Commission Directive 2005/28/EC of 8 April 2005 laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorisation of the manufacturing or importation of such products (Text with EEA relevance)
Date: 2005-04-08
Institutions: European Commission
Subjects: experiment on humans, import, medical research, medicinal product, pharmaceutical legislation

9.4.2005

EN

Official Journal of the European Union

L 91/13

COMMISSION DIRECTIVE 2005/28/EC

of 8 April 2005

laying down principles and detailed guidelines for good clinical practice as regards investigational
the
medicinal products for human use, as well as the requirements for authorisation of

manufacturing or importation of such products

(Text with EEA relevance)

THE COMMISSION OF THE EUROPEAN COMMUNITIES,

Having regard to the Treaty
Community,

establishing the European

Having regard to Directive 2001/20/EC of
the European
Parliament and of the Council of 4 April 2001 on the approx-
imation 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 (1), and in particular Article 1(3), Article
13(1) and Article 15(5) thereof,

Whereas:

(1)

(2)

(3)

Directive 2001/20/EC requires the adoption of principles
of good clinical practice and detailed guidelines in line
with those principles, minimum requirements for author-
isation of the manufacture or importation of investiga-
tional medicinal products, and detailed guidelines on the
documentation relating to clinical trials to verify their
compliance with Directive 2001/20/EC.

The principles and guidelines for good clinical practice
should be such as to ensure that the conduct of clinical
trials on investigational medicinal products, as defined in
Article 2(d) of Directive 2001/20/EC, is founded in the
protection of human rights and the dignity of the human
being.

for

are

products

provided

Manufacturing requirements to be applied to investiga-
tional medicinal
by
Commission Directive 2003/94/EC of 8 October 2003
laying down the principles and guidelines of good manu-
facturing practice in respect of medicinal products for
human use and investigational medicinal products for
human use (2). Title IV 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
the provisions
applied for the authorisation for the manufacture of
medicinal products as part of the requirements needed
for the application for a marketing authorisation. Article
3(3) of that Directive establishes that these requirements
are not applicable for medicinal products intended for

for human use (3) contains

(1) OJ L 121, 1.5.2001, p. 34.
(2) OJ L 262, 14.10.2003, p. 22.
(3) OJ L 311, 28.11.2003, p. 67. Directive as last amended by Directive

2004/27/EC (OJ L 136, 30.4.2004, p. 34).

research and development trials. It is therefore necessary
to lay down minimal requirements regarding applications
for and management of authorisations to manufacture or
import investigational medicinal products, as well as for
in
the granting and the content of the authorisations,
order to guarantee the quality of
the investigational
medicinal product used in the clinical trial.

that unnecessary clinical

(4) With regard to the protection of trial subjects and to
trials will not be
ensure
conducted,
to define principles and
detailed guidelines of good clinical practice whilst
allowing the results of the trials to be documented for
use in a later phase.

important

is

it

(5)

(6)

(7)

(8)

To ensure that all experts and individuals involved in the
design, initiation, conduct and recording of clinical trials
apply the same standards of good clinical practice, prin-
ciples and detailed guidelines of good clinical practice
have to be defined.

Provisions for the functioning of the Ethics Committees
should be established in each Member State on the basis
of common detailed guidelines,
in order to ensure the
protection of the trial subject while at the same time
allowing a harmonised application in the different
Member States of the procedures to be used by Ethics
Committees.

trials with the
To secure the compliance of clinical
provisions on good clinical practice, it is necessary that
inspectors ensure the practical effectiveness of
such
provisions.
It is essential therefore to provide detailed
guidelines on the minimum standards for the qualifi-
their
cation of
education and training. For the same reason, detailed
in particular on
guidelines on inspection procedures,
the
and the
follow-up to the inspections, should be laid down.

in particular as

cooperation of

the various

inspectors,

agencies,

regards

The International Conference on Harmonisation (ICH)
reached a consensus in 1995 to provide a harmonised
approach for Good Clinical Practice. The consensus paper
should be taken into account as agreed upon by the
Committee for Medicinal Products
for Human Use
(CHMP) of the European Medicines Agency, hereinafter
‘the Agency’, and published by the Agency.

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Official Journal of the European Union

9.4.2005

(9)

(10)

investigators and other
is necessary that sponsors,
It
participants take into account
the scientific guidelines
relating to the quality, safety and efficacy of medicinal
products for human use, as agreed upon by the CHMP
and published by the Agency, as well as the other phar-
maceutical Community guidelines published by the
Commission in the different volumes of The rules
governing medicinal
European
products
Community.

the

in

In conducting clinical trials on investigational medicinal
products for human use, the safety and the protection of
the rights of trial subjects should be ensured. The detailed
rules adopted by Member States pursuant to Article 3(1)
of Directive 2001/20/EC, to protect from abuse indi-
informed
viduals who are incapable of giving their
temporarily
consent
incapable of giving their
in
emergency situations.

informed consent, as

should also cover

individuals

specific

to the

trials are conducted,

(11) Non-commercial clinical trials conducted by researchers
without the participation of the pharmaceutical industry
may be of great benefit
to the patients concerned.
Directive 2001/20/EC recognises the specificity of these
non-commercial clinical trials. In particular, when trials
are conducted with authorised medicinal products and on
patients with the same characteristics as those covered by
the authorised indication, requirements already fulfilled
by these authorised medicinal products, as far as manu-
facturing or importation are concerned, should be taken
into consideration. However, it could also be necessary,
conditions under which non-
due
commercial
that Member States
foresee specific modalities to be applied to these trials
not only when conducted with authorised medicinal
products and on patients with the same characteristics,
in order to comply with the principles imposed by this
Directive,
in particular as far as the manufacturing or
import requirements for authorisation and the documen-
tation to be submitted and archived for the trial master
file are concerned. The conditions under which the non-
commercial research is conducted by public researchers
and the places where this research takes place, make the
application of certain of
the details of good clinical
practice unnecessary or guaranteed by other means.
Member States will
cases, when
providing for specific modalities, that the objectives of
the protection of the rights of patients who participate in
the trial, as well as, in general, the correct application of
the good clinical practice principles, are achieved. The
Commission will prepare a draft with guidance in this
respect.

in these

ensure

(12)

The measures provided for
accordance with
Committee on Medicinal Products for Human Use,

in this Directive are in
Standing
the

opinion

the

of

HAS ADOPTED THIS DIRECTIVE:

CHAPTER 1

SUBJECT-MATTER

Article 1

This Directive lays down the following provisions to be
1.
applied to investigational medicinal products for human use:

(a)

and detailed
the principles of good clinical practice
guidelines in line with those principles, as referred to in
Article 1(3) of Directive 2001/20/EC,
the design,
conduct and reporting of clinical trials on human subjects
involving such products;

for

(b) the requirements for authorisation of the manufacture or
importation of such products, as provided for in Article
13(1) of Directive 2001/20/EC;

(c)

the detailed guidelines, provided for in Article 15(5) of
Directive 2001/20/EC, on the documentation relating to
clinical
inspectors and
inspection procedures.

trials, archiving, qualifications of

into account

2. When applying the principles, detailed guidelines and
requirements referred to in paragraph 1, Member States shall
take
implementing modalities
technical
in the detailed guidance published by the
provided for
Commission in The Rules governing medicinal products in
the European Union.

the

3. When applying the principles, detailed guidelines and
requirements referred to in paragraph 1 to non-commercial
clinical trials conducted by researchers without the participation
of the pharmaceutical industry, Member States may introduce
specific modalities in order to take into account the specificity
of these trials as far as Chapters 3 and 4 are concerned.

4. Member States may take into account the special position
of trials whose planning does not require particular manufac-
turing or packaging processes, carried out with medicinal
products with marketing authorisations within the meaning of
Directive 2001/83/EC, manufactured or imported in accordance
with the same Directive and conducted on patients with the
same
indication
specified in the marketing authorisation.

covered by the

characteristics

those

as

Labelling of
investigational medicinal products intended for
trials of that nature may be subject to simplified provisions
laid down in the good manufacturing practice guidelines on
investigational medicinal products.

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inform the Commission as well as the
Member States shall
other Member States of any specific modalities implemented
in accordance with this paragraph. These modalities will be
published by the Commission.

SECTION 2

THE ETHICS COMMITTEE

Article 6

CHAPTER 2

GOOD CLINICAL PRACTICE FOR THE DESIGN, CONDUCT,
RECORDING AND REPORTING OF CLINICAL TRIALS

SECTION 1

GOOD CLINICAL PRACTICE

Article 2

The rights, safety and well being of the trial subjects shall

1.
prevail over the interests of science and society.

Each individual

2.
involved in conducting a trial shall be
qualified by education, training, and experience to perform his
tasks.

Clinical trials shall be scientifically sound and guided by

3.
ethical principles in all their aspects.

The necessary procedures to secure the quality of every

4.
aspect of the trials shall be complied with.

Each Ethics Committee established under Article 6(1) of
1.
Directive 2001/20/EC shall
rules of
adopt
procedure necessary to implement the requirements set out in
in Articles 6 and 7 thereof.
that Directive and,

in particular,

relevant

the

The Ethics Committees shall,

2.
in every case, retain the
essential documents relating to a clinical trial, as referred to
for at least three
in Article 15(5) of Directive 2001/20/EC,
years after completion of
retain the
that
documents for a longer period, where so required under other
applicable requirements.

trial. They shall

Communication of

information between the Ethics
the Member
shall be ensured through appropriate and efficient

3.
Committees and the competent authorities of
States
systems.

SECTION 3

THE SPONSORS

Article 7

Article 3

1.
A sponsor may delegate any or all of his trial-related
functions to an individual, a company, an institution or an
organisation.

The available non-clinical and clinical information on an inves-
tigational medicinal product shall be adequate to support the
proposed clinical trial.

trials

shall be conducted in accordance with the
Clinical
Declaration of Helsinki on Ethical Principles
for Medical
Research Involving Human Subjects, adopted by the General
Assembly of the World Medical Association (1996).

Article 4

The protocol referred to in point (h) of Article 2 of Directive
2001/20/EC shall provide for the definition of inclusion and
exclusion of subjects participating in a clinical trial, monitoring
and publication policy.

The investigator and sponsor shall consider all relevant guidance
with respect to commencing and conducting a clinical trial.

Article 5

All clinical trial
information shall be recorded, handled, and
stored in such a way that it can be accurately reported, inter-
preted and verified, while the confidentiality of records of the
trial subjects remains protected.

However, in such cases, the sponsor shall remain responsible for
ensuring that
the trials and the final data
generated by those trials comply with Directive 2001/20/EC
as well as this Directive.

the conduct of

2.

The investigator and the sponsor may be the same person.

SECTION 4

INVESTIGATOR’S BROCHURE

Article 8

The information in the investigator’s brochure, referred to
1.
in Article 2(g) of Directive 2001/20/EC, shall be presented in a
concise, simple, objective, balanced and non-promotional form
that enables a clinician or potential investigator to understand it
and make an unbiased risk-benefit assessment of the appropri-
ateness of the proposed clinical trial.

The first subparagraph shall apply also to any update of the
investigator’s brochure.

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If the investigational medicinal product has a marketing
2.
authorisation, the Summary of Product Characteristics may be
used instead of the investigator’s brochure.

The investigator’s brochure shall be validated and updated

3.
by the sponsor at least once a year.

include blood products,

For the purposes of point (a) of the first subparagraph, ‘types of
medicinal products’
immunological
products, cell therapy products, gene therapy products, biotech-
nology products, human or animal extracted products, herbal
products, homeopathic products, radiopharmaceutical products
and products containing chemical active ingredients.

CHAPTER 3

MANUFACTURING OR IMPORT AUTHORISATION

Article 9

1.
Authorisation, as provided for in Article 13(1) of Directive
2001/20/EC, shall be required for both total and partial manu-
facture of
the
various processes of dividing up, packaging or presentation.
Such authorisation shall be required even if the products manu-
factured are intended for export.

investigational medicinal products, and for

Authorisation shall also be required for imports from third
countries into a Member State.

Authorisation, as provided for in Article 13(1) of Directive
2.
2001/20/EC, shall not be required for reconstitution prior to
use or packaging, where those processes are carried out in
hospitals, health centres or clinics, by pharmacists or other
persons legally authorised in the Member States to carry out
such processes and if the investigational medicinal products are
intended to be used exclusively in those institutions.

Article 10

In order to obtain the authorisation the applicant must

1.
meet at least the following requirements:

(a) specify in his application the types of medicinal products
and pharmaceutical forms to be manufactured or imported;

(b) specify in his application the relevant manufacture or

import operations;

The applicant shall provide with his application docu-

2.
mentary evidence that he complies with paragraph 1.

Article 11

1.
The competent authority shall issue the authorisation only
after verifying the accuracy of the particulars provided by the
applicant pursuant to Article 10 by the means of an inquiry
carried out by its agents.

2. Member States shall
ensure that
completed within 90 days of
competent authority receives a valid application.

take all appropriate measures to
the procedure for granting an authorisation is
the day on which the

The competent authority of the Member State may require
3.
from the applicant further information concerning the parti-
culars supplied pursuant to Article 10(1), including in particular
information concerning the qualified person at the disposal of
the applicant in accordance with point (e) of Article 10(1).

Where the competent authority concerned exercises that right,
the application of the time-limits laid down in paragraph 2 shall
the additional data required have been
be suspended until
supplied.

Article 12

1.
In order to ensure that the requirements laid down in
Article 10 are complied with, authorisation may be made condi-
tional on the carrying out of certain obligations imposed either
when authorisation is granted or at a later date.

(c) specify in his application, where relevant as in the case of
viral or non-conventional agents’ inactivation, the manufac-
turing process;

2.
An authorisation shall apply only to the premises specified
in the application and to the types of medicinal products and
pharmaceutical forms specified in that application pursuant to
point (a) of Article 10(1).

(d) specify in his application the place where the products are
to be manufactured or have at his disposal, for their manu-
facture or importation, suitable and sufficient premises,
technical equipment and control facilities complying with
the requirements of Directive 2003/94/EC as regards the
manufacture, control and storage of the products;

Article 13

The holder of the authorisation shall at least comply with the
following requirements:

(e) have permanently and continuously at his disposal

the
services of at least one qualified person as referred to in
Article 13(2) of Directive 2001/20/EC.

(a)

to have at his disposal the services of staff that comply with
the
existing in the Member State
concerned both as regards manufacture and controls;

requirements

legal

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(b) to dispose of

the

products only in accordance with the legislation of
Member State concerned;

investigational/authorised medicinal
the

(c)

to give prior notice to the competent authority of any
changes he may wish to make to any of the particulars
to
supplied pursuant Article 10(1) and,
the
competent
inform the
qualified person referred to in Article 13(2) of Directive
2001/20/EC is replaced unexpectedly;

in particular,

immediately

authority

if

(d) to allow agents of the competent authority of the Member

State concerned access to his premises at any time;

(e)

to enable the qualified person referred to in Article 13(2) of
Directive 2001/20/EC to carry out his duties, for example
by placing at his disposal all the necessary facilities;

clinical practice and with the applicable requirements and,
particular, with Annex I to Directive 2001/83/EC.

in

The trial master file shall provide the basis for the audit by the
sponsor’s independent auditor and for the inspection by the
competent authority.

The content of the essential documents shall be in accordance
with the specificities of each phase of the clinical trial.

The Commission shall publish additional guidance in order to
specify the content of these documents.

Article 17

The sponsor and the investigator shall retain the essential
documents relating to a clinical
five years
after its completion.

for at

least

trial

(f)

to comply with the principles and guidelines for good
manufacturing practice for medicinal products as
laid
down by Community law.

They shall retain the documents for a longer period, where so
required by other applicable requirements or by an agreement
between the sponsor and the investigator.

(f) of

Detailed guidelines in line with the principles referred to in
point
the first paragraph will be published by the
Commission and revised where necessary to take account of
technical and scientific progress.

Article 14

If the holder of the authorisation requests a change in any of
the particulars referred to in points (a) to (e) of Article 10(1),
the time taken for the procedure relating to the request shall
not exceed 30 days. In exceptional cases, this period of time
may be extended to 90 days.

Essential documents shall be archived in a way that ensures that
they are readily available, upon request, to the competent autho-
rities.

The medical files of trial subjects shall be retained in accordance
with national legislation and in accordance with the maximum
period of time permitted by the hospital, institution or private
practice.

Article 18

Any transfer of ownership of the data or of documents shall be
documented. The new owner shall assume responsibility for
data retention and archiving in accordance with Article 17.

Article 15

The competent authority shall suspend or revoke the authori-
sation, as a whole or in part, if the holder of the authorisation
fails at any time to comply with the relevant requirements.

Article 19

The sponsor shall appoint individuals within its organisation
who are responsible for archives.

CHAPTER 4

THE TRIAL MASTER FILE AND ARCHIVING

Article 16

The documentation referred to Article 15(5) of Directive
2001/20/EC as the trial master file shall consist of essential
documents, which enable both the conduct of a clinical trial
and the quality of the data produced to be evaluated. Those
documents shall show whether the investigator and the sponsor
have complied with the principles and guidelines of good

Access to archives shall be restricted to the named individuals
responsible for the archives.

Article 20

The media used to store essential documents shall be such that
those documents remain complete and legible throughout the
required period of retention and can be made available to the
competent authorities upon request.

Any alteration to records shall be traceable.

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CHAPTER 5

INSPECTORS

Article 21

experts with appropriate qualifications and experience to fulfil
collectively the requirements necessary for conducting the
inspection.

1.
The inspectors, appointed by the Member States pursuant
to Article 15(1) of Directive 2001/20/EC, shall be made aware
of and maintain confidentiality whenever they gain access to
information as a result of good clinical practice
confidential
applicable Community
accordance with
in
inspections
requirements, national laws or international agreements.

2. Member States shall ensure that inspectors have completed
education at university level, or have equivalent experience, in
medicine, pharmacy, pharmacology,
toxicology or other
relevant fields.

3. Member States shall ensure that inspectors receive appro-
priate training, that their training needs are assessed regularly
and that appropriate action is taken to maintain and improve
their skills.

shall also ensure that

Member States
the inspectors have
knowledge of the principles and processes that apply to the
research.
development of medicinal products and clinical
Inspectors
applicable
have
Community and national
legislation and guidelines applicable
to the conduct of clinical trials and the granting of marketing
authorisations.

knowledge

shall

also

of

The inspectors shall be familiar with the procedures and systems
for recording clinical data, and with the organisation and regu-
lation of the healthcare system in the relevant Member States
and, where appropriate, in third countries.

4. Member States shall maintain up-to-date records of the
qualifications, training and experience of each inspector.

5.
Each inspector shall be provided with a document setting
out standard operating procedures and giving details of the
duties,
and ongoing training requirements.
Those procedures shall be maintained up to date.

responsibilities

CHAPTER 6

INSPECTION PROCEDURES

Article 23

Good clinical practice inspections may take place on any

1.
of the following occasions:

(a) before, during or after the conduct of clinical trials;

(b) as part of the verification of applications for marketing

authorisation;

(c) as a follow-up to the granting of authorisation.

2.
In accordance with Article 15(1) and (2) of Directive
inspections may be requested and coordinated
2001/20/EC,
by the European Medicines Agency within the scope of Regu-
lation (EC) No 726/2004 of the European Parliament and of the
Council (1), especially in connection with clinical trials relating
to applications through the procedure established by this Regu-
lation.

Inspections shall be conducted in accordance with the
the
the

3.
inspection guidance documents developed to support
mutual
findings within
Community.

recognition

inspection

of

4.
Improvement and harmonisation of inspection guidance
shall be achieved by the Member States, in collaboration with
the Commission and the Agency, through joint inspections,
agreed processes and procedures and sharing of experience
and training.

Article 24

Inspectors shall be provided with suitable means of iden-

6.
tification.

Member States shall make publicly available within their terri-
tories the documents relating to the adoption of good clinical
practice principles.

shall

Each inspector

sign a statement declaring any
7.
financial or other links to the parties to be inspected. That
statement shall be taken into consideration when inspectors
are to be assigned to a specific inspection.

Article 22

They shall establish the legal and administrative framework
within which their good clinical practice inspections operate,
with definition of
inspectors for entry into
clinical trial sites and access to data. In so doing they shall
ensure that, on request and where appropriate,
inspectors of
the competent authority of the other Member States also have
access to the clinical trial sites and data.

the powers of

In order to ensure the presence of skills necessary for specific
inspections, Member State may appoint teams of inspectors and

(1) OJ L 136, 30.4.2004, p. 1.

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Article 25

Article 30

Member States shall provide for sufficient resources and shall in
particular appoint an adequate number of inspectors to ensure
effective verification of compliance with good clinical practice.

Article 26

Member States shall establish the relevant procedures for veri-
fication of good clinical practice compliance.

The procedures shall include the modalities for examining both
the study management procedures and the conditions under
trials are planned, performed, monitored and
which clinical
recorded, as well as follow-up measures.

Article 27

Member States shall establish the relevant procedures for the
following:

(a) appointing experts for accompanying inspectors in case of

need;

(b) requesting inspections/assistance from other Member States,
in line with Article 15(1) of Directive 2001/20/EC and for
cooperating in inspections in another Member State;

(c) arranging inspections in third countries.

Article 28

Member States
if
applicable, international inspections including the good clinical
practice compliance status, and of their follow-up.

shall maintain records of national and,

Article 29

1.
In order to harmonise the conduct of inspections by the
competent authorities of the different Member States, guidance
documents containing the common provisions on the conduct
of those inspections shall be published by the Commission after
consultation with the Member States.

1. Member States shall lay down all necessary rules to ensure
that confidentiality is respected by inspectors and other experts.
With regard to personal data, the requirements of Directive
95/46/EC of the European Parliament and of the Council (1)
shall be respected.

2.
Inspection reports shall be made available by the Member
States only to the recipients referred to in Article 15(2) of
Directive 2001/20/EC, in accordance with national regulations
of
to any arrangements
concluded between the Community and third countries.

the Member States and subject

CHAPTER 7

FINAL PROVISIONS

Article 31

1. Member States shall bring into force the laws, regulations
and administrative provisions necessary to comply with this
the latest. They shall
Directive by 29 January 2006 at
forthwith communicate to the Commission the text of those
provisions and a correlation table between those provisions and
this Directive.

When Member States adopt these provisions, they shall contain
a reference to this Directive or be accompanied by such a
reference on the occasion of their official publication. Member
States shall determine how such reference is to be made.

2. Member States shall communicate to the Commission the
text of the main provisions of national law which they adopt in
the field covered by this Directive.

Article 32

This Directive shall enter into force on the twentieth day
following that of its publication in the Official
Journal of the
European Union.

Article 33

This Directive is addressed to the Member States.

inspection
2. Member States
procedures are in compliance with the guidance documents
referred in paragraph 1.

shall ensure that national

Done at Brussels, 8 April 2005.

The guidance documents referred to in paragraph 1 may
3.
be updated regularly according to scientific and technical devel-
opment.

For the Commission

Günter VERHEUGEN
Vice-President

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