10th European Conference on Rare Diseases & Orphan Products (ECRD 2020)

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Theme: When therapies meet the needs: enabling a patient-centric approach to therapeutic development. Background: Rare diseases (RD) often result in a wide spectrum of disabilities, on which information is lacking. There is a need for standardised, curated data on the functional impact of RD to facilitate the identification of relevant Patient Reported/Patient Centered Outcome Measures (PROMs/PCOMs) as well as for the use of validated Quality of Life instruments based on functional outcomes. To address these issues, Orphanet is partnering with Mapi Research Trust (MRT) in order to connect Orphanet to PROQOLID ™ , MRT's PROMs/PCOMs database, through disease codes. Visit Orphanet at www.orpha .net. Methods and materials: The Orphanet Functioning Thesaurus (OFT) is a multilingual controlled vocabulary derived from the ICF-CY. A subset of RD present in the Orphanet nomenclature is annotated with the OFT, with the addition of attributes for each functional impact (frequency, severity, and temporality) for each specific RD. Annotations result from structured interviews with clinical experts, medical-social sector care providers, and patient organisations. In order to link PROQOLID ™ data with Orphanet disability data, the taxonomy used to qualify RDs in PROQOLID ™ was reviewed and mapped to Orphanet's. All PROMs developed for RDs were identified, and all products approved by the FDA and EMA from 2002 to 2017 with an orphan drug designation (ODD) and a PRO claim were listed. Results: The Orphanet knowledge base contains over 6000 RD, of which 1073 RD have been assessed for their functional consequences, of which 675 RD have been annotated: the remaining 398 RD were annotated, after discussions with medical experts, as either being highly variable, non-applicable or resulting in early-death. Of the 390 most prevalent rare diseases, 156 have been annotated according to their functional consequences. 64 RDs had a PROM (n = 144) in PRO-QOLID ™ and 17.4% of ODD included a PRO claim. The RDs with the most PROM were sickle cell anemia, spinal cord injuries, cystic fibrosis, all forms of hemophilia A and B and Duchenne Muscular Dystrophy. PROM used in labels were primarily focusing on symptoms (100%), rarely on functioning (4%) or health-related quality of life (12%). Conclusions: Linking these two databases, and providing standardised, curated data, will enable the community to identify PROMs/ PCOMs for RD, and is the first step towards validated Quality of Life instruments based on functional outcomes. and Eurordis. Some patient organisations distributed the survey too more common disease patients as well, e.g. Hashimoto's disease, and these responses were excluded. The survey asked patients to give suggested topics (i.e. fertility, heritability, tiredness, daily medicine intake, sleep quality, physical discomfort, and ability to work, partake in social life, and sports) a priority score and to suggest their own topics for research in open fields. Open field responses were analysed with topic modelling and KLIPP-analysis. Results: After exclusion of responses from more common endocrine disease patients, 1378 survey responses were analysed. Most responses were received from Northern (47%) and Western Europeans (39%), while Southern (11%) and Eastern Europe (2%) were underrepresented. Of the suggested topics respondent were most interested in research concerning the ability to work and participate in social life, and on tiredness. When patients were open to suggest their own topics, common responses included long-term side effects of drugs and quality of life. However, priorities differed between disease groups. For example, adrenal, pituitary and thyroid patients were more interested in research concerning tiredness than others. Conclusion: With this survey Endo-ERN is provided with a large sample of responses from European patients with a rare endocrine condition, and those patients experience unmet needs in research, though these needs differ between the disease groups. The results of this study should be incorporated by clinical experts in the design of future studies in the rare endocrine disease field.
Purpose: When developing a health technology that requires clinical studies, developers institute working relations with clinical investigators. Patient representatives can also create and manage advisory boards with product developers. This was of high utility in the 1990s, in the development of products to treat HIV infection. Inspired by this model, the European Organisation for Rare Diseases (EURORDIS) proposes the EuroCAB programme to facilitate a two-way dialogue between patient representatives and medicine developers. As of 2019, 6 disease-specific CABs exist of approximately 12 members each and others are being formed. Methods: EURORDIS invites developers to sign a Charter for collaboration with patients in clinical research, and provides guidelines together with a mentoring and training programme for patient networks. CABs help set the agenda with the developer, work on topics as diverse as study design, feasibility, informed consent and site selection, QoL and PROMs, and organize the meetings. Discussions also cover compassionate use, pricing, relative efficacy, etc. Meetings last for 2 to 4 days with sessions with different developers, all under confidentiality. There are regular between-meeting teleconferences for trainings and action plan updates, and some CABs have instituted working groups on access, psychological support, etc. The collaboration is evaluated via a post-meeting survey send to both CAB members and medicine developers. In addition, CABs have recently started to monitor outcomes of the meeting and progress towards their goals with a tracker tool. Results: The results of the first surveys from 14 distinct CAB meetings with 19 companies show that this form of shared decision-making is valuable as well as ethical for both parties. We have seen that working relations always continue, even when discussions become heated. All involved show interest in the co-creation possibilities of such collaboration and we look forward to seeing progress and change via the tracker. Conclusions: Monitoring and evaluation are crucial to understand whether and how the CABs are making an impact on medicine development. Demonstrating impact is challenging because of the contextualized nature and complexity inherent to patient engagement collaborations in research design. EURORDIS is working within PARA-DIGM on our monitoring and evaluation strategy, focusing on improving its comprehensiveness and including multi-stakeholder perspectives. Our current experiences show that the EuroCAB programme, with collective thinking and exchange between patients and a collaborative mentality from both sides, ensures high-quality and constructive dialogue with researchers and developers and can eventually inform both HTA and regulatory decision-making (Fig. 1). We have started to work on the metrics of markers of success.   Purpose: The French national Network for rare sensory diseases SENSGENE launched in 2019 a 3-min motion design video ( Fig. 1) aiming at guiding healthcare professionals to welcome visually impaired patients in the hospital. This educational video was created to address patients' expectations and improve their experience in the network's hospital. The European Reference Network for Rare Eye Diseases (ERN-EYE) collaborated on the project and created an English version of the video in order to distribute it widely in Europe.

Fig. 1 Strategic development of the video: issues and objectives
Method: SENSGENE worked on this project with two big French associations of visually impaired people: Fédération des Aveugles et Amblyopes de France and Fédération des Aveugles Alsace Lorraine Grand Est. More than 15 French patients' associations actively contributed to the project through five focus groups (workshops) which collected testimonies and gathered the needs of visually impaired persons and health-care professionals (Fig. 2). An evaluation was made by the independent body IPSO FACTO: 30 health professionals answered to a survey before and after viewing the video. Results: The video deals with common situations in the delivery of care activities for different types of visual impairment: reception in a hospital center, consultations, moves and orientation in a hospital room (Fig. 3). This fits perfectly with the needs of the patients reported in the focus groups. Besides, the evaluation showed that 80% of them improved their knowledge on the topic.   Background: Traditional appraisal and reimbursement approaches such as cost/QALY are increasingly recognised as being potentially unsuitable for rare disease treatments (RDTs). Approaches to appraising RDTs vary across countries, from the same processes used for all medicines, to those completely separate from the standard, to adapted standard processes with greater willingness to pay (WTP). This study examines the impacts of standard versus special appraisal processes for specific RDTs in selected countries. Methodology: A case study analysis was conducted in which countries with a variety of RDT appraisal processes were selected, along with two RDTs representative of the following criteria: rare/ultra-rare treatment, affecting child/adult, cancer/non-cancer, life-threatening/disabling. Public HTA reports for each country's appraisal of the selected RDTs were retrieved and used to extract information into predesigned templates, which allowed for systematic comparison of the RDT processes across countries to compare and exemplify the impact of the different processes. Results: Reports from Belgium, England, France, Germany, U.S., Italy, Lithuania, Netherlands, Poland, Romania, Scotland, Slovakia, and Sweden were selected for Spinraza and Voretigene. Characteristics of each country's process were extracted, including special reimbursement for RDTs, special RDT committees, economic evaluation modifications, greater WTP, quality of evidence flexibility, additional considerations, etc. Special and standard processes seemed to have different impacts on the appraisal of RDTs. Special processes more consistently managed RDT issues such as evidential uncertainty and higher ICERs. Standard processes sometimes informally applied some of the characteristics included in special processes, such as broader consideration of value. Conclusions: Comparing case study country examples of RDT appraisal exemplified the complexity of these processes. Special processes were more consistent in managing the challenges in RDT appraisal than standard processes. Practical application: Findings suggest a need for adapted approaches for RDT appraisal, to facilitate management of associated challenges and more consistent decision-making.

P12
Estimating the broader fiscal impact of rare diseases using a public economic framework: A case study applied to acute hepatic porphyria (AHP) Mark P. Connolly 1,2  Background: The aim of this study was to apply a public economic framework to evaluate a rare disease, acute hepatic porphyria (AHP) taking into consideration a broad range of costs that are relevant to government in relation to social benefit payments and taxes paid by people with AHP. AHP is characterized by potentially life-threatening attacks and for many patients, chronic debilitating symptoms that negatively impact daily functioning and quality of life. The symptoms of AHP prevent many individuals from working and achieving lifetime work averages. We model the fiscal consequences for government based on reduced lifetime taxes paid and benefits payments for a person diagnosed aged 25 experiencing 12 attacks per year. Materials & Methods: A public economic framework was developed exploring lifetime costs for government attributed to an individual with AHP in Sweden. Work-activity and lifetime direct taxes paid, indirect consumption taxes and requirements for public benefits were estimated based on established clinical pathways for AHP and compared to the general population (GP). Results: Lifetime earnings are reduced in an individual with AHP by SEK6.5 million compared to the GP. This also translates to reduced lifetime taxes paid of SEK2.8 million for an AHP individual compared to the GP. We estimate increased lifetime disability benefits support of SEK3.1 million for an AHP individual compared to GP. We estimate average lifetime healthcare costs for AHP individual of SEK31.9 million compared to GP of SEK2.5 million. These estimates do not include other societal costs such as impact on caregiver costs. Conclusions: Due to severe disability during the period of constant attacks, public costs from disability are significant in the AHP patient. Lifetime taxes paid are reduced as these attacks occur during peak earning and working years. The cross-sectorial public economic analysis is useful for illustrating the broader government consequences attributed to health conditions. Ethics Approval: The study results described here are based on a modeling study. No data on human subjects has been collected in relation to this research.

Background:
The European Cystic Fibrosis (CF) Society Patient Registry collects demographic and clinical data from consenting people with CF in Europe. The Registry's database contains data of over 49,000 patients from 38 countries. High quality data is essential for use in annual reports, epidemiological research and postauthorisation studies. Methods: A validation programme was introduced to quantify consistency and accuracy of data-input at source level and verify that the informed consent, required to include data in the Registry, has been obtained in accordance with local and European legislation. Accuracy is defined as the proportion of values in the software matching the medical record, consistency as definitions used by the centre matching those defined and required by the Registry. Data fields to verify: demographic, diagnostic, transplantation, anthropometric and lung function measurement, bacterial infections, medications and complications. The number of countries to validate: 20% of the total countries/year. In the selected country ≥ 10% of the centres should be visited and 15-20% of the data validated. Results: In 2018, ten out of 41 centres (24%) in 4 countries (Austria, Portugal, Slovakia, Switzerland) with ≥ 50% of all patients in their countries were selected. In a 1 day visit, the data of the Registry were compared with the medical records, the outcomes and recommendations discussed, and a final report provided. Demographic, diagnostic and transplant data were checked for 489 patients (21%*), clinical data for 463 patients (20%*) (2016 data). Challenges were: informed consent, mutation information (genetic laboratory report missing), definitions interpretations. See Fig. 1 for the results. Conclusion: The Registry's data is highly accurate for most data verified. The validation visits proved to be essential to optimise data quality at source, raise awareness of the importance of correct informed consent and encourage dialogue to gain insight in how procedures, software, and support can be improved. *Of the total patients in these countries.
Background: People with Duchenne muscular dystrophy (DMD) adopt compensatory movement patterns to maintain independence as muscles get weaker. The Duchenne Video Assessment (DVA) tool provides a standardized way to document and assess quality of movement. Caregivers video record patients doing specific movement tasks at home using a secure mobile application. Physical therapists (PTs) score the videos using scorecards with prespecified compensatory movement criteria. Objective: To gather expert input on compensatory criteria indicative of clinically meaningful change in disease to include in scorecards for 15 movement tasks. Approach: We conducted 2 rounds of a Delphi panel, a method for building consensus among experts. We recruited 8 PTs who have evaluated ≥ 50 DMD patients in clinic and participated in ≥ 10 DMD clinical trials. In Round 1, PTs completed a preliminary questionnaire to evaluate compensatory criteria clarity and rate videos of 4 DMD patients performing each movement task using scorecards. In Round 2, PTs participated in an in-person discussion to reach consensus (≥ 75% agreement) on all compensatory criteria with disagreement or scoring discrepancies during Round 1. Results: Of the 8 PTs, 38% practiced physical therapy for ≥ 20 years, 75% provided physical therapy to ≥ 200 DMD patients, and 38% participated in ≥ 15 DMD clinical trials. Of 153 version 1 compensatory criteria, 70 (46%) were revised in Round 1. Of 150 version 2 compensatory criteria, 97 (65%) were revised in Round 2. The 8 PTs reached 100% agreement on all changes made to scorecards during the in-person discussion except the Run scorecard due to time restrictions. A subset of the panel (3 PTs) met after the in-person discussion and reached consensus on compensatory criteria to include in the Run scorecard. Conclusion: Expert DMD PTs confirmed that the compensatory criteria included in the DVA scorecards were appropriate and indicative of clinically meaningful change in the disease. Introduction: Fifty percent of rare disease cases occur in childhood. Despite this significant proportion of incidence, only 17% of adult medicines authorised by the European Medicines Agency (EMA) completed paediatric trials [1,2]. As a result, many clinical needs are left unmet. Various factors compound the development of treatments for paediatric rare diseases, including the need for new Clinical Outcome Assessments (COAs), as conventional endpoints such as the 6 Minute Walking Test (6MWT) have been shown to not be applicable in all paediatric age subsets, [3] and therefore may not be useful in elucidating patient capabilities. COAs are a well-defined and reliable assessment of concepts of interest, which can be used in adequate, well-controlled studies in a specified context. COAs capture patient functionality and can be deployed through the use of wearable sensor technology; this feasibility study presents data obtained from patients with paediatric rare diseases who were assessed with this type of technology. Methods: Niemann Pick-C (NP-C) (n = 10) and Duchenne Muscular Dystrophy (DMD) (n = 8) patients were asked to wear a wrist-worn wearable sensor at home for a minimum of 12 weeks. Feasibility was assessed qualitatively and quantitatively, with data captured in 30 minute epochs, measuring the mean of epoch's with the most steps over a month (ADM), average daily steps (ADS), average steps per 30 minute epoch (ADE) (table 1) and reasons for non-adherence (table 2). No restriction in the minimum number of epochs available for analysis were applied, and all patient data analysed. Results: Discrepancies in ambulatory capacity were observed between NP-C and DMD patients overall, with NP-C patients covering greater distances and taking more steps daily. Qualitative assessment of both patient groups highlighted their relationships with the technology, which in turn detailed adherence. Some patients exhibited behavioural issues which resulted in a loss of data and low engagement. Conclusions: The wearable sensor technology was able to capture the ambulatory capacity for NP-C/DMD patients. Insights into disease specific parameters that differed were gained, which will be used for developing the technology further for use in future trials. Additional work is required to correlate the wearable device data with other clinical markers, however the study displays the feasibility of wearable sensors/apps as potential outcome measures in clinical trials. Background: Neonatal surgery is decentralized in Germany. In 2015 there were 89 departments of pediatric surgery that treated 93% of the abdominal wall defects with an average case load of less than 5 per unit [1]. Patient organizations stress the importance of quality measurements for the care of children with rare diseases. Study plan: Currently, there is no nationwide data collection regarding the short term and long term care of patients with congenital malformations, who often need surgery during the first weeks of life. The German Society of Pediatric Surgery, which covers almost all of the 130 German pediatric surgical units, has initiated the work of creating a national patient registry (KiRaFe) for the following congenital malformations: Malformations of the gastrointestinal tract, the abdominal wall, the diaphragm, and meningomyelocele. The development of the registry involves three different patient organizations and health care professionals from all over Germany. The registry will be set up in 2020 based on the Open Source Registry System for Rare Diseases (OSSE). The primary objective of the registry is the measurement of quality attributes of rare congenital malformations. Furthermore, the registry will facilitate recruitment of patients to clinical trials. It will also serve as a basis for policy making and planning of health and social services for people with rare disorders. Informed consent will be obtained from the participants. The registry will include core data, mainly comprising information on the set of malformations of each patient. Each malformation will then prompt further different modules for data collection. This modular structure offers the greatest possible flexibility for the documentation of patients with more than one congenital malformation. Data will be collected by health care professionals. Results: Since the start of the preparation 47 individuals, either working in one of 27 hospitals or being member of one of the three patient organizations, have contributed in the ongoing activities. The registry is listed in the European Directory of Registries (ERDRI) [2]. Ethical approval was obtained, financial resources were secured. In 2020, 83 German hospitals and three non-German hospitals confirmed their intention to document their patients within the registry. Conclusion: The registry is an example for a nationwide collaboration with the goal to optimize the quality of care for a patient group with rare diseases. is a collaboration between CF Europe and five pharmaceutical companies (to date). Through biannual meetings, we aim to institute a longterm educational collaboration with companies with an interest in CF. Membership of industrial partners is dependent upon adherence to the CFRToC Code of Conduct and a financial contribution for CF Europe to fulfil its missions.

P17 Improving communication about clinical trials in Cystic Fibrosis
Common objectives include access to information. One strong example, applicable even beyond rare diseases, is the need for improved communication regarding clinical trials (CTs) which has been inconsistent and often difficult to understand. From 2021, the new European CT regulation 536/2014 will oblige sponsors to share CT results through lay summaries. To help move this initiative forward, CF Europe, with the active support of the Cystic Fibrosis Trust, is collaborating with the European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN) and CFRToC members to establish a glossary of relevant CF terms. It will be freely available so that all stakeholders can systematically use it in patient-friendly scientific summaries and wider communication. In a pilot project, people with CF and patient associations, together with industrial partners will shortlist 10 terms. These will be defined by lay members and subsequently subjected to the study and approval of the legal department of participating companies. Provided this process is successful, we aim to create 30 approved definitions by the end of 2020. CF Europe and ECFS-CTN intend to advertise the use of this glossary online and through communications at scientific events. National patient organisations will be further encouraged to provide translations in their national language. Alkaptonuria (AKU, ochronosis) is an inborn metabolic disease, resulting in the accumulation of the metabolic intermediate homogentisic acid (HGA). Oxidation of HGA by air or within connective tissue causes darkening of the urine, pigmentation of eyes and ears, kidney-and prostrate-stones, aortic stenosis, but most severely an early onset of arthritis called ochronotic arthropathy (ochronosis) due to deposition in the cartilage. Ochronosis is very painful, disabling and progresses rapidly. Starting in the thirties with the spine and affecting large joints in the forties, patients frequently require joint replacements in their fifties and sixties [1,2]. Like many of the rare diseases, AKU-patients undergo a long odyssey of several years until their diagnosis. The German AKU-Society "Deutschsprachige Selbsthilfegruppe für Alkaptonurie (DSAKU) e.V. " was founded in 2012 and became subsequently registered as a non-profit patient organization. First of all, the DSAKU identified AKU-patients, set up a homepage [3] and designed flyers with information for patients, their families, medical professionals and healthcare services. Second, it offered workshops on AKU-related issues and enabled personal exchange. Third, it raised awareness of AKU, both nationally and internationally by information booths, presentations and posters at scientific congresses as well as rare disease days (RDD). Fourth, in response to the needs of patients, it established collaborations and built up national networks for a better health care accordingly. Thus, patients were encouraged to visit the centers for metabolic diseases at the Charité (Berlin), Hannover Medical School (MHH), University of Düsseldorf and Institute of Human Genetics at the University of Würzburg to bundle knowledge and expertise. The DSAKU is member of ACHSE e.V., NAKOS, EURORDIS and MetabERN and registered in the databases SE-Atlas, ZIPSE and Orphanet. Finally, the DSAKU is nationally and internationally active in health politics regarding training in drug safety and evidence-based medicine.
Introduction: Autoinflammatory diseases are rare conditions characterized by recurrent episodes of inflammation with fever associated to elevation of acute phase reactants and symptoms affecting mainly the mucocutaneous, musculoskeletal or gastrointestinal system. These diseases affect the quality of life of patients and their families. Objectives: Aim of this project is to develop a tool able to ameliorate patients' management of the disease and to enhance patientphysician communication.

Methods:
To develop a tool based on real-life needs, we involved patients and caregivers since the initial phase of the project. A first workshop designed to capture their needs was organized. Innovative co-design activities were performed through "LegoSerious-Play ™ " (LSP) methodology [1][2][3]. During a first phase of "divergence" 13 patients (from teen-agers to adults) affected by different AIDs (FMF, TRAP, CAPS, MKD) and 2 physicians where involved in the LSP activities. Participants were asked to describe, through LEGO and metaphors: • The disease • Themselves in comparison with the disease • Solutions and supports which could help them in managing the disease After each step the participants presented their models, and everyone was engaged in the discussion. The ideas collected during the three phases allowed to make a list of functionalities identified as necessary for the app to be developed. Due to the actual Sars-CoV-2 sanitary emergency the second phase of the project, aimed at presenting the participants the results of the first meeting and proceed with the App finalization was performed through web-based meeting and surveys in which the patients and caregivers actively participated. Results: In the first phase patients and caregivers participated actively expressing various needs, that we subsequently summarized in 4 main areas (Table 1). Participants were then further involved and their opinion taken into consideration for the User Experience and Interface definition for the development of the Mobile App including the required functionalities (after a further activity of prioritization). Introduction: Gaps in communication and education are becoming one of the biggest key pain points for patients that are suffering rare diseases. Due to the limited resources and the misleading information on the internet we wanted to test the POC systems to deliver more efficiently the information to our patients and their relatives. Userfriendly information at the point of care should be well structured, rapidly accessible, and comprehensive. Method: We implemented a specific POC channel using several touchpoints to deliver the right content at the right time. We created and selected the video content that will be most helpful to our patients. Later on, we analyzed the patient journey and we decided to use a mobile app where the patients could search for information when they are at their home. At the medical practice, we use the waiting room and exam room as learning areas through monitors and tablets. Moreover, healthcare professionals are prescribing content to their patients that they reviewed when they are home.
Results: Thanks to the use of the POC channel and technologies related we were able to reduce the time needed to perform an explanation by 35%. Furthermore, our healthcare professionals reported that their conversations with the patients improved 50% and patient satisfaction increased by 60%. Conclusion: POC channel created a positive impact on our patient experience allowing us to be more efficient delivering the information to our patients and their relatives.  [1,2], realworld safety and efficacy data are limited -particularly for patients who receive > 1 treatment. We report initial data from the RESTORE Registry, including cohort clinical characteristics, treatments received, and outcomes. Materials and methods: RESTORE is a prospective, multicenter, treatment-agnostic registry of SMA patients. The primary objectives include assessment of contemporary SMA treatments; secondary objectives include assessment of healthcare resource utilization, caregiver burden, and changes in patient functional independence over time. Planned follow-up is 15 years from enrollment.

Results:
As of 31 January 2020, data were available for 67 patients, all from de novo clinical sites in the United States; information on treatment regimens was available for 56 patients (Table 1). Disease-modifying treatments were administered sequentially or in combination. 91% of treated patients showed symptoms at SMA diagnosis, with the most common being hypotonia and limb weakness ( Table 2).    Ågrenska, a Swedish national centre for rare diseases, has for thirty years arranged courses for families of children with rare diagnoses and has experienced that the conditions often have complex and varying consequences in the children ś everyday lives. Knowledge of these consequences and of how to adapt the treatment, environment and activities to create the best possible conditions for participation and learning, is often lacking. Many professionals also report lack of sources of knowledge. Knowledge formation and dissemination are thus of outmost importance. In order to aid knowledge formation and dissemination Ågrenska has developed an observation instrument for children with rare diagnoses, identifying both abilities and difficulties on a group level. The instrument consists of 144 quantitative and 71 qualitative items and covers ten areas: social/communicative ability, emotions and behaviours, communication and language, ability to manage his/her disability and everyday life, activities of daily life, gross and fine motor skills, perception and worldview, prerequisites for learning and basic school abilities.
Observations are made during the children ś school and pre-school activities during the Ågrenska course. Teachers and special educators, working with the children, are responsible observers. Some school-related abilities are difficult to observe during the five-day stay. This information is instead collected through a telephone interview with the children ś home teacher. The instrument was content validated against a number of existing instruments. The items were considered relevant as they, with few exceptions, appear in well-known assessment tools.
To test interrater reliability observations of six children were performed. Each child was observed by two educators. Interrater reliability was calculated for the 116 quantitative items usually observed during the course. Interrater reliability reached 92.5%. Background: SMA is a neurodegenerative disease caused by survival motor neuron 1 gene (SMN1) deletion or mutation [1,2]. Disease severity (SMA type) correlates with SMN2 copy number [1,2]. Gene therapy with onasemnogene abeparvovec provides sustained, continuous production of SMN protein, and is FDA approved [3], with ongoing trials for SMA type 2 (SMA2) and SMA3, and presymptomatic treatment for all SMA types. With treatment options available, many states in the United States (US) are implementing newborn screening (NBS) to detect SMN1 deletions and SMN2 copies, providing early diagnosis and the option of pre-symptomatic treatment [4]. We examine the economic consequences of implementing NBS for SMA and pre-symptomatic treatment with onasemnogene abeparvovec gene therapy among newborns in the US.

Materials and methods:
A decision-analytic model was built to assess the cost effectiveness of NBS in 10,000 hypothetical newborns from a US third-party payer perspective. The model included 3 separate arms, each allowing for a different treatment strategy. Model inputs for epidemiology, test characteristics, and screening and treatment costs were based on publicly available literature (Table 1). Inputs and assumptions of lifetime costs and utilities for SMA types were obtained from the 2019 Institute for Clinical and Economic Review SMA report [5]; other values were sourced from published literature. Model outputs included total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). Scenario and sensitivity analyses tested model robustness.

Patient and public involvement (PPI) is a key aspect of Wales Gene
Park's programme, particularly across education and engagement and prioritisation and development of research. In addition to representation on governance structures, Wales Gene Park (WGP) collaborates with patients and the public to involve them in rare disease and genetic research. WGP has co-produced a Rare Disease Research Gateway following consultation with patients and the public from its networks. The Gateway hosts relevant studies in genetic and rare disease research on the WGP website. It promotes involvement opportunities in addition to signposting to studies that patients and other members of the public can participate in. It also links to training opportunities for PPI representatives.
Consultation with patients and the public regarding the usability, design and development of the Gateway was undertaken. Feedback has enhanced the user experience and it was launched in October 2019. There are currently over 230 studies featured, and the Gateway is searchable according to condition or key word. Impact will be monitored through online usage and website analytics. Engagement with researchers through a Professional Network enables opportunities to be advertised from all areas of genetic and rare disease research and ensures that patient and public representatives are involved in the design and development of research from its inception. WGP were invited to present at the Welsh Health and Care Research Wales conference in 2019 as the Gateway was highlighted as an exemplar of good practice.
specialist visit, medications) and non-medical resource use (lost productivity and homecare or caregiver's time). Outcomes of interest for treatment options assessed the efficacy and safety of treatments for Rett syndrome. Results: The search on economic burden yielded 133 articles; intervention type and costs were extracted from 9, representing 4 studies.
In the economic burden studies, enteral feeding and assisted walking increased the risk of respiratory-related hospital admissions, while length-of-stay was lower in younger patients. Mean recovery-stay after scoliosis-correcting surgery was 18.2 days and 12.3 days in each of 2 studies. Care integration improved outcomes and reduced costs. The search on clinical trials yielded 652 articles; efficacy and safety were extracted from 28, representing 20 studies (15 randomized controlled trials, 5 single-arm; N = 8-82; follow-up 1-26 months). Of these, 19 focused on pharmacological symptom treatment; 1 examined environmental enrichment effects; none targeted the underlying cause. The most common primary endpoints are stated in Table 1. Naltrexone, trofinetide, and mecasermin demonstrated clinical benefits versus placebo, but most treatments yielded no significant improvement ( Table 1). The CML Advocates Network (CML AN) is an active network specifically for leaders of Chronic Myeloid Leukemia (CML) patient groups, connecting 123 patient organisations in 93 countries on all continents. It was set-up and is run by CML patients and carers. Its aim is to facilitate and support best practice sharing among patient advocates across the world. The CML Community Advisory Board (CML-CAB) is a working group of the CML Advocates Network. Since its inception the CML-CAB has met on nineteen occasions with five sponsors.

Fig. 1 Outlines the process by which the CML-CAB operates
The CML-CAB is comprised of two chairs and 17 CAB-members. CML-CAB organisation, sustainability and follow-up is supported by a part-time CML-CAB Officer and the CML-AN Executive Director. The principles of leaving no one behind are essential to the goals of World Health Organization (WHO) and United Nations (UN). In 2018, an ambitious objective to ensure that 1 billion more people will benefit from universal health coverage (UHC) until 2023 was entrenched in the WHO 13th General Programme of Work [1]. All UN Member States have agreed to try to achieve universal health coverage by 2030, as part of the Sustainable Development Goals [2]. However, it is essential, that rare disease (RD) patients are not left behind on our trip to UHC. In 2019, UN declared that RD are among the most vulnerable groups that are still on the fringes of UHC [3]. The first step on a way to the full UHC Cube [4] for RD is an identification of root causes of health inequities. Health determinants of RD fundamentally differ from those for common diseases. Some of them are unavoidable: up to 80% of RD have a genetic basis (individual or genetic determinants). Although socio-economic factors are highly important, in contrast to common diseases, they are a consequence rather than a cause of RD. Meanwhile, one of the major root cause amenable to change are health system determinants: organization of services for RD requires unique solutions in our health systems that are mostly adapted for common diseases. Political and legal determinants also play a key role: while RD is an explicit example of an area, loaded Orphanet J Rare Dis 2020, 15(Suppl 1):310 with needs for pan-European solutions, relative "weakness" of EU legal powers to regulate and have an impact on implementation of pan-European policies in health results in vast inequities among and inside Member States and lack of engagement at a national level. Health activism that includes strong advocacy and a loud voice of patient organizations has also been ascribed to health determinants and may have a crucial role in RD [5] To improve the situation, we already have some powerful tools at hand including national plans for RD, European Reference Networks [6] and European Joint Programme on Rare Diseases [7]. However, to reach the full potential of these, multiple obstacles have to be removed and full implementation ensured.
Since March 2020, there has been an explosion in digital health adoption as people look for remote ways to manage their health and wellbeing. National Government COVID-19 strategies, local authorities and consumers, have all turned to health apps, both as a potential means of slowing the spread of the virus, and a method of allowing people to self-manage their own health.
In the first few weeks of the COVID-19 pandemic, ORCHA worked with app developers to build a dedicated COVID-19 App Library full of evaluated apps. Free to use for all, it included relevant, quality assured apps that had been through ORCHA's rigorous Review process. To build such a tool in such a short space of time is testament to the speed of this market. More consumers have been using health and care apps. In just one week, ORCHA saw an increase of 182.5% in app downloads from its App Libraries, and a 6,500% increase in app recommendations from health and care professionals. ORCHA can see from the data across its App Libraries that the most popular search terms since the pandemic began have included: mental health, physiotherapy, fitness, anxiety, rehabilitation, diabetes, respiratory, and sleep.
Whereas 'COVID' was initially the most searched term at the beginning of the outbreak, people have since searched for specific condition areas. This indicates a shift in focus to actively self-managing health and wellbeing, and a desire for knowledge about particular health areas.
The recent increase in digital health adoption has highlighted that the challenge remains of helping consumers to understand which apps are potentially unsafe to use, and ensuring that consumers are armed with the full facts about the strengths and weaknesses of an app, before it is downloaded. While considerable progresses have been made in the last years in research on innovative medicinal products for adults, children have not benefited from progresses to the same extent as adults in terms of appropriate treatments and advanced tools. It is well known that the availability of drugs for paediatric use still represents a challenging issue, since research and development in this field is characterized by many that range from methodological, ethical and economic reasons, especially when neonates and rare diseases are involved. Moreover, even when Industry has the capacity to perform a paediatric drug development plan, there are many economic reasons limiting the commercial sponsors' interest (the paediatric population is a small population; paediatric diseases often concern rare disorders with unknown mechanism; it is very difficult to perform preclinical and clinical studies; ethical concerns are still relevant and additional regulatory requirements have to be considered).

S3 Expanded New born Screening -The Italian situation
In this scenario, EPTRI can make the different in closing the gap between innovative technologies and paediatric drug development processes. It is a EU-funded project that arises from the need to find answers to the serious lack of medicines for children in EU and worldwide, and aimed to design the framework for a European Paediatric Translational Research Infrastructure dedicated to paediatric research. An high interest is tailored on rare diseases (RD) as they affect mainly children and genetic RD start early in the prenatal/childhood life with an high frequent use of medicines not specifically tested (off-label, unlicensed). EPTRI will work to accelerate the paediatric drug development processes from medicines discovery, biomarkers identification and preclinical research to developmental pharmacology, age tailored formulations and medical devices. This will allow is to facilitate the translation of the acquired new knowledge and scientific innovation into paediatric clinical studies phases and medical use. Neonatal screening started in many countries around 1960-1970 after phenylketonuria turned out to be a treatable condition. If diagnosed early, a diet could help to avoid impaired brain development. Public health programmes were developed to offer all newborn children the possibility to be tested. Screening always has benefits and disadvantages, and only rarely pros outweigh cons at reasonable costs. The World Health Organization in 1968 published criteria to evaluate benefits and disadvantages, concerning amongst others (1) important health problem (2) treatment (3) suitable test and (4) appropriate use of resources. PKU was mentioned as an example of an important health problem [1]. Neonatal screening is more than a test. Information to parents, communication of results, ICT infrastructure, follow-up of affected infants, reimbursement of test and treatment and governance all need adequate attention [2]. Around 2010 the number of diseases covered in European countries in neonatal screening programs was very diverse: from zero in Albania to more than 20 in Austria, Hungary, Iceland, Portugal and Spain [3]. Many countries have seen an increase in the number of diseases covered because of new tests and treatments becoming available. Health authorities were almost always involved in changes in the programmes, HTA experts and parents organizations sometimes. Half of the countries had laws on NBD, and half had a body overseeing NBS programs. Less than half of the countries informed parents of the storage of dried blood spots [3]. After the EU initiated "Tender NBS" had provided advice to EU policy makers [4], little initiatives for harmonization were taken, because health is the mandate of Member States. From the perspective of newborns this implies that early diagnosis and adequate treatment for NBS conditions may differ very much for children being born in one or another EU country.
With more tests and more treatments becoming available, this makes it even more urgent to attune the perspectives of different EU stakeholders for the benefit of all newborns.
Background: As genome sequencing is rapidly moving from research to clinical practice, evidence is needed to understand the experience of patients with rare diseases and their families. In the presentation, we discuss families' experience of receiving, making sense of and living with genomic information. The presentation includes video-clips from two short films from families' narratives. Specifically, families struggled with the lack of information on the course of the disease, the difficulties to access support and navigate health and social care services, and the challenges related to making sense of the implications of genomic information for other family members. Despite these issues, families identified a wide range of benefits from taking part in genome sequencing, which were broader than the clinical utility of the diagnosis. The findings raise questions regarding how to talk about 'diagnosis' in a way that reflects families' experience, including their uncertainty but also their perceived benefits. They also have implications for the design and delivery of health services in the genomic era, pointing to the need to better support families after their search for a diagnosis.
Saluscoop [http://www.salus coop.org] is a non-profit data cooperative for health research that aims to make a greater amount and diversity of data available to a broader set of health researchers, and to help citizens to manage their data for the common good. Data heals. Health research is data-driven: the larger the universe, the greater the quantity, quality, and diversity of the data, the more potential the data has to cure. In our European context, it is clear: data belongs citizen. GDPR regulates ownership and our rights over data that include portability. Data protection laws rightly consider that health data deserves the maximum protection. However, the only truth, we note every day: In practice citizen often cannot access their data or control its use. The future of our health depends significantly on the ability to combine, integrate and share personal health data from different sources. The only one who can integrate all your information (public, private, clinical, personal, habits, genetics) is the citizen himself. Using data well, it is possible to obtain More and Better health for all.
We are a Cooperative that works to facilitate the transformation process towards this goals doing: -Dissemination, awareness, communication -Studies, Manifestos.
-Licenses to facilitate it -SALUS Common Good license -

Instruments -App Salus
It is necessary to dissociate the provision of services, of the possession of the data. The accumulation and centralization of the data is not necessary. Blockchain and the like allow the certification of transactions without the need for intermediaries. The need for the existence of new social institutions for the collective management of data for the common good is much clearer today: So that these citizens have the technological and legal tools effectively manage their data. So that health research can address the real problems of our societies.

Acknowledgements:
The abstract is being presented on behalf of a SALUSCOOP Management Board Group. The Region of Murcia, located on the southeast of Spain, has 1.5 million inhabitants. In 2015, approximately 5% of its population was identified with a RD, based on the Regional RD Information System, which showed a public health problem requiring an integral and coordinated approach. Results: In 2018, after 2 years of participative work (interdepartmental government representatives, patients associations and professionals) the Regional Plan for RD integrated (holistic) care was approved, for a period of 4 years (2018-2021) and a budget of 12 millions euros; with the goal of improving health, education and social care through interdisciplinary coordination and placing patients and families in the center of the actions. The plan includes ten different strategic areas related to information, prevention and early detection, healthcare, therapeutic resources, social-health care, social services, education, training of professionals, research, monitoring and evaluation A Regional RD Coordination Center, linked to the Medical Genetics Unit in the tertiary reference hospital, is connected to the 9 health areas, educational and social local services, through a case manager integrated in the multidisciplinary team. This was our building experience presented in the INNOVCare project, co-funded by the EU.

Conclusions:
To design a holistic care plan for RD we need to know the prevalence based on RD registries, available and needed resources and an interdisciplinary participative action approach with the appropriate government and financial support with periodic evaluation. Case management has an important role. The recognition of Clinical Genetics as health specialty is also urgent in Spain to provide equal access to RD patients and families all over the country.  [3]. These policies have served us well, but it is essential that the policies guiding us towards the future we wish to see are equipped to address the needs of the future RD population. The Rare 2030 project [4] is working towards precisely this goal, and has identified over a hundred future-facing trends likely to impact on the field. Some of these trends concern demographic changes about which we can be reasonably certain: whilst overwhelmingly positive, changes such as ageing RD populations will bring new challenges in managing comorbidities. They will also create new opportunities as well as risks in areas such as reproductive choice; however, these choices incur major ethical, legal and social concerns, and it is unclear how many countries really have robust frameworks in place to cope with this. Besides the fairly certain demographic changes, there are many topics -and many needs-for which the future is not clear. Will there be easier access to expert multidisciplinary teams? What will be the role of technology in care delivery? These fundamental issues are here debated in interview format [5]. Adrenoleukodystrophy, or ALD, is a complex x-linked genetic brain disorder which mainly affects males between the ages of four and 60 -males who are previously perfectly healthy and 'normal' . ALD damages the myelin in the brain and spinal cord, and those with cerebral symptoms become completely dependent on their loved ones or carers. This usually involves patients becoming wheelchair or bed bound, blind, unable to speak or communicate and tube fed. It is a difficult disorder to diagnose with behaviour problems usually the primary indicator.

S11
In males, cerebral ALD is a terminal illness with most dying within one to 10 years of symptoms developing. If diagnosed before symptoms become apparent, usually through identification of a family member, the condition can be successfully treated through bone marrow transplant. Some adults (males and females) develop a related condition called adrenomyeloneuropathy, or AMN. Symptoms include difficulty walking, bladder and bowel incontinence and sexual dysfunction. Tragically, around one third of males with AMN go on to develop cerebral ALD. Initial behavioural symptoms often have an impact on the individual's professional and personal lives -their capacity to work, maintain relationships and family ties -over time, they can become isolated and socially unacceptable. Commonly, those individuals without supportive family structures are missed or misdiagnosed. The presentation presents a personal case study detailing the impact of an ALD diagnosis on the whole family, moving on to Alex TLC's experience in applying to add ALD to the UK's New Born Screening Programme. The conclusion includes next steps following an initial negative response, and thoughts on the methods used to assess decisions on the prevention and treatment of rare disease. The Rare2030 foresight study gathers the input of a large group key opinion leaders through an iterative process to propose recommendations for a new policy framework for people living with rare diseases (RD) in Europe.

S13
Since the adoption of the Council Recommendation on European Action in the field of RD in 2009, the European Union has fostered tremendous progress in improving the lives of people living with RD. Rare2030 will recommendations for the next ten years and beyond. The Rare2030 Foresight Study includes 4 major stages (Fig. 1). The European Conference on Rare Diseases and Orphan Products (ECRD 2020) marked the occasion to present four proposed future scenarios (Fig. 2 The market-led approach first creates the technology innovation, then seeks out its market.

TYPE OF
Deep understanding of needs as the starting point of the innovation process. with symptoms and being suspected of having a rare disease can be the longest in many steps to getting a diagnosis. This is something we have the power to change now by providing content tailored to medics, early in their careers that will equip them to #daretothinkrare. To prepare for delivery of gene therapies, companies typically focus on four key areas: patient identification & diagnostics; treatment centre qualification; manufacturing & supply and market access. Timely diagnosis of patients is important as with progressive disorders, the earlier patients are treated, typically the better their long-term clinical outcomes will be. Targeted tools and resources are used to educate clinical specialists on the early symptoms of the disease. Improving access to the appropriate diagnostic tests is essential. If newborn screening is considered, validated assays and pilot studies are required. Gene therapies have to be administered in qualified treatment centres. After regulatory approval, treatment centres are relatively few so patients may need to cross borders and work is required to expand the recognition of patient rights to be treated in another EU country (e.g. through the S2 mechanism). Many companies partner with contract manufacturing organisations and are developing ways to preserve gene-corrected stem cells to enable their transportation from the manufacturing site to treatment centres. The final area is market access, whereby it is vital to evolve the way healthcare systems think about delivery, funding and value determination. Manufacturers have the responsibility to generate health economic evidence. Recent research [1] in metachromatic leukodystrophy showed that caregivers (n = 17) spend an average of 17 hours a day caring for their child. 83% of parents were forced to miss work with 68% of this being unpaid leave. In addition, it is recommended to have the optionality of payment models that allow the sharing of risk between the healthcare system and manufacturer (e.g. annuity or outcomes-based payments). Orchard has developed a holistic value framework as gene therapies are expected to benefit patients, families, communities, healthcare systems and society Reference Background: Employment has always been one of the fundamental human rights. It is important for people with rare diseases, because it helps to stay connected to the community and to continue professional development. Equal access to job employment can help to overcome the consequences of the condition and to gain financial independence. On the other hand unemployment can increase the social exclusion.

Materials and methods:
In the last few years there is an improvement in the European policies about job employment. In spite of this, people with rare diseases still have to overcome discrimination in this field.
As a proof of this statement is the recent online survey, conducted by EURORDIS. According to it, 70% of the respondents admitted they had to reduce their professional activities after they were diagnosed with rare condition. This means that more than half of the people with rare diseases in Europe face employment challenges. The analysis of this survey was important input to the presentation of the EPF Youth Group project -WAYS. Results: This is the abbreviation of Work and Youth Strategy and it is a two year project, disseminated among young patients with chronic conditions. The main purpose was to increase the awareness about positive and negative practices for young patients on the labour market and to develop recommendations to employers and decision makers. That is why EPF Youth Group conducted an online survey and provided different deliverables like factsheet with recommendations to employers and video about young patients' rights on the work place.

Conclusion:
The results of both survey provided important insight about the challenges people with rare diseases face in job employment. It proved the fact that only if we work together as a community of patients, we will be able to provide better opportunities for national and international inclusion.

S17 Reshaping Patient Access with Decentralized Registries
Paul Rieger 1 , Eberhard Scheuer 2 1 Centiva Health AG, Zug, Switzerland Correspondence: Paul Rieger -paul@centiva.health Orphanet Journal of Rare Diseases 2020, 15(Suppl 1):S17 The lack of access to research participants is the number one reason why medical studies fail [1]. Real-world data is often difficult to get despite USD 70 billion costs of patient data intermediation. Therefore, a new model for patient access is necessary where patients get paid fairly for their data, retain control over their data, and drive citizencentered research. On the other hand, researchers and industry must be enabled to access patients directly without violating their privacy, while reducing time and costs of data access at the same time. Current patient registries facilitate patient access and match patients with a centralized data flow while giving little to no incentives. Whereas, a decentralized patient registry allows for direct and confidential matchmaking between patients and organizations looking for data through the use of blockchain technology. It lets the patient decide with whom they want to share their data. On such a platform, patients can receive incentives in the form of digital currency. Currently, Centiva Health [2] is used in the context of rare diseases and population health, i.e., outbreak monitoring. In the area of rare diseases Centiva Health cooperates with patient advocacy groups by enhancing existing registries with the ability to collect real-world data. The access to patient via a decentralized registry leads to aligned incentives, real-time access to data, improved disease visibility while preserving patient privacy. Orphanet J Rare Dis 2020, 15(Suppl 1):310 the United Kingdom and in the Czech Republic, to co-design optimal methods/services for the communication of genomic results. Methods and results: Using a methodology called Experience-Based Co-Design (EBCD) 1 , we supported families and health professionals to shared and discuss their experiences, identify priories for improvement and then work together to prototype and test out interventions to address these. The process involved observations of clinical appointments (), interviews with families () and health professionals and a series of workshops and remote consultations at both sites. Results: Five shared priorities for improvement were identified by participants at the two sites, and eight quality improvement interventions were prototyped/tested to address these ( Table 1). Discussion: the findings clearly indicate the need for improved follow-up care to support families in the short, medium term after the sharing of the results, including when a diagnosis is confirmed. Different service models were prototyped, including follow up consultations with clinical geneticists and a dedicated role to facilitate co-ordinated care. The findings also demonstrate the need for continued workforce development on the psychosocial aspects of genomic and genetic communication, specifically on families' needs regarding genomic consent and the experience of guilt and (self-) blame. to use technology has been used in the home to provide objective seizure data prior to upcoming clinic appointments. The COVID-19 pandemic has prompted an acceleration in telemedicine and epihunter has improved the effectiveness of virtual consultations bringing opportunities for both diagnostics and informed changes in treatment.

Conclusions:
Epihunter is an example of technology repurposing to create a new normal for people with hidden disabilities such as those living with absence epilepsy. The rare disease patient community tried to get this well detailed plan to be transferred to regulation which usually means an adequate financial substitution of those expert services. The patients should benefit from a centralized expert treatment/care pathway. Esophageal atresia (EA) is a rare congenital condition with an estimated prevalence of 1 to 2 in 5,000 live births. Esophageal atresia patients require life-long attention. ERNICA has developed a 'patient journey' for EA patients, under the leadership of patient representatives from the international federation of EA support groups (EAT).

Fig. 1 Example of patient journey stage depicted pictorially
In Germany, patients with congenital malformations which need surgery in early life are treated in hospitals with (very) low experience. How can we as patient representatives get the fruits of the ERNs into the national health system? We don't have public money. We have no official contract and no political support. KEKS e.V., the German EA support group together with other support groups (e.g. SoMA e.V.), and with surgical expert teams across Germany, some of them members in ERNs, started to organize monthly virtual boards for those patients.
A self-commitment on ethical and medical standards following the ERN-criteria, and a collaborative attitude within the group, help us to get step by step the first ERNICA results to the bedside of EA patients.

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