Proposal for a European Parliament and Council Directive on the approximation of provisions laid down by law, regulation or administrative action relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use (97/C 306/10) (Text with EEA relevance) COM(97) 369 final - 97/0197(COD)

(Submitted by the Commission on 4 September 1997)

THE EUROPEAN PARLIAMENT AND THE COUNCIL OF THE EUROPEAN UNION,

Having regard to the Treaty establishing the European Community, and in particular Article 100a thereof,

Having regard to the proposal from the Commission,

Having regard to the opinion of the Economic and Social Committee,

Acting in accordance with the procedure laid down in Article 189b of the Treaty,

Whereas Council Directive 65/65/EEC (1) requires that applications for authorization 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; whereas Council Directive 75/318/EEC (2) lays down uniform rules on the compilation of dossiers including their presentation;

Whereas the accepted basis for the conduct of clinical trials in humans is founded in the current revision of the Declaration of Helsinki and the Council of Europe Convention for the protection of human rights and dignity of the human being with regard to the application of biology and medicine; whereas the trial subject's protection is safeguarded through risk assessment based on toxicological experiments prior to any clinical trial, screening by ethics committees and Member States authorities and the protection of personal data;

Whereas, in order to achieve optimum protection of health, the resources allocated to pharmaceutical research must not be squandered on obsolete or repetitive tests whether within the Community or in third countries; whereas, the harmonization of technical requirements for the development of medicinal products should therefore be pursued through the appropriate fora, including the International Conference on Harmonization,

Whereas, for multi-centre clinical trials conducted in more than one Member State, with many investigational sites involved, a delay in the commencement of the trial may be caused by the multiplicity and diversity of procedures for obtaining opinions of ethics committees; whereas, for such trials, a single opinion for each Member State concerned reduces delays without jeopardizing the well-being of the people participating in the trial with the possibility of rejecting it in specific sites if facilities are not appropriate;

Whereas information both on the commencement and on the termination of a clinical trial should be available to the Member States where the trial takes place, and relevant information on clinical trials should be exchanged between Member States;

Whereas the standards of good manufacturing practice should be applied to investigational medicinal products; whereas special provisions for the labelling of investigational medicinal products should be set out;

Whereas 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 is essential in order to justify the involvement of human subjects in clinical trials; whereas the person participating in a trial should be made aware of and consent to the scrutiny of personal information during inspection by competent authorities and properly authorized persons, provided that such personal information is treated as strictly confidential and is not made publicly available;

Whereas this Directive is without prejudice to Directive 95/46/EEC of the European Parliament and of the Council of 24 October 1995 on the protection of individuals with regard to the processing of personal data and on the free movement of such data (3);

Whereas it is also necessary to make provisions 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;

Whereas the conduct of clinical trials must regularly be adapted to scientific and technical progress in order to ensure optimum protection of the trial subject; whereas it is therefore necessary to introduce a rapid procedure for adapting to technical progress the requirements regarding the conduct of clinical trials, whilst ensuring close co-operation between the Commission and the Member States within a 'Committee for the Adaptation to Technical Progress of the Directives on the Removal of Technical Barriers to Trade in the Medicinal Products Sector`,

HAVE ADOPTED THIS DIRECTIVE:

CHAPTER I

Scope and definitions

Article 1

1. This Directive deals with clinical trials including multi-centre trials on human subjects involving medicinal products as defined in Article 1 of Directive 65/65/EEC but excludes non-interventional clinical trials.

2. Good clinical practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki (1964), and that the clinical trial data are credible.

3. The principles and guidelines of good clinical practice shall be adopted in the form of a directive addressed to the Member States, in accordance with the procedure laid down in Article 2c of Council Directive 75/318/EEC. Detailed guidelines in line with those principles shall be published by the Commission and revised as necessary to take account of technical and scientific progress.

4. All clinical trials, including bioavailability and bioequivalence studies shall be designed, conducted and reported in accordance with the standard of good clinical practice.

Article 2

For the purposes of this Directive the following definitions shall apply:

Adverse Event: Any untoward medical occurrence in a patient or clinical investigation subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment.

Adverse Reaction: All noxious and unintended responses to an investigational medicinal product related to any dose.

Clinical Trial: Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational medicinal product(s), and/or to identify any adverse reactions to an investigational medicinal product(s), and/or to study absorption, distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy.

This includes clinical trials done in either one site or multiple sites, whether in one Member State or more than one Member State; but excludes non-interventional trials.

Ethics Committee: An independent body constituted of healthcare professionals and non-medical members, whose responsibility it is to ensure the protection of 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 investigator(s), facilities, and the methods and material to be used in obtaining and documenting informed consent of the trial subjects.

Inspection: The act by a competent authority of conducting an official review of documents, facilities, records, arrangements for quality assurance, 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 organization's facilities, or at other establishments deemed appropriate by the competent authority.

Investigational medicinal product: A pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the authorized form, or when used for an unauthorized indication, or when used to gain further information about an authorized use.

Investigator: A person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called the principal investigator.

Investigator's Brochure: A compilation of the clinical and non-clinical data on the investigational medicinal product(s) which is relevant to the study of the investigational medicinal product(s) in human subjects.

Multi-centre Trial: A clinical trial conducted according to a single protocol but at more than one site, and therefore, carried out by more than one investigator.

Trial sites may be located in a single Member State, in a number of Member States and/or in Member States and third countries.

Non-interventional trial: A clinical trial where the selection of subjects or the attribution of medicinal products or the examinations carried out or medical and biological follow-up of subjects falls within current medical practice.

Protocol: A document that describes the objective(s), design, methodology, statistical considerations, and organization of a trial. The term protocol refers to protocol, successive versions of the protocol and protocol amendments.

Serious Adverse Event or Serious Adverse Reaction: Any untoward medical occurrence that at any dose results in death, is life-threatening, requires (non-elective) impatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.

Sponsor: An individual, company, institution, or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial.

Subject: An individual who participates in a clinical trial, either as a recipient of the investigational medicinal product or as a control.

Unexpected Adverse Reaction: An adverse reaction not mentioned in the investigator's brochure or in the summary of product characteristics, if any.

CHAPTER II

Protection of trial subjects

Article 3

1. This Directive is without prejudice to the measures laid down in Member States concerning the protection of trial subjects.

2. A clinical trial may only be undertaken if the risks to the subject are not disproportionate to the potential benefits of the medicinal research. The right of the subject to physical and mental integrity shall be respected, as well as the right to privacy.

3. The medical care given to, and medical decisions made on behalf of, subjects shall be the responsibility of an appropriately qualified healthcare practitioner or when appropriate, of a qualified dentist.

4. The trial subject shall be provided with a contact point, independent of the investigating team, where further information may be obtained.

Ethics Committee opinion

Article 4

1. The function and responsibility of an ethics committee shall be to safeguard the rights, safety and well-being of all trial subjects.

In preparing its opinion, the ethics committee shall consider, at least, the relevance of the trial and the trial design, the protocol, the suitability of the investigator, supporting staff, and available facilities; the adequacy and completeness of the written information to be given to the subjects, their relatives, guardians and, if necessary, legal representatives and by which consent is to be obtained; provision for compensation/treatment in the case of injury or death of a subject if attributable to a clinical trial, and any insurance or indemnity to cover the liability of the investigator and sponsor; the extent to which investigators and subjects may be rewarded or compensated for participation in the trial.

2. The opinion of an ethics committee shall be delivered before a clinical trial commences.

3. In order to apply for an opinion of an ethics committee, an application with documentation shall be submitted. The written opinion of the ethics committee shall be given to the applicant, in writing, within 30 days of receipt of a valid application.

4. Within that period, the ethics committee may send a single request for information supplementary to that already supplied. In this case the period shall be extended by a further 30 days.

Article 5

1. Member States shall establish a procedure by which a single ethics committee opinion can be achieved for that Member State. For multi-centre clinical trials conducted in more than one Member State, this procedure shall provide for the single opinion for that Member State.

2. Member States may, in addition, provide for an opinion of the ethics committee for each site on the facilities and capabilities of that site in relation to the proposed clinical trial. Within 15 days of receipt of the opinion provided for in paragraph 1, the ethics committee for the site shall, by issuing an opinion, either accept or reject the conduct of the trial in that site.

Article 6

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

CHAPTER III

Commencement of a clinical trial

Article 7

1. Before commencing a clinical trial, an application shall be submitted by the sponsor to the Member States where the trial will take place.

2. Member States shall authorize sponsors to commence clinical trials once the ethics committee has issued a favourable opinion. Member States may however decide that certain clinical trials will be subject to paragraph 3.

3. In the case of clinical trials not covered by the provisions of paragraph 2, Member States shall authorize a sponsor to commence clinical trials at the end of a period of 30 days after receipt of a valid application unless reasoned grounds for non-acceptance have been notified within this time period.

Within 30 days of receipt of the said grounds for non-acceptance, the sponsor may amend the application on one occasion only in order to take due account of the grounds set out in the notification. If the sponsor does not amend the application as provided for, the application is deemed to have been rejected.

4. Amendments to the protocol shall be notified to the Member States. These amendments shall be deemed to be accepted unless the competent authority notifies grounds for non-acceptance within 30 days.

In cases where grounds for non-acceptance are raised, the procedure in paragraph 3 shall be followed.

5. Notwithstanding paragraph 4, provisional urgent safety measures may be taken by the sponsor in order to eliminate an immediate hazard to trial subjects.

6. Within 90 days of the end of a clinical trial the sponsor shall notify the Member States that the clinical trial is ended. This period shall be reduced to 15 days in the case of early termination of the trial.

7. The Commission shall, in consultation with the Member States, draw up detailed guidance on the format and contents for applications as well as the documentation to be submitted in relation to the quality and manufacture of the investigational medicinal product, any toxicological and pharmacological tests, protocol and clinical information on the investigational medicinal product including the investigator's brochure, in addition to the content of the notification of the end of the clinical trial.

Exchange of information

Article 8

1. Extracts from the initial application, amendments as appropriate and the notification at the end of the clinical trial shall be entered by the Member States in whose territory the trial takes place into a database accessible only to Member States, the European Agency for the Evaluation of Medicinal Products and the Commission.

2. At the request of any Member State or the Commission, the competent authority to whom the trial was notified shall supply all appropriate information concerning that clinical trial.

3. In the case of multi-centre clinical trials conducted in more than one Member State where there are differences between the Member States, the Commission may request the Member States concerned to establish the reasons for the difference which shall be considered by all Member States.

4. The Commission, in consultation with the Member States, shall draw up detailed guidance on the relevant data to be included in this database as well as methods for the electronic communication of the data.

Article 9

1. Where the conditions of the application cease to be met or in the event that new information raising doubts as to safety or science becomes available, the Member State may suspend or prohibit the trial. It shall forthwith inform the other Member States and the Commission thereof.

The Member State shall inform the other Member States and the Commission of the decisions taken and the reasons for those decisions.

2. Where a Member State is of the opinion that the sponsor or the investigator is no longer fulfilling his obligations as laid down, it shall forthwith inform the other Member States and the Commission, stating the reasons in detail and indicating the course of action.

The Member State shall forthwith inform the Commission of the commencement of any infringement proceedings.

CHAPTER IV

Manufacture, import and labelling of investigational medicinal products

Article 10

1. Member States shall take all appropriate measures to ensure that the manufacture and import of investigational medicinal products is subject to the authorization referred to in Article 16 of Council Directive 75/319/EEC (4).

2. Chapters IV and V of Directive 75/319/EEC shall apply to investigational medicinal products.

3. A person engaging in the activities of a person referred to in Article 21 of Directive 75/319/EEC in a Member State as regards investigational medicinal products at the time when this Directive is brought into force in that State but without complying with the provisions of Article 23 and 24 of Directive 75/319/EEC shall be eligible to continue to engage in those activities for the purpose of manufacture of investigational medicinal products in the Member State concerned.

Article 11

For investigational medicinal products, the particulars to appear in, at least, the national language(s) 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 guideline on investigational medicinal products to be adopted in accordance with Article 19a of Directive 75/319/EEC.

CHAPTER V

Compliance

Article 12

1. Compliance with the provisions of good clinical practice shall be verified on behalf of the Community by inspection at relevant sites, including the trial site and manufacturing site, at any laboratory used in the trial and/or at the sponsor's premises, by inspectors appointed by Member States.

2. Following inspection, an inspection report shall be prepared which shall be made available, upon request, to the sponsor, any other Member State or the European Agency for the Evaluation of Medicinal Products.

3. Where there are differences between Member States as to whether the provisions of this Directive have been complied with, the Commission may request a new inspection. The co-ordination of such inspections shall be undertaken by the European Agency for the Evaluation of Medicinal Products.

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

5. The Commission, in consultation with the Member States, the European Agency for the Evaluation of Medicinal Products and interested parties, shall draw up detailed guidelines on the documentation, archiving, appropriate qualification of inspectors and inspection procedures for the demonstration of compliance with this Directive.

CHAPTER VI

Clinical safety reporting

Article 13

1. The investigator shall report all serious adverse events immediately to the sponsor except for those serious adverse events 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 trial subjects.

2. Adverse events and/or laboratory abnormalities identified in the protocol as critical to safety evaluations shall be reported to the ethics committee and the sponsor according to the reporting requirements and within the time periods specified in the protocol.

3. For reported deaths, the investigator shall supply the sponsor and the ethics committee with any additional requested information.

4. The sponsor shall ensure that all relevant information about fatal or life-threatening unexpected adverse reactions are recorded and reported as soon as possible to the Member State in whose territory the reaction occurred, but in any case no later than seven days after first knowledge by the sponsor that a case qualifies. All other serious adverse reactions that are not fatal or life-threatening shall be reported as soon as possible but no later than within 15 days. The sponsor shall also inform all investigators.

5. In addition, the sponsor shall maintain detailed records of all suspected adverse events which are reported to him by the investigator(s). These records shall be submitted to the Member States in whose territory the clinical trial is being conducted.

6. At least every 12 months during the clinical trial, the sponsor shall provide the Member States in whose territory the clinical trial is being conducted with a line listing of all suspected serious adverse reactions which have occurred in the whole study and a summary overview of the subjects' safety in the trial.

7. Each Member State shall ensure that all suspected serious unexpected adverse reactions to an investigational medicinal product occurring within their territory which are brought to their attention are recorded and reported immediately to the European Agency for the Evaluation of Medicinal Products, and in no case later than 15 days following the receipt of the information.

The European Agency for the Evaluation of Medicinal Products shall inform the competent authorities of the Member States.

8. The Commission, in consultation with the European Agency for the Evaluation of Medicinal Products, Member States, and interested parties, shall draw up guidance on the collection, verification and presentation of adverse event/reaction reports.

CHAPTER VII

General provisions

Article 14

This Directive is without prejudice to the general civil and criminal liability of the sponsor or the investigator.

Unless Member States have established precise conditions for exceptional circumstances, medicinal products used in clinical trials shall not be sold. Member States shall inform the Commission of such conditions.

Article 15

Any amendment which may be necessary to update the provisions of this Directive to take account of scientific and technical progress shall be adopted in accordance with the provisions of Article 2c of Directive 75/318/EEC.

Article 16

Member States shall take all appropriate measures to comply with this Directive before 1 January 1999. They shall forthwith inform the Commission thereof.

When Member States adopt these provisions, these shall contain a reference to this Directive or shall be accompanied by such reference at the time of their official publication. The procedure for such reference shall be adopted by Member States.

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 17

This Directive is addressed to the Member States.

(1) OJ 22, 9. 2. 1965, p. 369/65.

(2) OJ L 147, 9. 6. 1975, p. 1.

(3) OJ L 281, 23. 11. 1995, p. 31.

(4) OJ L 147, 9. 6. 1975, p. 13.