Inhaltsübersicht

Inhaltsübersicht

1. Introduction
2. Scope
3. References
4. Definitions
5. Abbreviations
6. General principles of clinical evaluation
6.1 What is clinical evaluation?
6.2. When is clinical evaluation undertaken and why is it important?
6.3 How is a clinical evaluation performed?
6.4 Who should perform the clinical evaluation?
7. Definition of the scope of the clinical evaluation (Stage 0)
8. Identification of pertinent data (Stage 1)
8.1 Data generated and held by the manufacturer
8.2 Data retrieved from literature
9. Appraisal of pertinent data (Stage 2)
9.1 General considerations
9.2 The appraisal plan
9.3 Conduct of the appraisal
10. Analysis of the clinical data (Stage 3)
10.1 General considerations
10.2 Specific considerations
10.3 Where demonstration of conformity based on clinical data is not deemed appropriate
11. The clinical evaluation report (CER, Stage 4)
12. The role of the notified body in the assessment of clinical evaluation reports

Anhänge

A1 Demonstration of equivalence
A2 When should additional clinical investigations be carried out?
A3 Device description – typical contents
A4 Sources of literature
A5 Literature search and literature review protocol, key elements
A5.1 Background to the literature search and the literature review
A5.2 Objective
A5.3 Methods
A6 Appraisal of clinical data – examples of studies that lack scientific validity for demonstration of adequate clinical performance and/or clinical safety
A7 Analysis of the clinical data – compliance to specific Essential Requirements
A7.1 Conformity assessment with requirement on safety (MDD ER1 / AIMDD ER1)
A7.2 Conformity Conformity assessment with requirement on acceptable benefit/risk profile (MDD ER1 / AIMDD ER1)
A7.3 Conformity assessment with requirement on performance (MDD ER3 / AIMDD ER2)
A7.4 Conformity assessment with requirement on acceptability of undesirable side-effects (MDD ER6 / AIMDD ER5)
A8 Devices for unmet medical needs – aspects to consider
A9 Clinical evaluation report – proposed table of contents, examples of contents
A10 Proposed checklist for the release of the clinical evaluation report
A11 Information on declarations of interests
A12 Activities of notified bodies
A12.1 Notified body assessment of clinical evaluation by conformity assessment route
A12.2 Examination of a design dossier (Annex II.4; Annex 2.4) or of a type examination dossier (Annex III; Annex 3)
A12.3 Evaluation as part of quality system related procedures
A12.4 Notified body specific procedures and expertise

6. General Principles of Clinical Evaluation

6.1. What is clinical evaluation?

Clinical evaluation is a methodologically sound ongoing procedure to collect, appraise
and analyse clinical data pertaining to a medical device and to assess whether there is
sufficient clinical evidence to confirm compliance with relevant essential requirements
for safety and performance when using the device according to the manufacturer’s
instructions for use.
In exceptional cases where an instruction for use is not required, the collection,
appraisal, and analysis are conducted taking into account generally recognised
modalities of use.
The requirements for clinical evaluation apply to all classes of medical devices. The
evaluation should be appropriate to the device under evaluation, its specific properties,
and its intended purpose.

Benefits and risks should be specified, e.g. as to their nature, probability, extent, duration
and frequency. Core issues are the proper determination of the benefit/risk profile in the
intended target groups and medical indications, and demonstration of acceptability of
that profile based on current knowledge/ the state of the art in the medical fields
concerned.
Clinical evaluation is a responsibility of the manufacturer and the clinical evaluation
report is an element of the technical documentation of a medical device.
For compliance with European medical device directives,

the clinical evaluation addresses the following Essential Requirements:
– Annex 1 sections 1, 2, 5 of AIMDD (for active implantable medical devices), or

– Annex I sections 1, 3, 6 of MDD (for medical devices);
see Appendix A7 (Analysis of the clinical data – compliance to specific Essential
Requirements);

the evaluation must follow defined and methodologically sound procedures as
described in:
– Annex 7 of AIMDD (for active implantable medical devices), or
– Annex X of MDD (for medical devices);

where demonstration of conformity with essential requirements based on clinical data
is not deemed appropriate, an adequate justification has to be given. The justification
is included in the clinical evaluation report with contents according to:
– Annex 7 section 1.5 of AIMDD (for active implantable medical devices), or
– Annex X section 1.1d of MDD (for medical devices).
Conformity to the Essential Requirements can only be assumed when the following
items are aligned with each other:

– the information materials supplied by the manufacturer
(the labelling, instructions for use, promotional materials, including accompanying

documents foreseen by the manufacturer)
– the clinical evaluation
(the device description used for the clinical evaluation, other contents of the clinical

evaluation report)
– the available clinical data
(such as results of Clinical Investigations, publications, PMS studies, etc.).

Particularly, evaluators should address if the following points are adequately supported by sufficient clinical evidence:

– the intended purpose described in the information materials
supplied by the manufacturer (including for all medical indications);
– the clinical performance and benefits described in the information materials supplied by the manufacturer (including, for example, any claims on product performance and safety);

– measures for risk avoidance and risk mitigation described in the information
materials supplied by the manufacturer (including, for example the declaration of
the residual risks, contraindications, precautions, warnings, instructions for
managing foreseeable unwanted situations);

the usability of the device for the intended users and the suitability of the information
materials supplied by the manufacturer for the intended users (including, if
applicable, for lay or disabled persons);
– instructi
ons for target population groups (including, for example, pregnant women,
paediatric populations).

6.2. When is clinical evaluation undertaken and why is it important?

Clinical evaluation is conducted throughout the life cycle of a medical device, as an ongoing process.

Usually, it is first performed during the development of a medical device in order to identify data that need to be generated for market access. Clinical evaluation is mandatory for initial CE-marking and it must be actively updated thereafter.

Clinical evaluation is necessary and important because it ensures that the evaluation of safety and performance of the device is based on sufficient clinical evidence throughout the lifetime that the medical device is on the market. This ongoing process enables manufacturers to provide notified bodies and competent authorities with sufficient clinical evidence for demonstration of conformity of the device with the Essential Requirements throughout its lifetime (for example for CE marking, fulfilment of post-market surveillance and reporting requirements, or during surveillance procedures).

6.2.1. Clinical evaluation undertaken for the development of a medical device

Premarket research and development are guided by clinical evaluation and risk management. Typically, manufacturers carry out clinical evaluations to

  • define needs regarding clinical safety and clinical performance of the device;
  • in case of possible equivalence to an existing device, evaluate if there are clinical data available and determine equivalence; for additional information, see Appendix A1 (Demonstration of equivalence);
  • carry out a gap analysis and define which data still need to be generated with the device under evaluation, whether clinical investigations are necessary and if so, to define the study design; for additional information, see Section 10 (Analysis of the clinical data) and Appendix A2 (When should additional clinical investigations be carried out?).

As the initial clinical evaluation identifies the questions to be answered by a clinical investigation, the clinical evaluation process should generally commence in advance of any clinical investigation.

6.2.2. Clinical evaluation for initial CE-marking

Clinical evaluation is required to be carried out for the conformity assessment process leading to the CE-marking and placing on the market of a medical device. The purpose is to:

  • document that there is sufficient clinical evidence to demonstrate conformity with the

Essential Requirements covering clinical performance and clinical safety;

  • identify aspects that need to be addressed systematically during post-market surveillance (PMS), e.g. in post market clinical follow-up studies (PMCF Studies) required under the medical device directives. Typically, these aspects include estimation of residual risks and uncertainties or unanswered questions (such as rare complications, uncertainties regarding long-term performance, safety under wide-spread use).

6.2.3. Updating the clinical evaluation

  1. Frequency of updates
    The manufacturer should define and justify the frequency at which the clinical evaluation needs to be actively updated.
    When doing so, the manufacturer should typically consider:
  • whether the device carries significant risks
    (e.g. based on design, materials, components, invasiveness, clinical procedures, high-risk anatomical locations, high-risk target populations (e.g. paediatrics, elderly), severity of disease/ treatment challenges).
  • whether the device is well established, taking into consideration:
    • innovation;
    • relevant changes in clinical sciences, materials sciences or other sciences related to the device under evaluation;
    • the current level of confidence in the evaluation of clinical performance and clinical safety of the device; the manufacturer should consider
      • the data available from clinical investigations, PMCF studies, registries or other systematic studies (including the number of devices used, if that usage was representative of the usage in the market, the results to date);
      • the total number of devices used so far in the market, and expected reporting rates under the vigilance system.
  • whether there are risks and uncertainties or unanswered questions, in the medium or long- term, that would influence the frequency of updates.
  • design changes or changes to manufacturing procedures (if any).
  • The clinical evaluation is actively updated:
    • when the manufacturer receives new information from PMS that has the potential to change the current evaluation;
    • if no such information is received, then
      • at least annually if the device carries significant risks or is not yet well established; or
      • every 2 to 5 years if the device is not expected to carry significant risks and is well established, a justification should be provided.

      When involvement of notified bodies is required, updates are usually coordinated with the notified body. Typically, they are aligned with the timetable for surveillance audits and the renewal of the certificates.

 

  • General considerations on updating the clinical evaluation
    Manufacturers are required to implement and maintain a PMS system that routinely monitors the clinical performance and clinical safety of the device as part of their quality management system2. The scope and nature of such PMS should be appropriate to the device and its intended purpose.
    PMS regularly generates new data (e.g. safety reports, results from published literature, registries, PMCF studies, and other data about device usage). Those data need to be evaluated for information that has a potential to change the evaluation of the risk/benefit profile, and the clinical performance and clinical safety of the device. Those data are required to be fed into the clinical evaluation process in a timely manner.
    In accordance with the Directives, the clinical evaluation and the clinical evaluation report must be actively updated with data obtained from post-market surveillance.
    When updating the clinical evaluation, the evaluators should verify:

 

  • if the benefit/risk profile, undesirable side-effects (whether previously known or newly emerged) and risk mitigation measures are still
    • compatible with a high level of protection of health and safety and acceptable according to current knowledge/ the state of the art;
    • correctly addressed in the information materials supplied by the manufacturer of the device;
    • correctly addressed by the manufacturer’s current PMS plan;
  • if existing claims are still justified;
  • if new claims the manufacturer intends to use are justified.While clinical evaluation requires data from PMS activities, it also generates new information that have to be fed into the PMS and risk management process. Clinical evaluation can therefore result in changes to the manufacturer’s risk management documents, instructions for use (IFU) and PMS activities.
    If the manufacturer concludes there is not sufficient clinical evidence to be able to declare conformity with the Essential Requirements, the manufacturer will need to :
  • stop placing the devices on the market until conformity is restored, and
  • take necessary corrective and preventive action.

6.3. How is a clinical evaluation performed?

The clinical evaluation is based on a comprehensive analysis of available pre- and post-market clinical data relevant to the intended purpose of the device in question, including clinical performance data and clinical safety data.
There are discrete stages in performing a clinical evaluation:

  • Stage 0: Define the scope, plan the clinical evaluation (also referred to as scoping and the clinical evaluation plan).
  • Stage 1: Identify pertinent data.
  • Stage 2: Appraise each individual data set, in terms of its scientific validity, relevance and weighting.
  • Stage 3: Analyse the data, whereby conclusions are reached about
    • compliance with Essential Requirements (including ER1, ER3, ER6) on performance and safety of the device, including its benefit/risk profile,
    • the contents of information materials supplied by the manufacturer (including the label, IFU of the device, available promotional materials, including accompanying documents possibly foreseen by the manufacturer),
    • residual risks and uncertainties or unanswered questions (including on rare complications, long term performance, safety under wide-spread use), whether these are acceptable for CE-marking, and whether they are required to be addressed during PMS.
  • Stage 4: Finalise the clinical evaluation report The clinical evaluation report summarises and draws together the evaluation of all the relevant clinical data documented or referenced in other parts of the technical documentation. The clinical evaluation report and the relevant clinical data constitute the clinical evidence for conformity assessment. Each of these stages is covered in separate sections later in this document (see the figure below). During the course of a clinical evaluation the stages are often iterative. Indeed, the appraisal and analysis stage may uncover new information and raise new questions, with a need to widen the scope of the evaluation, refine the clinical evaluation plan, and to retrieve, appraise and analyse
    additional data.

Each of these stages is covered in separate sections later in this document (see the
figure below). During the course of a clinical evaluation the stages are often iterative.
Indeed, the appraisal and analysis stage may uncover new information and raise new
questions, with a need to widen the scope of the evaluation, refine the clinical evaluation
plan, and to retrieve, appraise and analyse additional data.
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6.4. Who should perform the clinical evaluation?

The clinical evaluation should be conducted by a suitably qualified individual or a team.
The manufacturer should take the following aspects into consideration:

  • The manufacturer defines requirements for the evaluators that are in line with the nature of the device under evaluation and its clinical performance and risks.
  • The manufacturer should be able to justify the choice of the evaluators through reference totheir qualifications and documented experience, and to present a declaration of interest for each evaluator.
  • As a general principle, the evaluators should possess knowledge of the following:
    • research methodology (including clinical investigation design and biostatistics);
    • information management (e.g. scientific background or librarianship qualification; experience with relevant databases such as Embase and Medline);
    • regulatory requirements; and
    • medical writing (e.g. post-graduate experience in a relevant science or in medicine; training and experience in medical writing, systematic review and clinical data appraisal).
  • With respect to the particular device under evaluation, the evaluators should in addition have knowledge of:
    • the device technology and its application;
    • diagnosis and management of the conditions intended to be diagnosed or managed by the device, knowledge of medical alternatives, treatment standards and technology (e.g. specialist clinical expertise in the relevant medical specialty).
  • The evaluators should have at least the following training and experience in the relevant field:
    • a degree from higher education in the respective field and 5 years of documented professional experience; or
    • 10 years of documented professional experience if a degree is not a prerequisite for a given task.

There may be circumstances where the level of evaluator expertise may be less or different; this
should be documented and duly justified.

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