Page 1

EN

Official Journal of the European Communities

1.5.2001

L 121/34

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,

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)

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.

(2)

The accepted basis for the conduct of clinical trials in

humans is founded in the protection of human rights

and the dignity of the human being with regard to the

application of biology and medicine, as for instance

reflected in the 1996 version of the Helsinki Declaration.

The clinical trial subject's protection is safeguarded

through risk assessment based on the results of toxico-

logical experiments prior to any clinical trial, screening

by ethics committees and Member States' competent

authorities, and rules on the protection of personal data.

(3)

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 administering of 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)

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, in such cases the written consent of the

patient's legal representative, given in cooperation with

the treating doctor, is necessary before participation in

any such clinical trial.

(5)

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.

(6)

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

(

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).

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Official Journal of the European Communities

1.5.2001

L 121/35

of medicinal products should therefore be pursued

through the appropriate fora, in particular the Inter-

national Conference on Harmonisation.

(7)

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 further clinical trials.

Provision must therefore be made to allow the Agency

to have full information on the conduct of any clinical

trial for such medicinal products.

(8)

A single opinion for each Member State concerned

reduces delay in the commencement of a trial without

jeopardising the well-being of the people participating in

the trial or excluding the possibility of rejecting it in

specific sites.

(9)

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 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.

(10)

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.

(14)

Non-commercial clinical trials conducted by researchers

without the participation of the pharmaceuticals

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

on investigational products and in Directive 91/

356/EEC.

(15)

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.

(16)

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.

(17)

This Directive is to apply without prejudice to Directive

95/46/EEC of the European Parliament and 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

).

(18)

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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Official Journal of the European Communities

1.5.2001

L 121/36

(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

),

HAVE ADOPTED THIS DIRECTIVE:

Article 1

Scope

1.

This Directive establishes specific provisions regarding the

conduct of clinical trials, including multi-centre trials, on

human subjects involving medicinal products as defined in

Article 1 of Directive 65/65/EEC, in particular relating to the

implementation of good clinical practice. This Directive does

not apply to non-interventional trials.

2.

Good clinical practice is a set of internationally recog-

nised ethical and scientific quality requirements which must be

observed for designing, conducting, recording and reporting

clinical trials that involve the participation of human subjects.

Compliance with this good practice provides assurance that the

rights, safety and well-being of trial subjects are protected, and

that the results of the clinical trials are credible.

3.

The principles of good clinical practice and detailed

guidelines in line with those principles shall be adopted and, if

necessary, revised to take account of technical and scientific

progress in accordance with the procedure referred to in Article

21(2).

These detailed guidelines shall be published by the Commis-

sion.

4.

All clinical trials, including bioavailability and bioequiva-

lence studies, shall be designed, conducted and reported in

accordance with the principles of good clinical practice.

Article 2

Definitions

For the purposes of this Directive the following definitions

shall apply:

(a) ‘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 to one or more 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;

This includes clinical trials carried out in either one site or

multiple sites, whether in one or more than one Member

State;

(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

product(s) is (are) prescribed in the usual manner in

accordance with the terms of the marketing authorisation.

The assignment of the patient to a particular therapeutic

strategy is not decided in advance by a trial protocol but

falls within current practice and the prescription of the

medicine is clearly separated from the decision to include

the patient in the study. No additional diagnostic or

monitoring procedures shall be applied to the patients and

epidemiological methods shall be used for the analysis of

collected data;

(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, institution or organ-

isation which takes responsibility for the initiation,

management and/or financing of a clinical trial;

(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 trial at a trial site. If a trial is

conducted by a team of individuals at a trial site, the

investigator is the leader responsible for the team and may

be called the principal investigator;

(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;

(

1

) OJ L 184, 17.7.1999, p. 23.

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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

protocol, the suitability of the investigators and the

adequacy of facilities, and on the methods and documents

to be used to inform trial subjects and obtain their

informed consent;

(l) ‘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;

(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, results in

persistent or significant disability or incapacity, or is a

congenital anomaly or birth defect;

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

nature or severity of which is not consistent with the

applicable product information (e.g. investigator's

brochure for an unauthorised investigational product or

summary of product characteristics for an authorised

product).

Article 3

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:

(a) the foreseeable risks and inconveniences have been weighed

against the anticipated benefit for the individual trial

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;

(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, implications and risks of the clinical trial; if the

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.

4.

The subject shall be provided with a contact point where

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 to validate data obtained in clinical trials on

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;

(f) the corresponding scientific guidelines of the Agency have

been followed;

(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

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 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;

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

science and society; and

(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.

2.

The Ethics Committee shall give its opinion, before a

clinical trial commences, on any issue requested.

3.

In preparing its opinion, the Ethics Committee shall

consider, in particular:

(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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Official Journal of the European Communities

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L 121/39

(c) the protocol;

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

(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.

7.

No extension to the 60-day period referred to in para-

graph 5 shall be permissible except in the case of 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.

Article 7

Single opinion

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. If the sponsor fails to amend the request

accordingly, the request shall be considered rejected and the

clinical trial may not commence.

4.

Consideration of a valid request for authorisation by the

competent authority as stated in paragraph 2 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.

6.

Written

authorisation

shall

be

required

before

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, the Commission

shall draw up and publish detailed guidance on:

(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.

Article 10

Conduct of a clinical trial

Amendments may be made to the conduct of a clinical trial

following the procedure described hereinafter:

(a) after the commencement of the clinical trial, the sponsor

may make amendments to the protocol. If those amend-

ments are substantial and are likely to have an impact on

the safety of the trial subjects or to change the 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

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);

(

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).

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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.

2.

At the substantiated request of any Member State, the

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

1.

Where a Member State has objective grounds for consid-

ering that the conditions in the request 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 trial and of the reasons for the

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

1.

Member States shall take all appropriate measures to

ensure that the manufacture or importation of investigational

medicinal products is subject to the holding of authorisation.

In order to obtain the authorisation, the applicant and, 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, is responsible, in the

context of the procedures referred to in Article 25 of the said

Directive, for ensuring:

(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 referred to above cannot be

obtained, that each production batch has undergone all

relevant analyses, tests or checks necessary to confirm its

quality in accordance with the information notified

pursuant to Article 9(2) of this Directive.

Detailed guidance on the elements to be taken into account

when evaluating products with the object of releasing batches

within the Community shall be drawn up pursuant to the good

manufacturing practice guidelines, and in particular Annex 13

to the said guidelines. Such guidelines will be adopted in

accordance with the procedure referred to in Article 21(2) of

this Directive and published in accordance with Article 19a of

Directive 75/319/EEC.

(

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

complied with, investigational medicinal products shall not

have to undergo any further checks if they are imported into

another Member State together with batch release certification

signed by the qualified person.

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

1.

To verify compliance with the provisions on good clinical

and manufacturing practice, Member States shall appoint

inspectors to inspect the sites concerned by any clinical trial

conducted, particularly the trial site or sites, the manufacturing

site of the investigational medicinal product, any laboratory

used for analyses in the clinical trial and/or the sponsor's

premises.

The inspections shall be conducted by the competent authority

of the Member State concerned, which shall 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.

2.

Following inspection, an inspection report shall be

prepared. It must be made available to the sponsor while

safeguarding confidential aspects. It may be made available to

the other Member States, to the Ethics Committee and to the

Agency, at their reasoned request.

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.

4.

Subject to any arrangements which may have been

concluded between the Community and third countries, the

Commission, upon receipt of a reasoned request from a

Member State or on its own initiative, or a Member State may

propose that the trial site and/or the sponsor's premises and/or

the manufacturer established in a third country undergo an

inspection. The inspection shall be carried out by duly qualified

Community inspectors.

5.

The detailed guidelines on the documentation relating to

the clinical trial, which shall constitute the master file on the

trial, archiving, qualifications of inspectors and inspection

procedures to verify compliance of the clinical trial in question

with this Directive shall be adopted and revised in accordance

with the procedure referred to in Article 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.

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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3.

For reported deaths of a subject, the investigator shall

supply the sponsor and the Ethics Committee with any addi-

tional information requested.

4.

The sponsor shall keep detailed records of all adverse

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

adverse event/reaction reports, together with decoding proced-

ures for unexpected serious adverse reactions.

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

exceptional circumstances, investigational medicinal products

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 inform the Commission of such

conditions.

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 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.

Article 24

Addressees

This Directive is addressed to the Member States.

Done at Luxembourg, 4 April 2001.

For the European Parliament

The President

N. FONTAINE

For the Council

The President

B. ROSENGREN