COMMUNICATION FROM THE COMMISSION - A European initiative on transmissible spongiform encephalopathies (TSE)
Date: 1996-11-13
Institutions: European Commission
Subjects: EU financing, animal disease, cattle, infectious disease, medical research

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