2011 TECHNICAL PERIODIC REPORT

Transcription

1 P a g e 1 Programme of community action in the field of health ( ) 2011 TECHNICAL PERIODIC REPORT

2 P a g e 2 SECTION I Declaration by the scientific representative of the project coordinator I, as scientific representative of the coordinator of this project and in line with the obligations stated in the Grant Agreement declare that: the attached periodic report represents an accurate description of the work carried out in this project for this reporting period; The project (tick as appropriate) : has fully achieved its objectives and technical goals for the period; has achieved most of its objectives and technical goals for the period with relatively minor deviations. has failed to achieve critical objectives and/or is not at all on schedule. The public website, if applicable, is up to date is not up to date to my best knowledge, the financial statements that are being submitted as part of this report are in line with the actual work carried out and are consistent with the report on the resources used for the project and, if applicable, with the certificate of the financial statement all beneficiaries, in particular non-profit public bodies, have declared to have verified their legal status. Any changes have been reported under section wp1 Coordination and project management, in accordance with the requirements of the Grant Agreement. Name of the scientific representative of the project Coordinator:... Date:.../.../...

3 P a g e 3 SECTION II Checklist

4 P a g e 4 SECTION III Contract number Proposal title European Porphyria Network (EPNET) Acronym AP-HP-Porphyria_FY2011 Priority action Support to the continuation of existing performing EU networks on information and registers on rare diseases in several areas Duration of the operating grant Coordinator 12 months Assistance Publique Hôpitaux de Paris (APHP) Operating expenditure EC contribution in

5 P a g e 5 COORDINATOR Prof Jean-Charles Deybach ASSISTANCE PUBLIQUE HOPITAUX DE PARIS SERVICE DE BIOCHIMIE ET GENETIQUE MOLECULAIRE Centre Français des Porphyries INSERM U773 Pr. J-C. DEYBACH jean-charles.deybach@lmr.aphp.fr Tél : Secrétariat : secrétariat.biochimie@lmr.aphp.fr Tél : Fax : NETWORK MEMBERS Belgium Brussels Dr Frederic Centre Belges des porphyries Coton Leuven UZ Gasthuisberg, Metabool Centrum Bulgaria Sofia Dr Aneta University Hospital «St Ivan Rilski» Ivanova Czech Republic Prague Prof Pavel Martasek Charles II University Hospital, National lab for porphyric disease Denmark Viborg Dr Axel Brock Danish Porphyria Centre Estonia Tallinn/Tartu Dr Agnes Ivanov Finland Helsinki Prof Raili University Central Hospital of Helsinki Kauppinen France Bordeaux Germany Düsseldorf Dr Sandra Department of Dermatology, University hospital Haneken Karlsruhe Dr Thomas Stauch Deutsches Kompetenz Zentrum für Porphyriediagnostik ** Chemnitz-Dresden Dr Ulrich Stölzel Porphyria Center Saxony, Klinikum Chemnitz ggmbh ** Munich, Univ. Hosp Dr Michael Hospital of the University of Munich Vogeser Hungary Budapest Agnes Pusztai, Marta Bor Hungarian Porphyria Centre Ministry of Defence National Health Center Szeged Dr Maria Kiss Porphyrin Laboratory, Department of dermatology and allergology, University of Szeged Ireland Dublin Dr Vivion Crowley St James Hospital, Irish Porphyria Specialist Centre Israel Tel Aviv Prof Nili Schoenfeld Rabin Medical Centre National service for the biochemical diagnosis of porphyria Italy Milano Prof Domenica Cappellini Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico

6 P a g e 6 Modena Dr Paolo Ventura Dipartimento integrato di medicine e specialita mediche universita Rome Dr Gianfranco Biolcati Porphyria Centre and Hereditary Metabolic Diseases San Giovanni Rotondo Interregional Reference Centre for prevention, surveillance, diagnosis and therapy of porphyrias Norway Bergen Prof Sverre Norwegian Porphyria Centre (NAPOS) Sandberg Poland Warsaw Dr Robert Wasilewski Institute of Hematology and Transfusion Medicine Russia Moscow Dr Julia Luchinina Spain Barcelona Dr Jordi To Hospital Clinic University of Barcelona Madrid Prof Salamanco Centro de investigacion, Hospital Universitario Doce de Octubre Sweden Stockholm Prof Pauline Porphyria Centre Sweden Harper Switzerland Zurich Prof Elisabeth Triemli Hospital,Zurich Porphyrie-Referenzlabor Minder The Rotterdam Dr J Langendonk Porphyria Center Rotterdam Netherlands Turkey Ankara Prof Ismail Kurt Haceteppe University Hospital United Cardiff Dr Mike Cardiff SAS porphyria Service Kingdom Badminton Leeds Dr Felicity Leeds Teaching Hospital NHS trust Stewart London Dr Joanne King s College Hospital Porphyria Laboratory Maarsden Salford Dr Felicty Salford Royal NHS Foundation Trust Stewart Associate members Australia Dr Victor Poulos Brazil Dr Charles NSW porphyria reference laboratory Lourenco New Zealand Prof Chris Florkowski Porphyria center, Canterbury health Laboratories South Africa Pete Meissner Lennox Eales Porphyria Labs USA Karl Anderson Porphyria laboratory, Ewing Hall PMCH FOREWORD The porphyrias are rare diseases that can be chronically debilitating and life threatening, particularly affecting adults with young families who are at the start of their working life. Understanding and knowledge among healthcare professionals is low and there is a risk that without expert services and advice in all EU countries the conditions will be under-diagnosed and inadequately treated. Expanding the European Porphyria Network

7 P a g e 7 (EPNET), improving diagnostic services and enhancing access to evidence based information for patients and professionals will reduce health inequalities within Europe. EPNET improves the lives of people suffering from one of the porphyrias by improving information availability, organisation and quality of diagnostic services, agreeing best practice clinical guidelines, providing expert advice and ensuring that patients are cared for by a specialist centre. It is a stated aim of EPNET to have a registered specialist centre in every EU country and efforts will be made to achieve this. ACKNOWLEDGEMENTS EPNET would like to thank The European Union, in the framework of the Health Programme for funding and support. We also thank the British Porphyria Association and the French Porphyria Association for their contribution and advice KEYWORDS 1. Porphyria 2. European Reference Network 3. Registry 4. Quality care 5. Guidelines

8 P a g e 8 SECTION IV EXECUTIVE SUMMARY FOR PUBLIC DISSEMINATION The porphyrias are rare genetic diseases that can be chronically debilitating and life threatening, particularly affecting adults with young families who are at the start of their working life. Understanding and knowledge among general clinicians is low and there is a risk that without expert services and advice in all European countries the conditions will be under-diagnosed and inadequately treated. Porphyrias are an excellent example of a group of disorders where the limited number of patients and scarcity of relevant knowledge and expertise single them out as a distinctive domain of very high European added value. The European Porphyria Network (EPNET) ensures that scarce relevant knowledge is shared and resources combined. Scope and objectives Our mission is to improve the lives of porphyria patients by improving the diagnosis and treatment of these rare conditions. The objective is to provide an effective network of specialist porphyria centres in each country with a focus on: provision of information to patients in their own language and to healthcare professionals; use of external quality assessment scheme to develop quality standards for analytical quality, diagnosis and clinical advice; a web-based European Porphyria Registry (EPR) to collect data about the porphyrias to inform clinical practice and healthcare planning. Work achieved in 2011 EPNET is a network of porphyria expert centres providing specialist testing and clinical advice on all porphyrias. The network is composed of 31 network members in 26 countries (21 European Member States and 5 applicant countries). Centres are expected to see most of the patients in their region or country, participate in the laboratory external quality assessment scheme, attend board meetings and liaise with their national patient organizations if present. The network has allowed the exchange of ideas, particularly in relation to diagnostic problems, clinical management issues and preventive procedures. EPNET provides services to patients and families: Information for each type of porphyria, in lay language, is available in 11 languages and a network for answering queries has been set-up. The public website receives many hits and generates enquiries from patients and clinicians, many of which demonstrate the continuing need for expertise and information about porphyria. The development of a patient on-line community in collaboration with Eurordis is currently being discussed The European Porphyria Registry, originally set up to collect information on the incidence of the porphyrias, is now being developed to record clinical and laboratory information about patients with acute intermittent porphyria (AIP) in Europe. It has been designed for use by individual clinicians in, or collaborating with, specialist centres to register and follow the progress of patients with AIP whether symptomatic or not. The primary objective of the registry is to better understand the natural history of AIP, evaluate the effect and clinical efficacy of different treatment modalities and facilitate clinical trials and research projects. The EPNET prevalence survey collected retrospective data on numbers of known cases from 24 porphyria centres in 14 European countries. Strategic relevance and contribution to the health programme Because the porphyrias are rare diseases, it is not possible to achieve our objectives on a national level. Data from shows an overall incidence of new cases of AIP of 0.13 per million per year for 11 European

9 P a g e 9 countries. (95% confidence interval: ) Collaboration between countries is therefore required to pool experience from as large a number of patients and porphyria specialists as possible. EPNET is one of the reference network pilot projects funded in 2006 by the DGSanco supporting the exchange of information and experience on good practice. The network is coherent with the criteria for being a European Reference Network (ERN) as currently discussed by the European Committee of Experts on Rare Diseases (EUCERD). Conclusions EPNET is now a well established European Reference Network on Rare Diseases. EPNET Member s continuing enthusiasm and momentum are key factors in demonstrating the network s sustainability. Great effort has been spent in efficiently running, coordinating, expanding the network and establishing the European Porphyria Registry; these are powerful reasons for continuing.

10 P a g e 10 SECTION V 1. BACKGROUND AND PROJECT SCOPE The porphyrias are uncommon diseases that are rarely encountered by most healthcare professionals. Thus there is lack of uniformity in clinical practice. EPNET aims to improve porphyria healthcare across Europe. Since 2007 EPNET has built an outstanding web resource for information about the porphyrias. Quality standards and membership criteria for porphyria centres have been established and a self funding laboratory external quality assessment scheme (EQAS) has been running since Areas of current activity that add value to EPNET s initial achievements are: Extension of the network to European countries that are not part of EPNET. During the project, the number of porphyria centres applying for participation in EPNET EQAS and activity monitoring schemes has steadily increased. Informal contacts suggest that there is scope for including additional countries using the assessment methodology developed by EPNET. Furthermore not all countries with a rare disease plan have specialist porphyria centres. Improvement of diagnostic and analytical quality of centres. Results from the laboratory EQAS show a large variation among European Centres with regard to applied diagnostic strategies and analytical quality of porphyria related metabolites (Aarsand AK et al Clin Chem 2011;57: ). The goal will be to minimize variation. Data collected prospectively on the incidences of inherited porphyrias for shows variation between countries. During 2011 we set out to complete the collection of retrospectve data on the prevalence of porphyrias in European countries. The EPNET has now a major focus to expand the registry to collect clinical details on patients with acute intermittent porphyria. Information from the pilot project carried out in two countries will be used to inform the development of a Europe-wide porphyria registry for the prospective collection of clinical data from large numbers of patients to improve current knowledge in an evidence-based manner and for future clinical trials and other health projects. 2. GENERAL OBJECTIVES OF THE ORGANISATION AND ITS MAIN ACTIVITIES: Porphyrias are uncommon diseases for which diagnosis and treatment varies within the EU. The overall aim of EPNET is therefore to improve the clinical management of porphyria patients. The general objectives are to: increase accuracy of diagnosis; reduce delay in diagnosis and to expand specialist diagnostic and clinical centres in Europe, each of which conforms to agreed analytical and clinical quality criteria improve knowledge and understanding of porphyrias by providing continually updated information to patients in their own languages, and to health care professionals (HCPs), on a dedicated porphyria website provide continuously improving, evidence-based information about selection of drugs for use in patients with acute porphyria

11 P a g e 11 improve collective knowledge of clinical manifestations and phenotypic variability of porphyrias and their complications through collection of epidemiological data to inform Public Health Authorities promote and facilitate research into the porphyrias through collaboration within Europe, but also globally Therefore the main activities are: Coordinate the European Porphyria Network Host and manage the European Porphyria Network website to ensure regular updating of information for patients and healthcare professionals Establishing and supervising a European Porphyria Registry to collect and analyse data regarding clinical manifestations and phenotypic variability Run an analytical and clinical external quality assurance scheme with circulation of urine, blood and feces from known porphyria patient to all EPNET porphyria centres in Europe to monitor their analytical and clinical competence Collect yearly activity reports from each EPNET centre in Europe Develop and disseminate evidence-based best practice guidelines for diagnosis and treatment of porphyria Provide expert support to underperforming specialist laboratories identified through the External Quality Assurance Scheme to improve diagnostic testing quality Coordinate collection, update and maintenance of a searchable, evidence based database for selecting drugs for acute porphyria patients Disseminate information to EPNET members, patient support groups and the wider clinical community Identify opportunities to contribute to related European organisations and initiatives in rare disease such as Orphanet, EuroGentest and others 3. SPECIFIC OBJECTIVES OF THE PROJECT In 2011, the network had four specific objectives 1. Objective 1: to extend EPNET to all European countries 2. Objective 2: to improve diagnostic and analytical quality of specialist porphyria centres in Europe 3. Objective 4: to continue to improve the clinical evidence for selection of drugs for patients with acute porphyria 4. Objective 3: to expand the European Porphyria Registry. 4. DELIVERABLES

12 P a g e 12 Deliverable Title Description Planned delivery month Comments D1 List of countries where there is no porphyria centre A questionnaire will be sent and literature analysed to establish countries where patients do not have access to expertise 6 22 persons were contacted from 17 centres in under-represented countries and invited to give information about the status of existing porphyria centres or potential porphyria centres in their countries. They were invited to join the network 5 new centres have joined the network D2 List of specialist labs and services provided Overview of the status of lab-based porphyria services in European countries 12 List available on Manuscript submitted for publication D3 Quality diagnostic standards Establishing analytical and clinical quality standards 12 Quality specifications as well as the performance of the different centres were published : - in internal EPNET feed-back reports (annex 3) - in Aarsand AK, Villanger JH, Støle E, Deybach JC, Marsden J, To- Figueras J, Badminton M, Elder GH, Sandberg S. European specialist porphyria laboratories: diagnostic strategies, analytical quality, clinical interpretation, and reporting as assessed by an external quality assurance program. Clin Chem. 2011;57: D4 Enhanced registry Registry to be modified to include additional questions 4 A prospective detailed web-based European Porphyria Registry is under development to improve knowledge of clinical manifestations and phenotypic variability of the porphyrias and their complications D5 Report on the prevalence of porphyrias in selected countries The prevalence data will be collected in 5 pilot countries before extended to the whole of EU 9 Retrospective data on prevalence was collected from 25 centres (some centres representing the whole country) and these data will be evaluated and published D6 500 reports on drug usage from patients Patients will report usage of drugs to the pharmacists who will send the information via a web-based data 12 Information from reports collected in 2010 was used for updating the drug database. 31 monographs were updated resulting in the classification of 6 new drugs and the

13 P a g e 13 collection reclassification of 25 drugs 5. MAIN ACTIVITIES CARRIED OUT INCLUDING METHODS AND MEANS Summary of work in 1st 12 months Network coordination EPNET is managed from the APHP in France, with a part-time network manager based in Paris. There is a parttime registry manager in Bergen. The steering committee works with a patient representative, from France, who participates in the work of the network. Communications are maintained by: a newsletter, the website, regular meetings of the steering group; board meetings (two board meetings in 2011) and many s. The network has allowed the exchange of clinical conundrums and management issues. Establishment of a registry in Bergen and secure access The registry, originally developed to collect information on the incidence of the porphyrias, has been expanded as a new European Porphyria registry to record clinical and laboratory information about patients with AIP in Europe. We have changed the IT provider from a French company to a University Hospital based registry in Bergen Norway, in response to the need for developing a completely new platform for the registry. The European Porphyria Registry is being designed for use by individual clinicians in, or collaborating with, specialist centres to register and follow the progress of patients with AIP whether symptomatic or not. The primary objective of the registry is to better understand the natural history of AIP, evaluate the effect and clinical efficacy of different treatment modalities and facilitate clinical trials. Collection of prevalence data The EPNET prevalence survey collected retrospective data on numbers of known cases from 24 porphyria centres in 14 European countries Reaching out to under-represented countries We recognize that not all patients in all countries have access to a porphyria specialist centre. Therefore a main activity has been the contacting of potential new members from under-represented countries. We contacted 22 individuals in 17 new centres which resulted in 5 new centres joining the network in The new centres attend board meetings and will participate in the EQA scheme. Dissemination The website is our principle source of public dissemination. We also present data during all relevant scientific and policy congresses including the international Porphyrins and Porphyrias conference in Cardiff, Eurordis meeting, ESALM meeting, EUCERD clustering meeting. In 2011, we have published one article in a peer reviewed journal in 2011, one additional paper is submitted for publication and one is in preparation. EQA scheme

14 P a g e 14 The EPNET EQAS covers pre-analytical, analytical, post analytical and clinical aspects for all porphyrias related biochemical analyses. The EPNET EQAS included two shipments in Samples were sent to all network centres and feedback was provided to all participants. 6. TARGET GROUPS The EPNET target groups are: Patients with porphyria and their families Patients are faced with inequalities in terms of access to expertise and access to information. It is the aim of EPNET to provide consensus information in patients own language and to improve patients access to the best standard healthcare. Patient support groups EPNET encourages patient organizations throughout Europe to share their experience and resources in the same way that the porphyria centres are collaborating. We do this by providing the platform for different representatives from Europe to meet together. The first meeting took place in Cardiff In 2012 we will work with Eurordis with the aim of setting up a patient online community. Health care professionals Porphyrias are uncommon diseases that are rarely encountered by most healthcare professionals. Thus there is a lack of uniformity in clinical practice. EPNET provides HCP with up-to-date information and management recommendations which will lead to improved medical quality. National and EU health authorities EPNET is one of the first DG Sanco pilot projects for European Reference Networks. EPNET conforms to the EU recommendations and standards for ERNs and provides feed-back to the EUCERD. 7. EVALUATION OF THE DEGREE OF ACHIEVEMENT OF THE OBJECTIVES AND DISCUSSION BASED ON THE PROJECT S INDICATORS AS OUTLINED IN YOUR EVALUATION PLAN EPNET has achieved its main aims and objectives for Evidence of this is shown in the evaluation of the network specific indicators. However, the negotiations for the 2011 budget were completed in March 2011 which delayed the first pre installment for the network. Therefore, despite a theoretical start date on 1 st January 2011, there was a delay in the real start date by three months this has meant that we were unable to complete the ethics approval for the registry in 2011, but the work has been carried over to Success in reaching out to new centres (objective 1)

15 P a g e new centres were contacted and five new centres of which four are in new countries are now part of the network. There was an increase by over 10% of new centres participating to the EQAS scheme in Evaluation of improving diagnostic and analytical quality of labs (objective 2) Improvements have been seen in the selected diagnostic strategies and in analytical results between centres especially for erythrocyte protoporphyrin which is diagnostically a very central analyte. The definition of quality specifications has been reported in the feed-back forms and published in Clinical Chemistry Registry evaluation (objective 3) The items have been defined and the registry is presently being programmed. However as mentioned above there has been a 3 month delay in the start of this project. Furthermore, the complete transformation of the registry into a long-term prospective web-based European Porphyria Registry has required an extensive amount of work, and the data protection approval has been delayed due to a long reviewing process at the Norwegian Data Inspectorate. Therefore, it has not been possible to evaluate the quality of the individual record, the completeness of geographical coverage and compliance with guidelines as initially planned. This will be a priority as soon as the first data records from the two pilot countries are entered i.e. April Evaluation of drug reports (objective 4) There has been no expense for this activity (5000 was originally budgeted). After the successful collection of drug report and more than sufficient data from WP5 delivery, it was not necessary to collect new drug reports in 2011 as we have a large amount of work to reclassify drugs according to their porphyrinogenicity and to develop their respective monograph. The information that was collected in 2010 has been used in 2011 to update 31 monographs in the drug database 8. RESULTS AND KEY FINDINGS In 2011, EPNET has achieved some important outputs including the expansion of the network to underrepresented countries: Bulgaria, Estonia, Turkey and Russia. This is an important service to patients and families in these countries who will have information and access to expert centres and advice. These expert centres are supported by the network in help with difficult diagnosis and management issues and quality control. The two most important costs have been the advisory board meeting held in Paris October, 2011 (see list of participants in annex 1) and the expansion of the registry to include the collection of clinical long-term data on the acute porphyrias. The advisory board meeting is a wonderful opportunity for experts to meet from around Europe and the world, to share progress in the area of porphyrias, cooperate in research, and discuss clinical conundrums. The registry will be the mean to understand some of the most complex questions related to the pathophysiology of the acute porphyrias. 9. SUMMARY OF THE ORGANISATION S WORK PROGRAMME FOR NETWORK COORDINATION AND MEETINGS

16 P a g e 16 Network coordinator: Scientific manager: Prof Jean-Charles Deybach, (APHP) Prof Hervé Puy (APHP) Finance and admin manager: MS Anne Skrobot (APHP) Scientific support: Scientific support: Network & com manager: Registry manager: Prof Vasco Pereira da Silva (APHP) Prof Caroline Schmitt (APHP) Ms Samantha Parker (Interim) Dr Aasne Aarsand (NAPOS, Bergen) The European Porphyria Network (EPNET) is a network of centres of expertise providing specialist testing and clinical advice on all porphyrias. At the end of 2010 EPNET had 32 members in 21 countries (including 4 associate members from outside of Europe). Members are expected to liaise with their national scientific and patient networks, enter data into the patient registry, and collect information about drugs that may potentially precipitate an acute attack of porphyria. All network members constitute the board. Over the project period, EPNET has expanded to 5 new centres in 4 new countries (Bulgaria, Russia, Estonia and Turkey). The new members came to the board meetings. For all members, participation in the EPNET EQA scheme is mandatory as is being able to achieve a minimum quality standard, give detailed interpretation of laboratory results and expert clinical advice on management. Centres that do not fulfil these criteria will be supported by existing members and expected to achieve the full standard within two years of provisional membership. EPNET is coordinated by the APHP. The APHP team consists of Profs Deybach, Puy, Pereira da Silva, Schmitt and Ms Skrobot. Prof Deybach leads the group and attends all EPNET meetings. The team gives local support and some members attend the board meetings. A small executive group (EG), chaired by the network coordinator (Prof JC Deybach), meets more frequently to check progress against objectives. A part-time network manager (Ms S. Parker) assists the coordinator in the week by week running of EPNET. Members of the EG have responsibility for one of the four main network activities: information, drugs, laboratory and the registry; when necessary they set-up working groups for specific tasks. Mrs Sylvie le Moal, actual head of the French porphyria patient association (AFMAP) has participated to the network meetings and worked with the Executive Group. In 2011 we discussed with Eurordis the possibility of setting up an on-line platform for patients in collaboration with Eurordis. This activity will be pursued in Board meetings held: 12 th April 2011, Cardiff 14 th October 2011, Paris Meetings are minuted and reports circulated to the group. The meetings are an essential part of the project. They allow partners to raise issues, troubleshoot, share and build knowledge. Time is allocated to sharing clinical conundrums and discussion. Executive group meetings held: 4 th March 2011, Paris 25 th May 2011, Paris 10 th November, Paris 19 th December 2011, Paris

17 P a g e 17 The Executive group has members from France (Prof. Jean-Charles Deybach, Ms Samantha Parker), Norway (Prof. Sverre Sandberg) and the UK (Dr Mike Badminton, Prof. George Elder). As the registry has become a more important component of the network, two individuals involved in this work from Norway (Dr Aasne Aarsand) and Sweden (Dr. Pauline Harper) have joined the meetings Registry meetings held (in addition to discussions during the steering groups): September 2011, Bergen is the preferred method of communication in the network. It is used for regular communication, disseminating outputs and information. A previously developed Intranet has proved to be less efficient than regular . Appointments Part-time registry manager, Bergen, Norway (subcontracted by APHP): Dr. Aasne Aarsand, a highly successful appointment, was appointed in September Dr Aarsand is responsible for developing the items to be collected in the registry, piloting the registry and ultimately managing its content. Dr Aarsand works in close collaboration with Professor Sverre Sandberg. Part-time network manager, Paris, France (subcontracted by APHP). Ms. Samantha Parker has served on the EPNET project and has assumed a voluntary interim role in the management of the network OBJECTIVE 1: TO EXTEND EPNET TO ALL EUROPEAN COUNTRIES Deliverables linked to this objective Number D1 D2 Deliverable List of countries where there is no porphyria centre List of specialist labs and services provided An important activity has been the communication with new members from underrepresented countries. Map showing EPNET representatives in Europe (in orange) and new members in 2011 (in blue)

18 P a g e 18 Representatives in countries where there was still no porphyria centre were approached through: Personal contacts Internet browsing Table 1: list of countries where representatives were contacted

19 P a g e 19 These potential centres of expertises were asked to fill in the application form which is available online (see annex 2). This form gives minimum criteria for being a specialist porphyria centre. All the existing participants in EPNET were also asked to complete a similar annual activity report. All centres providing this activity report/application are invited to the network meetings. A feed-back activity report is provided to all centres (see annex 3) and an overview of the services provided by each laboratorybased porphyria service is provided on the website (see annex 3). As a result of the 2011 activities, the EPNET network has extended to six new centres and four new countries: Estonia, Bulgaria, Turkey, Russia and new centres in France & Italy. These labs also participate or will participate in the EQA scheme. Figure showing overview of services provided by each laboratory-based porphyria service

20 P a g e OBJECTIVE 2: TO IMPROVE DIAGNOSTIC AND ANALYTICAL QUALITY OF SPECIALIST PORPHYRIA CENTRES IN EUROPE Deliverables linked to this objective Number D3 Deliverable Quality diagnostic standards

21 P a g e 21 The EPNET EQAS covers pre-analytical, analytical, post analytical and clinical aspects for all porphyria-related biochemical analyses. The EPNET EQAS includes two shipments per year of biological materials for analysis: one in March and one in October/November. The biological materials consist of fresh frozen urine, faeces, plasma and whole blood from an actual patient and are delivered by express service to all participating laboratories. The samples are accompanied by a clinical case history and should be analysed in the routine procedures for all porphyrin analyses available at the laboratories. Participants are asked to report the results of their analyses and a diagnosis based on these. The feedback consists of a detailed report comparing the participating laboratory s results with anonymized results from other laboratories, as well as advice on methods of measurements and diagnostic procedures (see annex 4). Target values, quality specifications based on the biological variation of the different constituents as well as quality standard for the reporting of results were established for the EPNET EQAS. These were implemented in the 2011 feed-back reports and published as part of a publication of the EPNET EQAS structure and results (Aarsand AK, Villanger JH, Støle E, Deybach JC, Marsden J, To-Figueras J, Badminton M, Elder GH, Sandberg S. European specialist porphyria laboratories: diagnostic strategies, analytical quality, clinical interpretation, and reporting as assessed by an external quality assurance program. Clin Chem. 2011;57: ). In addition to the deliverables specified in the Annex, EPNET has continued to collaborate with the European Molecular Quality Network in an audit of laboratories undertaking molecular diagnosis of porphyria OBJECTIVE 3: TO EXPAND THE EUROPEAN PORPHYRIA REGISTRY Deliverables linked to this objective Number D4 D5 Deliverable Enhanced registry Report on the prevalence of porphyrias in selected countries PREVALENCE The minimum prevalence of each inherited porphyria in participating countries has been estimated from data held by specialist porphyria centres participating in EPNET. Each centre has returned to Bergen the total number of patients (not lists of individual patients) with each porphyria known to their centre. These lists have been derived from laboratory records. Duplication between centres has not been controlled by comparing overlap between centres. The data is therefore more accurate for countries where only one centre covers the whole country.

22 P a g e 22 The EPNET prevalence survey collected data from 24 porphyria centres in 14 European countries and the data is in the process of being validated (annex 6). A preliminary overview of the Erythropoietic Protoporphyria (EPP) prevalence is given in the figure below PATIENT REGISTRY The database developed by Medifirst from was designed to collect data on the incidence of the porphyrias and their major complications. Porphyria centres in 16 countries entered information into the database. The results of this study can be seen in the poster (annex 7) presented at the international Porphyrins and Porphyrias conference in Cardiff Full analysis of the data has now been completed and a paper is about to be submitted. In 2011, it was decided to expand the incidence database for the prospective collection of information about the clinical pattern of acute intermittent porphyria first and extended to all porphyrias. This required the establishment of a completely new registry to collect such detailed information. Three registry professionals were briefed and the most cost-efficient solution was to develop the registry at the Haukeland University Hospital in Bergen, Norway. The APHP rules for subcontracting were applied in the choice of the service provider. Aims and objectives of the European Porphyria Registry (EPR) The overall aim of the European Porphyria Registry is to pool scarce data without bias for epidemiological and/or clinical research. This will be a key instrument in the improvement of patient care and healthcare planning as well as social, economical and quality of life outcomes. The registry is at present developed for patients with AIP, but will be extended to the other porphyrias as scheduled. The primary objectives of the EPR AIP module are to: 1. Establish the natural history of AIP in the following four settings: 1.1. presymptomatic 1.2. current acute symptoms 1.3. chronic symptoms/ recurrent acute attacks 1.4. in remission 2. Evaluating the effect and clinical efficacy of different treatment modalities/control schemes

23 P a g e Expedite identification and recruitment of appropriate participants for clinical trials The secondary objectives of the registry are to: 1. Monitor the minimal incidence/prevalence current acute symptoms and recurrent acute attacks settings. 2. Identify factors that can predict penetrance of the disease and promote potential research on the subject 3. Find a link between phenotype characteristics with genetic and biochemistry data 4. Determine the effect of a screening program for liver cancer for the survival of patients with hepatocellular carcinoma 5. Creating a biobank of suitable biological samples for future research 6. Generating ideas, plans and opportunities for future research Data protection and ethical approvals The web-based password-protected European Porphyria Registry is under construction in Bergen by professional IT system developers with experience in health registries. The application will be built using Microsoft s.net Framework for a visually pleasing user experience and for strong security features. Data elements and codes are based on standard nomenclature coding systems where possible, for example the ICD- 10 and SNOMED CT. All records will be anonymised and the identity will only be known to the centre treating the patient. An application to the Norwegian Data Inspectorate in accordance with the EU Data Protection Directive (95/46/EC) has been submitted. Patient information sheets and consent forms have been prepared and thereafter reviewed both by porphyria experts and by patient representatives (the British Porphyria Association). Ethical approvals are ongoing in France and Sweden. The ethical approvals have needed to be redone because of the complete transformation of the registry, the web-based solution and its location. Items collected in the registry A working group in close cooperation with the advisory board has discussed and defined the items to be collected in the registry. Three meetings were held in 2011 and comments have been circulated by . Following a first comprehensive draft, a paper version of the data collection form was assessed by several external European content experts and was then revised following feedback. The registry includes standardized data from patients with acute intermittent porphyria when they are in contact with the health care system in the different clinical settings. Recruitment of patients and follow-up data is centralized by each network member for his country or region. To describe the natural history and outcome, standardized, prospective data will be registered, including basic patient data, family history, age at diagnosis, symptoms, frequency and duration of hospitalisation, medical history and clinical assessment. The detailed items to be collected can be seen in annex 5. Diagram 1 shows the organisation of the European Porphyria Registry data collection form

24 P a g e 24 Data administration, statistical analyses and updating of results will be performed by Bergen in collaboration with the working group. Case ascertainment of patients will be provided by all partners. Pilot testing by France and Sweden will be carried out in spring 2012 and the EPR is expected to be rolled out to other European countries in autumn Table 2 shows the activities in 2011: Activities Apr. 11 May 11 Jun. 11 Jul. 11 Aug. 11 sep.11 Oct.11 nov.11 dec.11 Application for data protection approval (Norway) Application for ethical approval (Sweden and France) Patient information consent form X X X X X Data collection form development Protocol development X X X X X X X X X X X X X X X X We have been delayed compared to plan on the registry for the following reasons: 1. Negotiations with the PHEA for the 2011 budget were not completed until end of March. Therefore we lost time at the beginning of the year.

25 P a g e The in principle design of a completely new registry has required an extensive amount of work in order to develop the items to be collected and to plan, design, set up and program the database. It has also required changing the IT provider. We have preferred to work in a transparent and collaborative manner with the network as this is the key to success. During the two advisory board meetings the items to be collected were discussed and then approved in October Obtaining data protection approval has been delayed due to a heavy workload at the Norwegian Data Inspectorate. We will start entering data from two pilot countries in spring 2012 and extend the registry to other countries in the autumn OBJECTIVE 4: TO CONTINUE TO IMPROVE THE CLINICAL EVIDENCE FOR SELECTION OF DRUGS FOR PATIENTS WITH ACUTE PORPHYRIA Deliverables linked to this objective Number D6 Deliverable 500 reports on drug usage from patients Activities and methods: In a simplified reporting system has been used to collect information about drug usage from patients in as many EU countries as possible. This has produced hundreds of clinical evidence of the affects of drugs in patients with porphyria. A steering group for the drug database, composed of members from Bergen and Karolinska, continually review the drug data, draft SOP and guidelines. Generic drug information is disseminated on the Drug Database for Acute Porphyria (drugs-porphyria.org) The validation of drugs is organized according to a flow-scheme starting at observations of the drug in clinical use and running through progressively more specific theoretical and pharmacological markers for ALAS-inducing capacity see diagram 2 Diagram 2: work flow for drug classification.

26 P a g e 26. The information from reports collected in 2010 was used for updating the drug database. Thirty one monographs were updated resulting in the classification of 6 new drugs and the reclassification of 25 drugs. The information is disseminated on the website Thunell S, Pomp E, Brun A. Guide to drug porphyrogenicity prediction and drug prescription in the acute porphyrias. Br J Clin Pharmacol. 2007;64(5): Epub 2007 Jun DISSEMINATION The EPNET website is used to disseminate consensus agreed information: The website has received over visitors in 2011, spending an average of 6 minutes on the website

27 P a g e 27 Statistiques Accès Nombre total d'accès effectifs 3,106,778 Moyenne par jour 8,511 Nombre d'accès à la page d'accueil 33,668 Impressions Pages vues 408,262 Moyenne par jour 1,118 Moyenne par visiteur unique 7 Nombre d'impressions de document 337,881 Sessions Nombre total de sessions 158,018 Moyenne par jour 432 Durée moyenne des sessions 00:06:13 Durée de visite médiane 00:00:02 Nb de sessions d'origine internationale % Nb de sessions d'origine inconnue 0.00% Nb de sessions du pays d'origine (France métropolitaine) 0.00% Visites référées par moteurs de recherche 3,861 Visites en provenance des araignées 17,689 Utilisateurs Nombre de visiteurs unique 55,506 Nombre de visiteurs qui sont venus une seule fois 45,679 Nombre de visiteurs qui sont venus plusieurs fois 9,827

28 P a g e 28 The drug database website is used to disseminate drug information: The EPNET steering group and assembly have been involved in producing and disseminating information for patients and professionals via the website ( The information for patients is in the form of patient information leaflets for each porphyria which have been translated into 11 European languages. The information for professionals has concentrated on the investigation of patients for porphyria and providing up to date information and contact details for specialist porphyria centres. Each partner has in addition improved dissemination about porphyria and the EPNET project within their individual countries by a variety of methods, including the establishment of national networks eg the British and Irish Porphyria Network (BIPNET). These have focused on promoting the information available for patients and the involvement of centres of expertise to support the diagnosis and management of patients with each of the different types of porphyria. The network has also allowed the exchange of ideas and difficult diagnostic and clinical management issues between porphyria centres. A. Peer review journal publications. 1. Aarsand AK, Villanger JH, Støle E, Deybach JC, Marsden J, To-Figueras J, Badminton M, Elder GH, Sandberg S. European Specialist Porphyria Laboratories: Diagnostic Strategies, Analytical Quality, Clinical Interpretation, and Reporting As Assessed by an External Quality Assurance Program. Clin Chem 2011;57, 11, Tollånes MC et al. Diagnostic activities and services offered by European porphyria specialist centres during (submitted to Clin Chem Lab Med). B. Poster and oral presentations to patient associations and leaned societies 3. Tollånes MC, Villanger JE, Støle E, Aarsand AK, Marsden J, To-Figueras J, Deybach JC, Sandberg S. Activity of specialist porphyria centres Oral presentation, Porphyrin and Porphyrias 2011 Conference, Cardiff, United Kingdom, april British Journal of Dermatology, Volume 164, Issue 5, pp Porphyrins and Porphyrias, Cardiff April th 5. Sandberg S. Optimizing Porphyria Diagnostics, Pre-analytical, analytical and post-analytical aspects. Oral presentation, Porphyrin and Porphyrias 2011 Conference, Cardiff, United Kingdom, april 2011 British Journal of Dermatology, Volume 164, Issue 5, side Sandberg S. Experience with an international EQAS for a rare disease: a clinical and analytical scheme for porphyrias, Oral presentation. EQALM meeting, Szeged October 2-6 th 7. Deybach J.C. European Commission clustering meeting October 2011, Luxembourg 8. Parker S. Eurordis meeting May 2011, Brussels C. Peer reviewed publications in preparation 9. The incidence of inherited porphyrias in Europe. George Elder, Pauline Harper, Raili Kauppinen, Michael Badminton, Sverre Sandberg, Jean-Charles Deybach on behalf of the European Porphyria Network (EPNET) (in preparation).

29 P a g e EVALUATION Measures Evaluation Success in reaching out to new centres (objective 1) (a) Number of contacts made with porphyria centres in countries where no specialist centre exists. In 2010, we covered 14 European countries (from the 27 MS). We did not have partners from 13 member countries. (b) Number of new centres subscribing to the EQA scheme. In 2010 the scheme had 28 labs subscribed, a 10% increase i.e. 2-3 new labs would be considered successful, although we recognize that we probably would not achieve this within the current operating grant. Twenty two contacts were made with centres in underrepresented countries. As a result four new countries and five new centres are part of the network, participate to board meetings and the EQAS In centres participated to the EQAS scheme. In centres participated. According to our evaluation measure, this is successful. Evaluation of improving diagnostic and analytical quality of labs (objective 2) (c) Analysis of 2010 and 2011 QA schemes (d) Definition of quality specifications for the EQAS and acceptable analytical and clinical quality published An improvement has been seen in the between centre variation of the results especially for erythrocyte protoporphyrin Analytical quality specification as well as specificaitons for reporting have been set and are reported in the feedback reports. This is also published in Clin Chem see references Registry evaluation (objective 3) (e) Items for the enhanced registry defined (f) quality of the individual record i.e. time between diagnosis and record creation The items were defined and have been included in the annex 5 (f), (g), (h) have not been assessed in 2011 as data have not yet been entered into the database (g) completeness of geographical coverage (h) compliance with guidelines where quantifiable Evaluation of drug reports (objective 4) (i) Number of drug reports sent to database The simplified drug reporting system functioned well in as we had employed pharmacists to encourage patients self reporting. This activity has not been pursued in 2011 due to successful and sufficient data collection before. Therefore this activity had no cost and the budget

30 P a g e 30 of 5000 was not spent (j) Number of drugs classified in the database Information from reports collected in 2010 was used for updating the drug database. 31 monographs were updated resulting classification of 6 new drugs, reclassification of 21 and 3 without reclassification EPNET originally began working with Eurordis, Anna Kole, in the evaluation of the network activities. Anna Kole has since left Eurordis. Her input to the network was very important and the supportive role she offered to disease specific patient organisations. We are also working with the EUCERD and feeding back our experience to the recommendations for ERN s. 10. CONCLUSION The network was formally recognized in 2007 and EPNET is now well established among the European networks of centers of expertise on rare diseases. EPNET is highly successful in its objective of improving healthcare for patients with porphyria and their families wherever they live in Europe. The network of participating centres of expertise on porphyrias is large and partners enthusiastically embrace the principles of widening access to and improving quality of diagnostic and clinical services. The external quality assessment scheme (EQAS) is self-funding and all partners participate and commit to improving standards and decreasing variability. Audit and assessment of the quality of laboratory diagnosis has allowed key diagnostic criteria to be defined and services to be measured against these standards which will enhance quality. Information for patients, families and non-expert clinicians is available in a large variety of European languages and there is a commitment of partners to expand this library to include more international languages where possible, specifically we will update the website with languages from the new expert centres (Russia, Estonia, Turkey and Bulgaria). Finally, the establishment of a European Porphyria Registry is a major step forward in understanding some of the very complex clinical and biochemical issues related to the porphyrias, for example why does a small minority of acute porphyrias become chronic. The network has engendered a momentum and enthusiasm among professionals working in this field to continue and build on what has been achieved so far this is a good indicator that the network can be sustained through the understanding that collaboration is required in these rare diseases.