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This document is meant purely as a documentation tool and the institutions do not assume any liability
for its contents
â–ºB 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
(OJ L 121, 1.5.2001, p. 34)
Amended by:
â–ºM1 Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006
â–ºM2 Regulation (EC) No 596/2009 of the European Parliament and of the Council of 18 June 2009
Official Journal
No page date
L 378 1 27.12.2006
L 188 14 18.7.2009
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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,
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 approx- imation of provisions laid down by law,
regulation or adminis- trative action relating to medicinal products (4) requires that appli- cations 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 safe- guarded 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
(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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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 individuals 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, obsolete or repetitive tests will not be
carried out, whether within the Community or in third countries. The harmonisation of
technical requirements for the development of medicinal products should therefore be pursued
through the appropriate fora, in particular the International 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 European Agency for the Evaluation of
Medicinal Products (1), which include products intended for gene therapy or cell therapy, prior
scientific evaluation by the European Agency for the Evaluation of Medicinal Products (here- inafter 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
(1) OJ L 214, 24.8.1993, p. 1. Regulation as amended by Commission Regu- lation (EC) No 649/98 (OJ L
88, 24.3.1998, p. 7)
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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 participants and several trial sites, often in different Member States. Member States'
current practices diverge considerably on the rules on commencement and conduct of the
clinical trials and the requirements for carrying them out vary widely. 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 coordi-
nation 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 problems, 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 individuals with regard to the processing of personal data and on
the free movement of such data (1).
(1) OJ L 281, 23.11.1995, p. 31.
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(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 clinical trial in which there is an unacceptable level of risk.
(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-interven- tional trials.
2. Good clinical practice is a set of internationally recognised 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 Commission shall adopt the principles relating to good clinical practice and detailed
rules in line with those principles and shall, if necessary, revise those principles and detailed rules
to take account of technical and scientific progress. Those measures, designed to amend non-essential
elements of this Directive, shall be adopted in accordance with the regulatory procedure with scrutiny
referred to in Article 21(3).
The principles and detailed rules shall be published by the Commission.
4. All clinical trials, including bioavailability and bioequivalence 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 phar- macodynamic effects of one or more investigational medicinal
product(s), and/or to identify any adverse reactions to one or more investigational medicinal
product(s) and/or to study absorption, distribution, metabolism and excretion of one or more
investigational medicinal product(s) with the object of ascertaining its (their) safety and/or efficacy;
(1) OJ L 184, 17.7.1999, p. 23.
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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 author- isation
but used or assembled (formulated or packaged) in a way different from the authorised form, or
when used for an unauthorised indication, or when used to gain further information about the authorised
form;
(e) ‘sponsor’: an individual, company, institution or organisation 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 back- ground and the experience in patient care it requires. The inves- tigator 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, meth- odology, statistical considerations and
organisation of a trial. The term protocol refers to the protocol, successive versions of the protocol
and protocol amendments;
(i) ‘subject’: an individual who participates in a clinical trial as either a recipient of the
investigational medicinal product or a control;
(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, implications 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 representative; 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;
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(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 inca- pacity, 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 inves-
tigational 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 objectives, risks and inconveniences of the trial, and the conditions
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, significance, 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;
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(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 appropriately 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.
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 participation 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 compen- sation;
(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, discomfort, fear and any other foreseeable risk in
relation to the disease and devel- opmental 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 requirements, 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:
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(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
participation 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 compen- sation;
(e) such research is essential to validate data obtained in clinical trials on persons able to give
informed consent or by other research methods and relates directly to a life-threatening or debilitating
clinical condition from which the incapacitated adult concerned suffers;
(f) clinical trials have been designed to minimise pain, discomfort, fear and any other foreseeable risk in
relation to the disease and devel- opmental 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 establishment 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;
(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;
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(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 consideration
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 supple- mentary 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 paragraph 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 regu- lations 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, notwith- standing 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.
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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.
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 Regulation (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 appli- cation of Council Directives
90/219/EEC of 23 April 1990 on the contained use of genetically modified micro-organisms (1)
and
(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).
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90/220/EEC of 23 April 1990 on the deliberate release into the envi- ronment of genetically modified
organisms (1).
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 paragraph 2 as well as the documentation to be
submitted to support that request, on the quality and manufacture of the investigational medicinal product,
any toxicological and pharmacological 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 amendments 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
amendments are substantial and are likely to have an impact on the safety of the trial subjects or to change the
interpretation 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 implement the
amendment to the protocol.
If the opinion of the Ethics Committee is favourable and the competent authorities of the
Member States have raised no grounds for non-acceptance of the 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 withdraw the proposed
amendment;
(b) without prejudice to point (a), in the light of the circumstances, notably the occurrence of any
new event relating to the conduct of the trial or the development of the investigational medicinal
product where that new event is likely to affect the safety of the subjects, the sponsor and the
investigator shall take appropriate urgent safety measures to protect the subjects against
any immediate hazard. The sponsor shall forthwith inform the competent authorities 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
(1) OJ L 117, 8.5.1990, p. 15. Directive as last amended by Commission Directive 97/35/EC (OJ
L 169, 27.6.1997, p. 72).
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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 autho- rities 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);
(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 operates with the assistance of the
Agency, as well as the methods for electronic communication of the data. The detailed guidance thus drawn up
shall ensure that the confidentiality of the data is strictly observed.
4. By way of derogation from paragraph 1, the Agency shall make public part of the information on
paediatric clinical trials entered in the European database in accordance with the provisions of Regulation (EC) No
1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal
products for paediatric use (1).
Article 12
Suspension of the trial or infringements
1. Where a Member State has objective grounds for considering 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.
(1) OJ L 378, 27.12.2006, p. 1.
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2. Where a competent authority has objective grounds for considering that the sponsor or
the investigator or any other person involved in the conduct of the trial no longer meets the
obligations laid down, it shall forthwith inform him thereof, indicating the course of action which he
must take to remedy this state of affairs. The competent authority concerned shall forthwith inform
the Ethics Committee, the other competent authorities and the Commission of this course of action.
Article 13
Manufacture and import of investigational medicinal products
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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.
The Commission shall lay down the minimum requirements which the applicant and, subsequently, the holder of
the authorisation must meet in order to obtain the authorisation.
Those measures, designed to amend non-essential elements of this Directive, by supplementing it,
shall be adopted in accordance with the regulatory procedure with scrutiny referred to in Article 21(3).
2. Member States shall take all appropriate measures to ensure that the holder of the authorisation
referred to in paragraph 1 has perma- nently 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 approximation of provisions laid down by law, regulation or
administrative 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 manufactured 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
manufac- turing practice for medicinal 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 manufactured in a third country, that each production
batch has been manufactured and checked in accordance with standards 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 certifying that
(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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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 eval- uating 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.
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 document shall be kept
up to date as operations are carried out and shall remain at the disposal of the agents of the competent
authority for the period specified in the provisions of the Member States concerned. This period shall
in any event be not less than five years.
5. Any person engaging in activities as the qualified person referred to in Article 21 of Directive
75/319/EEC as regards investigational medicinal products at the time when this Directive is applied in
the Member State where that person is, but without complying with the conditions laid down in Articles
23 and 24 of that Directive, shall be authorised to continue those activities in the Member State
concerned.
Article 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 Commission in the good manu- facturing practice guidelines on
investigational 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 manufacturing or packaging processes;
— the trial is conducted with medicinal products with, in the Member States concerned by the study, a
marketing authorisation within the meaning of Directive 65/65/EEC, manufactured or imported in
accordance with the provisions of Directive 75/319/EEC;
— the patients participating in the trial have the same characteristics as those covered by the indication
specified in the abovementioned authorisation.
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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 Regulation (EEC) No 2309/93. A Member State may request
assistance from another Member State in this matter.
2. Following inspection, an inspection report shall be prepared. It must be made available to the
sponsor while safeguarding confidential aspects. It may be made available to the other Member States, to
the Ethics Committee and to the Agency, at their reasoned request.
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 consultation 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 imme- diately 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.
3. For reported deaths of a subject, the investigator shall supply the sponsor and the Ethics
Committee with any additional information requested.
4. The sponsor shall keep detailed records of all adverse events which are reported to him by the
investigator or investigators. These
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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 reactions 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 unexpected 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 unex- pected serious adverse
reactions to an investigational medicinal product which are brought to its attention are imme- diately 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 procedures 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 established in
the Community.
Unless Member States have established precise conditions for excep- tional circumstances, investigational
medicinal products and, as the case may be, the devices used for their administration shall be made
available free of charge by the sponsor.
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The Member States shall inform the Commission of such conditions.
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Article 20
The Commission shall adapt this Directive to take account of scientific and technical progress.
Those measures, designed to amend non-essential elements of this Directive, shall be adopted
in accordance with the regulatory procedure with scrutiny referred to in Article 21(3).
Article 21
1. The Commission shall be assisted by the Standing Committee on Medicinal Products for Human Use,
referred to in Article 121(1) of Directive 2001/83/EC of the European Parliament and of the Council of 6
November 2001 on the Community Code relating to medicinal products for human use (1).
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. Where reference is made to this paragraph, Article 5a(1) to (4) and Article 7 of Decision 1999/468/EC
shall apply, having regard to the provisions of Article 8 thereof.
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Article 22
Application
1. Member States shall adopt and publish before 1 May 2003 the laws, regulations and administrative
provisions necessary to comply with this Directive. They shall forthwith inform the Commission
thereof.
They shall apply these provisions at the latest with effect from 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.
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 publication in the Official Journal of the European
Communities.
(1) OJ L 311, 28.11.2001, p. 67.
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Article 24
Addressees
This Directive is addressed to the Member States.