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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)

THE COMMISSION OF THE EUROPEAN COMMUNITIES,

Having regard to the Treaty establishing the European

Community,

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)

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.

(2)

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.

(3)

Manufacturing requirements to be applied to investiga-

tional medicinal products are provided for 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 for human use(

3

) contains 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

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

the granting and the content of the authorisations, in

order to guarantee the quality of the investigational

medicinal product used in the clinical trial.

(4)

With regard to the protection of trial subjects and to

ensure that unnecessary clinical trials will not be

conducted, it is important 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.

(5)

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.

(6)

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.

(7)

To secure the compliance of clinical trials with the

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-

cation of inspectors, in particular as regards their

education and training. For the same reason, detailed

guidelines on inspection procedures, in particular on

the cooperation of the various agencies, and the

follow-up to the inspections, should be laid down.

(8)

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.

EN

9.4.2005

Official Journal of the European Union

L 91/13

(

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).

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(9)

It is necessary that sponsors, investigators and other

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 products in the European

Community.

(10)

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-

viduals who are incapable of giving their informed

consent should also cover individuals temporarily

incapable of giving their informed consent, as in

emergency situations.

(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,

due to the specific conditions under which non-

commercial trials are conducted, 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 ensure in these 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.

(12)

The measures provided for in this Directive are in

accordance with the opinion of the Standing

Committee on Medicinal Products for Human Use,

HAS ADOPTED THIS DIRECTIVE:

CHAPTER 1

SUBJECT-MATTER

Article 1

1.

This Directive lays down the following provisions to be

applied to investigational medicinal products for human use:

(a) the principles of good clinical practice and detailed

guidelines in line with those principles, as referred to in

Article 1(3) of Directive 2001/20/EC, for the design,

conduct and reporting of clinical trials on human subjects

involving such products;

(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 trials, archiving, qualifications of inspectors and

inspection procedures.

2.

When applying the principles, detailed guidelines and

requirements referred to in paragraph 1, Member States shall

take into account the technical implementing modalities

provided for in the detailed guidance published by the

Commission in The Rules governing medicinal products in

the European Union.

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 characteristics as those covered by the indication

specified in the marketing authorisation.

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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Member States shall inform the Commission as well as the

other Member States of any specific modalities implemented

in accordance with this paragraph. These modalities will be

published by the Commission.

CHAPTER 2

GOOD CLINICAL PRACTICE FOR THE DESIGN, CONDUCT,

RECORDING AND REPORTING OF CLINICAL TRIALS

SECTION 1

GOOD CLINICAL PRACTICE

Article 2

1.

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

prevail over the interests of science and society.

2.

Each individual involved in conducting a trial shall be

qualified by education, training, and experience to perform his

tasks.

3.

Clinical trials shall be scientifically sound and guided by

ethical principles in all their aspects.

4.

The necessary procedures to secure the quality of every

aspect of the trials shall be complied with.

Article 3

The available non-clinical and clinical information on an inves-

tigational medicinal product shall be adequate to support the

proposed clinical trial.

Clinical trials shall be conducted in accordance with the

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.

SECTION 2

THE ETHICS COMMITTEE

Article 6

1.

Each Ethics Committee established under Article 6(1) of

Directive 2001/20/EC shall adopt the relevant rules of

procedure necessary to implement the requirements set out in

that Directive and, in particular, in Articles 6 and 7 thereof.

2.

The Ethics Committees shall, in every case, retain the

essential documents relating to a clinical trial, as referred to

in Article 15(5) of Directive 2001/20/EC, for at least three

years after completion of that trial. They shall retain the

documents for a longer period, where so required under other

applicable requirements.

3.

Communication of information between the Ethics

Committees and the competent authorities of the Member

States shall be ensured through appropriate and efficient

systems.

SECTION 3

THE SPONSORS

Article 7

1.

A sponsor may delegate any or all of his trial-related

functions to an individual, a company, an institution or an

organisation.

However, in such cases, the sponsor shall remain responsible for

ensuring that the conduct of the trials and the final data

generated by those trials comply with Directive 2001/20/EC

as well as this Directive.

2.

The investigator and the sponsor may be the same person.

SECTION 4

INVESTIGATOR’S BROCHURE

Article 8

1.

The information in the investigator’s brochure, referred to

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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2.

If the investigational medicinal product has a marketing

authorisation, the Summary of Product Characteristics may be

used instead of the investigator’s brochure.

3.

The investigator’s brochure shall be validated and updated

by the sponsor at least once a year.

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 investigational medicinal products, and for the

various processes of dividing up, packaging or presentation.

Such authorisation shall be required even if the products manu-

factured are intended for export.

Authorisation shall also be required for imports from third

countries into a Member State.

2.

Authorisation, as provided for in Article 13(1) of Directive

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

1.

In order to obtain the authorisation the applicant must

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;

(c) specify in his application, where relevant as in the case of

viral or non-conventional agents’ inactivation, the manufac-

turing process;

(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;

(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.

For the purposes of point (a) of the first subparagraph, ‘types of

medicinal products’ include blood 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.

2.

The applicant shall provide with his application docu-

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 take all appropriate measures to

ensure that the procedure for granting an authorisation is

completed within 90 days of the day on which the

competent authority receives a valid application.

3.

The competent authority of the Member State may require

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

be suspended until the additional data required have been

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.

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).

Article 13

The holder of the authorisation shall at least comply with the

following requirements:

(a) to have at his disposal the services of staff that comply with

the legal requirements existing in the Member State

concerned both as regards manufacture and controls;

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(b) to dispose of the investigational/authorised medicinal

products only in accordance with the legislation of the

Member State concerned;

(c) to give prior notice to the competent authority of any

changes he may wish to make to any of the particulars

supplied pursuant Article 10(1) and, in particular, to

inform the competent authority immediately if the

qualified person referred to in Article 13(2) of Directive

2001/20/EC is replaced unexpectedly;

(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;

(f) to comply with the principles and guidelines for good

manufacturing practice for medicinal products as laid

down by Community law.

Detailed guidelines in line with the principles referred to in

point (f) of 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.

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.

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

clinical practice and with the applicable requirements and, in

particular, with Annex I to Directive 2001/83/EC.

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 trial for at least five years

after its completion.

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.

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 19

The sponsor shall appoint individuals within its organisation

who are responsible for archives.

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

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

confidential information as a result of good clinical practice

inspections in accordance with applicable Community

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.

Member States shall also ensure that the inspectors have

knowledge of the principles and processes that apply to the

development of medicinal products and clinical research.

Inspectors shall also have knowledge of applicable

Community and national legislation and guidelines applicable

to the conduct of clinical trials and the granting of marketing

authorisations.

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, responsibilities and ongoing training requirements.

Those procedures shall be maintained up to date.

6.

Inspectors shall be provided with suitable means of iden-

tification.

7.

Each inspector shall sign a statement declaring any

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

In order to ensure the presence of skills necessary for specific

inspections, Member State may appoint teams of inspectors and

experts with appropriate qualifications and experience to fulfil

collectively the requirements necessary for conducting the

inspection.

CHAPTER 6

INSPECTION PROCEDURES

Article 23

1.

Good clinical practice inspections may take place on any

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

2001/20/EC, inspections may be requested and coordinated

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.

3.

Inspections shall be conducted in accordance with the

inspection guidance documents developed to support the

mutual recognition of inspection findings within the

Community.

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

Member States shall make publicly available within their terri-

tories the documents relating to the adoption of good clinical

practice principles.

They shall establish the legal and administrative framework

within which their good clinical practice inspections operate,

with definition of the powers 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.

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Article 25

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

which clinical trials are planned, performed, monitored and

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 shall maintain records of national and, if

applicable, international inspections including the good clinical

practice compliance status, and of their follow-up.

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.

2.

Member States shall ensure that national inspection

procedures are in compliance with the guidance documents

referred in paragraph 1.

3.

The guidance documents referred to in paragraph 1 may

be updated regularly according to scientific and technical devel-

opment.

Article 30

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 the Member States and subject to any arrangements

concluded between the Community and third countries.

CHAPTER 7

FINAL PROVISIONS

Article 31

1.

Member States shall bring into force the laws, regulations

and administrative provisions necessary to comply with this

Directive by 29 January 2006 at the latest. They shall

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.

Done at Brussels, 8 April 2005.

For the Commission

Günter VERHEUGEN

Vice-President

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1

) OJ L 281, 23.11.1995, p. 31.