(Codecision procedure: second reading)

The European Parliament,

-  having regard to the Council common position 8878/1/2000 - C5-0424/2000 )(1) ,

-  having regard to its position at first reading(2) on the Commission proposal to Parliament and the Council (COM(1997) 369 (3) ),

-  having regard to the Commission's amended proposal (COM(1999) 193 (4) ) ,

-  having regard to Article 251(2) of the EC Treaty,

-  having regard to Rule 80 of its Rules of Procedure,

-  having regard to the recommendation for second reading of the Committee on the Environment, Public Health and Consumer Policy (A5-0349/2000 ),

1.  Amends the common position as follows;

2.  Instructs its President to forward its position to the Council and Commission.

Council common position   Amendments by Parliament (Amendment 28) Recital 3    (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.    (3) Persons who are incapable of giving legal consent to clinical trials should be given special protection. It is incumbent on the Member States to lay down rules to this effect. Such persons may not be included in clinical trials if the same results can be obtained using persons capable of giving consent. Normally these persons should only be included in clinical trials when there are grounds for expecting that the administering of the medicinal product would be of direct benefit to the patient, thereby outweighing the risks. However, there is a need for clinical trials involving children to improve the treatment available to them. Children represent a vulnerable population with developmental, physiological and psychological differences from adults, which make age- and development-related research important for their benefit. Medicinal products, including vaccines, for children need to be tested scientifically before widespread use. This can only be achieved by ensuring that medicinal products which are likely to be of significant clinical value for children are fully studied. The clinical trials required for this purpose should be carried out under conditions affording the best possible protection for the subjects. Criteria for the protection of children in clinical trials therefore need to be laid down. (Amendment 2) Recital 3a (new) (3a) In the case of other persons incapable of giving their consent, such as persons with dementia, psychiatric patients etc., inclusion in clinical trials in such cases should be on an even more restrictive basis. Medicinal products for trial may be administered to all such individuals when there are grounds for assuming that the direct benefit to the patient outweighs the risks. Moreover, in such cases the written agreement of the patient's legal representative, given in cooperation with the treating doctor, is necessary before participation in any such clinical trial. (Amendment 29) Recital 3b (new) (3b) The notion of legal representative refers back to existing national law and consequently may include natural or legal persons, an authority and/or a body provided for by national law. (Amendment 3) Recital 8a (new) (8a) As a rule authorisation should be implicit, i.e. if there has been a vote in favour by the Ethics committee and the competent authority has not objected within a given period, it should be possible to begin the clinical trials. In exceptional cases raising especially complex problems, explicit written authorisation shall however be required. (Amendment 30) Recital 10a (new) (10a) Non-commercial clinical trials conducted by researchers without the participation of the pharmaceuticals industry may be of great benefit to the patients concerned. The Directive should therefore take account of the special position of trials whose planning does not require particular manufacturing or packaging processes, if these trials are carried out with medicinal products with a marketing authorisation within the meaning of Directive 65/65/EEC , manufactured or imported in accordance with the provisions of Directives 75/319/EEC and 91/356/EEC , and on patients with the same characteristics as those covered by the indication specified in this marketing authorisation. Labelling of the investigational medicinal products for trials of this nature should be subject to simplified provisions laid down in the good manufacturing practice guidelines on investigational products and in Directive 91/356/EEC . (Amendment 31) Article 2(f)    (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;    (f) “Investigator”: A doctor or a person following a profession agreed in the Member State for investigations because of the scientific background and the experience in patient care it requires. The investigator is responsible for the conduct of a clinical trial at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the leader responsible for the team and may be called the principal investigator; (Amendment 32) Article 2(j)    (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.    (j) “Informed written consent”: decision, which must be dated and signed, to take part in a clinical trial, taken freely after being duly informed of its nature, significance, implications and risks and appropriately documented, by any person capable of giving consent or, where the person is not capable of giving consent, by his or her legal representative. If the person concerned is unable to write, oral consent in the presence of at least one witness may be given in exceptional cases, as provided for in national legislation; (Amendment 7) Article 3(1)    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 time-scales specified therein.    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 time-scales specified therein. Member States shall, in so far as they have not already done so, adopt detailed rules to protect from abuse individuals who are incapable of giving their informed consent. (Amendment 33) Article 3(2)(a)    (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 ;    (a) the foreseeable risks and inconveniences have been weighed against the anticipated benefit for the individual trial subject and other present and future patients . A clinical trial may be initiated only if the Ethics committee and/or the competent authority comes to the conclusion that the anticipated therapeutic and public health benefits justify the risks and continued only if compliance with this requirement is permanently monitored ; (Amendment 34) Article 3(2)(aa) (new)    (aa) the trial subject or, when the person is not able to give informed consent, his legal representative has had the opportunity, in a prior interview with the investigator or a member of the investigating team, to understand the objectives, risks and inconveniences of the trial, and the conditions under which it is to be conducted. The subject will also be informed of his right to withdraw from the trial at any time; (Amendment 35) Article 3(2)(c)    (c) informed consent in the appropriate form has been obtained;    (c) the trial subject or, when the person is not able to give informed consent, his legal representative has given his written consent after being informed of the nature, significance, implications and risks of the clinical trial. If the individual is unable to write, oral consent in the presence of at least one witness may be given in exceptional cases, as provided for in national legislation; (Amendment 11) Article 3(2)(da) (new)    (da) provision has been made for insurance or indemnity to cover the liability of the investigator and sponsor; (Amendment 36) Article 3a (new) Article 3a Clinical trials on minors In addition to any other relevant restriction, a clinical trial on minors may be undertaken only if    (a) the informed consent of the parents or legal representative has been obtained; consent must represent the minor's presumed will and may be revoked at any time, without detriment to the minor;    (b) the minor has received information according to its capacity of understanding, from staff with experience with minors, regarding the trial, the risks and the benefits;    (c) the explicit wish of a minor who is capable of forming an opinion and assessing this information to refuse participation or to be withdrawn from the clinical trial at any time is considered by the investigator or where appropriate the principal investigator;    (d) no incentives or financial inducements are given except compensation;    (e) some direct benefit for the group of patients is obtained from the clinical trial and only where such research is essential to validate data obtained in clinical trials on persons able to give informed consent or by other research methods. Additionally, such research should either relate directly to a clinical condition from which the minor concerned suffers or be of such a nature that it can only be carried out on minors;    (f) the corresponding scientific guidelines of the Agency have been followed;    (g) clinical trials have been designed to minimise pain, discomfort, fear and any other foreseeable risk in relation to the disease and developmental stage; both the risk threshold and the degree of distress have to be specially defined and constantly monitored;    (h) the Ethics committee, with paediatric expertise or after taking advice in clinical, ethical and psychosocial matters in the field of paediatrics, has endorsed the protocol;    (i) the interests of the patient always prevail over those of science and society. (Amendment 37) Article 3b (new) Article 3b Clinical trials on incapacitated adults not able to give informed legal consent In the case of other persons incapable of giving informed legal consent, all relevant requirements listed for persons capable of giving consent shall apply. In addition to these requirements, inclusion in clinical trials of incapacitated adults who have not given or not refused informed consent prior to the onset of their incapacity shall be allowed only if:    (a) the informed consent of the legal representative has been obtained; consent shall represent the subject's presumed will and may be revoked at any time, without detriment to the subject;    (b) the person not able to give legal informed consent has received information according to his/her capacity of understanding regarding the trial, the risks and the benefits;    (c) the explicit wish of a subject who is capable of forming an opinion and assessing this information to refuse participation or to be withdrawn from the clinical trial at any time is considered by the investigator or where appropriate the principal investigator;    (d) no incentives or financial inducements are given except compensation;    (e) such research is essential to validate data obtained in clinical trials on persons able to give informed consent or by other research methods and which relates directly to a life-threatening or debilitating clinical condition from which the incapacitated adult concerned suffers;    (f) clinical trials have been designed to minimise pain, discomfort, fear and any other foreseeable risk in relation to the disease and developmental stage; both the risk threshold and the degree of distress have to be specially defined and constantly monitored;    (g) the Ethics committee, with expertise in the relevant disease and the patient population concerned or after taking advice in clinical, ethical and psychosocial questions in the field of the relevant disease and patient population concerned, has endorsed the protocol;    (h) the interests of the patient always prevail over those of science and society;    (i) there are grounds for expecting that administering the medicinal product to be tested will produce a benefit to the patient outweighing the risks or produce no risk at all. (Amendment 14) Article 4(3)(aa) (new)    (aa) whether the evaluation of the anticipated benefits and risks as required under Article 3(2)(a) is satisfactory and whether the conclusions are justified; (Amendment 38) Article 4(3)(f)    (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;    (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 and the justification for the research on persons incapable of giving informed consent as regards the specific restrictions laid down in Article 3; (Amendment 39) Article 4(7)    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.    7. No extension to the 60-day period referred to in paragraph 5 shall be permissible except in the case of trials involving medicinal products for gene therapy or somatic cell therapy or medicinal products containing genetically modified organisms, for which an extension of a maximum of 30 days shall be permitted. For these products, this 90-day period may be extended by a further 90 days in the event of consultation of a group or a committee in accordance with the Member State regulations and procedures. In the case of xenogenic cell therapy there shall be no time limit to the authorisation period. (Amendment 40) Article 7(4)    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.    4. Consideration of a valid request for authorisation by the competent authority as stated in paragraph 2 shall be carried out as rapidly as possible and may not exceed 60 days. The Member States may lay down a shorter period than 60 days within their area of responsibility if that is in compliance with current practice. The competent authority can nevertheless notify the sponsor before the end of this period that it has no 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. No further extensions to the period referred to in the first subparagraph shall be permissible except in the case of trials involving the medicinal products listed in paragraph 6, for which an extension of a maximum of 30 days shall be permitted. For these products, the 90-day period may be extended by a further 90 days in the event of consultation of a group or a committee in accordance with the Member State regulations and procedures. In the case of xenogenic cell therapy there shall be no time limit to the authorisation period. (Amendment 41) Article 7(5)    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.    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, such as medicinal products whose active ingredient(s) is a biological product of human or animal origin, or contains biological components of human or animal origin, or manufacturing of which requires such components. (Amendment 42) Article 7(6)    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.    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. No gene therapy trials may be carried out which result in modifications to the subject's germ line genetic identity. (Amendment 21) Article 10(1), first subparagraph a (new) Before the Member State reaches its decision it shall ask the sponsor and/or the investigator for their opinion, to be delivered within one week - except where delay involves risk. (Amendment 43) Article 12, second paragraph (new) In addition, these guidelines shall lay down adapted provisions relating to labelling for investigational medicinal products for clinical trials with the following characteristics:    - the planning of the trial does not require particular manufacturing or packaging processes;    - the trial is conducted with medicinal products with, in the Member States concerned by the study, a marketing authorisation within the meaning of Directive 65/65/EEC , manufactured or imported in accordance with the provisions of Directive 75/319/EEC ;    - the patients participating in the trial have the same characteristics as those covered by the indication specified in the abovementioned authorisation. (Amendment 23) Article 15(3)(a)    (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 .    (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 immediately entered in a European database to which, in accordance with Article 9(1), only the competent authorities of the Member States, the Agency and the Commission, shall have access .

(1) OJ C 300, 20.10.2000, p. 32. (2) OJ C 379, 7.12.1998, p. 27. (3) OJ C 306, 8.10.1997, p. 9. (4) OJ C 161, 8.6.1999, p. 5.