Clinical evaluation represents a methodologically sound ongoing procedure to collect, evaluate and examine the clinical data relevant to a medical device.
As the application date for the new Medical Device Regulation MDR approaches, many clients have turned to us to ask how to prepare or update clinical evaluation documentation in accordance with the new MDR requirements.
The medical device clinical evaluation documentation usually includes a clinical evaluation plan, a clinical development plan, a clinical evaluation report, a Post-Market Surveillance PMS plan, a Post Market Clinical Follow Up PMCF plan and a Periodic Safety Update Report PSUR.
We decided to summarize all the information relating to medical device clinical evaluation which can be found in a number of places throughout the medical device regulation MDR document so that it would all be in one place in the hope that the reader will find this helpful.
As you know, medical device clinical evaluation is a crucial part of the technical documentation. Every medical device manufacturer should confirm compliance with the relevant general safety and performance requirements for the intended use of the device, as well as the satisfactoriness of the benefit-risk ratio based on clinical data providing sufficient clinical evidence of this. The level of clinical evidence shall be appropriate in terms of the characteristics of the device and its intended purpose.
How to perform medical device clinical evaluation
In order to plan, continuously conduct and document a clinical evaluation, manufacturers should:
- establish and update a Clinical evaluation plan which shall include at least:
- 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 the acceptability of the benefit-risk ratio for the various indications and for the intended purpose(s) 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;
- 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;
- if necessary, generate, through properly designed clinical investigations, any new or additional clinical data necessary to address outstanding issues; and
- analyse all relevant clinical data in order to reach conclusions about the safety and clinical performance of the device including its clinical benefits.
A medical device clinical evaluation shall be thorough and objective, and take into account both favourable and unfavourable 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.
Clinical evaluation procedure
A clinical evaluation shall follow a defined and methodologically sound procedure based on the following:
- a critical evaluation of the relevant scientific literature currently available relating to the safety, performance, design characteristics and intended purpose of the device, where the following conditions are satisfied:
- it is demonstrated that the device subject to clinical evaluation for the intended purpose is equivalent to the device to which the data relate and
- the data adequately demonstrate compliance with the relevant general safety and performance requirements;
- a critical evaluation of the results of all available clinical investigations, and
- a consideration of currently available alternative treatment options for that purpose, if any.
The manufacturer should also evaluate collected product-specific clinical post-market surveillance PMS data for the product generated according the post-market surveillance plan.
Post Marketing Surveillance – PMS is a collection of processes and activities used to monitor the performance of a medical device. These activities are designed to generate information regarding use of the device to expediently identify device design and/or usage problems and accurately characterize the real-world device behavior and clinical outcomes.
Post Marketing Clinical Follow Up – PMCF is a continuous process that updates the clinical evaluation which is the assessment and analysis of clinical data pertaining to a medical device to verify the clinical safety and performance of the device when used as intended by the manufacturer. If required, PMCF plan will be included within the manufacturer’s PMS plan.
A well-designed post-market surveillance plan and PMCF can often replace clinical investigation studies assuming such approval is granted following discussions with the responsible Notified Body.
Clinical evaluation based on the equivalent device
A clinical evaluation may be based on clinical data relating to a device for which equivalence to the device in question can be demonstrated. The following technical, biological and clinical characteristics shall be taken into consideration for the demonstration of such 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. The clinical characteristics listed here will be considered similar to the extent that there would be no clinically significant difference in the safety and clinical performance of the device.
Considerations of equivalence shall be based on proper scientific justification. It shall be clearly demonstrated that manufacturers have sufficient levels of access to the data relating to devices with which they are claiming equivalence in order to justify their claims of equivalence. For more info regarding to demonstration of equivalence and clinical evaluation in general, refer to important guidance MEDDEV 2.7/1 revision 4.
Clinical evaluation report
The results of the clinical evaluation and the clinical evidence on which it is based shall be documented in a Clinical evaluation report. 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 should be part of the device technical documentation.
For class III implantable devices, and for class IIb active devices intended to administer and/or remove a medicinal product (according to Rule 12), the notified body shall, having verified the quality of clinical data supporting the clinical evaluation report of the manufacturer, 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.
The notified body shall transmit its clinical evaluation assessment report, along with the manufacturer’s clinical evaluation documentation to the Commission. The Commission shall immediately transmit those documents to the relevant expert panel. The notified body may be requested to present its conclusions to the expert panel concerned.
For class III devices and implantable medical devices, the PMCF evaluation report and, if indicated, the summary of safety and clinical performance shall be updated at least annually with such data.
The summary of safety and clinical performance
For implantable medical devices and for class III devices, other than custom-made or investigational devices, the manufacturer shall draw up a Summary of safety and clinical performance.
The summary of safety and clinical performance shall be written in a way that is clear to the intended user and, if relevant, to the patient and shall be made available to the public via Eudamed. The draft of the summary of safety and clinical performance shall be part of the documentation to be submitted to the notified body involved in the conformity assessment and shall be validated by that body. After its validation, the notified body shall upload the summary to Eudamed. The manufacturer shall mention on the label or instructions for use where the summary is available.
The summary of safety and clinical performance shall include at least the following aspects:
- the identification of the device and the manufacturer, including the Basic UDI-DI and, if already issued, the SRN;
- the intended purpose of the device and any indications, contraindications and target populations;
- a description of the device, including a reference to previous generation(s) or variants if such exist, and a description of the differences, as well as, where relevant, a description of any accessories, other devices and products, which are intended to be used in combination with the device;
- possible diagnostic or therapeutic alternatives;
- reference to any harmonized standards and common specifications (CS) applied;
- the summary of clinical evaluation and relevant information on post-market clinical follow-up;
- suggested profile and training for users;
- information on any residual risks and any undesirable effects, warnings and precautions.
Implantable devices and Class III devices
In the case of implantable medical devices and class III medical device, clinical investigations shall be performed, except if:
- the device has been designed by modifications of a device already marketed by the same manufacturer,
- the modified device has been demonstrated by the manufacturer to be equivalent to the marketed device, and this demonstration has been endorsed by the notified body, and
- the medical device clinical evaluation of the marketed device is sufficient to demonstrate conformity of the modified device with the relevant safety and performance requirements. In this case, the notified body shall check that the PMCF plan is appropriate and includes post market studies to demonstrate the safety and performance of the device.
In addition, and with compliance with abovementioned, clinical investigations need not be performed by manufacturer of a device which has demonstrated equivalence to an already marketed device not manufactured by him provided that:
- the two manufacturers have a contract in place that explicitly allows the manufacturer of the second device full access to the technical documentation on an ongoing basis, and
- the original clinical evaluation has been performed in compliance with the requirements of MDR medical device regulation, and the manufacturer of the second device provides clear evidence thereof to the notified body.
In addition, the requirement to perform clinical investigations shall not apply to implantable medical devices and class III medical devices:
- which have been lawfully placed on the market in accordance with Directive 90/385/EEC or Directive 93/42/EEC and for which the clinical evaluation:
- is based on sufficient clinical data, and
- is in compliance with the relevant product-specific CS for the clinical evaluation of that kind of device, where such a CS is available; or
- that are sutures, staples, dental fillings, dental braces, tooth crowns, screws, wedges, plates, wires, pins, clips or connectors for which the clinical evaluation is based on sufficient clinical data and is in compliance with the relevant product-specific CS, where such a CS is available.
The products without an intended medical purpose
According to Annex XVI of MDR medical device regulation, the products without an intended medical purpose include:
- Contact lenses or other items intended to be introduced into or onto the eye;
- Products intended to be totally or partially introduced into the human body through surgically invasive means for the purpose of modifying the anatomy or fixation of body parts with the exception of tattooing products and piercings;
- Substances, combinations of substances, or items intended to be used for facial or other dermal or mucous membrane filling by subcutaneous, submucous or intradermal injection or other introduction, excluding those for tattooing;
- Equipment intended to be used to reduce, remove or destroy adipose tissue, such as equipment for liposuction, lipolysis or lipoplasty;
- High intensity electromagnetic radiation (e.g. infra-red, visible light and ultra-violet) emitting equipment intended for use on the human body, including coherent and non-coherent sources, monochromatic and broad spectrum, such as lasers and intense pulsed light equipment, for skin resurfacing, tattoo or hair removal or other skin treatment;
- Equipment intended for brain stimulation that apply electrical currents or magnetic or electromagnetic fields that penetrate the cranium to modify neuronal activity in the brain.
For these products, the manufacturers should demonstrate a clinical benefit through the demonstration of performance of the device. Medical device clinical evaluation of those products shall be based on relevant data concerning safety, including data from post-market surveillance, PMCF, and, where applicable, specific clinical investigation. Clinical investigations shall be performed for those products unless reliance on existing clinical data from an analogous medical device is duly justified.
Where the demonstration of conformity with general safety and performance requirements based on clinical data is not deemed appropriate, adequate justification for any such exception shall be given based on the results of the manufacturer’s risk management.
In such a case, the manufacturer shall duly substantiate in the technical documentation why it considers a demonstration of conformity with general safety and performance requirements that is based on the results of non-clinical testing methods alone, including performance evaluation, bench testing and pre- clinical evaluation, to be adequate.
With reference to medical device clinical evaluation and the accompanying documentation required for all products, this will be updated throughout the life cycle of the device with which the clinical data is concerned and will be obtained from the implementation of the manufacturer’s PMCF plan in accordance with Part B of Annex XIV of the new MDR regulations and the Post-Market Surveillance Plan.
Clinical evaluation and role of notified bodies
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. 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.
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.
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. The notified body shall clearly document the outcome of its assessment in the clinical evaluation assessment report.
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 MDR medical device 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.
Periodic Safety Update Report – PSUR
The manufacturers of class IIa, class IIb and class III medical devices should prepare a Periodic Safety Update Report PSUR for each device and where relevant for each category or group of devices summarising the results and conclusions of the analyses of the post-market surveillance data together with a rationale and description of any preventive and corrective actions taken.
Throughout the lifetime of the device concerned, that PSUR shall set out:
- the conclusions of the benefit-risk determination;
- the main findings of the Post Market Clinical Follow Up PMCF; and
- the volume of sales of the device and an estimate evaluation of the size and other characteristics of the population using the device and, where practicable, the usage frequency of the device.
Manufacturers of class IIb and class III devices shall update the Periodic Safety Update Report at least annually. That PSUR shall, except in the case of custom-made devices, be part of the technical documentation.
Manufacturers of class IIa devices shall update the PSUR when necessary and at least every two years. For class III devices or implantable devices, manufacturers shall submit PSURs by means of the electronic system to the notified body involved in the conformity assessment in accordance. The notified body shall review the report and add its evaluation to that electronic system with details of any action taken. Such PSURs and the evaluation by the notified body shall be made available to competent authorities through that electronic system.
Manufacturers of class I devices shall prepare a post-market surveillance report summarising the results and conclusions of the analyses of the post-market surveillance data gathered as a result of the post-market surveillance plan together with a rationale and description of any preventive and corrective actions taken. The report shall be updated when necessary and made available to the competent authority upon request.
How Bioreg can assist to you
- Build strategy to reduce or remove the need for additional clinical investigations
- Perform clinical evaluation
- Review and update Clinical evaluation plan
- Review and update Clinical evaluation report
- Prepare or review Post-market surveillance PMS plan
- Prepare or review Post Marketing Clinical Follow Up PMCF plan
- Review and update Clinical Evaluation Report according to MEDDEV 2.7/1 revision 4
- Analyze and demonstrate equivalence to the comparator device
- Review and update a Summary of safety and clinical performance
- Check whether your product falls within the category of Products without an intended medical purpose
- Review and update product Periodic Safety Update Report PSUR