Clinical evaluation of medical devices under the EU MDR

Conformity assessment of a medical device under the EU MDR requires a demonstration that the device meets the relevant General Safety and Performance Requirements (GSPRs), which shall include a clinical evaluation. This article covers the most frequent misconceptions regarding clinical evaluation under the EU MDR and intends to help manufacturers understand what is required and how to document it.

Replaces the previous version of 26.04.2022

Key Takeaways

• Clinical evidence is required for all medical devices under the EU MDR. It is incorrect to claim that Class I devices have low risk, and thus do not require a clinical evaluation.
• EU MDR Art. 61(10) cannot be invoked as justification for not collecting clinical data when clinical claims are made. And even when not using clinical data to demonstrate GSPR conformity is deemed appropriate, a Clinical Evaluation Report is still required.
• Clinical investigations are required for Class III and implantable medical devices, with a few exceptions. Make sure you understand them well.

Content

What is the purpose of the clinical evaluation under the EU MDR? Is it always required?

The clinical evaluation is meant to assess the performance and safety of a medical device under the normal conditions of its intended purpose, including any undesirable side-effects and the acceptability of its benefit-risk ratio. It is therefore the cornerstone of medical device validation and conformity assessment under the EU MDR. Any regulatory strategy for CE-marking should also address the most suitable clinical strategy.

As part of the clinical evaluation, the manufacturer is expected to prove the clinical benefits of the device, i.e. “the positive impact of a device on the health of an individual, expressed in 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” [EU MDR, Art. 2(53)].

In brief, if clinical claims regarding clinical benefits are made, supporting clinical data is needed, and a clinical evaluation is therefore required. This applies to all medical device classes without exception. It is incorrect to claim that Class I devices have low risk, and thus do not require a clinical evaluation. Moreover, the manufacturer must specify and justify the level of clinical evidence necessary to demonstrate conformity of the device with the relevant General Safety and Performance Requirements (GSPRs) in Annex I of the EU MDR. That level of clinical evidence shall be appropriate in view of the characteristics of the device and its intended purpose.

The clinical evaluation is one of the most labor-intensive and expensive parts of a device’s conformity assessment. If clinical data needs to be generated (i.e. through clinical investigations), the process can take several years.

EU MDR Art. 61(10) is sometimes incorrectly invoked as an excuse for not conducting a clinical evaluation. This approach is not possible for Class III or implantable devices. For all other devices, Art. 61(10) allows an exception for not demonstrating conformity with GSPRs based on clinical data. Because GSPRs nr. 1, 5, and 8 involve demonstrating safety and performance of the device in consideration of the State of the Art (commonly referred to with the acronym SOTA), mitigating use-related errors, and achieving an acceptable risk-benefit profile, it is very difficult to successfully fulfill these requirements without clinical data for any medical device that exhibits clinical benefits and potential use-related errors. 

Any regulatory strategy for CE-marking should also address the most suitable clinical strategy.

Moreover, if a manufacturer makes clinical claims relative to clinical benefits, then Art. 61(10) is not appropriate and clinical data is required. In brief, Art. 61(10) is not an approach for devices where clinical data is missing or is insufficient.

If clinical data is indeed not appropriate, the manufacturer must document an appropriate justification as to why demonstration of conformity with the GSPRs may be achieved via non-clinical testing methods alone (including performance evaluation, bench testing and pre-clinical evaluation). Such justification must consider the specifics of the interaction between the device and the human body, the clinical performance intended and the claims of the manufacturer. Now, Notified Bodies expect that under Art. 61(10) a Clinical Evaluation Plan and a Clinical Evaluation Report are compiled, where the manufacturer discusses how the relevant GSPRs can be met in the absence of clinical data and, at a minimum systematic literature searches are conducted to establish the State of the Art (SOTA) and to demonstrate that there is no clinical data available. See also, Where should clinical evidence be documented under the EU MDR?

What does the clinical evaluation entail?

Any clinical evaluation shall follow a defined and methodologically sound procedure based on the following: 

“(a) 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, in accordance with Section 3 of Annex XIV, and 

— the data adequately demonstrate compliance with the relevant general safety and performance requirements; 

(b) a critical evaluation of the results of all available clinical investigations, taking duly into consideration whether the investigations were performed under Articles 62 to 80, any acts adopted pursuant to Article 81, and Annex XV; and 

(c) a consideration of currently available alternative treatment options for that purpose, if any.”
[EU MDR, Art. 61(3)]

Part A in Annex XV of the EU MDR provides further details on the methodology and documentation required for a clinical evaluation. See also, Where should clinical evidence be documented under the EU MDR?

The clinical evaluation and its documentation must be maintained up-to-date throughout the entire life cycle of the medical device [EU MDR, Art. 61(11)]. This is achieved with the collection and analysis of clinical data through the Post-Market Clinical Follow-up (PMCF) activities. Therefore, where a Clinical Evaluation Report (CER) exists, a PMCF Plan and Report are required as the mechanisms to keep the CER updated. For more details, see Where should clinical evidence be documented under the EU MDR?

What clinical data is required for the clinical evaluation? When can clinical investigations be avoided?

According to the legal definition in EU MDR Art. 2(48), “clinical data” refers to information concerning device safety or performance that is generated from the use of the device under evaluation, or of a device for which equivalence can be duly demonstrated, and is sourced from:

• clinical investigations or other studies reported in scientific literature, 
• reports published in peer reviewed scientific literature, as well as  
• clinically relevant information coming from post-market surveillance, in particular the post-market clinical follow-up.

For establishing device conformity to the relevant GSPRs, the suitability, quality, and quantity of different clinical data sources and the required “level of clinical evidence” must be justified by the manufacturer in view of the characteristics of the device and its intended purpose device [EU MDR, Art. 61(1)]. 

Not all clinical data sources have the same level of clinical evidence. Appendix III in MDCG 2020-6 on the clinical evidence needed for legacy devices transitioning to the EU MDR, proposes a ranking with 12 levels that can be also useful for newly developed medical devices. 

• High-quality clinical investigations and data collected from registries rank at the top. Notably, for implantable and class III devices, clinical data from these high-quality data sources must include data obtained with the device under evaluation.
• For “well-established technology” (WET), lower weighted “level of clinical evidence” data sources, can be used via a cumulative assessment to support their conformity assessment. In any case, reliance on Vigilance and complaint data alone is not sufficient. WET, as described in the same MDCG 2020-6, concerns devices that display a simple, common, and stable design, with well-known performance and safety across the generic device group, as well as a long history on the market.

Note that Team-NB expects manufacturers to consider off-label data as part of the overall clinical evaluation, but such data cannot be used to expand the device’s intended purpose or indicates as it lacks sufficiency.

In the case of implantable devices and Class III devices, clinical investigations are mandatory [EU MDR, Art. 61(4)] but certain exemptions apply. These are summarized in the below table.

MDCG 2023-7 provides further interpretation and guidance on these exemptions.

As to devices that are neither Class III nor implantable, the need for a clinical investigation is determined by the objectives of the clinical evaluation that the manufacturer needs to establish as part of the Clinical Development Plan, in order to achieve conformity with the applicable GSPRs.

What constitutes an “equivalent” device under the EU MDR? 

In simplified terms, an “equivalent” device under the EU MDR is a device with similar technical characteristics, and both the same biological and clinical characteristics, when compared to the device under evaluation. In the case of medical device software (MDSW), logically, biological characteristics are irrelevant.

To confirm equivalence, a side-by-side comparison of technical, biological, and clinical parameters should be made, as indicated in Annex I of guidance document MDCG 2020-5. Any differences in technical, biological, and clinical characteristics between the two devices must be identified, and for each difference a scientific justification provided as to why these differences would not have a clinically significant impact on performance and safety. 

“Equivalence” according to the EU MDR should not be mistaken with similar terms from other jurisdictions, such as “predicate” or “substantially equivalent”.

Additionally, it must 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” [EU MDR, Annex XIV, Part A (3)]. As a device’s data related to technical characteristics is commonly only detailed within internal documentation, access to this information is often unattainable. For implantable and class III devices, the extent of this level of access must be contractually agreed between the manufacturer of the equivalent device and the manufacturer of the device under evaluation to ensure full and ongoing access to the technical documentation of the equivalent device.

Consequently, equivalence according to the EU MDR should not be mistaken with similar terms from other jurisdictions, such as “predicate” or “substantially equivalent” devices, as used in the US. “Predicate” devices may function to support approval in the US market, but the higher requirements for equivalence under the EU MDR mean that such devices would only qualify as “similar” devices under the EU MDR. This is now also the case for many devices that used to be considered “equivalent” under the former MDD, where equivalency criteria were not so strict.

¨“Similar” devices are defined in the EU MDR as devices with shared characteristics which can be considered to belong to the same generic device group.These “similar” devices may provide input for various aspects of the clinical evaluation process and provide contextual support to observed clinical performance and safety of the device under evaluation, for example as a benchmark device when establishing the state of the art. However, the clinical data from “similar” devices cannot be used as part of the clinical evidence demonstrating equivalent performance and safety for the device under evaluation.

What differentiates clinical investigations from usability studies?

Usability engineering (also referred to as human factors engineering) relates to activities performed to assess the appropriateness of a medical device’s user interface, when used as intended. The goal is to identify risks or limitations that may impede the specified users from appropriately using the device. Outcomes from usability testing allow the manufacturer to take action to eradicate or minimize these aspects in the final device, and they are therefore an inherent component of device development. Once standard EN 62366-1 relative to usability engineering for medical devices is harmonised with the EU MDR, it can be used to demonstrate compliance with EU MDR usability requirements.

Some testing for validation of usability aspects is unavoidable to comply with GSPR nr. 5, i.e. to address use-related hazards. If the preliminary risk analysis for the device reveals few use-related hazards of minor severity, the type of usability testing required can be much simpler and does not involve clinical investigations.

Usability studies that are a “systematic investigation involving one or more human subjects” correspond to the definition of clinical investigation since they are intended to assess the safety and/or performance of the device [EU MDR, Art. 2(45)]. These studies can be formative, in the early stages of device development, or summative, as final validation of usability aspects.

Formative usability studies can be integrated into feasibility studies (also referred to as exploratory studies), which are small-scale clinical investigations intended to establish preliminary safety and effectiveness of the device. Feasibility studies inform the design of subsequent pivotal or confirmatory clinical investigations to generate clinical data that demonstrates device safety and performance. 

Both feasibility and pivotal clinical investigations must be performed in compliance with EU MDR Chapter VI and Annex XV, as well as with Good Clinical Practice (EN ISO 14155). 

Can data from clinical studies performed outside the EU be used for CE-marking under the EU MDR?

Clinical investigations in support of CE-marking under the EU MDR are expected to be performed in the EU and according to Good Clinical Practice (i.e. per EN ISO 14155), have ethics committee’s approval, patient’s informed consent, and respect any additional national/local requirements of the EU Member State in which they are performed. 

The EU MDR does not specifically address clinical investigations performed in different regulatory jurisdictions. However, Appendix D in IMDRF guidance on clinical evaluation (IMDRF MDCE WG/N56FINAL:2019) does, stating that “when clinical investigations are conducted ethically in accordance with applicable Good Clinical Practice (GCP), the clinical data should be accepted for consideration in any jurisdiction”. However, the guideline stresses that this is dependent on the clinical investigation being conducted to the same regulatory standards, and reflects the population and intended use of the jurisdiction in which it will be marketed.

Clinical investigations in support of CE-marking under the EU MDR are expected to be performed in the EU.

This means that clinical investigations performed outside the EU would need to be performed according to EN ISO 14155 and EU MDR Annex XV, and their study plans would need to ensure that any differences have no clinically significant impact on the resulting clinical data. Therefore, any non-EU clinical data generated must be critically assessed and a scientific justification must be provided as to why any regional, intrinsic, and extrinsic factors, like regional population genetics or regional diseases, have not impacted the validity of the resulting clinical data and conclusions, relative to the intended population and intended clinical use setting in the EU. This is also the expectation of Notified Bodies, as explicitly stated in Team-NB’s Best Practice Guidance for the submission of Technical Documentation under the EU MDR.

Where should clinical evidence be documented under the EU MDR?

The clinical evaluation must follow a specific plan that needs to be documented in a Clinical Evaluation Plan (CEP) and includes the Clinical Development Plan (CDP). Then, the outcome of the clinical evaluation conducted according to the CEP must be documented in a Clinical Evaluation Report (CER), which shall support the assessment of the conformity of the device.

The clinical evaluation is continuously maintained up-to-date through Post-Market Clinical Follow-up (PMCF) activities, which in turn require a PMCF Plan (PMCFP) and a resulting PMCF Report (PMCFR). Thus, the CEP, CER, PMCF Plan and PMCF Report are living documents that are updated throughout the device’s lifetime. 

The manufacturer must follow EU MDR Annex XIV to establish a compliant clinical evaluation process within its Quality Management System that yields appropriate CEP, CER, PMCF Plan and PMCF Report.

Details on the contents expected by Notified Bodies for these documents can be found in Team-NB’s Best Practice Guidance for the submission of Technical Documentation under the EU MDR. For example, this document points to the old MEDDEV 2.7/1 Rev. 4 guideline, as reference for a helpful layout for the contents of a CER.

In the specific case of Class III devices and Class IIb active devices intended to administer and/or remove a medicinal product, a Clinical Development Strategy with proposals for clinical investigation is a preliminary document that may be submitted to an expert panel for review, and would need to be considered [EU MDR, Art. 61(2)].

The below infographic illustrates the interrelation between the different documents involved in a clinical evaluation.

The CEP, CER, PMCF Plan and PMCF Report are continuously updated throughout the device’s lifetime.

To avoid objections from Notified Bodies who will review the manufacturer’s clinical evidence, the relevant MDCG guidance documents should be followed as closely as possible. This includes:

• MDCG 2020-1, on clinical evaluation (under the EU MDR) and performance evaluation (under the IVDR) of medical device software,
• MDCG 2020-5, on equivalence for clinical evaluation, and
• MDCG 2020-6, on clinical evidence needed for medical devices previously CE marked under the MDD or AIMDD.
• MDCG 2020-7, PMCF Plan template.
• MDCG 2020-8, PMCF Report template.

Note also that the clinical evaluators must be suitably qualified, and can be in-house personnel or subcontracted experts. The Notified Body’s expectation is that the clinical evaluators have a full range of expertise (e.g. clinical research methods, relevant regulatory requirements, device technology, and of course diagnosis and management of the conditions to be treated). The qualification needs are better described in chapter 6.4 of the old guideline MEDDEV 2.7/1 rev.4 that is still used as reference for aspects not covered in the above MDCG guidance documents.

In addition, MDCG 2020-13 is a tremendously helpful document, as it is the template of the clinical evaluation assessment report that Notified Bodies must complete upon conformity assessment and, as such, provides valuable insights on what they look for during CER audits. For example, for manufacturers claiming that demonstration of conformity with general safety and performance requirements based on clinical data is not deemed appropriate in accordance with Article 61(10), section J indicates that “a clinical evaluation is still required and the above information and evidence-based justification shall be presented in the clinical evaluation report.”

How can Decomplix help?

Understanding the requirements regarding clinical data is crucial for establishing a meaningful clinical strategy, and ultimately achieving CE-marking smoothly and without unnecessary efforts. For example, do you have questions on what clinical data are required for your devices to successfully undergo the conformity assessment under the EU MDR? Do you wonder how to merge usability engineering and clinical evidence?

Our team of experts will be happy to support you in developing the regulatory strategy including a roadmap and specific questions on clinical data, clinical evaluation reports and clinical studies.

Learn more about Decomplix services here.

Further reading

• The intended purpose – or, what does your medical device do?
• Medical device regulatory strategy – US vs. EU
• Medical device classification under the EU MDR: 8 things you need to know
• How to obtain a CE mark for a medical device
• Post-market Surveillance (PMS) for medical devices under EU MDR and IVDR

This article was last updated in September 2024 to shift the focus to a few frequent misconceptions about clinical evaluation under the EU MDR, as well as to include information from relevant MDCG guidance documents and Notified Body’s expectations.