Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 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: 2001-04-04
Institutions: Council of the European Union, European Parliament
Subjects: approximation of laws, code of conduct, experiment on humans, medicinal product

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DIRECTIVE 2001/20/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL

of 4 April 2001

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

THE EUROPEAN PARLIAMENT AND THE COUNCIL OF THE
EUROPEAN UNION,

(3)

Having regard to the Treaty establishing the European
Community, 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),

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

Whereas:

(1)

(2)

Council Directive 65/65/EEC of 26 January 1965 on the
approximation of provisions laid down by law, regula-
tion or administrative action relating to medicinal prod-
ucts (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 protocols in
respect of the testing of medicinal products (5) lays down
uniform rules on the compilation of dossiers including
their presentation.

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.
trial subject's protection is safeguarded
The clinical
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.

(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 (OJ C 300, 20.10.2000, p. 32) and Decision of the European
Parliament of 12 December 2000. Council Decision of 26 February
2001.

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

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

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

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

the administering of

Persons who are incapable of giving legal consent to
clinical trials should be given special protection. It is
incumbent on the Member States to lay down rules to
this effect. Such persons may not be included in clinical
trials if the same results can be obtained using persons
capable of giving consent. Normally these persons
should be included in clinical trials only when there are
grounds for expecting that
the
medicinal product would be of direct benefit to the
patient, thereby outweighing the risks. However, there is
a need for clinical trials involving children to improve
the treatment available to them. Children represent a
vulnerable population with developmental, physiological
and psychological differences from adults, which make
age- and development- related research important for
their benefit. Medicinal products, including vaccines, for
children need to be tested scientifically before wide-
spread use. This can only be achieved by ensuring that
medicinal products which are likely to be of significant
clinical value for children are fully studied. The clinical
trials required for this purpose should be carried out
under conditions affording the best possible protection
for the subjects. Criteria for the protection of children in
clinical trials therefore need to be laid down.

(4)

(5)

(6)

In the case of other persons incapable of giving their
consent, such as persons with dementia, psychiatric
patients, etc.,
inclusion in clinical trials in such cases
should be on an even more restrictive basis. Medicinal
products for trial may be administered to all such indi-
viduals only when there are grounds for assuming that
the direct benefit to the patient outweighs the risks.
Moreover,
the
patient's legal representative, given in cooperation with
the treating doctor, is necessary before participation in
any such clinical trial.

in such cases the written consent of

The notion of legal representative refers back to existing
national law and consequently may include natural or
legal persons, an authority and/or a body provided for
by national

law.

In order to achieve optimum protection of health, obso-
lete or repetitive tests will not be carried out, whether
within the Community or in third countries. The harmo-
nisation of technical requirements for the development

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(7)

(8)

(9)

(10)

of medicinal products should therefore be pursued
through the appropriate fora,
in particular the Inter-
national 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 Euro-
pean Agency for the Evaluation of Medicinal Prod-
ucts (1), which include products
intended for gene
therapy or cell therapy, prior scientific evaluation by the
European Agency for the Evaluation of Medicinal Prod-
ucts (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
in which these trials were conducted and the same
Committee may go so far as to require the applicant for
such authorisation to conduct
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.

further clinical

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.

commencement

Information on the
and
content,
termination 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 consid-
erably 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.

(11) As a rule, authorisation should be implicit, i.e. if there
has been a vote in favour by the Ethics Committee and
the competent authority has not objected within a given
period, it should be possible to begin the clinical trials.
In exceptional cases raising especially complex prob-
lems, explicit written authorisation should, however, be
required.

(12)

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

(13)

Special provisions should be laid down for the labelling
of these products.

the participation of

(14) Non-commercial clinical trials conducted by researchers
the pharmaceuticals
without
industry may be of great benefit
to the patients
concerned. The Directive should therefore take account
of the special position of trials whose planning does not
require particular manufacturing or packaging processes,
if these trials are carried out with medicinal products
with a marketing authorisation within the meaning of
Directive 65/65/EEC, manufactured or
imported in
accordance with the provisions of Directives 75/
319/EEC and 91/356/EEC, and on patients with the
same characteristics as those covered by the indication
specified in this marketing authorisation. Labelling of the
investigational medicinal products intended for trials of
this nature should be subject to simplified provisions
laid down in the good manufacturing practice guidelines
and in Directive 91/
on investigational products
356/EEC.

(15)

(16)

(17)

(18)

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,
recorded and reported are essential in order to justify the
involvement of human subjects in clinical trials.

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.

the European Parliament and of

This Directive is to apply without prejudice to Directive
95/46/EEC of
the
Council of 24 October 1995 on the protection of indi-
viduals with regard to the processing of personal data
and on the free movement of such data (2).

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

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

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

(2) OJ L 281, 23.11.1995, p. 31.

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(19)

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 (1),

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

HAVE ADOPTED THIS DIRECTIVE:

Article 1

Scope

trials,

This Directive establishes specific provisions regarding the
1.
including multi-centre trials, on
conduct of clinical
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.

The principles of good clinical practice and detailed
3.
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
21(2).

These detailed guidelines shall be published by the Commis-
sion.

All clinical trials, including bioavailability and bioequiva-
4.
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) ‘clinical trial’: any investigation in human subjects intended
to discover or verify the clinical, pharmacological and/or
other pharmacodynamic effects of one or more investiga-
tional medicinal product(s), and/or to identify any adverse
reactions
investigational medicinal
product(s) and/or to study absorption, distribution, metab-
olism and excretion of one or more investigational medi-
cinal product(s) with the object of ascertaining its (their)
safety and/or efficacy;

to one or more

(1) OJ L 184, 17.7.1999, p. 23.

(b) ‘multi-centre clinical

trial’: a clinical

trial conducted
according 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;

(c) ‘non-interventional

trial’: a study where the medicinal
is (are) prescribed in the usual manner in
product(s)
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;

(d) ‘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 (formu-
lated 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 the author-
ised form;

(e) ‘sponsor’: an individual, company,

isation which takes
management and/or financing of a clinical trial;

responsibility for

institution or organ-
initiation,

the

(f) ‘investigator’: a doctor or a person following a profession
agreed in the Member State for investigations because of
the scientific background and the experience in patient
care it requires. The investigator is responsible for the
conduct of a clinical
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

trial at a trial site.

investigator;

If a trial

(g) ‘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;

(h) ‘protocol’: a document

that describes the objective(s),
design, methodology, statistical considerations and organ-
isation of a trial. The term protocol refers to the protocol,
successive versions of the protocol and protocol amend-
ments;

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

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(j) ‘informed consent’: decision, which must be written, dated
and signed, to take part in a clinical trial, taken freely after
being duly informed of its nature, significance,
implica-
tions and risks 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 repres-
entative; if the person concerned is unable to write, oral
consent in the presence of at least one witness may be
given in exceptional cases, as provided for in national
legislation.

(k) ‘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 wellbeing 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
the investigators and the
protocol,
adequacy of facilities, and on the methods and documents
to be used to inform trial subjects and obtain their
informed consent;

the suitability of

(l) ‘inspection’:

a

the

competent

authority of
act by
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 sponsor's and/or contract
research organisation's facilities, or at other establishments
which the competent authority sees fit to inspect;

the trial, at

(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;

(n) ‘adverse reaction’: all untoward and unintended responses
to an investigational medicinal product related to any dose
administered;

(o) ‘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,
in
persistent or significant disability or incapacity, or is a
congenital anomaly or birth defect;

results

(p) ‘unexpected adverse reaction’: an adverse reaction,

the
nature or severity of which is not consistent with the
applicable
investigator's
information
brochure for an unauthorised investigational product or
summary of product characteristics for an authorised
product).

product

(e.g.

Article 3

Protection of clinical trial 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. Member States shall, insofar as they have not
already done so, adopt detailed rules to protect from abuse
individuals who are incapable of giving their informed consent.

2.

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

for

the anticipated benefit

(a) the foreseeable risks and inconveniences have been weighed
trial
against
subject and other present and future patients. A clinical
trial may be initiated only if the Ethics Committee and/or
the competent authority comes to the conclusion that the
anticipated therapeutic and public health benefits justify the
risks and may be continued only if compliance with this
requirement is permanently monitored;

the individual

(b) the trial subject or, when the person is not able to give
informed consent, his legal representative has had the
opportunity, in a prior interview with the investigator or a
member of the investigating team, to understand the objec-
tives, risks and inconveniences of the trial, and the condi-
tions under which it is to be conducted and has also been
informed of his right to withdraw from the trial at any
time;

(c) 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 safeguarded;

(d) the trial subject or, when the person is not able to give
informed consent, his legal representative has given his
written consent after being informed of the nature, signifi-
cance,
if the
implications and risks of the clinical trial;
individual is unable to write, oral consent in the presence
of at least one witness may be given in exceptional cases, as
provided for in national

legislation;

(e) the subject may without any resulting detriment withdraw
from the clinical trial at any time by revoking his informed
consent;

(f) provision has been made for insurance or indemnity to

cover the liability of the investigator and sponsor.

3.
The medical care given to, and medical decisions made
on behalf of, subjects shall be the responsibility of an appro-
priately 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.

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Article 4

Clinical trials on minors

In addition to any other relevant restriction, a clinical trial on
minors may be undertaken only if:

(a) the informed consent of the parents or legal representative
has been obtained; consent must represent the minor's
presumed will and may be revoked at any time, without
detriment to the minor;

(b) the minor has

received information according to its
capacity of understanding, from staff with experience with
minors, regarding the trial, the risks and the benefits;

(c) the explicit wish of a minor who is capable of forming an
opinion and assessing this information to refuse participa-
tion or to be withdrawn from the clinical trial at any time
is considered by the investigator or where appropriate the
principal

investigator;

(d) no incentives or financial

inducements are given except

compensation;

(e) some direct benefit for the group of patients is obtained
from the clinical trial and only where such research is
essential
trials on
to validate data obtained in clinical
persons able to give informed consent or by other research
methods; additionally, such research should either relate
directly to a clinical condition from which the minor
concerned suffers or be of such a nature that it can only be
carried out on minors;

(a) the informed consent of the legal representative has been
obtained; consent must represent the subject's presumed
will and may be revoked at any time, without detriment to
the subject;

(b) the person not able to give informed legal consent has
received information according to his/her capacity of
understanding regarding the trial, the risks and the benefits;

(c) the explicit wish of a subject who is capable of forming an
opinion and assessing this information to refuse participa-
tion in, or to be withdrawn from, the clinical trial at any
time is considered by the investigator or where appropriate
the principal

investigator;

(d) no incentives or financial

inducements are given except

compensation;

(e) such research is essential to validate data obtained in clin-
ical trials on persons able to give informed consent or by
other research methods and relates directly to a life-threat-
ening or debilitating clinical condition from which the
incapacitated adult concerned suffers;

(f) clinical trials have been designed to minimise pain, discom-
fort, fear and any other foreseeable risk in relation to the
disease and developmental stage; both the risk threshold
and the degree of distress shall be specially defined and
constantly monitored;

(g) the Ethics Committee, with expertise in the relevant disease
and the patient population concerned or after taking advice
in clinical, ethical and psychosocial questions in the field of
the relevant disease and patient population concerned, has
endorsed the protocol;

(f) the corresponding scientific guidelines of the Agency have

been followed;

(h) the interests of the patient always prevail over those of

science and society; and

(g) clinical trials have been designed to minimise pain, discom-
fort, fear and any other foreseeable risk in relation to the
disease and developmental stage; both the risk threshold
and the degree of distress have to be specially defined and
constantly monitored;

(h) the Ethics Committee, with paediatric expertise or after
taking advice in clinical, ethical and psychosocial problems
in the field of paediatrics, has endorsed the protocol; and

(i) the interests of the patient always prevail over those of

science and society.

Article 5

Clinical trials on incapacitated adults not able to give
informed legal consent

(i) there are grounds for expecting that administering the
medicinal product to be tested will produce a benefit to the
patient outweighing the risks or produce no risk at all.

Article 6

Ethics Committee

1.
For the purposes of implementation of the clinical trials,
Member States shall take the measures necessary for establish-
ment 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:

In the case of other persons incapable of giving informed legal
consent, all relevant requirements listed for persons capable of
giving such consent shall apply. In addition to these require-
ments, inclusion in clinical trials of incapacitated adults who
have not given or not refused informed consent before the
onset of their incapacity shall be allowed only if:

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

(b) whether the evaluation of the anticipated benefits and risks
as required under Article 3(2)(a) is satisfactory and whether
the conclusions are justified;

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(c) the protocol;

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

Article 7

Single opinion

(e) the investigator's brochure;

(f) the quality of the facilities;

(g) the adequacy and completeness of the written information
to be given and the procedure to be followed for the
purpose of obtaining informed consent and the justification
for the research on persons incapable of giving informed
consent as regards the specific restrictions laid down in
Article 3;

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

injury or death attributable to a clinical trial;

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

investigator and sponsor;

(j) 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;

(k) 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 9 shall be responsible for the consid-
eration of, and the giving of an opinion on,
the matters
referred to in paragraph 3(h), (i) and (j) 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.

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.

in the case of

No extension to the 60-day period referred to in para-
7.
graph 5 shall be permissible except
trials
involving medicinal products for gene therapy or somatic cell
therapy or medicinal products containing genetically modified
organisms. In this case, an extension of a maximum of 30 days
shall be permitted. For these products, this 90-day period may
be extended by a further 90 days in the event of consultation
of a group or a committee in accordance with the regulations
and procedures of the Member States concerned. In the case of
xenogenic cell therapy, there shall be no time limit to the
authorisation period.

For multi-centre 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 multi-centre 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 8

Detailed guidance

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.

Article 9

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.

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.

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.
the sponsor fails to amend the request
accordingly, the request shall be considered rejected and the
clinical trial may not commence.

If

4.
Consideration of a valid request for authorisation by the
competent authority as stated in paragraph 2 shall be carried
out as rapidly as possible and may not exceed 60 days. The
Member States may lay down a shorter period than 60 days
within their area of responsibility if that is in compliance with
current practice. The competent authority can nevertheless
notify the sponsor before the end of this period that it has no
grounds for non-acceptance.

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No further extensions to the period referred to in the first
subparagraph shall be permissible except in the case of trials
involving the medicinal products listed in paragraph 6, for
which an extension of a maximum of 30 days shall be
permitted. For these products,
this 90-day period may be
extended by a further 90 days in the event of consultation of a
group or a committee in accordance with the regulations and
procedures of the Member States concerned. In the case of
xenogenic cell therapy there shall be no time limit to the
authorisation period.

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 Directive 65/
65/EEC and are referred to in Part A of the Annex to Regula-
tion (EEC) No 2309/93, and other medicinal products with
special characteristics, such as medicinal products the active
ingredient or active ingredients of which is or are a biological
product or biological products of human or animal origin, or
contains biological components of human or animal origin, or
the manufacturing of which requires such components.

be

shall

required

authorisation

before
6. Written
commencing clinical trials involving medicinal products for
gene therapy, somatic cell therapy including xenogenic cell
therapy and all medicinal products containing genetically
modified organisms. No gene therapy trials may be carried out
which result in modifications to the subject's germ line genetic
identity.

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-organ-
isms (1) and 90/220/EEC of 23 April 1990 on the deliberate
release into the environment of genetically modified organ-
isms (2).

8.
In consultation with Member States,
shall draw up and publish detailed guidance on:

the Commission

(a) the format and contents of the request referred to in para-
graph 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 tests, the protocol and clinical information
on the investigational medicinal product
including the
investigator's brochure;

(b) the presentation and content of the proposed amendment
referred to in point (a) of Article 10 on substantial amend-
ments made to the protocol;

(c) the declaration of the end of the clinical trial.

(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 inter-
pretation 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 6 and 9.

On the basis of the details referred to in Article 6(3) and in
accordance with Article 7, 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 imple-
ment 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 abovementioned
substantial amendments,
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 the grounds for non-acceptance and adapt the
proposed amendment to the protocol accordingly or with-
draw the proposed amendment;

(b) without prejudice to point (a), in the light of the circum-
stances, 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 safety meas-
ures to protect the subjects against any immediate hazard.
The sponsor shall forthwith inform the competent authori-
ties of those new events and the measures taken and shall
ensure that the Ethics Committee is notified at the same
time;

(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 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.

Article 11

Exchange of information

Article 10

Conduct of a clinical trial

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

(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 Commis-

sion Directive 97/35/EC (OJ L 169, 27.6.1997, p. 72).

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) extracts from the request for authorisation referred to in

Article 9(2);

(b) any amendments made to the request, as provided for in

Article 9(3);

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(c) any amendments made to the protocol, as provided for in

point a of Article 10;

(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 oper-
ates 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 confidentiality of
the data is strictly observed.

Article 12

Suspension of the trial or infringements

the conditions in the request

1. Where a Member State has objective grounds for consid-
ering that
for authorisation
referred to in Article 9(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.

Before the Member State reaches its decision it shall, except
where there is imminent risk, ask the sponsor and/or the
investigator for their opinion, to be delivered within one week.

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 reasons for the
the trial and of
decision.

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 13

Manufacture and import of

investigational medicinal

products

In order to obtain the authorisation, the applicant and, subse-
quently, the holder of the authorisation, shall meet at least the
requirements defined in accordance with the procedure referred
to in Article 21(2).

2. Member States shall take all appropriate measures to
ensure that the holder of the authorisation referred to in para-
graph 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 approx-
imation 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) 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 medi-
cinal products for human use (2), the product specification
file and the information notified pursuant to Article 9(2) of
this Directive;

(b) 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 stan-
dards of good manufacturing practice at least equivalent to
those laid down in Commission Directive 91/356/EEC, in
accordance with the product specification file, and that
each production batch has been checked in accordance
with the information notified pursuant to Article 9(2) of
this Directive;

(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 certi-
fying that each production batch has been manufactured in
conditions at least equivalent to the standards of good
manufacturing practice
cannot be
obtained, that each production batch has undergone all
relevant analyses, tests or checks necessary to confirm its
information notified
quality in accordance with the
pursuant to Article 9(2) of this Directive.

referred to above

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 21(2) of
this Directive and published in accordance with Article 19a of
Directive 75/319/EEC.

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.

(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.

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(b) or (c) are
Insofar as the provisions laid down in (a),
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.

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.

4.
In all cases, the qualified person must certify in a register
or equivalent document that each production batch satisfies the
provisions of this Article. The said register or equivalent docu-
ment 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 14

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 Commis-
sion in the good manufacturing practice guidelines on investi-
gational medicinal products adopted in accordance with Article
19a of Directive 75/319/EEC.

In addition, these guidelines shall lay down adapted provisions
relating to labelling for investigational medicinal products
intended for clinical trials with the following characteristics:

— the planning of the trial does not require particular manu-

facturing or packaging processes;

— the trial is conducted with medicinal products with, in the
Member States concerned by the study, a marketing author-
isation within the meaning of Directive 65/65/EEC, manu-
factured or imported in accordance with the provisions of
Directive 75/319/EEC;

— the patients participating in the trial have the same charac-
teristics as those covered by the indication specified in the
abovementioned authorisation.

Article 15

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

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 Regula-
tion (EEC) No 2309/93. A Member State may request assis-
tance from another Member State in this matter.

Following inspection, an inspection report

shall be
2.
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.

3.
At the request of the Agency, within the framework of its
powers as provided for in Regulation (EEC) No 2309/93, or of
one of the Member States concerned, and following consulta-
tion with the Member States concerned, the Commission may
request a new inspection should verification of compliance
with 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, 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
inspectors and inspection
trial, archiving, qualifications of
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 21(2).

Article 16

Notification of adverse events

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.

To verify compliance with the provisions on good clinical
1.
and manufacturing practice, Member States
shall appoint
inspectors to inspect the sites concerned by any clinical trial

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

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For reported deaths of a subject, the investigator shall
3.
supply the sponsor and the Ethics Committee with any addi-
tional

information requested.

adverse event/reaction reports, together with decoding proced-
ures for unexpected serious adverse reactions.

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

Article 17

Notification of serious adverse reactions

1.

(a) The sponsor shall ensure that all relevant information
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 commu-
nicated within an additional eight days.

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

(c) Each Member State shall ensure that all suspected unex-
pected serious adverse reactions to an investigational
medicinal product which are brought to its attention are
recorded.

(d) The sponsor shall also inform all

investigators.

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 see to it that all suspected
unexpected serious adverse reactions to an investiga-
tional medicinal product which are brought to its atten-
tion are immediately entered in a European database to
which,
in accordance with Article 11(1), only the
competent authorities of the Member States, the Agency
and the Commission shall have access.

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

Article 18

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

Article 19

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 estab-
lished in the Community.

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

The Member States shall
conditions.

inform the Commission of such

Article 20

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 21(2).

Article 21

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).

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.

3.

The Committee shall adopt its rules of procedure.

Article 22

Application

1. Member States shall adopt and publish before 1 May
2003 the laws, regulations and administrative provisions neces-
sary to comply with this Directive. They shall forthwith inform
the Commission thereof.

They shall apply these provisions at the latest with effect from
1 May 2004.

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.

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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 24

Addressees

Article 23

Entry into force

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

This Directive is addressed to the Member States.

Done at Luxembourg, 4 April 2001.

For the European Parliament

For the Council

The President

N. FONTAINE

The President

B. ROSENGREN