How does basic scientific knowledge become medical progress? What is necessary for patients to benefit quickly from research results?
The Eva Luise and Horst Köhler Foundation for People with Rare Diseases invited guests to the 6th Rare Disease Symposium in Berlin on June 13 and 14, 2022 to discuss these and other questions relating to translational medicine. About 100 guests, who are engaged with rare diseases out of professional interest or personal concern, accepted the invitation. It was clearly noticeable how important and beneficial the personal get-together and direct exchange was after a year of pandemic-related break. 6. Rare Disease Symposium nach Berlin eingeladen. Rund 100 Gäste, die sich aus beruflichem Interesse oder aus persönlicher Betroffenheit mit Seltenen Erkrankungen befassen, waren der Einladung gefolgt. Deutlich war zu spüren, wie wichtig und wohltuend das persönliche Zusammenkommen und der direkte Austausch nach einem Jahr pandemiebedingter Pause war.
In her opening address entitled "15 years of joint action", Eva Luise Köhler revisited the developments in the field of rare diseases. She named important milestones such as the founding of NAMSE, the german National Action Alliance for People with Rare Diseases in 2010, or the establishment of now 37 centers for rare diseases in Germany and their certification. But she also called for further efforts: A variety of innovative projects and initiatives such as genomDE, the medical informatics initiative CORD-MI, the EU research project Screen4Rare or NARSE, the National Registry for Rare Diseases, must now be bundled, the forces and ideas combined and implemented as a joint movement in such a way that they bring the greatest benefit to patients. At the end of her speech Eva Luise Köhler quoted the German poet Friedrich Schiller "United, even the weak become powerful" and appealed to the audience to work together to fill these words with life and create solidarity "for the few who are so many”.
The subsequent series of lectures was started by Prof. Dr. Christopher Baum, Chairman of the Board of Directors of the Berlin Institute of Health (BIH). Under the title "Translation: A magic word of the future or already reality?" he positioned the term translation as a connecting element in the triad of healing, teaching and research. Using the Charité strategy 2030 as an example, Prof. Baum explained how the goal of a relevant medical benefit for patients and citizens is taken into account throughout the entire care and treatment process with through a cross-organ and systemic understanding of health and disease. Developments such as the digital revolution, new technologies and innovative approaches in diagnostics and therapy development at the cellular level open up fundamentally new opportunities to successfully meet the challenges posed by the high complexity of the translational value chain.
Prof. Dr. Toni Cathomen, Director of the Center for Chronic Immunodeficiency
and the Institute for Transfusion Medicine and Gene Therapy at the University Hospital Freiburg, gave an overview of the rapid development and current status of gene therapy in his lecture entitled "Gene Editing - Superpower of Translation?”. He presented various therapeutic approaches and outlined their potential applications using the Crispr Cas technology as an example. Prof. Cathomen linked the outlook on the expected strong growth of the field of gene therapy products within the next years with a critical view on the situation in Germany, where a strong research landscape is too often slowed down by bureaucratic hurdles and fragmented structures.
At the subsequent roundtable, moderated by ZEIT journalist Martin Spiewak , Prof. Dr. Christopher Baum, Prof. Dr. Toni Cathomen, Prof. Dr. Annette Grüters-Kieslich, Chairwoman of the Eva Luise and Horst Köhler Foundation, and Prof. Dr. Eva Winkler from the National Center for Tumor Diseases in Heidelberg, discussed how translation can be better performed despite condensed work processes, economic orientation of the health care system and IT standards and structures that are still being developed. While the status of translation in Germany was assessed differently, there was agreement that close cooperation between research and care is indispensable for successful translation. Prof. Grüters called for overcoming silo thinking in university medicine. In Germany, she said, university medicine is the only place with structures that simultaneously enable knowledge-based and patient-oriented research and meaningfully combine this with basic research and the clinical development of innovative therapies. Prof. Baum pointed out the need for early identification of suitable partners, such as the German Centers for Health Research (DZG), the National Center for Tumor Diseases (NCT) and the Berlin Institute of Health (BIH) and including (inter)national networks. Scientific, technical and regulatory dimensions would always have to be taken together into account. All agreed that, in addition to the provision of sufficient financial resources, the early involvement of patients and their representatives is crucial for the success of translation.
The first lecture in the afternoon series was held by Dr. Ruth Biller, Chair of ARVC (Arrhythmogenic Right Ventricular Cardiomyopathy) patient advocacy group. She emphasized the great importance of networks for representing the interests of patients with rare diseases and their families. Following the tragic death of her undiagnosed young daughter which would have been preventable she wanted to make a difference for other children affected by ARVC. Drawing on her personal experience in patient advocacy in the field of rare heart disease, she highlighted also the importance of the 24 European Reference Networks (ERNs), which have been working since 2017 with the goal of "Share - Care - Cure" for various rare diseases. Dr. Biller explained the important role of the rare heart disease network ERN GUARD-Heart and the European umbrella organization EURORDIS in networking patients and physicians, as well as the support of the European Patient Advocacy Groups, which organize much-needed participation of patient representatives in the development of guidelines, registries, and research projects. With regard to an improvement of the situation in Germany, Dr. Biller pleaded for more digitalization in the health care system, the creation of national or at least a participation in international registries, the expansion of genetic examinations and autopsies and screening programs as well as for an adequate funding of the centers for rare diseases.
Prof. Dr. Stephan Ehl, Director of the Institute for Immunodeficiency at the Center for Chronic Immunodeficiency (CCI) of the University Hospital Freiburg, then demonstrated the importance of (inter)national consortia using the example of immunodeficiencies. Looking back on various stages of his professional life, he explained from the perspective of a pediatrician and immunologist which aspects are crucial for the successful treatment of "medical hummingbirds": In addition to interdisciplinarity, he said, these include in particular close collaboration between research and the clinic, as well as the creation of translational structures, in that the therapeutic area is already being considered as part of the research. As an example of successful collaboration, he cited the Integrated Research and Treatment Centers (IFB) project funded by the German Federal Ministry of Education and Research between 2008 and 2018. Regarding future programs, Prof. Dr. Ehl advocated longer funding periods, as sustainable and trustful networking takes time.
Dr. Alexander Lehmann, who is responsible for the funding lines for research group of the Else Kröner-Fresenius Foundation (EKFS), which are primarily committed to promoting medical science, gave an overview of the foundation's funding approaches. As a bridge between research and clinical practice, the EKFS currently supports 28 research colleges of clinician scientists, including two joint colleges in the field of rare diseases together with the Eva Luise and Horst Köhler Foundation. Dr. Lehmann emphasized the key role of clinician and medical scientists in maintaining the innovative strength of university medicine. Through cross-site and cross-disciplinary networking, an exchange of methods and experience, and joint publications, the programs make a concrete contribution to improving applied and patient-oriented medical research.
At the end of the first day Markus Algermissen, Head of Subdivision 31 Medical and Professional Law at the Federal Ministry of Health, Prof. Dr. Reinhard Berner, Director of the Clinic for Pediatrics and Adolescent Medicine at the University Hospital Dresden, Prof. Dr. Corinna Grasemann, , Head of the Center for Rare Diseases Ruhr and Chairwoman of NAMSE Netz e.V., and Dr. Alexander Lehmann rom the Else Kröner Fresenius Foundation exchanged views on research networking in practice moderated by journalist Martin Spiewak “ZEIT”. In the discussion it became clear that in the field of rare diseases there is an essential need for cooperation between "top down" approaches such as the register law laid down in the coalition agreement and "bottom up" movements such as NAMSE Netz e.V., which as an non-governmental association promotes the establishment, further development and networking of the german centers for rare diseases and has initiated the process of their certification. Networking plays an essential role - not only of institutions and individuals, but also in sharing data within the healthcare system. For example, the registry report commissioned by the Federal Ministry of Health (BMG), which was presented in December 2021, has already led to better networking among the many registry operators in the field of rare diseases, as Markus Algermissen explained. Well-staffed centers for rare diseases, long-term perspectives for motivated physicians who want to get involved in clinical practice and research, as well as strong alliances such as TRANSLATE-NAMSE and the ALLIANCE4RARE have successfully exemplified, in the opinion of the panel, indispensable models of the future for successful translation in the field of rare diseases.
At the start of the second day of the symposium, Prof. Dr. Peter Krawitzscientific director and chairman of the Institute for Genomic Statistics and Bioinformatics (IGSB) of the University Hospital in Bonn, gave an overview of new possibilities in diagnostics through exome and genome analysis as well as computer-assisted phenotyping through Face2Gene and GestaltMatcher. In addition, he explained the results of the innovation fund project TRANSLATE-NAMSE, in which the University Hospital Bonn was involved as a partner, on behalf of Prof. Dr. Heiko Krude. In the three-year joint project of nine centers for rare diseases and four university based institutes of human genetics in cooperation with two consortium health insurance companies (AOK Nordost and Barmer Ersatzkasse) and the patient advocacy group Alliance of Chronic Rare Diseases (ACHSE) e.V., central proposals for measures from the National Action Plan were implemented nationwide and successfully tested with regard to adoption into standard care. In the project TRANSLATE-NAMSE, thanks to expert panels and the possibility and funding of exome sequencing a diagnosis could be made in a good third of cases after a preceeding odyssey in the german healthcare and 28 complete new disease entities were described. According to Prof. Krawitz, the future will lie in the field of genome sequencing and multi-omics methods and genome based medicine.
Gabriele Müller from the Center for Evidence-Based Health Care (ZEGV) at the TU Dresden, which was responsible for the evaluation of TRANSLATE-NAMSE together with the Berlin School of Public Health (BSPH), then presented project results from the perspective of patients and health services research. She showed, that within the framework of the project a confirmed diagnosis could be made in about 30% of the 5600 participating patients, whereby the spectrum of diagnoses was very broad and about a quarter of these diagnoses were made only once. A significant result was, that the project was able to significantly accelerate the diagnosis through interdisciplinary, cross-site case conferences, the use of pilots and innovative (genetic) diagnostics: On average, this amounted to about half a year in the project, whereas children had previously been without a diagnosis for four years, and adults for more than eight years. The fact, that more than 80% of the patients surveyed associate a diagnosis with the hope of a therapy, underlines the importance of structured care. The recent recommendation by the Innovation Committee of the Federal Joint Committee (G-BA) to transfer the structures and processes tested in the TRANSLATE NAMSE project to standard care is a major step in improving the care for people with rare diseases.
With the title "Registries: Bottom Up Solutions for People with Rare Diseases", Prof. Dr. Holger Storf, Head of the Institute for Medical Informatics at the University Hospital Frankfurt, and his colleague Dr. Alexandra Berger from the Center for Rare Diseases then gave an overview of the status of registry projects in the field of rare diseases and showed how the process of creating registries from planning to set-up can be facilitated and optimized by IT support. For example, the Open Source Registry System for Rare Diseases (OSSE) offers generic software for the creation of patient registries with high data quality standards tailored to the special needs of rare diseases. Specifically, Dr. Berger used the example of registries for patients with an unclear diagnosis or without a diagnosis to show where the opportunities and challenges of registries in the field of rare diseases lie. Based on the findings of a retrospective registry set up at the Frankfurt ZSE, a prospective registry is to be set up with the aim of networking, improved health care research and enabling pattern analyses. All centers are cordially invited to participate, because also for registries applies: Together you can achieve more!
Prof. Dr. Stefanie Weber rom the Federal Institute for Drugs and Medical Devices (BfArM) focused on the aspect of data quality in research. In order to bring rare diseases into the focus of epidemiology, the most specific and unambiguous coding possible is necessary, which, however, is not provided by the ICD-10-GM. Dr. Weber explained the introduction of the Alpha-ID-SE (Rare Diseases), with which a simplified uniform and standardized coding of rare diseases according to the ICD-10-GM on the one hand and the Orpha identification number on the other hand will be implemented in the inpatient sector from 2023. She showed how, on the basis of Orpha coding, information on specific clinical pictures and, building on this, the quality of research and care can be improved. In the subsequent discussion, there was agreement, that the extension of Alpha-ID-SE coding to the outpatient sector, where a large proportion of treatments take place, is essential and urgently needed, because the patients with rare diseases are predominantly in ambulatory care.
Michael Byczkowski, Global Vice President and Head of Healthcare Industry at SAP, then gave an overview of key technology trends in healthcare from the perspective of the IT industry and highlighted the opportunities and challenges of linking data to information. He showed examples of possible uses for software solutions across the entire treatment path and outlined approaches to further automate processes, enable data-driven decisions and support healthcare employees. Based on the quote by the British mathematician Clice Humby that “data is the new oil”, he emphasized that even with data, good processing is a necessary prerequisite for meaningful use. In the discussion that followed, it became clear that, from the perspective of university hospitals, there is still more need for collaboration with the IT industry.
The discussions and lectures were followed by moving and evocative images: In a film project by the Eva Luise and Horst Köhler Foundation, realized by Grimme Prize winner Britta Wauer, 15 people involved in the field of rare diseases give very personal insights into what the "medicine of tomorrow" means for them specifically and for "the rare " in general. Four of them were then available for an in-depth exchange in the discussion round moderated by Sanna Börgel, office manager of the Eva Luise and Horst Köhler Foundation for People with Rare Diseases: Prof. Dr. Jutta Gärtner, Professor of Pediatrics at the University Hospital Göttingen, Dr. Julien Park from the University Hospital Münster as well as Yvonne Möller and Jens Kiefer, parents of children with rare diseases, described personal experiences from the perspective of doctors and patients. They reported on diagnosis, dealing with feelings such as ignorance and helplessness, but also hope and joy. It became clear: It helps research, when patients and families build networks with researchers and thus advance knowledge about diseases. Because together, hand in hand, every path is easier to follow.
The series block of lectures focused on the transfer of research results into therapy. Prof. Dr. Ger van Zandbergen, Head of the Department of Immunology at the Paul Ehrlich Institute, showed that biologica also represent a therapeutic approach with steadily increasing relevance in the field of rare diseases. The number of approved monoclonal antibodies successfully used in immunotherapy has increased rapidly from 20 in 2010 to 118 to date. Therapeutic approaches are thus available for many indications that were previously without treatment options. Monoclonal antibodies are also available for treatment in COVID-19. Increasingly, multi-specific antibodies are also being developed that can simultaneously bind to multiple targets in the body involved in a disease. The hope is, that this will lead to improved therapeutic success for patients. While Prof. Zandbergen showed that randomized, multicenter, double-blind and placebo-controlled studies can also be conducted in the field of rare diseases, it became very clear in the subsequent discussion, that this cannot and should not apply to all studies especially in patients with ultrarare diseases.
In the final presentation of this year's symposium, Aylin Tüzel, Country CEO of Pfizer Pharma GmbH, spoke on the topic of "Lessons from the covid 19 pandemic". Using the example of the rapid and successful vaccine development in collaboration with Biontech, she explained the need for an open and cooperative approach in order to be able to implement effective therapies as quickly as possible through joint action. Experience from the pandemic, she said, shows that "if we pool our strengths and resources, we can achieve extraordinary things." To achieve this, however, the framework conditions for research in Germany must be improved, planning and approval procedures must be further accelerated and facilitated, and cooperation between public and private research must be driven forward. Finally, Aylin Tüzel focused on the area of prevention. Easily accessible prevention services are crucial to making the healthcare system fit for the future and creating scope for important and necessary research in areas such as rare diseases.
At the end of the event, Frau Prof. Grüters Dr. Frank Wissing , secretary general of the German Medical Faculty Association, Dr. Matthias Wilkenfrom the German Pharmaceutical Industry Association, Prof. Dr. Hildegard Büning f rom the Hannover Medical School and Jean Luc Delay, General Manager of Takeda, to the stage for an exchange on the topic of "Academia and Industry - New Ways of Cooperation". There was agreement that rare diseases offer no room for competition and working in silos, but require comprehensive networking and cooperation between all players. In order to intensify this cooperation, research, industry and politics must be brought together regularly, for example in the context of think tanks and symposia such as this one. It was emphasized that successful collaboration needs both space and time. Researchers should not think only in terms of publications, industry not only in terms of patents. Rather, the two worlds need to be linked at an early stage so that research can actually become health.