Clinical evaluation under the EU MDR
EU MDR Clinical Evaluation Guide: CEP, CER & PMCF
Under the EU MDR, clinical evaluation is a systematic and ongoing procedure where the manufacturer proves that the medical device to be placed on the market in the European Union meets the General Safety and Performance Requirements (GSPRs) specified in Annex I, operates properly, and provides an acceptable benefit risk ratio. The need to perform clinical evaluation is laid down in Article 61 and further specified in Annex XIV (Parts A & B).
Regulatory Background & Objective
Legal Background
According to Article 61 of the MDR, “The manufacturer shall plan, conduct and document a clinical evaluation for the purpose of demonstrating: conformity with the relevant GSPRs when used under normal conditions of intended use; and acceptable benefit risk ratio and potential undesirable side effects.”
Annex XIV – Part A provides the detailed requirements on the clinical evaluation process (planning, data identification/evaluation, analysis and conclusion).
Annex XIV – Part B deals with the Post Market Clinical Follow Up (PMCF) process, which is one of the steps within the clinical evaluation lifecycle.
MDCG 2020-6 (“Sufficient clinical evidence for legacy devices”) and MDCG 2020-5 ("Equivalence under MDR") can be considered additional EU guidance.
Objective Of The Clinical Evaluation
The objective of the clinical evaluation process involves the following:
Validation of compliance with applicable GSPRs (Annex I) of the device as intended.
Providing adequate, credible clinical evidence for the demonstration of safety and performance (clinical benefit).
Ensuring that there is a favourable benefit risk ratio from the available clinical evidence.
Development of clinical evidence continuously through the life cycle of the device.
It should be noted that the clinical evaluation is not a single event but rather a continuous loop of planning, gathering, evaluating, analysing, documenting, performing PMCF and updating the clinical evidence.
The Clinical Evaluation Process
Clinical evaluation process under EU MDR is a step by step procedure that is clearly presented in the Annex XIV, Part A. Some of the main stages are listed below.
Clinical Evaluation Plan (CEP)
Prior to the start of collecting data, the manufacturer should develop a comprehensive Clinical Evaluation Plan according to Annex XIV, Part A(1). Main aspects include:
Device objective, indications, intended population, user, and context.
Description of the clinical advantage (direct or indirect) and the outcome.
Description of the GSPRs (Annex I) to which the device is subject.
Description of the literature research methodology, inclusion and exclusion criteria, databases, search words, time frame.
Reasons for equivalence (if any) and reasons for reliance on non clinical data or literature.
Description of how the clinical evaluation programme will fit into the manufacturer’s QMS and risk management file (ISO 14971).
Description of the alignment of new clinical studies where necessary with standards like ISO 14155:2020.
The guidance specifies that the CEP should clearly describe its objectives, methods, criteria, and that it be justified and reproducible.
Identification and Evaluation of the Clinical Evidence Base
After having established the plan, the manufacturers are then required to identify all the available clinical data. These include:
Published scientific literature (scientific journals, meta analyses).
Clinical investigations either sponsored by the manufacturer or carried out independently.
Post market surveillance (PMS), PMCF, real world clinical experience, registries, complaint/failure databases.
Data from equivalent devices (under strict conditions according to MDR).
After identification, the data need to be appraised on their relevance, validity, reliability, methodology, scientific validity (such as sample size, bias control, follow up period) and applicability to the device, its indications, and user population.
The manufacturers are supposed to use specific tools for this purpose (such as PICO framework, risk of bias checklists, and hierarchy of evidence).
Integration of the plan into the manufacturer’s quality management system (QMS) and risk management file (ISO 14971).
In case of new clinical investigations, alignment with ISO 14155:2020.
It is important that in CEP, the objectives, methods, and criteria are well defined.
Generation of New Clinical Data
When the existing data are not enough to prove compliance with the GSPRs and the benefit risk profile, the manufacturers will have to undertake new clinical studies under Articles 62 to 82 and Annex XV of the MDR. This is generally mandatory for high risk (Class III) and implantable medical devices as well as for innovative technologies, when equivalency is proven convincingly. Such new data should be gathered following good clinical practice (such as ISO 14155).
Analysis and Benefit Risk Assessment
On completion of data collection and evaluation, the manufacturer is responsible for analysis of the combined clinical data in order to:
Prove that the device functions as intended and has its proposed benefits.
Show that the residual risks are reasonable taking into account the benefits (benefit risk balance).
Link clinical results with the GSPRs and risk management documentation.
Consider different variants of the device, accessories, time of use, sub groups of users, and unmet indications. It should be noted that guidance stresses the need for conclusions that are device specific, indication specific, and population specific.
The conclusion of the manufacturer must clearly reflect whether the available information is enough, what deficiencies may exist, and what residual uncertainties still exist.
Clinical Evaluation Report (CER)
Results of the evaluation have to be recorded in a Clinical Evaluation Report (CER). The CER has to:
Summarize the evaluation plan, data sources, assessment methods, analysis, results and any updates.
Link to the technical documentation, risk management files, and PMS/PMCF data of the device.
Contain positive and negative information (transparent approach).
Be approved by a competent evaluator and be included in technical documentation which is submitted to the Notified Body (NB) as part of conformity assessment procedure. Templates of CER can be found in guidance documents such as MDCG 2020‑13.
Be updated throughout the lifecycle of the medical device as long as there are new relevant data.
Equivalence And The Issues Associated With It
In relation to MDR, equivalence may be claimed based on clinical data of the equivalent device, subject to certain requirements. This is specified in Annex XIV, Part A(3).
Requirements for claiming equivalence are as follows:
Evidence of equivalence in terms of its technical, biological and clinical characteristics.
Access to all technical information about the equivalent device (design, manufacturing, materials, sterilization, biological safety, residual risk).
The equivalent device should comply with the MDR clinical evaluation requirements itself.
Due to high requirements, for many manufacturers it becomes difficult to claim the equivalence and Notified Bodies ask to perform clinical studies instead.
Post Market Clinical Follow Up (PMCF) And Lifecycle Approach PMCF Obligations
Under the MDR, clinical evaluation must continue throughout the lifecycle of the product. Annex XIV, Part B outlines the activities and obligations for PMCF. Important PMCF activities include:
Ongoing updating of literature searches and analysis of the literature.
Gathering of information on clinical performance of the device in actual practice (from registries, surveys, observational studies).
Identification and analysis of new/updated risks and ensuring the acceptance of benefit risk ratio remains valid.
Off label use, abuse, changes to the device, novel populations of users, accessories.
The manufacturer should describe a PMCF plan and a PMCF evaluation report; the latter is included in the CER.
Life Cycle Maintenance of Clinical Evaluation
According to Article 61(12), there must be maintenance of current information in clinical evaluations. For high risk/implantable devices, it is important to have an annual review; for low risk devices, review must take into account risk and PMS results. It is recommended that clinical evaluation be seen as a dynamic process.
Updates should be considered: Changes in the design or intended purpose of the device, new clinical data, any corrective action due to PMS, any technology advances (state of the art).
Common Challenges And Compliance Issues
Manufacturers face some of the following challenges:
Lack of adequate literature search: insufficient, not reproducible, lack of grey literature/ scientific literature review. It reduces the credibility of CER.
Inadequate appraisals: lack of methodological quality appraisal, bias appraisal, statistical appraisal or mapping data to GSPRs and associated risks.
Equivalence without adequate documentation: Notified Bodies usually reject equivalence rationale if the manufacturer is unable to provide sufficient documentation for equivalence.
Insufficient clinical data if required: for novel devices, literature alone or even literature + equivalence can be inadequate.
Inadequate connection between risk management and clinical evaluation: CER needs to refer to residual risks from risk assessment files and provide clinical evidence addressing them.
Lack of PMCF integration: some manufacturers consider clinical evaluation an activity that is conducted prior to market launch, however, MDR requires regular updates of the CER and its integration with post market surveillance activities.
Avoiding such pitfalls requires cross functional collaboration (regulatory, clinical, quality, manufacturing), proper version control, methodology for literature/ data appraisal.
Key Takeaways For Manufacturers
Clinical evaluation is an obligatory activity for all medical devices regulated under MDR (Articles 5(3), 61 together with Annex XIV).
It is a process through the entire device life cycle, not a single time activity.
The CEP defines the plan; the CER proves its rationale and results.
Evidence should be device specific, indication specific and relate to the target population and user environment.
Equivalence is possible only under strict requirements; most companies will need clinical evidence of their own.
PMCF and life cycle management guarantee that the device is still safe and operates properly post market.
Make sure that you have updated the procedure of clinical evaluation according to the latest guidance (MDCG 2020-6, 2020-5, 2020-13) and QMS correspondingly.
Conclusion
In the current era of regulation based on EU MDR 2017/745, an effective clinical evaluation process is no longer about mere compliance. It is a tool that helps to gain market access, ensures patient safety, and sustains the value of the device throughout its life cycle. For the manufacturers that integrate the clinical evaluation process in the overall QMS and PMS, this will be more advantageous during interactions with Notified Bodies.
How Morulaa Can Help You
Morulaa offers support to manufacturers at all stages of the clinical evaluation process in accordance with EU MDR 2017/745. Our services include the development of Clinical Evaluation Plans (CEP), systematic literature review, assessment of equivalence, and preparation of CER according to Article 61 and Annex XIV. Our experts make sure that data is traceable to GSPRs, develop plans for Post Market Clinical Follow up and lifecycle changes for high risk devices. Morulaa is knowledgeable in ISO 14155 and MDR compliant documents.
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