Proposal for a European Parliament and Council Directive on the approximation of provisions laid down by law, regulation or administrative action relating to the implementation of Good Clinical Practice in the conduct of clinical trials on medicinal products for human use
Date: 1997-09-03
Institutions: European Commission
Subjects: approximation of laws, market approval, pharmaceutical product, testing, therapeutics

SffitiPfffPP 

COMMISSION OF THE EUROPEAN COMMUNITIES 

Brussels,  03.09.1997 
COM(97) 369  final 

97/0197  (COD) 

Proposal  for  a 

EUROPEAN  PARLIAMENT  AND  COUNCIL  DIRECTIVE 

on the approximation  of provisions laid down by law, regulation or administrative action 
relating to the implementation of Good Clinical Practice in the conduct  of clinical trials on 
medicinal products for human use 

(presented  by the  Commission) 

Explanatory Memorandum 

1.  BACKGROUND 

With  the  introduction  of  the  first  legislation  dealing  with  pharmaceuticals,  twin 
principles  of  protection  of  public  health  and  free  movement  of  products  were 
enshrined.  Directive  65/65/EEC  on  the  approximation  of  provisions  laid  down  by 
law,  regulation  or  administrative  action  relating  to  medicinal  products  requires  that 
medicinal  products  must  have a marketing  authorisation  prior  to  being  placed  on  the 
market  in  the  European  Community.  Further,  the  criteria  upon  which  access  to  the 
marketplace  is  determined  -  quality,  safety  and  efficacy  -  have  been  clearly  set  out. 
Demonstration,  particularly  of the latter  two generally  rely  on clinical  trials  in  human 
subjects. 

The  standards  for  the  conduct  of  clinical  trials  have  been  developed  progressively, 
both  within  the  European  Community  and  internationally.  These  standards  were 
codified  in the  European  Union  guideline  on  Good  Clinical  Practice  (GCP)  in  1990 
and  are  followed  in  clinical  research  by  the  pharmaceutical  industry.  With  the 
globalisation  of  the  pharmaceutical  industry,  the  international  harmonisation  of  the 
standards  of were  also  undertaken  - in the  forum  of the  International  Conference  on 
Harmonisation. 

Since  January  1997,  the  internationally  harmonised  GCP  is  now  incorporated  into 
'The  rules 
clinical  practice  within  the  Community  by  virtue  of  their  inclusion  in 
governing  medicinal  products  in the European  Union'  published  by  the  Commission 
in  accordance  with  the  annex  to  Directive  75/318/EEC  on  the  approximation  of  the 
laws  of  Member  States  relating  to  analytical,  pharmacotoxicological  and  clinical 
standards  and  protocols  in  respect  of the  testing  of  medicinal  products  as  amended. 
Because  such  guidelines  are  not  binding,  a  supportive  legislative  framework  is 
required.  This  is to  be  achieved  using  two  approaches:  firstly,  by this  proposal  for  a 
Council  Directive  reinforcing  existing  practice  and  harmonising  procedures  for  the 
commencement  of  clinical  trials;  secondly,  with  a  delegation  of  power  to  the 
Commission  to  adopt  a Directive  containing  the  detailed  principles  and  guidelines  on 
GCP. 

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\-

2. 

SUBSIDIARITY  AND  PROPORTIONALITY 

All Member  States have  either legislative and/or  administrative  provisions relating  to 
the  commencement  of  a  clinical'trial.  However,  the  requirements, are  not  the  same 
and given that current  approaches to the demonstration  of clinical safety  and  efficacy 
(for  example,  placebo  controlled  double blind  trials)  frequently  involve thousands  of 
subjects,  the  practice  has  developed  of  applying  the  same  trial  protocol  in  multiple 
investigational  sites.  These  'multi-centre*  clinical  trials,  when  conducted  in  the 
European Union, would frequently take place in more than one Member  State. Thus, 
currently, the conduct  of the same trial must comply with different  national provisions 
resulting  in  delays  of  up  to  nine  months  in  the  initiation  of  a  clinical  trial  with 
consequential delays for patients.. 

Therefore  this legislative proposition is designed to build on the existing experience of 
the  Member  States  ,  ensuring  the  same  level  of  patient  protection  and  scientific 
standards,  but  with  à  rationalisation  of  the  documentary  and  administrative 
procedures  involved  in multi-centre  clinical trials. Additionally,  the proposal  includes 
a  series  of  definitions  which  have  been  internationally  agreed  and  which  codify  the 
terms used in the Member  States, on the basis of which clinical trial data generated  in 
the European Union is internationally mobile. 

It  is  important  to  note  that  this  proposal,  based  on  article  100a,  is  in  fact  a 
rationalisation  of  legislation  since  overall  the  administrative  and  bureaucratic 
requirements  will be  reduced  in line with  a 'risk-based'  approach,  thus  allowing  new 
medicines  to  be  made  available to  patients  in a timely manner.  It  is  also  intended  to 
simplify  the  regulatory  burden  for  small  and  medium  companies  e.g.  start  up 
biotechnology  companies, for  whom  the current  complexity  of national  requirements 
makes it almost impossible to conduct trials in more than one Member State. 

3.  PROTECTION  OF THE TRIAL  SUBJECT 

The accepted  basis for the conduct of clinical trials in humans is founded  in the current 
revision of the Declaration  of Helsinki and the Council of Europe draft  Convention  for 
the  protection  of  human  rights  and  dignity  of  the  human  being  with  regard  to  the 
application  of  biology  and  medicine  (The  Convention  on  Human  Rights  and 
Biomedicine). 

In  practice,  this  means  that  the  clinical  trial  has  been  considered  by  an  Ethics 
Committee  and  by  the  competent  authority  of  the  Member  State.  Further,  the 
investigator  is  responsible  for  the  personal  safety  and  well-being  of  subjects  in  a 
clinical  trial.  In  the  laws  of  the  Member  States,  the  protection  of  the  trial  subject  is 
provided  for  both  through  adoption  of  international  conventions  and  additional 
legislative  provisions.  In  accordance  with  the  principle  of  subsidiarity  and  given  that 
the protection  afforded  by the different  Member  States appears sufficient  and  does  not 
jeopardise  the  internal  market,  harmonisation  is  not  proposed.  However,  some 
fundamental  principles which are currently applied  in all Member  States  are recalled in 
the proposal. 

2-

For  the  protection  of  subjects  in  a  clinical  trial,  it  is  important  that  complete 
information  is  provided  and  that,  as  necessary,  additional  information  may  be 
requested.  The subjects participation  in the clinical trial is confidential  and, as the data 
relating to the study may be available to third  parties such as monitors  and  regulatory 
bodies,  it  should  remain  anonymous.  All data  should  be  secured  against  unauthorised 
access  and  confidentiality  should  be  observed  at  all  times.  This  directive  is  without 
prejudice  to  Directive  95/46/EEC  on the  protection  of  individuals  with  regard  to  the 
processing of personal data and on the free movement of such data. 

Prior to enrolment  in a clinical trial, the trial subject  should  receive easy to  understand 
information  on  the  nature  of  the  trial  (Patient  information)  and  be  afforded  the 
opportunity  to  ask  and  receive  answers  to  questions.  Consent  to  participate  is  then 
confirmed  by the 'Informed  consent' record. 

Legal  texts  in  themselves  provide  only  a  framework  within  which  to  work.  Ethics 
cannot be grafted  onto a trial - it must be built in from  the outset. Ultimately  an ethical 
attitude  must  pervade  the  approach  to  clinical  investigation,  its  establishment  and 
follow  through. 

4.  ETHICS  COMMITTEES 

The Treaty  on European Union recognise the need to  respect  the history,  culture  and 
traditions  of  the  peoples  of  the  Union.  In  Europe  there  is  a  diversity  of  cultural 
traditions.  Equally  there  is  diversity  in  religious  beliefs.  This  combination  has  led  to 
differing  expectations  and  practices,  both legal  and  ethical. Nonetheless,  the  solidarity 
of  the  peoples  of  the  Union  creates  a  firm  basis  for  the  construction  of  the  future 
Europe. 

Ethical  principles  therefore  reflect  the  culture,  tradition  and  expectation  of  peoples. 
Ethics also reflect  the views of their time, and perforce  must be adjusted  in time. Thus 
the  expression  of  detailed  ethical  requirements  in  legislative  texts  has  not  been  the 
practice in the Member  States. Rather the  standards  and  principles  to  be followed  are 
enshrined in legal  form. 

This  experience  has  been  followed 
in  this  proposal.  Thus,  the  principles  of 
consultation,  opinions  in  writing  and  the  necessity  of  on-going  submission  of 
information  to  the  independent  ethics  committee  are  set  out.  Generally,  each  centre 
where  a  clinical  trial  is  conducted  sets  up  an  independent  ethics  committee  the 
membership  of which  consists of doctors  other  than  those  involved  in the trial,  nurses 
and/or  other  healthcare  professionals  as well  as  non  medical  people  such  as  lawyers, 
administrator,  and  lay people.  This  committee  acts to  screen  the  clinical  trial  in  order 
to ensure the protection  of the rights, safety  and well-being of human subjects  involved 
in the trial. By virtue of this independent  review, public assurance  of that  protection  is 
also attained. 

3  -

Thus the following principles have been elaborated: 

•  For the  same  clinical  trial,  all Ethics  Committees  must be supplied  with  the same 

information; 

•  The opinion of the Ethics committee of the site where the trial actually takes place 
must be obtained, particularly as it is this committee that will be most familiar with 
the facilities and qualifications of the investigator. 

However,  the  administrative  procedures  including  the  scientific  documentation  to  be 
made available in order to  obtain an ethical committee  opinion do  lend themselves to 
rationalisation, at the high standard necessary for the protection of trial subjects. 

For  multi-centre  multi  Member  State  clinical  trials,  up  to  50  or  60  sites  might  be 
involved.  The  co-ordination  of  ethical  opinions  from  all  of  these  sites  can  impose 
difficulties  and delays. In a number of Member  States,  procedures  have  already been 
set  up  whereby  either  a  national  ethics  committee,  or  a  co-ordination  of  regional 
committees  or  the  ethics  committee  of  the  principal  investigator  takes  the  lead  in 
giving  an opinion  for  the  trial.  Thereafter,  the  ethics  committees  of  each  site  either 
accepts or rejects the trial for that site. 

This approach has been followed in the proposal - each Member State would establish 
its own procedure for achieving a 'lead' opinion for a multi-centre multi-Member State 
clinical trial. Thus instead of say 50 or 60 separate opinions, there would be an opinion 
per Member State, with an acceptance or rejection of the trial by the Ethics Committee 
of the investigational site. 

5.  INNOVATIVE ENVBRONMENT 

The pharmaceutical  industry in Europe is highly innovatory  and contributes  to  public 
health  by  virtue  of  bringing  forth  new  medicines  for  disease  conditions  for  which 
treatment  is  currently  insufficient  or  not  available.  The  innovative  nature  of  the 
industry  relies  on  research,  particularly  clinical  research.  Equally,  the  conduct  of 
research in Europe contributes to  the knowledge base  of the performance  in practice 
of the medicinal product in the European patient,  and permits clinical  investigators to 
work  intimately with evolving  science.  Therefore  it is important  that  clinical  research 
should not be inhibited by unnecessary administrative duplication. 

In most Member States there is a requirement to either notify or receive approval from 
the  competent  authority  before  commencing  a  clinical  trial  in  the  territory  of  that 
Member  State.  In addition to  protecting the trial  subject,  the current  experience  with 
systems of notification/approval  has proven effective  and therefore  provides the basis 
for this part of the proposal.  Thus, a sponsor would notify  the competent  authority  of 
the  clinical  trial,  the  competent  authority  would  have  the  opportunity  to  react  but  if 
there was no reaction, the trial would be deemed to be approved. This approval would 
be valid for the duration of the trial. 

Major pharmaceutical innovations rely, for the demonstration of safety and efficacy  on 
multi-centre  clinical trials. Recent publications have illustrated  that a base  of 2000  to 
3000  human  subjects  would  not  be  exceptional  in the  development  of  a  new  active 
substance.  As  such  clinical  trials  are  conducted  in  universities,  hospitals  or  clinics, 
none  df  which  would  individually  be  capable  of  recruiting  the  required  number  of 
subjects, up to  50 or 60  centres would be involved in a single trial.  In the European 
Union  these  centres  are  spread  across  more  than  one  Member  State.  Initially  the 
possibility for a single procedure for the commencement of trans-national  clinical trials 
had been considered, this would have provided the possibility whereby,  at the request 
of  the  sponsor,  a  single  application  could  have  been  submitted  to  the  recently 
established  European  Agency  for  the  Evaluation  of  Medicinal  Products.  However, 
concerns were raised that the experiences of Good Clinical Practices and the extent  of 
co-operation between Member States in this area were thus far insufficient  to provide 
a  basis  for  a  Community  procedure  at  this  time.  The  Commission  regrets  that  it 
therefore  was not  possible to propose  such a Community  dimension  in this proposal, 
but would wish to revisit this aspect when some experience has been gained. 

It is important that on-going information on clinical trials be available to all competent 
authorities. Thus selected elements of the initial application,  as well as amendments to 
the trial along with the  summary notification of the end of the trial, whether this is due 
to  an early interruption of the trial or in line with the  anticipated  duration,  would be 
registered  in  a  database,  accessible  only  to  competent  authorities.  Equally,  the 
information  to  be  submitted  to  Member  States  prior to  commencement  of  a  clinical 
trial is to  be harmonised,  both  in content  and format,  thus  ensuring  that  all Member 
States  receive  the  same  information.  Included  as  part  of  this  information  is  the 
necessary  toxicological  and  pharmacological  tests  in  animals  performed  as  a  pre 
determination of risk for human health. 

The potential for risk to the environment which may be associated with investigational 
medicinal products containing or consisting of genetically modified  organisms needs to 
be  subjected  to  an  environmental  risk  assessment  similar  to  that  provided  for  by 
Directive  90/220/EEC  on  the  deliberate  release  into  the  environment  of  genetically 
modified organisms. The Report1 on the review of Directive 90/220/EEC is favourable 
to  the  'verticalisation'  of  part  B  as  this  would  allow  for  more  efficient  and  sector-
adapted approaches.  Also,  it seems likely in the future that the pharmaceutical  sector 
would  be  a sector  where  this would  be  particularly  relevant.  Thus  once  appropriate 
experience  has  been  gained,  this  Directive  would  be  reconsidered  with  a  view  to 
verticalising the assessment of part B of Directive 90/220/EEC. 

l  COM(96) 630  final 

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Currently,  trials undertaken  in  other Member  States  are  not  required  to  be  notified, 
thus  there  is  a  gap  in  the  information  available  to  competent  authorities  -  this  is 
particularly the  case for multi-centre trials.  Given the importance  of this information, 
including  for  the  marketing  authorisation  assessment  process,  the  need  to  exchange 
information  on  clinical  trials  becomes  evident.  Therefore  the  establishment  of  a 
database repository capable of providing access to the above-mentioned  data elements 
and accessible to all competent authorities is provided for. 

In the pharmaceutical  sector,  an electronic network  linking the  competent  authorities 
of the Member States, the European Agency for the Evaluation of Medicinal Products 
and the  Commission  is  being  established  under the  name EudraNet.  Within  this the 
exchange  of  summary  information  on  clinical  trials  can  readily  be  achieved  and  the 
possibility  for  electronic  transmission  of  information  by  sponsors  could  also  be 
explored.  Further,  this  exchange  would  benefit  the  equivalence  of  the  evaluation 
process conducted in the Member States such that there can be mutual confidence and 
trust in the conduct of clinical trials. 

6.  GOOD MANUFACTURING  PRACTICE 

In  Directive  65/65/EEC,  article  2,  and  in  Article  34  of  Directive  75/319/EEC  an 
exemption from chapters II to V of the Directive 65/65/EEC is provided for 'medicinal 
products intended for research and development trials'. Thus such medicinal  products 
do not require a marketing authorisation, and their manufacture has not been subjected 
to  a manufacturing  authorisation,  nor do trie labelling  provisions  apply.  Nonetheless, 
all Member States agreed, at the time that the Commission Directive 91/356/EEC was 
adopted that the principles of Good Manufacturing  Practice  should be complied with 
in  the  manufacture  of  medicinal  products  intended  for  use  in  clinical  trials.  Many 
Member States have introduced this requirement in their national legislation. 

In order to avoid differing  requirements which are particularly problematic in the case 
of multi-centre multi-Member State clinical trials, the proposal applies the principles of 
Good  Manufacturing  Practice  to  investigational  medicinal  products,  including  a 
manufacturing authorisation from the competent authority. 

Equally  the  provisions  for  labelling  need  to  be  codified  so  as  to  ensure  that 
investigational  medicinal  products  can  move  across  national  boundaries.  The 
Commission's  working  party  of  Inspectors  had  already  considered  these  issues,  and 
had  prepared  a  guideline  (111/3004/91  of  22.12.92)  which  recommended  minimum 
information for inclusion in the label. To support the application of GMP, the annex to 
the Guide for Good Manufacturing Practice is being revised to include  an updating of 
the guideline III/3 004/91 and will be available shortly. 

Because  of  the  (sometimes)  small  quantities  required  for  a  clinical  trial,  many 
investigational  medicinal  products  are  manufactured  in  laboratories  or  even  hospital 
pharmacies.  The progressive  application of the training requirements  of the  'qualified 
person' as set out in article 2^ of Directive 75/319/EEC would  avoid disruption of the 
current supplies of such products and therefore a special derogation is provided for. 

-6 

7.  VERIFICATION  OF COMPLIANCE 

The concept of GCP serves to emphasise the need for and importance of a clear paper 
trail of the clinical trial, from its inception to its completion and analysis. Implicit in the 
requirement that  clinical  trials meet the  standard of GCP is the need  for  audit  of the 
study.  Audit may be carried out by an independent  internal unit of the  sponsor  or by 
external contractors. An audit certificate should result. 

Inspection by the relevant  competent  authority is an officially  conducted  audit.  Thus 
the  adherence  to  the  standard  can be  assured.  Some Member  States  have  legislative 
provisions  empowering  inspection  of  clinical  trial  sites  and/or  sponsors  and/or 
individual patient files. The absence of a Community mechanism of mutual recognition 
of inspections done by the Member States may cause difficulties  in the acceptability  of 
studies carried out in other Member States. 

The  international  acceptability  of  clinical  trials  conducted  in  the  Community, 
particularly  by  authorities  outside  the  European  Community,  requires  a  legislative 
underpinning of the compliance of clinical trials with the standard of GCP. 

Further,  in order to  achieve  optimum  protection  of health,  the resources  allocated  to 
pharmaceutical  research  should  not  be  squandered  on  obsolete  or  repetitive  tests 
whether  within  the  Community  or  in  third  countries.  Therefore,  the  international 
harmonisation  of  technical  requirements  for  the  development  of  medicinal  products 
should  continue  to  be  pursued.  International  fora,  including  the  International 
Conference  on  Harmonisation,  allow  for  the  scientific  establishment  of  standards 
which can prevent duplication. 

Thus the proposal  provides for verification  of compliance with GCP on behalf of the 
Community by inspectors  appointed  by Member States.  The possibility  for inspection 
of trials done outside the Community, the results of which are submitted as part of the 
marketing  authorisation  application  is also  provided  for  as is a requirement  on  those 
subject to inspection to allow inspection. 

The need to  share knowledge  and experience,  and to build a system for  inspection is 
evident.  The  establishment  of  common  criteria for  conducting  inspection  in order  to 
ensure  mutual  recognition  between  Member  States,  the  inspection  procedures  for 
multi-centre  multi-national  studies,  the qualification  of  inspectors  and the  elaboration 
of inspection reports are practical aspects which would be elaborated in guidelines. As 
it  would  not  be  practicable  or  an  effective  use  of  resources  to  inspect  every  trial, 
inspection  of  quality  systems  would  be  developed.  Equally,  the  inspection  report 
indicating the level of compliance with GCP following inspection would need to be set 
out. 

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8.  PHARMACOVIGILANCE 

It  is  clear  that  the  same  standards  of  monitoring  the  safety  in  use  of  medicinal 
products should be used for investigational medicinal products. Thus the provisions for 
pharmacovigilance are extended to include investigational medicinal products. 

In  the  exercise  on  codification  of  the  Community  legislation  relating  to  medicinal 
products  for  human use,  the  procedures  for  reporting  pharmacovigilance  are  being 
rationalised. The updated procedures for reporting have thus been incorporated in this 
proposal. 

9. 

I N T E R N A T I O N AL  H A R M O N I S A T I ON 

A process of technical harmonisation of technical requirements for pharmaceutical has 
been on-going for the last number of years.  This is called International  Conference  on 
Harmonisation  (ICH).  Within  ICH,  a  Good  Clinical  Practice  guideline  has  been 
elaborated on the basis of the European guideline of 1990. 

In  order  to  maintain  international  consistency,  the  definitions  of  ICH  as  well  as 
procedures where relevant have been retained in the proposal. The only exceptions are 
in the terminology for medicinal products (in USA the word 'drug' is frequently  used) 
and  in the  definition  of  Independent  Ethics  Committee  where  the  description  of  the 
membership  reflects  European  expressions  rather  than  international  ones 
i.e. 
and  non-medical/(non' scientific) 
professionals 
"healthcare  medical/scientific 
members". 

The  need  to  establish  international  harmonisation  of  inspection  and  assurance  of 
compliance with GCP, with the possibility of mutual recognition of inspections, is also 
recognised and needs to be addressed. 

- 8-

Proposal for a 

EUROPEAN PARLIAMENT AND COUNCIL DIRECTIVE 

of... 

on the approximation of provisions laid down by law, regulation or administrative action 
relating to the implementation of Good Clinical Practice in the conduct of clinical trials on 

'  ' medicinal products for human use 

THE EUROPEAN PARLIAMENT AND THE COUNCIL OF THE EUROPEAN 
UNION, 

Having  regard  to  the  Treaty  establishing  the  European  Community,  and  in  particular 
Article 100a thereof, 

Having regard to the proposal from the Commission, 

Having regard to the opinion of the Economic and Social Committee, 

Acting in accordance with the procedure laid down in Article 189b of the Treaty, 

Whereas  Directive  65/65/EEC  requires  that  applications  for  authorisation  to  place  a 
medicinal  product  on  the  market  should  be  accompanied  by  a  dossier  containing 
particulars and documents relating to the results of tests and clinical trials carried out on 
lays down uniform rules on the compilation 
the product; whereas Directive 75/318/EEC 
of dossiers including their presentation; 

Whereas the accepted basis for the conduct of clinical trials in humans is founded  in the 
current revision of the Declaration of Helsinki and the Council of Europe Convention for 
the  protection  of  human  rights  and  dignity  of  the  human  being  with  regard  to  the 
application of biology and medicine; whereas, the trial subject's protection is safeguarded 
through  risk  assessment  based  on  toxicological  experiments  prior  to  any  clinical  trial, 
screening by ethics committees, Member States authorities and the protection of personal 
data; 

Whereas,  in  order  to  achieve  optimum  protection  of  health,  the  resources  allocated  to 
pharmaceutical  research  must not be squandered  on obsolete or  repetitive tests whether 
within  the  Community  or  in  third  countries;  whereas,  the  harmonisation  of  technical 
requirements  for  the  development  of  medicinal  products  should  therefore  be  pursued 
through the appropriate fora, including the International Conference on Harmonisation, 

2  OJ No L22,  9.2.65, p. 1 

3  OJNoL147,9.6.75,p.l 

9-

Whereas,  for  multi-centre  clinical trials conducted  in more than one Member  State, with 
many  investigational  sites  involved,  a  delay  in  the  commencement  of  the  trial  may  be 
caused  by  the  multiplicity  and  diversity  of  procedures  for  obtaining  opinions  of  ethics 
committees; whereas,  for  such trials,  a single opinion for  each Member  State  concerned 
reduces delays without jeopardising  the well-being of the people  participating  in the trial 
with the possibility of rejecting it in specific sites if facilities are not appropriate; 

Whereas information both on the commencement and on the termination of a clinical trial 
should  be  available  to  the  Member  States  where 
the  trial  takes  place,  and  relevant 
information on clinical trials should be exchanged between Member States; 

4 

Whereas  the  standards  of  Good  Manufacturing  Practice  should  be  applied  to 
investigational  medicinal  products;  whereas  special  provisions  for  the  labelling  of 
investigational medicinal products should be set out; 

Whereas verification  of compliance with the standards of Good  Clinical Practice  and the 
need  to  subject  data,  information  and  documents  to  inspection  in  order  to  confirm  that 
they have been properly generated,  recorded  and reported,  is essential  in order to justify 
the involvement  of human subjects in clinical trials; whereas the person participating  in a 
trial should be made aware of and consent to the scrutiny of personal  information  during 
inspection  by competent  authorities  and properly  authorised  persons,  provided  that such 
personal information is treated as strictly confidential  and is not made publicly available; 

Whereas  this  Directive  is  without  prejudice  to  Directive  95/46/EEC  of  the  European 
Parliament  and  of the  Council  of 24  October  1995  on the  protection  of individuals with 
regard to the processing of personal data and on the free movement of such data4. 

Whereas  it  is  also  necessary  to  make provisions  for the  monitoring  of  adverse  reactions 
occurring  in clinical  trials using  Community  surveillance  (pharmacovigilance)  procedures 
in  order  to  ensure  the  immediate  cessation  of  any  clinical  trial  in  which  there  is 
unacceptable level of risk; 

Whereas the conduct of clinical trials must regularly be adapted to scientific  and technical 
progress in order to ensure optimum protection of the trial subject; whereas it is therefore 
necessary  to  introduce  a  rapid  procedure  for  adapting  to  technical  progress  the 
requirements  regarding  the  conduct  of  clinical  trials,  whilst  ensuring  close  co-operation 
between the Commission and the Member States within a 'Committee for the Adaptation 
to Technical Progress of the Directives on the Removal  of Technical Barriers to Trade in 
the Medicinal Products Sector' ; 

HAVE ADOPTED THIS DIRECTIVE: 

4  OJ No L281, 23.11.95, p.31 

10 

CHAPTER I 

Scope and  definitions 

Article 1 

1.  This Directive  deals with  clinical trials including multi-centre trials  on  human  subjects 
involving  medicinal  products  as  defined  in  Article  1  of  Directive  65/65/EEC  but 
excludes non-interventional clinical trials. 

2.  Good  Clinical Practice  (GCP) is an international  ethical  and  scientific  quality  standard 
for  designing,  conducting,  recording  and reporting trials that  involve the  participation 
of  human  subjects.  Compliance  with  this  standard  provides  public  assurance  that  the 
rights,  safety  and  well-being  of  trial  subjects  are  protected,  consistent  with  the 
principles  that  have  their  origin  in  the  Declaration  of  Helsinki  (1964),  and  that  the 
clinical trial data are credible. 

3.  The principles and guidelines of Good Clinical Practice shall be adopted  in the form  of 
a  directive  addressed  to  the  Member  States,  in  accordance  with  the  procedure  laid 
down in Article  2c  of  Council  Directive  75/318/EEC. Detailed  guidelines  in  line with 
those principles shall be published by the Commission  and revised  as necessary to  take 
account of technical and scientific progress. 

4.  All clinical trials, including bioavailability and bioequivalence  studies shall be  designed, 
conducted  and reported  in accordance with the standard  of Good  Clinical Practice. 

Article 2 

For the purposes of this Directive the following  definitions  shall apply: 

Adverse  Event:  Any  untoward  medical  occurrence  in  a  patient  or  clinical  investigation 
subject  administered  a  medicinal  product  and  which  does  not  necessarily  have  a  causal 
relationship with this treatment. 

Adverse  Reaction:  All  noxious  and  unintended  responses  to  an  investigational  medicinal 
product related to any dose. 

Clinical  Trial:  Any  investigation  in  human  subjects  intended  to  discover  or  verify  the 
clinical,  pharmacological  and/or  other  pharmacodynamic  effects  of  an  investigational 
medicinal  product(s),  and/or  to  identify  any  adverse  reactions  to  an  investigational 
medicinal  product(s),  and/or  to  study  absorption,  distribution,  metabolism,  and  excretion 
of an investigational product(s) with the object of ascertaining its safety  and/or  efficacy. 

This  includes  clinical  trials  done  in  either  one  site  or  multiple  sites,  whether  in  one 
Member State or more than one Member  State; but excludes non-interventional  trials. 

-U~ 

Ethics  Committee:  An independent  body  constituted  of healthcare  professionals  and  non 
medical  members,  whose  responsibility  it  is to  ensure  the  protection  of  the  rights,  safety 
and  well-being  of  human  subjects  involved  in  a trial  and  to  provide  public  assurance  of 
that  protection,  by,  among  other  things,  expressing  an  opinion  on,  the  trial  protocol,  the 
suitability  of  the  investigator(s),  facilities,  and  the  methods  and  material  to  be  used  in 
obtaining and documenting informed  consent of the trial subjects. 

Inspection:  The  act  by  a  competent  authority  of  conducting  an  official  review  of 
documents, facilities, records, arrangements for  quality assurance,  and any other  resources 
that  are deemed by the competent  authority to be related  to the clinical trial  and that  may 
be  located  at  the  site  of the trial,  at the  sponsor's  and/or  contract  research  organisation's 
facilities,  or at other establishments deemed appropriate by the competent  authority. 

Investigational  medicinal  product:  A  pharmaceutical  form  of  an  active  substance  or 
placebo being  tested  or  used  as  a  reference  in  a  clinical  trial,  including  a  product  with  a 
marketing  authorisation  when  used  or  assembled  (formulated  or  packaged)  in  a  way 
different  from  the  authorised  form,  or when used  for  an unauthorised  indication,  or  when 
used to gain further  information  about an authorised use. 

Investigator:  A person  responsible  for  the  conduct  of  the  clinical  trial  at  a trial  site.  If  a 
trial is conducted  by a team of individuals at a trial  site, the investigator  is the  responsible 
leader of the team and may be called the principal investigator. 

Investigator's  Brochure:  A  compilation  of  the  clinical  and  non  clinical  data  on  the 
investigational  medicinal  product(s)  which  is  relevant  to  the  study  of  the  investigational 
medicinal product(s) in human subjects. 

Multi  centre  Trial:  A  clinical  trial  conducted  according  to  a  single  protocol  but  at  more 
than one site, and therefore,  carried out by more than one investigator. 

Trial sites may be located  in a single Member State, in a number of Member  States  and/or 
in Member  States and third countries. 

Non-interventional  trial:  A clinical trial where the  selection  of  subjects  or  the  attribution 
of medicinal products  or the examinations carried  out  or medical  and biological  follow-up 
of subjects falls within current medical practice. 

Protocol:  A  document  that  describes  the  objective(s),  design,  methodology,  statistical 
considerations,  and  organisation  of  a  trial.  The  term  protocol  refers  to  protocol, 
successive versions of the protocol and protocol  amendments. 

Serious Adverse  Event  or  Serious Adverse  Reaction:  Any  untoward  medical  occurrence 
that  at  any  dose  results  in  death,  is  life-threatening,  requires  (non-elective)  inpatient 
hospitalisation  or  prolongation  of  existing  hospitalisation,  results  in  persistent  or 
significant  disability/incapacity,  or is a congenital anomaly/birth  defect. 

Sponsor.  An  individual,  company,  institution,  or  organisation  which  takes  responsibility 
for the initiation, management,  and/or financing  of a clinical trial. 

12 

Subject:  An  individual  who  participates  in  a  clinical  trial,  either  as  a  recipient  of  the 
investigational medicinal product or as a control. 

Unexpected Adverse  Reaction:  An  adverse  reaction  not  mentioned  in  the  investigator's 
brochure or in the summary of product characteristics, if any. 

CHAPTER II 

Protection of trial subjects 

Article  3 

1.  This  Directive  is  without  prejudice  to  the  measures  laid  down  in  Member  States 

concerning the protection of trial subjects. 

2.  A  clinical  trial  may  only  be  undertaken  if  the  risks  to  the  subject  are  not 
disproportionate  to  the  potential  benefits  of  the  medicinal  research.  The  right  of  the 
subject  to  physical  and  mental  integrity  shall  be  respected,  as  well  as  the  right  to 
privacy. 

3.  The medical  care given  to,  and  medical  decisions made on behalf  of,  subjects  shall be 
the  responsibility  of  an  appropriately  qualified  healthcare  practitioner  or  when 
appropriate,  of a qualified  dentist. 

4.  The trial subject  shall be provided with a contact point,  independent  of the investigator 

team, where further  information  may be obtained. 

Ethics Committee opinion 

Article  4 

1.  The function  and responsibility  of an ethics committee  shall be to  safeguard  the rights, 

safety and well-being of all trial subjects. 

In preparing  its  opinion,  the ethics  committee  shall consider,  at  least,  the  relevance  of 
the trial and the trial design, the protocol, the suitability of the investigator,  supporting 
staff,  and available facilities; the adequacy and completeness of the written  information 
to  be  given  to  the  subjects,  their  relatives,  guardians  and,  if  necessary,  legal 
representatives  and  by  which  consent 
for 
compensation/treatment  in the  case  of injury  or  death  of  a  subject  if  attributable  to  a 
clinical  trial,  and  any  insurance  or  indemnity  to  cover  the  liability  of  the  investigator 
and  sponsor;  the  extent  to  which  investigators  and  subjects  may  be  rewarded  or 
compensated  for  participation in the trial. 

to  be  obtained;  provision 

is 

-  13 -

2.  The  opinion  of  an  ethics  committee  shall  be  delivered  before  a  clinical  trial 

commences. 

3.  In  order  to  apply  for  an  opinion  of  an  ethics  committee,  an  application  with 
documentation  shall be submitted. The written opinion of the ethics committee shall be 
given to the applicant, in writing, within 30 days of receipt of a valid application. 

4.  Within  that  period,  the  ethics  committee  may  send  a  single  request  for  information 
supplementary  to  that  already  supplied.  In this  case the  period  shall  be  extended  by a 
further  30 days. 

Article  5 

1.  Member  States  shall establish a procedure by which a  single ethics  committee  opinion 
can  be  achieved  for  that  Member  State.  For  multi-centre  clinical  trials  conducted  in 
more  than  one  Member  State,  this  procedure  shall  provide  for  the  single  opinion  for 
that Member  State. 

2.  Member  States may, in addition, provide for an opinion of the ethics committee  for 

each site on the facilities  and capabilities of that  site in relation to the proposed  clinical 
trial. Within  15 days of receipt of the opinion provided for in paragraph  1, the ethics 
committee for the site shall, by issuing an opinion, either accept or reject the conduct 
of the trial in that site. 

Article  6 

The Commission,  in consultation  with the Member  States  and  interested  parties,  shall 
draw  up  detailed  guidance  on  the  application  format  and  documentation  to  be 
submitted  in  an  application  for  an  ethical  committee  opinion,  and  on  the  appropriate 
safeguards  for  the protection  of personal  data,  in particular  regarding  the  information 
that is given to trial  subjects. 

CHAPTER III 

Commencement  of a clinical  trial 

Article 7 

1.  Before  commencing  a clinical trial,  an  application  shall  be  submitted  by the  sponsor 

to the Member  States where the trial will take place. 

2.  Member  States  shall  authorise  sponsors  to  commence  clinical  trials  once  the  ethics 
committee  has  issued  a favourable  opinion.  Member  States  may  however  decide  that 
certain clinical trials will be subject  to paragraph 3. 

- 14 

3.  In the  case  of  clinical  trials  not  covered  by the  provisions  of  paragraph  2,  Member 
States shall authorise a sponsor to commence clinical trials at the end of a period of 30 
days  after  receipt  of  a valid  application unless  reasoned  grounds  for  non-acceptance 
have been notified within this time period. 

Within 30  days  of  receipt  of  the  said  grounds  for  non-acceptance,  the  sponsor  may 
amend  on  one  occasion  only  the  application  in  order  to  take  due  account  of  thé 
grounds  set  out  in the notification.  If the sponsor  does  not  amend the  application  as 
provided for, the application is deemed to have been rejected. 

4.  Amendments  to  the  protocol  shall  be  notified  to  the  Member  States.  These 
amendments  shall be  deemed  to be  accepted  unless  the  competent  authority  notifies 
grounds for non-acceptance within 30 days. 

In cases where  grounds for  non-acceptance  are raised,  the  procedure  in paragraph 3 
shall be followed. 

5.  Notwithstanding paragraph 4, provisional urgent safety measures may be taken by the 

sponsor in order to eliminate an immediate hazard to trial subjects. 

6.  Within 90 days of the end of a clinical trial the sponsor shall notify the Member States 
that the clinical trial is ended.  This period  shall be reduced  to  15  days in the  case  of 
early termination of the trial. 

7.  The  Commission  shall,  in  consultation  with  the  Member  States,  draw  up  detailed 
guidance on the format and contents for applications as well  as the  documentation to 
be submitted in relation to the quality and manufacture of the investigational medicinal 
product, any toxicological and pharmacological tests,*protocol and clinical  information 
on  the  investigational  medicinal  product  including  the  investigator's  brochure,  in 
addition to the content of the notification of the end of the clinical trial. 

Exchange of information 

Article 8 

Extracts from the initial application, amendments as appropriate and the notification at 
the end of the clinical trial shall be entered by the Member States in whose territory the 
trial  takes  place  into  a  database  accessible  only  to  Member  States,  the  European 
Agency for the Evaluation of Medicinal Products and the Commission. 

At  the request  of  any Member  State  or the  Commission,  the  competent  authority  to 
whom  the  trial  was  notified  shall  supply  all  appropriate  information  concerning  that 
clinical trial. 

15-

3.  In the  case  of  multi-centre  clinical  trials  conducted  in more  than  one  Member  State 
where there are differences between the Member States, the Commission  may request 
the Member States concerned to establish the reasons for the difference which shall be 
considered by all Member States. 

4.  The  Commission,  in  consultation  with  the  Member  States,  shall  draw  up  detailed 
guidance on the relevant data to be included in this database as well as methods for the, 
electronic communication of the data.  » 

Article 9 

1.  Where  the  conditions  of  the  application  cease  to  be  met  or  in  the  event  that  new 
information raising doubts as to safety or science becomes available, the Member State 
may  suspend  or  prohibit  the  trial.  It  shall  forthwith  inform the  other Member  States 
and the Commission thereof. 

The Member  State  shall inform the  other Member  States  and the  Commission  of the 
decisions taken and the reasons for those decisions. 

2.  Where  a Member  State  is  of  the  opinion  that  the  sponsor  or  the  investigator  is  no 
longer fulfilling  their obligations laid down, it shall forthwith inform the other Member 
States  and the  Commission,  stating the reasons  in detail  and indicating  the  course  of 
action. 

The Member  State  shall  forthwith  inform  the  Commission  of  the  commencement  of 
any infringement proceedings. 

CHAPTER IV 

Manufacture,  import and labelling of investigational  medicinal  products 

Article 10 

1.  Member States shall take all appropriate measures to ensure that the manufacture and 
import of investigational medicinal products is subject to the authorisation referred  to 
in Article  16 of Council Directive 75/319/EEC5. 

2.  Chapters IV  and  V  of Directive  75/319/EEC  shall  apply  to  investigational  medicinal 

products. 

5  OJNoL147, 9.6.75, p. 13 

- 16 

3.  A person engaging in the activities of the person referred to in Article 21  of Directive 
75/319/EEC  in a Member  State  as  regards  investigational  medicinal  products  at the 
time when this Directive is brought into force in that State but without complying with 
the  provisions  of  Article  23  and  24  of  Directive  75/319/EEC  shall  be  eligible  to 
continue to engage in those activities for the purpose of manufacture of investigational 
medicinal products in the Member State concerned. 

Article 11 

For investigational  medicinal products,  the particulars to  appear in,  at least,  the national 
language(s) on the outer packaging of investigational medicinal products or where there is 
no outer packaging,  on the immediate packaging shall be published by the Commission in 
the  Good  Manufacturing  Practice  guideline  on  investigational  medicinal  products  to  be 
adopted in accordance with Article 19a of Directive 75/319/EEC. 

CHAPTER V 

Compliance 

Article 12 

i. 

1.  Compliance with the provisions of Good Clinical Practice shall be verified  on behalf of 
including  the  trial  site  and 
the  Community  by  inspection  at  relevant  sites, 
manufacturing site, at any laboratory used in the trial and/or at the sponsor's premises, 
by inspectors appointed by Member States. 

2.  Following  inspection,  an  inspection  report  shall  be  prepared  which  shall  be  made 
available,  upon  request,  to  the  sponsor,  any  other  Member  State  or  the  European 
Agency for the Evaluation of Medicinal Products. 

3.  Where there  are differences  between Member  States  as to  whether  the  provisions  of 
this Directive have been complied with, the Commission may request a new inspection. 
The co-ordination of such inspections shall be undertaken by the European Agency for 
the Evaluation of Medicinal Products. 

4.  Subject to any arrangements which may have been concluded between the Community 
arid third countries,  the Commission may, upon receipt  of  a reasoned  request  from a 
Member  State  or  on  its  own  initiative,  require  that  the  trial  site  ,  and/or  at  the 
sponsor's premises and/or the manufacturer established in a third country submit to an 
inspection.  The  inspection  shall  be  undertaken  by  appropriately  qualified  inspectors 
from  the Community. 

5.  The  Commission,  in consultation  with the Member  States,  the European  Agency  for 
the  Evaluation  of  Medicinal  Products  and  interested  parties,  shall  draw  up  detailed 
guidelines on the documentation,  archiving, appropriate qualification  of inspectors and 
inspection procedures for the demonstration of compliance with this Directive. 

17 

CHAPTER VI 

Clinical safety reporting 

Article 13 

1.  The  investigator  shall  report  all  serious  adverse  events  immediately  to  the  sponsor 
except  for  those  serious  adverse  events that  the  protocol  or  investigator's  brochure 
identifies as not requiring immediate reporting. The immediate report shall be followed 
by  detailed,  written  reports.  The  immediate  and  follow-up  reports  shall  identify 
subjects by unique code numbers assigned to the trial subjects. 

2.  Adverse events and/or laboratory abnormalities identified  in the protocol as critical to 
safety evaluations shall be reported to the ethics committee and the sponsor according 
to the reporting requirements and within the time periods specified in the protocol. 

3.  For reported deaths, the investigator shall supply the sponsor and the ethics committee 

with any additional requested information. 

« 

4.  The  sponsor  shall  ensure that  all relevant  information  about  fatal  or  life-threatening 
unexpected  adverse  reactions  are recorded  and  reported  as  soon  as  possible  to  the 
Member State in whose territory'the reaction occurred, but in any case no later than 7 
days  after  first  knowledge  by  the  sponsor  that  a  case  qualifies.  All  other  serious 
adverse  reactions  that  are  not  fatal  or  life-threatening  shall  be  reported  as  soon  as 
possible but no later than 15 days. The sponsor shall also inform all investigators. 

5.  In addition, the sponsor shall maintain detailed records of all suspected adverse events 
which are reported to him by the investigator(s). These records shall be submitted to 
the Member States in whose territory the clinical trial is being conducted. 

6.  At  least  every  twelve  months  during the  clinical  trial,  the  sponsor  shall  provide  the 
Member States in whose territory the clinical trial is being conducted with a line listing 
of all suspected  serious adverse reactions which have occurred in the whole study and 
a summary overview of the subjects' safety in the trial. 

7.  Each  Member  State  shall  ensure  that  all  suspected  serious  unexpected  adverse 
reactions occurring within their territory to an investigational medicinal product which 
are brought to their attention are recorded and reported immediately to the European 
Agency for  the Evaluation  of Medicinal Products,  and  in no case later  than  15 days 
following the receipt of the information. 

The  European  Agency  for  the  Evaluation  of  Medicinal  Products  shall  inform  the 
competent authorities of the Member States. 

8.  The  Commission  in  consultation  with  the  European  Agency  for  the  Evaluation  of 
Medicinal Products, Member States, and interested parties, shall draw up guidance on 
the collection, verification and presentation of adverse event/reaction reports. 

CHAPTER VII 

General  provisions 

Article 14 

This Directive is without prejudice to the general civil and criminal liability of the sponsor 
or the investigator. 

Unless Member States have established  precise conditions for exceptional  circumstances, 
medicinal products used in clinical trials shall not be sold. Member States shall inform the 
Commission of such conditions. 

Article 15 

Any amendment which may be necessary to update the provisions of this Directive to take 
account  of  scientific  and  technical  progress  shall  be  adopted  in  accordance  with  the 
provisions of Article 2c of Directive 75/318/EEC. 

Article 16 

Member States shall take all appropriate measures to  comply with this Directive before 1 
January 1999. They shall forthwith inform the Commission thereof. 

When  Member  States  adopt  these  provisions,  these  shall  contain  a  reference  to  this 
Directive  or  shall  be  accompanied  by  such  reference  at  the  time  of  their  official 
publication. The procedure for such reference shall be adopted by Member States. 

Member States shall communicate to the Commission the text of the provisions of national 
law which they adopt in the field governed by this Directive. 

This Directive is addressed to the Member States. 

Article 17 

DoneatXXXX, 
For the European Parliament 
The President 

For the Council 
The President 

-  19-

FINANCIAL  STATEMENT 

TITLE OF OPERATION: 

1 
Proposal for a European Parliament and Council Directive on the approximation of 
provisions laid down by law, regulation or administrative action relating to the 
implementation of Good Clinical Practice in the conduct of clinical trials on medicinal 
products for human use 

BUDGET HEADING INVOLVED: 

2 
B-5 3000 

LEGAL BASIS: 

3 
Article 100a of the Treaty establishing the European Community. 

4 

DESCRIPTION OF OPERATION 
4.1  General objective: 
To contribute to achieving the objectives laid down by the Treaty: 
• 

ensuring a high-level of human health protection particularly for human 
subjects in clinical trials for new medicinal products; 
harmonisation of the Member States' requirements in order to avoid 
duplication" of effort and waste of resource. 

• 

4.2 

Period covered and,arrangements for renewal: 

After  the adoption of the Directive, the Commission would have a delegation of 
power to introduce a Commission Directive on Good Clinical Practice 
(technical standards). This could be foreseen  for  1999. 

5 CLASSIFICATION OF EXPENDITURE OR REVENUE 

5.1 

5.2 

5.3 

Compulsory/Non-compuIsory expenditure 
Some expert working parties (see 7.1) - non-compulsory  expenditure 
Differentiated/Non-differentiated  appropriations 
Differentiated  appropriation  (B5-3000) 
Type of revenue involved: 
There are no receipts following  this action. 

6 TYPE OF EXPENDITURE OR REVENUE 

Technical work directly linked to the preparation of the Commission Directive through 
the Regulatory  Committee procedure (A). 
Technical work in the development of guidelines - working parties of experts from 
Member States (B). 

Zo 

7FINANCIAL IMPACT 

Method of calculating total cost of operation  (relation between 

7.1 
individual and total costs): 
The expected cost could be estimated on the basis of number of meetings: 
(a) Preparation of the proposal: -
•  expert working parties (2 meetings in  1997, and in  1998); 
•  consultation of the Pharmaceutical Committee (during a regular meeting). 
(b) Action following adoption of the proposal: -
•  Regulatory Committee for adoption of the Commission Directive (1 meeting in 

1999); 

•  expert working groups (on average, 2 meetings per annum) 

7.2 

Itemised breakdown of cost 

Commitment appropriations ECU million 

1997 

1998 

1999 

(at current prices) 
2001 
2000 

2002 

Total 

50,000 

-  50,000 

50,000 

50,000 

75,000 
75,000 

50,000 
50,000 

50,000 
•-•  50,000 

50,000 
50,000 

100,000 
225,000 
325,000 

Break 
down 
a 
b 
Total 

7.3  Operational  expenditure  for studies, experts  etc.  included  in Part B  of  the 

budget 

Publication  of  guidelines  supporting  the  operation  and  implementation  of  the 
directive which would be included in the 'Rules governing medicinal products in the 
European Union'  as part of volume 3. Therefore  there is no additional  cost  (already 
covered by the annual budget for publications). 

2\ 

7.4  Schedule of commitment and payment  appropriations 

ECU mi] 

lion 
Total 

1997 

1998 

1999 

2000 

2001 

50,000 

50,000 

75,000 

50,000 

50,000 

2002 and 
subs, yrs 
50,000 

» 

50,000 

50,000 

75,000 

50,000 

50,000 

50,000 

Commitment 
appropriations 
Payment 
appropriations 

1997 
1998 
1999 
2000 
2001 
2002 
and subs, yrs 

Total 

325,000 

50,000 
50,000 
75,000 
50,000 
50,000 
50,000 

325,000 

FRAUD PREVENTION MEASURES 

The normal measures for control of expenditure, used for meetings, will apply. 

ELEMENTS OF COST-EFFECTIVENESS ANALYSIS 

9.1  Specific and quantified  objectives; target  population 

Delays in the initiation of multi centre clinical trials have been identified  by the 
pharmaceutical industry as well as bodies such as the European Organisation  for 
Research and Treatment of Cancer (EORTC). A memorandum regarding these 
delays and the disadvantages of collaborative clinical research in Europe as 
compared to the U.S. have pointed to delays of up to six months in the 
initiation of research. 

The Industrial Research and Development Advisory Committee of the European 
Commission (IRDAC) has proposed that future legislation for the initial testing 
of new medicinal products should be standardised throughout the EC - the 
establishment of a fast-acting procedure for approving and facilitating  the 
initiation of clinical trials would make clinicalresearch  more efficient  n Europe 
(a rough guide to cost of clinical research is 2.5 million ECU per month). 

The proposal also includes measures to improve both of these problems and 
aims at contributing towards ensuring a high level of health protection  for 
human subjects in clinical trials. 

22-

9.2 

Grounds for the operation 

This proposal is designed to harmonise the legislative provisions relating to the 
conduct of clinical trials for medicinal products for human use.  It incorporates 
internationally established standards and principles of protection for the human 
subject,  streamlines the administrative procedures for initiating a clinical trial, 
harmonises the reporting procedures for on-going  safety  monitoring and 
introduces surveillance measures through inspection. 

The technical harmonisation required to achieve the Single market for 
pharmaceuticals was completed in  1992. As part of this process,  clinical trials 
which have been conducted in accordance with Community rules do not require 
to be repeated within the Community. 

For the protection of European citizens who participate in clinical  trials, the 
principles of  Good Clinical Practices which find their origin in the Declaration 
of Helsinki are a fundamental requirement.  The EC guidelines on Good Clinical 
Practice (GCP), adopted by the Committee for Proprietary Medicinal Products 
in July  '90,  was acclaimed internationally as setting out,  in a clear and concise 
manner,  the standard for GCP. This was further evidenced by the GCP of the 
World Health Organisation which was largely based on the Community text. In 
addition,  the European guideline provided the framework for a tripartite GCP 
guideline between the EC, the USA and Japan within the International 
Conference  on Harmonisation of technical requirements for registration of 
pharmaceuticals for human use (ICH). 

Recent reports and correspondence have highlighted real difficulties  in the area 
of clinical development of new medicinal products particularly delays in the 
initiation of  multi centre clinical trials (ethics committee opinion and competent 
authority acceptance);  manufacture and labelling of investigational  medicinal 
products; demonstration of compliance to GCP. These delays can cost industry 
up to six  months delay  (at an average of  1 million ECU per month). 

9.3 

Monitoring and evaluation of the operation 

Evaluation will be by means of tracking implementation of  Community 
legislation  in Member States and monitoring the rate of development of new 
medicinal products. 

10  ADMINISTRATIVE EXPENDITURE  (SECTION m,  PART  A  OF THE BUDGET) 

Actual  mobilization of the necessary administrative resources will  depend on the 
Commission's  annual  decision  on  the  allocation  of  resources,  taking  into 
account  the number of  staff  and additional amounts authorized  by  the budgetary 
authority. 

2*3 

10.1 

Effect  on the number of posts 

Type of post 

Staff to be assigned to 
managing the operation 
Temporary 
Permanent 
posts 
posts 

0.25 

A 
Officials  or 
B 
temporary 
staff 
C 
Other resources 
Total 

% 

Source 

Duration 

Additional 
resources 

Existing 
resources in 
theDGor 
department 
concerned 
Yes 

on-going 

If  additional  resources  are  required,  indicate  the pace  at  which  they  will  have  to  be 
made available. 

10.2  Overall financial impact of additional human resources 

No additional staff are required. 

10.3 
operation 

Increase  in  other  administrative  expenditure  as  a  result  of  the 

Budget heading 
B5-3000 

Amounts 
Marginal  Publication already exists, additional 

ECU 
Method of calculation 

Total  1 

'. 

pages only 
1 

*v 

ISSN 0254-1475 

COM(97) 369 final 

DOCUMENTS 

EN 

05  14  15 

Catalogue number  :  CB-CO-97-451-EN-C 

ISBN  92-78-24346-9 

Office  for Official  Publications of the European Communities 

L-2985  Luxembourg 

, 2 s ".