Common Position (EC) No 44/2000

adopted by the Council on 20 July 2000

with a view to adopting Directive 2000/.../EC of the European Parliament and of the Council 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

(2000/C 300/03)

THE EUROPEAN PARLIAMENT AND THE COUNCIL OF THE EUROPEAN UNION,

Having regard to the Treaty establishing the European Community, and in particular Article 95 thereof,

Having regard to the proposal from the Commission(1),

Having regard to the opinion of the Economic and Social Committee(2),

Acting in accordance with the procedure laid down in Article 251 of the Treaty(3),

Whereas:

(1) Council Directive 65/65/EEC of 26 January 1965 on the 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 20 May 1975 on the approximation of the laws of Member States relating to analytical, pharmaco-toxicological and clinical standards and protocols in respect of the testing of medicinal products(5) lays down uniform rules on the compilation of dossiers including their presentation.

(2) The accepted basis for the conduct of clinical trials in humans is founded in the protection of human rights and the dignity of the human being with regard to the application of biology and medicine, as for instance reflected in the 1996 version of the Helsinki Declaration. The clinical trial subject's protection is 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) It is incumbent on Member States to lay down rules to safeguard the protection of individuals who are incapable of giving their consent, such as minors and incapacitated adults. Since such persons are incapable of giving their free consent to taking part in a clinical trial, consent to their participation must be given by a person or body provided for by law.

(4) 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 forums, in particular the International Conference on Harmonisation.

(5) 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.

(6) A single opinion for each Member State concerned reduces delay in the commencement of a trial without jeopardising the well-being of the people participating in the trial or excluding the possibility of rejecting it in specific sites.

(7) 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.

(8) 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.

(9) The principles of good manufacturing practice should be applied to investigational medicinal products.

(10) Special provisions should be laid down for the labelling of these products.

(11) 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.

(12) 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.

(13) This Directive is to apply without prejudice to Directive 95/46/EC 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).

(14) 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.

(15) 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 multicentre 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 19(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 Member State;

(b) "Multicentre 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 person 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 to take part in a clinical trial, taken freely after being duly informed of the details 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 and/or an authority and/or a person and/or body provided for by law;

(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 well-being 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 timescales specified therein.

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 society. A clinical trial may be initiated and continued only if anticipated benefits justify the risks;

(b) 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;

(c) informed consent in the appropriate form has been obtained;

(d) the subject may without any resulting detriment withdraw from the clinical trial at any time by revoking his informed consent.

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

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) the protocol;

(c) the suitability of the investigator and supporting staff;

(d) the investigator's brochure;

(e) the quality of the facilities;

(f) the adequacy and completeness of the written information to be given and the procedure to be used for the purpose of obtaining informed consent;

(g) provision for indemnity or compensation in the event of injury or death attributable to a clinical trial;

(h) any insurance or indemnity to cover the liability of the investigator and sponsor;

(i) 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;

(j) 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 7 shall be responsible for the consideration of, and the giving of an opinion on, the matters referred to in paragraph 3, points (g), (h) and (i) of this Article.

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

5. The Ethics Committee shall have a maximum of 60 days from the date of receipt of a valid application to give its reasoned opinion to the applicant and the competent authority in the Member State concerned.

6. Within the period of examination of the application for an opinion, the Ethics Committee may send a single request for information 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 time period referred to in paragraph 5 shall be permissible except in the case of trials involving medicinal products for gene therapy and somatic cell therapy, including xenogenic cell therapy.

Article 5

Single opinion

For multicentre 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 multicentre 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 6

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 7

Commencement of a clinical trial

1. Member States shall take the measures necessary to ensure that the procedure described in this Article is followed for commencement of a clinical trial.

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

2. Before commencing any clinical trial, the sponsor shall be required to submit a valid request for authorisation to the competent authority of the Member State in which the sponsor plans to conduct the clinical trial.

3. If the competent authority of the Member State notifies the sponsor of grounds for non-acceptance, the sponsor may, on one occasion only, amend the content of the request referred to in paragraph 2 in order to take due account of the grounds given. If the sponsor fails to amend the request accordingly, the request shall be considered rejected and the clinical trial may not commence.

4. Consideration of a valid request for authorisation by the competent authority as stated in paragraph 2 must not exceed 60 days. After those 60 days, the sponsor can consider that the competent authority does not object to the commencement of the trial if it has not notified the sponsor of any grounds for non-acceptance.

No 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.

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 the list of which is adopted in accordance with the procedure referred to in Article 19(2) of this Directive.

Until the said list is adopted, Member States shall continue to apply their national procedures.

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.

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 8 on substantive amendments made to the protocol;

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

Article 8

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 4 and 7.

On the basis of the details referred to in Article 4(3) and in accordance with Article 5, 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 9

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 Member States, the Agency and the Commission:

(a) extracts from the request for authorisation referred to in Article 7(2);

(b) any amendments made to the request, as provided for in Article 7(3);

(c) any amendments made to the protocol, as provided for in point (a) of Article 8;

(d) the favourable opinion of the Ethics Committee;

(e) the declaration of the end of the clinical trial; and

(f) a reference to the inspections carried out on conformity with good clinical practice.

2. At the substantiated request of any Member State, the Agency or the Commission, the competent authority to which the request for authorisation was submitted shall supply all further information concerning the clinical trial in question other than the data already in the European database.

3. In consultation with the Member States, the Commission shall draw up and publish detailed guidance on the relevant data to be included in this European database, which it operates with the assistance of the Agency, as well as the methods for electronic communication of the data. The detailed guidance thus drawn up shall ensure that the confidentiality of the data is strictly observed.

Article 10

Suspension of the trial or infringements

1. Where a Member State has objective grounds for considering that the conditions in the request for authorisation referred to in Article 7(2) are no longer met or has information raising doubts about the safety or scientific validity of the clinical trial, it may suspend or prohibit the clinical trial and shall notify the sponsor thereof.

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 11

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 19(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 7(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 7(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 7(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 19(2) of this Directive and published in accordance with Article 19a of Directive 75/319/EEC.

In so far as the provisions laid down in points (a), (b) or (c) are complied with, investigational medicinal products shall not have to undergo any further checks if they are imported into another Member State together with batch release certification signed by the qualified person.

4. In all cases, the qualified person must certify in a register or equivalent document that each production batch satisfies the provisions of this Article. The said register or equivalent document shall be kept up to date as operations are carried out and shall remain at the disposal of the agents of the competent authority for the period specified in the provisions of the Member States concerned. This period shall in any event be not less than five years.

5. Any person engaging in activities as the qualified person referred to in Article 21 of Directive 75/319/EEC as regards investigational medicinal products at the time when this Directive is applied in the Member State where that person is, but without complying with the conditions laid down in Articles 23 and 24 of that Directive, shall be authorised to continue those activities in the Member State concerned.

Article 12

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.

Article 13

Verification of compliance of investigational medicinal products with good clinical and manufacturing practice

1. To verify compliance with the provisions on good clinical and manufacturing practice, Member States shall appoint inspectors to inspect the sites concerned by any clinical trial conducted, particularly the trial site or sites, the manufacturing site of the investigational medicinal product, any laboratory used for analyses in the clinical trial and/or the sponsor's premises.

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

2. Following inspection, an inspection report shall be prepared. It must be made available to the sponsor while safeguarding confidential aspects. It may be made available to the other Member States, to the Ethics Committee and to the Agency, at their reasoned request.

3. At the request of the Agency, within the framework of its powers as provided for in Regulation (EEC) No 2309/93, or of one of the Member States concerned, and following consultation with the Member States concerned, the Commission may request a new inspection should verification of compliance with this Directive reveal differences between Member States.

4. Subject to any arrangements which may have been concluded between the Community and third countries, the Commission, upon receipt of a reasoned request from a Member State or on its own initiative, or a Member State, may propose that the trial site and/or the sponsor's premises and/or the manufacturer established in a third country undergo an inspection. The inspection shall be carried out by duly qualified Community inspectors.

5. The detailed guidelines on the documentation relating to the clinical trial, which shall constitute the master file on the trial, archiving, qualifications of inspectors and inspection procedures to verify compliance of the clinical trial in question with this Directive shall be adopted and revised in accordance with the procedure referred to in Article 19(2).

Article 14

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 15

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 15 days of first knowledge by the sponsor.

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

(d) The sponsor shall also inform all investigators.

2. Once a year throughout the clinical trial, the sponsor shall provide the Member States in whose territory the clinical trial is being conducted and the Ethics Committee with a listing of all suspected serious adverse reactions which have occurred over this period and a report of the subjects' safety.

3. (a) Each Member State shall ensure that all suspected unexpected serious adverse reactions to an investigational medicinal product which are brought to its attention are reported immediately to the Agency by the sponsor of the clinical trial.

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

Article 16

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 17

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 18

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 19(2).

Article 19

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 20

Application

1. Member States shall adopt and publish before ...(13) the laws, regulations and administrative provisions necessary to comply with this Directive. They shall forthwith inform the Commission thereof.

They shall apply these provisions at the latest with effect from ...(14).

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 21

Entry into force

This Directive shall enter into force on the day of its publication in the Official Journal of the European Communities.

Article 22

Addressees

This Directive is addressed to the Member States.

Done at ...

For the European Parliament

The President

For the Council

The President

(1) OJ C 306, 8.10.1997, p. 9 and OJ C 161, 8.6.1999, p. 5.

(2) OJ C 95, 30.3.1998, p. 1.

(3) Opinion of the European Parliament of 17 November 1998 (OJ C 379, 7.12.1998, p. 27). Council Common Position of 20 July 2000 and Decision of the European Parliament of ... (not yet published in the Official Journal).

(4) OJ 22, 9.2.1965, p. 1/65. Directive as last amended by 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.

(13) Twenty-four months after the date on which this Directive enters into force.

(14) Thirty-six months after the date on which this Directive enters into force.

STATEMENT OF THE COUNCIL'S REASONS

I. INTRODUCTION

1. On 4 September 1997, the Commission submitted to the Council(1) a proposal for a Directive 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.

2. The Economic and Social Committee delivered its opinion on 28 January 1998(2).

3. The European Parliament delivered its opinion at first reading on 17 November 1998(3). In the light of the opinion of the European Parliament, the Commission submitted an amended proposal(4) to the Council in a letter dated 27 April 1999.

4. On 20 July 2000, the Council adopted its Common Position in accordance with Article 251 of the Treaty.

II. OBJECTIVE OF THE PROPOSAL

5. The objective of the proposal for a Directive is to rationalise and approximate the national documentary and administrative procedures relating to the clinical trials of medicinal products for human use by means of the homogeneous implementation of good clinical practices (GCP).

6. The Community guidelines on GCP, harmonised at international level, are not binding and are not implemented in the same way by all Member States. This situation often leads to long delays in the programme of clinical experiments, particularly in multicentre clinical trials, where the same trial is carried out in several Member States simultaneously.

It is therefore important to transform the Community principles and guidelines into a binding Community legislative act.

III. ANALYSIS OF THE COMMON POSITION

7. The Council's Common Position is essentially based on the amended Commission proposal, and therefore includes the letter or spirit of most of the amendments suggested by Parliament and taken up by the Commission.

8. An important exception concerns the procedure for starting a clinical trial, which has been substantially amended by the Council (amendments 13, 15, 18 and 31) in order to simplify and speed up decision-making by the competent authorities of the Member States.

9. Another exception concerns the provisions for the protection of subjects in clinical trials, in particular certain aspects relating to minors and incapacitated adults (amendments 1, 10 and 28), which could only be partly accepted by the Council and the Commission, both institutions nevertheless considering that the protection guarantees for subjects in clinical trials would not be reduced as a result (see point 21).

10. The Commission approves all the amendments made by the Council.

11. It should be pointed out that the amended Commission proposal contains, in addition to new provisions in the light of Parliament's opinion, important editorial changes to the original text.

Similarly, the Council has introduced a number of editorial changes to the text of the Common Position. Some of the original provisions to which the European Parliament's proposals for amendments refer have consequently undergone subsequent re-drafting or re-editing.

Amendments accepted without modification, with minor editorial modifications or in principle

12. The Council accepted amendment 6, in so far as it supplemented the list of definitions in Article 2 by a definition of "informed consent". The definition selected by the Council differs from that proposed by Parliament in that it also covers persons who are not in a position to give their consent with full knowledge of the facts.

13. The Council accepted amendment 9 concerning the definition of "unexpected adverse reaction" in Article 2(p), subject to certain editorial modifications.

14. The second part of amendment 12 (Article 4(7)), concerning an exceptional extension of the 60-day period for the Ethics Committee to give its opinion in cases where trials involve medicinal products for gene therapy was accepted by the Council and extended to include somatic cell therapy, including xenogenic cell therapy.

15. The Council accepted amendment 19 (Article 9(3)) concerning strict observance of the confidentiality of data to be entered in the European database.

16. Amendment 21 (Article 10(1)), which makes it obligatory to inform the sponsor, the competent authorities, the Ethics Committee concerned and the Commission in cases where a suspension of the clinical trial must be contemplated, was accepted by the Council, subject to the additional obligation that the Agency be informed.

17. Likewise, it accepted amendment 22 (Article 10(2)), obliging the sponsor to provide for a course of action to take in the event that he no longer meets his obligations and to notify the Ethics Committee, the other competent authorities and the Commission.

18. The Council agreed in principle to amendments 23, 24 and 25, concerning provisions relating to the manufacture and importation of investigational medicinal products (Article 11).

19. The Council accepted amendment 33 making the inspection report available subject to a reasoned request (Article 13(2)).

20. The Council accepted amendment 27, while making some editorial changes (Article 15(1)(a) to (d)).

Partly accepted amendments

21. The Council partly accepted amendments 1, 10 and 28, concerning the protection of trial subjects in clinical trials. It therefore incorporated part of the proposed amendment 1, modifying recital 2, in a new recital 3.

It also accepted the proposed changes to Article 3(1) as well as paragraph 2(a) concerning the trial subject's right to have his mental and physical integrity safeguarded.

The Council introduced a functional definition of "informed consent" (Article 28(j)) which corresponds to that contained in the Convention on Human Rights and Biomedicine.

Furthermore, it supplemented the provisions of Article 3 by clarifying the arrangements for giving and revoking consent (Article 3(2)(a) and (b)) and by making it obligatory to establish a contact point where the trial subject can be provided with further information (Article 3(4)).

Amendments not accepted

22. Amendments 2 and 3 are superfluous, since the Directive no longer contains provisions relating to trial sites.

23. The Council did not accept amendment 7, which was intended to replace the idea of "person responsible" in the definition of "investigator" by "doctor responsible" (Article 2(f)).

24. The Council did not accept the addition to the definition of "serious adverse event or serious adverse reaction" of the provision proposed by Parliament (amendment 8 - Article 2(o)).

25. The Council did not accept the deletion of the provision on the arrangements for rewarding or compensating investigators and trial subjects as one of the elements to be considered when the Ethics Committee prepares its opinion (amendment 11 - Article 4(3)(i)).

26. Amendments 13, 15, 18 and 31 are superfluous because the procedure for the commencement of a clinical trial chosen by the Council differs considerably from those contained both in the original proposal and in the amended proposal for a Directive (Article 7) (see also point 8).

27. The Council did not accept amendment 26 concerning the indication on the packaging that the medicinal product is being used in the framework of a clinical trial and that it cannot be sold (Article 12).

28. The Council did not accept amendment 32, which provides for the deletion of the indication that inspections for the purpose of verifying compliance with good clinical and manufacturing practice are carried out "on behalf of the Community" (Article 13(1)).

(1) OJ C 306, 8.10.1997, p. 9.

(2) OJ C 95, 30.3.1998, p. 1.

(3) OJ C 379, 7.12.1998, p. 27.

(4) OJ C 161, 8.6.1999, p. 5.