EU MDR Clinical Evaluation

EU MDR Clinical Evaluation

Our team can assist you with EU MDR Clinical Evaluation, including:

• Build a clinical evaluation strategy aimed at waiving or reducing clinical investigations
• Write Clinical Evaluation procedure (SOP)
• Analyze and demonstrate equivalence to the comparator device
• Write or review the Clinical Evaluation Plan
• Write or review the Clinical Evaluation Report
• Write a Literature Plan and Report

See 31 tips for Successful MDR Clinical Evaluation and CER here

Clinical Evaluation is an ongoing procedure to collect, appraise and analyze clinical data on a medical device or its equivalent to conclude whether sufficient clinical evidence exists for compliance with relevant General Safety and Performance Requirements (GSPR). Clinical Evaluation is required for all medical devices (MDR, Article 61).
Clinical Evaluation is part of manufacturer QMS and should be aligned with and reflected in Risk management, Post-market surveillance (PMS), Post-market clinical follow-up (PMCF) plan, and, where appropriate, the PMCF report, and Instructions for use.

The Notified Body’s expectations regarding the company’s clinical evaluation process and documentation are clearly presented in the guidance of the MDCG 2020-13 Clinical evaluation assessment report template (July 2020).
Clinical Evaluation is based on the company’s Clinical Evaluation Plan (see MDR Article 61 and Part A of Annex XIV).
A Clinical Evaluation Report (CER) summarizes the clinical evaluation methodology and results.
See our blog about Clinical evaluation here.
For more information, don’t hesitate to contact the BioReg team.

Commonly Asked Questions

Question: What clinical guidelines and standards are binding according to MDR & IVDR?

Answer: The text of the MDR (IVDR) is the only which is authentic in law – legally binding. The Medical Device Coordination Group issues MDCG documents to assist stakeholders in effectively applying MDR and IVDR (as per Article 105 of the MDR and Article 99 of the IVDR).
So, although MDCG guidance are not legally binding, you should consider them since there are considered a “state of art” interpretation of MDR and IVDR requirements. At the moment, you will find a dozen documents related to the clinical investigation and Evaluation on the official European commission MDCG page.
Even though MEDDEV 2.7/1 Rev. 4 guidance is related to MDD, compliance with this guidance is expected in addition to MDR requirements when writing Clinical Evaluation Report (CER) and Literature search report. Some experts advised not citing this guidance in the CER list of standards but still following it. We prefer a more traditional approach – if you followed the standard, state so. In addition, you should review MDCG 2020-6, Appendix I for the sections of MEDDEV 2.7/1 rev. 4, which are specifically relevant under the MDR.
Do not forget ISO 14155:2020 Clinical investigation of medical devices for human subjects — Good clinical practice.
Regarding the standards in general, you should follow the most updated standard (even if it is not harmonized under MDR). You are expected to justify if you partially followed the updated standard or followed non-updated standard or guidance to demonstrate compliance with MDR.
Some Notified Bodies advised following the guidance documents in this descending order of significance: common specifications, harmonized standards (under MDR), and MDCG documents.
If you plan to write your first Clinical Evaluation Report (CER) and don’t know how to start – we advise you to use our CER template.

Question:  What should the clinical evaluation via literature include?

Answer: In general, a clinical evaluation shall follow a defined and methodologically sound procedure based on a critical evaluation of the relevant scientific literature currently available relating to the safety, performance, design characteristics, and intended purpose of the device, where 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 GSPR. You should have a literature search plan.

Question: Which product characteristics should be considered for the demonstration of equivalence?

Answer: The following technical, biological and clinical characteristics should considered for the demonstration of equivalence:

• Technical: the device is of similar design; is used under similar conditions of use; has similar specifications and properties;
• 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.

Question: Could the company use the clinical data from a similar device during MDR clinical evaluation?
Answer: MDR does not define the term similar device. Instead, the clinical data definition mentions only the device in question and its equivalent device (MDR, Article 2(48)). MDCG 2020-6 Clinical Evidence needed for the legacy devices defines similar devices as those belonging to the same generic device group. The MDR defines a generic device group as a set of devices with the same or similar intended purposes or commonality of technology (MDR, Article 2(7).
MDCG 2020-6 states that it is vital to identify all available clinical data sources from both the pre-market and post-market phases, including all clinical data generated and held by the manufacturer and clinical data for equivalent or equivalent or similar devices. In addition, one of the proposed uses of similar devices’ clinical data mentioned in MDCG 2020-5 Clinical Evaluation – Equivalence (section 5) is to provide input for clinical investigation design or PMCF design and the PMS system.
MDR clearly states that Notified Body’s assessment of clinical evaluations should cover (among others): the validity of equivalence claimed concerning other devices, the demonstration of equivalence, and the suitability and conclusions data from equivalent and similar devices (Annex VII, 4.5.5; 4.10).
Further, according to MDR, the PMCF plan should include evaluating the clinical data relating to equivalent or similar devices (Annex XIV, Part B, 6.2(f)).
Based on this, we argue that clinical data from similar devices are subsumed in the last paragraph of MDR clinical data definition, for it is stated: clinically relevant information coming from post-market surveillance, in particular the post-market clinical follow-up (as it is clarified in MDCG 2020-5 and 2020-6).
Thus, we can conclude that similar devices are a useful and important source of clinical data. For a more specific response, we need to review all pre-clinical & clinical data generated or identified for the product in case.

Question: Does the manufacturer of the Class IIb (non-implantable) device need to have full access to the Technical Documentation of the device to which the equivalence is claimed?
Answer: MDR ANNEX XIV PART A states that a clinical evaluation may be based on clinical data relating to a device for which equivalence to the device in question can be demonstrated considering Technical, Biological and Clinical parameters. The analysis of equivalence should be based on proper scientific justification. Also, it shall be demonstrated that manufacturers have sufficient access to the data relating to devices with which they claim equivalence.

Recent MDCG 2023-7 clarified that it should also be noted that Annex XIV Section 3 refers specifically to the data required to justify claims of equivalence: i.e., the requirement is for sufficient access to establish the clinical, technical and biological characteristics against which equivalence is evaluated, not access to the complete technical documentation.

Devices that are neither class III nor implantable are outside the scope of this guidance, so manufacturers are left with much older MDCG 2020-5 and MDCG 2020-6 for further guidance for the “sufficient access to the data” question.
MDCG 2020-5 states that if a manufacturer is not able to demonstrate sufficient levels of access to the data relating to the presumed equivalent device and needed for the consideration of equivalence, equivalence claims cannot be made for the purpose of conformity assessment. The same guidance says that manufacturers of implantable devices and class III devices claiming equivalence to an already marketed device not manufactured by him must have a contract in place that allows full access to the technical documentation on an ongoing basis, which is not what MDCG 2023-7 claims.
Therefore, we advise manufacturers of devices not Class III or implantable to follow MDCG 2023-7. Therefore, a requirement for sufficient access is specifically related to establishing the clinical, technical, and biological characteristics against which equivalence is evaluated, and not necessarily to full access, ongoing or not, to the complete technical documentation.

Question: One company discussed the necessity of defining a clinical benefit for accessories that are part of a therapy system.

Answer: The MDR term “clinical benefit” refers to the product (medical device) only and not its accessories separately. The company may use the word “benefit” in a lay fashion, but this is not to be confused with the “clinical benefit” that MDR refers to.
See MDR definitions of accessory and clinical benefit below:

Article 2(2)‘accessory for a medical device’ means an article which, whilst not being itself a medical device, is intended by its manufacturer to be used together with one or several particular medical device(s) to specifically enable the medical device(s) to be used in accordance with its/their intended purpose(s) or to specifically and directly assist the medical functionality of the medical device(s) in terms of its/their intended purpose(s);
Article 2(53) ‘clinical benefit’ means the positive impact of a device on the health of an individual, expressed in terms of a meaningful, measurable, patient-relevant clinical outcome(s), including outcome(s) related to diagnosis, or a positive impact on patient management or public health;

Question: Since accessories are also referred to as devices (Article 1:4), they are not excluded from the definition of “clinical benefit” in the MDR, and therefore, we thought we should assess “clinical benefit” for each accessory in our product. Is our approach correct?

Answer: We understand your logic; however, if you follow it to its full potential, you will have to do GSPR, PMS, PMCF, Risk, etc., for each accessory of the product, which was not, in our opinion, the legislator’s intention.   Each accessory contributes to the final product’s overall “clinical benefit,” benefit-risk ratio, etc. of the product, and we can describe such contributions in TD. Still, we would reserve the term “clinical benefit” for the final product only. I think that your approach may apply to a greater extent to the products contained in the “Procedure pack” (MDR 2(10) or “System” (MDR 2(11)). Similarly, for devices incorporating a medicinal product (Rule 14), you need to justify (clinical benefit, etc.) the addition of medicinal substance(s).

Question: A manufacturer asked for advice on the wording (phrasing) of a certain diagnostic device’s clinical benefits and clinical outcome parameters.

Answer: Our advice is to search the internet for the labeling of similar products on the market and see which clinical benefits and outcome parameters are used. An SoA literature analysis would also be useful in this respect.

Question: A clinical evaluation provider for medical device manufacturers wrote that one of their customers was audited by a Notified Body (NB). They told them that our ISO 13485:2016 certificate was invalid as it had not been issued by an NB. They explain that non-NB parties are not aware of MDR quality issues and, therefore, don’t accept such certificates. Is the approach of NB correct?

Answer: No, such NB approach is not correct. We received similar complaints from our clients. NBs could be concerned about everything. However, such concern doesn’t give them the right to “invalidate” the ISO 13485 certificate issued by the non-NB accreditation body. If NB suspects that the non-NB party that issued the ISO 13485 certificate is unaware of MDR-related quality aspects, they should check them during their annual audit. After all, the manufacturer is expected to meet quality MDR expectations, and it can summarize them, e.g., in the Strategy for regulatory compliance procedure, which may include the control of your service providers.

Question: What are the clinical evaluation requirements for orphan devices?

Answer: As per  MDCG 2024-10 Clinical evaluation of orphan medical devices, the clinical evaluation requirements for the orphan devices are the same as for the other medical devices (as per MDR, Article 61 and Annex XIV). The clinical evaluation includes the following stages:

• establish and update a clinical evaluation plan;
• identify relevant clinical data and any limitations in clinical data;
• appraise all relevant clinical data;
• analyze all relevant clinical data;
• generate new or additional clinical data needed to address outstanding issues;
• document this evaluation in a clinical evaluation report; and
• update the clinical evaluation through PMCF activities.

Question: Do implantable devices and/or class III orphan devices (OD) require clinical investigation?

Answer: Yes, these group devices would require clinical investigations unless they are exempt under MDR (Article 61). Due to the complexity of OD clinical trials, new guidance advises to involve clinical experts for the appropriate clinical design. In addition, engagement with patients, patient associations, parents and/or caregivers of the target population may also be helpful in confirming whether the study includes patient-relevant clinical outcomes.

In Appendix A.2 of MDCG 2024-10 Clinical evaluation of orphan medical devices, you can find additional considerations for clinical investigation design (for all medical device classes), including:

• Defining the study population
• Selecting appropriate objectives and endpoints
• Choice of study design
• Choice of comparator
• Study monitoring

The company should also assess the possibility of using clinical data extrapolated from the use of the device in other, non-orphan populations (see Appendix A.3 of the guidance on extrapolation).

Question: What information should be included in the Clinical evaluation plan (CEP) for the orphan device (OD) according to EU-MDR and new guidance (MDCG 2024-10)?

Answer: In your CEP you should relate to disease-specific factors, which include:

• Information on the relevant disease or condition – Epidemiology, including incidence supporting the OD status; Patient population in which the OD is intended to be used; Severity of the disease/condition, including details on its morbidity and mortality; Factors of the disease or condition that contribute to the challenges and difficulties to generate pre-market clinical data in this population, including (if applicable) legal or ethical challenges to conducting clinical investigations in relevant vulnerable populations.
• The current state of the art in the management of the disease/condition in question: Identify and describe all relevant alternative diagnostic and/or therapeutic options (if any); Explain the relevant limitations (if any) in the clinical management of the disease in the existing state of the art.

In addition, CEP for OP should include device-specific factors, including:

• Summary of supporting information to justify that the device meets the criteria for orphan device status;
• Summary of pre-clinical evaluation, including relevant non-clinical data;
• Justification for acceptability of limitations in pre-market clinical data.

Question: What are EU-MDR requirements for class I devices?

Answer: All requirements for the Class I devices are summarized in MDCG 2019-15 rev.1

Question: According to EU-MDR, what is considered a non-significant change for medical devices? We assume such a change wouldn’t affect the product’s clinical evaluation. Is that correct?

Answer: The assessment of non-significant change should be made on a case-to-case basis. In general, we can say that non-significant changes could include:

• Change that doesn’t alter built-in control mechanism, operating principle
• Replacement of a component with the same specifications
• New supplier/producer of a material within the defined specifications
• Security updates (e.g. cyber-security enhancements)
• Updates/upgrades of operating systems, e.g., Microsoft Windows, iOS, and others

Such a change wouldn’t usually affect the clinical evaluation of the product, assuming the device’s risk/benefit ratio is not negatively affected.

Question: Which content should be included in the Clinical Evaluation Report (CER) for Orphan Device (OD)

Answer:  CER for OD should include summary descriptions of the orphan device-specific considerations laid out in MDCG 2024-10  device, including:

• Summary of how the device meets the criteria for orphan device status;
• summary of any identified limitations in clinical data and residual risks, including a description of how these were identified;
• acceptability of these limitations in clinical data and residual risks, with particular justification that:
  • all available non-clinical and clinical data relevant to the OD have been evaluated, and any limitations in clinical data have been identified;
  • the existing non-clinical and limited clinical data is sufficient to demonstrate that the relevant GSPRs in Annex I MDR are met, that the benefit-risk ratio is acceptable, and that it is expected that the device will provide a clinical benefit considering the clinical condition, the state of the art, and the safety of patients;
  • it is not feasible or proportionate to generate further clinical data within an acceptable time frame in the pre-market setting;
  • the manufacturer has an adequate PMCF plan that, once executed, will generate clinical data in an appropriate timeframe that will fully address the remaining limitations in clinical data.
  • users of the device will be adequately informed (e.g. by provision of information in the IFU, SSCP (for implantable and class III devices), and/or other accompanying documentation) of the orphan status of the device, the limitations in pre-market clinical data, and instructions to users on how to report incidents, complaints, and other clinical experience to the manufacturer.
• summary of the applicable non-clinical data that was evaluated as part of clinical evaluation planning;
• summary of pre-market clinical data that have been identified and evaluated, including any clinical investigations;
• a clear, stringent, and detailed PMCF plan with due regard to section, including:
  • summary of the risk management plan;
  • description of the type and quality of data that needs to be generated in the post-market phase in order to further evaluate the clinical performance and clinical safety of the device and address identified limitations in clinical data;
  • description on how the manufacturer plans to generate these data in an appropriate, timely manner;
  • projections on the number of patients that will be managed with the device per year in the EU;
  • a summary of planned PMCF activities including, as applicable, PMCF investigations and registries in the EU and globally for this device;
  • for orphan devices that carry significant risks (i.e. significant residual risks and/or high risk of causing serious adverse events), confirmation that the manufacturer will prospectively enroll a representative majority (e.g. greater than 90% if feasible) of patients into PMCF activities including PMCF investigations and/or registries;

• summary of any interactions with expert panels;
• a plan to update the clinical evaluation report at pre-defined intervals as appropriate, based on the PMCF plan, and whenever new information becomes available that may change the device’s benefit-risk profile.

Question: What is considered a reasonably foreseeable misuse? Should we address such use in a clinical evaluation?

Answer: A reasonably foreseeable misuse (intentional or unintentional) is the use of a product or system in a way not intended by the manufacturer but which can result from readily predictable human behavior. Note that readily predictable human behavior includes the behavior of all types of users, e.g. lay and professional users (ISO 14971:2019 (3.15). Yes, you should address such us in the clinical evaluation.

Question: During the audit our Notified Body (NB) reviewer asked to see Clinical Evaluation Report – CER (according to EU-MDR Article 23) for the critical part included in our device. We disagree with such an opinion. Is our NB correct?

Answer:  According to MDR Article 23 (Parts and components) only “An item that is intended specifically to replace a part or component of a device and that significantly changes the performance or safety characteristics or the intended purpose of the device shall be considered to be a device” and needs to comply with MDR.
This means that company which repairs the device by replacing a part or component of a device that significantly changes the performance or safety characteristics or the intended purpose of the device – such item/part/component will be considered medical device and be CE certified (which includes CER); and such entity would be regarded as – a legal entity.