EU MDR clinical evaluation

EU MDR clinical evaluation

EU MDR clinical evaluation requirements are quite overwhelming. There are a lot of requirements and the strategy to achieve conformity is not always clear. We cover those requirements in detail.

In order to show conformity with general requirements in terms of safety and performance to determine adverse effects and to evaluate the benefit/risk ratio under normal use of the product, the manufacturer must create a clinical evaluation. This clinical evaluation needs to be planned, documented, and formalized as a report contained in the technical documentation. It must be based on sufficient clinical data and in accordance with the requirements set out in Annex XIV of  European Medical Device Regulation 2017/745.

Clinical data and evidence

The approach to clinical evaluation described in MEDDEV 2.7/1 Rev. 4 is similar to that described in the MDR , however, the requirement for demonstrating clinical benefits of a medical device has been added to the MDR definition of “clinical evaluation”: “a systematic and planned process to continuously generate, collect, analyze and assess the clinical data pertaining to a device in order to verify the safety and performance, including clinical benefits, of the device when used as intended by the manufacturer” (Chapter I, Article 2 (44)).

The MDR definition of “clinical evidence” also stresses clinical benefits with MDR defining it as: “clinical data and clinical evaluation results pertaining to a device of a sufficient amount and quality to allow a qualified assessment of whether the device is safe and achieves the intended clinical benefit(s), when used as intended by the manufacturer” (Chapter I, Article 2 (51)).

One of the greatest challenges will be putting together sufficient clinical data to satisfy the MDR’s more stringent clinical evidence requirements. EU MDR clinical evaluation requirements, therefore, emphasizes the importance of early planning. The contents of a Clinical Evaluation Plan are described in more detail than in MEDDEV 2.7/1 Rev 4; these should include, among other requirements: consideration of clinical benefits with clinical outcome parameters; methods to examine safety with reference to the determination of residual risks and side effects; and parameters to determine benefit-risk ratio acceptability based on state of the art and a clinical development plan (Annex XIV, Part A1).

Stricter rules will apply to clinical data requirements. For implantable and class III devices, clinical investigations that have been carried out under the responsibility of a sponsor should, as a general rule, serve as the source of clinical data (Article 63). Manufacturers may only base the clinical evaluation on data from an equivalent device under very strict conditions – for implantable and Class III devices, only if it is the same manufacturer or if there is a contract for full access to technical documentation (Chapter VI, Article 61(5)). Manufacturers of non-implantable and non-class III devices who wish to use clinical data relating to equivalent devices will not require a contract but will need to demonstrate “sufficient levels of access” (Annex XIV, Part A3).

Manufacturers will also face increased PMS requirements.

Both MEDDEV 2.7/1 Rev 4 (Section 4) and MDR (Article 2 (48)) state that clinical data should be sourced from:

• Clinical investigation(s) of the device concerned
• Clinical investigation(s) or other studies reported in the scientific literature, of a similar device for which equivalence to the device in question can be demonstrated; or
• Reports on other clinical experience of either the device in question or a similar device for which equivalence to the device in question can be demonstrated. However, MDR specifies: “reports published in peer-reviewed scientific literature”

The MDR adds an additional key source:

• “Clinically relevant information coming from post-market surveillance, in particular the post-market clinical follow-up” (PMCF).

PMCF must be proactive and appropriately planned (Annex XIV, Part B(5)): “PMCF shall be understood to be a continuous process that updates the clinical evaluation. When conducting PMCF, the manufacturer shall proactively collect and evaluate clinical data”.

PMCF must be documented in the form of a PMCF plan and the outcomes assessed in a PMCF evaluation report which should be included in the CER, the post-market surveillance report and, if applicable, findings should be included in the summary of safety and clinical performance and Periodic Safety Update Report (PSUR).

The MDR does not discuss who should perform clinical evaluation. However, the increased stringency and scope of clinical evaluation under MDR will place additional demands on the clinical evaluators.

PMCF must be documented in the form of a PMCF plan and the outcomes assessed in a PMCF evaluation report which should be included in the CER, the post-market surveillance report and, if applicable, findings should be included in the summary of safety and clinical performance and Periodic Safety Update Report (PSUR).

The MDR does not discuss who should perform clinical evaluation. However, the increased stringency and scope of clinical evaluation under MDR will place additional demands on the clinical evaluators.

Article 61 – EU MDR clinical evaluation

Confirmation of conformity with relevant general safety and performance requirements set out in Annex I under the normal conditions of the intended use of the device, and the evaluation of the undesirable side-effects and of the acceptability of the benefit-risk- ratio referred to in Sections 1 and 8 of Annex I, shall be based on clinical data providing sufficient clinical evidence, including where applicable relevant data as referred to in Annex III.

The manufacturer shall specify and justify the level of clinical evidence necessary to demonstrate conformity with the relevant general safety and performance requirements. That level of clinical evidence shall be appropriate in view of the characteristics of the device and its intended purpose.

To that end, manufacturers shall plan, conduct and document a clinical evaluation in accordance with this Article and Part A of Annex XIV.

 

Clinical evidence means clinical data and clinical evaluation results pertaining to a device of a sufficient amount and quality to allow a qualified assessment of whether the device is safe and achieves the intended clinical benefit(s), when used as intended by the manufacturer;

 

Clinical data means information concerning safety or performance that is generated from the use of a device and is sourced from the following: — clinical investigation(s) of the device concerned, — clinical investigation(s) or other studies reported in scientific literature, of a device for which equivalence to the device in question can be demonstrated, — reports published in peer reviewed scientific literature on other clinical experience of either the device in question or a device for which equivalence to the device in question can be demonstrated, — clinically relevant information coming from post-market surveillance, in particular the post-market clinical follow-up;

Annex IV part A

To plan, continuously conduct and document a clinical evaluation manufacturers shall:

1. establish and update a clinical evaluation plan,
2. identify available clinical data relevant to the device and its intended purpose and any gaps in clinical evidence through a systematic scientific literature review;
3. appraise all relevant clinical data by evaluating their suitability for establishing the safety and performance of the device;
4. generate, through properly designed clinical investigations in accordance with the clinical development plan, any new or additional clinical data necessary to address outstanding issues; and
5. analyze all relevant clinical data in order to reach conclusions about the safety and clinical performance of the device including its clinical benefits.

Equivalence

Equivalence for EU MDR clinical evaluation shall be demonstrated from 2 aspects.

Clinical

• Used for the same clinical condition (including similar severity and stage of disease), and
• Used for the same medical indication, and
• Used for the same intended purpose, and
• Used at the same site in the body, and
• Used in a similar population (e.g. age, gender, anatomy, physiology etc.), and
• Not foreseen to deliver significantly different performances (in the relevant critical performances such as the expected clinical effect, the specific intended purpose, the duration of use, etc.).

Technical

• Be of similar design, and
• Used under the same conditions of use, and
• Have similar specifications and properties (e.g. physicochemical properties such as type and intensity of energy, tensile strength, viscosity, surface characteristics, wavelength, surface texture, porosity, particle size, nanotechnology, specific mass, atomic inclusions such as nitrocarburising, oxidability), and
• Use similar deployment methods (if relevant), and
• Have similar principles of operation and critical performance requirements.

Biological

• Use the same materials or substances in contact with the same human tissues or body fluids.

EU MDR Clinical evaluation plan

Content of clinical evaluation plan based on EU MDR clinical evaluation requirements.

• an identification of the general safety and performance requirements that require support from relevant clinical data;
• a specification of the intended purpose of the device;
• a clear specification of intended target groups with clear indications and contra-indications;
• a detailed description of intended clinical benefits to patients with relevant and specified clinical outcome parameters;
• a specification of methods to be used for examination of qualitative and quantitative aspects of clinical safety with clear reference to the determination of residual risks and side-effects;
• an indicative list and specification of parameters to be used to determine, based on the state of the art in medicine, the acceptability of the benefit-risk ratio for the various indications and for the intended purpose or purposes of the device;
• an indication how benefit-risk issues relating to specific components such as use of pharmaceutical, non-viable animal or human tissues, are to be addressed; and
• a clinical development plan indicating progression from exploratory investigations, such as first-in-man studies, feasibility and pilot studies, to confirmatory investigations, such as pivotal clinical investigations, and a PMCF with an indication of milestones and a description of potential acceptance criteria;

Clinical Evaluators

What is expected ?

Specific requirements for the expertise and experience of evaluators are introduced, including a relevant higher education degree and five years’ related professional experience, or ten years’ professional experience if a degree is not considered a prerequisite for the task. Deviations from these requirements should be documented and duly justified. For every device under evaluation the manufacturers are required to define requirements for the evaluators and justify the choice of the evaluators through reference to their qualifications and experience.

Clause 6.4 states “The clinical evaluation should be conducted by a suitably qualified individual or a team” and goes on to specify a wide range of required competencies.

 

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 librarian qualification, experience with relevant databases such as Embase and Medline)
• Regulatory requirements
• Medical writing
• Training and experience in medical writing

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 the medical alternatives, treatment standards and technology (e.g. specialist clinical expertise in the relevant specialty)

 

You may go back to our EU MDR guide.

If you are interested in the European market you can contact us for a preliminary discussion. You can also look at our dedicated page for European medical device registration.