Common Position (EC) No 44/2000 of 20 July 2000 adopted by the Council, acting in accordance with the procedure referred to in Article 251 of the Treaty establishing the European Community, with a view to adopting a Directive of the European Parliament and of the Council on the approximation of the, laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use
Date: 2000-07-20
Institutions: Council of the European Union
Subjects: approximation of laws, ethics, experiment on humans, medicinal product, scientific research

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COMMON POSITION (EC) No 44/2000

adopted by the Council on 20 July 2000

with a view to adopting Directive 2000/.../EC of the European Parliament and of the Council on
the approximation of the laws, regulations and administrative provisions of the Member States
relating to the implementation of good clinical practice in the conduct of clinical trials on
medicinal products for human use

(2000/C 300/03)

THE EUROPEAN PARLIAMENT AND THE COUNCIL OF THE
EUROPEAN UNION,

(2)

Having regard to the Treaty establishing the European Com-
munity, and in particular Article 95 thereof,

Having regard to the proposal from the Commission (1),

Having regard to the opinion of the Economic and Social
Committee (2),

(3)

Acting in accordance with the procedure laid down in
Article 251 of the Treaty (3),

(4)

(5)

Whereas:

(1)

Council Directive 65/65/EEC of 26 January 1965 on
the approximation of provisions laid down by law,
regulation or administrative action relating to medicinal
products (4) 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 the product. Council Directive
75/318/EEC of 20 May 1975 on the approximation
of the laws of Member States relating to analytical,
pharmaco-toxicological and clinical standards and pro-
tocols in respect of the testing of medicinal products (5)
lays down uniform rules on the compilation of dossiers
including their presentation.

(1) OJ C 306, 8.10.1997, p. 9 and OJ C 161, 8.6.1999, p. 5.
(2) OJ C 95, 30.3.1998, p. 1.
(3) Opinion of the European Parliament of 17 November 1998 (OJ
C 379, 7.12.1998, p. 27). Council Common Position of 20 July
2000 and Decision of the European Parliament of ... (not yet
published in the Official Journal).

(4) OJ 22, 9.2.1965, p. 1/65. Directive as last amended by Directive

93/39/EEC (OJ L 214, 24.8.1993, p. 22).

The accepted basis for the conduct of clinical trials in
humans is founded in the protection of human rights
and the dignity of the human being with regard to the
application of biology and medicine, as for instance
reflected in the 1996 version of the Helsinki Declaration.
The clinical
trial subject’s protection is safeguarded
through risk assessment based on the results of toxico-
logical experiments prior to any clinical trial, screening
by ethics committees and Member States’ competent
authorities, and rules on the protection of personal data.

It is incumbent on Member States to lay down rules to
safeguard the protection of
individuals who are
incapable of giving their consent, such as minors and
incapacitated adults. Since such persons are incapable of
giving their free consent to taking part in a clinical trial,
consent to their participation must be given by a person
or body provided for by law.

In order to achieve optimum protection of health,
obsolete or repetitive tests will not be carried out,
whether within the Community or in third countries.
The harmonisation of technical requirements for the
development of medicinal products should therefore be
pursued through the appropriate forums, in particular
the International Conference on Harmonisation.

For medicinal products falling within the scope of Part
A of the Annex to Council Regulation (EEC) No 2309/93
of 22 July 1993 laying down Community procedures
for the authorisation and supervision of medicinal
products for human and veterinary use and establishing
a European Agency for the Evaluation of Medicinal
Products (6), which include products intended for gene
therapy or cell therapy, prior scientific evaluation by
the European Agency for the Evaluation of Medicinal
Products (hereinafter referred to as the ‘Agency’), assisted
by the Committee for Proprietary Medicinal Products, is
mandatory before the Commission grants marketing
authorisation. In the course of this evaluation, the said
Committee may request full details of the results of the
clinical trials on which the application for marketing
authorisation is based and, consequently, on the manner

(5) OJ L 147, 9.6.1975, p. 1. Directive as last amended by Com-

(6) OJ L 214, 24.8.1993, p. 1. Regulation as amended by Commission

mission Directive 1999/83/EC (OJ L 243, 15.9.1999, p. 9).

Regulation (EC) No 649/98 (OJ L 88, 24.3.1998, p. 7).

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in which these trials were conducted and the same
Committee may go so far as to require the applicant for
such authorisation to conduct further clinical trials.
Provision must therefore be made to allow the Agency
to have full information on the conduct of any clinical
trial for such medicinal products.

(12) The person participating in a trial must 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.

(6)

(7)

(8)

A single opinion for each Member State concerned
reduces delay in the commencement of a trial without
jeopardising the well-being of the people participating
in the trial or excluding the possibility of rejecting it in
specific sites.

Information on the content, commencement and ter-
mination of a clinical trial should be available to the
Member States where the trial takes place and all the
other Member States should have access to the same
information. A European database bringing together this
information should therefore be set up, with due regard
for the rules of confidentiality.

Clinical trials are a complex operation, generally lasting
one or more years, usually involving numerous partici-
pants and several trial sites, often in different Member
States. Member States’ current practices diverge consider-
ably on the rules on commencement and conduct of the
clinical trials and the requirements for carrying them
out vary widely. This therefore results in delays and
complications detrimental to effective conduct of such
trials in the Community. It is therefore necessary to
simplify and harmonise the administrative provisions
governing such trials by establishing a clear, transparent
procedure and creating conditions conducive to effective
coordination of such clinical trials in the Community by
the authorities concerned.

(9)

The principles of good manufacturing practice should
be applied to investigational medicinal products.

(10) Special provisions should be laid down for the labelling

of these products.

(11) The 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, re-
corded and reported are essential in order to justify the
involvement of human subjects in clinical trials.

(13) This Directive is to apply without prejudice to Directive
95/46/EC 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 data (1).

(14)

It is also necessary to make provision for the monitoring
of adverse reactions occurring in clinical trials using
(pharmacovigilance) pro-
Community
cedures in order to ensure the immediate cessation of
any clinical trial in which there is an unacceptable level
of risk.

surveillance

(15) The measures necessary for the implementation of this
Directive should be adopted in accordance with Council
Decision 1999/468/EC of 28 June 1999 laying down
the procedures for the exercise of implementing powers
conferred on the Commission (2),

HAVE ADOPTED THIS DIRECTIVE:

Article 1

Scope

This Directive establishes specific provisions regarding
1.
the conduct of clinical trials, including multicentre trials, on
human subjects involving medicinal products as defined in
Article 1 of Directive 65/65/EEC, in particular relating to the
implementation of good clinical practice. This Directive does
not apply to non-interventional trials.

2.
Good clinical practice is a set of internationally recog-
nised ethical and scientific quality requirements which must
be observed for designing, conducting, recording and reporting
clinical trials that involve the participation of human subjects.
Compliance with this good practice provides assurance that
the rights, safety and well-being of trial subjects are protected,
and that the results of the clinical trials are credible.

3.
The principles of good clinical practice and detailed
guidelines in line with those principles shall be adopted and, if
necessary, revised to take account of technical and scientific
progress in accordance with the procedure referred to in
Article 19(2).

(1) OJ L 281, 23.11.1995, p. 31.
(2) OJ L 184, 17.7.1999, p. 23.

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These detailed guidelines shall be published by the Com-
mission.

(f)

4.
All clinical trials, including bioavailability and bioequiva-
lence studies, shall be designed, conducted and reported in
accordance with the principles of good clinical practice.

Article 2

Definitions

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

(a)

(b)

(c)

(d)

‘Clinical trial’: any investigation in human subjects in-
tended to discover or verify the clinical, pharmacological
and/or other pharmacodynamic effects of one or more
investigational medicinal product(s), and/or to identify
any adverse reactions to one or more investigational
medicinal product(s) and/or to study absorption, distri-
bution, metabolism and excretion of one or more investi-
gational medicinal product(s) with the object of ascer-
taining its (their) safety and/or efficacy.

This includes clinical trials carried out in either one site
or multiple sites, whether in one or more than one
Member State;

‘Multicentre clinical trial’: a clinical trial conducted accord-
ing to a single protocol but at more than one site, and
therefore by more than one investigator, in which the
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 study where the medicinal
product(s) is (are) prescribed in the usual manner in
accordance with the terms of the marketing authorisation.
The assignment of the patient to a particular therapeutic
strategy is not decided in advance by a trial protocol but
falls within current practice and the prescription of the
medicine is clearly separated from the decision to include
the patient in the study. No additional diagnostic or
monitoring procedures shall be applied to the patients
and epidemiological methods shall be used for the
analysis of collected data;

‘Investigational medicinal product’: a pharmaceutical
form of an active substance or placebo being tested or
used as a reference in a clinical trial, including products
already with a marketing authorisation but used or
assembled (formulated or packaged) in a way different
from the authorised form, or when used for an unauthor-
ised indication, or when used to gain further information
about the authorised form;

(g)

(h)

(i)

(j)

(k)

(l)

‘Investigator’: a person responsible for the conduct of a
clinical trial at a trial site. If a trial is conducted by a team
of individuals at a trial site, the investigator is the leader
responsible for 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
or products which are relevant to the study of the product
or products in human subjects;

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

considerations

statistical

‘Subject’: an individual who participates in a clinical trial
as either a recipient of the investigational medicinal
product or a control;

‘Informed consent’: decision to take part in a clinical trial,
taken freely after being duly informed of the details and
appropriately documented, by any person capable of
giving consent or, where the person is not capable of
giving consent, by his or her legal representative and/or
an authority and/or a person and/or body provided for
by law;

‘Ethics committee’: an independent body in a Member
State, consisting of healthcare professionals and non-
medical members, whose responsibility it is to protect
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 investigators
and the adequacy of facilities, and on the methods and
documents to be used to inform trial subjects and obtain
their informed consent;

‘Inspection’: the act by a competent authority of con-
ducting an official review of documents, facilities, records,
quality assurance arrangements, 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 which
the competent authority sees fit to inspect;

(m)

‘Adverse event’: any untoward medical occurrence in a
patient or clinical trial subject administered a medicinal
product and which does not necessarily have a causal
relationship with this treatment;

(e)

‘Sponsor’: an individual, company, institution or organis-
ation which takes responsibility for the initiation, man-
agement and/or financing of a clinical trial;

(n)

‘Adverse reaction’: all untoward and unintended responses
to an investigational medicinal product related to any
dose administered;

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(o)

(p)

‘Serious adverse event or serious adverse reaction’: any
untoward medical occurrence or effect that at any dose
results in death, is life-threatening, requires hospitalisation
or prolongation of existing hospitalisation, results in
persistent or significant disability or incapacity, or is a
congenital anomaly or birth defect;

‘Unexpected adverse reaction’: an adverse reaction, the
nature or severity of which is not consistent with
the applicable product information (e.g.
investigator’s
brochure for an unauthorised investigational product or
summary of product characteristics for an authorised
product).

Article 3

Article 4

Ethics Committee

For the purposes of

1.
implementation of the clinical
trials, Member States shall take the measures necessary for
establishment and operation of Ethics Committees.

The Ethics Committee shall give its opinion, before a

2.
clinical trial commences, on any issue requested.

In preparing its opinion, the Ethics Committee shall

3.
consider, in particular:

(a)

the relevance of the clinical trial and the trial design;

Protection of clinical trial subjects

(b)

the protocol;

1.
This Directive shall apply without prejudice to the
national provisions on the protection of clinical trial subjects
if they are more comprehensive than the provisions of this
Directive and consistent with the procedures and timescales
specified therein.

2.

A clinical trial may be undertaken only if, in particular:

(a)

(b)

the foreseeable risks and inconveniences have been
weighed against the anticipated benefit for the individual
trial subject and society. A clinical trial may be initiated
and continued only if anticipated benefits justify the risks;

the rights of the subject to physical and mental integrity,
to privacy and to the protection of the data concerning
him in accordance with Directive 95/46/EC are safe-
guarded;

(c)

informed consent in the appropriate form has been
obtained;

(d)

the subject may without any resulting detriment withdraw
from the clinical
trial at any time by revoking his
informed consent.

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

The subject shall be provided with a contact point where

4.
he may obtain further information.

(c)

the suitability of the investigator and supporting staff;

(d)

the investigator’s brochure;

(e)

the quality of the facilities;

(f)

the adequacy and completeness of the written infor-
mation to be given and the procedure to be used for the
purpose of obtaining informed consent;

(g) provision for indemnity or compensation in the event of

injury or death attributable to a clinical trial;

(h)

(i)

any insurance or indemnity to cover the liability of the
investigator and sponsor;

the amounts and, where appropriate, the arrangements
for rewarding or compensating investigators and trial
subjects and the relevant aspects of any agreement
between the sponsor and the site;

(j)

the arrangements for the recruitment of subjects.

4.
Notwithstanding the provisions of this Article, a Member
State may decide that the competent authority it has designated
for the purpose of Article 7 shall be responsible for the
consideration of, and the giving of an opinion on, the matters
referred to in paragraph 3, points (g), (h) and (i) of this Article.

When a Member State avails itself of this provision, it shall
notify the Commission, the other Member States and the
Agency.

5.
The Ethics Committee shall have a maximum of 60 days
from the date of receipt of a valid application to give its
reasoned opinion to the applicant and the competent authority
in the Member State concerned.

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6. Within the period of examination of the application for
an opinion, the Ethics Committee may send a single request
for information supplementary to that already supplied by the
applicant. The period laid down in paragraph 5 shall be
suspended until receipt of the supplementary information.

No extension to the time period referred to in paragraph
7.
5 shall be permissible except in the case of trials involving
medicinal products for gene therapy and somatic cell therapy,
including xenogenic cell therapy.

Article 5

Single opinion

For multicentre clinical trials limited to the territory of a single
Member State, Member States shall establish a procedure
providing, notwithstanding the number of Ethics Committees,
for the adoption of a single opinion for that Member State.

In the case of multicentre clinical trials carried out in more
than one Member State simultaneously, a single opinion shall
be given for each Member State concerned by the clinical trial.

Article 6

Detailed guidance

3.
If the competent authority of the Member State notifies
the sponsor of grounds for non-acceptance, the sponsor may,
on one occasion only, amend the content of the request
referred to in paragraph 2 in order to take due account of the
grounds given. If the sponsor fails to amend the request
accordingly, the request shall be considered rejected and the
clinical trial may not commence.

4.
Consideration of a valid request for authorisation by the
competent authority as stated in paragraph 2 must not exceed
60 days. After those 60 days, the sponsor can consider that
the competent authority does not object to the commencement
of the trial if it has not notified the sponsor of any grounds for
non-acceptance.

No extensions to the period referred to in the first sub-
paragraph shall be permissible except in the case of trials
involving the medicinal products listed in paragraph 6.

5. Without prejudice to paragraph 6, written authorisation
may be required before the commencement of clinical trials
for such trials on medicinal products which do not have a
marketing authorisation within the meaning of Direct-
ive 65/65/EEC and are referred to in Part A of the Annex to
Regulation (EEC) No 2309/93, and other medicinal products
with special characteristics the list of which is adopted in
accordance with the procedure referred to in Article 19(2) of
this Directive.

Until the said list is adopted, Member States shall continue to
apply their national procedures.

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

6. Written authorisation shall be required before commenc-
ing clinical
trials involving medicinal products for gene
therapy, somatic cell therapy including xenogenic cell therapy
and all medicinal products containing genetically modified
organisms.

Article 7

Commencement of a clinical trial

1. Member States shall take the measures necessary to
ensure that the procedure described in this Article is followed
for commencement of a clinical trial.

The sponsor may not start a clinical trial until the Ethics
Committee has issued a favourable opinion and inasmuch as
the competent authority of the Member State concerned has
not informed the sponsor of any grounds for non-acceptance.
The procedures to reach these decisions can be run in parallel
or not, depending on the sponsor.

7.
This authorisation shall be issued without prejudice to
the application of Council Directives 90/219/EEC of 23 April
1990 on the contained use of genetically modified micro-
organisms (1) and 90/220/EEC of 23 April 1990 on the
deliberate release into the environment of genetically modified
organisms (2).

In consultation with Member States, the Commission

8.
shall draw up and publish detailed guidance on:

(a)

the format and contents of the request referred to in
paragraph 2 as well as the documentation to be submitted
to support that request, on the quality and manufacture
of the investigational medicinal product, any toxicological
and pharmacological
the protocol and clinical
information on the investigational medicinal product
including the investigator’s brochure;

tests,

2.
Before commencing any clinical trial, the sponsor shall
be required to submit a valid request for authorisation to the
competent authority of the Member State in which the sponsor
plans to conduct the clinical trial.

(1) OJ L 117, 8.5.1990, p. 1. Directive as last amended by Directive

98/81/EC (OJ L 330, 5.12.1998, p. 13).

(2) OJ L 117, 8.5.1990, p. 15. Directive as last amended by
Commission Directive 97/35/EC (OJ L 169, 27.6.1997, p. 72).

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(b)

the presentation and content of the proposed amendment
referred to in point (a) of Article 8 on substantive amend-
ments made to the protocol;

(c)

the declaration of the end of the clinical trial.

Article 9

Exchange of information

Article 8

Conduct of a clinical trial

Amendments may be made to the conduct of a clinical trial
following the procedure described hereinafter.

(a) After the commencement of the clinical trial, the sponsor
may make amendments to the protocol. If those amend-
ments are substantial and are likely to have an impact on
the safety of the trial subjects or to change the interpret-
ation of the scientific documents in support of the
conduct of the trial, or if they are otherwise significant,
the sponsor shall notify the competent authorities of the
Member State or Member States concerned of the reasons
for, and content of, these amendments and shall inform
the Ethics Committee or Committees concerned in
accordance with Articles 4 and 7.

On the basis of the details referred to in Article 4(3) and
in accordance with Article 5, the Ethics Committee shall
give an opinion within a maximum of 35 days of the date
of receipt of the proposed amendment in good and due
form. If this opinion is unfavourable, the sponsor may
not implement the amendment to the protocol.

If the opinion of the Ethics Committee is favourable and
the competent authorities of the Member States have
raised no grounds for non-acceptance of the above-
mentioned substantial amendments, the sponsor shall
following the
the clinical
proceed to conduct
amended protocol. Should this not be the case, the
sponsor shall either take account of the grounds for non-
acceptance and adapt the proposed amendment to the
protocol accordingly or withdraw the proposed amend-
ment.

trial

(b) Without prejudice to point

(a),

in the light of

the
circumstances, notably the occurrence of any new event
relating to the conduct of the trial or the development of
the investigational medicinal product where that new
event is likely to affect the safety of the subjects, the
sponsor and the investigator shall take appropriate urgent
the subjects against any
safety measures to protect
immediate hazard. The sponsor shall forthwith inform
the competent authorities of those new events and the
measures taken and shall ensure that the Ethics Com-
mittee is notified at the same time.

1. Member States in whose territory the clinical trial takes
place shall enter in a European database, accessible only to the
competent authorities of the Member States, the Agency and
the Commission:

(a)

(b)

(c)

extracts from the request for authorisation referred to in
Article 7(2);

any amendments made to the request, as provided for in
Article 7(3);

any amendments made to the protocol, as provided for
in point (a) of Article 8;

(d)

the favourable opinion of the Ethics Committee;

(e)

the declaration of the end of the clinical trial; and

(f)

a reference to the inspections carried out on conformity
with good clinical practice.

At the substantiated request of any Member State, the
2.
Agency or the Commission, the competent authority to which
the request for authorisation was submitted shall supply all
further information concerning the clinical trial in question
other than the data already in the European database.

3.
In consultation with the Member States, the Commission
shall draw up and publish detailed guidance on the relevant
data to be included in this European database, which it
operates with the assistance of the Agency, as well as the
methods for electronic communication of
the data. The
detailed guidance thus drawn up shall ensure that the confiden-
tiality of the data is strictly observed.

Article 10

Suspension of the trial or infringements

1. Where a Member State has objective grounds for con-
sidering that the conditions in the request for authorisation
referred to in Article 7(2) are no longer met or has information
raising doubts about the safety or scientific validity of the
clinical trial, it may suspend or prohibit the clinical trial and
shall notify the sponsor thereof.

(c) Within 90 days of the end of a clinical trial the sponsor
shall notify the competent authorities of the Member
State or Member States concerned and the Ethics Com-
mittee that the clinical trial has ended. If the trial has to
be terminated early, this period shall be reduced to
15 days and the reasons clearly explained.

In this case, the competent authority concerned shall forthwith
inform the other competent authorities, the Ethics Committee
concerned, the Agency and the Commission of its decision to
suspend or prohibit the trial and of the reasons for the
decision.

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2. Where a competent authority has objective grounds for
considering that the sponsor or the investigator or any other
person involved in the conduct of the trial no longer meets the
obligations laid down, it shall forthwith inform him thereof,
indicating the course of action which he must take to remedy
this state of affairs. The competent authority concerned shall
forthwith inform the Ethics Committee, the other competent
authorities and the Commission of this course of action.

Article 11

Manufacture and import of

investigational medicinal

products

1. Member States shall take all appropriate measures to
ensure that the manufacture or importation of investigational
medicinal products is subject to the holding of authorisation.
In order to obtain the authorisation,
the applicant and,
subsequently, the holder of the authorisation, shall meet at least
the requirements defined in accordance with the procedure
referred to in Article 19(2).

2. Member States shall take all appropriate measures to
ensure that the holder of the authorisation referred to in
paragraph 1 has permanently and continuously at his disposal
the services of at least one qualified person who, in accordance
with the conditions laid down in Article 23 of the second
Council Directive 75/319/EEC of 20 May 1975 on the approxi-
mation of provisions laid down by law, regulation or adminis-
trative action relating to proprietary medicinal products (1), is
responsible in particular for carrying out the duties specified
in paragraph 3 of this Article.

3. Member States shall take all appropriate measures to
ensure that the qualified person referred to in Article 21 of
Directive 75/319/EEC, without prejudice to his relationship
with the manufacturer or importer,
in the
context of the procedures referred to in Article 25 of the said
Directive, for ensuring:

is responsible,

(a)

(b)

in the case of investigational medicinal products manufac-
tured in the Member State concerned, that each batch of
medicinal products has been manufactured and checked
in compliance with the requirements of Commission
Directive 91/356/EEC of 13 June 1991 laying down the
principles and guidelines of good manufacturing practice
for medicinal products for human use (2), the product
specification file and the information notified pursuant
to Article 7(2) of this Directive;

in the case of investigational medicinal products manufac-
tured in a third country, that each production batch has
been manufactured and checked in accordance with
standards of good manufacturing practice at least equiva-
lent
laid down in Commission Direct-
ive 91/356/EEC, in accordance with the product specifi-
cation file, and that each production batch has been
checked in accordance with the information notified
pursuant to Article 7(2) of this Directive;

to those

(1) OJ L 147, 9.6.1975, p. 13. Directive as last amended by Council

Directive 93/39/EC (OJ L 214, 24.8.1993, p. 22).

(2) OJ L 193, 17.7.1991, p. 30.

(c)

in the case of an investigational medicinal product which
is a comparator product from a third country, and which
has a marketing authorisation, where the documentation
certifying that each production batch has been manufac-
tured in conditions at least equivalent to the standards of
good manufacturing practice referred to above cannot be
obtained, that each production batch has undergone all
relevant analyses, tests or checks necessary to confirm its
quality in accordance with the information notified
pursuant to Article 7(2) of this Directive.

Detailed guidance on the elements to be taken into account
when evaluating products with the object of releasing batches
within the Community shall be drawn up pursuant to the
good manufacturing practice guidelines, and in particular
Annex 13 to the said guidelines. Such guidelines will be
adopted in accordance with the procedure referred to in
Article 19(2) of this Directive and published in accordance
with Article 19a of Directive 75/319/EEC.

In so far as the provisions laid down in points (a), (b) or (c) are
complied with, investigational medicinal products shall not
have to undergo any further checks if they are imported into
another Member State together with batch release certification
signed by the qualified person.

In all cases, the qualified person must certify in a register
4.
or equivalent document that each production batch satisfies
the provisions of this Article. The said register or equivalent
document shall be kept up to date as operations are carried
out and shall remain at the disposal of the agents of the
competent authority for the period specified in the provisions
of the Member States concerned. This period shall in any event
be not less than five years.

5.
Any person engaging in activities as the qualified person
referred to in Article 21 of Directive 75/319/EEC as regards
investigational medicinal products at the time when this
Directive is applied in the Member State where that person is,
but without complying with the conditions laid down in
Articles 23 and 24 of that Directive, shall be authorised to
continue those activities in the Member State concerned.

Article 12

Labelling

The particulars to appear in at least the official language(s) of
the Member State on the outer packaging of investigational
medicinal products or, where there is no outer packaging, on
the immediate packaging, shall be published by the Com-
mission in the good manufacturing practice guidelines on
investigational medicinal products adopted in accordance with
Article 19a of Directive 75/319/EEC.

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Article 13

Article 14

Verification of compliance of investigational medicinal
products with good clinical and manufacturing practice

Notification of adverse events

1.
To verify compliance with the provisions on good
clinical and manufacturing practice, Member States shall
appoint inspectors to inspect the sites concerned by any
clinical trial conducted, particularly the trial site or sites, the
manufacturing site of the investigational medicinal product,
any laboratory used for analyses in the clinical trial and/or the
sponsor’s premises.

the Member State concerned, which shall

The inspections shall be conducted by the competent authority
of
inform the
Agency; they shall be carried out on behalf of the Community
and the results shall be recognised by all the other Member
States. These inspections shall be coordinated by the Agency,
within the framework of
its powers as provided for in
Regulation (EEC) No 2309/93. A Member State may request
assistance from another Member State in this matter.

2.
Following inspection, an inspection report shall be
prepared. It must be made available to the sponsor while
safeguarding confidential aspects. It may be made available to
the other Member States, to the Ethics Committee and to the
Agency, at their reasoned request.

1.
The investigator shall report all serious adverse events
immediately to the sponsor except for those 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
latter.

2.
Adverse events and/or laboratory abnormalities ident-
ified in the protocol as critical to safety evaluations shall be
reported to the sponsor according to the reporting require-
ments and within the time periods specified in the protocol.

3.
For reported deaths of a subject, the investigator shall
supply the sponsor and the Ethics Committee with any
additional information requested.

4.
The sponsor shall keep detailed records of all adverse
events which are reported to him by the investigator or
investigators. These records shall be submitted to the Member
States in whose territory the clinical trial is being conducted, if
they so request.

3.
At the request of the Agency, within the framework of
its powers as provided for in Regulation (EEC) No 2309/93, or
the Member States concerned, and following
of one of
consultation with the Member States concerned, the Com-
mission may request a new inspection should verification of
compliance with this Directive reveal differences between
Member States.

1.

(a)

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

5.
The detailed guidelines on the documentation relating to
the clinical trial, which shall constitute the master file on the
trial, archiving, qualifications of inspectors and inspection
procedures to verify compliance of the clinical trial in question
with this Directive shall be adopted and revised in accordance
with the procedure referred to in Article 19(2).

Article 15

Notification of serious adverse reactions

The sponsor shall ensure that all relevant infor-
mation about
suspected serious unexpected
adverse reactions that are fatal or life-threatening
is recorded and reported as soon as possible to the
competent authorities in all the Member States
concerned, and to the Ethics Committee, and in
any case no later than seven days after knowledge
by the sponsor of such a case, and that relevant
follow-up information is subsequently communi-
cated within an additional eight days.

(b) All other suspected serious unexpected adverse
reactions shall be reported to the competent
authorities concerned and to the Ethics Com-
mittee concerned as soon as possible but within a
maximum of 15 days of first knowledge by the
sponsor.

(c)

Each Member State shall ensure that all suspected
unexpected serious adverse reactions to an investi-
gational medicinal product which are brought to
its attention are recorded.

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(d) The sponsor shall also inform all investigators.

Article 18

2.
Once a year throughout the clinical trial, the sponsor
shall provide the Member States in whose territory the clinical
trial
is being conducted and the Ethics Committee with a
listing of all suspected serious adverse reactions which have
occurred over this period and a report of the subjects’ safety.

3.

(a)

Each Member State shall ensure that all suspected
unexpected serious adverse reactions to an investi-
gational medicinal product which are brought to
its attention are reported immediately to the
Agency by the sponsor of the clinical trial.

Adaptation to scientific and technical progress

This Directive shall be adapted to take account of scientific
and technical progress in accordance with the procedure
referred to in Article 19(2).

Article 19

Committee procedure

1.
The Commission shall be assisted by the Standing
Committee on Medicinal Products for Human Use, set up by
Article 2b of Directive 75/318/EEC (hereinafter referred to as
the Committee).

(b) The Agency shall make the information notified
by the sponsor available to the competent auth-
orities of the Member States.

2. Where reference is made to this paragraph, Articles 5
and 7 of Decision 1999/468/EC shall apply, having regard to
the provisions of Article 8 thereof.

The period referred to in Article 5(6) of Decision 1999/468/EC
shall be set at three months.

Article 16

3.

The Committee shall adopt its rules of procedure.

Guidance concerning reports

The Commission, in consultation with the Agency, Member
States and interested parties, shall draw up and publish detailed
guidance on the collection, verification and presentation
of adverse event/reaction reports, together with decoding
procedures for unexpected serious adverse reactions.

Article 17

General provisions

This Directive is without prejudice to the civil and criminal
liability of the sponsor or the investigator. To this end, the
sponsor or a legal representative of the sponsor must be
established in the Community.

Unless Member States have established precise conditions for
exceptional circumstances, investigational medicinal products
and, as the case may be, the devices used for their adminis-
tration shall be made available free of charge by the sponsor.

The Member States shall
conditions.

inform the Commission of such

Article 20

Application

1. Member States shall adopt and publish before ... (*) the
laws, regulations and administrative provisions necessary to
comply with this Directive. They shall forthwith inform the
Commission thereof.

They shall apply these provisions at the latest with effect from
... (**).

When Member States adopt these provisions, they shall contain
a reference to this Directive or shall be accompanied by such
reference on the occasion of their official publication. The
methods of making such reference shall be laid down by
Member States.

2. 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.

Article 21

Entry into force

This Directive shall enter into force on the day of its publication
in the Official Journal of the European Communities.

(*) Twenty-four months after the date on which this Directive enters

into force.

(**) Thirty-six months after the date on which this Directive enters

into force.

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Article 22

Addressees

Done at ...

For the European Parliament

For the Council

The President

The President

This Directive is addressed to the Member States.

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STATEMENT OF THE COUNCIL’S REASONS

I.

INTRODUCTION

1. On 4 September 1997, the Commission submitted to the Council (1) a proposal for a Directive
on the approximation of the laws, regulations and administrative provisions of the Member
States relating to the implementation of good clinical practice in the conduct of clinical trials
on medicinal products for human use.

2.

3.

The Economic and Social Committee delivered its opinion on 28 January 1998(2).

The European Parliament delivered its opinion at first reading on 17 November 1998 (3). In the
light of the opinion of the European Parliament, the Commission submitted an amended
proposal (4) to the Council in a letter dated 27 April 1999.

4. On 20 July 2000, the Council adopted its Common Position in accordance with Article 251 of

the Treaty.

II. OBJECTIVE OF THE PROPOSAL

5.

6.

The objective of the proposal for a Directive is to rationalise and approximate the national
documentary and administrative procedures relating to the clinical trials of medicinal products
for human use by means of the homogeneous implementation of good clinical practices (GCP).

The Community guidelines on GCP, harmonised at international level, are not binding and are
not implemented in the same way by all Member States. This situation often leads to long
delays in the programme of clinical experiments, particularly in multicentre clinical trials,
where the same trial is carried out in several Member States simultaneously.

It is therefore important to transform the Community principles and guidelines into a binding
Community legislative act.

III. ANALYSIS OF THE COMMON POSITION

7.

The Council’s Common Position is essentially based on the amended Commission proposal,
and therefore includes the letter or spirit of most of the amendments suggested by Parliament
and taken up by the Commission.

8. An important exception concerns the procedure for starting a clinical trial, which has been
substantially amended by the Council (amendments 13, 15, 18 and 31) in order to simplify
and speed up decision-making by the competent authorities of the Member States.

9. Another exception concerns the provisions for the protection of subjects in clinical trials, in
particular certain aspects relating to minors and incapacitated adults (amendments 1, 10 and
28), which could only be partly accepted by the Council and the Commission, both institutions
nevertheless considering that the protection guarantees for subjects in clinical trials would not
be reduced as a result (see point 21).

10. The Commission approves all the amendments made by the Council.

(1) OJ C 306, 8.10.1997, p. 9.
(2) OJ C 95, 30.3.1998, p. 1.
(3) OJ C 379, 7.12.1998, p. 27.
(4) OJ C 161, 8.6.1999, p. 5.

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11.

It should be pointed out that the amended Commission proposal contains, in addition to new
provisions in the light of Parliament’s opinion, important editorial changes to the original text.

Similarly, the Council has introduced a number of editorial changes to the text of the Common
Position. Some of the original provisions to which the European Parliament’s proposals for
amendments refer have consequently undergone subsequent re-drafting or re-editing.

Amendments accepted without modification, with minor editorial modifications or in
principle

12. The Council accepted amendment 6,

in so far as it supplemented the list of definitions
in Article 2 by a definition of ‘informed consent’. The definition selected by the Council differs
from that proposed by Parliament in that it also covers persons who are not in a position to
give their consent with full knowledge of the facts.

13. The Council accepted amendment 9 concerning the definition of ‘unexpected adverse reaction’

in Article 2(p), subject to certain editorial modifications.

14. The second part of amendment 12 (Article 4(7)), concerning an exceptional extension of the
60-day period for the Ethics Committee to give its opinion in cases where trials involve
medicinal products for gene therapy was accepted by the Council and extended to include
somatic cell therapy, including xenogenic cell therapy.

15. The Council accepted amendment 19 (Article 9(3)) concerning strict observance of

the

confidentiality of data to be entered in the European database.

16. Amendment 21 (Article 10(1)), which makes it obligatory to inform the sponsor, the competent
authorities, the Ethics Committee concerned and the Commission in cases where a suspension
of the clinical trial must be contemplated, was accepted by the Council, subject to the additional
obligation that the Agency be informed.

17. Likewise, it accepted amendment 22 (Article 10(2)), obliging the sponsor to provide for a
course of action to take in the event that he no longer meets his obligations and to notify the
Ethics Committee, the other competent authorities and the Commission.

18. The Council agreed in principle to amendments 23, 24 and 25, concerning provisions relating

to the manufacture and importation of investigational medicinal products (Article 11).

19. The Council accepted amendment 33 making the inspection report available subject to a

reasoned request (Article 13(2)).

20. The Council accepted amendment 27, while making some editorial changes (Article 15(1)(a) to

(d)).

Partly accepted amendments

21. The Council partly accepted amendments 1, 10 and 28, concerning the protection of trial
It therefore incorporated part of the proposed amendment 1,

subjects in clinical trials.
modifying recital 2, in a new recital 3.

It also accepted the proposed changes to Article 3(1) as well as paragraph 2(a) concerning the
trial subject’s right to have his mental and physical integrity safeguarded.

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The Council introduced a functional definition of ‘informed consent’ (Article 28(j)) which
corresponds to that contained in the Convention on Human Rights and Biomedicine.

Furthermore, it supplemented the provisions of Article 3 by clarifying the arrangements for
giving and revoking consent (Article 3(2)(a) and (b)) and by making it obligatory to establish a
contact point where the trial subject can be provided with further information (Article 3(4)).

Amendments not accepted

22. Amendments 2 and 3 are superfluous, since the Directive no longer contains provisions

relating to trial sites.

23. The Council did not accept amendment 7, which was intended to replace the idea of ‘person

responsible’ in the definition of ‘investigator’ by ‘doctor responsible’ (Article 2(f)).

24. The Council did not accept the addition to the definition of ‘serious adverse event or serious
adverse reaction’ of the provision proposed by Parliament (amendment 8 — Article 2(o)).

25. The Council did not accept the deletion of the provision on the arrangements for rewarding or
compensating investigators and trial subjects as one of the elements to be considered when the
Ethics Committee prepares its opinion (amendment 11 — Article 4(3)(i)).

26. Amendments 13, 15, 18 and 31 are superfluous because the procedure for the commencement
of a clinical trial chosen by the Council differs considerably from those contained both in the
original proposal and in the amended proposal for a Directive (Article 7) (see also point 8).

27. The Council did not accept amendment 26 concerning the indication on the packaging that
the medicinal product is being used in the framework of a clinical trial and that it cannot be
sold (Article 12).

28. The Council did not accept amendment 32, which provides for the deletion of the indication
that inspections for the purpose of verifying compliance with good clinical and manufacturing
practice are carried out ‘on behalf of the Community’ (Article 13(1)).