EATRIS Centre Norway: a Norwegian node for the European Advanced Translational Research Infrastructure in Medicine Host institution: Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo on behalf of a national consortium Project contacts: Kjetil Taskén, MD, PhD, Director Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, and The Biotechnology Centre of Oslo, University of Oslo. Torunn Berge, PhD, Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo. Category 

Advanced scientific equipment/facilities (2-200 mill NOK)

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Scientific databases and collections (2-200 mill NOK)

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e-Infrastructure (2-200 mill NOK)

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Participation in international research infrastructure (e.g. ESFRI)

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Large-scale research facilities (> 200 mill NOK)

1. Relevance Relevance in relation to call for proposals and in relation to societal challenges EATRIS, the European Advanced Translational Research Infrastructure in Medicine, is an international research infrastructure initiative aimed at strengthening health R&D in Europe to allow more efficient transfers of research discoveries into new clinical applications for disease prevention, diagnosis and treatment. The infrastructure will operate to increase the return on investments made in publicly funded biomedical research by reducing, removing or bypassing existing bottlenecks to translation. Building on a vibrant and well-resourced basic science base closely associated with clinical research units, EATRIS will be bringing new discoveries closer and faster to the clinic - ‘bench-to-bedside’ - and to society in general. EATRIS was initiated by the European Strategy Forum on Research Infrastructures (ESFRI), a forum consisting of representatives from the EU and associated states and the European Commission. The challenge of ESFRI was to identify and address the needs for large research infrastructures in Europe for the next 10-20 years covering all scientific areas. In October 2006, ESFRI published its first "European Roadmap for Research Infrastructures" including EATRIS as one of six prioritised life science infrastructures. Benefitting from €4.2 million of EU funding under FP7, EATRIS finished a three-year Preparatory Phase in 2010. This backing enabled the project partners, including Norway, to formulate strategic objectives and establish a governance and operational structure. The invitation now goes out to all European partners for commitment to the Construction & Implementation Phase (ending 2015) to build national EATRIS centres, supplemented by funds from Governmental stakeholders. EATRIS Centre Norway secured a 2-year participation in this interim period after receiving an overall score of 7 (Excellent) in the scientific evaluation of the National Financing Initiative for Research Infrastructures, the Research Council of Norway, in 2011. As a participant in EATRIS, Norwegian research groups will join an infrastructure with a vision in direct compliance with the strategic goals set by the Norwegian Government in the White Paper “Climate for Research”, working for “better health, levelling social differences in health, and developing high-quality health services” as well as for creating a “knowledge based industry in all regions”1. The Norwegian EATRIS node will play to its strengths by offering services based on scientific excellence, recruiting partners already producing acknowledged high-quality research on national and international arenas. Participation in EATRIS will provide an important 1

Quoted from Report no. 30 to the Norwegian Storting, the Ministry of Education and Research

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international anchoring of biomedical science and innovation to strengthen Norway’s strategic and competitive positioning in academia and the medical and biotech industry sector. With an aging population and modern lifestyle challenges, rising numbers of expensive-totreat chronic conditions and disabilities will result in an increasing strain on health-care systems. Combined with the demands of technological advances, health care costs in Norway and throughout the world will continue to rise and have a widespread impact on health care spending, design of national systems and delivery of care services. The current health care challenges will demand cost-effective, innovative solutions such as development of new drugs, vaccines and other means of preventing or reducing the incidence and severity of serious conditions (e.g. cancers and heart disease) and chronic illnesses (e.g. diabetes). Responding to these challenges, EATRIS will provide a favourable climate for translational research by creating a network of academic research centres, clinical units and industry to make the most of biomedical science in a joint effort to foster innovation for the benefit of public health. The recent recession and increasing economic pressures on resources imply that collaborative working is now more relevant than ever. EATRIS will allow scientists to focus their research capabilities more efficiently, a strategy that will be beneficial to academic research groups and also to biotech businesses during a vital economic recovery phase.

2. Vision and scientific goals Vision; long and short-term scientific goals The vision of EATRIS is to establish a globally competitive infrastructure for translational research, providing biomedical researchers across Europe with wide access to state-of-the-art facilities, training and supporting services for product development in prevention, diagnosis and therapy (Fig. 1). Simply put, EATRIS will catalyze and increase the number of discoveries in Europe that are translated into successfully approved clinical applications across a wide range of diseases, thus boosting industry product innovation with the long-term goal of improving population health.

Figure 1 Overview of translational R&D steps covered by EATRIS. A project may enter the infrastructure at any point after ‘Proofof-Principle’ has been achieved and stay within EATRIS until clinical Phase I has been completed.

EATRIS’ goals are:  Facilitate and enhance synergy between basic research groups, clinical units and industry. Improving alignment between these groups through better communication and interaction will accelerate the move from bench-to-bedside and improve the equally important process of reverse translation, the transfer of feedback from the clinic to bench scientists.  Provide coordination between scientists, core facilities, platform technologies and infrastructure stakeholders in a transparent scientific environment. Coordinated actions and a professional project management integrated with access to regulatory expertise, promotion of best practises and establishment of standardised protocols for translational projects are vital to a successful translational infrastructure and efficient product development.  Establish and develop training concepts specifically tailored for the particular demands of translational research. A new generation of translational scientists is needed to build capacity and competence to carry new therapeutic, preventive and diagnostic concepts 2

forward to society. This will improve the European research culture for interdisciplinary translational medicine. Expected impact on Norwegian science, technology and innovation Norway has biomedical research groups producing world-class results in major areas such as cancer biology and neuroscience, and efforts have already been made to improve the innovative potential of Norwegian biomedical research through cluster organisations such as Oslo Cancer Cluster and Nansen Neuroscience Network. The success of these efforts is highly dependent on access to drug development expertise, advanced imaging technologies, suitable libraries, animal models etc. In this context, EATRIS will make a real difference by offering access to its state-ofthe-art facilities as well as to product development and regulatory expertise to biomedical researchers in Norway. Furthermore, participation in EATRIS will position Norway strategically in the rapidly evolving field of translational research, giving Norwegian scientists an opportunity to influence the development of ethical guidelines, best practises and new standards. In fact, this potential of the infrastructure has already been realised as the EATRIS product group for advanced therapy medicinal products (ATMPs) has been accepted as an ‘interested party’ by the European Medicines Agency Committee for Advanced Therapies (EMA-CAT). ATMPs, gene and stem cell therapies included, are a complex group of products holding great promise for tomorrow’s medical applications, and involvement at an early stage, laying the foundations for future developmental processes in a potentially difficult ethical field, is of particular importance. In Norway and throughout Europe, EATRIS is expected to make an impact on knowledge concentration and capacity building in translational research with regard to both human resources and technical facilities, and thorugh EATRIS, Norwegian scientists will get access to technologies currently not available in Norway. Improving translational competence through training of professional research staff, from PhD students to research nurses, is central to EATRIS, and the infrastructure will cover areas where Norway clearly has needs but not the capacity to develop national training courses. Similarly, EATRIS will promote mobility of researchers, providing a means to attract and retain highly-qualified specialists to research positions in Norway. This is central to competence and capacity building in emerging national research initiatives, such as the development of PET imaging and PET tracers. A successful EATRIS, perceived as a good infrastructure with capacity and initiative and a flexible, professional approach to product development, will have a great potential for attracting more investment and generating greater economic activity. Using EATRIS to increase the innovative potential of Norwegian research as well as shifting the balance from discovery towards end product will also result in enhanced commercial and industrial competence, creating a foundation for spin-off companies and strengthening a commercial Norwegian biomedical network. Biotechnology and health-related research industries have been projected as substitute candidates to oil for the Norwegian economy, as limited supply will force a shift away from a natural resource-based economy. To keep this option open and strengthen it in a long-term perspective, participation in international collaborations and infrastructures such as EATRIS is important strategically to Norwegian research, higher education and biomedical innovation and will provide a solid national base as well as an international network for further development in this area. (See also 5. Impact on science, technology and innovation.)

3. Scientific and technological status Status of current research, main scientific challenges, national and international ‘state-of-theart’, scientific environment, level of existing infrastructure Recent years have seen an increasing number of translational research studies requiring multidisciplinary teams and facilities not widely available to most biomedical scientists. The limitations are often financially based; no single institution have the necessary funds to bring together the required technologies and qualified staff to afford these initiatives. Thus, development 3

of efficient infrastructures offering shared resources is key to providing the required tools for translational research to the scientific community and considered a major goal for institutions involved in translational research programs. The need has been recognised worldwide — in 2006 the NIH launched its Clinical and Translational Science Awards (CTSA) consortium, linking together about 60 institutions to streamline clinical and translational science and training environments2. The initiative culminated in establishment of the new entity NCATS — the National Center for Advancing Translational Sciences3. Similar national efforts have been made in Europe, albeit on a smaller scale, with the Medical Research Council (MRC) awarding over £16 million in 2006-2008 to translational research in 14 universities across the UK to strengthen infrastructure resources. Despite discrepancies in biomedical research budgets, however, when comparing the US to the EU, the output in publications and citations of European scientists is more than competitive. In the pharmaceutical industry sector, European R&D investments show less growth than those of the USA and Japan, and the USA has also overtaken Europe in product output ratio, bringing more new chemical entities to the market4. The need to bring back investments and improve the competitive position of Europe in the biomedical arena is critical and has been recognised by the European Commission by the inclusion of EATRIS on the European Roadmap. Thus, it is now timely to develop and establish a translational research infrastructure available to European scientists, speeding the process of translation across Europe. Successful translation, however, is not only dependent on funding the physical build-up of an infrastructure but also on overcoming several bottlenecks currently blocking European translational research. Following a needs analysis of existing research resources available to EATRIS, the major gaps needed to be bridged for improving the current situation have been identified as follows:  Throughout Europe, there is a general lack of comprehensive translational project management necessary to professionalise the process of taking discoveries to medicinal products. To remedy this, EATRIS wants to implement a defined management structure to systematically aid scientific project supervision as well as administrative and financial tasks and provide access to expertise on regulatory and legal issues. The project management will also deal with issues related to quality management and technology transfer, liaising with technology transfer offices.  Presently, there is not adequate access to human resources and expertise relevant for development of preventives, therapeutics and diagnostics. EATRIS aims to build capacity by focussing on early recruitment, rotation training and creating attractive career perspectives. In addition, it is a particular aim to develop training programmes for translational research staff as well as to create a pool of PhD students and post docs performing research in multi-disciplinary teams in collaboration with universities, hospitals and industry.  Translational research is naturally dependent on multidisciplinary and cross-organisational collaborations, and EATRIS will also develop communication resources and infrastructure related to data capture, storing, annotation and analysis, both of pre-clinical and clinical data, for this purpose to ensure that information is rapidly made available to all stakeholders.  Target-based drug discovery focuses on developing drugs that only affect one gene or molecular mechanism, the target, to selectively treat a condition with minimal side effects. Target validation, the process of evaluating the therapeutic value of the target in a patient population, is central to the early product development phases; however, European scientists are lacking access to state-of-the-art expertise and infrastructure to carry out the necessary in vitro and in vivo validation of product candidates during pre-clinical development. EATRIS wishes to establish, maintain and standardise pre-clinical validation facilities (protocols, research tools and data sharing) and re-validate projects that enters the infrastructure using relevant disease models. 2 3

Clinical &Translational Science Awards: https://www.ctsacentral.org/ National Center for Advancing Translational Sciences http://www.ncats.nih.gov/

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

When moving a new pharmaceutical product forward to clinical trials, there is a requirement for consistent production of the compound complying with quality standards appropriate for the intended use. In academia, the need for GMP production is largely unmet, and EATRIS aims at providing R&D support by providing GMP expertise and performing or managing the outsourcing to commercially available or publicly funded GMP production facilities.  Lack of access to early clinical trial facilities and expertise on how to carry out such studies often lead to insufficient predictability in humans. EATRIS will include clinical trial centres as part of the infrastructure to cover phase I and early phase II trials. Close interaction with clinical staff (vaccinologists, immunologists, biologists, pharmaceutical biotechnologists, epidemiologists, imaging experts and bio-statisticians) at an early stage will be encouraged to detect and overcome potential bottlenecks and define the right study concept. EATRIS will also handle the quality assurance activities during study realisation and data analysis, including implementation and development of standardised IT tools for archiving and reporting adverse events.  Access to a comprehensive pre-clinical and clinical imaging centre to enable multimodality imaging (e.g. CT, MRI, US, SPECT, PET, optical and/or hybrid) in various animal models or in patient cohorts when needed is central to development of medicinal products, tracers and biomarkers. Building capacity and competence is essential to meet the demands of an increasing number of translational research studies, and EATRIS will develop programmes and set up collaborations to train tomorrow’s translational multimodality imaging experts. Building and maintaining data analysis centres with up-to-date infrastructure is an integrated part of this effort. By removing the existing gaps, EATRIS will overcome fragmentation along the translational pathway and foster knowledge exchange and alignment between the various research units. The infrastructure also aims at encouraging exchange between public and private institutions as a way of shortening the process from scientific discovery to marketable product.

4. Description of the Research Infrastructure Scientific, technological and physical description of the new development, national character, user modes EATRIS aims to build a translational research infrastructure by establishing a core structure of “translational centres” across Europe, containing all necessary technologies to develop new medicinal applications. Each EATRIS Centre will consist of one or more institutions excelling in translational research, providing specialised services according to their core expertise in the relevant technologies and/or in disease areas such as cancer, infection, cardiovascular, metabolic and neurological disorders. Specifically, a Norwegian EATRIS Centre will consist of a network of translational research clusters located at sites in Oslo, Bergen, Trondheim and Tromsø, thus bringing strong national innovative efforts together complemented by large-scale advanced technology platforms (Fig. 2). Building on existing excellent research and knowledge has been central to development of EATRIS to limit the need for new construction and investments and to avoid duplication of already wellfunctioning research environments. It is important to note that the national definitions of a “Centre” will differ depending on the existing level of infrastructure in each country. Figure 2 The network of Norwegian units making up EATRIS Centre Norway. Clinical Phase I units are found at every location, with contributions to product pipelines for small molecules, molecular imaging, vaccines and advanced therapeutic medicinal products (ATMPs) as indicated. 4

European Federation of Pharmaceutical Industries and Associations: http://www.efpia.org/

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Services provided by EATRIS will be organised into product pipelines, covering all R&D steps necessary to take research discoveries from ‘Proof-of-Principle’ to early clinical phase I/IIa. When fully operational, EATRIS plans to provide development pipelines for molecular diagnostics (biomarkers and tracers), small molecules, vaccines and advanced therapy medicinal products (ATMPs). Molecular imaging is a core technology area of EATRIS, and development and validation of imaging methods, image analysis and interpretation is a parallel activity to the molecular diagnostics pipeline. A pipeline for biologics - therapeutic molecules based on antibodies, recombinant/fusion proteins or small interfering RNAs - will not be developed by EATRIS at the early stage, but may be included following increasing demands and/or capacity changes in the field. In summary, EATRIS Translational Centres (Fig. 3) will offer access to stateof-the-art facilities and technologies combined with training and support services to maximise the output of both basic and clinical research. Figure 3 Schematic of an EATRIS Translational Centre showing the various building blocks necessary for creating a comprehensive R&D environment for translation of discoveries into clinical applications.

Providing comprehensive services over a specific product pipeline requires a highly integrated environment and the involvement of different research disciplines and resources, such as animal facilities, laboratories for medicinal chemistry, libraries and associated screening facilities, ‘omics’-platforms, pre-clinical and clinical imaging facilities, GMP facilities, as well as hospitals and early clinical trial units. The exact nature and composition of research units in each Centre is therefore dependent on the nature and number of pipelines offered and available technologies. The current proposal is focussed on bringing together existing Norwegian resources, creating product pipelines and providing expertise and access to specific technologies in a new distributed infrastructure. This will be professionally organised and managed in a transparent environment to take a comprehensive and systematic approach to translational science. The physical composition of the infrastructure has been defined after evaluation and discussion with a national Reference Group, appointed by each regional ‘Samarbeidsorgan’ – the steering groups for collaborations between University and the Regional Health Authority, endorsed by the National Collaborative Group for the Health Regions and Universities (Table 1). Table 1 Current members of the national Reference Group for EATRIS Name

Institution

Prof. Einar Bugge

University Hospital of North Norway

Prof. Anne Husebekk

University of Tromsø

Assoc. Prof. Henrik Hjorth-Hansen

St. Olav’s Hospital

Prof. Olav Haraldseth Prof. Bjørn Tore Gjertsen

Norwegian University of Science and Technology Haukeland University Hospital

Prof. James Lorens

University of Bergen

Prof. Erlend B. Smeland

Oslo University Hospital

Prof. Kjetil Taskén

University of Oslo

The EATRIS Centre Norway will integrate into a pan-European network of EATRIS centres in consortia as described below. Small molecules pipeline: Small molecules, the classical pharmaceutical drugs, are low molecular weight organic compounds capable of altering the functional effects of their targets such as 6

proteins or nucleic acids. In 2004-2006, almost 85% of all new pharmaceutical products approved globally were small molecules, covering most disease areas such as cancer, immunological disorders and infections. A typical development pathway may start with a known target accessible for modulation and the identification of a lead compound for this target. Subsequent optimisation of the lead compound is complex and rarely follows a linear path, influenced by continuous feedback from several intermediate assays as well as from the original screening and in silico modelling processes. Small molecule development also involves evaluation of the pre-clinical drugs by pharmacodynamics and -kinetics, leading to ‘early development candidates’ that eventually progress to clinical trials; Small molecules — European partners the final steps covered by EATRIS. An inventory of the national pipeline contributions is given in Table 2.  The Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany The EATRIS small molecules group will also interact with partners of other related infrastructure initiatives,  Helsingin Yliopisto, Helsinki, Finland such as EU-Openscreen, an ESFRI-initiated chemical  Palacky University, Olomouc, Czech Rebiology infrastructure included on the European public Roadmap 2010. Cross-interactions and synergies  Istituto di Ricerche Farmacologiche Mario between the clusters are expected to create a Negri (IRFMN), Milan, Italy favourable setting to promote and strengthen all research environments. In Norway, the small molecules pipeline will focus on developing drugs for cancer, cardiovascular, immunological and neurological disorders. Table 2 Inventory for the small molecules pipeline — EATRIS Centre Norway Institution

The Biotechnology Centre of Oslo, University of Oslo

Inventory        

 

Target validation and re-validation Hit discovery High-throughput screening Multilabel plate reader (AlphaScreen, Enhanced luminescence, FI, FP, TRF, abs.) Fluorometric imaging plate reader (FLIPR) GE Healthcare Biacore T100 BD FACSCanto II HTS flow cytometry Assay development, o liquid handling robot o reagent dispensers o microplate washer Chemical Libraries: o ChemBioNet collection: 17000 (+3000) compounds, o LOPAC1280TM: 1280 compounds Intavis MultiPep SPOT synthesizer

School of Pharmacy, University of Oslo

Analytical/synthetic chemistry, medicinal chemistry

FUGE Molecular Imaging Platform, University of Bergen

HTS/HCS Bioimaging

BerGenBio AS, Bergen

RNAi-based approach for validation and high-throughput discovery

Norwegian Structural Biology Centre, University of Tromsø

Drug discovery and design, virtual ligand screening

Development of vaccines: Development of vaccines for infectious diseases starts with identification of a candidate antigen, capable of stimulating a protective immune response against 7

a specific disease. After validation of the antigen by in vitro and in vivo assays, vaccine preparation and vaccine formulation are evaluated and optimised, followed by selection of delivery and adjuvantation strategies. Selection criteria are typically based on provision of an adequate type of immune response and stimulation of memory as well as compatibility with current vaccination programs and implementation strategies. Vaccine development progresses further in a pre-clinical validation facility with evaluation of safety, immunogenicity and efficacy in in vitro and in vivo assays using animal models. Having accomplished these steps, vaccine candidates will transfer to a go/no-go decision point; prior to GMP production of Vaccines — European partners the vaccine components and further translational  The Helmholtz Centre for Infection Redevelopment concluded with phase I/early phase IIa search (HZI), Braunschweig, Germany studies in a clinical trial unit.  Servicio Andaluz de Salud, Sevilla, Spain EATRIS envisions that most candidates for this pipeline will enter at an advanced stage, starting with  Biomedical Primate Research Centre, Rieither (i) vaccine formulation, (ii) preclinical jswijk, Netherlands validation or (iii) clinical development. In Norway,  Istituto Superiore di Sanitá (ISS), Rome, contributions to the product group encompass Italy technology and expertise related to targeted antigen delivery (Table 3).

Table 3 Inventory for the vaccines pipeline — EATRIS Centre Norway Institution Centre for Immune Regulation (CIR), University of Oslo/Oslo University Hospital and Vaccibody AS, Oslo

Inventory   

Targeted delivery of new molecules delivered as DNA vaccines Vaccine preclinical validation facility Read-out systems o in vitro and in vivo validation for immunogenicity o efficacy o toxicity

Development of advanced therapy medicinal products (ATMPs): Advanced therapy medicinal products are new medicinal products based on genes (GTMP) or cells (CTMP) used for therapeutic, diagnostic or preventive effects, or tissue engineered products used to repair, restore or replace human tissues (regenerative medicine). To date, there is only one ATMP registered in Europe — ChondroCelect, a cartilage cell replacement product, however, development of ATMPs holds a huge potential both for patients and industry and offer new therapeutic approaches for a range of diseases and conditions. GTMP involves transfer of genetic material into cells, autologous or allogeneic, by methods such as viral and bacterial vectors to modify, control, inhibit or express a particular target. CTMPs may consist of stem cells, progenitor cells or differentiated cells capable of performing a defined physiological function alone or in combination with other substances. Tissue engineered products combine cells and materials science in complex, threedimensional products intended for replacing diseased or ATMPs — European partners missing tissue or restoring tissue function, e.g. artificial  VU University Medical Center (VUmc), heart valves. Because of the specific nature of these Eindhoven, The Netherlands products, ATMP candidates for EATRIS are likely to be  Helsingin Yliopisto, Helsinki, Finland taken up at an advanced level, with some pre-clinical work already completed.  Istituto Superiore di Sanitá (ISS), Rome, The Norwegian ATMP pipeline (Table 4) is divided between the Norwegian Radium Hospital (Oslo University Hospital) and the Norwegian Centre for Stem Cell Research, focussing on development of cell

Italy  Fundació Institut de Recerca de L’Hospital Universitari Vall d’Hebron, Barcelona, Spain

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therapies for various cancers and on developing stem cell-based therapies for neurological disorders and tissue replacement, respectively. Table 4 Inventory for the ATMPs pipeline — EATRIS Centre Norway

Institution

Inventory 

The Norwegian Radium Hospital, Oslo University Hospital

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 The Norwegian Centre for Stem Cell Research, University of Oslo/ Oslo University Hospital

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Production (procurement, primary cell culture, vectors): o 1 dedicated GMP grade laboratory Preclinical development facility (cell differentiation & expansion): o 7 GMP grade production rooms Production (procurement, primary cell culture): o Ex vivo laboratory Preclinical development facility (cell differentiation & expansion): o 1 dedicated GMP grade production room Preclinical validation: o in vitro and xenotypic in vivo models for testing human cells. Assay development: functional assays for human stem cells (molecular, physiological)

Development of biomarkers: Biomarkers are diagnostic tools for detection of disease states and conditions and are used to identify the appropriate treatment for patients. Development of is based on Biomarkers — European partners recognition of a disease-specific molecule, e.g. a protein,  VU University Medical Center (VUmc), after in silico analysis or laboratory analysis of patient Eindhoven, The Netherlands samples. Prototype assay development requires disease Helsingin Yliopisto, Helsinki, Finland specific sample collections of a certain size matched with  Istituto Superiore di Sanitá (ISS), Rome, samples from a disease-free group, and EATRIS will Italy offer a standardised platform for this, with emphasis on  Fundació Institut de Recerca de L’Hospital multiplexed and tissue– and imaging-based development Universitari Vall d’Hebron, Barcelona, with access to patient materials, biobanks and clinical Spain data. At this phase of the project, there is no Norwegian  Palacky University, Olomouc, Czech Recontribution to the early stages of the molecular public diagnostics pipeline; however, EATRIS Centre Norway will be involved in validation and evaluation of this product type through contributions to the tracer development and molecular imaging pipeline (see Table 5), and several of the contributors to other pipelines have experience in biomarker discovery through the Norwegian Research Council Functional Genomics programme (e.g. Profs. Taskén, Lorens and Gjertsen). Development of tracers/molecular imaging: Molecular imaging plays an important role in individualised health care by providing information used for diagnosis, evaluation of prognosis and monitoring of treatment and disease outcome. EATRIS will provide molecular imaging solutions (nuclear, radiological and optical) at all critical stages of the care cycle for a broad spectrum of diseases. Furthermore, the imaging pipeline will include components for target revalidation and tracer production, animal facilities with relevant animal models, tracer metabolite analysis, preclinical imaging laboratories as well as clinical imaging centres for acquirement of multimodality imaging data (PET, SPECT, MRI, US, optical and hybrid scanners). An important activity of this product group is development of improved solutions for analysis, handling, storage and processing of multimodality imaging data. 9

Table 5 Inventory for the tracers/molecular imaging pipeline — EATRIS Centre Norway Institution SAFE, University of Oslo

Centre for Molecular Biology and Neuroscience (CMBN), University of Oslo/ Oslo University Hospital

Inventory

 

Scanditronix MC-35 cyclotron GMP-compliant lab with hot cells

Animal imaging facilities:  Small animal PET/CT  MR scanner with animal coil  High throughput animal/ex vivo functional imaging for transgenic models Animal imaging facilities:  7 Tesla MR animal scanner  Advanced ultrasound animal scanner

Clinical imaging facilities:  Ultrasound technology R&D  Advanced MR imaging methods (functional, molecular and quantitative anatomy), 2 3T clinical MRI scanners  Cardiac ultrasound for diagnosis, therapy monitoring and image guided surgery and interventions St. Olav’s Hospital/ Norwegian University of Science  Foetal ultrasound and Technology (NTNU)  Image post-processing and soft-ware programs (incl. statistical image analysis/ post-processing, tracer kinetics, automatic segmentation etc.)  Nanoparticles for imaging and image-guided drug delivery  Neuronavigation  Robotics  MR metabolomics (biopsies, tissue samples, body fluids) High-field 600 MHz MR spectrometer dedicated 100% to MR metabolomics (biopsies, tissue samples, body fluids)  64 channels CT  Operating Room of the Future - ORF - clinical R&D on image-guided minimally invasive surgery  Preclinical imaging facilities for molecular imaging and image-guided drug delivery Production facilities:  GE PET-trace cyclotron  7 GMP hot cells, 1 non-GMP hot cell University of Bergen/ Haukeland University Hospital

Imaging facilities:  Clinical ultrasound, endoscopic ultrasound  11T MRI (Bruker Pharmascan), clinical MRI  PET-CT (clinical and animal)  SPECT-CT  Image co-registration and –fusion, post-processing software  Time-domain and continual wavelength optical imaging for in vivo probe development

Biomarker/tracer development and evaluation are key components of the molecular imaging efforts in EATRIS. Tracer development starts with a recognized ligand molecule (e.g. antibody) interacting with a validated target; subsequently, a precursor is made through coupling to dyes or contrast agents to enable detection. Paramagnetic agents are used for MRI, fluorescent dyes for optical imaging, microbubbles for ultrasound, gamma emitters for SPECT and positron emitters for PET detection. Such multi-modal and –functional tracers often reach micro- or nanometre size, referred to as ‘nanoparticles for imaging’. 10

In EATRIS, cyclotron facilities and appropriate Tracers/molecular imaging — European hot cells will be available for production of radiotracers, partners and chemical and nanotechnology facilities will be  VU University Medical Center (VUmc), available for production of tracers for MRI and Eindhoven, The Netherlands ultrasound. With identification of a lead tracer,  Istituto Superiore di Sanitá (ISS), Rome, development proceeds with Proof-of-Concept studies in Italy relevant animal modela, description of tracer kinetics  Fundacion IDICHUS, Santiago di Composand metabolite analysis. These studies are concluded tela, Spain with toxicology and pharmacodynamics combined with ex vivo analysis of tissue uptake. Satisfactory results  Palacky University, Olomouc, Czech Republic may then bring the development process forward to GMP production and evaluation in humans. In Norway,  Turku University Central Hospital, Turku, the preclinical and clinical imaging facilities at NTNU/ Finland St. Olav’s Hospital will focus on development of MRI  Cluster for Molecular Imaging, University and ultrasound tracers and biomarkers as well as of Copenhagen, Denmark building expertise on image analysis, interpretation and processing, while PET tracer development activities will be located groups in Bergen and Oslo (Table 5). The research environments involved in PET imaging are early stage developments, however, a needs analysis performed during the pre-project has pointed to a lack of capacity and expertise in the field and strengthening these initiatives through anchoring in EATRIS is essential. Clinical trials units: Projects running in the EATRIS pipelines may culminate in first-in-man clinical trials testing the new medicinal product. EATRIS Centre Norway will develop a national network of clinical units for this purpose encompassing units from all four Health Regions (Table 6), aiming at building best practises and competence in assessment of bio-analytical and clinical feasibility, protocol development, recruitment planning and screening and regulatory submission. A collaborative approach and an open and transparent communication with NorCRIN, the Norwegian chapter of ECRIN, is central to this development. Table 6 EATRIS Centre Norway — clinical trial units Institution

Unit

The Norwegian Radium Hospital , OUS Clinical cancer research unit Rikshospitalet , OUS

Dept. of Clinical Pharmacology, clinical trial unit

St. Olav’s Hospital

Clinical research facility

Haukeland University Hospital

Clinical trial unit for children, clinical trial unit for adults (adjoining ICU, clinical intervention centre)

University Hospital of North Norway

Clinical trial unit

Generic components in translational research In addition to the specific requirements for the various product pipelines, certain elements of the infrastructure are generic and will be shared by all such as access to laboratories for molecular biology and biochemistry, expertise in bioinformatics, basic microscopy facilities and animal housing. These facilities will be provided by the local project partners. More specifically, R&D activities involving metabolic profiling for new medicinal products will be supported through access to the Proteomics Laboratory at NTNU (managed by Prof. Geir Slupphaug in collaboration with Prof. Odd. G. Nilsen, Dept. of Cancer Research and Molecular Medicine). Analysis of pharmacokinetics, -dynamics and toxicology may be considered outsourced or performed on site. The children’s trial unit at Haukeland University Hospital (HUS) represents a unique effort in this respect, testing pharmacokinetics (not first-in-man) of new drugs in children (medical director 11

Prof. Ansgar Berg). Furthermore, the HUS unit collaborate closely with the pharmacy at Western Norway Regional Health Authority for GMP production and clinical pharmacologist Assoc. Prof. Jan Schjøtt for cooperation with pharmacovigilance centres (RELIS). Implementation of standardised IT tools for data capture, storage, annotation and analysis, both of pre-clinical and clinical data is central to organisation of the network. It is important for handling quality assurance activities as well as for effective communication during multidisciplinary and cross-organisational collaborations. While the pan-European EATRIS network will develop tools for this purpose, organised by its Coordination & Support hub, it is envisioned that the Norwegian node also develops and/or adopt local data handling solutions in collaboration with other infrastructure initiatives. For example, the national EATRIS consortium will consider employing WebCRF, a net-based remote data entry system developed by the Norwegian University for Science and Technology (NTNU), for collection of clinical data. Interface with other ESFRI projects: EATRIS will interact and collaborate with several Biological and Medical Science (BMS) infrastructures both at a national and at a European level. This will be used as an advantage to generate momentum by joint goals, sharing of technologies and knowledge exchange, creating a strong and flexible network of related research infrastructures. The EATRIS product pipelines will interact closely with their sister BMS RIs, particularly with the European Infrastructure for Open Screening Platforms (EU-OpenScreen), the European Biomedical Imaging Infrastructure (Euro-BioImaging), the Integrated Structural Biology Infrastructure for Europe (INSTRUCT), the European Infrastructure for Phenotyping and Archiving of Model Mammalian Genomes (Infrafrontier), the European Life Science Infrastructure for Biological Information (ELIXIR), the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI) and the European Clinical Research Infrastructures Network (ECRIN). The interplay between EATRIS and ECRIN is perhaps of particular importance, as ECRIN will handle research projects from Clinical Phase II and onwards. Alignment between the two infrastructures will ensure that projects completing the EATRIS pipeline will transfer efficiently to the next clinical phases in ECRIN.

5. Impact on science, technology and innovation New research opportunities; impact on science, recruitment, internationalisation, future innovation The European Strategy Forum on Research Infrastructures (ESFRI) initiated EATRIS after assessing the needs for large research infrastructures in Europe for the next 10-20 years. Responding to this, EATRIS will be constructed to meet future demands in translational research, building competence and capacity as well as strengthening biomedical and clinical research by removing or bypassing bottlenecks and improving communication and interaction between translational research scientists.  EATRIS will develop a simple and effective procedure for access to its state-of-the-art infrastructure, offering scientists the opportunity to work with the best European researchers at the forefront of biomedical translational research. With support from EATRIS, scientists will gain greater control and greater return on early research investments, aiming to create material value and real clinical benefit from their research.  Added value will spin from shared use of expertise and the unique technologies available in EATRIS. Using a shared infrastructure will to a large extent avoid costly duplication of efforts and reduce the need for outsourcing. Similarly, EATRIS will speed up development and standardisation of generic research tools and common technical procedures; all product pipelines require similar expertise and infrastructure for IT tools, regulatory affairs, IP and technology transfer, preclinical validation studies in different animal species, clinical development facilities, and clinical trial centres.

12



 











Organising training programmes or courses encompassing all activities across each pipeline (e.g. immune monitoring, GXPs, IP and regulatory affairs) will contribute to generation of human resources and will also facilitate harmonisation within EATRIS centres. Complementary facilities will enhance cross-validation, harmonisation and assist in establishment of cross-cutting, common quality assurance and control. EATRIS partner institutions have considerable capacity for pre-clinical validation in different experimental animal models (including conventional, modified and humanized mice, rats, large animals and primates). These resources will be made available to other scientists through the infrastructure. A European translational research infrastructure will contribute significantly to innovation and standard setting for medicinal products and lead to faster introduction of new technology. For example, in the field of PET tracer development, it is hoped that EATRIS will provide the critical mass needed to serve academic centres as well as pharma industry. Added value and synergy also stem from collaboration between research units making it possible to pool samples and data from multiple sites to speed up development of products such as diagnostics, where access to stratified patient groups is essential. The panEuropean network of centres would also provide the capability for multi-site testing which is required for the approval of molecular diagnostic products with the national and international registration agencies. Production of ATMPs often requires development and validation of new assays. This is both time-consuming and expensive, and sharing and pooling of EATRIS resources such as GMP facilities specialising in production of different types of ATMPs and animal facilities for larger animals would speed up the process to the advantages of the participants. Enrolling patients for a clinical trial targeting rare diseases is often a difficult task. The availability of multiple clinical sites connected by a uniform management structure will aid the recruitment process and speeding the process of treatment development. Furthermore, EATRIS will not have the same economic constraints as industry, making it possible to pursue rare diseases or highly innovative projects that are not a primary interest of the pharma industry. Drug candidates emerging from EATRIS will be more advanced on the translational path, making industry take-over easier and less risky. Improving the interactions with pharmaceutical industry and SMEs have a high potential of creating new innovation clusters in translational research, thus providing a boost to national economies. This will also help maximising the return on investments in basic research.

6. Importance for User groups Justification of the level of national participation, national needs and estimation of total use. As a member of EATRIS, Norway will contribute to an infrastructure with open user access as a central mission, and resources of the infrastructure will be made available to the whole European biomedical research community to support researchers wanting to bring their discoveries to the pre -clinical and clinical stage. Although the primary focus of EATRIS is to serve the academic researchers and research institutions with a public mission, collaboration between academia and industry will be encouraged, and EATRIS will also be open to researchers located at independent research institutions, SMEs and industry. Norwegian user groups are expected to primarily encompass academic researchers involved in translational research through networks and collaborations, companies involved in cluster organisations such as Oslo Cancer Cluster and Nansen Neuroscience Network and the university technology transfer offices. Competence building is a specific priority of the infrastructure, and user groups will therefore also include PhD students, post docs and research nurses affiliated with universities or university hospitals. (Added 13

value, see also 2. Vision and scientific goals and 5. Impact on science, technology and innovation.) Access for user projects will be handled by a central service unit residing in Amsterdam (EATRIS Coordination & Support) through an open call, evaluating projects by peer-review by the following criteria: established Proof-of-Principle, scientific excellence, degree of innovation, medical need that can be addressed and clinical relevance/potential of becoming standard clinical practice. It is envisioned that projects enter EATRIS via different access models for user projects:  collaborative model (sponsored services, results and IPs shared user/Centre)  contract research model (fee-for-service)  industry contract model (full cost model, covering all institutional fees and project costs). Several of the national project partners already deliver services on a regular basis using these cost models. As cost examples, the Chemical Biology screening platform at the Biotechnology Centre of Oslo (UiO) perform assay development (researcher w/supervision, collaborative overhead, duration 1-6 months) for 60 – 360 kNOK and a full library HTS screen (personnel costs, materials, duration 1-2 weeks) for 62 – 84 kNOK. Similarly, MILab at NTNU performs evaluation of therapeutic effect of new drug in rodent model (personnel costs, experimental animals and material, duration 7-15 weeks) for a cost of 30-70 kNOK. In Norway, the infrastructures will be set up to handle 3-5 new projects per year in each product pipeline, thus providing an annual estimate of up to 20 new projects. The national portfolio will consist of both academic and industry projects as well as of user projects from spinout companies and existing EATRIS partners. Expanding the national infrastructure’s involvement with small biotechnology companies and spin-outs, both as contributors of specific research competences and users of EATRIS services, will be considered continuously. As an example, EATRIS Centre Norway is currently evaluating services from Biosergen AS (Trondheim), a spin-out from NTNU and SINTEF researching antibiotic-producing bacteria and genetic manipulation of bacteria. Strengthening of the academic/industry interface is also important for speeding the process of bringing new products to the market, and continuous interaction with regional technology transfer offices will aid identification of potential users and partners for the infrastructure. At the European level, EATRIS will also actively explore the potential of research funding organisations for financing projects, such as the European Commission, the European Investment Bank, non-governmental organisations and others with the aim of setting up a hybrid venture fund (public/investor) to support end-to-end translational projects. The goal of these activities is to gradually generate sufficient revenues to sustain operation. Membership in EATRIS will result in participation in other EU-funded consortia, as EATRIS institutes will use the network to build specific groups to respond to calls. The European Commission is planning to dedicate a part of the H2020 budget to the running of infrastructures on the ESFRI Roadmap, thus, EATRIS would provide access to funds otherwise not available. EATRIS aims at being fully operational and providing services on a regular basis by 2016. In the light of this, a likely estimate of total use in 2016 is five user projects a year per pipeline in each EATRIS Centre. With a total of 9 participating countries, the estimated total project throughput is estimated to exceed €20–30 million per year.

7. Partners Description of consortium, research groups, institutions, industry, competence The Centre for Molecular Medicine Norway (NCMM, UiO) operated as host institution for EATRIS during the Preparatory Phase (2008-2010) and has continued to coordinate actions and construction of a Norwegian translational research network. The national consortium is recruited from all four Health Regions and consists of institutions, research groups, technology platforms and selected small biotech companies sourced after a capacity analysis of Norwegian translational

14

research resources. Scientific coordinators for the various EATRIS product pipelines in Norway are given in Table 7. Table 7 National consortium profile, product group coordinators Name, Institution

Pipeline

Prof. Kjetil Taskén, The Biotechnology Centre of Oslo, UiO

Small molecules

Prof. James Lorens, UiB and BerGenBio AS

Small molecules

Prof. Arne Smalås, Norstruct, UiT

Small molecules

Prof. Bjarne Bogen, CIR, UiO/OUS and Vaccibody AS

Vaccines

Prof. Olav Haraldseth, MI lab, NTNU

Tracers/Molecular Imaging

Prof. Odd Helge Gilja, UiB/HUS MedViz consortium

Tracers/Molecular Imaging

Prof. Jan G. Bjaalie, UiO

Tracers/Molecular Imaging

Prof. Joel Glover, Norwegian Stem Cell Centre, UiO

ATMPs

Prof. Gunnar Kvalheim, The Norwegian Radium Hospital, OUS

ATMPs

Dr. Hassan Khiabani, Rikshospitalet, OUS

Clinical trials unit

Prof. Steinar Aamdal, The Norwegian Radium Hospital, OUS

Clinical trials unit

Prof. Bjørn Tore Gjertsen, Haukeland University Hospital

Clinical trials unit

Prof. Ola Dale/Dr. Magnus Strømmen, St. Olav’s Hospital

Clinical trials unit

Prof. Einar Bugge/Dr. Sameline Grimsgaard, UNN

Clinical trials unit

Development of small molecules: The pipeline includes the chemical biology platform located at the Biotechnology Centre of Oslo (BiO), University of Oslo (UiO) headed by Centre Director Prof. Kjetil Taskén. The platform manager Dr. Anne Jorun Stokka is in charge of designated research staff and project activities running on the platform, which contains various technologies for high through-put screening and characterisation of ligand-protein and protein-protein interactions. The BiO platform is partner in the initiative ChemBioNet Norway, thereby linked to an international network of research facilities through the ChemBioNet in Germany and the ESFRI-project EU-OpenScreen. In addition, BiO has peptide array and peptide chemistry technologies and expertise for developing high-affinity binders and disruptors of protein-protein interactions. Expertise and setup for studies of ligand-receptor interactions and ligand-mediated signalling will be sought from School of Pharmacy/Dept. of Pharmacology, UiO. The small molecules pipeline is complemented by resources located at the Chemical Biology Platform node, University of Bergen (UiB), coordinated by Prof. James B. Lorens. Prof. Lorens has developed a new approach to cancer drug discovery based on integrated HTS cytometry and is a collaborator in the EU European Cooperation in Science and Technology (COST) initiative consortia CM0602 (Angiokem) and CM0804 (Chemical Biology with Natural Products). The pipeline includes the UiB branch of FUGE Molecular Imaging Centre (HTS/HCS Bioimaging) and BerGenBio AS, a UiB spin-off company offering comprehensive target validation studies based on novel RNA interference technology as well as compound and therapeutic screening services. The small molecules product group also integrates the Norwegian Structural Biology Centre (NorStruct), Centre Director Prof. Arne Smalås, at University of Tromsø (UiT). NorStruct is a national research and service centre within the national initiative in functional genomics (FUGE) and offers consultancy, service and research collaborations to the Norwegian research community in structural biology techniques. Services on drug discovery and design, including analysis of protein complexes using molecular modelling/docking, virtual ligand screening and biophysical characterization by microcalorimetric methods, are of particular relevance to the Norwegian EATRIS centre. Vaccine development: The pipeline for vaccine development contains technology and expertise linked to targeted delivery of antigens and adjuvantation. The technology has been developed by Prof. Bjarne Bogen’s group at the Centre for Immune Regulation (CIR), OUS/UiO. CIR has been established as a 15

Centre of Excellence by the Research Council of Norway in 2007 and was designated a FOCIS (Federation of Clinical Immunology Societies) Centre of Excellence (FCE) in 2009. Services to the pipeline will be offered in conjunction with Vaccibody AS, a CIR spin-off company, using proprietary vaccine technology to induce strong immunological responses even with weak antigens. Development of tracers/molecular imaging: The Norwegian EATRIS Centre is building its pipeline on molecular imaging and biomarker/tracer development by creating a network of facilities in Oslo, Bergen and Trondheim. At the core of this development is the Medical Imaging Lab (MILab) at Dept. of Circulation and Medical Imaging, NTNU. MILab is headed by Prof. Olav Haraldseth, who is also leader of the whole animal imaging network of the national FUGE technology consortium NorMIC, head of the Norwegian Interdisciplinary Research School in Medical Imaging, research leader at Dept. of Medical Imaging (St. Olav’s Hospital) as well as a member of National User Committee for the PET Centre in Oslo. The FUGE platform has dedicated research staff and offers services in in vivo MRI and MRS of small animals. Furthermore, MILab is a Centre for Research-based Innovation (SFI), combining an internationally recognised scientific track record with a strong industrial background and a close integration between technology researchers and medical doctors at the university hospital (St. Olav’s Hospital). MI Lab has several partner companies, three of which having won the European Information Society Technology (IST) prize for their products. Finally, Prof. Haraldseth is a founding member of Nansen Neuroscience Network, a knowledge network working within the frame of EATRIS on reducing the distance between idea and patient/product. Efforts in molecular imaging are complemented by research groups located at the University of Bergen (UiB) and Haukeland University Hospital (HUS), coordinated by Prof. Odd Helge Gilja (Institute of Medicine, UiB), Director of MedViz cluster. This cluster performs interdisciplinary research in advanced image analysis and visualisation to bridge the gap between “bench and bedside”. MedViz includes imaging physics and fundamental biomedical translational research and develops new clinical methods for potential commercialisation by means of de novo software analysis, decision support and visual communication. Assoc. Prof. Martin Biermann is acting medical chief of the Centre for Nuclear Medicine and PET, which has a strong focus on multimodal imaging (PET-CT, SPECT-CT) and ultrasound including software-based coregistration of multiple modalities. The centre has a chief radiochemist, Dr. Tom Christian Holm Adamsen, who has more than 10 years experience in radiochemistry and tracer synthesis. In Oslo, the molecular imaging product group is headed by Prof. Jan G. Bjaalie, Centre for Molecular Biology and Neuroscience (CMBN, UiO) and group leader for the Neural Systems and Graphics Computing Laboratory (NeSys Lab). Prof. Bjaalie is also Senior Advisor to the International Neuroinformatics Coordinating Facility located at Karolinska Institutet, Stockholm. The group provides expertise on high resolution MRI and microPET as well as on development of new and powerful methods for computerised data acquisition, 3-D reconstruction, visualization and quantitative analyses, focussing on investigations on organisation and re-organisation of brain systems architecture in rat and mouse models, and in vivo imaging in the context of multimodality brain atlasing. CMBN is acknowledged as a Norwegian Centre of Excellence by the RCN. Advanced Therapy Medicinal Products (ATMPs): Development of ATMPs, cellular therapies, for cancer treatment will be coordinated by Prof. Gunnar Kvalheim, director of the Laboratory for Cellular Therapy, OUS, in a joint effort with the Clinical Cancer Research Unit, OUS, headed by Prof. Steinar Aamdal. The Kvalheim group is a member of CAST, the Cancer Stem Cell Innovation Centre, a multidisciplinary network and biomedical innovation centre working towards the identification and characterisation of stem cell parameters in tumours. CAST has several industry partners and is an acknowledged Centre for Research-based Innovation (SFI). Prof. Joel Glover (Dept. of Physiology, UiO) will be coordinating the ATMP pipeline on cell therapy products for neurological disorders and tissue replacement. Prof. Glover is a founding partner and director of the Norwegian Centre for Stem Cell Research (NCS), which has a particular focus on the use of stem cells for regenerative medicine. 16

8. Project management Project management, administration, host localisation, construction and operation During its FP7-funded preparatory phase (2008-2010), the Centre for Molecular Medicine Norway (NCMM, UiO) hosted EATRIS Centre Norway with Centre Director Prof. Kjetil Taskén acting as scientific contact for the project supported by project coordinator Dr. Torunn Berge and the NCMM administration (CAO and Financial Officer). The project period ended with completion of a Business Plan presented to the European Commission January 2011. NCMM has since continued as host in the interim period (2011-2012), responsible for maintaining national coordination and European contact having received funds from the Norwegian Research Council’s National Financing Initiative for Research Infrastructures to cover a 2-year EATRIS participation fee. During this period, eight EATRIS member states have agreed to send an application to establish EATRIS as a European Research Infrastructure Consortium (ERIC) to the European Commission. These countries were the Czech Republic, Denmark, Finland, Germany, Italy, Netherlands, Norway and Spain. The formal establishment of the EATRIS-ERIC is expected in the first half of 2013. The national Reference Group (Table 1) has operated a steering group for EATRIS Centre Norway, providing representation of all four health regions with members from both Universities and University Hospital environments will ensure a broad national representation and ‘drive’ for the project, while resources are kept to a reasonable level. New members of the Steering Group will be identified by the individual institutions at their discretion after consultancy with each regional ‘Samarbeidsorgan’. The Group will assist in national management decisions as well as in decisions about organisation and investments for the coming operational phase. Among these is the decision of a permanent localisation of EATRIS Centre Norway, and it is a specific milestone of the early project phase to find consensus for a host within the national consortium and the Reference Group. In the early project phase, EATRIS Centre Norway will focus on establishing the necessary regulatory expertise and project management structures as well as identifying the required standards to enable efficient exchange of information and data throughout the infrastructure. The main tasks of the project management entail:  Coordination and communication between the individual institutions  User access to the Norwegian EATRIS Centre  Standardisation, quality management, regulatory expertise  IP management support, liaising with technology transfer offices  Marketing of the research infrastructure nationally (and internationally)  Communication with other EATRIS Centres and the central EATRIS Coordination & Support unit These management tasks are vital to every EATRIS Centre on a local level and are necessary for the making of a functional research infrastructure. As an added value of the ESFRI project, partners will benefit from centralised support that will cover some of these tasks via the Coordination & Support unit. Close collaboration between local Centres and the central unit will allow synergies to be fully explored and create economies amongst the Centres as well as provide access to a larger customer base shared by the European infrastructure. As an ESFRI project partner, the Norwegian infrastructure will also benefit from closer contact with a greater international public-private environment, participate in international training programmes and gain access to centralised funding options. One of the most important tasks of the project management and a key to the success of EATRIS is development of an efficient communications strategy, both within the infrastructure (internal) and with users, stakeholders, media etc. (external). Efficient communication is central to speeding the process of translational research, thus, particular care will be taken to optimising ways of relating information within the national network. Formal structures such as regular project meetings, on a regional and national level, will be established. Furthermore, it is a specific aim to construct a webportal for the Norwegian EATRIS Centre in the early project phase containing an 17

overview of national EATRIS services, its project partners and competences aimed at users of the infrastructure and relevant biotech and pharmaceutical companies. Additionally, the portal will be used to update project partners continuously with regular newsletters as a complement to project meetings. As a partner of the ESFRI project, EATRIS Centre Norway will be also take part in a common dissemination and marketing strategy established by EATRIS Coordination &Support. In addition to creating a common, corporate identity and promoting exchange of knowledge and human resources within the infrastructure, efficient communication of EATRIS activities and services is essential for acquisition of external user projects. The latter is perhaps of greatest importance for smaller research communities (such as Norway), which will gain access to a large customer base throughout Europe as an ESFRI project partner. EATRIS Coordination & Support will also work with other ESFRI initiatives facing similar challenges such as BBMRI (biobanks & databases), ECRIN (clinical trials procedures) and Elixir (-omics and genotype data). The first projects are expected to be taken up in EATRIS during the first half of 2013, and project support for these projects will be provided by the national EATRIS coordinator and the host institution using the Steering Group as consultants. An increasing number of projects entering the pipelines will require additional management capacity and competence, particularly as projects move forward to early clinical trials. Thus, EATRIS Centre Norway will employ a second project manager during 2013 with specific responsibilities for maintaining regulatory competency and liaising with national clinical researchers (including NorCRIN) as well as with other EATRIS clinical trials units.

9. Plan for access and use, data and knowledge management Access management, project selection, knowledge management, dissemination, use of electronic services The infrastructure will be open to researchers wanting to develop basic research discoveries into medicinal products and applications. The EATRIS goal is to take up discoveries and develop them to a stage where a Proof-of-Concept in human (clinical phase I/IIa) can be demonstrated. Additionally, industry will also be given the opportunity to use the sophisticated and specialised facilities of the EATRIS research environment to encourage closer cooperation with academia. At the European level, EATRIS Coordination & Support (Amsterdam) serves as an entrance portal for external scientists and industry. The unit functions as a ‘one-stop-shop’ for access, also taking care of quality management and technology transfer issues. Through an open call for proposals followed by a review procedure, the most innovative projects with the highest quality combined with a medical need and clinical relevance will be selected (see also 6. User groups). The call for project proposals will be disseminated broadly with application forms and guidance readily available online. A pre-proposal checklist helping applicants to determine whether their proposal is eligible for EATRIS support will be made available together with an EATRIS User Access Unit available to the users for questions. The national infrastructure will provide access and support for national users of the infrastructure in alignment with this model. Exchange of information and knowledge between researchers is currently often restricted to conference papers, publications and e-mail between authors. More effective collaboration during the course of research may be achieved by establishing more sophisticated exchange mechanisms, drawing from practical examples already established in the translational context or in other scientific and technical domains. Specifically, three areas will be tackled:  Better organisation of shared workspace, knowledge management and communication facilities using electronic services.  Standardisation of data (e.g. biological data, *omics data, tissue data, pre-clinical and clinical images, clinical data).  Standardisation of data management systems (e.g. virtual PACS, biobanks, clinical trial management systems, electronic patient records such as WebCRF, as mentioned in part 4.). 18

Additionally, project partners will be present at national and international meetings, in professional societies as well as actively contributing to communication with governments, funding agencies and relevant industry.

10. Time-schedule and deliverables Main activities and progress, milestones and deliverables, funding and commitments

The formal establishment of the EATRIS-ERIC is expected in the first half of 2013, after which the infrastructure will be ready to initiate its first translational project work. EATRIS Centre Norway will follow the development plan of the international network to phase-in its operation and gradually expand capacities. By 2016, EATRIS will be fully operational and offer support on a regular basis for all product groups. In Norway, the following milestones and activities have been identified for the first five-year phase: Table 8 Project milestones and deliverables Activities

2013

2014

2015

2016

2017

Establish web portal, information for users Hire project managers Identify phase-in projects (yearly activity) Run first projects, phase-in operation Decision host localisation Review capacity/competence of RI Collect input on regulatory processes Evaluate needs for investment (physical) Potential follow-up grant (physical units)

% of research capacity

100%

11. Budget and funding plan The outlined national research infrastructure has been drawn up consisting of existing units with the necessary capacity (staff, equipment, technology etc.) to take up external translational projects. Thus, construction of EATRIS Centre Norway is initially limited to establishing the framework essential for bringing together these units to create functional product pipelines and close efficiency gaps in translational research. EATRIS Centre Norway will operate independently as a stand-alone research infrastructure as described, however, participation in the ESFRI-project has obvious advantages and a great potential to create added value also at a national level. The total financial plan covering structural and organisational support of EATRIS Centre Norway is given in a separate worksheet. In the construction phase (2012-2017), Table 9, EATRIS Centre Norway will employ three project managers responsible for coordinating and setting up the product pipelines, manage the first projects entering the infrastructure and develop a network for regulatory project support. Coordinating activities and contact with EATRIS C&S and European partners will be the responsibility of one project manager, located at the EATRIS host institution, while the two remaining positions will be distributed to the four health regions. Distribution key (%) to these positions will be decided in agreement with the National Steering Group for EATRIS.

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Table 9 Budget, EATRIS Centre Norway (kNOK, incl. VAT) Activity

2013

2014

2015

2016

2017

Total

Norwegian participation in EATRIS at the European level

1000

1000

1000

1000

1000

5000

Project manager 1

1247

1303

1374

1443

1515

6882

Project manager 2

1247

1303

1374

1443

1515

6882

Project manager 3

1247

1303

1374

1443

1515

6882

Dissemination (webportal, partner meetings, conferences etc.)

100

100

60

60

60

380

QA/QC (data handling software, acquisition, monitoring, regulatory expertise)

100

100

30

30

30

290

1000

1000

1000

1000

1000

5000

-

-

*

*

*

5941

6109

6212

6419

6635

Phase-in first projects, contribution to running costs Physical infrastructure investment TOTAL

31316

*monitoring activity in 2013-2014 may reveal needs for physical infrastructure investments, which may be requested in a follow-up application.

12. Environmental and ethical perspectives Environmental consequences and ethical issues of the infrastructure and research activities This project conforms to the principles of the Declaration of Helsinki in its latest version, the Council of Europe’s Convention on Human Rights and Biomedicine, the Universal Declaration on the Human Genome and Human Rights, as well as to all the EEC Directives concerning medical research and animal experimentation and the corresponding Norwegian legislation including the Norwegian Health Research Act. Translational research may have environmental consequences that are difficult to predict, for example resulting from the use of successful medicinal products against microbes or endogenous molecules that could have significant long-term effects on our environment, both positive and negative. Careful continuous monitoring of potential effects needs to be performed to keep on top of a potential negative situation. When taking research observations from bench to the bedside, there are a set of ethical and legal issues to consider and deal with in an appropriate and proactive manner. In EATRIS, these are primarily related to the handling and use of human samples, the use of laboratory animals for testing and the design and conduct of clinical trials. In Norway, the infrastructure is responsible for fulfilment of all national ethical and legal requirements and will operate as warranted by national legislations. Of particular relevance to EATRIS’ operations are the Norwegian acts on medical and health research, the act relating to biobanks, the personal health data filing system act, the biotechnology act and the act on ethics and integrity in research. Protocols used in the national network will be approved by the Regional Ethical Committees. In addition to adhering to national provisions, members of the international EATRIS consortium will rely on available relevant information, such as hSERN (human sample exchange regulation navigator, http://www.hsern.eu/) and maintain a open dialogue with the evolving ethical environment of European translational science.

20