SOP Clinical Evaluation

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1. Purpose

This SOP describes the process of clinical evaluation for medical devices in accordance with regulatory requirements of MDR 2107/745 Article 62 and Annex XIV.

2. Scope

The clinical evaluation according to MDR is defined as 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.

The clinical evaluation takes into account the processes and outputs outlined in risk management. It ensures the level of demonstrated safety and risk-benefit ratio that is required for our medical devices both for initial certification and for continued safe use in the market.

3. Definitions

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4. Clinical Evaluation Process

The clinical evaluation shall be thorough and objective, and take into account both favorable and unfavorable data. Its depth and extent shall be proportionate and appropriate to the nature, classification, intended purpose and risks of the device in question, as well as to the manufacturer's claims in respect of the device.

The clinical evaluation is initiated for the following reasons including others, as required:

• New product entering the market for the first time
• Scheduled update of the clinical evaluation information based on EU MDR 2107/745 and MEDDEV 2.7/1 Rev. 4
• When information from the post-market surveillance (PMS) data received has a potential to significantly change the current clinical evaluation
• Significant changes to the product features, benefits or risks in so that the benefit risk ratio is changed.

The MEDDEV 2.7/1 Rev. 4 provides the stages for clinical evaluation which are identified in the figure below.

Figure 1 - Stages of clinical evaluation according to MEDDEV 2.7/1 Rev. 4

4.1 Clinical Evaluation Plan

A clinical evaluation plan is to be established and updated for each product. The clinical evaluation plan shall occur following the creation and testing of the product as defined in the SOP Design Control. In reference to the stages identified in Figure 1, the clinical evaluation plan occurs in stage 0.

The clinical evaluation plan shall contain in it at least the following as determined by Annex XIV of MDR 2017/745:

• 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 post-market clinical follow-up (PMCF) with an indication of milestones and a description of potential acceptance criteria;

The clinical evaluation plan shall be initiated and approved prior to the approval of the clinical evaluation report.

The clinical evaluation documentation will be created by the quality team and include members of the business and product / software for review. Additionally, a separate clinical team can be used to manage the clinical evaluation process as well as other clinical processes as needed. See Section 4.2 for more information on the clinical evaluation team.

4.2 Clinical Evaluation Team

The clinical evaluation should be conducted by a suitably qualified individual or team. The requirements of the evaluators should be in line with the nature of the device and its clinical performance risks. The choice of an evaluator should be justifiable through reference to their qualifications and documented interest. Each evaluator shall have a declaration of interest.

According to MEDDEV 2.7/1 Rev. 4 Section 6.4, as a general principle, evaluators should possess knowledge of:

• 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; and
• training and experience in medical writing, systematic review and clinical data appraisal).

With respect to the particular device, evaluators should also 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 speciality).

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 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 which should be documented and duly justified.

External partners can be involved in both conducting the initial clinical evaluation and the post-market clinical follow-up in order to provide higher clinical expertise for the clinical evaluation team.

4.3 Clinical Evaluation Report

The clinical evaluation plan is executed to generate the clinical evaluation report. Relevant data is collected and analyzed as part of writing the Clinical Evaluation Report to evaluate clinical performance and safety.

The clinical evaluation report shall achieve the following:

• Identify available clinical data relevant to the device and its intended purpose and any gaps in clinical evidence through a systematic scientific literature review
• Appraise all relevant clinical data by evaluating their suitability for establishing the safety and performance of the device.
• Generate, through properly designed clinical investigations in accordance with the clinical development plan, any new or additional clinical data necessary to address outstanding issues, as needed.
• Analyze all relevant clinical data in order to reach conclusions about the safety and clinical performance of the device including its clinical benefits.

The results of the clinical evaluation and the clinical evidence on which it is based shall be documented in a clinical evaluation report which shall support the assessment of the conformity of the device. The clinical evidence together with non-clinical data generated from non-clinical testing methods and other relevant documentation shall allow the manufacturer to demonstrate conformity with the general safety and performance requirements and shall be part of the technical documentation for the device in question. Both favorable and unfavorable data considered in the clinical evaluation shall be included in the technical documentation.

Additional information that should be included in the clinical evaluation report or references within the report as needed includes:

• Description of the device
• Features and principles of operation, including configurations, accessories, compatible devices, or previous generations (if applicable)
• Regulatory classification
• Information materials including labeling and IFU information
• Clinical claims and benefits
• Description of the state of the art, benchmark devices, and other available treatment options including safety, performance, and benefit-risk claims (as necessary)
• Demonstration of equivalence (as needed, see Section 3.4.1)
• Literature search, appraisal, review, and evaluation
• Clinical investigations (as needed)
• Post-market surveillance (PMS) information including periodic safety update reports, post-market clinical follow-up, PMS plans/reports, and summary of safety and clinical performance as needed
• Benefit-risk conclusions
• Support for relevant general safety and performance requirements

4.3.1 Equivalence

A clinical evaluation may be based on clinical data relating to a device for which equivalence to the device in question can be demonstrated. Equivalence should be claimed according to guidance found in MDCG 2020-5. Devices considered for equivalence should be CE marked in the EU or have a justification provided for why they are not.

The following technical, biological and clinical characteristics shall be taken into consideration for the demonstration of equivalence:

• Technical: the device is of similar design; is used under similar conditions of use; has similar specifications and properties including physicochemical properties such as intensity of energy, tensile strength, viscosity, surface characteristics, wavelength and software algorithms; uses similar deployment methods, where relevant; has similar principles of operation and critical performance requirements;
• Biological: the device uses the same materials or substances in contact with the same human tissues or body fluids for a similar kind and duration of contact and similar release characteristics of substances, including degradation products and leachables;
• Clinical: the device is used for the same clinical condition or purpose, including similar severity and stage of disease, at the same site in the body, in a similar population, including as regards age, anatomy and physiology; has the same kind of user; has similar relevant critical performance in view of the expected clinical effect for a specific intended purpose

4.3.2 Valid Clinical Association

For software as a medical device (SAMD), also called medical device software (MDSW), a valid clinical association should be identified in accordance with MDCG 2020-1.

A valid clinical association is understood as the extent to which the MDSW’s output (e.g. concept, conclusion, calculations) based on the inputs and algorithms selected, is associated with the targeted physiological state or clinical condition. This association should be well founded or clinically accepted (e.g. existence of a scientific framework or sufficient level of evidence). The valid clinical association of a MDSW should demonstrate that it corresponds to the clinical situation, condition, indication or parameter defined in the intended purpose of the MDSW.

It should be noted that the Valid Clinical Association may not always be readily established. Thus, the clinical performance of the MDSW can serve as an additional valid clinical association from a clinical perspective for the specific intended purpose.

The valid clinical association shall include the validation of technical performance and clinical performance independently.

• Technical Performance: demonstration of the MDSW's ability to accurately, reliably and precisely generate the intended output from the input data.
• Clinical Performance: demonstration of the MDSW's ability to yield clinically relevant output in accordance with the intended purpose. The clinical relevance of a MDSW's output is a positive impact on the health of an individual expressed in terms of measurable, patient-relevant clinical outcome(s), including outcome(s) related to diagnosis, prediction of risk, prediction of treatment response(s), or related to its function, such as that of screening, monitoring, diagnosis or aid to diagnosis of patients, or on patient management or public health.

4.4 Post-Market Clinical Activities

Following the initial clinical evaluation, a post-market clinical follow-up (PMCF) for the medical device shall be planned to ensure its continuing safety and clinical performance during the marketing phase. The PMCF serves as input to regularly update the clinical evaluation.

The quality team (or clinical team if available) is responsible to compile and implement a PMCF Plan, including at minimum:

• Methodology for data collection and justification for selected methods
• Consideration of new data related to the risk management file, the claims discussed in the Clinical Evaluation Report or applicable regulations
• Specification of the PMCF plan period (no longer than one year), including a time plan for PMCF activities and the next update of the clinical evaluation

The corrective and preventive action (CAPA) process must be initiated according to SOP Corrective and Preventive Action if new information collected as part of the PMCF activities indicates that a balanced risk-benefit ratio and the safety of the device is in question.

All PMCF activities conducted per PMCF period are documented in a Post-Market Clinical Follow-Up Report if required.

5. Update of the Clinical Evaluation

According to MEDDEV 2.7/1 Rev. 4 section 6.2.3, the clinical evaluation should be updated 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. Generally, Class I devices should be updated 5 years while Class IIA and above devices should be updated annually to every 2 years, as needed provided a justification.

Mapping of Requirements

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