1. The sponsor and the investigator shall ensure that the clinical investigation is conducted in accordance with the approved clinical investigation plan.
2. In order to verify that the rights, safety and well-being of subjects are protected, that the reported data are reliable and robust, and that the conduct of the clinical investigation is in compliance with the requirements of this Regulation, the sponsor shall ensure adequate monitoring of the conduct of a clinical investigation. The extent and nature of the monitoring shall be determined by the sponsor on the basis of an assessment that takes into consideration all characteristics of the clinical investigation including the following:
(a)
the objective and methodology of the clinical investigation; and
(b)
the degree of deviation of the intervention from normal clinical practice.
3. All clinical investigation information shall be recorded, processed, handled, and stored by the sponsor or investigator, as applicable, in such a way that it can be accurately reported, interpreted and verified while the confidentiality of records and the personal data of the subjects remain protected in accordance with the applicable law on personal data protection.
4. Appropriate technical and organisational measures shall be implemented to protect information and personal data processed against unauthorised or unlawful access, disclosure, dissemination, alteration, or destruction or accidental loss, in particular where the processing involves transmission over a network.
5. Member States shall inspect, at an appropriate level, investigation site(s) to check that clinical investigations are conducted in accordance with the requirements of this Regulation and with the approved investigation plan.
6. The sponsor shall establish a procedure for emergency situations which enables the immediate identification and, where necessary, an immediate recall of the devices used in the investigation.
1. Member States shall ensure that the persons validating and assessing the application, or deciding on it, do not have conflicts of interest, are independent of the sponsor, the investigators involved and of natural or legal persons financing the clinical investigation, as well as free of any other undue influence.
2. Member States shall ensure that the assessment is done jointly by an appropriate number of persons who collectively have the necessary qualifications and experience.
3. Member States shall assess whether the clinical investigation is designed in such a way that potential remaining risks to subjects or third persons, after risk minimization, are justified, when weighed against the clinical benefits to be expected. They shall, while taking into account applicable CS or harmonised standards, examine in particular:
(a)
the demonstration of compliance of the investigational device(s) with the applicable general safety and performance requirements, apart from the aspects covered by the clinical investigation, and whether, with regard to those aspects, every precaution has been taken to protect the health and safety of the subjects. This includes, where appropriate, assurance of technical and biological safety testing and pre-clinical evaluation;
(b)
whether the risk-minimisation solutions employed by the sponsor are described in harmonised standards and, in those cases where the sponsor does not use harmonised standards, whether the risk-minimisation solutions provide a level of protection that is equivalent to that provided by harmonised standards;
(c)
whether the measures planned for the safe installation, putting into service and maintenance of the investigational device are adequate;
(d)
the reliability and robustness of the data generated in the clinical investigation, taking account of statistical approaches, design of the investigation and methodological aspects, including sample size, comparator and endpoints;
(e)
whether the requirements of Annex XV are met;
(f)
in the case of devices for sterile use, evidence of the validation of the manufacturer’s sterilisation procedures or information on the reconditioning and sterilisation procedures which have to be conducted by the investigation site;
(g)
the demonstration of the safety, quality and usefulness of any components of animal or human origin or of substances, which maybe considered medicinal products in accordance with Directive 2001/83/EC.
4. Member States shall refuse the authorisation of the clinical investigation if:
(a)
the application dossier submitted pursuant to Article 70(1) remains incomplete;
(b)
the device or the submitted documents, especially the investigation plan and the investigator’s brochure, do not correspond to the state of scientific knowledge, and the clinical investigation, in particular, is not suitable for providing evidence for the safety, performance characteristics or benefit of the device on subjects or patients,
(c)
the requirements of Article 62 are not met, or
(d)
any assessment under paragraph 3 is negative.
Member States shall provide for an appeal procedure in respect of a refusal pursuant to the first subparagraph.
1. The sponsor of a clinical investigation shall submit an application to the Member State(s) in which the clinical investigation is to be conducted (referred to for the purposes of this Article as ‘Member State concerned’) accompanied by the documentation referred to in Chapter II of Annex XV.
The application shall be submitted by means of the electronic system referred to in Article 73, which shall generate a Union-wide unique single identification number for the clinical investigation, which shall be used for all relevant communication in relation to that clinical investigation. Within 10 days of it receiving the application, the Member State concerned shall notify the sponsor as to whether the clinical investigation falls within the scope of this Regulation and as to whether the application dossier is complete in accordance with Chapter II of Annex XV.
2. Within one week of any change occurring in relation to the documentation referred to in Chapter II of Annex XV, the sponsor shall update the relevant data in the electronic system referred to in Article 73 and make that change to the documentation clearly identifiable. The Member State concerned shall be notified of the update by means of that electronic system.
3. Where the Member State concerned finds that the clinical investigation applied for does not fall within the scope of this Regulation or that the application dossier is not complete, it shall inform the sponsor thereof and shall set a time limit of maximum 10 days for the sponsor to comment or to complete the application by means of the electronic system referred to in Article 73. The Member State concerned may extend this period by a maximum of 20 days where appropriate.
Where the sponsor has not provided comments nor completed the application within the time limit referred to in the first subparagraph, the application shall be deemed to have lapsed. Where the sponsor considers the application does fall under the scope of this Regulation and/or is complete but the Member State concerned does not, the application shall be considered to have been rejected. The Member State concerned shall provide for an appeal procedure in respect of such refusal.
The Member State concerned shall notify the sponsor within five days of receipt of the comments or of the requested additional information, whether the clinical investigation is considered as falling within the scope of this Regulation and the application is complete.
4. The Member State concerned may also extend the period referred to in paragraph 1 and 3 each by a further five days.
5. For the purposes of this Chapter, the date on which the sponsor is notified in accordance with paragraph 1 or 3 shall be the validation date of the application. Where the sponsor is not notified, the validation date shall be the last day of the periods referred to in paragraphs 1, 3 and 4 respectively.
6. During the period when the application is being assessed, the Member State may request additional information from the sponsor. The expiry of the period laid down in point (b) of paragraph 7 shall be suspended from the date of the first request until such time as the additional information has been received.
7. The sponsor may start the clinical investigation in the following circumstances:
(a)
in the case of investigational class I devices or in the case of non-invasive class IIa and class IIb devices, unless otherwise stated by national law, immediately after the validation date of the application pursuant to paragraph 5, and provided that a negative opinion which is valid for the entire Member State, under national law, has not been issued by an ethics committee in the Member State concerned in respect of the clinical investigation;
(b)
in the case of investigational devices, other than those referred to in point (a), as soon as the Member State concerned has notified the sponsor of its authorisation, and provided that a negative opinion which is valid for the entire Member State, under national law, has not been issued by an ethics committee in the Member State concerned in respect of the clinical investigation. The Member State shall notify the sponsor of the authorisation within 45 days of the validation date referred to in paragraph 5. The Member State may extend this period by a further 20 days for the purpose of consulting with experts.
8. The Commission is empowered to adopt delegated acts in accordance with Article 115 amending, in the light of technical progress and global regulatory developments, the requirements laid down in Chapter II of Annex XV.
9. In order to ensure the uniform application of the requirements laid down in Chapter II of Annex XV, the Commission may adopt implementing acts to the extent necessary to resolve issues of divergent interpretation and of practical application. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3).
1. Member States shall ensure that systems for compensation for any damage suffered by a subject resulting from participation in a clinical investigation conducted on their territory are in place in the form of insurance, a guarantee, or a similar arrangement that is equivalent as regards its purpose and which is appropriate to the nature and the extent of the risk.
2. The sponsor and the investigator shall make use of the system referred to in paragraph 1 in the form appropriate for the Member State in which the clinical investigation is conducted.
1. By way of derogation from point (f) of Article 62(4), from points (a) and (b) of Article 64(1) and from points (a) and (b) of Article 65, informed consent to participate in a clinical investigation may be obtained, and information on the clinical investigation may be given, after the decision to include the subject in the clinical investigation, provided that that decision is taken at the time of the first intervention on the subject, in accordance with the clinical investigation plan for that clinical investigation and that all of the following conditions are fulfilled:
(a)
due to the urgency of the situation, caused by a sudden life-threatening or other sudden serious medical condition, the subject is unable to provide prior informed consent and to receive prior information on the clinical investigation;
(b)
there are scientific grounds to expect that participation of the subject in the clinical investigation will have the potential to produce a direct clinically relevant benefit for the subject resulting in a measurable health-related improvement alleviating the suffering and/or improving the health of the subject, or in the diagnosis of its condition;
(c)
it is not possible within the therapeutic window to supply all prior information to and obtain prior informed consent from his or her legally designated representative;
(d)
the investigator certifies that he or she is not aware of any objections to participate in the clinical investigation previously expressed by the subject;
(e)
the clinical investigation relates directly to the subject’s medical condition because of which it is not possible within the therapeutic window to obtain prior informed consent from the subject or from his or her legally designated representative and to supply prior information, and the clinical investigation is of such a nature that itmay be conducted exclusively in emergency situations;
(f)
the clinical investigation poses a minimal risk to, and imposes a minimal burden on, the subject in comparison with the standard treatment of the subject’s condition.
2. Following an intervention pursuant to paragraph 1 of this Article, informed consent in accordance with Article 63 shall be sought to continue the participation of the subject in the clinical investigation, and information on the clinical investigation shall be given, in accordance with the following requirements:
(a)
regarding incapacitated subjects and minors, the informed consent shall be sought by the investigator from his or her legally designated representative without undue delay and the information referred toin Article 63(2) shall be given as soon as possible to the subject and to his or her legally designated representative;
(b)
regarding other subjects, the informed consent shall be sought by the investigator without undue delay from the subject or his or her legally designated representative, whichever can be done sooner, and the information referred to in Article 63(2) shall be given as soon as possible to the subject or his or her legally designated representative, as applicable.
For the purposes of point (b) where informed consent has been obtained from the legally designated representative, informed consent to continue the participation in the clinical investigation shall be obtained from the subject as soon as he or she is capable of giving informed consent.
3. If the subject or, where applicable, his or her legally designated representative does not give consent, he or she shall be informed of the right to object to the use of data obtained from the clinical investigation.
Member States may maintain additional measures regarding persons performing mandatory military service, persons deprived of liberty, persons who, due to a judicial decision, cannot take part in clinical investigations, or persons in residential care institutions.
Clinical investigations on pregnant or breastfeeding women
A clinical investigation on pregnant or breastfeeding women may be conducted only where, in addition to the conditions set out in Article 62(4), all of the following conditions are met:
(a)
the clinical investigation has the potential to produce a direct benefit for the pregnant or breastfeeding woman concerned, or her embryo, foetus or child after birth, outweighing the risks and burdens involved;
(b)
where research is undertaken on breastfeeding women, particular care is taken to avoid any adverse impact on the health of the child;
(c)
no incentives or financial inducements are given to the subject except for compensation for expenses and loss of earnings directly related to the participation in the clinical investigation.
A clinical investigation on minors may be conducted only where, in addition to the conditions set out in Article 62(4), all of the following conditions are met:
(a)
the informed consent of their legally designated representative has been obtained;
(b)
the minors have received the information referred to in Article 63(2) in a way adapted to their age and mental maturity and from investigators or members of the investigating team who are trainedor experienced in working with children;
(c)
the explicit wish of a minor who is capable of forming an opinion and assessing the information referred to in Article 63(2) to refuse participation in, or to withdraw from, the clinical investigation at any time, is respected by the investigator;
(d)
no incentives or financial inducements are given to the subject or his or her legally designated representative except for compensation for expenses and loss of earnings directly related to the participation in the clinical investigation;
(e)
the clinical investigation is intended to investigate treatments for a medical condition that only occurs in minors or the clinical investigation is essential with respect to minors to validate data obtained in clinical investigations on persons able to give informed consent or by other research methods;
(f)
the clinical investigation either relates directly to a medical condition from which the minor concerned suffers or is of such a nature that it can only be carried out on minors;
(g)
there are scientific grounds for expecting that participation in the clinical investigation will produce a direct benefit to the minor subject outweighing the risks and burdens involved;
(h)
the minor shall take part in the informed consent procedure in a way adapted to his or her age and mental maturity;
(i)
if during a clinical investigation the minor reaches the age of legal competence to give informed consent as defined in national law, his or her express informed consent shall be obtained before that subject can continue to participate in the clinical investigation.
1. In the case of incapacitated subjects who have not given, or have not refused to give, informed consent before the onset of their incapacity, a clinical investigation may be conducted only where, in addition to the conditions set out in Article 62(4), all of the following conditions are met:
(a)
the informed consent of their legally designated representative has been obtained;
(b)
the incapacitated subjects have received the information referred to in Article 63(2) in a way that is adequate in view of their capacity to understand it;
(c)
the explicit wish of an incapacitated subject who is capable of forming an opinion and assessing the information referred to in Article 63(2) to refuse participation in, or to withdraw from, the clinical investigation at any time, is respected by the investigator;
(d)
no incentives or financial inducements are given to subjects or their legally designated representatives, except for compensation for expenses and loss of earnings directly related to the participation in the clinical investigation;
(e)
the clinical investigation is essential with respect to incapacitated subjects and data of comparable validity cannot be obtained in clinical investigations on persons able to give informed consent, or by other research methods;
(f)
the clinical investigation relates directly to a medical condition fromwhich the subject suffers;
(g)
there are scientific grounds for expecting that participation in the clinical investigation will produce a direct benefit to the incapacitated subject outweighing the risks and burdens involved.
2. The subject shall as far as possible take part in the informed consent procedure.
1. Informed consent shall be written, dated and signed by the person performing the interview referred to in point (c) of paragraph 2, and by the subject or, where the subject is not able to give informed consent, his or her legally designated representative after having been duly informed in accordance with paragraph 2. Where the subject is unable to write, consent may be given and recorded through appropriate alternative means in the presence of at least one impartial witness. In that case, the witness shall sign and date the informed consent document. The subject or, where the subject is not able to give informed consent, his or her legally designated representative shall be provided with a copy of the document or the record, as appropriate, by which informed consent has been given. The informed consent shall be documented. Adequate time shall be given for the subject or his or her legally designated representative to consider his or her decision to participate in the clinical investigation.
2. Information given to the subject or, where the subject is not able to give informed consent, his or her legally designated representative for the purposes of obtaining his or her informed consent shall:
(a)
enable the subject or his or her legally designated representative to understand: (i) the nature, objectives, benefits, implications, risks and inconveniences of the clinical investigations; (ii) the subject’s rights and guarantees regarding his or her protection, in particular his or her right to refuse to participate in and the right to withdraw from the clinical investigation at any time without any resulting detriment and without having to provide any justification; (iii) the conditions under which the clinical investigations is to be conducted, including the expected duration of the subject’s participation in the clinical investigation; and (iv) the possible treatment alternatives, including the follow-up measures if the participation of the subject in the clinical investigation is discontinued;
(b)
be kept comprehensive, concise, clear, relevant, and understandable to the subject or his or her legally designated representative;
(c)
be provided in a prior interview with a member of the investigating team who is appropriately qualified under national law;
(d)
include information about the applicable damage compensation system referred to in Article 69; and
(e)
include the Union-wide unique single identification number of the clinical investigation referred to in Article 70(1) and information about the availability of the clinical investigation results in accordance with paragraph 6 of this Article.
3. The information referred to in paragraph 2 shall be prepared in writing and be available to the subject or, where the subject is not able to give informed consent, his or her legally designated representative.
4. In the interview referred to in point (c) of paragraph 2, special attention shall be paid to the information needs of specific patient populations and of individual subjects, as well as to the methods used to give the information.
5. In the interview referred to in point (c) of paragraph 2, it shall be verified that the subject has understood the information.
6. The subject shall be informed that a clinical investigation report and a summary presented in terms understandable to the intended user will be made available pursuant to Article 77(5) in the electronic system on clinical investigations referred to in Article 73 irrespective of the outcome of the clinical investigation, and shall be informed, to the extent possible, when they have become available.
7. This Regulation is without prejudice to national law requiring that, in addition to the informed consent given by the legally designated representative, a minor who is capable of forming an opinion and assessing the information given to him or her, shall also assent in order to participate in a clinical investigation.
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