A4-0407/98

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 (COM(97)0369 - C4-0446/97 - 97/0197(COD))

The proposal was approved with the following amendments:

(Amendment 1)

Recital 2

>Original text>

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;

>Text following EP vote>

Whereas the accepted basis for the conduct of clinical trials in humans is founded in the current revision of the Declaration of Helsinki

; 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 the Member States must adopt detailed rules to protect individuals who are incapable of giving their informed consent (e.g. the mentally handicapped or children); whereas under no circumstances shall individuals who are incapable of giving their informed consent be enlisted for clinical studies in which no individuals capable of giving their informed consent are willing to take part; whereas the person legally responsible for such individuals must approve participation in clinical studies in each case;

(Amendment 2)

Recital 4

>Original text>

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 jeopardising the well-being of the people participating in the trial with the possibility of rejecting it in specific sites if facilities are not appropriate;

>Text following EP vote>

Whereas, for multi-centre clinical trials conducted in more than one Member State, a delay in the commencement of the trial may be caused by the

existence of several diverse procedures for obtaining opinions of ethics committees; whereas, for such trials, a single opinion for each Member State concerned reduces delays without jeopardising the well-being of the people participating in the trial with the possibility of rejecting it in specific sites if facilities and expertise are not appropriate;

(Amendment 3)

Recital 4a (new)

>Original text>

>Text following EP vote>

Whereas there should be the possibility, for multi-centre clinical trials conducted in more than one Member State, of deferring or terminating the trial at specific locations if the requirements of good clinical practice are not satisfied; whereas measures should be taken to protect trial subjects from the consequences of deferring or terminating a trial;

(Amendment 4)

Article 1(3)

>Original text>

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.

>Text following EP vote>

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. The guidelines to be observed for GCP shall be those laid down by the International Conference on Harmonisation. Detailed guidelines in line with those principles shall be published by the Commission, which at regular intervals shall also publish the adaptations habitually made in this field to take account of technical, scientific, and clinical progress.

(Amendment 6)

Article 2, definition 4a (new)

>Original text>

>Text following EP vote>

Informed Consent: The decision by a subject to participate voluntarily in a trial after having been informed of all the significant aspects by means of a written document which must be dated and signed.

(Amendment 7)

Article 2, definition 7

>Original text>

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.

>Text following EP vote>

Investigator: A doctor 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.

(Amendment 8)

Article 2, definition 12, 2nd paragraph (new)

>Original text>

>Text following EP vote>

Medical and scientific criteria shall be applied in determining whether immediate reporting is required in other situations, for example in the event of important medical occurrences which are not directly life-threatening and do not directly occasion death, but which may necessitate action to prevent one of the aforementioned consequences. As a rule, these shall also be regarded as serious.

(Amendment 9)

Article 2, definition 15

>Original text>

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

>Text following EP vote>

Unexpected Adverse Drug Reaction: An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g. investigator's brochure, company core safety information or summary of product characteristics, if any).

(Amendments 10 and 28)

Article 3(1) to (3)

>Original text>

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

>Text following EP vote>

1.

This Directive is without prejudice to the measures laid down in Member States concerning the protection of trial subjects, where these are more comprehensive than this Directive and consistent with the procedures and time-scales specified therein.

>Original text>

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.

>Text following EP vote>

2.

A clinical trial may only be undertaken if, in particular,

(a) the right of the subject to physical and mental integrity is respected, as well as the right to privacy,

(b) the subject has given his written consent after being informed of the nature, significance and implications of the clinical trial,

(c) the medical care given to, and medical decisions made on behalf of, subjects are the responsibility of an appropriately qualified doctor or, when appropriate, of a qualified dentist,

(d) treatment/compensation is available in the event of injury or death of a subject which is attributable to the clinical trial, and insurance or indemnity are guaranteed to cover the liability of investigators and sponsors.

>Original text>

>Text following EP vote>

2a. In addition to any other restrictions, research on any person who is incapable of giving informed consent shall be prohibited unless the trial is for his or her direct benefit.

>Original text>

>Text following EP vote>

3. The Member States shall, in so far as they have not yet done so, adopt detailed rules to protect from abuse individuals who are incapable of giving their informed consent. Individuals who are incapable of giving their informed consent may participate in clinical trials only if the person legally responsible for them has given his informed consent.

>Original text>

>Text following EP vote>

3a. If a subject is incapable of entering into legal transactions or if his capacity to do so is restricted, the informed consent of relatives, guardian and, where necessary, a legal representative shall be required.

>Original text>

>Text following EP vote>

3b. Consent to participate in clinical trials may be revoked at any time without prejudice to the subject.

(Amendment 11)

Article 4(1), 2nd subparagraph

>Original text>

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 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.

>Text following EP vote>

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 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.

(Amendment 12)

Article 4(4)

>Original text>

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.

>Text following EP vote>

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 15 days. However, no additional extension shall be permissible beyond that limit, except in the case of trials involving gene therapy and xenotransplantation.

(Amendment 13)

Article 7(1)

>Original text>

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

>Text following EP vote>

1.

Before commencing a clinical trial, the sponsor shall inform the authorities of the Member States where the trial will take place. Sponsors are recommended to do this when applying for an opinion of an ethics committee pursuant to Article 4(3).

(Amendment 31)

Article 7(2)

>Original text>

2. Member States shall authorise 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.

>Text following EP vote>

2. The trial shall begin only after the ethics committee has issued a favourable opinion. The ethics committee shall have a period of 30 days in which to deliver its opinion as provided for under Article 4(3). The sponsor shall notify the Member States of the commencement of the clinical trial. Member States may however decide that certain clinical trials will be subject to paragraph 3.

(Amendment 15)

Article 7(3), 1st subparagraph

>Original text>

3. In the case of clinical trials not covered by the provisions of paragraph 2, Member States shall authorise 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.

>Text following EP vote>

3.

In the case of clinical trials not covered by the provisions of paragraph 2, a sponsor may 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.

(Amendment 16)

Article 7(4), 1st subparagraph

>Original text>

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.

>Text following EP vote>

4. In the case of an amendment to be made to the protocol - and not in the case of an administrative change - 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. The sponsor shall notify the competent authorities at the time of taking those measures.

(Amendment 35)

Article 7(5)

>Original text>

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

>Text following EP vote>

5.

Notwithstanding paragraph 4 and in the event of unexpected side-effects, provisional urgent safety measures may be taken by the sponsor in order to eliminate an immediate hazard to trial subjects, in particular by suspending all recruitment for the study concerned. The sponsor shall notify the competent authorities when taking such measures.

(Amendment 18)

Article 7(7)

>Original text>

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.

>Text following EP vote>

7.

The Commission shall, in consultation with the Member States, draw up detailed guidance on the format and contents for notifications 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.

(Amendment 19)

Article 8(4)

>Original text>

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.

>Text following EP vote>

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. The guidance in question shall ensure that the confidentiality of the data is strictly observed.

(Amendment 20)

Article 8(4a) (new)

>Original text>

>Text following EP vote>

4a. The data shall not be entered in the database until the study has been completed. Furthermore, the express consent of the sponsor must be obtained regarding the substance of the information. The database may not include any information concerning an investigational medicinal product if the sponsor certifies that the dissemination thereof would undermine the legal protection granted under industrial property law and if such dissemination would be damaging to his competitiveness.

(Amendment 21)

Article 9(1)

>Original text>

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.

>Text following EP vote>

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, the sponsor, the ethics committees concerned and the Commission thereof.

>Original text>

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

>Text following EP vote>

The Member State shall inform the other Member States

, the sponsor, the relevant ethics committees and the Commission of the decisions taken and the reasons for those decisions.

>Original text>

>Text following EP vote>

Before the Member State takes its decisions, the sponsor and/or investigator shall be consulted, unless delay would be dangerous.

(Amendment 22)

Article 9(2)

>Original text>

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.

>Text following EP vote>

2.

Where a Member State has objective grounds for believing that the sponsor or the investigator is no longer fulfilling his obligations as laid down, it shall forthwith inform the other Member States, its own relevant ethics committees, the Commission, the sponsor and/or the investigator, stating the reasons in detail and indicating the course of action.

>Original text>

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

>Text following EP vote>

After consulting the sponsor and/or the investigator, the Member State shall forthwith inform the Commission of the commencement of any infringement proceedings.

(Amendment 23)

Article 10(1)

>Original text>

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

__________

(1) OJ L 147, 9.6.1975, p. 13.

>Text following EP vote>

1.

Member States shall take all appropriate measures to ensure that the manufacture of investigational medicinal products, whether manufactured in a Member State or imported from a third country, is in accordance with the principles of good manufacturing practice laid down in Directive 91/356/EEC(1) and in the specific guidelines applicable to investigational medicinal products.

__________

(1) OJ L 193, 17.7.1991, p. 30

(Amendment 24)

Article 10(2)

>Original text>

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

>Text following EP vote>

2. Under the supervision of a qualified person within the meaning of paragraph 3, the Member States shall authorise imports from third countries and the free movement thereof within the Member States, provided that there is documented proof to the effect that quality control and batch approval have been carried out appropriately in the third country in accordance with paragraph 1.

(Amendment 25)

Article 10(3)

>Original text>

3. A person engaging in the activities of the 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.

>Text following EP vote>

3. All manufacturing processes shall be carried out under the supervision of an authorised person. Persons involved in the approval of investigational substances shall have received appropriate training in quality systems, good manufacturing practices and the specific administrative requirements relating to this kind of production. Such persons shall be independent of those in charge of the manufacturing process. Qualified persons shall meet the requirements laid down in Article 2, second indent, of Directive 91/356/EEC in conjunction with Directive 75/318/EEC.

(Amendment 26)

Article 11, 2nd paragraph (new)

>Original text>

>Text following EP vote>

The outer packaging of investigational medicinal products or, where there is no outer packaging, the immediate packaging shall state in, at least, the national language(s) that the medicinal product is being used for a clinical trial and that it may not be sold.

(Amendment 32)

Article 12(1)

>Original text>

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.

>Text following EP vote>

1.

Compliance with the provisions of good clinical practice shall be verified 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.

(Amendment 33)

Article 12(2)

>Original text>

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.

>Text following EP vote>

2.

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

(Amendment 27)

Article 13(4)

>Original text>

4. The sponsor shall ensure that all relevant information about fatal or life-threatening unexpected adverse reactions is 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 15 days. The sponsor shall also inform all investigators.

>Text following EP vote>

4.

The sponsor shall ensure that all relevant information about fatal or life-threatening unexpected adverse reactions is 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 unexpected adverse reactions that are not fatal or life-threatening shall be reported as soon as possible but no later than 15 days to the Member State in whose territory the reaction occurred and to the ethics committee. The sponsor shall also inform all investigators of other serious unexpected adverse reactions to the medicinal product.

Legislative resolution embodying Parliament's opinion on the 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 (COM(97)0369 - C4-0446/97 - 97/0197(COD))(Codecision procedure: first reading)

The European Parliament,

- having regard to the Commission proposal to Parliament and the Council, COM(97)0369 - 97/0197(COD) ((OJ C 306, 8.10.1997, p. 9)),

- having regard to Articles 189b(2) and 100a of the EC Treaty pursuant to which the Commission submitted the proposal to Parliament (C4-0446/97),

- having regard to Rule 58 of its Rules of Procedure,

- having regard to the report of the Committee on the Environment, Public Health and Consumer Protection and the opinion of the Committee on Research, Technological Development and Energy (A4-0407/98),

1. Approves the Commission proposal, subject to Parliament's amendments;

2. Calls on the Commission to alter its proposal accordingly, pursuant to Article 189a(2) of the EC Treaty;

3. Calls on the Council to incorporate Parliament's amendments in the common position that it adopts in accordance with Article 189b(2) of the EC Treaty;

4. Should the Council intend to depart from the text approved by Parliament, calls on the Council to notify Parliament and requests that the conciliation procedure be initiated;

5. Points out that the Commission is required to submit to Parliament any modification it may intend to make to its proposal as amended by Parliament;

6. Instructs its President to forward this opinion to the Council and Commission.