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

Article 1

Scope

The principles and detailed rules shall be published by the Commission.

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 Member State;

• (b) ‘multi-centre clinical trial’: a clinical trial conducted according to a single protocol but at more than one site, and therefore by more than one investigator, in which the trial sites may be located in a single Member State, in a number of Member States and/or in Member States and third countries;

• (c) ‘non-interventional trial’: a study where the medicinal product(s) is (are) prescribed in the usual manner in accordance with the terms of the marketing authorisation. The assignment of the patient to a particular therapeutic strategy is not decided in advance by a trial protocol but falls within current practice and the prescription of the medicine is clearly separated from the decision to include the patient in the study. No additional diagnostic or monitoring procedures shall be applied to the patients and epidemiological methods shall be used for the analysis of collected data;

• (d) ‘investigational medicinal product’: a pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial, including products already with a marketing authorisation but used or assembled (formulated or packaged) in a way different from the authorised form, or when used for an unauthorised indication, or when used to gain further information about the authorised form;

• (e) ‘sponsor’: an individual, company, institution or organisation which takes responsibility for the initiation, management and/or financing of a clinical trial;

• (f) ‘investigator’: a doctor or a person following a profession agreed in the Member State for investigations because of the scientific background and the experience in patient care it requires. The investigator is responsible for the conduct of a clinical trial at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the leader responsible for the team and may be called the principal investigator;

• (g) ‘investigator's brochure’: a compilation of the clinical and non-clinical data on the investigational medicinal product or products which are relevant to the study of the product or products in human subjects;

• (h) ‘protocol’: a document that describes the objective(s), design, methodology, statistical considerations and 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

• (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.

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

• (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.

When a Member State avails itself of this provision, it shall notify the Commission, the other Member States and the Agency.

Article 7

Single opinion

For multi-centre clinical trials limited to the territory of a single Member State, Member States shall establish a procedure providing, notwithstanding the number of Ethics Committees, for the adoption of a single opinion for that Member State.

In the case of multi-centre clinical trials carried out in more than one Member State simultaneously, a single opinion shall be given for each Member State concerned by the clinical trial.

Article 8

Detailed guidance

The Commission, in consultation with Member States and interested parties, shall draw up and publish detailed guidance on the application format and documentation to be submitted in an application for an ethics committee opinion, in particular regarding the information that is given to subjects, and on the appropriate safeguards for the protection of personal data.

Article 9

Commencement of a clinical trial

The sponsor may not start a clinical trial until the Ethics Committee has issued a favourable opinion and inasmuch as the competent authority of the Member State concerned has not informed the sponsor of any grounds for non-acceptance. The procedures to reach these decisions can be run in parallel or not, depending on the sponsor.

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.

• (a) the format and contents of the request referred to in paragraph 2 as well as the documentation to be submitted to support that request, on the quality and manufacture of the investigational medicinal product, any toxicological and pharmacological tests, the protocol and clinical information on the investigational medicinal product including the investigator's brochure;

• (b) the presentation and content of the proposed amendment referred to in point (a) of Article 10 on substantial amendments made to the protocol;

• (c) the declaration of the end of the clinical trial.

Article 10

Conduct of a clinical trial

Amendments may be made to the conduct of a clinical trial following the procedure described hereinafter:

• (a) after the commencement of the clinical trial, the sponsor may make amendments to the protocol. If those amendments are substantial and are likely to have an impact on the safety of the trial subjects or to change the interpretation of the scientific documents in support of the conduct of the trial, or if they are otherwise significant, the sponsor shall notify the competent authorities of the Member State or Member States concerned of the reasons for, and content of, these amendments and shall inform the ethics committee or committees concerned in accordance with Articles 6 and 9. On the basis of the details referred to in Article 6(3) and in accordance with Article 7, the Ethics Committee shall give an opinion within a maximum of 35 days of the date of receipt of the proposed amendment in good and due form. If this opinion is unfavourable, the sponsor may not implement the amendment to the protocol. If the opinion of the Ethics Committee is favourable and the competent authorities of the Member States have raised no grounds for non-acceptance of the abovementioned substantial amendments, the sponsor shall proceed to conduct the clinical trial following the amended protocol. Should this not be the case, the sponsor shall either take account of the grounds for non-acceptance and adapt the proposed amendment to the protocol accordingly or withdraw the proposed amendment;

• (b) without prejudice to point (a), in the light of the circumstances, notably the occurrence of any new event relating to the conduct of the trial or the development of the investigational medicinal product where that new event is likely to affect the safety of the subjects, the sponsor and the investigator shall take appropriate urgent safety measures to protect the subjects against any immediate hazard. The sponsor shall forthwith inform the competent authorities of those new events and the measures taken and shall ensure that the Ethics Committee is notified at the same time;

• (c) within 90 days of the end of a clinical trial the sponsor shall notify the competent authorities of the Member State or Member States concerned and the Ethics Committee that the clinical trial has ended. If the trial has to be terminated early, this period shall be reduced to 15 days and the reasons clearly explained.

Article 11

Exchange of information

• (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.

Article 12

Suspension of the trial or infringements

Before the Member State reaches its decision it shall, except where there is imminent risk, ask the sponsor and/or the investigator for their opinion, to be delivered within one week.

In this case, the competent authority concerned shall forthwith inform the other competent authorities, the Ethics Committee concerned, the Agency and the Commission of its decision to suspend or prohibit the trial and of the reasons for the decision.

Article 13

Manufacture and import of investigational medicinal products

The Commission shall lay down the minimum requirements which the applicant and, subsequently, the holder of the authorisation must meet in order to obtain the authorisation.

Those measures, designed to amend non-essential elements of this Directive, by supplementing it, shall be adopted in accordance with the regulatory procedure with scrutiny referred to in Article 21(3).

By way of derogation from the first subparagraph, the competent authorities of the United Kingdom in respect of Northern Ireland and, until 31 December 2024, the competent authorities of Cyprus, Ireland and Malta shall allow investigational medicinal products to be imported from parts of the United Kingdom other than Northern Ireland without such an authorisation provided that all of the following conditions are fulfilled:

• (a) the investigational medicinal products imported into Cyprus, Ireland, Malta or Northern Ireland have undergone certification of batch release either in the Union, as provided for in paragraph 3, point (a), or in parts of the United Kingdom other than Northern Ireland in compliance with the requirements set out in paragraph 3, point (b);

• (b) the investigational medicinal products are only made available to subjects in the Member State into which those investigational medicinal products are imported, or, if imported into Northern Ireland, are only made available to subjects in Northern Ireland.

• (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 ([^E0005]), 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 Member State together with batch release certification signed by the qualified person.

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

The inspections shall be conducted by the competent authority of the Member State concerned, which shall inform the Agency; they shall be carried out on behalf of the Community and the results shall be recognised by all the other Member States. These inspections shall be coordinated by the Agency, within the framework of its powers as provided for in Regulation (EEC) No 2309/93. A Member State may request assistance from another Member State in this matter.

Article 16

Notification of adverse events

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 Member State shall ensure that all suspected unexpected serious adverse reactions to an investigational medicinal product which are brought to its attention are recorded.

• (d) The sponsor shall also inform all investigators.

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 Member States, the Agency and the Commission shall have access.

• (b) The Agency shall make the information notified by the sponsor available to the competent authorities of the Member States.

Article 18

Guidance concerning reports

The Commission, in consultation with the Agency, Member States and interested parties, shall draw up and publish detailed guidance on the collection, verification and presentation of adverse event/reaction reports, together with decoding procedures for unexpected serious adverse reactions.

Article 19

General provisions

This Directive is without prejudice to the civil and criminal liability of the sponsor or the investigator. To this end, the sponsor or a legal representative of the sponsor must be established in the Community.

Unless Member States have established precise conditions for 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

The Commission shall adapt this Directive to take account of scientific and technical progress.

Those measures, designed to amend non-essential elements of this Directive, shall be adopted in accordance with the regulatory procedure with scrutiny referred to in Article 21(3).

Article 21

The period referred to in Article 5(6) of Decision 1999/468/EC shall be set at three months.

Article 22

Application

They shall apply these provisions at the latest with effect from 1 May 2004.

When Member States adopt these provisions, they shall contain a reference to this Directive or shall be accompanied by such reference on the occasion of their official publication. The methods of making such reference shall be laid down by Member States.

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.

[^E0001]: 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).

[^E0002]: 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).

[^E0003]: OJ L 378, 27.12.2006, p. 1.

[^E0004]: 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).

[^E0005]: OJ L 193, 17.7.1991, p. 30.

[^E0006]: OJ L 311, 28.11.2001, p. 67.