1. EU type-examination is the procedure whereby a notified body ascertains and certifies that a device, including its technical documentation and relevant life cycle processes and a corresponding representative sample of the device production envisaged, fulfils the relevant provisions of this Regulation.
2. Application
The manufacturer shall lodge an application for assessment with a notified body. The application shall include:
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the name of the manufacturer and address of the registered place of business of the manufacturer and, if the application is lodged by the authorised representative, the name of the authorised representative and the address of its registered place of business,
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the technical documentation referred to in Annexes II and III. The applicant shall make a representative sample of the device production envisaged (‘type’) available to the notified body. The notified body may request other samples as necessary, and
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a written declaration that no application has been lodged with any other notified body for the same type, or information about any previous application for the same type that was refused by another notified body or was withdrawn by the manufacturer or its authorised representative before that other notified body made its final assessment.
3. Assessment
The notified body shall:
(a)
examine the application by using staff with proven knowledge and experience regarding the technology concerned and its clinical application. The notified body may require the application to be completed by having further tests carried out or requesting further evidence to be provided to allow assessment of conformity with the relevant requirements of this Regulation. The notified body shall carry out adequate physical or laboratory tests in relation to the device or request the manufacturer to carry out such tests;
(b)
examine and assess the technical documentation for conformity with the requirements of this Regulation that are applicable to the device and verify that the type has been manufactured in conformity with that documentation; it shall also record the items designed in conformity with the applicable standards referred to in Article 8 or with applicable CS, and record the items not designed on the basis of the relevant standards referred to in Article 8 or of the relevant CS;
(c)
review the clinical evidence presented by the manufacturer in the clinical evaluation report in accordance with Section 4 of Annex XIV. The notified body shall employ device reviewers with sufficient clinical expertise and, if necessary, use external clinical experts with direct and current experience relating to the device in question or to the clinical condition in which it is utilised, for the purposes of that review;
(d)
in circumstances in which the clinical evidence is based partly or totally on data from devices which are claimed to be similar or equivalent to the device under assessment, assess the suitability of using such data, taking into account factors such as new indications and innovation. The notified body shall clearly document its conclusions on the claimed equivalence, and on the relevance and adequacy of the data for demonstrating conformity;
(e)
clearly document the outcome of its assessment in a pre-clinical and clinical evaluation assessment report as part of the EU type examination report referred to in point (i);
(f)
carry out or arrange for the appropriate assessments and the physical or laboratory tests necessary to verify whether the solutions adopted by the manufacturer meet the general safety and performance requirements laid down in this Regulation, in the event that the standards referred to in Article 8 or the CS have not been applied. Where the device has to be connected to another device or devices in order to operate as intended, proof shall be provided that it conforms to the general safety and performance requirements when connected to any such device or devices having the characteristics specified by the manufacturer;
(g)
carry out or arrange for the appropriate assessments and the physical or laboratory tests necessary to verify whether, in the event that the manufacturer has chosen to apply the relevant harmonised standards, those standards have actually been applied;
(h)
agree with the applicant on the place where the necessary assessments and tests are to be carried out; and
(i)
draw up an EU type-examination report on the results of the assessments and tests carried out under points (a) to (g).
4. Certificate
If the type conforms to this Regulation, the notified body shall issue an EU type-examination certificate. The certificate shall contain the name and address of the manufacturer, the conclusions of the type examination assessment, the conditions of the certificate’s validity and the data needed for identification of the type approved. The certificate shall be drawn up in accordance with Annex XII. The relevant parts of the documentation shall be annexed to the certificate and a copy kept by the notified body.
5. Changes to the type
5.1. The applicant shall inform the notified body which issued the EU type-examination certificate of any planned change to the approved type or of its intended purpose and conditions of use.
5.2. Changes to the approved device including limitations of its intended purpose and conditions of use shall require approval from the notified body which issued the EU type-examination certificate where such changes may affect conformity with the general safety and performance requirements or with the conditions prescribed for use of the product. The notified body shall examine the planned changes, notify the manufacturer of its decision and provide him with a supplement to the EU type-examination report. The approval of any change to the approved type shall take the form of a supplement to the EU type-examination certificate.
5.3. Changes to the intended purpose and conditions of use of the approved device, with the exception of limitations of the intended purpose and conditions of use, shall necessitate a new application for a conformity assessment.
6. Specific additional procedures
Section 5 of Annex IX shall apply with the proviso that any reference to an EU technical documentation assessment certificate shall be understood as a reference to an EU type-examination certificate.
7. Administrative provisions
The manufacturer or, where the manufacturer does not have a registered place of business in a Member State, its authorised representative shall, for a period ending no sooner than 10 years, and in the case of implantable devices no sooner than 15 years, after the last device has been placed on the market, keep at the disposal of the competent authorities:
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the documentation referred to in the second indent of Section 2,
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information on the changes referred to in Section 5, and
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copies of EU type-examination certificates, scientific opinions and reports and their additions/supplements.
Conformity assessment based on a quality management system and on assessment of technical documentation
CHAPTER I
Quality management system
1. The manufacturer shall establish, document and implement a quality management system as described in Article 10(9) and maintain its effectiveness throughout the life cycle of the devices concerned. The manufacturer shall ensure the application of the quality management system as specified in Section 2 and shall be subject to audit, as laid down in Sections 2.3 and 2.4, and to surveillance as specified in Section 3.
2. Quality management system assessment
2.1. The manufacturer shall lodge an application for assessment of its quality management system with a notified body. The application shall include:
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the name of the manufacturer and address of its registered place of business and any additional manufacturing site covered by the quality management system, and, if the manufacturer’s application is lodged by its authorised representative, the name of the authorised representative and the address of the authorised representative’s registered place of business,
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all relevant information on the device or group of devices covered by the quality management system,
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a written declaration that no application has been lodged with any other notified body for the same device- related quality management system, or information about any previous application for the same device- related quality management system,
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a draft of an EU declaration of conformity in accordance with Article 19 and Annex IV for the device model covered by the conformity assessment procedure,
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the documentation on the manufacturer’s quality management system,
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a documented description of the procedures in place to fulfil the obligations arising from the quality management system and required under this Regulation and the undertaking by the manufacturer in question to apply those procedures,
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a description of the procedures in place to ensure that the quality management system remains adequate and effective, and the undertaking by the manufacturer to apply those procedures,
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the documentation on the manufacturer’s post-market surveillance system and, where applicable, on the PMCF plan, and the procedures put in place to ensure compliance with the obligations resulting from the provisions on vigilance set out in Articles 87 to 92,
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a description of the procedures in place to keep up to date the post-market surveillance system, and, where applicable, the PMCF plan, and the procedures ensuring compliance with the obligations resulting from the provisions on vigilance set out in Articles 87 to 92, as well as the undertaking by the manufacturer to apply those procedures,
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documentation on the clinical evaluation plan, and
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a description of the procedures in place to keep up to date the clinical evaluation plan, taking into account the state of the art.
2.2. Implementation of the quality management system shall ensure compliance with this Regulation. All the elements, requirements and provisions adopted by the manufacturer for its quality management system shall be documented in a systematic and orderly manner in the form of a quality manual and written policies and procedures such as quality programmes, quality plans and quality records.
Moreover, the documentation to be submitted for the assessment of the quality management system shall include an adequate description of, in particular:
(a)
the manufacturer’s quality objectives;
(b)
the organisation of the business and in particular: — the organisational structures with the assignment of staff responsibilities in relation to critical procedures, the responsibilities of the managerial staff and their organisational authority, — the methods of monitoring whether the operation of the quality management system is efficient and in particular the ability of that system to achieve the desired design and device quality, including control of devices which fail to conform, — where the design, manufacture and/or final verification and testing of the devices, or parts of any of those processes, is carried out by another party, the methods of monitoring the efficient operation of the quality management system and in particular the type and extent of control applied to the other party, and — where the manufacturer does not have a registered place of business in a Member State, the draft mandate for the designation of an authorised representative and a letter of intention from the authorised representative to accept the mandate;
(c)
the procedures and techniques for monitoring, verifying, validating and controlling the design of the devices and the corresponding documentation as well as the data and records arising from those procedures and techniques. Those procedures and techniques shall specifically cover: — the strategy for regulatory compliance, including processes for identification of relevant legal requirements, qualification, classification, handling of equivalence, choice of and compliance with conformity assessment procedures, — identification of applicable general safety and performance requirements and solutions to fulfil those requirements, taking applicable CS and, where opted for, harmonised standards or other adequate solutions into account, — risk management as referred to in Section 3 of Annex I, — the clinical evaluation, pursuant to Article 61 and Annex XIV, including post-market clinical follow-up, — solutions for fulfilling the applicable specific requirements regarding design and construction, including appropriate pre-clinical evaluation, in particular the requirements of Chapter II of Annex I, — solutions for fulfilling the applicable specific requirements regarding the information to be supplied with the device, in particular the requirements of Chapter III of Annex I, — the device identification procedures drawn up and kept up to date from drawings, specifications or other relevant documents at every stage of manufacture, and — management of design or quality management system changes; and
(d)
the verification and quality assurance techniques at the manufacturing stage and in particular the processes and procedures which are to be used, particularly as regards sterilisation and the relevant documents; and
(e)
the appropriate tests and trials which are to be carried out before, during and after manufacture, the frequency with which they are to take place, and the test equipment to be used; it shall be possible to trace back adequately the calibration of that test equipment.
In addition, the manufacturer shall grant the notified body access to the technical documentation referred to in Annexes II and III.
2.3. Audit
The notified body shall audit the quality management system to determine whether it meets the requirements referred to in Section 2.2. Where the manufacturer uses a harmonised standard or CS related to a quality management system, the notified body shall assess conformity with those standards or CS. The notified body shall assume that a quality management system which satisfies the relevant harmonised standards or CS conforms to the requirements covered by those standards or CS, unless it duly substantiates not doing so.
The audit team of the notified body shall include at least one member with past experience of assessments of the technology concerned in accordance with Sections 4.3. to 4.5. of Annex VII. In circumstances where such experience is not immediately obvious or applicable, the notified body shall provide a documented rationale for the composition of that team. The assessment procedure shall include an audit on the manufacturer’s premises and, if appropriate, on the premises of the manufacturer’s suppliers and/or subcontractors to verify the manufacturing and other relevant processes.
Moreover, in the case of class IIa and class IIb devices, the quality management system assessment shall be accompanied by the assessment of technical documentation for devices selected on a representative basis in accordance with Sections 4.4 to 4.8. In choosing representative samples, the notified body shall take into account the published guidance developed by the MDCG pursuant to Article 105 and in particular the novelty of the technology, similarities in design, technology, manufacturing and sterilisation methods, the intended purpose and the results of any previous relevant assessments such as with regard to physical, chemical, biological or clinical properties, that have been carried out in accordance with this Regulation. The notified body in question shall document its rationale for the samples taken.
If the quality management system conforms to the relevant provisions of this Regulation, the notified body shall issue an EU quality management system certificate. The notified body shall notify the manufacturer of its decision to issue the certificate. The decision shall contain the conclusions of the audit and a reasoned report.
2.4. The manufacturer in question shall inform the notified body which approved the quality management system of any plan for substantial changes to the quality management system, or the device-range covered. The notified body shall assess the changes proposed, determine the need for additional audits and verify whether after those changes the quality management system still meets the requirements referred to in Section 2.2. It shall notify the manufacturer of its decision which shall contain the conclusions of the assessment, and where applicable, conclusions of additional audits. The approval of any substantial change to the quality management system or the device-range covered shall take the form of a supplement to the EU quality management system certificate.
3. Surveillance assessment applicable to class IIa, class IIb and class III devices
3.1. The aim of surveillance is to ensure that the manufacturer duly fulfils the obligations arising from the approved quality management system.
3.2. The manufacturer shall give authorisation to the notified body to carry out all the necessary audits, including on- site audits, and supply it with all relevant information, in particular:
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the documentation on its quality management system,
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documentation on any findings and conclusions resulting from the application of the post-market surveillance plan, including the PMCF plan, for a representative sample of devices, and of the provisions on vigilance set out in Articles 87 to 92,
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the data stipulated in the part of the quality management system relating to design, such as the results of analyses, calculations, tests and the solutions adopted regarding the risk-management as referred to in Section 4 of Annex I, and
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the data stipulated in the part of the quality management system relating to manufacture, such as quality control reports and test data, calibration data, and records on the qualifications of the personnel concerned.
3.3. Notified bodies shall periodically, at least once every 12 months, carry out appropriate audits and assessments to make sure that the manufacturer in question applies the approved quality management system and the post- market surveillance plan. Those audits and assessments shall include audits on the premises of the manufacturer and, if appropriate, of the manufacturer’s suppliers and/or subcontractors. At the time of such on-site audits, the notified body shall, where necessary, carry out or ask for tests in order to check that the quality management system is working properly. It shall provide the manufacturer with a surveillance audit report and, if a test has been carried out, with a test report.
3.4. The notified body shall randomly perform at least once every five years unannounced audits on the site of the manufacturer and, where appropriate, of the manufacturer’s suppliers and/or subcontractors, which may be combined with the periodic surveillance assessment referred to in Section 3.3. or be performed in addition to that surveillance assessment. The notified body shall establish a plan for such unannounced on-site audits but shall not disclose it to the manufacturer.
Within the context of such unannounced on-site audits, the notified body shall test an adequate sample of the devices produced or an adequate sample from the manufacturing process to verify that the manufactured device is in conformity with the technical documentation, with the exception of the devices referred to in the second subparagraph of Article 52(8). Prior to unannounced on-site audits, the notified body shall specify the relevant sampling criteria and testing procedure.
Instead of, or in addition to, sampling referred to in the second paragraph, the notified body shall take samples of devices from the market to verify that the manufactured device is in conformity with the technical documentation, with the exception of the devices referred to in the second subparagraph of Article 52(8). Prior to the sampling, the notified body in question shall specify the relevant sampling criteria and testing procedure.
The notified body shall provide the manufacturer in question with an on-site audit report which shall include, if applicable, the result of the sample test.
3.5. In the case of class IIa and class IIb devices, the surveillance assessment shall also include an assessment of the technical documentation as referred to in Sections 4.4 to 4.8 for the device or devices concerned on the basis of further representative samples chosen in accordance with the rationale documented by the notified body in accordance with the second paragraph of Section 2.3.
In the case of class III devices, the surveillance assessment shall also include a test of the approved parts and/or materials that are essential for the integrity of the device, including, where appropriate, a check that the quantities of produced or purchased parts and/or materials correspond to the quantities of finished devices.
3.6. The notified body shall ensure that the composition of the assessment team is such that there is sufficient experience with the evaluation of the devices, systems and processes concerned, continuous objectivity and neutrality; this shall include a rotation of the members of the assessment team at appropriate intervals. As a general rule, a lead auditor shall neither lead nor attend audits for more than three consecutive years in respect of the same manufacturer.
3.7. If the notified body finds a divergence between the sample taken from the devices produced or from the market and the specifications laid down in the technical documentation or the approved design, it shall suspend or withdraw the relevant certificate or impose restrictions on it.
CHAPTER II
Assessment of the technical documentation
4. Assessment of the technical documentation applicable to class III devices and to the class IIb devices referred to in the second subparagraph of Article 52(4)
4.1. In addition to the obligations laid down in Section 2, the manufacturer shall lodge with the notified body an application for assessment of the technical documentation relating to the device which it plans to place on the market or put into service and which is covered by the quality management system referred to in Section 2.
4.2. The application shall describe the design, manufacture and performance of the device in question. It shall include the technical documentation as referred to in Annexes II and III.
4.3. The notified body shall examine the application by using staff, employed by it, with proven knowledge and experience regarding the technology concerned and its clinical application. The notified body may require the application to be completed by having further tests carried out or requesting further evidence to be provided to allow assessment of conformity with the relevant requirements of the Regulation. The notified body shall carry out adequate physical or laboratory tests in relation to the device or request the manufacturer to carry out such tests.
4.4. The notified body shall review the clinical evidence presented by the manufacturer in the clinical evaluation report and the related clinical evaluation that was conducted. The notified body shall employ device reviewers with sufficient clinical expertise and, if necessary, use external clinical experts with direct and current experience relating to the device in question or the clinical condition in which it is utilised, for the purposes of that review.
4.5. The notified body shall, in circumstances in which the clinical evidence is based partly or totally on data from devices which are claimed to be equivalent to the device under assessment, assess the suitability of using such data, taking into account factors such as new indications and innovation. The notified body shall clearly document its conclusions on the claimed equivalence, and on the relevance and adequacy of the data for demonstrating conformity. For any characteristic of the device claimed as innovative by the manufacturer or for new indications, the notified body shall assess to what extent specific claims are supported by specific pre-clinical and clinical data and risk analysis.
4.6. The notified body shall verify that the clinical evidence and the clinical evaluation are adequate and shall verify the conclusions drawn by the manufacturer on the conformity with the relevant general safety and performance requirements. That verification shall include consideration of the adequacy of the benefit-risk determination, the risk management, the instructions for use, the user training and the manufacturer’s post-market surveillance plan, and include a review of the need for, and the adequacy of, the PMCF plan proposed, where applicable.
4.7. Based on its assessment of the clinical evidence, the notified body shall consider the clinical evaluation and the benefit-risk determination, and whether specific milestones need to be defined to allow the notified body to review updates to the clinical evidence that result from post-market surveillance and PMCF data.
4.8. The notified body shall clearly document the outcome of its assessment in the clinical evaluation assessment report.
4.9. The notified body shall provide the manufacturer with a report on the technical documentation assessment, including a clinical evaluation assessment report. If the device conforms to the relevant provisions of this Regulation, the notified body shall issue an EU technical documentation assessment certificate. The certificate shall contain the conclusions of the technical documentation assessment, the conditions of the certificate’s validity, the data needed for identification of the approved design, and, where appropriate, a description of the intended purpose of the device.
4.10. Changes to the approved device shall require approval from the notified body which issued the EU technical documentation assessment certificate where such changes could affect the safety and performance of the device or the conditions prescribed for use of the device. Where the manufacturer plans to introduce any of the above- mentioned changes it shall inform the notified body which issued the EU technical documentation assessment certificate thereof. The notified body shall assess the planned changes and decide whether the planned changes require a new conformity assessment in accordance with Article 52 or whether they could be addressed by means of a supplement to the EU technical documentation assessment certificate. In the latter case, the notified body shall assess the changes, notify the manufacturer of its decision and, where the changes are approved, provide it with a supplement to the EU technical documentation assessment certificate.
5. Specific additional procedures
5.1. Assessment procedure for certain class III and class IIb devices
(a)
For class III implantable devices, and for class IIb active devices intended to administer and/or remove a medicinal product as referred to in Section 6.4. of Annex VIII (Rule 12), the notified body shall, having verified the quality of clinical data supporting the clinical evaluation report of the manufacturer referred to in Article 61(12), prepare a clinical evaluation assessment report which sets out its conclusions concerning the clinical evidence provided by the manufacturer, in particular concerning the benefit-risk determination, the consistency of that evidence with the intended purpose, including the medical indication or indications and the PMCF plan referred to in Article 10(3) and Part B of Annex XIV.
The notified body shall transmit its clinical evaluation assessment report, along with the manufacturer’s clinical evaluation documentation, referred to in points (c) and (d) of Section 6.1 of Annex II, to the Commission.
The Commission shall immediately transmit those documents to the relevant expert panel referred to in Article 106.
(b)
The notified body may be requested to present its conclusions as referred to in point (a) to the expert panel concerned.
(c)
The expert panel shall decide, under the supervision of the Commission, on the basis of all of the following criteria: (i) the novelty of the device or of the related clinical procedure involved, and the possible major clinical or health impact thereof; (ii) a significantly adverse change in the benefit-risk profile of a specific category or group of devices due to scientifically valid health concerns in respect of components or source material or in respect of the impact on health in the case of failure of the device; (iii) a significantly increased rate of serious incidents reported in accordance with Article 87 in respect of a specific category or group of devices, whether to provide a scientific opinion on the clinical evaluation assessment report of the notified body based on the clinical evidence provided by the manufacturer, in particular concerning the benefit-risk determination, the consistency of that evidence with the medical indication or indications and the PMCF plan. That scientific opinion shall be provided within a period of 60 days, starting on the day of receipt of the documents from the Commission as referred to in point (a). The reasons for the decision to provide a scientific opinion on the basis of the criteria in points (i), (ii) and (iii) shall be included in the scientific opinion. Where the information submitted is not sufficient for the expert panel to reach a conclusion, this shall be stated in the scientific opinion.
(d)
The expert panel may decide, under the supervision of the Commission, on the basis of the criteria laid down in point (c) not to provide a scientific opinion, in which case it shall inform the notified body as soon as possible and in any event within 21 days of receipt of the documents as referred to in point (a) from the Commission. The expert panel shall within that time limit provide the notified body and the Commission with the reasons for its decision, whereupon the notified body may proceed with the certification procedure of that device.
(e)
The expert panel shall within 21 days of receipt of the documents from the Commission notify the Commission, through Eudamed whether it intends to provide a scientific opinion, pursuant to point (c), or whether it intends not to provide a scientific opinion, pursuant to point (d).
(f)
Where no opinion has been delivered within a period of 60 days, the notified body may proceed with the certification procedure of the device in question.
(g)
The notified body shall give due consideration to the views expressed in the scientific opinion of the expert panel. Where the expert panel finds that the level of clinical evidence is not sufficient or otherwise gives rise to serious concerns about the benefit-risk determination, the consistency of that evidence with the intended purpose, including the medical indication(s), and with the PMCF plan, the notified body shall, if necessary, advise the manufacturer to restrict the intended purpose of the device to certain groups of patients or certain medical indications and/or to impose a limit on the duration of validity of the certificate, to undertake specific PMCF studies, to adapt the instructions for use or the summary of safety and performance, or to impose other restrictions in its conformity assessment report, as appropriate. The notified body shall provide a full justification where it has not followed the advice of the expert panel in its conformity assessment report and the Commission shall without prejudice to Article 109 make both the scientific opinion of the expert panel and the written justification provided by the notified body publicly available via Eudamed.
(h)
The Commission, after consultation with the Member States and relevant scientific experts shall provide guidance for expert panels for consistent interpretation of the criteria in point (c) before 26 May 2020.
5.2. Procedure in the case of devices incorporating a medicinal substance
(a)
Where a device incorporates, as an integral part, a substance which, if used separately, may be considered to be a medicinal product within the meaning of point 2 of Article 1 of Directive 2001/83/EC, including a medicinal product derived from human blood or human plasma and that has an action ancillary to that of the device, the quality, safety and usefulness of the substance shall be verified by analogy with the methods specified in Annex I to Directive 2001/83/EC.
(b)
Before issuing an EU technical documentation assessment certificate, the notified body shall, having verified the usefulness of the substance as part of the device and taking account of the intended purpose of the device, seek a scientific opinion from one of the competent authorities designated by the Member States in accordance with Directive 2001/83/EC or from the EMA, either of which to be referred to in this Section as ‘the medicinal products authority consulted’ depending on which has been consulted under this point, on the quality and safety of the substance including the benefit or risk of the incorporation of the substance into the device. Where the device incorporates a human blood or plasma derivative or a substance that, if used separately, may be considered to be a medicinal product falling exclusively within the scope of the Annex to Regulation (EC) No 726/2004, the notified body shall seek the opinion of the EMA.
(c)
When issuing its opinion, the medicinal products authority consulted shall take into account the manufacturing process and the data relating to the usefulness of incorporation of the substance into the device as determined by the notified body.
(d)
The medicinal products authority consulted shall provide its opinion to the notified body within 210 days of receipt of all the necessary documentation.
(e)
The scientific opinion of the medicinal products authority consulted, and any possible update of that opinion, shall be included in the documentation of the notified body concerning the device. The notified body shall give due consideration to the views expressed in the scientific opinion when making its decision. The notified body shall not deliver the certificate if the scientific opinion is unfavourable and shall convey its final decision to the medicinal products authority consulted.
(f)
Before any change is made with respect to an ancillary substance incorporated in a device, in particular related to its manufacturing process, the manufacturer shall inform the notified body of the changes. That notified body shall seek the opinion of the medicinal products authority consulted, in order to confirm that the quality and safety of the ancillary substance remain unchanged. The medicinal products authority consulted shall take into account the data relating to the usefulness of incorporation of the substance into the device as determined by the notified body, in order to ensure that the changes have no negative impact on the risk or benefit previously established concerning the incorporation of the substance into the device. The medicinal products authority consulted shall provide its opinion within 60 days after receipt of all the necessary documentation regarding the changes. The notified body shall not deliver the supplement to the EU technical documentation assessment certificate if the scientific opinion provided by the medicinal products authority consulted is unfavourable. The notified body shall convey its final decision to the medicinal products authority consulted.
(g)
Where the medicinal products authority consulted obtains information on the ancillary substance, which could have an impact on the risk or benefit previously established concerning the incorporation of the substance into the device, it shall advise the notified body as to whether this information has an impact on the risk or benefit previously established concerning the incorporation of the substance into the device. The notified body shall take that advice into account in reconsidering its assessment of the conformity assessment procedure.
5.3. Procedure in the case of devices manufactured utilising, or incorporating, tissues or cells of human or animal origin, or their derivatives, that are non-viable or rendered non-viable
5.3.1. Tissues or cells of human origin or their derivatives
(a)
For devices manufactured utilising derivatives of tissues or cells of human origin that are covered by this Regulation in accordance with point (g) of Article 1(6) and for devices that incorporate, as an integral part, tissues or cells of human origin, or their derivatives, covered by Directive 2004/23/EC, that have an action ancillary to that of the device, the notified body shall, prior to issuing an EU technical documentation assessment certificate, seek a scientific opinion from one of the competent authorities designated by the Member States in accordance with Directive 2004/23/EC (‘human tissues and cells competent authority’) on the aspects relating to the donation, procurement and testing of tissues or cells of human origin or their derivatives. The notified body shall submit a summary of the preliminary conformity assessment which provides, among other things, information about the non-viability of the human tissues or cells in question, their donation, procurement and testing and the risk or benefit of the incorporation of the tissues or cells of human origin or their derivatives into the device.
(b)
Within 120 days of receipt of all the necessary documentation, the human tissues and cells competent authority shall provide to the notified body its opinion.
(c)
The scientific opinion of the human tissues and cells competent authority, and any possible update, shall be included in the documentation of the notified body concerning the device. The notified body shall give due consideration to the views expressed in the scientific opinion of the human tissues and cells competent authority when making its decision. The notified body shall not deliver the certificate if that scientific opinion is unfavourable. It shall convey its final decision to the human tissues and cells competent authority concerned.
(d)
Before any change is made with respect to non-viable tissues or cells of human origin or their derivatives incorporated in a device, in particular relating to their donation, testing or procurement, the manufacturer shall inform the notified body of the intended changes. The notified body shall consult the authority that was involved in the initial consultation, in order to confirm that the quality and safety of the tissues or cells of human origin or their derivatives incorporated in the device are maintained. The human tissues and cells competent authority concerned shall take into account the data relating to the usefulness of incorporation of the tissues or cells of human origin or their derivatives into the device as determined by the notified body, in order to ensure that the changes have no negative impact on the established benefit-risk ratio of the addition of the tissues or cells of human origin or their derivatives in the device. It shall provide its opinion within 60 days of receipt of all the necessary documentation regarding the intended changes. The notified body shall not deliver a supplement to the EU technical documentation assessment certificate if the scientific opinion is unfavourable and shall convey its final decision to the human tissues and cells competent authority concerned.
5.3.2. Tissues or cells of animal origin or their derivatives
In the case of devices manufactured utilising animal tissue which is rendered non-viable or utilising non-viable products derived from animal tissue, as referred to in Regulation (EU) No 722/2012, the notified body shall apply the relevant requirements laid down in that Regulation.
5.4. Procedure in the case of devices that are composed of substances or of combinations of substances that are absorbed by or locally dispersed in the human body
(a)
The quality and safety of devices that are composed of substances or of combinations of substances that are intended to be introduced into the human body via a body orifice or applied to the skin and that are absorbed by, or locally dispersed in, the human body, shall be verified where applicable and only in respect of the requirements not covered by this Regulation, in accordance with the relevant requirements laid down in Annex I to Directive 2001/83/EC for the evaluation of absorption, distribution, metabolism, excretion, local tolerance, toxicity, interaction with other devices, medicinal products or other substances and potential for adverse reactions.
(b)
In addition, for devices, or their products of metabolism, that are systemically absorbed by the human body in order to achieve their intended purpose, the notified body shall seek a scientific opinion from one of the competent authorities designated by the Member States in accordance with Directive 2001/83/EC or from the EMA, either of which to be referred to in this Section as ‘the medicinal products authority consulted’ depending on which has been consulted under this point, on the compliance of the device with the relevant requirements laid down in Annex I to Directive 2001/83/EC.
(c)
The opinion of the medicinal products authority consulted shall be drawn up within 150 days of receipt of all the necessary documentation.
(d)
The scientific opinion of the medicinal products authority consulted, and any possible update, shall be included in the documentation of the notified body concerning the device. The notified body shall give due consideration to the views expressed in the scientific opinion when making its decision and shall convey its final decision to the medicinal products authority consulted.
6. Batch verification in the case of devices incorporating, as an integral part, a medicinal substance which, if used separately, would be considered to be a medicinal product derived from human blood or human plasma as referred to in Article 1(8)
Upon completing the manufacture of each batch of devices that incorporate, as an integral part, a medicinal substance which, if used separately, would be considered to be a medicinal product derived from human blood or human plasma as referred to in the first subparagraph of Article 1(8), the manufacturer shall inform the notified body of the release of the batch of devices and send it the official certificate concerning the release of the batch of human blood or plasma derivative used in the device, issued by a Member State laboratory or a laboratory designated for that purpose by a Member State in accordance with Article 114(2) of Directive 2001/83/EC.
CHAPTER III
Administrative provisions
7. The manufacturer or, where the manufacturer does not have a registered place of business in a Member State, its authorised representative shall, for a period ending no sooner than 10 years, and in the case of implantable devices no sooner than 15 years, after the last device has been placed on the market, keep at the disposal of the competent authorities:
—
the EU declaration of conformity,
—
the documentation referred to in the fifth indent of Section 2.1 and in particular the data and records arising from the procedures referred to in point (c) of the second paragraph of Section 2.2,
—
information on the changes referred to in Section 2.4,
—
the documentation referred to in Section 4.2, and
—
the decisions and reports from the notified body as referred to in this Annex.
8. Each Member State shall require that the documentation referred to in Section 7 is kept at the disposal of competent authorities for the period indicated in that Section in case a manufacturer, or its authorised representative, established within its territory goes bankrupt or ceases its business activity prior to the end of that period.
By 27 May 2026, the Commission shall submit to the European Parliament and to the Council a report on experience gained from the application of Article 78 and, if necessary, propose a review of Article 78(14) and point (h) of Article 123(3).
Coordinated assessment procedure for clinical investigations
1. By means of the electronic system referred to in Article 73, the sponsor of a clinical investigation to be conducted in more than one Member State may submit, for the purpose of Article 70, a single application that, upon receipt, is transmitted electronically to all Member States in which the clinical investigation is to be conducted.
2. The sponsor shall propose in the single application referred to in paragraph 1 that one of the Member States in which the clinical investigation is to be conducted acts as coordinating Member State. The Member States in which the clinical investigation is to be conducted shall, within six days of submission of the application, agree on one of them taking the role of the coordinating Member State. If they do not agree on a coordinating Member State, the coordinating Member State proposed by the sponsor shall assume that role.
3. Under the direction of the coordinating Member State referred to in paragraph 2, the Member States concerned shall coordinate their assessment of the application, in particular of the documentation referred to in Chapter II of Annex XV.
However, the completeness of the documentation referred to in Sections 1.13, 3.1.3, 4.2, 4.3 and 4.4 of Chapter II of Annex XV shall be assessed separately by each Member State concerned in accordance with Article 70(1) to (5).
4. With regard to documentation other than that referred to in the second subparagraph of paragraph 3, the coordinating Member State shall:
(a)
within six days of receipt of the single application, notify the sponsor that it is the coordinating Member State (‘notification date’);
(b)
for the purpose of the validation of the application, take into account any considerations submitted within seven days of the notification date by any Member State concerned;
(c)
within 10 days of the notification date, assess whether the clinical investigation falls within the scope of this Regulation and whether the application is complete, and shall notify the sponsor accordingly.Article 70(1) and (3) to (5) shall apply to the coordinating Member State in relation to that assessment;
(d)
establish the results of its assessment in a draft assessment report to be transmitted within 26 days of the validation date to the Member States concerned. By day 38 after the validation date, the other Member States concerned shall transmit their comments and proposals on the draft assessment report and the underlying application to the coordinating Member State which shall take due account of those comments and proposals in its finalisation of the final assessment report, to be transmitted within 45 days of the validation date to the sponsor and the other Member States concerned.
The final assessment report shall be taken into account by all Member States concerned when deciding on the sponsor’s application in accordance with Article 70(7).
5. As regards the assessment of the documentation referred to in the second subparagraph of paragraph 3, each Member State concerned may request, on a single occasion, additional information from the sponsor. The sponsor shall submit the requested additional information within the period set by the Member State concerned, which shall not exceed 12 days from the receipt of the request. The expiry of the last deadline pursuant to point (d) of paragraph 4 shall be suspended from the date of the request until such time as the additional information has been received.
6. For class IIb and class III devices, the coordinating Member State may also extend the periods referred to in paragraph 4 by a further 50 days, for the purpose of consulting with experts.
7. The Commission may, by means of implementing acts, further specify the procedures and timescales for coordinated assessments to be taken into account by Member States concerned when deciding on the sponsor’s application. Such implementing acts may also set out the procedures and timescales for coordinated assessment in the case of substantial modifications pursuant to paragraph 12 of this Article, in the case of reporting of adverse events pursuant to Article 80(4) and in the case of clinical investigations of combination products between medical devices and medicinal products, where the latter are under a concurrent coordinated assessment of a clinical trial under Regulation (EU) No 536/2014. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3).
8. Where the conclusion of the coordinating Member State concerning the area of coordinated assessment is that the conduct of the clinical investigation is acceptable or acceptable subject to compliance with specific conditions, that conclusion shall be deemed to be the conclusion of all Member States concerned.
Notwithstanding the first subparagraph, a Member State concerned may only disagree with the conclusion of the coordinating Member State concerning the area of coordinated assessment on the following grounds:
(a)
when it considers that participation in the clinical investigation would lead to a subject receiving treatment inferior to that received in normal clinical practice in that Member State concerned;
(b)
infringement of national law; or
(c)
considerations as regards subject safety and data reliability and robustness submitted under point (b) of paragraph 4.
Where one of the Member States concerned disagrees with the conclusion on the basis of the second subparagraph of this paragraph, it shall communicate its disagreement, together with a detailed justification, through the electronic system referred to in Article 73, to the Commission, to all other Member States concerned and to the sponsor.
9. Where the conclusion of the coordinating Member State concerning the area of coordinated assessment is that the clinical investigation is not acceptable, that conclusion shall be deemed to be the conclusion of all Member States concerned.
10. A Member State concerned shall refuse to authorise a clinical investigation if it disagrees with the conclusion of the coordinating Member State as regards any of the grounds referred to in the second subparagraph of paragraph 8, or if it finds, on duly justified grounds, that the aspects addressed in Sections 1.13, 3.1.3, 4.2, 4.3 and 4.4 of Chapter II of Annex XV are not complied with, or where an ethics committee has issued a negative opinion in relation to that clinical investigation, which is valid, in accordance with national law, for that entire Member State. That Member State shall provide for an appeal procedure in respect of such refusal.
11. Each Member State concerned shall notify the sponsor through the electronic system referred to in Article 73 as to whether the clinical investigation is authorised, whether it is authorised subject to conditions, or whether authorisation has been refused. Notification shall be done by way of one single decision within five days of the transmission, pursuant to point (d) of paragraph 4, by the coordinating Member State of the final assessment report. Where an authorisation of a clinical investigation is subject to conditions, those conditions may only be such that, by their nature, they cannot be fulfilled at the time of that authorisation.
12. Any substantial modifications as referred to in Article 75 shall be notified to the Member States concerned by means of the electronic system referred to in Article 73. Any assessment as to whether there are grounds for disagreement as referred to in the second subparagraph of paragraph 8 of this Article shall be carried out under the direction of the coordinating Member State, except for substantial modifications concerning Sections 1.13, 3.1.3, 4.2, 4.3 and 4.4 of Chapter II of Annex XV, which shall be assessed separately by each Member State concerned.
13. The Commission shall provide administrative support to the coordinating Member State in the accomplishment of its tasks under this Chapter.
14. The procedure set out in this Article shall, until 27 May 2027, be applied only by those of the Member States in which the clinical investigation is to be conducted which have agreed to apply it. After 27 May 2027, all Member States shall be required to apply that procedure.
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.
Mechanism for scrutiny of conformity assessments of certain class III and class IIb devices
1. A notified body shall notify the competent authorities of certificates it has granted to devices for which the conformity assessment has been performed pursuant to Article 54(1). Such notification shall take place through the electronic system referred to in Article 57 and shall include the summary of safety and clinical performance pursuant to Article 32, the assessment report by the notified body, the instructions for use referred to in Section 23.4 of Annex I, and, where applicable, the scientific opinion of the expert panels referred to in Section 5.1 of Annex IX or Section 6 of Annex X, as applicable. In the case of divergent views between the notified body and the expert panels, a full justification shall also be included.
2. A competent authority and, where applicable, the Commission may, based on reasonable concerns apply further procedures in accordance with Article 44, 45, 46, 47 or 94 and, where deemed necessary, take appropriate measures in accordance with Articles 95 and 97.
3. The MDCG and, where applicable, the Commission, may, based on reasonable concerns, request scientific advice from the expert panels in relation to the safety and performance of any device.
1. The authority responsible for notified bodies shall within 30 days check that the application referred to in Article 38 is complete and shall request the applicant to provide any missing information. Once the application is complete that authority shall send it to the Commission.
The authority responsible for notified bodies shall review the application and supporting documentation in accordance with its own procedures and shall draw up a preliminary assessment report.
2. The authority responsible for notified bodies shall submit the preliminary assessment report to the Commission which shall immediately transmit it to the MDCG.
3. Within 14 days of the submission referred to in paragraph 2 of this Article, the Commission, in conjunction with the MDCG, shall appoint a joint assessment team made up of three experts, unless the specific circumstances require a different number of experts, chosen from the list referred to in Article 40(2). One of the experts shall be a representative of the Commission who shall coordinate the activities of the joint assessment team. The other two experts shall come from Member States other than the one in which the applicant conformity assessment body is established.
The joint assessment team shall be comprised of experts who are competent to assess the conformity assessment activities and the types of devices which are the subject of the application or, in particular when the assessment procedure is initiated in accordance with Article 47(3), to ensure that the specific concern can be appropriately assessed.
4. Within 90 days of its appointment, the joint assessment team shall review the documentation submitted with the application in accordance with Article 38. The joint assessment team may provide feedback to, or require clarification from, the authority responsible for notified bodies on the application and on the planned on-site assessment.
The authority responsible for notified bodies together with the joint assessment team shall plan and conduct an on-site assessment of the applicant conformity assessment body and, where relevant, of any subsidiary or subcontractor, located inside or outside the Union, to be involved in the conformity assessment process.
The on-site assessment of the applicant body shall be led by the authority responsible for notified bodies.
5. Findings regarding non-compliance of an applicant conformity assessment body with the requirements set out in Annex VII shall be raised during the assessment process and discussed between the authority responsible for notified bodies and the joint assessment team with a view to reaching consensus and resolving any diverging opinions, with respect to the assessment of the application.
At the end of the on-site assessment, the authority responsible for notified bodies shall list for the applicant conformity assessment body the non-compliances resulting from the assessment and summarise the assessment by the joint assessment team.
Within a specified timeframe, the applicant conformity assessment body shall submit to the national authority a corrective and preventive action plan to address the non-compliances.
6. The joint assessment team shall document any remaining diverging opinions with respect to the assessment within 30 days of completion of the on-site assessment and send them to the authority responsible for notified bodies.
7. The authority responsible for notified bodies shall following receipt of a corrective and preventive action plan from the applicant body assess whether non-compliances identified during the assessment have been appropriately addressed. This plan shall indicate the root cause of the identified non-compliances and shall include a timeframe for implementation of the actions therein.
The authority responsible for notified bodies shall having confirmed the corrective and preventive action plan forward it and its opinion thereon to the joint assessment team. The joint assessment team may request of the authority responsible for notified bodies further clarification and modifications.
The authority responsible for notified bodies shall draw up its final assessment report which shall include:
—
the result of the assessment,
—
confirmation that the corrective and preventive actions have been appropriately addressed and, where required, implemented,
—
any remaining diverging opinion with the joint assessment team, and, where applicable,
—
the recommended scope of designation.
8. The authority responsible for notified bodies shall submit its final assessment report and, if applicable, the draft designation to the Commission, the MDCG and the joint assessment team.
9. The joint assessment team shall provide a final opinion regarding the assessment report prepared by the authority responsible for notified bodies and, if applicable, the draft designation within 21 days of receipt of those documents to the Commission, which shall immediately submit that final opinion to the MDCG. Within 42 days of receipt of the opinion of the joint assessment team, the MDCG shall issue a recommendation with regard to the draft designation, which the authority responsible for notified bodies shall duly take into consideration for its decision on the designation of the notified body.
10. The Commission may, by means of implementing acts, adopt measures setting out the detailed arrangements specifying procedures and reports for the application for designation referred to in Article 38 and the assessment of the application set out in this Article. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3).
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