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 
become concerned over the consequences of this 
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 
very poorly understood, in addition, there is no 
treatment at present. 
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): 
clinical and epidemiological research on human 
spongiform encephalopathies (SE); 
the infectious agent and its transmission 
mechanisms; 
diagnosis of SE; 
evaluation of the risk of SE; 
treatment and prevention of SE. 
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. For example, 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). 
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 
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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 
1. The funding of research projects on TSE can only be 
carried out through the 3 "Life Sciences". specific 
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: "Research on Aids, 
Tuberculosis and other infectious 
diseases" 
BIOTECH 2: Area 4: "Cell Communication in 
Neurosciences" 
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 
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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. 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 for 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 the 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. 
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 
the action plan on TSE research annexed to this 
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 for research and 
development, for which the Commission is preparing a 
second revised proposal to be submitted to the council 
and European Parliament for opinion. 
A i 
European Initiative into Bovine Spongiform Encephalopathy 
and Subacute Spongiform Encephalopathies 
SUMMARY 
1. Introduction 
2. The Needs 
3. Current Research Activities in the Field of SEs at Community and 
National Levels 
4. 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 
5.1 The coordination of activities between Member States 
5.2 Specific Call for Proposals 
6. Priority Setting and Financial Arrangements 
6.1 Total estimated costs and additional resources needed to 
address the specific Call for Proposals 
6.2 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: 
In 1990, a European Community seminar on "Subacute spongiform 
encephalopathies" was organised. The meeting was attended by scientists from 18 
countries, representatives of the World Health Organisation (WHO) and 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. 
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 Biomedicine and Health Research programme (1990-1994, BlOMED 1), which 
supported the establishment of a network 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 development of harmonized procedures for the 
identification and characterization of the disease(s). 
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: 
"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 in the United Kingdom and will be 
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 in order to include all Member States and 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). 
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 
transmission modalities has so far not been supported by any Community research 
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. It is therefore 
essential to: 
"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) 
Intracerebral inoculation of pigs with the BSE agent leads to infection. 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. 
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: 
° "develop a sensitive assay in transgenic mice carrying cattle transgenes or 
cattle/mouse chimeric PrP genes" 
° "explore surrogate markers" 
"explore the presence of PrPsc in tonsils and spleen of man" 
0 "sponsor a large-scale facility for assaying BSE infectivity in calves" 
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 the first mechanism in the sequence of events leading to final 
neurodegeneration, and is being supported within the BlOMED 2 programme. 
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: 
"determine where and how the agent enters the organism after ingestion" 
0 "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 : 
"identify the genetic factors which contribute to susceptibility and determine 
incubation time" 
° "determine which factors other than the sequence of PrP determines the species 
barrier" 
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 line communication system (through 
informatisation), 
- the exchange of staff. 
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 a comparison of agent strains recovered from variant CJD patients with BSE and 
"normal" CJD, GSSS and FFI strains 
1.2 the incidence (including réévaluation of previously diagnosed CJD cases), 
geographical distribution and role of specific risk factors (genotype, diet, exposure, 
environment); 
1.3 the process of identification of suspected cases and the sensitivity of the 
surveillance system; 
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 the characterization of the agent; 
2.2 the mechanisms of propagation, transport and pathogenesis including elucidation of 
possible common links with other neurodegenerative diseases; 
2.3 the characterization of the different strains, including comparison of scrapie strains 
with BSE; 
2.4 the structure of both PrPc and PrPsc, the normal function of PrPc and the mechanisms 
of conversion of PrPc into PrPsc; 
2.5 the basis of species barriers limiting inter- and intra-species transmission; 
2.6 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: 
3.1 further development of cell cultures and banks for tissues and cells; 
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 the identification of covert disease in cattle 
4.4 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 
4.5 the potential exposure of the human population 
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 
4.8 investigation of possible biological mechanisms of maternal transmission of BSE 
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 
(food, pharmaceutical, cosmetics) 
5.2 the development of therapeutic approaches; 
5.3 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 in the support of 11 research projects within several Community research 
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 
The implementation of this research area could be done within the three specific 
programmes (BlOMED 2, BIOTECH 2 and FAIR), depending on the specific issues to be 
tackled. 
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 issues such as the mechanisms of propagation, transport and 
pathogenesis of the prion agent. 
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 in order to allow a proper implementation, supplementary funds are 
necessary. 
6.1.4 Risk assessment of SEs 
The research areas included are covered by the BlOMED 2, BIOTECH and FAIR 
programmes. 
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 
The area coverr research approaches aimed at developing inactivation procedures, 
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. 
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 
1. Clinical, epidemiological and social research on human SE's 
1.1 compare agent strains recovered from vCJD patients with BSE and "normal" 
CJD, GSSS and FFI strains; a * 
1.2 the incidence (including réévaluation of previously diagnosed CJD cases), 
geographical distribution and role of specific risk factors (genotype, diet 
exposure, environment);D * 
1.3 '• the process of identification of suspected cases and the sensitivity of the 
surveillance system 
1.4 the research on risk perception of the population in relation to prion 
diseases;D 
2. The infectious agent and its mechanisms of transmission 
2.1 the characterization of the agent;D * 
2.2 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 * 
2.3 characterization of the different strains, compare scrapie strains with 
BSE;D* 
2.4 the structure of both PrPc and PrP", the normal function of PrPc and the 
mechanisms of conversion of PrP° into PrP" in vitro;D * 
2.5 the basis of species barrier limiting inter- and intra-species transmission;!!) * 
2.6 the susceptibility factors for the development of animal and human prion 
diseasesD * 
3. Diagnrsis OF SE's 
3.1 further develonment of cell cultures, and banks for tissues and cells;D * 
3.2 development of rapid and sensitive early diagnostic tests including surrogate 
markers, specially in living animals and humans;D * 
3.3 development of sensitive assay In transgenic mice D * Priority 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A Total Estimated 
cost in ** 
MECU's 
1.5 
2.0 
•0.5 
0.5 
Total: 4.5 
2.5 
4.8 
0.8 
1.5 
1.4 
1.1 
Total: 12.1 
1.0 
7.6 
1.3 
Total: 9.9 Existing EU 
contribution *** 
MECU's 
0.4 Biomed 
0.5 Biomed 
0.5 Biomed 
0.1 Biomed 
Total: 1.5 Prospects for EU 
funding MECU's 
0.5 Biomed 
Total: 0.5: 
0.4 Biomed 
0.5 Biomed 
0.4 Biomed 
Total: 1.3 
2.0 Fair 
0.6 Biomed 
Total: 2.6 Possible EU 
funding with 
redeployment 
MECU's 
0.5 Biotech 
0.3 Fair 
0.5 Fair 
Total: 1.3 
0.5 Biotech 
1.5 Fair 
0.5 Fair 
Total: 2.5 Additional resources needed ** 
MECU's 
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 
0.5 Biotech 
3.5 Fair/Biom/Biotech 
0.8 Biotech/Fair 
Total: 4.8 
4. Risk assessment of SE's 
4.1 an evaluation of SE's transmission modalities (including oral transmission) 
from cattle to man and other food animals, environmental vectorsD * 
4.2 extended surveillance programme on BSE and related diseasesD * 
4.3 Identification of covert disease in cattle * 
4.4 determination of the infectivity titres in cattle tissues and cattle derived 
products entering the human food chain or used in pharmaceutical and 
cosmetics productsD * 
4.5 the potential exposure of the human population D * 
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 responses to BSE 
agent and whether multiple doses is cumulative * 
4.8 investigation of possible biological mechanisms of maternel transmission of 
BSE* 
5. 
Treatment and prevention of SE's 
5.1 Assessment and development of inactivation procedures currently used in 
industry; * (food, pharmaceuticals, cosmetics) 
5.2 development of therapeutic approachesD * 
5.3 generation of cattle and sheep devoid of PrPD * 
TOTAL 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 
45.7 1-5 4.4 2.0 Fair 
1.5 Fair 
0.5 Fair 
0.5 Fair 
0.5 Fair 
Total: 5.0 
1.0 Fair 
Total: 1.0 
Î.8 4.5 Biomed/Fair 
2.0 Fair — 
2.0 Fair/Biotech 
0.5 Biomed 
0.5 Fair 
0.5 Fair 
Total: 10 
0.7 Fair/Biotech 
2.0 Biomed/Biotech 
0.5 Fair 
Total: 3.2 
30.0 
Priorities are: A>B>C 
* Weissmann report 
D 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 
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)D 
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 D 
G. A continuous inventory of the progress of national research 
programmes D 
H. Harmonisation and control of diagnostic methods for human 
and animal SE's D 
TOTAL Priority 
A 
A 
A 
A 
A 
A 
A 
A Total 
Estimated 
cost in ** 
MECU's 
1.00 
.0.50 
0.35 
0.35 
0.35 
0.60 
0.35 
1.50 
5.0 Existing EU 
- contribution 
MECU's 
-Prospects 
for EU 
funding 
MECU's 
-Possible EU 
funding with 
redeployment 
MECU's Additional resources 
needed** MECU's 
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 is being carried out at the Deutsches Primatenzentrum and Institute of 
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 
0 Genetic resistance to scrapie 
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: 
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. 
3. 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 
agents infectieux de ces maladies, de même que de nombreux facteurs 
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 
5. 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. 
TYPE DE CREDITS 
6. Dépenses non obligatoires/Crédits dissociés 
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: 
Biotechnologie 
Biomédecine et Santé 
Agriculture et Pêche Coordination des 
activités 
3,5 
1,5 Recherches 
prioritaires 
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 
1. Clinical and epidemiological and social research on human SE's 
1.1 compare agent strains recovered from vCJD patients with BSE and "normal" 
CJD, GSSS and FFI strains; D * 
1.2 the incidence (including réévaluation of previously diagnosed CJD cases), 
geographical distribution and role of specific risk factors (genotype, diet 
exposure, environment);D * 
1.3 the process of identification of suspected cases and the sensitivity of the 
surveillance system 
1.4 the research on risk perception of the population in relation to prion 
diseases;D 
2. The infectious agent and its mechanisms of transmission 
2.1 the characterization of the agent;• * 
2.2 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 * 
2.3 characterization of the different strains, compare scrapie strains with 
BSE;D* 
2.4 the structure of both PrP' and PrP", the normal function of PrP° and the 
mechanisms of conversion of PrPc into PrP" in vitro;D * 
2.5 the basis of species barrier limiting inter- and intra-species transmission^ * 
2.6 the susceptibility factors for the development of animal and human prion 
diseasesD * 
3. Diagnosis OF SE's 
3.1 further development of cell cultures, and banks for tissues and cells;D * 
3.2 development of rapid and sensitive early diagnostic tests including surrogate 
markers, specially in living animals and humans;D * 
3.3 development of sensitive assay in transgenic mice • * Priority 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A Total Estimated 
cost in ** 
MECU's 
1.5 
2.0 
0.5 
0.5 
Total: 4.5 
2.5 
4.8 
0.8 
1.5 
1.4 
1.1 
Total: 12.1 
1.0 
7.6 
1.3 
Total: 9.9 Existing EU 
contribution *** 
MECU's 
0.4 Biomed 
0.5 Biomed 
0.5 Biomed 
0.1 Biomed 
Total: 1.5 Prospects for EU 
funding MECU's 
0.5 Biomed 
Total: 0.5 
0.4 Biomed 
0.5 Biomed 
0.4 Biomed 
Total: 1.3 
2.0 Fair 
0.6 Biomed 
Total: 2.6 Possible EU 
funding with 
, redeployment 
MECU's 
0.5 Biotech 
0.3 Fair 
0.5 Fair 
Total: 1.3 
0.5 Biotech 
1.5 Fair 
' 0.5 Fair 
Total: 2.5 Additional resources needed ** 
MECU's 
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 
0.5 Biotech 
3.5 Fair/Biom/Biotech 
0.8 Biotech/Fair 
Total: 4.8 ; 
# 
LM\w\abco»t 
4. Risk assessment of SE's 
4.1 an evaluation of SE's transmission modalities (including oral transmission) 
from cattle to man and other food animals, environmental vectorsD * 
4.2 extended surveillance programme on BSE and related diseasesD * 
4.3 identification of covert disease in cattle * 
4.4 determination of the infectivity titres in cattle tissues and cattle derived 
products entering the human food chain or used in pharmaceutical and 
cosmetics productsD * 
4.5 the potential exposure of the human population D * 
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 responses to BSE 
agent and whether multiple doses is cumulative * 
4.8 investigation of possible biological mechanisms of maternel transmission of 
BSE* 
5. 
Treatment and prevention of SE's 
5.1 Assessment and development of inactivation procedures currently used in 
industry; * (food, pharmaceuticals, cosmetics) 
5.2 development of therapeutic approachesD * 
5.3 generation of cattle and sheep devoid of PrPD * 
TOTAL 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 
45.7 1.5 4.4 2.0 Fair 
1.5 Fair 
0.5 Fair 
0.5 Fair 
0.5 Fair 
Total: 5.0 
1.0 Fair 
Total: 1.0 
9.8 ^^__^__ 
4.5 Biomed/Fair 
2.0 Fair **" 
2.0 Fair/Biotech 
0.5 Biomed 
0.5 Fair 
0.5 Fair 
Total: 10 
0.7 Fair/Biotech 
2.0 Biomed/Biotech 
0.5 Fair 
Total: 3.2 
30.0 
Priorities are: A>B>C 
* 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 
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)D 
C. 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 D 
F. Exchange and mobility activities including training of 
research staff D 
G. A continuous inventory of the progress of national research 
programmes • 
H. Harmonisation and control of diagnostic methods for human 
and animal SE's D 
TOTAL Priority 
A 
A 
A 
A 
A 
A 
A 
A Total 
Estimated 
cost in ** 
MECU's 
1.00 
0.50 
. 0.35 
0.35 
0.35 
0.60 
0.35 
1.50 
5.0 Existing EU 
contribution 
MECU's Prospects 
for EU 
funding 
MECU's Possible EU 
funding with 
redeployment 
MECU's Additional resources 
needed** MECU's 
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 
Crédits 
d'engagement( ' 
Crédits d'engagement 
additionnels 
Crédits de paiement0' 
Crédits de paiement 
additionnels 1995 
70,037 
19,789 1996 
230,000 
115,666 1997 
132,000 
2,250 
124,200 1998 
155,963 
5,250 
163,000 
4,500 1999 + 
PM 
165,345 
3,000 TOTAL 
588,000 
7,500 
588,000 
7,500 
i 
Pour le programme spécifique "biomédecine" - ligne budgétaire : B6 - 7142 
En MECU 
Crédits 
d'engagemenr ' 
Crédits d'engagement 
additionnels 
Crédits de paiement(1) 
Crédits de paiement 
additionnels 1995 
37,833 
10,831 1996 
126,000 
49,000 1997 
90,000 
4,800 
85,800 1998 
104,167 
11,200 
95,000 
9,600 1999 + 
PM 
117,369 
6,400 TOTAL 
358,000 
16,000 
358,000 
16,000 
Pour le programme spécifique "Agriculture et Pêche" - ligne budgétaire : B6-7143 
En MECU 
Crédits 
d'engagemenr * 
Crédits d'engagement 
additionnels 
Crédits de paiement(1) 
Crédits de paiement 
additionnels 1995 
120,737 
19,768 1996 
181,000 
70,000 1997 
162,000 
3,450 
U4.7C0 1998 
182,763 
8,050 
230,000 
6,900 1999 + 
PM 
212,032 
4,600 TOTAL 
646,500 
11,500 
646,500 
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 
par ailleurs évaluée dans le cadre de l'évaluation globale des activités 
communautaires faisant partie du quatrième programme-cadre. En effet, la 
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. 
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 
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