Amended proposal for a European Parliament and Council 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
Date: 1999-04-26
Institutions: European Commission
Subjects: approximation of laws, market approval, pharmaceutical product, testing, therapeutics

8.6.1999

EN

Official Journal of the European Communities

C 161/5

II

(Preparatory Acts)

COMMISSION

Amended proposal for a European Parliament and Council Directive on the approximation of the
laws, regulations and administrative provisions of the Member States relating to the implemen-
tation of good clinical practice in the conduct of clinical trials on medicinal products for human
use (1)

(1999/C 161/05)

(Text with EEA relevance)

COM(1999) 193 final (cid:151) 97/0197(COD)

(Submitted by the Commission pursuant to Article 189a(2) of the EC-Treaty on 27 April 1999)

(1) OJ C 306, 8.10.1997, p. 9.

ORIGINAL TEXT

AMENDED TEXT

Proposal for a European Parliament and Council Directive
on the approximation of provisions laid down by law,
regulation or
to the
implementation of good clinical practice in the conduct
of clinical trials on medicinal products for human use

action relating

administrative

Proposal for a European Parliament and Council Directive
on the approximation of the laws, regulations and admin-
istrative 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

THE EUROPEAN PARLIAMENT AND THE COUNCIL OF THE
EUROPEAN UNION,

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

Having regard to the proposal from the Commission,

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

Having regard to the opinion of
Committee,

the Economic and Social

Having regard to the opinion of
Committee (2),

the Economic and Social

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

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

requires

65/65/EEC (1)

that
Whereas Council Directive
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
trials carried out on the product; whereas Council
clinical
lays down uniform rules on the
Directive 75/318/EEC (2)
compilation of dossiers including their presentation;

(1) (Unchanged)

___________
(1) OJ L 22, 9.2.1965, p. 1.
(2) OJ L 147, 9.6.1975, p. 1.

___________
(1) OJ C 306, 8.10.1997, p. 9.
(2) OJ C 95, 30.3.1998, p. 1.

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Official Journal of the European Communities

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ORIGINAL TEXT

AMENDED TEXT

Whereas the accepted basis for the conduct of clinical trials in
humans is founded in the current revision of the Declaration of
the
Helsinki and the Council of Europe Convention for
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 and Member
States authorities and the protection of personal data;

(2) 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
trial
subject’s protection is safeguarded through risk assessment
based on the results of toxicological experiments prior to
any clinical
trial, screening by ethics committees and
Member States’ competent authorities, and rules on the
protection of personal data;

the clinical

(3) Whereas it is incumbent on the Member States to lay
down rules to safeguard protection of individuals who
are incapable of giving their consent, such as minors
such persons are
and incapacitated adults; whereas
incapable of giving their free consent to take part in a
clinical trial; whereas, therefore, such consent must be
given in writing by their parents or their guardian or
their legal representative;

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;

(4) (Unchanged)

for

(5) Whereas for medicinal products falling within the scope
of Part A of the Annex to Council Regulation (EEC) No
2309/93 (1), which include products intended for gene
therapy or cell therapy, prior scientific evaluation by the
European Agency
the Evaluation of Medicinal
Products, assisted by the Committee for Proprietary
Medicinal Products, is mandatory before the Commission
grants marketing authorisation; whereas in the course of
this evaluation the 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 in which these trials were conducted, and the
same Committee may go so far as to request the applicant
for marketing authorisation to conduct
further clinical
therefore, provision must be made to
trials; whereas,
full
allow the
information on the
trial
proposed for such medicinal products;

abovementioned Agency

have
clinical

conduct of

any

to

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 jeop-
ardising the well-being of the people participating in the trial
with the possibility of rejecting it in specific sites if facilities are
not appropriate;

(6) (Unchanged)

___________
(1) OJ L 214, 24.8.1993, p. 1.

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ORIGINAL TEXT

AMENDED TEXT

(7) Whereas information on the content, commencement and
termination of a clinical trial should be available to the
Member States where the trial takes place and all the
other Member States must have access to the same
information which will be indispensable for them at the
time of mutual recognition of the marketing authoris-
corresponding medicinal product or
for
ations
products; whereas,
European database
bringing together this confidential information should be
set up;

therefore,

the

a

(8) Whereas clinical trials are a complex operation, generally
lasting one or more years, usually involving numerous
participants and several
sites, often in different
trial
Member States; whereas Member States’ current practices
diverge considerably on the rules on commencement and
conduct of the clinical trials and the requirements for
carrying them out vary widely; whereas this therefore
results
to
in the Community;
effective conduct of
whereas it
is therefore necessary to harmonise these
practices in order to simplify and shorten them by estab-
lishing a
and creating
conditions conducive to effective coordination of such
clinical trials by the Community authorities concerned,
thereby favouring completion of the internal market;

and complications detrimental

transparent procedure

such trials

in delays

clear,

(9) (Unchanged)

(10) (Unchanged)

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

Whereas the standards of good manufacturing practice should
be applied to investigational medicinal products; whereas
special
investigational
medicinal products should be set out;

provisions

labelling

the

for

of

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;

this Directive is without prejudice to Directive
Whereas
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);

(11)

(Unchanged)

Whereas it is also necessary to make provisions for the moni-
toring 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 an unacceptable level of risk;

(12) (Unchanged)

___________
(1) OJ L 281, 23.11.1995, p. 31.

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ORIGINAL TEXT

AMENDED TEXT

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
the
Commission and the Member States within a (cid:145)Committee for
the Adaptation to Technical Progress of the Directives on the
Removal of Technical Barriers
to Trade in the Medicinal
Products Sector(cid:146),

cooperation

ensuring

between

close

(13) 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 tecnnical progress the requirements regarding
the conduct of clinical trials, whilst ensuring close coop-
eration between the Commission and the Member States
within a (cid:145)Standing Committee on Medicinal Products for
Human Use(cid:146),

HAVE ADOPTED THIS DIRECTIVE:

HAVE ADOPTED THIS DIRECTIVE:

CHAPTER I

Scope and definitions

Article 1

Scope

Article 1

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

The purpose of this Directive is to lay down provisions
1.
relating to the implementation of good clinical practice in the
conduct of clinical
including multi-centre trials, on
human subjects disigned to develop medicinal products, as
defined in Article 1 of Council Directive 65/65/EEC. This
Directive shall not apply to non-interventional clinical trials.

trials,

Good clinical practice (GCP)

2.
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.

a

is

set of

Good clinical practice

2.
internationally
recognised ethical and scientific quality requirements which
must be observed for designing, conducting, recording and
reporting clinical
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, consistent with the principles set out in the
amended 1964 Declaration of Helsinki, and that the results
of the clinical trials are credible.

trials

that

The principles and guidelines of good clinical practice
3.
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
shall be published by the
in line with those principles
Commission and revised as necessary to take account of
technical and scientific progress.

3.

(Unchanged)

All clinical trials,

4.
including bioavailability and bioequi-
valence studies, shall be designed, conducted and reported in
accordance with the standard of good clinical practice.

4.

(Unchanged)

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ORIGINAL TEXT

Article 2

AMENDED TEXT

Definitions

Article 2

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

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.

effects of

Clinical trial: Any investigation in human subjects intended to
discover or verify the clinical, pharmacological and/or other
pharmacodynamic
an investigational medicinal
product(s), and/or to identify any adverse reactions to an inves-
tigational 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.

1. Clinical trial: Any investigation in human subjects intended
to discover or verify the clinical, pharmacological and/or
other pharmacodynamic effects of one or more investi-
to identify any
gational medicinal products,
one
adverse
investigational
reactions
absorption,
and/or
medicinal
distribution, metabolism and excretion of one or more
investigational medicinal products with the object of ascer-
taining their safety and/or efficacy.

and/or
or more

products

study

to

to

This includes clinical trials performed either on a single
site or on multiple sites in the course of these clinical
trials.

2. Multi-centre clinical trial: A clinical trial conducted according
to a single protocol but at more than one site, and
in which the
therefore, 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.

3. Non-interventional clinical

subjects or

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

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
things,
assurance of
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.

that protection, by,

among other

4. 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
assembled
(formulated or packaged) in a way different from the auth-
orised form, or when used for an unauthorised indication,
or when used to gain further information about the auth-
orised form.

authorisation but used or

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ORIGINAL TEXT

AMENDED TEXT

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
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.

trial,

5. Sponsor: An individual, company,

sation which takes
management and/or financing of a clinical trial.

responsibility

institution or organi-
initiation,

the

for

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

individuals at a trial

the investigator

is

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

7. Investigator’s brochure: A compilation of

the clinical and
non-clinical data on the investigational medicinal product
or products which is relevant to the study of the product
or products in human subjects.

Investigator’s brochure: A compilation of
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.

the

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

the term (cid:145)protocol(cid:146)

protocol

versions

the

of

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.

9. Subject: An individual who takes part in a clinical trial,
either as a recipient of
the investigational medicinal
product or as a control receiving a placebo or other
medicinal product.

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

10. Informed consent: Decision to take part in a clinical trial,
taken freely and given in writing after being duly informed
of the full details, by any responsible adult trial subject or,
where appropriate, by the parents, guardian or
legal
representative, on behalf of minors and incapacitated
adults.

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AMENDED TEXT

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.

11. Ethics

professionals

committee: An independent body constituted of
healthcare
non-medical members,
and
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
facilities, and the
the investigator(s),
methods and documents to inform trial subjects and
obtain their informed consent.

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
congenital
anomaly/birth defect.

disability/incapacity,

or

is

a

Sponsor: An individual, company,
which takes
and/or financing of a clinical trial.

responsibility for

institution or organisation
the initiation, management,

12. Inspection: The act by a competent authority of conducting
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.

13. Adverse

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

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

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

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

reaction that at any dose results

15. Serious adverse event or serious adverse reaction: Any untoward
in death,
event or
threatens the life of
the subject, requires non-elective
inpatient hospitalisation or prolongation of existing hospi-
talisation, results in persistent or significant disability or
incapacity or is a congenital anomaly or birth defect.

16. Unexpected

adverse

reaction: An adverse

mentioned in the investigator’s brochure or,
of medicinal
already
summary of product characteristics.

products

authorised,

reaction not
in the case
the
in

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ORIGINAL TEXT

CHAPTER II

AMENDED TEXT

Protection of trial subjects

Protection of clinical trial subjects

Article 3

Article 3

This Directive is without prejudice to the measures laid
trial

1.
down in Member States concerning the protection of
subjects.

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 time-scales
specified therein.

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.

2.

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

(a) the risks to the subject are not disproportionate to the

benefits expected for human health;

(b) the rights of the subject to physical and mental integrity

and to privacy are safeguarded;

(c) the subject has given informed consent in the appropriate

form;

(d) the subject may withdraw from the clinical tiral at any
time, without any resulting detriment to the subject, by
revoking the informed consent, as defined in Article 2.

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

3.

(Unchanged)

The trial subject shcall be provided with a contact point,
further

4.
independent
of
information may be obtained.

team, where

investigating

the

On the responsibility of the sponsor, who shall adopt the
clinical
trial
independent
information
tiral,

4.
consequent organisational arrangements,
subject shall be provided with a contact point,
from which further
team,
of
may be obtained on the procedure for
whenever it could affect the trial subject personally.

the investigator

the clinical

the

Ethics Committee opinion

Ethics committee opinion

Article 4

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.

1.
For the purposes of implementation of the clinical trials
provided for by this Directive, the Member States shall take the
measures necessary for establishment and operation of ethics
committees, as defined in Article 2.

The ethics committee shall give its opinion on any

2.
subject requested before a clinical trial commences.

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AMENDED TEXT

In prepararing 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
to be obtained; provision for compensation/
treatment in the case of injury or death of a subject if attrib-
utable to a clinical trial, and any insurance or indemnity to
cover the liability of the investigator and sponsor; the extent to
which investigators
rewarded or
compensated for participation in the trial.

and subjects may be

is

In preparing its opinion,

3.
consider, in particular:

the ethics committee shall

(a) the relevance of the clinical trial and the trial dsesign;

(b) the protocol;

(c) the suitability of the investigator and supporting staff;

(d) the quality of the facilities;

(e) 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 informed
consent is to be obtained;

(f) provision for compensation in the case of injury or death

attributable to a clinical trial;

(g) any insurance or indemnity to cover the liability of the

investigator and sponsor;

(h) the arrangements for rewarding or compensating inves-

tigators ans subjects for participation in the trial.

The opinion of an ethics committee shall be delivered

2.
before a clinical trial commences.

(see paragraph 2)

3.
In order to apply for an opinion af 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.
In order to obtain the opinion of an ethics committee,
the sponsor shall submit to the committee a request for an
opinion with documentation giving the reasons
the
proposed clinical trial. Within 30 days of official submission
of the application for an opinion, the ethics committee shall
give its reasoned opinion to the sponsor and the competent
authority in the Member State concerned.

for

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.

5. 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
sponsor.
In this case the ethics committee shall have a
further 30 days from receipt of the supplementary information
to give its definitive opinion on the proposed clinical trial.

Article 5

Article 5

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

1.
For multi-centre clinical trials limited to a single Member
State, Member States shall establish a procedure providing for
adoption of a single ethics committee opinion for that Member
State. In the case of multi-centre clinical trials involving more
than one Member State
ethics
committee opinion shall be given for each Member State
concerned by the clinical trial.

simultaneously,

single

a

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AMENDED TEXT

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

In the case of multi-centre clinical

2.
trials the Member
States may provide for the ehtics committee for a particular
centre amongst all the centres involved in the multi-centre
clinical trial to give an opinion covering only the facilities
and capabilities of that particular centre to conduct the trial.
The ethics committee for this particular centre shall have a
maximum of 15 days from the date of receipt of the opinion
referred to in paragraph 1 to give its own duly reasoned
opinion: if this opinion is negative, the clinical trial may not
be conducted at this single centre, without prejudice to the
situation in the other centres concerned or to the opinion
referred to in paragraph 1.

Article 6

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 information that
is given to trial subjects.

(Unchanged)

CHAPTER III

Commencement of a clinical trial

Commencement of a clinical trial

Article 7

Article 7

The Member States shall take the measures necessary to ensure
that
followed for
commencement of a clinical trial.

the procedure described hereinafter

is

1.
Before commencing a clinical trial, an application shall be
submitted by the sponsor to the Member States where the trial
will take place.

1. Before commencing any clinical trial, the sponsor shall be
required to submit notification thereof to the competent
authorities of
the Member State or States where the
sponsor plans to conduct the trial at the same time as
submitting the request
for an opinion referred to in
paragraph 4 of Article 4.

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.

2. The sponsor may not start a clinical trial until the ethics
committee has issued a favourable opinion and unless the
competent authorities of the Member State concerned have
notified the sponsor of no grounds for non-acceptance
within 30 days of receipt of the notification referred to in
paragraph 1.

In the case of clinical trials not covered by the provisions
3.
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 grouns for
non-acceptance have been notified within this time period.

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AMENDED TEXT

the

Within 30 days of
for
receipt of
non-acceptance, the sponsor may amend the application on
the
one occasion only in order
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.

to take due account of

said grounds

Should this not be the case, within 30 days of receipt of the
grounds for non-acceptance from the competent authorities
of the Member State concerned, the sponsor may amend, on
one occasion only, the content of the notification referred to
in paragraph 1 of this Article in order to take due account
of the grounds given.
If the sponsor fails to amend the
notification accordingly, the notification shall be considered
rejected and the clinical trial may not commence.

to Council Regulation

3. In the case of clinical trials on investigational medicinal
products corresponding to the medicinal products corre-
sponding to the characteristics defined in Part A of the
2309/93,
Annex
particularly products
therapy and
products intended for cell therapy, a copy of the notification
referred to in paragraph 1 of this Article or of the amended
notification provided for in paragraph 2 of this Article shall
be sent
to the European Agency for the Evaluation of
Medicinal Products.

intended for gene

(EEC) No

In the case of clinical trials on investigational medicinal
products corresponding to the characteristics defined in
Part B of
the Annex to Council Regulation (EEC) No
2309/93, the sponsor shall have the option of sending the
notification referred to in paragraph 1 of this Article or the
amended notification provided for in paragraph 2 of this
Article to the European Agency for
the Evaluation of
Medicinal Products.

clinical

commencing

4. However, prior written authoristation shall be required
trials on the medicinal
before
products referred to in Part A of the Annex to Council
Regulation (EEC) No 2309/93 and on all other medicinal
products with special characteristics defined and approved
in the form of a directive adopted by the procedure laid
down in Article 2c of Council Directive 75/318/EEC.

This authorisation to commence shall be granted by the
competent authorities of
the Member States within 60
days of receipt of the notification referred to in paragraph
1 of this Article and after the ethics committee has given a
favourable opinion, without prejudice to the procedure
applicable in the event of the grounds for non-acceptance
referred to in paragraph 2 of this Article.

The abovementioned authorisation to commence the clinical
trial shall be sent to the sponsor. The ethics committee and
the Evalutation of Medicinal
the European Agency for
this authorisation has
Products
been granted.

shall be informed that

(see new Article 8 (1))

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,
procedure in paragraph 3 shall be followed.

the

5.
Notwithstanding paragraph 4, provisional urgent safety
measures may be taken by the sponsor in order to eliminate
an immediate hazard to trial subjects.

(see new Article 8, (2))

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ORIGINAL TEXT

AMENDED TEXT

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.

(see new Article 8, (3))

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,
investigational
protocol
medicinal product
in
addition to the content of the notification of the end of the
clinical trial.

including the investigator’s brochure,

information on the

and clinical

5. In consultation with the Member States, the Commission
shall draw up detailed guidance on the format and
contents of the notification referred to in paragraph 1 of
this Article as well as the documentation to be submitted to
support this notification on 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 inves-
tigator’s brochure,
the
end of the clinical trial.

in addition to the declaration of

Conduct of a clinical trial

Article 8

(new)

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

1. After commencement of the clinical trial, the sponsor may
make substantial amendments to the protocol likely to have
an impact on the safety of the trial subjects or to change the
criteria for scientific evaluation, the criteria for inclusion or
exclusion of trial subjects, the number of trial subjects, the
duration of the treatment, the doses of the investigational
medicinal products and the clinical and biological exam-
inations carried out in the course of follow-up of the trial
subjects. In this case the sponsor shall notify the competent
the Member State or Member States
authorities of
these
the
concerned of
for and content of
amendments and shall
inform the ethics committee or
committees concerned thereof and the European Agency
for the Evaluation of Medicinal Products if
the clinical
trial in question meets the requirements of the first indent
of Article 7(4).

reasons

to the requirements of Article 5,

On the basis of the details referred to in Article 4(3) and
subject
the ehtics
an opinion on the proposed
committee
amendment within 30 days of notification thereof. If this
opinion is unfavourable, the sponsor may not implement
the amendment to the protocol.

shall

give

for

non-acceptance

If the opinion of the ethics committee is favourable and the
competent authorities of the Member States have raised no
grounds
abovementioned
substantial amendments within 30 days of notification
thereof, the sponsor shall proceed to conduct the clinical
trial following the amended protocol. Should this not be the
case, the sponsor shall either take account of these grounds
and adapt
to the protocol
the proposed amendment
accordingly or withdraw the proposed amendment.

the

of

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ORIGINAL TEXT

AMENDED TEXT

In the case of clinical trials subject to the prior written
authorisation referred to in Article 7(4), the sponsor may
following the
not proceed to conduct
amended protocol unless the ethics committee has given a
favourable opinion and the competent authorities of the
Member States have given a new authorisation taking
account of these amendments.

the clinical

tiral

in the light of

2. Without prejudice to paragraph 1,

the
circumstances, notably
the occurrence of unexpected
adverse reactions or events, the sponsor shall take appro-
priate urgent safety measures to protect the subjects in a
clinical
tiral against any immediate hazard. The sponsor
shall
inform the competent authorities and the ethics
committee of these measures.

3. 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 committee 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.

Exchange of information

Exchange of information

Article 8

Article 9

(ex 8)

the end of
shall be entered by the Member States

Extracts from the initial application, amendments as
1.
the clinical
appropriate and the notification at
trial
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.

The Member States in whose territory the clincial trial
1.
takes place shall enter in a European database, accessible
only to the competent authorities of the Member States, the
European Agency for the Evaluation of Medicinal Products and
the Commission, extracts from the notification referred to in
Article 7(1), any amendments made to the notification, as
provided for in Article 7(2), any amendments made to the
protocol, as provided for
the favourable
opinion of the ethics comittee and the declaration of termi-
nation of the clinical trial.

in Article 8(1),

2.
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.

In the case of multi-centre clinial

3.
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.

the request of any Member State,

the Evaluation of Medicinal Products or

the European
2.
At
Agency for
the
Commission, the competent authority to which the notification
referred to in Article 7(1) was submitted shall supply all further
information concerning the clinical trial in question other than
the data already in the European database.

3.
In the case of multi-centre clinical trials involving more
than one Member State, where there are differences between
for
the Member States with regard to the
commencement
the
the Member States concerned to
Commission may request
the differences, which shall be
establish the reasons
for
in consultations
considered by
the Member
organised by the Commission with the assistance of
the
European Agency for the Evaluation of Medicinal Products.

conditions
trial,

conduct

clinical

States

the

all

or

of

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ORIGINAL TEXT

AMENDED TEXT

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.

4.
In consultation with the Member States, the Commission
shall draw up detailed guidance on the relevant data to be
included in this European database which it operates with
the assistance of the European Agency for the Evaluation of
Medicinal Products as well as the methods for electronic
communication of the data. This detailed guidance drawn up
shall keep the data strictly confidential.

Article 9

Infringements

Article 10

(ex 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
forthwith inform the other
Member States and the Commission thereof.

the trial.

It shall

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 invesigator is no longer fulfilling his obligations as laid
down, it shall forthwith inform the other Member States and
the Commission, stating the reasons in detail and idicating the
course of action.

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

1. Where a Member State has objective grounds
for
considering that the conditions in the notification referred to
in Article 7(1) are no longer met or has information raising
doubts about the safety or science of the clinical trial, it may
suspend or prohibit
trial and shall notify the
sponsor thereof.

the clinical

In this case, the Member State concerned shall fortwith inform
the other Member States, the ethics committee concerned, the
European Agency for the Evaluation of Medicinal Products and
the Commission of its decision to suspend or prohibit the trial
and the reasons for the decision.

a Member State hs objective grounds

2. Where
for
considering that the sponsor or the investigator is no longer
it shall forthwith inform
meeting the obligations laid down,
them,
indicating the course of action which it considers
necessary to remedy this state of affairs. The Member State
concerned shall
forthwith inform the ethics committee, the
other Member States and the Commission of this plan.

3. Where non-observance of the provisions governing the
conduct of clinical trials prompts a Member State to initiate
administrative or legal proceedings against
the sponsor or
forthwith inform the other Member
investigator,
States, the Commission and, where appropriate, the European
Agency for the Evaluation of Medicinal Products.

shall

it

CHAPTER IV

Manufacture, import and labelling of investigational
medicinal products

Manufacture and import of investigational medicinal
products

Article 10

Article 11

(ex 10)

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

take all appropriate measures to
1. Member States shall
ensure that the manufacture, whether in a Member State or
in a third country, of investigational medicinal products used in
a clinical tiral conducted in the European Community meets
the requirements of Commission Directive 91/356/EEC (1)
laying down the principles of good manufacturing practice
for medicinal products and of the related texts.

___________
(1) OJ L 147, 9.6.1975, p. 13.

___________
(1) OJ L 193, 17.7.1991, p. 30.

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ORIGINAL TEXT

AMENDED TEXT

Chapters IV and V of Directive 75/319/EEC shall apply to

2.
investigational medicinal products.

The Member States shall authorise imports of

2.
investi-
gational medicinal products from third countries and free
thereof within the Community, provided the
movement
qualified person referred to in paragraph 3 can certify that
quality control and batch approval have been carried out in
accordance with paragraph 1.

A person engaging in the activities of the person referred
3.
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 investi-
gational medicinal products in the Member State concerned.

Any person engaging in the activities of the qualified
3.
person referred to in Article 21 of Council Directive
75/319/EEC as regards investigational medicinal products at
the time when this Directive is brought
into force in the
Member State where that person is but without complying
with the conditions laid down in Article 23 and 24 of
Council Directive 75/319/EEC shall be authorised to continue
those
investigational medicinal
products in the Member State concerned.

to manufacture

activities

Article 11

the national

1.
For investigational medicinal products, the particulars to
appear in, at
language(s) on the outer
least,
investigational medicinal products or, where
packaging of
there is no outer packaging, on the immediate packaging
shall be published by the Commission in the good manufac-
turing practice guideline on investigational medicinal products
to be adopted in accordance with Article 19a Directive
75/319/EEC.

(Unchanged)

Labelling

Article 12

(ex 11)

CHAPTER V

Compliance

Article 12

Compliance with good clinical practice

Article 13

(ex 12)

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

Following inspection, an inspection report

2.
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.

sites

concerned with any

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

clinical

trial

inform the European Agency for

The inspections shall be conducted by a Member State, which
shall
the Evaluation of
Medicinal Products; 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
European Agency for the Evaluation of Medicinal Products.

Following inspection, an inspection report

2.
shall be
prepared and sent to the sponsor. A copy of this report shall
be sent to the European Agency for the Evaluation of Medicinal
Products. Upon reasoned request, the investigator, the ethics
committee, any other Member State and the Commission
may consult this report.

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8.6.1999

ORIGINAL TEXT

AMENDED TEXT

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 coor-
dination of
shall be undertaken by the
European Agency for the Evaluation of Medicinal Products.

such inspections

At the behest of the European Agency for the Evaluation
3.
of Medicinal Products,
the Commission may request rein-
spection should verification of compliance with the provisions
of this Directive reveal differences between Member States.

Subject

4.
to any arrangements which may have been
concluded between the Community and 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 the sponsor’s premises and/or the manufacturer estab-
lished in a third country submit
to an inspection. The
inspection shall be undertaken by appropriately qualified
inspectors from the Community.

4.

(Unchanged)

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,
of
inspectors and inspection procedures for the demonstration
of compliance with this Directive.

qualification

appropriate

archiving,

5.
In consultation with the Member States, the European
Agency for the Evaluation of Medicinal Products and interested
parties, the Commission shall draw up 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
by the clinical trial in question with this Directive and with the
texts adopted to implement it

CHAPTER VI

Clinical safety reporting

Notification of adverse events

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 immdiate and
follow-up reports
identify subjects by unique code
numbers assigned to the trial subjects.

shall

Article 14

(ex 13)

1.

(Unchanged)

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.

2.

(Unchanged)

For reported deaths,
ethics

3.
sponsor
requested information.

and the

the investigator shall supply the
committee with any additional

3.

(Unchanged)

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ORIGINAL TEXT

AMENDED TEXT

The sponsor shall ensure that all relevant information
4.
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 seven 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 within 15 days. The sponsor shall
also inform all investigators.

4.
The sponsor shall keep detailed records of all suspected
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.

Notification of adverse reactions

Article 15

(ex 13(4), (6) and (7))

1.
The sponsor shall ensure that all relevant information
about unexpected serious adverse reactions which are fatal or
trial subject are recorded and
life-threatening to a clinical
reported to the Member State in whose territory the reaction
occurred as soon as possible, but no later than 7 days after the
sponsor first knew of a case of this type.

All other unexpected serious adverse reactions that are not fatal
or life-threatening to a subject shall be reported by the sponsor
as soon as possible, within not more than 15 days, to the
Member State in whose territory the reaction occored and to
the ethics committee.

The sponsor shall also inform all the other investigators of the
unexpected serious adverse reactions to the medicinal product.

In addition, the sponsor shall maintain detailed records of
5.
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.

(see new Article 14(4))

6.
At least every 12 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.

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

trial

7.
Each Member State shall ensure that all suspected serious
unexpected adverse reactions to an investigational medicinal
product occurring within their territory 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.

3.
Each Member State shall ensure that, no later than 15
days following occurrence within their territory, all suspected
unexpected serious adverse reactions referred to in paragraph 2
are recorded and brought to its knowledge immediately and
the
subsequently notified to the European Agency for
forthwith
Evaluation of Medicinal Products, which shall
inform the competent authorities of the other Member States.

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

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Official Journal of the European Communities

8.6.1999

ORIGINAL TEXT

The Commission,

8.
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.

(Unchanged)

CHAPTER VII

General provisions

Article 14

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

(Unchanged)

Unless Member States have established precise conditions for
exceptional circumstances, medicinal products used in clinical
trials
inform the
Commission of such conditions.

shall not be sold. Member States shall

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.

(Unchanged)

Article 16

AMENDED TEXT

Article 16

(ex 13(8))

General provisions

Article 17

(ex 14)

Article 18

(ex 15)

Article 19

(ex 16)

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

Member States shall take all measures necessary to comply with
this Directive before 1 . . . 2001. They shall forthwith inform
the Commission thereof.

these provisions,

When Member States adopt
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.

(Unchanged)

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.

(Unchanged)

Article 17

Article 20

(ex 17)

This Directive is addressed to the Member States.

(Unchanged)