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A12. Activities of notified bodies

A12.1. Notified body assessment of clinical evaluation by conformity assessment route

The notified body assessment of clinical Evaluation reports and the supporting data presented by manufacturers is required for all medical devices. The timing and frequency of the notified body reviews will vary according to the risk carried by the device, how well established the device is (see Section 6.2.3) and the conformity assessment procedure that is applied.

This includes for medical devices in accordance with Directive 93/42/EEC:

• An audit as part of a quality system approval procedure (Annex II, section 3):
  • the notified body assesses the manufacturer’s procedure for clinical evaluation, PMS plan and PMCF plan and (if applicable) results of PMCF.
  • as part of the representative sampling of devices21; for review of their technical documentation the notified body assesses the clinical evaluation report presented for class IIa22 and IIb devices as presented below for a design dossier.

• A design dossier (Annex II, section 4) or type examination dossier (Annex III) assessment:
• the notified body assesses the data presented in the clinical evaluation report,
• assesses the validity of the conclusions drawn by the manufacturer, and
• the conformity of the device to relevant essential requirements.

For active implantable medical devices in accordance with Directive 90/385/EEC:

• A design dossier (Annex 2, section 4) or type examination dossier (Annex 3) assessment:
  • the notified body assesses the data presented in the clinical evaluation report,
  • assesses the validity of the clinical evaluation report and the conclusions drawn by the manufacturer, and
  • the conformity of the device to relevant essential requirements.

The notified body should also have documented procedures to address the review of updates to clinical evaluation reports during their scheduled surveillance activities and at the time of changes to or extensions of EC design-examination/EC type-examination certificates. The review should take into account aspects described in Section 6.2.3. This arises from the obligation placed on the manufacturer to actively update the clinical evaluation with data obtained from PMS e.g. PMCF and ongoing literature reviews/surveys.

In addition, notified bodies should refer to guidance, checklists and other documents available on the assessment of clinical evaluations by notified bodies from the Notified Body Operations Group (NBOG). These should be considered in addition to this guidance. Any such checklists are intended only as an aide memoire for assessment and should not replace the Clinical Evaluation Assessment Report (CEAR) outlined below.

A12.2. Examination of a design dossier (Annex II.4; Annex 2.4) or of a type examination dossier (Annex III; Annex 3)

The notified body examines the clinical evaluation documentation submitted (relevant documentation referenced in previous sections of this MEDDEV), assesses the manufacturer’s identification, appraisal and analysis of that data, and validates the conclusions drawn by the manufacturer. In order to do so, the notified body should possess enough knowledge and experience in clinical evaluation as stated in previous sections of this document.

A12.2.1. Decision-making by the notified body

In reviewing the evaluation of clinical data submitted by the manufacturer, the notified body verifies and concludes whether or not the manufacturer has adequately:

• supplied clinical evaluation documentation (as referenced in previous sections);
• followed relevant procedures (as addressed by previous sections);
• described and verified the intended characteristics and performances related to clinical aspects;
• performed an appropriate risk analysis and estimated the undesirable side-effects which are aligned with the clinical evaluation;
• involved appropriate clinical expertise in the clinical evaluation and in the compilation of the risk analysis to ensure risks and benefits associated with real clinical use are adequately defined;
• provided a solid justification as the basis for their estimations of benefits, risks, undesirable side-effects, indications and contraindications of the device in question;
• justified the chosen route(s) of clinical data retrieval (according to previous sections);
• identified, appraised, analysed and assessed the clinical data (according to previous sections) and demonstrated the relevance and any limitations of the clinical data identified in demonstrating compliance with particular requirements of the Directive or cited in particular aspects of the risk analysis;
• identified all clinical data, favourable and unfavourable, that is relevant to the device and using an appropriately robust, reproducible and systematic search strategy;
• provided sufficient clinical evidence relating to the safety, including benefits to the patients, the clinical performance intended by the manufacturer (including any clinical claims for the device the manufacturer intends to use), design characteristics and intended purpose of the device, in order to demonstrate conformity with each of the relevant essential requirements;
• conducted and provided a critical evaluation of relevant scientific literature and data relating to the safety, benefits, performance, design characteristics and intended purpose of the device;
• demonstrated the equivalence of the device under evaluation to the device to which the data relates in all necessary areas, i.e. clinical, technical, biological and that the data available adequately addresses conformity to each of the relevant essential requirements (if a critical evaluation of relevant scientific literature is provided as the only source of clinical data);
• designed appropriate clinical investigations, when necessary, to address specific questions arising from the critical review of the scientific literature and address each of the relevant essential requirements;
• provided specific justification if a specific clinical investigation was not performed for class III or implantable devices;
• provided evidence that clinical investigations presented are in compliance with applicable regulatory and ethical requirements e.g. scientific validity, ethics committee approval, competent authority approval;
• provided detail of the PMS plan in place for the particular device and justified the appropriateness and adequacy of this plan;
• clearly identified which areas in the clinical evaluation and related data need to be further addressed and confirmed in the post-market phase, with specific alignment to the PMCF;
• justified the appropriateness of the planned PMCF;
• justified and documented if PMCF is not planned as part of the PMS plan for the device;
• identified the sources of clinical data which will be gathered from the manufacturer’s PMS system and PMCF;
• concluded that the contents of the IFU are supported by clinical evidence (description of the intended purpose, handling instructions, type and frequency of risks, warnings, precautions, contraindications, others) and are in line with the risk analysis and clinical evaluation;
• concluded on the basis of documented evidence:
  • that the risks are acceptable when weighed against the intended benefits and are compatible with a high level of protection of health and safety,
  • that the intended clinical performances described by the manufacturer are achieved by the device, and
  • that any undesirable side-effect constitutes an acceptable risk when weighed against the performances intended.

The assessment carried out by the notified body will in addition typically confirm the following aspects of the manufacturer’s clinical evaluation:

• appraisal to determine suitability and any limitations of the data presented to address the essential requirements in particular relating to the safety, and performance of the device as outlined in previous sections;
• the validity of any justification given;
• characterisation and evidence-based proof of the clinical performance of the device intended by the manufacturer and the expected benefits for the defined patient group(s);
• the application of all relevant harmonised standards or appropriate justifications if not;
• identified hazards to be addressed through analysis of clinical data as described in Section 10;
• the adequate estimation of the associated risks for each identified hazard by:
  • characterising the severity of the hazard;
  • estimating and characterising the probability of occurrence of harm, impairment of health or loss of benefit of the treatment (documented and discussed based on scientifically valid clinical data);
  • the adequate description and estimation of the current state of the art in the corresponding medical field;
• a justifiable and reasoned basis for estimation of risks and hazards.

Where a device incorporates, as an integral part, a substance which, if used separately, may be considered to be a medicinal product, the notified body is responsible for verifying the usefulness of the medicinal substance as part of the device prior to the submission of an application for scientific opinion from a medicines authority.

For drug-device combination products and products incorporating stable human blood derivatives, where a scientific opinion from a medicinal competent authority or from the European Medicines Agency (EMA) has been sought, the notified body should consider any comments or considerations raised in the medicinal clinical assessment when making its final decision on the device. In the case of devices with a human blood derivative the notified body may not deliver a positive decision to issue a certificate if the EMA’s scientific opinion is unfavourable.

A12.2.2. The report of the notified body

The notified body should write a Clinical Evaluation Assessment Report (CEAR) based on its assessment of the submitted clinical evaluation report and supporting documentation.

If a design dossier report is applicable to the device, the CEAR may be incorporated into this report or referenced from it. The report should clearly identify the notified body’s assessment, verification on each of the critical elements and overall conclusions.

The CEAR at a minimum should address the notified body’s assessment of manufacturer’s application relating to the following:

• device description and product specification
• intended purpose of the device
• classification proposed for the device
• pre-clinical evaluation data presented by the manufacturer
• risk analysis and risk management and alignment with the clinical evaluation report
• clinical evaluation process
• clinical evaluation report authors
• equivalence assessment – if data from equivalent is used
• clinical investigation plans and reports
• justification if no clinical investigation has been performed
• instructions for use, labelling and, when necessary, the training plan for users
• justification if no PMCF is planned
• PMS
• PMCF
• planned frequency/ criteria for updates to the clinical evaluation
• summary of review
• conclusion on clinical benefit/risk profile
• conformance of the device to the relevant Essential Requirements

The CEAR should also provide details relating to the submission and notified body review (including staff and experts involved in the review and the aspects assessed by each, signatures of responsible reviewers, etc.)

The notified body should justify and document each step of the decision making process referred in section A12.2.1 above.

The CEAR at a minimum should include a summary of the information provided by the manufacturer relating to the following:

• Record whether the clinical evaluation documentation is complete in accordance with this document and adequate to demonstrate conformance to the Essential Requirements of the relevant Directive.
• Record the notified body’s verification of each step of the clinical evaluation process, from the planning of the clinical evaluation, choice of route(s), identification, appraisal, analysis and overall assessment of the clinical data, to concluding and reporting
• Record the notified body’s assessment of the clinical investigation data and/or literature review assembled, relevant procedures and compliance to relevant standards
• Verify that the device has met the claimed performance/ intended purpose and benefits, and that undesirable side-effects and risks have been properly evaluated
• Record the notified body’s assessment of the clinical safety, clinical performance and benefit/risk profile
• Record the notified body’s assessment of the overall conclusions drawn by the manufacturer from the clinical data presented
• Record the notified body’s assessment of the validity of the clinical evaluation and its steps
• Record the notified body’s conclusions on the clinical evaluation, documenting each step in the decision making process as per Section A12.2.1.

A12.2.3. Clinical data from an equivalent device and other products

1. Equivalent devices
   The notified body should clearly document its assessment of clinical data presented from an equivalent device as part of a clinical evaluation. This should critically review and conclude on the equivalence or not of the device under assessment to the devices presented as equivalent in terms of their technical, biological and clinical characteristics. The relevance of each dataset from an equivalent device should be clearly evident and assessed by the notified body.
   The notified body should also assess and document the level of access to the technical and clinical data from an Equivalent device that the manufacturer has. Relevant information may be commercially sensitive/ confidential and not available to the manufacturer. The notified body should challenge the ability of the manufacturer to access information that are relevant to the demonstration of equivalence. Demonstration of equivalence might be difficult or impossible in case of limited access to the technical documentation of the devices.
2. Other products
   For hazard identification and when assessing the benefit/risk profile of the device, the notified body should consider current knowledge/ the state of the art.
   The notified body should assess the appropriateness of the use of data from benchmark devices, other devices, and medical alternatives.

A12.3. Evaluation as part of quality system related procedures23

A12.3.1. Review of the manufacturer’s procedures

The notified body shall, as part of the review of the manufacturer’s quality system, assess the establishment, maintenance and application of the manufacturer’s documented procedures for the evaluation of clinical data. This should cover:

1. the proper assignment of responsibilities to suitably qualified persons involved in the clinical evaluation (e.g. clinical evaluator(s), information retrieval expert(s), expert(s) in clinical research);
2. the integration of clinical evaluation into the quality system as a continuous process, to be specifically inter-related to, and informed by, pre clinical evaluation and risk management;
3. standard operating procedures to assure proper planning, conduct, evaluation, control and documentation planning of the clinical evaluation, identification of clinical data (previous section), literature searching (previous section), collection of clinical experience (previous section), clinical investigation (previous section and EN ISO 14155), appraisal of clinical data (previous section), analysis of clinical data (previous section), concluding, reporting (previous section) and update of clinical evaluation, procedures, reporting and updating based on data from the PMS system and from PMCF (MEDDEV 2.12/2 rev.2);
4. document control as part of overall documentation of procedures, reporting, qualifications and technical documentation/design dossier(s);
5. identification and evaluation of undesirable side-effects and of clinical performance(s). This involves identification of known or reasonably foreseeable hazards and verification of unfavourable and favourable outcome(s), qualification of their severity/magnitude and of their probability of occurrence. (It is part of the manufacturer’s documented risk analysis based on both favourable and unfavourable data identified as relevant in order to give a balanced view).

A12.3.2. Review of the technical documentation of representative samples

The notified body is required to assess the technical documentation for class IIa and class IIb devices on a representative basis. The clinical evaluation report should be assessed by the notified body for at least one representative sample for each device subcategory for class IIa devices and at least one representative sample for each generic device group for class IIb devices. Further representative samples have to be assessed as part of the annual surveillance assessment cycle.

Regarding the choice of representative sample(s) the notified body will consider the novelty of the technology, similarities in design, technology, manufacturing and sterilisation methods, the intended purpose, and the results of previous relevant assessments. Assessment of representative samples includes assessment of the clinical evaluation report and available clinical data in accordance with the review procedure in this document rather than solely confirming that the manufacturer has a clinical evaluation procedure in place or that the clinical evaluation report is available.

The criteria for the technical documentation assessment on a representative basis outlined in

NBOG BPG 2009-4 should be applied.

When performing the assessment on samples of a manufacturer’s clinical evaluation, the notified body will follow the steps indicated in previous sections of this document.

A clinical evaluation assessment report should be completed and available for each device sampled and assessed.

A12.4. Notified body specific procedures and expertise

A notified body should have formal procedures in place controlled by their quality system relating to the assessment of clinical evaluation reports and associated data provided by medical device manufacturers. These procedures should also cover the review of updates to the clinical evaluation report during their scheduled surveillance activities and at the time of changes to or extensions of EC design-examination/EC type-examination certificates.

Notified bodies should establish and implement internal policies and procedures for the assessment of clinical evaluation reports and associated data in order to:

1. Ensure that suitable resources, especially clinical competence necessary for such assessment, are available within24 the notified body to conduct and manage assessments of clinical evaluations for the notified body, normally a qualified medical doctor.
   Such expertise should be sufficient to conduct a complete review of the clinical data and clinical evaluation presented for a particular device, to identify and estimate the risks and benefits associated with the use of the medical devices and to identify what, if any, specific clinical expertise is required for the full assessment of the device.
   The assessment team should be able to assess a risk analysis, the risk management strategy performed by the manufacturer, and the scientific validity of clinical investigations and publications.
   The assessment team should have sufficient expertise in the device technology as the associated medical procedures.
   Such an assessment requires input from a qualified medical practitioner (for example physician, dentist, nurse, etc.), as appropriate for the particular device, who has clinical experience in using the device or similar devices, the pathology of the condition being treated, the usual treatment, other medical alternatives, etc.
   The notified body clinical assessor may work with external clinical experts. The notified body clinical assessor should ensure that any experts are appropriately aware of the relevant legislation, guidance and standards and to identify specific aspects of the clinical data evaluation for their specific review.
   Notified bodies should have robust procedures around the recruitment, selection, training, conflict of interest and interaction with external clinical experts including clear procedures around how the expert opinion is documented and integrated with the notified body assessment and considered as part of the overall certificate decision.
   When examining the results of clinical investigations, the assessment team shall have knowledge in planning, conduct and interpretation of clinical investigations. All assessors should be appropriately trained and qualified.
   Particular attention should be drawn to training of external experts on the conformity assessment procedure(s), relevant guidance, standards and the context of the assessment they are providing. The notified body should be responsible for reviewing the opinion of these experts, taking account of their level of knowledge of the provisions of the Directives.
   The opinion of an external clinical expert may form part of the assessment conducted by the notified body. The opinion and conclusions of the notified body, in part based on this external opinion, should be clearly documented.
   The impartiality and the potential for conflict of interest of an external expert reviewer should be assessed and documented by the notified body.
2. Review the clinical evaluation report and clinical data provided by the manufacturer. The notified body should verify the validity of key statements made in the clinical evaluation report. The notified body should consider
   • statements based on published literature using the full text version of publications;
   • statements based on clinical data generated from PMS systems in particular PMCF and source verification of such data;
   • tatements regarding equivalence to other devices using the original full text version of pre-market study reports assessing parameters of interest.
   • statements regarding results of own clinical investigations of the manufacturer using the original full text version of the clinical investigation plan and the clinical investigation report.

   The review of the notified body should consider the scientific validity of the clinical data set presented as part of the clinical evaluation and decide as to whether it provides evidence that the clinical benefit outweighs all associated risks.
   The data presented by the manufacturer should be scientifically robust and well presented, it should be complete and clear in its reasoning and should be of sufficient quality and validity to demonstrate the conclusions which are being drawn.
   All clinical data relevant to the device in question, both favourable and unfavourable, should be considered, appraised and assessed by the manufacturer and likewise by the notified body. An absence of unfavourable data relating to a medical device should be carefully examined.
   Clinical evaluation reports which are based on incomplete, unclear or uncertain datasets should not be accepted.
   Clinical Evaluation reports which are based on incomplete clinical investigations or clinical investigations which were halted or terminated earlier than their intended duration should be carefully examined and a robust justification for halting or termination should be sought. The original endpoints, objectives and statistical basis for the manufacturer’s clinical investigation are unlikely to remain valid in circumstances when an investigation is completed prior to its original planned duration and so it is unlikely that scientific conclusions can be drawn.

3. Document the opinion with rationale of all experts involved.
4. Document the result of their assessment. This is achieved through a specific clinical evaluation assessment report which may be part of, or may be referenced, in the overall audit report, design / type examination report (as per A12.2.2 of this document) or the report on the assessment of representative samples’ documentation.
5. Preserve confidentiality of the information and data received from the manufacturer, especially within the terms for contracting external experts.
6. Clearly identify how data from PMS conducted by manufacturers, vigilance and market surveillance information from competent authorities, PMCF data, and data from other relevant sources (e.g. clinical literature) is identified and reviewed by the notified body. This should clearly describe how, when and what criteria are used by the notified body to judge when a re- assessment of the benefit/risk profile of a particular device is deemed necessary.