators, has been a valuable reference for the exemplification of platform indicators and the definition of other useful measures, which have been developed in the EPIRARE Deliverable 9.1. These indicators also fulfil the information needs of the stakeholders, as resulting from the surveys and consultations carried out by this project (Table 1).

It is noted that the data needed to produce the pre-defined indicators and other measures do not include clinical disease-specific data beyond the diagnosis, except for the indicators supporting research and development. On the other hand, the production of meaningful indicators, based on clinical parameters, requires a number of additional conditions and studies beyond the agreement of experts on the selection of clinical parameters, and may be seen as a goal achievable by the platform in the long-term only..

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 dramatically extend the information produced by the analysis of the platform data (see the EPIRARE Deliverable 9.3).

3. The platform services

A rather clear picture of the services and predefined outputs to be provided by the platform can be drawn on the basis of the analysis of the information and resource needs of the stakeholders emerge from the surveys and consultations carried out by this project (see Table 1).

The tools and services meeting the needs of the registries and the scientists feeding data are exemplified in Table 2. 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 structures and data entry masks, expanding the core mask and structure of the set of Common Data Elements of the Registry Data Hub. In this case, the collaboration of disease experts will be necessary to assess the clinical implications of the technological choices. Another very important service, which may result in dramatically reduced costs is assistance in the development of the internal quality assurance system and supervision by a platform External Quality Assurance System.

The software application is also an important instrument that should fully meet the needs of the registry users, as opposed to being merely a data collection tool. The development of this application may provide an opportunity to promote the 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 at the 1st International Workshop on Rare Disease and Orphan Drug Registries, organized by EPIRARE (Rome, 8-9 October 2012): dynamic data selection and plotting 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; and extensive dictionaries, to name a few. A recent publication highlights the importance of well designed open source software applications to support patient data registration15.

Finally, the platform should ensure appropriate dissemination of information in order to extend registration activities and ensure the effective use of the information produced (Table 3). To this aim, a number of strategies for communication, registration promotion and use of information should be

15 M. Bellgard, C. Beroud, K. Parkinson, T. Harris, S. Ayme, G. Baynam, T. Weeramanthri, H. Dawkins, A. Hunter: Dispelling myths about rare disease registry system development. Source Code for Biology and Medicine (2013) 8:21

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established. Moreover, the platform, which continually manages scientific activities, has at hand most updated data, and in fact promotes cooperation and dialogue between RD experts, is ideallt suited to provide 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 at the request of EU bodies.

4. Quality assurance function

The activities that the platform should consider in this area, should include the preparation of a guidebook or a training program for new-comers and should be based on an External Quality Assurance System (EQAS). The definition of the platform framework related to quality assurance is the subject of the EPIRARE Deliverable D4.

D. Financial and other circuits

Although an economic analysis of the platform is beyond the scope of this project, some considerations can be developed regarding the mechanisms that could 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 European Commission and member states, as the target users of the platform’s pre-defined outputs and the bodies with major responsibilities in terms of 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, for example with other statistical data flows, avoiding duplication of tasks and exploiting technological developments. The EU can prominently fund the platform’s overall operation as well as the coordination activities of the participating registries. It can also take care of the framework regulation. The member states can fund registry centres within their territory and regulate national registration activities. It is expected that, under current conditions, the national funds allocated to registries will not increase. At the same time, however, the information collected and delivered to the EU and national authorities can stimulate a more efficient allocation of funds to the RD dedicated public health service and generate 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 easier and less expensive registry development and routine activities; sustained and more secure funding; 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, e.g. treatment effectiveness or disease course of the cohort of patients cared for 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 trade-offs can be expected. With successful registries, some negotiation may be appropriate to identify the mutual beneficial 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 is generated through 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. Greater confidence in the platform activities can also be procured through the provision of social network applications which are completely safe and do not stealthily record data from

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communications between patients. Higher levels of trust, together with the provision - by the platform - of appropriate information regarding their specific condition, is expected to result in increased numbers of registered patients. This information, which can be uniquely provided by the platform, regarding at the comparison of the condition of a single patient against cohorts of similar patients, 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 existing platforms, like ORPHANET, should by assured. Patients themselves may also be the source of outcomes information. The entry of data directly by patients is a controversial issue. However, while it is necessary to ensure that data entered are reliable and accurate, it should not be forgotten that this additional data source provides a possible means of detecting 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.

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 clinical trials. The platform may especially attract studies designed and conducted by researchers or small centres by providing advice and a system ready to start, with all necessary facilities for safe data transfer and storage, and by assuring an external quality assurance system to facilitate acceptance of the study for assessment purposes. This type of user is not particularly 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

Access to statistical data;Supporting Legislation;Funds

Ad hocoutputs

Ad hoc studies,Ad hoc funds

Patients for registration

Patient reported

outcomes

centre

Exp

ert

ad

vice

, d

ata,

to

ols

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

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E. Governance mechanisms

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, registries participating in the platform and 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 and not too time consuming or bureaucratic, in order to avoid creation of further barriers to the establishment of registries.

A detailed proposal for the platform governance within different scenarios is presented in the EPIRARE deliverable D3.

V. The EU Platform implementation process

An effective platform implementation requires a number of preparatory actions to be coordinated and carried out in a timely manner. An outline of specific objectives to be addressed within different environments in the initial phase of the platform implementation is presented below.

A. Policy work

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

Coordinated action on legal issues related to the legislation governing Personal Data Protection. The legal and ethical landscape of rare diseases and the basis for changing the Personal Data Protection Regulation are presented in the EPIRARE Deliverable D2.1 and its summary document (Deliverable D2.2.1), while epidemiological and public health arguments indicating the need for identifiable patient registration are dealt with in the EPIRARE Deliverable D2.2. These documents were the basis of a technical proposal of amendments to the Regulation, presented to the EU Parliament (EPIRARE Deliverable 2.3), of a Briefing Paper to the European Parliament (Deliverable 2.4) and of an on-line petition (Deliverable 2.5; http://www.change.org/petitions/don-t-stop-research-on-rare-diseases-2). A short video (EPIRARE Deliverable 2.6) has also been produced and published (http://www.youtube.com/watch?v=bLTNqoukbc8&feature=youtu.be) to explain the need for RD patient registration. This video has also been distributed to the MEPs composing the European Parliament Committee “Civil Liberties, Justice and Home Affairs” as well as to the Ministers of Justice of all EU Member States. Lobbying activity is to be carried out, following the indications of the EPIRARE Deliverables, to influence the outcomes of the EU Parliamentary discussion of the General Data Protection Regulation, in a way that ensures 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 the 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

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necessity. Integration of selected data sources and use of secondary data sources should be possible to ensure data completeness and reliability. Ultimately, 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 between national registries’ core data sets and the EU platform sets of common data elements; data flows (outbound) and output flows (inbound); and a common mechanism for encryption of identifiers, possibly compatible with the Global Unique Identifier (GUID)16.

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; and 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 summoned 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 dimensions 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.)

B. Expert work

This work is carried out most suitably by Expert Committees composed 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

Adoption of final definitions, formats, permissible values and procedures of Platform Common Data Elements and of the set of metadata for disease-Specific Data Elements.

Adoption of a Common Coding system. The Coding system of Rare Diseases should be adopted in view of the future ICD11: ORPHA- codes 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.

16 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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C. 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 platform becomes operational.

D. 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 supporting the platform implementation process. This work should take into account and exploit any advances in the electronic access to data, in standards for data communication and interoperability of different platforms (from the genetic, genomic and phenomic platforms, to national population registries, relevant ERICs17 and to environmental and spatial information18) and in tools for the expert analysis, controlled access and communication of data.

Data repository development: o Developing a new ICT 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 an 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 (distance training modules; advice on data protection, ethics...)

Communication with basic additional sources

E. Temporary Platform management

A small team should be tasked with 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 the subsequent identification of registries ready to join the platform whilst defining “contingency plans” for those registries requiring quality improvements. This activity is undertaken with the aim of populating the platform as rapidly as possible with quality data.

17 E.g.: BBMRI (BioBanks Medical Research Infrastructure); ECRIN (European Clinical Research Infrastructure Network. 18 Directive 2007/2/EC of the European Parliament and of the Council of 14 March 2007 establishing an Infrastructure for Spatial Information in the European Community (INSPIRE)

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VI. TABLES

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

Stakeholders and their needs Role expected from stakeholders

Researchers and Clinicians (based on EPIRARE Survey of registries (see EPIRARE Deliverable 1.3)

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 set up 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 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 (based on EPIRARE Survey of patients (see EPIRARE Deliverable 1.2)

Improved care for RD patients: information for improved healthcare and social services planning; registration of all RDs, especially most rare and undiagnosed; improved scientific knowledge and accelerated research on RD and OMP/treatments;; participation in clinical trials.

Information: efficacy/safety of a treatment; natural history of the disease; quality of life; disability; epidemiology of the disease; Contact for expert and individual counselling.

Networking, empowerment and capacity building: Participation in the governance of registration (regarding scientific objectives, data to be collected, use of the data, legal and ethical issues); 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 institutional health insurances (based on replies from HTA experts, EUCERD country representatives, experts

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from ESIP and the German Federation of Health Insurance Companies)

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: Socio-economic costs of disease (medical products, hospitalization, social support, disability of patients; quality of life of patients, their families and caregivers, productivity losses, intangible costs); treatment alternatives and treatment patterns; use appropriateness and relative effectiveness of treatments. Social Health insurances (payers): relative effectiveness of OMP; treatment patterns and outcomes; statistics of hospital treatments, regarding HTA, outcomes and costs

Support the establishment and operation of registries participating in the platform

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

Protect patient security regarding data confidentiality

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

Provide access to databases of healthcare utilization, for epidemiology and healthcare research

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

registries)(based on the opinions of industry experts consulted by the Industry representative in EPIRARE)

One stop shop for accessing information on diseases

System for obtaining information on a disease by 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

Partly fund registries supporting specific projects of interest.

Partly 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 (based on personal opinion of EMA expert)

Post-marketing follow-up of RD patients treated with drugs (safety and effectiveness in normal practice and long term)

Natural history of scantly studied rare diseases for which there are no treatments yet (to serve as baselines for assessing adverse effects and effectiveness of first treatments for a disease)

Monitoring utilisation of drugs in RD patients (dosage and pattern of use)

Encourage the use of existing qualified RD patient registries and treatment centres in post-authorisation safety and efficacy studies

Extend the evidence base of safety and effectiveness

Exchange of information between the EU RDR platform and ENCePP regarding their registries and centres networks. Inclusion of registries and participating centres as RD data sources in the ENCePP network.

Advice on and revision of protocols of selected studies of safety and effectiveness of OMP undertaken with the support of the platform facility for ad hoc collaborative projects.

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studies, by promoting data sharing and development of joint registries

A facility to do ad hoc studies would be a very useful asset for both ENCePP and the EMA.

EU Commission (based on general information from published documents)

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 implementation and effectiveness of EU actions on RD and OMP; 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 potential temporary stakeholders (Health Organizations; Statistical Services, Private Health Insurance Companies) (presumed needs and roles)

High quality, efficient, flexible system, able to respond quickly to new requests

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

Targeted funding for platform resources development and/or specific outputs

19 Council Conclusions on Common values and principles in European Union Health Systems (2006/C 146/01) Official Journal of the European Union C 146/1, of 22.6.2006 (available at: http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:C:2006:146:0001:0003:EN:PDF (accessed on 1 March 2011)

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Table 2 – Non exhaustive list of services and tools for use of the registries

Type of services and tools Examples

Start up support

Provide advice on data protection, ethics and ethical approval, quality control, use of internationally accepted data standards and nomenclature, use of existing curational tools (e.g. Mutalyzer sequence variant nomenclature checker)

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

Collect and make available common resources from most successful 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. Facilitate access to licensed on-line standards, dictionaries, and tools.

Develop and make available software applications for secure collection of all registry data and for data sharing among the registry centres; make available 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 set of Common Data Elements of the Registry Data Hub; tools for data communication between registries and the platform; develop software application "interfacing" with existing local applications of patients registration and patient management to reduce or eliminate workload on data entry; develop toolkits (e.g.: standard data elaborations or statistical analysis packages) for integration in the platform software applications).

Set out data quality management criteria and model procedures

Operational support

Provide a web service for the attribution of a global univocal patient code, complying with EU legal regulations

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

Provide access to useful external resources and information

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

Support networking among experts and centres; promote collaboration between researchers and healthcare professionals

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 ICT platform operation maintenance

Protected servers for data storage, communication and sharing

FINAL

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Table 3 – 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 the scientific and organizational achievements of platform registries, addressed 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 dissemination to registries (in collaboration with ORPHANET (ORPHANEWS?) or other EU projects?); dissemination of updates on relevant clinical trials and other research studies to patient associations, for patient enrolment and information.

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

Establishing and updating directories of experts and centres participating in the platform registries to support direct counselling and to enhance 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