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DIRECTIVE 2001/20/EC |
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
Official Journal L 121 ,
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
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,
regulation or administrative action relating to medicinal products(4)
requires that applications for authorisation to place a medicinal product on
the market should be accompanied by a dossier containing particulars and
documents relating to the results of tests and clinical trials carried out on
the product. Council Directive 75/318/EEC of
(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 toxicological 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 widespread 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(6),
which include products intended for gene therapy or cell therapy, prior
scientific evaluation by the European Agency for the Evaluation of Medicinal
Products (hereinafter referred to as the "Agency"), assisted by the
Committee for Proprietary Medicinal Products, is mandatory before the
Commission grants marketing authorisation. In the course of this evaluation,
the said Committee may request full details of the results of the clinical
trials on which the application for marketing authorisation is based and,
consequently, on the manner 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
(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 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
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 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(7).
(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(8),
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 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 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 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 pharmacodynamic effects of one or more
investigational medicinal product(s), and/or to identify any adverse reactions
to one or more investigational medicinal product(s) and/or to study absorption,
distribution, metabolism and excretion of one or more investigational medicinal
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
(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 (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
(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 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;
(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 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;
(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
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, discomfort, 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 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:
(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
compensation;
(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 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 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;
(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
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
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 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 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
In the case of multi-centre clinical trials
carried out in more than one
Article 8
Detailed guidance
The Commission, in consultation with
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
2. Before
commencing any clinical trial, the sponsor shall be required to submit a valid
request for authorisation to the competent authority of the
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 application of Council
Directives 90/219/EEC of 23 April 1990 on the contained use of genetically
modified micro-organisms(9) and 90/220/EEC of 23 April 1990 on the deliberate
release into the environment of genetically modified organisms(10).
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
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
(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
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.
Article 12
Suspension of the trial or infringements
1. Where
a
Before the
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,
subsequently, 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 paragraph 1 has permanently and continuously at
his disposal the services of at least one qualified person who, in accordance
with the conditions laid down in Article 23 of the second Council Directive
75/319/EEC of 20 May 1975 on the approximation of provisions laid down by law,
regulation or administrative action relating to proprietary medicinal
products(11), 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 manufacturing
practice for medicinal products for human use(12), 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 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.
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
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
manufacturing 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.
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
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 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.
3. For
reported deaths of a subject, the investigator shall supply the sponsor and the
Ethics Committee with any additional information requested.
4. The
sponsor shall keep detailed records of all adverse events which are reported to
him by the investigator or investigators. These records shall be submitted to
the Member States in whose territory the clinical trial is being conducted, if
they so request.
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 communicated 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
(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 investigational medicinal product
which are brought to its attention are immediately entered in a European
database to which, in accordance with Article 11(1), only the competent
authorities of the
(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,
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 exceptional 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.
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
They shall apply these provisions at the latest
with effect from
When Member States adopt these provisions, they
shall contain a reference to this Directive or shall be accompanied by such
reference on the occasion of their official publication. The methods of making
such reference shall be laid down by Member States.
2. Member
States shall communicate to the Commission the text of the provisions of
national law which they adopt in the field governed by this Directive.
Article 23
Entry into force
This Directive shall enter into force on the
day of its publication in the Official Journal of the European Communities.
Article 24
Addressees
This Directive is addressed to the Member
States.
Done at
For the European Parliament
The President
N. Fontaine
For the Council
The President
B. Rosengren
(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
(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).
(6) 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)
(7) OJ L 281, 23.11.1995, p. 31.
(8) OJ L 184, 17.7.1999, p. 23.
(9) 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).
(10) 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).
(11) 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).
(12) OJ L 193, 17.7.1991, p. 30.
End of the document