title: COMMUNICATION FROM THE COMMISSION - A European initiative on transmissible spongiform encephalopathies (TSE)

eurovoc_concepts:
EU financing
animal disease
cattle
infectious disease
medical research

text: COMMISSION OF THE EUROPEAN COMMUNITIES Brussels, 13. 11. 1996 COM(96) 582 final COMMUNICATION FROM THE COMMISSION A European initiative on transmissible spongiform encephalopathies (TSE) COMMUNICATION FROM THE COMMISSION A European initiative on transmissible spongiform encephalopathies (TSE) I introduction 1. Since the announcement by the UK authorities on 20 March 1996 that the appearance of 9 cases of a new variant of CREUTZFELDT-JAKOB disease (nvCJD) - a rare human disease - could be linked to exposure to bovine spongiform encephalopathy (BSE), European citizens have this become concerned over the consequences of likelihood for human health. Known cases of nvCJD currently stand at 15 (14 in the UK, 1 in France). The infectious agent and transmission mechanisms for these diseases, which are always fatal, are is no very poorly understood, treatment at present. in addition, there 2. in this context, a sizeable research initiative within the EU would appear to be essential. This is why in April 1996 the Commission gave a group chaired by Prof. WEISSMANN the task of drawing up an inventory of the state of knowledge and proposing research priorities on BSE. Since 20 June 1996, the Commission has made public its intention of proposing an action plan for research on BSE and CJD. It set out this intention at the Research Council of 7 October 1996, indicating that supplementary funding would be needed. The research council of 7 October invited the commission to reinforce its research activities on BSE„and related diseases and to present a communication to the next Research Council on 5 December. This communication is in response to that invitation and includes an action plan in annex. S)A. II The requirements 1. The report of the group chaired by Prof. WEISSMANN was made public on 16 October, it constitutes a full analysis of research needs on BSE and related diseases. There are numerous questions -16 altogether • for which answers are required, both on practical aspects and basic research. Each question covers several research topics on average. 2. on the basis of the WEISSMANN report, research which needs to be carried out on BSE and related diseases can be divided into five areas (see table 1 of the action plan): infectious agent and clinical and epidemiological research on human spongiform encephalopathies (SE); the mechanisms; diagnosis of SE; evaluation of the risk of SE; treatment and prevention of SE. transmission its Within these areas, 24 research topics have been identified. Given the complexity of the subject, several research projects per topic are often required. 3. From a careful analysis of the figures, the Commission has evaluated funding requirements at 45. 7 MECU (table 1 of the action plan), to which 5 MECU should be added for coordination (table 2 of the action plan), i. e. 50. 7 MECU overall. These are minimum requirements both in terms of quantity of high priority research and overall cost. This analysis is not surprising when one considers that a serious research project in these areas costs at least 1 MECU and sometimes more. the development and perfection of essential diagnostic tests and the study of means of transmission are extremely costly (7. 6 and 4. 5 MECU respectively). For example, Reinforcement of coordination of research activities on TSE between Member States is also needed. The cost of 5 MECU for this may seem relatively high compared with the yjL lightweight coordination which is usually practised in research matters. Here, though, it is a matter of very serious coordination with a view to harmonising the collection of data and diagnostic criteria for the detection and identification of the disease(s) concerned. To this end, the creation of databases and training programmes are both essential and, inevitably, costly. ill Funding through 1. The funding of research projects on TSE can only be the 3 "Life Sciences". specific carried out programmes, BIOMED, BIOTECH and FAIR. The council decisions on these specific programmes set out indicative breakdowns between areas within the overall funding for each of them (the Amount Deemed Necessary). Only certain areas could incorporate research projects on TSE in any significant way: BIOMED 2: Area 3: "Brain Research" Area 4. 2: Tuberculosis and other diseases" "Research on Aids, infectious BIOTECH 2: Area 4: "Cell Communication Neurosciences" in FAIR1: Sub-area "Animal Health", one of the 22 sub-areas of Area 4 "Agriculture, Forestry and Rural Development" At the Research Council of 7 October, several delegations ruled out the possibility of BSE affecting the breakdown of the current financial envelope of the Framework Programme between specific programmes or even the breakdown between areas within the "Life Sciences" specific programmes. This is why it is not politically possible to carry out a redeployment in favour of research on TSE: Sub area 3. 4 "Generic science of Food" could be slightly concerned. Sub area 4. 2 "Quality Policy" could also be concerned. //c either between specific programmes, which would result in the overall funding (Amount Deemed Necessary) for the "Life Sciences" programmes being overshot by underusing other specific programmes; or between areas within the "Life Sciences" specific programmes. The only redeployment which is foreseeable is thus within the areas of the "Life Sciences" programmes which are relevant for research on TSE. 2. in order to finance the 50. 7 MECU required for the action plan, there are three complementary possibilities (see table 1 of the action plan): 2. 1 Research projects on TSE currently being or about to be financed. These amount to 5. 9 MECU, of which 1. 5 MECU have already been allocated in the first BlOMED call for proposals, and 2. 4 MECU and 2 MECU are about to be allocated in the BlOMED and FAIR calls for proposals which closed on 17 June and 20 September 1996, respectively. 2. 2 Redeployment within the areas of the BlOMEDr BIOTECH and FAIR programmes relevant for TSE. The total sum which it is possible to redeploy amounts to 9. 8 MECU (8. 8 MECU for FAIR, 1 MECU for BIOTECH). The situation within each of the areas relevant for TSE is as follows: •BIOMEP 2 The second call for proposals which closed on 17 June used up the last appropriations for areas 3 (18. 5 MECU) and 4. 2 (12. 4 MECU). Several proposals on TSE were received under area 3. Some of them could be retained for a funding of around 2. 4 MECU (see point 2. 1). The third and last call for proposals was launched on 1 I 15 September and does not cover any of the relevant areas as all the appropriations have been used up (see above). «BIOTECH 2 The third call for proposals closed on 18 October and does not cover area 4. The fourth and last call for proposals will be launched on 15 June 1997. it will use up the appropriations for area 4 (4. 9 MECU). Of this sum, one could envisage 1 MECU being used for TSE, around 20% of the funding for this area. •EA1E Animal health, a relevant sub-area for TSE is only one of 22 sub-areas of area 4. This means that there is only around 12 MECU left for 1997 for all animal health areas, to be shared with other important diseases (salmonellosis, rabies, foot and mouth disease, swine fever), of which some are transmissible to man. in this context, it would be difficult to provide for more than 8. 8 MECU of redeployment in favour of BSE, i. e. 15% of area 4 and around 75% of research on animal health. A call for proposals for FAIR, as foreseen in the work programme, is planned for launch on 15 December. At the same time, the commission intends to launch a specific FAIR call for proposals for BSE using 8. 8 MECU. However, it is clear from the outset that any possible redeployment within the FAIR programme would be very insufficient with respect to the financial needs and the subjects of projects limited to animal health which could be financed. 2. 3 Supplementary funding 35 MECU of supplementary funding with respect to the current overall funding for the Framework Programme are thus essential for the three Life 2 Sub area 3. 4 "Generic science on Food" could also be slightly concerned. 5 /\JL Sciences specific programmes in order to respond to the minimum requirements of 50 MECU identified by the WEISSMANN report. These 35 MECU would be attributed according to the subjects of the research themes (cf table 1 of action plan) and will be divided up as follows: 16 MECU for BlOMED 7. 5 MECU for BIOTECH 11. 5 MECU for FAIR IV Conclusion 1. for in parallel with this communication, the Commission has adopted a communication on orientations with a view to a revised proposal for a financial supplement to the fourth Framework Programme research and technological development. These orientations propose setting aside 35 MECU for research on BSE. The adoption in due course by the Council and Parliament of a common political position on financial supplement containing a substantial extra amount for research on TSE is a condition for the Commission being able to launch a specific joint call for proposals for the three Life Sciences programmes, on the basis of its own powers. the Thus, the EU would be in a position to respond rapidly to the expectations of European citizens by putting into practice the recommendations of the WEISSMANN report with an ambitious action plan. 2. in conclusion, the Commission hereby informs the Council and the European Parliament of its intention to launch this the action plan on TSE research annexed to communication, for a total sum of 50. 7 MECU, 35 MECU of which is new funding. This will come from the financial supplement to the fourth Framework Programme research and development, for which the Commission is preparing a second revised proposal to be submitted to the council and European Parliament for opinion. for A i European Initiative into Bovine Spongiform Encephalopathy and Subacute Spongiform Encephalopathies SUMMARY 1. 2. 3. 4. Introduction The Needs Current Research Activities in the Field of SEs at Community and National Levels Weissmann Group Advice in the Context of Ongoing Research Activities 4. 1 Questions related to practical aspects 4. 2 Questions related to basic research on prion diseases 5. Action Plan for Future Activities The coordination of activities between Member States Specific Call for Proposals 5. 1 5. 2 Priority Setting and Financial Arrangements 6. 6. 1 6. 2 Total estimated costs and additional resources needed to address the specific Call for Proposals Total estimated costs and additional resources needed for the coordination of activities between Member States ANNEXES: Table 1 Table 2 Annex 1 European Initiative on Research into Bovine Spongiform Encephalopathy and Subacute Spongiform Encephalopathies 1. Introduction Spongiform encephalopathies (SEs) are a group of fatal transmissible neurodegenerative diseases of humans (e. g. kuru, Creutzfeldt-Jakob Disease (CJD), Gerstmann-Straussler- Scheinker Disease (GSSD)) and animals (e. g. scrapie, bovine spongiform encephalopathy (BSE)). These diseases have become an increasingly important research area both because of their unique biology and also the recent situation concerning the epidemic animal prion disease, which led to legitimate public anxieties over a risk to human health from eating infected tissues. The recent identification by the National CJD Surveillance Unit (Edinburgh, UK), the coordinator of the European network on epidemiological surveillance supported by the European Community Biomedical and Health Research Programme (BlOMED), of an apparently new clinicopathological variant of CJD in fifteen teenagers and young adults has raised new concerns about the transmission of the BSE agent to man via the food chain. 2. The needs Despite existing basic and clinical research in this field it has not been possible to identify the nature of the agent, and many factors :n the epidemiology of SEs are yet to be explained. It is therefore essential to focus and stimulate research efforts at Community level and to mobilise new research teams in order to attain a critical mass. The need to intensify research activity in order to address many of the questions still outstanding in relation to BSE was highlighted by the Agriculture Council of 1-3 April 1996. Similarly, at its meeting of May 1996, the Health Council concluded that the issue of BSE constitutes a problem in the field of public health and therefore all appropriate measures should be taken to eliminate the risk of possible transmission of the disease. Finally, the Ministers of Research at the Research Council of October 1996 emphasized the need to improve cooperation and coordination of research efforts and called upon the Commission to reinforce its research activities on topics in this field covering both basic and applied biology and human and animal health aspects, as well as diagnostic aspects. These efforts, to be implemented by the Commission, and which may be termed an "action plan", will essentially be performed through the coordination of activities between all Member States and a specific Call for Proposals. The action plan should identify the real needs in terms of research priorities and budgetary position based on the most recent experiences, taking into account the recommendations from the Weissmann Report and the Multidisciplinary Scientific Committee. It will also take into account ongoing Community research activities, including proposals received within the last calls of the BlOMED and FAIR programmes and work under way and planned in Member States. 3. Current research activities in the field of SEs at Community and national level Research on SEs has been sponsored at EU level since 1990. During that year, and in order to give a prompt response to the needs in this field, an emergency procedure was launched and 1 MECU was allocated to three specific projects identified by the Scientific Veterinary Committee as covering the most important areas for research investment in this field. The projects were implemented within the RTD programme in the field of Competitiveness of Agriculture and Management of Agricultural Resources (1989-1993, CAMAR, a specific programme of the 2nd Framework Programme), and were concerned with the isolation and identification of the infective agent; the monitoring of the presence of BSE in cattle by examining cattle brains after a negative diagnosis for rabies; and the assessment of European rendering systems in order to determine their effectiveness against the scrapie and BSE agents. In 1991 an additional project was sponsored, aimed at assessing modifications in the prion protein as a pathogenetic mechanism for BSE and related disorders. The Commission has also been involved in the organisation and financing of the following initiatives and workshops: 1990, a European Community In spongiform encephalopathies" was organised. The meeting was attended by scientists from 18 countries, the Organisation Internationale des Epizooties (OIE). The proceedings of this seminar, the first authoritative book on BSE, were published for the Commission by Kluwer Academic Publishers. the World Health Organisation representatives of (WHO) and "Subacute seminar on Similarly, a seminar on the issue of "Prion diseases in humans and animals" was held in London in 1991. Over 100 participants from Member States and third countries attended. In addition, two diagnostic workshops were jointly organised by the European Commission and the Central Veterinary Laboratory of the United Kingdom in 1990 (16-20 July, "EEC workshop on BSE diagnosis") and 1991 (8-11 April, "Spongiform encephalopathy diagnosis workshop"). This was further strengthened with the adoption of the 3rd Framework Programme (1990- 1994) for research and technological development which provided the basis to tackle the issue of research on transmissible spongiform encephalopathies at European level. Indeed, research on this issue was addressed as a priority within several European Community research programmes, namely: * * The Agriculture and Agro-industry, including Fisheries, programme (1990-1994, AIR), which supported one project aimed at characterizing the nature of the BSE agent; the establishment of a network The Biomedicine and Health Research programme (1990-1994, BlOMED 1), which supported for epidemiological surveillance of Creutzfeldt-Jakob Disease (originally funded by Directorate General VI in 1990, building on the existing EURODEM project), and the development of harmonized criteria for the neuropathological diagnosis of CJD and related human spongiform encephalopathies; The Biotechnology programme (1990-1994, BIOTECH 1), which supported one project on the molecular mechanisms involved in the pathogenesis of BSE and related neurodegenerative disorders, and also aimed at developing suitable experimental animal models. The network of epidemiological surveillance of CJD is, at present, the only existing structure able to provide a systematic evaluation of the incidence and the geographic distribution of this disease in the five countries involved. Indeed, the Health Council at its last meeting (20 May 1996) proposed that this structure should be taken as a model to implement the surveillance of CJD in all Member States. In September 1993, the Commission organised a consultation on BSE with the European Community Scientific Veterinary Committee and the scientists engaged on research in this field to assess the scientific information available. A book of proceedings entitled "Transmissible spongiform encephalopathies" was published by the European Commission. In 1994, a report depicting protocols for the laboratory diagnosis and confirmation of BSE and scrapie was issued by the Scientific Veterinary Committee. This report was produced in consultation with all Community research laboratories leaders in the field together with several laboratories from third countries. With the adoption of the 4th Framework Programme for RTD (1994-1998), reinforcement of prion diseases has continued within the European Community research programmes (BlOMED, BIOTECH, FAIR), allowing this issue to be addressed with different methodologies and perspectives. This has resulted in the funding of three additional projects in the first call of the BlOMED 2 programme. The most important one is using animal models to address the issue of interspecies transmission and to assess the efficacy of the species barrier in limiting the transmission of BSE to humans. Although the available resources are limited, the second call for proposals of the BlOMED 2 programme, which had a deadline of 17 June 1996, will give the possibility to support a few proposals in this field. Within Member States and associated countries, research in the field of SEs has been addressed at two levels: - Clinical research and surveillance of human SEs. - Basic biology of human and animal SEs. An overview of the activities undertaken at national level in this field is presented in Annex 1. This text, which is not exhaustive, has been compiled on the basis of information provided during the meeting of Directors-General for Research from Member States (held in Brussels, June 1996) aimed at exchanging information on activities undertaken in the field of SEs and establishing mechanisms reinforcing cooperation and coordination, and reports presented at the last meeting of the Office International des Epizooties (OIE), held in Paris on 8-10 October 1996. Community activities have initiated. the possibility of reinforcing the surveillance system for CJD and related diseases in the countries involved and have allowed the establishment of inter-country comparisons and the identification and characterization of the disease(s). the development of harmonized procedures for Such a system could be used as a base for the development of standard procedures for disease identification and surveillance in all Member States. 4. Weissmann Group advice in the context of ongoing research activities The Weissmann Report presents a thorough analysis of the needs in the field of BSE research and addresses two types of questions, namely questions related to practical aspects of BSE and questions related to basic research on prion diseases. 4. 1. Questions related to practical aspects. These include: 4. 1. 1 Has BSE been transmitted to man perorallv? The appearance since 1996 of an apparently new clinicopathological variant of Creutzfeldt- Jakob disease in fifteen teenagers and young adults (14 in UK, 1 in France) has raised concerns about the possible transmission of the BSE agent to man via the food chain. Evidence in favour of such a possibility is based on the fact that the BSE agent can be experimentally transmitted perorally to mice, mink, cattle, goats and sheep, and it could be that the strain-specific properties of the BSE agent are retained after passaging through a variety of animals such as sheep, pigs, goats or mice and differ from those of the passaged scrapie agent. However, given the present state of the art, no definite conclusions on such a possibility can be reached. Several experimental approaches are proposed in order to throw more light on this question: in the United Kingdom and will be "Comparison of agent strains recovered from patients affected by vCJD with BSE and normal CJD, GSSS and FFI strains" (Table 1, item 1. 1). Such experiments are partly under way underpinned by Community research activities but should be reinforced; "Extension of a surveillance programme for CJD" (Table 1, item 1. 2). A European surveillance programme on CJD has been running since 1990, contributing to the identification of the new variant of the disease. Such an initiative should be reinforced to ensure identification at European level of all CJD cases which may correspond to the new variant of the disease, reinforcement of epidemiological analysis of the data and identification of all epidemiological tools which may be necessary for broadening the assessment of risk transmission; "Experimental peroral transmission of BSE to primates". Such an approach has not yet been pursued but it is considered to be the best way to answer the above- mentioned question" (Table 1, item 4. 1). include all Member States and in order to 4. 1. 2 Assessment of risk associated with consumption of cattle-derived products "The assessment of risk for the transmission of BSE to man as a function of BSE incidence in the cattle population and of consumption of cattle-derived products is one of the most important issues to be solved. In order to be able to perform a proper risk assessment, the following actions should be implemented": "Extension of the surveillance programme of BSE to all Member States, establishing wide and reliable standardized criteria for BSE detection and characterization". Such an initiative will allow to obtain exact figures on the incidence of the disease in the different Member States (Table 1, item 4. 2); "Determination of the incidence of covert disease in cattle", allowing to obtain figures on the number of animals that, although symptomless at present, show the infectious agent in the nervous system (Table 1, item 4. 3); "Determination of infectivity titers of brain, spinal cord and other tissues of BSE- infected cattle before and after outbreak of clinical disease" (Table 1, item 4. 4); ° ° "Determination of the level of meat contamination with brain/spinal cord after standard butchering procedures" (Table 1, item 4. 6); "Determination of oral feeding and intracerebral dose responses to BSE agent in primates and whether multiple dosing is cumulative" (Table 1, item 4. 7); "Determination of the utilization of offal in different human products prior to the ban and the consumption of such products by individual age groups and by socio economic criteria" (Table 1, item 4. 5). Research on risk assessment in relation to consumption of cattle-derived products and research transmission modalities has so far not been supported by any Community programme. This important area of research could be addressed mainly in the FAIR programme, but also in the BlOMED programme. 4. 1. 3 Determination of possible infectivity in BSE infected cattle-derived products other than SBO (Table 1, item 4. 4) At present, infectivity has been found in the brain, eye and spinal cord of diseased cattle and in the intestinal wall of calves experimentally infected with brain from BSE-infected cattle. However, the available assays for detecting infectivity are not very sensitive. essential to: It is therefore "implement detection assays in order to examine all products entering the human food chain (muscle, milk, cheese, blood) and used in pharmaceutical products (gelatin, collagen, etc. )" 4. 1. 4 Evaluation of maternal risk factors for BSE in cattle (Table 1, item 4. 8). "Determine infectivity in placenta, blood, colostrum, milk and excrements of BSE cattle using sensitive assays" Transmission studies on a wide range of tissues from confirmed cases of BSE have already been carried out in the UK using mice as the model for bioassay. These studies have had all negative results to date. The objective now is to repeat these studies using a more sensitive bioassay. 4. 1. 5 Did BSE originate in cattle and has it been transmitted to sheep in recent years? (Table 1, item 4. 1) To address this issue it would be necessary to develop the following initiatives: "To extend the surveillance of scrapie in UK sheep" "To examine the infectious agent derived from recent cases of sheep scrapie in regard to its strain properties" "To feed scrapie-infected brain from sheep to cattle and then monitor for appearance of BSE-like disease" 4. 1. 6 Can BSE be transmitted orally to pigs and chickens? (Table 1, item 4. 1) inoculation of pigs with Intracerebral Peroral transmissibility of BSE from BSE cattle brain to pigs is actually being tested in the UK. Inoculation of chickens with BSE intracerebral^ has not so far resulted in signs of disease. the BSE agent infection. leads to It would be of interest to determine whether pig-to-pig transmission occurs, in particular orally. Therefore, it is proposed to: "feed and inject brain extract of experimentally BSE infected pigs to pigs" 4. 1. 7 Diagnostic research (Table 1, item 3. 2) "There is still no rapid, specific and sensitive method to detect human and animal SEs. than by analysis of central nervous system (CNS) tissue, by infectivity assays". It is therefore proposed to: ° ° 0 in transgenic mice carrying cattle "develop a sensitive assay cattle/mouse chimeric PrP genes" "explore surrogate markers" "explore the presence of PrPsc in tonsils and spleen of man" "sponsor a large-scale facility for assaying BSE infectivity in calves" transgenes or On this issue, infectivity assays in calves (currently the most sensitive assay for the BSE agent) are being performed on a large-scale basis by the Ministry of Agriculture, Fisheries and Food in the United Kingdom. Also bioassays in mice are sensitive but may. not be able to detect low levels of the agent. Development of diagnostics must be underpinned by basic research on the infectious agent. 4. 1. 8 Inactivation of the BSE agent under different conditions (Table 1, item 5. 1). ° "Determine inactivation kinetics of BSE infectivity under conditions used currently in industry and explore additional procedures" This will allow to determine the efficiency of BSE agent inactivation by procedures used in food and the pharmaceutical industry. Industry studies have been carried out on inactivation (i. e. gelatin) but these should be further validated under the FAIR programme. Provisional results of a study on the inactivation of BSE and scrapie in rendering processes (supported by the CAMAR programme) have been received during 1996. 4. 1. 9 Therapeutic research (Table 1, item 5. 2), No therapy is at present available. Possible approaches for further research in this field could include: "specific inhibition of PrP synthesis" prevention of the conversion of PrPc into the pathological form PrPsc Not addressed so far by any Community research programme. Should be based on fundamental research which will establish and identify the nature of the agent. 4. 1. 10 Can BSE-resistant cattle and sheep be generated and would these be of practical use? (Table 1, item 5. 3) It has been shown that inactivation of the prion protein (PrP) gene has no major detrimental effect on the mouse and it confers absolute protection against the disease. Further research should be pursued on the means to: "determine whether sheep devoid of the prion protein are viable and resistant to scrapie", develop methods for generating cattle devoid of PrP. ° Transgenic cattle devoid of the prion protein may be of practical use in the pharmaceutical industry. 8 4. 2 Questions related to basic research on prion diseases The following issues deserving further investigation are as follows: 4. 2. 1 The nature of the infectious agent The exact nature of the infectious agent is still not understood. Reinforcement of research in this area should be pursued with the aim of : * * "Purification of the infected agent from BSE-infected cattle brain and analysis" (Table 1, item 2. 1) "Identification of the three-dimensional structure of both PrPc and PrP"" (Table 1, item 2. 4) Several Community research programmes are at present addressing this issue. 4. 2. 2. Multiplication of the agent In order to assess the issue of multiplication, the following approaches should be pursued: * * "Determine whether PrPc can be converted into the infectious agent in vitro" (Table 1, item 2. 4) "Determine which other components (receptors?, etc) are required for propagation of the infectious agent" (Table 1, item 2. 2). 4. 2. 3. Pathogenesis (Table 1, item 2. 2) The pathogenesis of the disease is not yet understood. Further research should be pursued in order to acquire knowledge of the precise mechanism of pathogenesis, the cell types and tissues which can replicate the infectious agent, and the biochemical requirements for such a process. On the issue of pathogenesis of SEs, one research project is actually being supported at Community level. The project intends to assess the role of the prion protein in the activation of glial cells as final neurodegeneration, and is being supported within the BlOMED 2 programme. the sequence of events first mechanism leading the to in 4. 2. 4. Transport of the infectious agent (Table 1, item 2. 2) Further research should be pursued on the issue of transport of the agent within the organism, in order to: 0 "determine where and how the agent enters the organism after ingestion" "determine how the agent passes from the periphery to the central nervous system and vice-versa". 4. 2. 5. Research on different agent strains (Table 1, item 2. 3) Further research should be pursued in order to: "explain what is the molecular feature of the infectious agent that determines strain specificity" The mechanisms of prion propagation and the characteristics of strain specificity are being partly assessed in an ongoing Community research project supported within the BlOMED 2 programme. 4. 2. 6. Susceptibility of the host to the infectious agent (Table 1, item 2. 6) Research in this area should be pursued in order to : ° the genetic factors which contribute "identify incubation time" "determine which factors other than the sequence of PrP determines the species barrier" to susceptibility and determine The identification of genetic factors which could contribute to confer susceptibility to the disease are currently being partly assessed in an ongoing Community research project supported within the BlOMED 2 programme. 4. 2. 7. Natural function of PrP (Table 1, item 2. 4) At present its function is unknown. Research should be pursued in order to obtain further knowledge of the normal function of this protein and to characterize what happens in its absence. 5. Action plan for future activities The action plan has been established taking into account the recommendations put forward in the Weissmann Report and the Multidisciplinary Scientific Committee as well as analysis of ongoing Community and national research activities. It will comprise two levels: the coordination of activities between Member States; - - a specific Call for Proposals, in order to create a critical mass by pooling the best research centres in Europe. 5. 1. The coordination of activities between all Member States (see Table 2) Harmonisation of data collection and diagnostic criteria for the detection and identification of the disease(s) within Member States is essential for a proper comparatibility. Coordination of activities between Member States should therefore essentially ensure: a) standardization of case definitions for collection of data, of data analysis and of dissemination of information in order to ensure a proper surveillance, b) harmonised procedures for early detection and diagnosis of the disease(s), c) continuous updating and dissemination of scientific knowledge in this field, d) fluent and rapid dissemination of these data, e) activation of an early warning system in case of crucial developments, f) exchange and mobility activities including training of research staff, g) a continuous inventory of the progress of national research programmes, h) the establishment of harmonized procedures and quality control of diagnostic methods for human and animal SEs. To this aim coordination of national specialized reference centres on SEs should be fostered, notably by the setting up of a research network of these centres aimed at: - - - the establishment and use of harmonized criteria for collection and evaluation of data, case definition and classification of the disease(s) the development of an efficient and on informatisation), the exchange of staff. line communication system (through 10 The participants should be able to harmonise and share scientific and technical resources and services provided by each agreed centre. The network should have an user-oriented approach providing European researchers with regular distribution of and access to relevant information and training activities. This coordination with Member States will need active input from the relevant Programme Committees. 5. 2. Specific Call for Proposals The following areas of research have been identified (see Table 1, point 7. 1 of the Financial Statement): 5. 2. 1. Clinical, epidemiological and social research on human SEs (see Table 1, item 1) The continued analysis of incidence, clinical features and risk factors for diseases of the CJD type in European countries is likely to be crucial in an assessment of any change of the incidence of the disease(s). Reinforcement and further development of the epidemiological surveillance of CJD and related diseases should therefore be pursued with the aim of assessing: 1. 1 1. 2 1. 3 incidence (including a comparison of agent strains recovered from variant CJD patients with BSE and "normal" CJD, GSSS and FFI strains réévaluation of previously diagnosed CJD cases), the geographical distribution and role of specific risk factors (genotype, diet, exposure, environment); the process of identification of suspected cases and the sensitivity of surveillance system; the 5. 2. 2. The infectious agent and its mechanisms of transmission (see Table 1. item 2) The precise structure of the agent is unknown, as are the mechanisms of transmission. Research reinforcing the characterization of the agent and the mechanisms involved in the pathological process should be pursued with the aim of assessing: 2. 1 2. 2 2. 3 2. 4 2. 5 2. 6 the characterization of the agent; the mechanisms of propagation, transport and pathogenesis including elucidation of possible common links with other neurodegenerative diseases; the characterization of the different strains, including comparison of scrapie strains with BSE; the structure of both PrPc and PrPsc, the normal function of PrPc and the mechanisms of conversion of PrPc into PrPsc; the basis of species barriers limiting inter- and intra-species transmission; the susceptibility factors for the development of animal and human prion diseases. 5. 2. 3. Diagnosis of SEs (see Table 1, item 3) Despite the urgent need, no early diagnostic tools are available at present. Reinforcement of research allowing for the production of diagnostic tools should therefore be pursued with the aim of allowing: further development of cell cultures and banks for tissues and cells; 3. 1 3. 2 development of rapid and sensitive early diagnostic tests including surrogate markers, especially in living animals and humans; 11 3. 3 development of sensitive assay in transgenic mice carrying cattle transgenes or cattle/mouse chimeric PrP genes 5. 2. 4. Risk assessment of SEs (see Table 1, item 4) Epidemiological evidence has raised concerns that the so called variant CJD is linked to the consumption of products derived from BSE-infected cattle. Moreover, the BSE agent is orally transmissible to a number of species including: mice, mink, cats, cattle, sheep, goats and various other ruminants. In order to perform an estimation of the risk of transmission of the disease, the following areas should therefore be pursued: 4. 1 an evaluation of SEs transmission modalities (including oral transmission) from cattle to man and other food animals, environmental vectors e. g. mites. 4. 2 an extended surveillance programme of BSE and related diseases 4. 3 4. 4 the identification of covert disease in cattle the determination of the infectivity titers in cattle tissues and cattle derived products entering the human food chain or used in pharmaceutical and cosmetic products the potential exposure of the human population 4. 5 4. 6 determination of the level of meat contamination by brain/spinal cord after standard butchering procedures 4. 7 determination of oral feeding and intracerebral dose response to BSE agent and whether multiple dosing is cumulative investigation of possible biological mechanisms of maternal transmission of BSE 4. 8 5. 2. 5. Treatment and prevention of SEs (see Table 1, item 5) At present no therapies are available. Reinforcement of research in this field should be pursued with the aim of allowing: 5. 1 Assessment and development of inactivation procedures currently used in industry 5. 2 5. 3 (food, pharmaceutical, cosmetics) the development of therapeutic approaches; the development of methods for generating cattle and sheep devoid of PrP and practical use of these animals. 6. Priority setting and financial arrangements The European Union has been involved in research on SEs since 1990. This initiative has resulted research in the support of 11 research projects within several Community programmes (CAMAR, BlOMED 1 and 2, BIOTECH 1 and AIR) with an overall budget contribution of 3. 545 MECU (2. 120 MECU during the 2nd and 3rd Framework Programmes and 1. 425 MECU for the 4th Framework Programme). Table 1 depicts the total estimated costs and additional resources needed to address the research priorities in the field of BSE and prion-associated diseases for the period 1997- 1998. The specific Call for Proposals outlined in item 5 identifies five priority areas in the field of SEs deserving further investment. The breakdown provided for each area is based on the assumption that at least one research project and, in several cases, more than one, should be supported in order to fully implement the research priorities outlined. 12 The setting of a usual research Community project involves up to five research laboratories with an average contribution per laboratory, per year, of 100,000 ECU. This amount has demonstrated to cover the salary of one scientist (66,000 ECU/year), half the salary of a technician (20,000 ECU/year) and the necessary consumable and equipment material to perform the research tasks to be carried out by the laboratory. For the implementation of a concerted action, where the main objective is the sharing of information and the gathering of different expertises and methodologies, the average contribution deemed necessary to implement the work is estimated to be 10,000 ECU per laboratory, per year. This will cover the costs for travel meetings, short-term exchange of staff and exchange of material for each laboratory. For the implementation of a centralized facility, defined as a unique general service tool for other projects supported by the specific action plan in order to enable standardization, joint experiments, data collection and analysis with access to particular products, experimental materials, specialised services (e. g primate research expertise), the Community funding may cover 100% of the costs of the costs of services rendered by the Centralized Facility to the research center, universities, undertakings and enterprises participating in shared cost and concerted actions. 6. 1 Total estimated costs and additional resources needed to address the specific Call for Proposals Table 1 point 7. 1 of the Financial Statement provides an overview of the total financial resources needed to implement each of the areas depicted in the specific call for proposals. These include: 6. 1. 1 Clinical and epidemiological research on human SEs The BlOMED 2 programme, key specific programme in terms of research on human SEs, will be in charge of the implementation of this area. At present the BlOMED 2 programme is practically completed with all Calls for Proposals having already been launched. Strategies for the redeployment of financial resources could therefore not be envisaged. However, it is expected that, as a result of the last Call for Proposals in BlOMED 2, one project could be supported. Therefore, and in order to fully implement this research area, additional resources are necessary. 6. 1. 2 The infectious agent and its mechanisms of transmission implementation of The three specific programmes (BlOMED 2, BIOTECH 2 and FAIR), depending on the specific issues to be tackled. this research area could be done within the At present, ongoing research activities in this area within the BlOMED 2 programme partially address issues such as the pathogenic mechanisms of prion diseases, the structure of the normal and abnormal prion protein, the basis of species barriers and the susceptibility factors for the development of human prion diseases, with an overall Community contribution of 1. 425 MECU. In addition, and as a result of the 2nd Call for Proposals of the BlOMED 2 programme (deadline 17 June 1996), a further budgetary commitment is expected. Within the BIOTECH. 2 and FAIR programmes, a limited budget could be reshifted in order to address specific transport and pathogenesis of the prion agent. the mechanisms of propagation, issues such as 13 Additional resources are therefore needed in order to fully implement research in this field. 6. 1. 3 Diagnosis of SEs This area of research will be implemented by the three programmes. At present, no ongoing Community research activities are implementing the outlined priorities. Ongoing calls in the BlOMED 2 and FAIR programmes could be able to mobilise funds aiming at addressing the issue of the development of rapid and sensitive early diagnostic tests. Similarly, an estimated budget could be reshifted towards this area of research from the BIOTECH 2 and the FAIR programmes. Therefore, and necessary. in order to allow a proper implementation, supplementary funds are 6. 1. 4 Risk assessment of SEs The research areas programmes. included are covered by the BlOMED 2, BIOTECH and FAIR At present, no ongoing research activity within the Community research programmes is addressing this issue. The possibility of reshifting financial resources within the FAIR programme towards this domain could be envisaged. This initiative will allow to initiate the financial support of projects addressing areas such as the evaluation of BSE transmission modalities, the determination of the infectivity titers in cattle tissues or the evaluation of the risk of maternal transmission for BSE. Therefore, and in order to fully implement the important aspect of the transmission modalities of BSE (including oral transmission) where studies on primates may be necessary (BlOMED 2), additional resources are necessary. 6. 1. 5 Treatment and prevention of SEs research approaches aimed at developing The area coverr therapeutic compounds and prevention strategies and could be developed within the three specific programmes (BlOMED 2, BIOTECH and FAIR), depending on the specific issue to be tackled. inactivation procedures, At present, no ongoing Community research activities are dealing with these issues. The possibilities of reshifting resources towards the FAIR programme are envisaged and will allow to initiate supporting research irw this area. Additional resources are heeded to allow a full implementation of the tasks. 6. 2 Total estimated costs and additional resources needed for the coordination of activities between Member States The total estimated costs necessary for the full implementation of this activity, based on the assumption of the participation of one laboratory per Member State, are depicted in Table 2, point 7. 1 of the Financial Statement. 14 TOTAL ESTIMATED COSTS AND ADDITIONAL RESOURCES NEEDED TO ADDRESS THE RESEARCH PRIORITIES IN THE FIELD OF BSE AND SUBACUTE SPONGIFORM ENCEPHALOPATHIES (1997-1998) TABLE 1 Research area Priority Total Estimated cost in ** MECU's Existing EU contribution *** MECU's Prospects for EU funding MECU's Possible EU funding with redeployment MECU's Additional resources needed ** MECU's 1. 1. 1 1. 2 1. 3 '• 1. 4 2. 2. 1 2. 2 2. 3 2. 4 2. 5 2. 6 3. 3. 1 3. 2 3. 3 Clinical, epidemiological and social research on human SE's compare agent strains recovered from vCJD patients with BSE and "normal" CJD, GSSS and FFI strains; a * the incidence (including réévaluation of previously diagnosed CJD cases), geographical distribution and role of specific risk factors (genotype, diet exposure, environment);D * the process of identification of suspected cases and the sensitivity of the surveillance system the research on risk perception of the population in relation to prion diseases;D The infectious agent and its mechanisms of transmission the characterization of the agent;D * the mechanisms of propagation, transport and pathogenesis (special attention will be given to the possibility of oral transmission) including elucidation of possible common links with other neurodegenerative diseases;D * characterization of the different strains, compare scrapie strains with BSE;D* the structure of both PrPc and PrP", the normal function of PrPc and the mechanisms of conversion of PrP° into PrP" in vitro;D * the basis of species barrier limiting inter- and intra-species transmission;!!) * the susceptibility factors for the development of animal and human prion diseasesD * Diagnrsis OF SE's further develonment of cell cultures, and banks for tissues and cells;D * development of rapid and sensitive early diagnostic tests including surrogate markers, specially in living animals and humans;D * development of sensitive assay In transgenic mice D * A A A A A A A A A A A A A 1. 5 2. 0 •0. 5 0. 5 Total: 4. 5 2. 5 4. 8 0. 8 1. 5 1. 4 1. 1 0. 5 Biomed Total: 0. 5: 0. 4 Biomed 0. 4 Biomed 0. 5 Biotech 1. 5 Biomed 1. 5 Biomed 0. 5 Biomed 0. 5 Biomed Total: 4. 0 2. 5 Biotech/Fair 3. 5 Biotech Biomed/Fair 0. 3 Fair 0. 5 Biomed/Biotech 0. 5 Biomed 0. 5 Biomed 0. 1 Biomed 0. 5 Biomed 0. 4 Biomed 0. 5 Fair Total: 12. 1 Total: 1. 5 Total: 1. 3 Total: 1. 3 0. 5 Biomed / Biotech 0. 5 Biomed/Biotech 0. 5 Biomed Total: 8. 0 1. 0 7. 6 1. 3 2. 0 Fair 0. 6 Biomed 0. 5 Biotech 0. 5 Biotech 1. 5 Fair 3. 5 Fair/Biom/Biotech 0. 5 Fair 0. 8 Biotech/Fair Total: 9. 9 Total: 2. 6 Total: 2. 5 Total: 4. 8 4. 4. 1 4. 2 4. 3 4. 4 4. 5 4. 6 4. 7 4. 8 5. 5. 1 5. 2 5. 3 Risk assessment of SE's an evaluation of SE's transmission modalities (including oral transmission) from cattle to man and other food animals, environmental vectorsD * extended surveillance programme on BSE and related diseasesD * Identification of covert disease in cattle * determination of the infectivity titres in cattle tissues and cattle derived products entering the human food chain or used in pharmaceutical and cosmetics productsD * the potential exposure of the human population D * determination of the level of meat contamination by brain/spinal cord after standard butchering procedures * determination of oral feeding and intracerebral dose responses to BSE agent and whether multiple doses is cumulative * investigation of possible biological mechanisms of maternel transmission of BSE* Treatment and prevention of SE's Assessment and development of inactivation procedures currently used in industry; * (food, pharmaceuticals, cosmetics) development of therapeutic approachesD * generation of cattle and sheep devoid of PrPD * A A A A A A A A A A C 4. 5 2. 0 2. 0 3. 5 0. 5 0. 5 1-0 1. 0 Total: 15 1. 7 2. 0 0. 5 Total: 4. 2 2. 0 Fair 1. 5 Fair 0. 5 Fair 0. 5 Fair 0. 5 Fair Total: 5. 0 4. 5 Biomed/Fair 2. 0 Fair — 2. 0 Fair/Biotech 0. 5 Biomed 0. 5 Fair 0. 5 Fair Total: 10 1. 0 Fair 0. 7 Fair/Biotech 2. 0 Biomed/Biotech 0. 5 Fair Total: 1. 0 Total: 3. 2 TOTAL Priorities are: A>B>C 45. 7 1-5 4. 4 Î. 8 30. 0 * D ** Weissmann report Background for the proposal of an European Initiative at the Research Council of October 7, 1996 The following assumption is made: 100. 000 ECU's per laboratory per year (including 1 scientist for 12 months = 66. 000 ECU, 1/2 technician for 12 months = 20. 000 ECU, consumables and equipment) *** EU-contribution under IV FP **** in collaboration with national authorities LM\w\tabcost ^ TOTAL ESTIMATED COSTS AND ADDITIONAL RESOURCES NEEDED TO ADDRESS THE COORDINATION OF ACTIVITIES BETWEEN MEMBER STATES IN THE FIELD OF BSE AND SUBACUTE SPONGIFORM ENCEPHALOPATHIES (1997-1998) TABLE 2 Research area Priority Total Estimated cost in ** MECU's Existing EU - contribution MECU's Prospects for EU funding MECU's Possible EU funding with redeployment MECU's Additional resources needed** MECU's A. B. C. Standardization of case definitions for collection of data, of data analysis and of dissemination of information in order to ensure a proper surveillance Harmonised procedures for early detection and diagnosis of the disease(s)D Continuous updating and dissemination of scientific knowledge in this field • D. Fluent and rapid dissemination of these data • Activation of an early warning system in case of crucial developments • Exchange and mobility activities including training of research staff D A continuous inventory of the progress of national research programmes D Harmonisation and control of diagnostic methods for human and animal SE's D E. F. G. H. TOTAL A A A A A A A A 1. 00. 0. 50 0. 35 0. 35 0. 35 0. 60 0. 35 1. 50 5. 0 - - 1. 00 0. 50 0. 35 0. 35 0. 35 0. 60 0. 35 1. 50 5. 0 • ** Background for the proposal of an European Initiative at the Research Council of October 7, 1996 For area A and H the following assuption is made: +/- 75,000 ECU per laboratory in each Member State and associated c. ountries for 2 years (including 1/2 scientist, consumables, travel and equipment) and additional 10,000 ECU to the laboratory responsible for the overall coordination. For areas B, C, D, F, E the following assuption is made: +/- 20,000 ECU per laboratory in each Member State and associated countries for 2 years (including 1/4 scientist, technician, equipment, consumables and travel costs) For area F, the following assumption is made: +/- 35,000 ECU per laboratory in each Member State and associated countries for 2 years. LNf\w\tabcosl2 OVERVIEW ON NATIONAL RESEARCH ACTIVITIES IN THE FIELD OF BSE/CJD ANNEX 1 MEMBER STATES 1. Austria Research on spongiform encephalopathies (SEs) in Austria is centred at the Department of Neuropathology and Neurochemistry, Institute of Neurology of the University of Vienna. The main areas of research in this centre includes the epidemiology (the department has performed an epidemiological study of the incidence of CJD in Austria) and neuropathology of human SEs (CJD and gerstmann-Straussler-Scheiker disease (GSS)). In addition, the above mentioned department coordinates a Community research programme gathering 100 European neuropathological and basic research laboratories dealing with neuropathologic diagnosis of, and tissue based research in, human SEs. The network has defined criteria for neuropathological diagnosis of, and tissue handling in human SEs. 2. Belgium This country is involved in research in the field of SEs in the following areas: Epidemiological surveillance of BSE/scrapie, funded by the Agricultural ministry. * No specific programme on SEs is set up at present. 3. Denmark No specific programme on SEs exists at present. A new national register for CJD has been set up and a programme on mutation screening for PrP is going to be developed. 4. Finland Research in this field is focused on the following areas: * * * Neuropathology of human SEs Surveillance of human SEs (familial form of CJD) Molecular pathology of SEs The work is being carried out at the University of Helsinki. At present, no special programmes on the subject have been set up. 5. France A national reference centre for animal SEs was set up in 1990 (CNEVA, Lyon). A National Advisory Expert Committee for SEs has been established in 1996. Sixteen laboratories are working in the field of prion diseases. The main areas of research include: * * Characterization of the french BSE strains (CNEVA, Lyon) Characterization of the PrP gene polymorphism linked to scrapie resistance (INRA, Toulouse) 18 * * * * Characterization of the number of infected cattle in a herd where a single case has been identified (CNEVA, Lyon) Research for new diagnostic tools Research for criteria of inactivation of MBM in various rendering systems (CNEVA, INRA, CEMAGREF, to be implemented) Transmission studies (using transgenic animals) and studies on the structure of the agent and on the function of PrP. These include: - Study of the role of the immune system in the development of the prion agent at early stages of infection Role of PrP in the development of the disease In vitro studies, using a cellular model, of normal and pathological PrP Conformational studies on PrP structure Cellular localisation of normal and pathologic PrP and structure of amyloid plaques Research on possibilities, using two experimental models, to block accumulation of PrP at different stages of the disease Analysis of transmission mechanisms of the disease * Epidemiological research including research on risk factors for the development of SEs (genetic, diet, environmental): surveillance of CJD and related diseases research on genetic factors favouring the development of SEs and comparison with Alzheimer and related diseases Genetic and clinic follow-up of a cohort of 1000 individuals receiving growth hormone apparently contaminated with the infectious agent (1984-1985) among which 35 cases of CJD have been diagnosed. The above mentioned work is being carried out at the CNRS, Units 9026 (Bordeaux), 2420 and 2431 (Gif sur Yvette) and 9045 (Villejuif), INSERM, Units 415 (Lille), 153 and 360 (Paris), 180 and 431 (Montpellier), INRA (Jouy-en-Josas, Tours, Toulouse), CEA-DSV (Fontenay-aux- Roses). 6. Germany TSE research in Germany is supported by the ministries of Research, Health and Agriculture. Major areas of research involve both animal and human SEs in the following areas: * * * Structure and function of PrP including the structure and structural transformation of the infectious prion protein and the structural mapping Pathogenesis, function and therapy including investigations on pathogenic mechanisms of SEs in cell cultures of PrP% mice, the use of PrP% mice as an experimental system for the investigation of infectivity and cell biology of the prion proteins, the characterization of the prion protein domains responsible for the disease, the chemoprophylaxis and chemotherapy of prion infections Diagnostics and transmission including the establishment of cell culture titration methods for the detection of the scrapie agent, the oral infection of hamster with the scrapie agent and the production of antibodies against prion proteins of humans and animals This work Institute of is being carried out at the Deutsches Primatenzentrum and Neuropathology (Gottingen), DKFZ (Heidelberg), Robert Koch Institut (Berlin), Institute for 19 Molecular Biology (Mùnchen), Federal Research Institut for Viral Diseases of Animals (Tubingen), Institut for Physiological Chemistry (Mainz), Institut for Physical Biology. (Dusseldorf) and GBF, Structural Research (Braunschweig). 7. Greece Research in the field of SEs is developed within the following areas: * * * Comparative study of carbohydrates in BSE and normal cow brains Improvement of scrapie diagnosis and study of scrapie infectious agent Characterization of the BSE infectious agent. On this subject the University of Thessaloniki (Department of Pharmacology) is coordinator of a Community research. In addition, this laboratory is participating to three other Community research projects. Sponsoring bodies are the Greek National Research Foundation, the Greek Ministry of Development and the National Office of Programming in Cyprus. At present, no special programmes on SEs have been set up. 8. Ireland Research in this field is mainly developed at the Veterinary Research Laboratory Abbottown (Dublin) and the Zoology Department University College of Dublin. The main area of research include the development of rabbit polyclonal antisera to a number of synthetic PrP peptides which have been assessed immunohistochemically for their ability to differentiate BSE and scrapie affected tissues from negative tissues. Recently, a Scientific Committee has been set up to establish priorities in this field. 9. Italy Italy is performing research in this field within two main areas: Surveillance epidemiology of CJD and other prion related encephalopathies in humans and animals; identification of patients with mutations and/or polymorphisms in the PrPN gene collection of CJD patients information in selected institutions and studies of familial clusters with identification of genotypes and possible point mutations. ° Neuropathology and basic research identification of new phenotypes for these diseases; study of synthetic PrP peptides: biological effects, physico-chemical properties relevant to biology, interaction with plasma membranes; study of cells with mutated PrPN fragments; interaction drug-amyloid in vitro and in vivo. The National Research Council (CNP) has recently launched a strategic research project on BSE covering the areas of: physiopathology of SEs research about transmission mechanisms between italian breeds. ° 20 The Ministry of Health, through the Institute of Zooprofilaxis and Veterinary Diseases, is sponsoring a programme on "Integrative measures for the permanent surveillance of BSE". The Istituto Superiore di Sanità is supporting the National Registry for Surveillance of CJD (coordinator Prof. M. Pocchiari). The two main institutions in Italy developing research in this field are the Istituto Superiore di Sanità (Rome) and the Istituto Neurologico Carlo Besta (Milan). 10. Netherlands The main areas of research in the field of SEs include: Development of tools for diagnostic methods on scrapie and BSE Antigenic studies of bovine prion protein Immunohistochemical detection of PrP in brain for scrapie diagnosis Immunohistochemical detection of prion protein on lymphoid tissues of diseased and infected sheeps Genetic resistance to scrapie ° ° 0 The above mentioned work is being carried out at the Institute for Animal Science and Health (ID-DLO) Lelystad. In addtion, this Institute is coordinator of a Community research programme aimed at assessing the role of PrPsc in glial activation. This country has also been deeply involved, through the work carried out at the Department of Epidemiology and Biostatistics (Erasmus University Medical School), in the epidemiological surveillance of CJD, as part of the Community research project on surveillance for this disease. The Dutch Health Council is at present preparing a strategy for research on SEs which will be available soon. 11. Portugal A national programme on surveillance of scrapie has been recently set up. They are also setting up the basis to develop a national registry for CJD. 12. Spain No specific programme on SEs research exists at present. This country has been taking part, as an observer, to the European surveillance network on CJD and is setting up a national register for the disease. 13. Sweden No specific programme set up for SEs. No BSE, few cases of scrapie 14. United Kingdom Priorities for government research on animal SEs are currently based on specific needs as they are identified and advice from the Spongiform Encephalopathy Advisory Committee (SEAC). 21 The Ministry for Agriculture, Fisheries and Food (MAFF) programme is complemented by the research programmes of the Biotechnological and Biological Science Research Council (BBSRC); the Medical Research Council (MRC); the Department of Health (DH) and the Wellcome Trust. Coordination between these group is achieved by liaison at several levels most recently through the Transmissible Spongiform Encephalopathy Research and Development Funders Coordination Group, chaired by the Department of Health. Five main areas are addressed (as defined in the SEAC report, 1995) covering both human and animal prion diseases: a) Nature of the agent Research on this issue is being sponsored by the MAFF, the BSEP, the Biotechnological and Biological Science Research Council (BBSRC), the MRC, the BBSRC/MRC Core and the Wellcome Trust. Institutions involved include the Universities of Edinburgh, Reading, the Imperial College of Science, Technology and Medicine of London, the Animal Health Trust and the Institute for Animal Health. b) Pathological changes Research in this field is. being carried out by the Universities of Edinburgh, Birmingham, Nottingham, the Imperial College of London, the Institute of Zoology and the Central Veterinary Laboratory (CVL). Sponsoring bodies include the MAFF, BBSRC/MRC, the MRC, the BSEP and the Wellcome Trust. c) Transmission studies including transgenic animals Substantial research in this field is being performed at the Neuropathogenesis Unit of the Institute for Animal Health (NPU, Edinburgh), University of Cambridge and Imperial College of London, the CVL, the Scottish Agricultural College and the Agricultural Development Advisory Board. Sponsoring bodies include the MAFF, BSEP, the BBSRC/MRC Core and Wellcome Trust. d) Control of BSE epidemic Research on this issue is being sponsored mainly by the MAFF, at the NPU, the CVL, the Agricultural Development Advisory Board and the University of Edinburgh. e) Applied guestions including CJD surveillance CJD has been monitored nationally since 1990. This issue is being carried out at the National CJD Surveillance Unit (Edinburgh), the NPU, the CVL and the Imperial College of London, St. Mary's Hospital, and is mainly supported by the MAFF, DH, Scottish Home and Health Department (SHHD), EC and MRC. A specific Coordination Programme on Health Aspects of Transmissible Spongiform Encephalopathies (SEs) has been recently set up in this country, with major fundings from the Agricultural Ministry, the Medical Research Council and the Welcome Trust. 22 The MRC, jointly with the Department of Health, has proposed a 10 year initiative to be developed in two 5-year phases. This initiative intends to strengthen research capacity (skills and infrastructure), increase collaboration between existing centres of expertise and to improve understanding by public and health professionals of prion diseases and associated risks. A call for proposals has recently been launched in identified areas. The programme has a strong human health orientation with broad biological approach. The main priority scientific themes are: * * * * * * * * Molecular, cellular, genetic and functional approaches to elucidating mechanisms of TSEs transmission, PrP replication, pathogenesis and clinical progression Integrated molecular, epidemiological and clinical approaches to understanding the cause(s) of sporadic CJD Biological and epidemiological relationship between BSE and CJD and atypical dementias Early disease progression and diagnosis in life Analysis, perception and communication of risk in relation to CJD The biological function of normal PrP The molecular structure of prion proteins Rational approaches to developing therapy ASSOCIATED COUNTRIES AND THIRD COUNTRIES 1. Norway A research programme in the field of animal and human SEs has been recently proposed. The programme includes: ° Norwegian College of Veterinary Medicine Prevalence studies of scrapie changes in scrapie affected herds Genetic disposition of scrapie in Norwegian herds Comparative studies of absorption and persistence of scrapie-agent in intestine and lymphatic tissues in sheep and CDJ in humans Comparative studies of post mortefn changes in scrapie affected sheep and CJD in humans Survey on genetic disposition in sheep herds for factors involved in the normal function of prion proteins and the development of disease. Central Veterinary Laboratories Development of sensitive methods for detection of prion proteins in vivo Epidemiological studies of risk factors in outbreaks of scrapie in sheep herds National Institute of Public Health Epidemiological studies of risk factors involved in development of CJD in humans Improved surveillance of CJD and other human spongiform encephalopathies in Norway by establishing criteria for diagnosis Development of models of cooperation between human and veterinary medicine in the field of prion diseases The three above mentioned institutions will be in charge of implementing the proposed plan. 23 2. Iceland In Iceland there is a specific knowledge on the pathology and epidemiology of scrapie, as scrapie has been endemic in some parts of this country. The work carried out at the Institute of Experimental Pathology at Keldur has been the basis for the eradication programme of scrapie in Iceland. In addition, two new areas of research are being implemented: ° 3. ° ° Research on the effect of prion gene genotypes on scrapie susceptibility in Icelandic sheep Study of mutations and DNA polymorphism in three CJD patients in Iceland. Switzerland Two reference centres for human and animal SEs In situ hybridization and immunochemistry for PrP in BSE (Institute of Animal neuropathology, Bern) Case control study / BSE risk assessment in Switzerland (Institut for virology and immunoprophylaxis, Mittelhausern). 24 \e 7S. (0. $ t FICHE FINANCIERE 1. INTITULE DE L'ACTION Communication de la Commission au Conseil relative à la recherche sur l'encéphalopathie spongiforme bovine (ESB) et les encephalopathies spongiformes subaigûes. 2. LIGNE BUDGETAIRE IVème P. C. : - Biotechnologie - B6 7141 - Biomédecine - B6 7142 - Agriculture et pêche - B6 7143 3. BASE LEGALE Décision du Conseil n° 94/912/CE du 15/12/94 adoptant un programme spécifique dans le domaine de la Biotechnologie. Décision du Conseil n° 94 913/CE du 15/12/94 adoptant un programme spécifique dans le domaine de la Biomédecine et de la Santé. Décision du Conseil n° 94/805/CE du 23/11/94 adoptant un programme spécifique dans le domaine de l'Agriculture et de la Pêche. Décision n° 616/96/CE du Conseil et du Parlement européen du 25 mars 1996 4. OBJECTIFS ET DESCRIPTION Malgré les efforts actuellement déployés dans îa recherche fondamentale et clinique en matière d'Encéphalopathie Spongiforme Bovine (ESB) et d'Encéphalopathies Spongiformes subaigiies, il n'a pas été possible à ce jour d'identifier la nature des facteurs infectieux de ces maladies, de même que de nombreux agents épidémiologiques des encephalopathies spongiformes humaines. Ces facteurs doivent pourtant être identifiés pour que la lutte contre ces maladies puisse s'avérer efficace. Il est par conséquent essentiel de mobiliser la communauté scientifique et de stimuler les efforts de recherche à un niveau communautaire. Ces efforts nécessiteront la mobilisation de nouvelles équipes de recherche afin de créer une masse critique. Dans cette optique, l'objectif fondamental de la présente communication est de renforcer les activités de recherche sur l'Encéphalopathie Spongiforme Bovine (ESB) et les Encephalopathies Spongiformes subaigiies. Cet objectif comporte deux volets d'actions , à savoir : la coordination des activities nationales ; -L7 \e 2S. /0. J 4 les travaux à lancer sur base d'un appel à propositions supplémentaire, spécifique aux domaines de la recherche clinique et épidémiologique, de l'agent infectieux et des mécanismes de transmission, du diagnostic, de l'évaluation du risque, du traitement et de la prévention. 5. TYPE DE CREDITS Dépenses non obligatoires/Crédits dissociés 6. TYPE DE DEPENSES Les actions à frais partagés qui consistent en projets de RDT et des projets de démonstration font l'objet d'une participation ne dépassant pas 50- %. Les universités et autres centres de recherche qui participent à des projets de RDT et des projets de démonstration, et qui ne peuvent justifier leurs coûts totaux avec suffisamment de précision, selon la Commission, sur la base d'un système de comptabilité analytique, seront financés à 100 % des coûts additionnels. Les actions concertées peuvent faire l'objet d'une participation allant jusqu'à 100 % des coûts additionnels. 7. INCIDENCE FINANCIERE 7. 1 Mode de calcul du coût total de l'action (en MECU) Les crédits nécessaires à la réalisation des objectifs visés au point 4 font partie de l'augmentation prévue dans la proposition intitulée "Proposition de décision du Parlement Européen et du Conseil portant deuxième adaptation de la décision 1110/94/CE. telle qu'adaptée par la décision 616/96/CE, relative au quatrième programme cadre pour des actions de recherche, de développement technologique et de démonstration (1994-1998)", qui est soumise à l'approbation en codécision du Parlement et du Conseil et à l'allocation préalable des fonds par l'autorité budgétaire. Du point de vue financier, la présente fiche financière ne concerne que la ventilation des crédits en engagement et en paiement entre l'année 1997 et 1999+ des montants suivants: Coordination des activités Recherches prioritaires Biotechnologie Biomédecine et Santé Agriculture et Pêche 3,5 1,5 7,5 12,5 10 Total 7,5 16 11,5 Cette estimation globale peut être détaillée, à titre purement indicatif, suivant les données reprises dans les tableaux 1 et 2 ci-après. ic TOTAL ESTIMATED COSTS AND ADDITIONAL RESOURCES NEEDED TO ADDRESS THE RESEARCH PRIORITIES IN THE FIELD OF BSE AND SUBACUTE SPONGIFORM ENCEPHALOPATHIES (1997-1998) TABLE 1 Research area Priority Total Estimated cost in ** MECU's Existing EU contribution *** MECU's Prospects for EU funding MECU's Possible EU funding with , redeployment MECU's Additional resources needed ** MECU's 1. 1. 1 1. 2 1. 3 1. 4 2. 2. 1 2. 2 2. 3 2. 4 2. 5 2. 6 3. 3. 1 3. 2 3. 3 Clinical and epidemiological and social research on human SE's compare agent strains recovered from vCJD patients with BSE and "normal" CJD, GSSS and FFI strains; D * the incidence (including réévaluation of previously diagnosed CJD cases), geographical distribution and role of specific risk factors (genotype, diet exposure, environment);D * the process of identification of suspected cases and the sensitivity of the surveillance system the research on risk perception of the population in relation to prion diseases;D The infectious agent and its mechanisms of transmission the characterization of the agent;• * the mechanisms of propagation, transport and pathogenesis (special attention will be given to the possibility of oral transmission) including elucidation of possible common links with other neurodegenerative diseases;D * characterization of the different strains, compare scrapie strains with BSE;D* the structure of both PrP' and PrP", the normal function of PrP° and the mechanisms of conversion of PrPc into PrP" in vitro;D * the basis of species barrier limiting inter- and intra-species transmission^ * the susceptibility factors for the development of animal and human prion diseasesD * Diagnosis OF SE's further development of cell cultures, and banks for tissues and cells;D * development of rapid and sensitive early diagnostic tests including surrogate markers, specially in living animals and humans;D * development of sensitive assay in transgenic mice • * A A A A A A A A A A A A A LM\w\abco»t 1. 5 2. 0 0. 5 0. 5 Total: 4. 5 2. 5 4. 8 0. 8 1. 5 1. 4 1. 1 0. 5 Biomed Total: 0. 5 0. 4 Biomed 0. 4 Biomed 0. 5 Biotech 0. 5 Biomed 0. 5 Biomed 0. 1 Biomed 0. 5 Biomed 0. 4 Biomed 0. 3 Fair 0. 5 Fair Total: 12. 1 Total: 1. 5 Total: 1. 3 Total: 1. 3 1. 5 Biomed 1. 5 Biomed 0. 5 Biomed 0. 5 Biomed Total: 4. 0 2. 5 Biotech/Fair 3. 5 Biotech Biomed/Fair 0. 5 Biomed/Biotech 0. 5 Biomed / Biotech 0. 5 Biomed/Biotech 0. 5 Biomed Total: 8. 0 1. 0 7. 6 1. 3 2. 0 Fair 0. 6 Biomed 0. 5 Biotech 0. 5 Biotech 1. 5 Fair 3. 5 Fair/Biom/Biotech ' 0. 5 Fair 0. 8 Biotech/Fair Total: 9. 9 Total: 2. 6 Total: 2. 5 Total: 4. 8 ; # 4. 4. 1 4. 2 4. 3 4. 4 4. 5 4. 6 4. 7 4. 8 5. 5. 1 5. 2 5. 3 Risk assessment of SE's an evaluation of SE's transmission modalities (including oral transmission) from cattle to man and other food animals, environmental vectorsD * extended surveillance programme on BSE and related diseasesD * identification of covert disease in cattle * determination of the infectivity titres in cattle tissues and cattle derived products entering the human food chain or used in pharmaceutical and cosmetics productsD * the potential exposure of the human population D * determination of the level of meat contamination by brain/spinal cord after standard butchering procedures * determination of oral feeding and intracerebral dose responses to BSE agent and whether multiple doses is cumulative * investigation of possible biological mechanisms of maternel transmission of BSE* Treatment and prevention of SE's Assessment and development of inactivation procedures currently used in industry; * (food, pharmaceuticals, cosmetics) development of therapeutic approachesD * generation of cattle and sheep devoid of PrPD * A A A A A A A A A A C 4. 5 2. 0 2. 0 3. 5 0. 5 0. 5 1. 0 1. 0 Total: 15 1. 7 2. 0 0. 5 Total: 4. 2 ^ ^ _ _ ^ __ 4. 5 Biomed/Fair 2. 0 Fair * *" 2. 0 Fair/Biotech 0. 5 Biomed 0. 5 Fair 0. 5 Fair Total: 10 2. 0 Fair 1. 5 Fair 0. 5 Fair 0. 5 Fair 0. 5 Fair Total: 5. 0 1. 0 Fair 0. 7 Fair/Biotech 2. 0 Biomed/Biotech 0. 5 Fair Total: 1. 0 Total: 3. 2 TOTAL Priorities are: A>B>C 45. 7 1. 5 4. 4 9. 8 30. 0 * • Weissmann report Background for the proposal of an European Initiative at the Research Council of October 7, 1996 ** The following assumption is made: 100. 000 ECU's per laboratory per year (including 1 scientist for 12 months = 66. 000 ECU, 1/2 technician for 12 months = 20. 000 ECU, consumables and equipment) *** EU-contribution under IV FP **** in collaboration with national authorities 64 LM\w\ubco*t TOTAL ESTIMATED COSTS AND ADDITIONAL RESOURCES NEEDED TO ADDRESS THE COORDINATION OF ACTIVITIES BETWEEN MEMBER STATES IN THE FIELD OF BSE AND SUBACUTE SPONGIFORM ENCEPHALOPATHIES (1997-1998) TABLE 2 Research area Priority Total Estimated cost in ** MECU's Existing EU contribution MECU's Prospects for EU funding MECU's Possible EU funding with redeployment MECU's Additional resources needed** MECU's A. B. C. Standardization of case definitions for collection of data, of data analysis and of dissemination of information in order to ensure a. proper surveillance Harmonised procedures for early detection and diagnosis of the disease(s)D Continuous updating and dissemination of scientific knowledge in this field • D. Fluent and rapid dissemination of these data • £. F. G. H. Activation of an early warning system in case of crucial developments D Exchange and mobility activities including training of research staff D A continuous inventory of the progress of national research programmes • Harmonisation and control of diagnostic methods for human and animal SE's D TOTAL A A A A A A A A 1. 00 0. 50. 0. 35 0. 35 0. 35 0. 60 0. 35 1. 50 5. 0 1. 00 0. 50 0. 35 0. 35 0. 35 0. 60 0. 35 1. 50 5. 0 D ** Background for the proposal of an European Initiative at the Research Council of October 7, 1996 For area A and H the following assuption is made: +/- 75,000 ECU per laboratory in each Member State and associated countries for 2 years (including 1/2 scientist, consumables, travel and equipment) and additional 10,000 ECU to the laboratory responsible for the overall coordination. For areas B, C, D, F, E the following assuption is made: +/- 20,000 ECU per laboratory in each Member State and associated countries for 2 years (including 1/4 scientist, technician, equipment, consumables and travel costs) I For area F, the following assumption is made: +/- 35,000 ECU per laboratory in each Member State and associated countries for 2 years. LM\vv\iabcosi2 \<*î. {0. 3<o 7. 2 Echéancier indicatif(1) Pour le programme spécifique " Biotechnologie" - ligne budgétaire : B6 - 7141 En MECU 1995 1996 1997 1998 1999 + TOTAL Crédits d'engagement( ' Crédits d'engagement additionnels 70,037 230,000 132,000 155,963 PM 588,000 2,250 5,250 7,500 Crédits de paiement0' 19,789 115,666 124,200 163,000 165,345 588,000 Crédits de paiement additionnels 4,500 3,000 7,500 i Pour le programme spécifique "biomédecine" - ligne budgétaire : B6 - 7142 En MECU 1995 1996 1997 1998 1999 + TOTAL Crédits d'engagemenr ' Crédits d'engagement additionnels 37,833 126,000 90,000 104,167 PM 358,000 4,800 11,200 16,000 Crédits de paiement(1) 10,831 49,000 85,800 95,000 117,369 358,000 Crédits de paiement additionnels 9,600 6,400 16,000 Pour le programme spécifique "Agriculture et Pêche" - ligne budgétaire : B6-7143 En MECU 1995 1996 1997 1998 1999 + TOTAL Crédits d'engagemenr * Crédits d'engagement additionnels 120,737 181,000 162,000 182,763 PM 646,500 3,450 8,050 11,500 Crédits de paiement(1) 19,768 70,000 U4. 7C0 230,000 212,032 646,500 Crédits de paiement additionnels 6,900 4,600 11,500 Les montants annuels définitifs seront déterminés par l'Autorité Budgétaire. (1) Crédits du PC IV, tels que repris dans l'APB 1997 o~ ^ o. i^io. sy 7. 3 Dépenses administratives et de personnel En ce qui concerne les dépenses administratives, les programmes veilleront à ce que le montant global du complément financier alloué soit prioritairement utilisé pour financer les actions de recherche (tel que prévu dans la proposition visée au point 4). 8. MESURES ANTI-FRAUDES De nombreux contrôles administratifs et financiers existent à tous les stades de la passation et de l'exécution des contrats de recherche. Parmi ces contrôles, on peut citer: Au stade antérieur de la conclusion : Sélection initiale des propositions sur base de la valeur scientifique du projet et du réalisme du coût de la recherche par rapport à sa nature, sa durée et ses impacts potentiels. Analyse des informations financières transmises par les proposants dans le formulaire de négociation. Après la signature du contrat :» Examen des relevés de dépenses avant paiement, à plusieurs niveaux (gestionnaire financier, responsable scientifique). Audit interne réalisé par le Contrôleur financier Contrôle sur place permettant, par l'examen des documents justificatifs, de détecter les erreurs ou autres irrégularités. Afin de renforcer l'efficacité de ces contrôles,- les services de la Commission ont créé une cellule audit qui centralise l'ensemble dès contrôles effectués. Ces contrôles sont effectués soit par les membres de la cellule audit, soit confiés à des firmes d'audit avec lesquelles la Commission a conclu des contrats-cadre, sous la supervision du personnel de la cellule d'audit. Inspections sur place réalisées par le Contrôleur financier et par la Cour des Comptes de l'Union européenne. 9. ELEMENTS D'ANALYSE COUT-EFFICACITE 9. 1 Objectifs spécifiques et quantifiables L'objectif général, tel que décrit dans le point 4, se traduit dans 6 objectifs spécifiques. Ces objectifs peuvent être groupés comme suit : 3/ s-^ïSjojC a. Les priorités de la recherche en matière d'Encéphalopathie Spongiforme Bovine (ESB) et les Encephalopathies Spongiformes subaigiies : - recherche clinique et épidémiologique des encephalopathies spongiformes humaines ; - les agents infectieux et leurs mécanismes de transmission ; - le diagnostic des encephalopathies spongiformes humaines ; - l'évaluation du risque des encephalopathies spongiformes humaines ; - le traitement et la prévention des encephalopathies spongiformes humaines. b. La coordination des activités de recherche, en matière d'Encéphalopathie Spongiforme Bovine (ESB) et les Encephalopathies Spongiformes subaigiies, entre les Etats membres. Les ressources nécessaires à la réalisation de ces objectifs ont été calculées en fonction des critères suivants : - Une proposition comportera en moyenne 5 laboratoires. - La contribution de la Communauté européenne à chaque laboratoire devra varier entre 10. 000 Ecus et 100. 000 Ecus par an. Ces objectifs seront réalisés par les modalités suivantes : actions à frais partagés, ainsi que des actions concertées. Ces actions seront renforcées par des outils à vocation générale au service des chercheurs et par une formation ciblée de ces chercheurs ("workshops", conférences interdisciplinaires, études, etc. ). 9. 2 Population visée Destinataires immédiats : les chercheurs de l'industrie et du monde académique ainsi que les cliniciens des hôpitaux et les ingénieurs. Destinataires finaux : les citoyens européens ayant accès aux résultats de la recherche ; les consommateurs ; les secteurs alimentaires ; les agriculteurs. 9. 3 Justification de l'action Les encephalopathies spongiformes (ES) sont un groupe de maladies transmissibles neurodegeneratives létales humaines (kuru, maladie de Creutzfeldt-Jakob (MCJ), maladie de Gerstmann-Straussler-Scheinker (MGSS), et animales (Scrapie, encéphalopathie spongiforme bovine (ESB). 3t Hf; Z5. /o. ;H Ces maladies sont l'objet de recherches de plus en plus importantes en raison d'une part de leur biologie particulière, et d'autre part des inquiétudes concernant la possible transmission à l'homme de l'agent infectieux. Il est donc essentiel que ce groupe de maladies devienne une priorité scientifique. Cela nécessite une stimulation des efforts de recherche au niveau communautaire et la construction de nouveaux équilibres scientifiques, afin de créer une masse critique. 9. 4 Suivi et évaluation de l'action Le suivi de l'action sera effectué par les services des DG responsables de son exécution, aidés par les Comités de programme. Afin de contribuer à l'évaluation globale des activités communautaires prévues à l'article 4. 2 de la décision arrêtant le quatrième programme-cadre de la Communauté européenne pour des actions de recherche, de développement technologique et de démonstration, la Commission fait procéder, en temps utile, par des experts indépendants, à une évaluation des activités menées dans le domaine directement couvert par les présents programmes et de leur gestion durant les cinq années qui précèdent l'évaluation. Cette action sera activités par ailleurs évaluée dans la faisant partie du quatrième programme-cadre. communautaires Commission fait procéder, en temps utile, par des experts indépendants, à une évaluation des activités et de leur gestion durant les cinq années qui précèdent cette évaluation. l'évaluation globale des le cadre de En effet, Les contrats qui seront signés dans le cadre de l'action décrite au point 4 et 9. 1 feront l'objet d'un rapport intermédiaire, ainsi que d'un rapport final. Il sera tenu compte des rapports suivants lors de la préparation du cinquième programme- cadre : - Rapport annuel de la Commission relatif aux activités de recherche et de développement technologique de l'Union européenne basé sur l'article 130P du Traité CE. - Un rapport annuel de contrôle continu de chaque programme spécifique ainsi que du programme-cadre. Celui-ci sera élaboré par des experts indépendants. - Un rapport d'évaluation quinquennal de chaque programme spécifique ainsi que du programme-cadre. Celui-ci sera également élaboré par des experts indépendants et publié en 1996. 13 ISSN 0254-1475 COM(96) 582 final DOCUMENTS EN 03 15 Catalogue number : CB-CO-96-589-EN-C ISBN 92-78-11627-0 Office for Official Publications of the European Communities L-2985 Luxembourg


title: Γνωμοδότηση της Επιτροπής των Περιφερειών για την «Ευρωπαϊκή εθελοντική Θητεία για τους νέους»

eurovoc_concepts:
action programme
voluntary military service
young person

formats: html pdfa1b print


title: Πρόταση ΑΠΟΦΑΣΗΣ ΤΟΥ ΣΥΜΒΟΥΛΙΟΥ για τη χορήγηση κοινοτικής εγγύησης στην Ευρωπαϊκή Τράπεζα Επενδύσεων σε περίπτωση ζημιών από δάνεια που έχουν χορηγηθεί για σχέδια εκτός της Κοινότητας - (Κεντρική και Ανατολική Ευρώπη, χώρες της Μεσογείου, Λατινική Αμερική και Ασία και Νότιος Αφρική)

eurovoc_concepts:
Community budget
EIB loan
credit guarantee
financial aid
third country


title: KOMISSION ASETUS (EY) N:o 2183/96, annettu 13 päivänä marraskuuta 1996, oliiviöljyn enimmäisvientitukien vahvistamisesta asetuksella (EY) N:o 2081/96 avatun pysyvän tarjouskilpailun osana toteutettua ensimmäistä osittaista tarjouskilpailua varten

eurovoc_concepts:
award of contract
export refund
olive oil


title: 96/643/EY: Komission päätös, tehty 13 päivänä marraskuuta 1996, suu- ja sorkkatautitapausten vuoksi toteutettavista Bulgariasta peräisin olevien tiettyjen eläinten ja niistä saatujen tuotteiden tuontia koskevista suojatoimenpiteistä (ETA:n kannalta merkityksellinen teksti)

eurovoc_concepts:
Bulgaria
animal product
foot-and-mouth disease
health certificate
import
milk product


title: Entschließung zum Bericht der Kommission an den Rat und das Europäische Parlament über den Binnenmarkt 1995 (KOM(96) 0051 - C4-0146/96)

eurovoc_concepts:
European Commission
activity report
single market

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