ANNEX XV

Clinical investigations

CHAPTER I

General requirements

1. Ethical principles

Each step in the clinical investigation, from the initial consideration of the need for and justification of the study to the publication of the results, shall be carried out in accordance with recognised ethical principles.

2. Methods

2.1. Clinical investigations shall be performed on the basis of an appropriate plan of investigation reflecting the latest scientific and technical knowledge and defined in such a way as to confirm or refute the manufacturer’s claims regarding the safety, performance and aspects relating to benefit-risk of devices as referred to in Article 62(1); the clinical investigations shall include an adequate number of observations to guarantee the scientific validity of the conclusions. The rationale for the design and chosen statistical methodology shall be presented as further described in Section 3.6 of Chapter II of this Annex.

2.2. The procedures used to perform the clinical investigation shall be appropriate to the device under investigation.

2.3. The research methodologies used to perform the clinical investigation shall be appropriate to the device under investigation.

2.4. Clinical investigations shall be performed in accordance with the clinical investigation plan by a sufficient number of intended users and in a clinical environment that is representative of the intended normal conditions of use of the device in the target patient population. Clinical investigations shall be in line with the clinical evaluation plan as referred to in Part A of Annex XIV.

2.5. All the appropriate technical and functional features of the device, in particular those involving safety and performance, and their expected clinical outcomes shall be appropriately addressed in the investigational design. A list of the technical and functional features of the device and the related expected clinical outcomes shall be provided.

2.6. The endpoints of the clinical investigation shall address the intended purpose, clinical benefits, performance and safety of the device. The endpoints shall be determined and assessed using scientifically valid methodologies. The primary endpoint shall be appropriate to the device and clinically relevant.

2.7. Investigators shall have access to the technical and clinical data regarding the device. Personnel involved in the conduct of an investigation shall be adequately instructed and trained in the proper use of the investigational device, and as regards the clinical investigation plan and good clinical practice. This training shall be verified and where necessary arranged by the sponsor and documented appropriately.

2.8. The clinical investigation report, signed by the investigator, shall contain a critical evaluation of all the data collected during the clinical investigation, and shall include any negative findings.

CHAPTER II

Documentation regarding the application for clinical investigation

For investigational devices covered by Article 62, the sponsor shall draw up and submit the application in accordance with Article 70 accompanied by the following documents:

1. Application form

The application form shall be duly filled in, containing information regarding:

1.1. name, address and contact details of the sponsor and, if applicable, name, address and contact details of its contact person or legal representative in accordance with Article 62(2) established in the Union;

1.2. if different from those in Section 1.1, name, address and contact details of the manufacturer of the device intended for clinical investigation and, if applicable, of its authorised representative;

1.3. title of the clinical investigation;

1.4. status of the clinical investigation application (i.e. first submission, resubmission, significant amendment);

1.5. details and/or reference to the clinical evaluation plan;

1.6. If the application is a resubmission with regard to a device for which an application has been already submitted, the date or dates and reference number or numbers of the earlier application or in the case of significant amendment, reference to the original application. The sponsor shall identify all of the changes from the previous application together with a rationale for those changes, in particular, whether any changes have been made to address conclusions of previous competent authority or ethics committee reviews;

1.7. if the application is submitted in parallel with an application for a clinical trial in accordance with Regulation (EU) No 536/2014, reference to the official registration number of the clinical trial;

1.8. identification of the Member States and third countries in which the clinical investigation is to be conducted as part of a multicentre or multinational study at the time of application;

1.9. a brief description of the investigational device, its classification and other information necessary for the identification of the device and device type;

1.10. information as to whether the device incorporates a medicinal substance, including a human blood or plasma derivative or whether it is manufactured utilising non-viable tissues or cells of human or animal origin, or their derivatives;

1.11. summary of the clinical investigation plan including the objective or objectives of the clinical investigation, the number and gender of subjects, criteria for subject selection, whether there are subjects under 18 years of age, design of the investigation such as controlled and/or randomised studies, planned dates of commencement and of completion of the clinical investigation;

1.12. if applicable, information regarding a comparator device, its classification and other information necessary for the identification of the comparator device;

1.13. evidence from the sponsor that the clinical investigator and the investigational site are capable of conducting the clinical investigation in accordance with the clinical investigation plan;

1.14. details of the anticipated start date and duration of the investigation;

1.15. details to identify the notified body, if already involved at the stage of application for a clinical investigation;

1.16. confirmation that the sponsor is aware that the competent authority may contact the ethics committee that is assessing or has assessed the application; and

1.17. the statement referred to in Section 4.1.

2. Investigator’s Brochure

The investigator’s brochure (IB) shall contain the clinical and non-clinical information on the investigational device that is relevant for the investigation and available at the time of application. Any updates to the IB or other relevant information that is newly available shall be brought to the attention of the investigators in a timely manner. The IB shall be clearly identified and contain in particular the following information:

2.1. Identification and description of the device, including information on the intended purpose, the risk classification and applicable classification rule pursuant to Annex VIII, design and manufacturing of the device and reference to previous and similar generations of the device.

2.2. Manufacturer’s instructions for installation, maintenance, maintaining hygiene standards and for use, including storage and handling requirements, as well as, to the extent that such information is available, information to be placed on the label, and instructions for use to be provided with the device when placed on the market. In addition, information relating to any relevant training required.

2.3. Pre-clinical evaluation based on relevant pre-clinical testing and experimental data, in particular regarding in- design calculations, in vitro tests, ex vivo tests, animal tests, mechanical or electrical tests, reliability tests, sterilisation validation, software verification and validation, performance tests, evaluation of biocompatibility and biological safety, as applicable.

2.4. Existing clinical data, in particular:

—from relevant scientific literature available relating to the safety, performance, clinical benefits to patients, design characteristics and intended purpose of the device and/or of equivalent or similar devices;
—other relevant clinical data available relating to the safety, performance, clinical benefits to patients, design characteristics and intended purpose of equivalent or similar devices of the same manufacturer, including length of time on the market and a review of performance, clinical benefit and safety-related issues and any corrective actions taken.

2.5. Summary of the benefit-risk analysis and the risk management, including information regarding known or foreseeable risks, any undesirable effects, contraindications and warnings.

2.6. In the case of devices that incorporate a medicinal substance, including a human blood or plasma derivative or devices manufactured utilising non-viable tissues or cells of human or animal origin, or their derivatives, detailed information on the medicinal substance or on the tissues, cells or their derivatives, and on the compliance with the relevant general safety and performance requirements and the specific risk management in relation to the substance or tissues, cells or their derivatives, as well as evidence for the added value of incorporation of such constituents in relation to the clinical benefit and/or safety of the device.

2.7. A list detailing the fulfilment of the relevant general safety and performance requirements set out in Annex I, including the standards and CS applied, in full or in part, as well as a description of the solutions for fulfilling the relevant general safety and performance requirements, in so far as those standards and CS have not or have only been partly fulfilled or are lacking.

2.8. A detailed description of the clinical procedures and diagnostic tests used in the course of the clinical investigation and in particular information on any deviation from normal clinical practice.

3. Clinical Investigation Plan

The clinical investigation plan (CIP) shall set out the rationale, objectives, design methodology, monitoring, conduct, record-keeping and the method of analysis for the clinical investigation. It shall contain in particular the information as laid down in this Annex. If part of this information is submitted in a separate document, it shall be referenced in the CIP.

3.1. General

3.1.1. Single identification number of the clinical investigation, as referred to in Article 70(1).

3.1.2. Identification of the sponsor — name, address and contact details of the sponsor and, where applicable, the name, address and contact details of the sponsor’s contact person or legal representative in accordance with Article 62(2) established in the Union.

3.1.3. Information on the principal investigator at each investigational site, the coordinating investigator for the investigation, the address details for each investigational site and the emergency contact details for the principal investigator at each site. The roles, responsibilities and qualifications of the various kinds of investigators shall be specified in the CIP.

3.1.4. A brief description of how the clinical investigation is financed and a brief description of the agreement between the sponsor and the site.

3.1.5. Overall synopsis of the clinical investigation, in an official Union language determined by the Member State concerned.

3.2. Identification and description of the device, including its intended purpose, its manufacturer, its traceability, the target population, materials coming into contact with the human body, the medical or surgical procedures involved in its use and the necessary training and experience for its use, background literature review, the current state of the art in clinical care in the relevant field of application and the proposed benefits of the new device.

3.3. Risks and clinical benefits of the device to be examined, with justification of the corresponding expected clinical outcomes in the clinical investigation plan.

3.4. Description of the relevance of the clinical investigation in the context of the state of the art of clinical practice.

3.5. Objectives and hypotheses of the clinical investigation.

3.6. Design of the clinical investigation with evidence of its scientific robustness and validity.

3.6.1. General information such as type of investigation with rationale for choosing it, for its endpoints and for its variables as set out in the clinical evaluation plan.

3.6.2. Information on the investigational device, on any comparator and on any other device or medication to be used in the clinical investigation.

3.6.3. Information on subjects, selection criteria, size of investigation population, representativeness of investigation population in relation to target population and, if applicable, information on vulnerable subjects involved such as children, pregnant women, immuno-compromised or, elderly subjects.

3.6.4. Details of measures to be taken to minimise bias, such as randomisation, and management of potential confounding factors.

3.6.5. Description of the clinical procedures and diagnostic methods relating to the clinical investigation and in particular highlighting any deviation from normal clinical practice.

3.6.6. Monitoring plan.

3.7. Statistical considerations, with justification, including a power calculation for the sample size, if applicable.

3.8. Data management.

3.9. Information about any amendments to the CIP.

3.10. Policy regarding follow-up and management of any deviations from the CIP at the investigational site and clear prohibition of use of waivers from the CIP.

3.11. Accountability regarding the device, in particular control of access to the device, follow-up in relation to the device used in the clinical investigation and the return of unused, expired or malfunctioning devices.

3.12. Statement of compliance with the recognised ethical principles for medical research involving humans, and the principles of good clinical practice in the field of clinical investigations of devices, as well as with the applicable regulatory requirements.

3.13. Description of the Informed consent process.

3.14. Safety reporting, including definitions of adverse events and serious adverse events, device deficiencies, procedures and timelines for reporting.

3.15. Criteria and procedures for follow-up of subjects following the end, temporary halt or early termination of an investigation, for follow-up of subjects who have withdrawn their consent and procedures for subjects lost to follow-up. Such procedures shall for implantable devices, cover as a minimum traceability.

3.16. A description of the arrangements for taking care of the subjects after their participation in the clinical investigation has ended, where such additional care is necessary because of the subjects’ participation in the clinical investigation and where it differs from that normally expected for the medical condition in question.

3.17. Policy as regards the establishment of the clinical investigation report and publication of results in accordance with the legal requirements and the ethical principles referred to in Section 1 of Chapter I.

3.18. List of the technical and functional features of the device, with specific mention of those covered by the investigation.

3.19. Bibliography.

4. Other information

4.1. A signed statement by the natural or legal person responsible for the manufacture of the investigational device that the device in question conforms to the general safety and performance requirements apart from the aspects covered by the clinical investigation and that, with regard to those aspects, every precaution has been taken to protect the health and safety of the subject.

4.2. Where applicable according to national law, copy of the opinion or opinions of the ethics committee or committees concerned. Where according to national law the opinion or opinions of the ethics committee or committees is not required at the time of the submission of the application, a copy of the opinion or opinions shall be submitted as soon as available.

4.3. Proof of insurance cover or indemnification of subjects in case of injury, pursuant to Article 69 and the corresponding national law.

4.4. Documents to be used to obtain informed consent, including the patient information sheet and the informed consent document.

4.5. Description of the arrangements to comply with the applicable rules on the protection and confidentiality of personal data, in particular:

—organisational and technical arrangements that will be implemented to avoid unauthorised access, disclosure, dissemination, alteration or loss of information and personal data processed;
—a description of measures that will be implemented to ensure confidentiality of records and personal data of subjects; and
—a description of measures that will be implemented in case of a data security breach in order to mitigate the possible adverse effects.

4.6. Full details of the available technical documentation, for example detailed risk analysis/management documentation or specific test reports, shall, upon request, be submitted to the competent authority reviewing an application.

CHAPTER III

Other obligations of the sponsor

1. The sponsor shall undertake to keep available for the competent national authorities any documentation necessary to provide evidence for the documentation referred to in Chapter II of this Annex. If the sponsor is not the natural or legal person responsible for the manufacture of the investigational device, that obligation may be fulfilled by that person on behalf of the sponsor.

2. The Sponsor shall have an agreement in place to ensure that any serious adverse events or any other event as referred to in Article 80(2) are reported by the investigator or investigators to the sponsor in a timely manner.

3. The documentation mentioned in this Annex shall be kept for a period of at least 10 years after the clinical investigation with the device in question has ended, or, in the event that the device is subsequently placed on the market, at least 10 years after the last device has been placed on the market. In the case of implantable devices, the period shall be at least 15 years.

Each Member State shall require that this documentation is kept at the disposal of the competent authorities for the period referred to in the first subparagraph in case the sponsor, or its contact person or legal representative as referred to in Article 62(2) established within its territory, goes bankrupt or ceases its activity prior to the end of this period.

4. The Sponsor shall appoint a monitor that is independent from the investigational site to ensure that the investigation is conducted in accordance with the CIP, the principles of good clinical practice and this Regulation.

5. The Sponsor shall complete the follow-up of investigation subjects.

6. The Sponsor shall provide evidence that the investigation is being conducted in line with good clinical practice, for instance through internal or external inspection.

7. The Sponsor shall prepare a clinical investigation report which includes at least the following:

—Cover/introductory page or pages indicating the title of the investigation, the investigational device, the single identification number, the CIP number and the details with signatures of the coordinating investigators and the principal investigators from each investigational site.
—Details of the author and date of the report.
—A summary of the investigation covering the title, purpose of the investigation, description of the investigation, investigational design and methods used, the results of the investigation and conclusion of the investigation. The completion date of the investigation, and in particular details of early termination, temporary halts or suspensions of investigations.
—Investigational device description, in particular clearly defined intended purpose.
—A summary of the clinical investigation plan covering objectives, design, ethical aspects, monitoring and quality measures, selection criteria, target patient populations, sample size, treatment schedules, follow-up duration, concomitant treatments, statistical plan, including hypothesis, sample size calculation and analysis methods, as well as a justification.
—Results of the clinical investigation covering, with rationale and justification, subject demographics, analysis of results related to chosen endpoints, details of subgroup analysis, as well as compliance with the CIP, and covering follow-up of missing data and of patients withdrawing from the clinical investigation, or lost to follow-up.
—Summary of serious adverse events, adverse device effects, device deficiencies and any relevant corrective actions.
—Discussion and overall conclusions covering safety and performance results, assessment of risks and clinical benefits, discussion of clinical relevance in accordance with clinical state of the art, any specific precautions for specific patient populations, implications for the investigational device, limitations of the investigation.

MDR – Article 73 – Electronic system on clinical investigations

Article 73

Electronic system on clinical investigations

1. The Commission shall, in collaboration with the Member States, set up, manage and maintain an electronic system:

(a)to create the single identification numbers for clinical investigations referred to in Article 70(1);
(b)to be used as an entry point for the submission of all applications ornotifications for clinical investigations referred to in Articles 70, 74, 75 and 78 and for all other submission of data, or processing of data in this context;
(c)for the exchange of information relating to clinical investigations inaccordance with this Regulation between the Member States and
between them and the Commission including the exchange of
information referred to in Articles 70 and 76;
(d)for information to be provided by the sponsor in accordance with
Article 77, including the clinical investigation report and its
summary as required in paragraph 5 of that Article;
(e)for reporting on serious adverse events and device deficiencies and related updates referred to in Article 80.

2. When setting up the electronic system referred in paragraph 1 of this Article, the Commission shall ensure that it is interoperable with the EU database for clinical trials on medicinal products for human use set up in accordance with Article 81 of Regulation (EU) No 536/2014 of the European Parliament and of the Council (1) as concerns combined clinical investigations of devices with a clinical trial under that Regulation.

3. The information referred to in point (c) of paragraph 1 shall only be accessible to the Member States and the Commission. The information referred to in the other points of that paragraph shall be accessible to the public, unless, for all or parts of that information, confidentiality of the information is justified on any of the following grounds:

(a)protection of personal data in accordance with Regulation (EC) No
45/2001;
(b)protection of commercially confidential information, especially in
the investigators brochure, in particular through taking into account the status of the conformity assessment for the device, unless there
is an overriding public interest in disclosure;
(c)effective supervision of the conduct of the clinical investigation by
the Member State(s) concerned.

4. No personal data of subjects shall be publicly available.

5. The user interface of the electronic system referred to in paragraph 1 shall be available in all official languages of the Union.

(1) Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC (OJ L 158, 27.5.2014, p. 1).

MDR – Article 70 – Application for clinical investigations

Article 70

Application for clinical investigations

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).

MDR – Article 68 – Clinical investigations in emergency situations

Article 68

Clinical investigations in emergency situations

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.

MDR – Article 66 – Clinical investigations on pregnant or breastfeeding women

Article 66

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.

MDR – Article 65 – Clinical investigations on minors

Article 65

Clinical investigations on minors

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.

MDR – Article 62 – General requirements regarding clinical investigations conducted to demonstrate conformity of devices

Article 62

General requirements regarding clinical investigations conducted to demonstrate conformity of devices

1. Clinical investigations shall be designed, authorised, conducted, recorded and reported in accordance with the provisions of this Article and of Articles 63 to 80, the acts adopted pursuant to Article 81, and Annex XV, where carried out as part of the clinical evaluation for conformity assessment purposes, for one or more of the following purposes:

(a)to establish and verify that, under normal conditions of use, a device is designed, manufactured and packaged in such a way that it is
suitable for one or more of the specific purposes listed in point (1) of Article 2, and achieves the performance intended as specified by itsmanufacturer;
(b)to establish and verify the clinical benefits of a device as specified by its manufacturer;
(c)to establish and verify the clinical safety of the device and to determine any undesirable side-effects, under normal conditions of use of the device, and assess whether they constitute acceptable risks when weighed against the benefits to be achieved by the device.

2. Where the sponsor of a clinical investigation is not established in the Union, that sponsor shall ensure that a natural or legal person is established in the Union as its legal representative. Such legal representative shall be responsible for ensuring compliance with the sponsor’s obligations pursuant to this Regulation, and shall be the addressee for all communications with the sponsor provided for in this Regulation. Any communication with that legal representative shall be deemed to be a communication with the sponsor.

Member States may choose not to apply the first subparagraph to clinical investigations to be conducted solely on their territory, or on their territory and the territory of a third country, provided that they ensure that the sponsor establishes at least a contact person on their territory in respect of that clinical investigation who shall be the addressee for all communications with the sponsor provided for in this Regulation.

3. Clinical investigations shall be designed and conducted in such a way that the rights, safety, dignity and well-being of the subjects participating in a clinical investigation are protected and prevail over all other interests and the clinical data generated are scientifically valid, reliable and robust.

Clinical investigations shall be subject to scientific and ethical review. The ethical review shall be performed by an ethics committee in accordance with national law. Member States shall ensure that the procedures for review by ethics committees are compatible with the procedures set out in this Regulation for the assessment of the application for authorisation of a clinical investigation. At least one lay person shall participate in the ethical review.

4. A clinical investigation as referred to in paragraph 1 may be conducted only where all of the following conditions are met:

(a)the clinical investigation is the subject of an authorisation by the
Member State(s) in which the clinical investigation is to be
conducted, in accordance with this Regulation, unless otherwise
stated;
(b)an ethics committee, set up in accordance with national law, has notissued a negative opinion in relation to the clinical investigation,
which is valid for that entire Member State under its national law;
(c)the sponsor, or its legal representative or a contact person pursuant to paragraph 2, is established in the Union;
(d)vulnerable populations and subjects are appropriately protected in accordance with Articles 64 to 68;
(e)the anticipated benefits to the subjects or to public health justify the foreseeable risks and inconveniences and compliance with this
condition is constantly monitored;
(f)the subject or, where the subject is not able to give informed
consent, his or her legally designated representative has given
informed consent in accordance with Article 63;
(g)the subject or, where the subject is not able to give informed
consent, his or her legally designated representative, has been
provided with the contact details of an entity where further
information can be received in case of need;
(h)the rights of the subject to physical and mental integrity, to privacy
and to the protection of the data concerning him or her in
accordance with Directive 95/46/EC are safeguarded;
(i)the clinical investigation has been designed to involve as little pain,
discomfort, fear and any other foreseeable risk as possible for the
subjects, and both the risk threshold and the degree of distress are
specifically defined in the clinical investigation plan and constantlymonitored;
(j)the medical care provided to the subjects is the responsibility of an
appropriately qualified medical doctor or, where appropriate, a
qualified dental practitioner or any other person entitled by national law to provide the relevant patient care under clinical investigation conditions;
(k)no undue influence, including that of a financial nature, is exerted on the subject, or, where applicable, on his or her legally designated representatives, to participate in the clinical investigation;
(l)the investigational device(s) in question conform(s) to the applicablegeneral safety and performance requirements set out in Annex I
apart from the aspects covered by the clinical investigation and that, with regard to those aspects, every precaution has been taken to
protect the health and safety of the subjects. This includes, where
appropriate, technical and biological safety testing and pre-clinical
evaluation, as well as provisions in the field of occupational safety
and accident prevention, taking into consideration the state of the
art;
(m)the requirements of Annex XV are fulfilled.

5. Any subject, or, where the subject is not able to give informed consent, his or her legally designated representative, may, without any resulting detriment and without having to provide any justification, withdraw from the clinical investigation at any time by revoking his or her informed consent. Without prejudice to Directive 95/46/EC, the withdrawal of the informed consent shall not affect the activities already carried out and the use of data obtained based on informed consent before its withdrawal.

6. The investigator shall be a person exercising a profession which is recognised in the Member State concerned as qualifying for the role of investigator on account of having the necessary scientific knowledge and experience in patient care. Other personnel involved in conducting a clinical investigation shall be suitably qualified, by education, training or experience in the relevant medical field and in clinical research methodology, to perform their tasks.

7. The facilities where the clinical investigation is to be conducted shall be suitable for the clinical investigation and shall be similar to the facilities where the device is intended to be used.