Clinical Evaluation for Medical Device Approval

The definitive guide to how effective Clinical Evaluation drives EU MDR Compliance

Clinical Evaluation & the EU MDR

Conducting a Clinical Evaluation is a vital step in securing regulatory approval for any medical device in the EU and UK. Clinical Evaluation is one of the most important — and most challenging — phases of any medical device regulatory submission, meaning that it’s vital to be well prepared and well informed.

This guide offers a deep-dive into the anatomy of a successful Clinical Evaluation, exploring requirements, top-tips and detailed insights into each component of the process. It also provides links to useful resources and guidance documents that can help support your Clinical Evaluation submission.

What is a Clinical Evaluation?

A Clinical Evaluation is a systematic and planned process to assess the safety and performance of a medical device. It can be thought of as a ‘pulling together’ of all available evidence relating to a medical device, along with evidence relating to similar devices already on the market.

A Clinical Evaluation seeks to address four fundamental questions:

1. Is the device suitable for its intended purpose?
2. Does it conform with the relevant Annex I General Safety and Performance Requirements (GSPRs)?
3. Is it at least non-inferior to safety & performance objectives derived from the SOTA?
4. Does the device have an acceptable benefit-risk profile?

A Clinical Evaluation is fed by information from multiple sources and processes, incorporating evidence generated and held by the manufacturer as well as evidence produced independently and published in the literature. Specific sourse of data include systematic literature reviews, Post-Market Surveillance (PMS), Post-Market Clinical Follow-up (PMCF) and Vigilance systems, as well as conclusions drawn from Risk Management and Quality Management Systems (QMS).

Because Clinical Evaluation draws upon so many sources, it can be challenging to stay on top of the process while remaining organised and ahead of timelines. For these reasons and others, it’s vital to have a detailed understanding of the steps involved in the correct performance of a medical device Clinical Evaluation.

The Clinical Evaluation process

Clinical Evaluation is a continuous process that is constantly fed by data from the sources identified above. Periodically, however, the results of Clinical Evaluation must be summarised in a technical document known as a Clinical Evaluation Report (CER).

The CER must be an extensive summary of the findings of Clinical Evaluation, written objectively and structured appropriately. CER writing is a demanding and time-consuming undertaking that requires a high level of regulatory expertise and medical writing capability.

Performing MDR Clinical Evaluation draws heavily upon an ability to work with clinical evidence. Medical device manufacturers will need to show that Clinical Evaluators of their products are appropriately qualified to perform the work and able to demonstrate a commitment to objectivity when handling data. Because Clinical Evaluation requires that appropriate weight is given to both favourable and unfavourable evidence, it is often beneficial for manufacturers to consider working with external specialists to maintain this level of objectivity.

Legislative requirements for performing a medical device Clinical Evaluation can be found in MDR Article 61 and Annex XIV Part A. The Annex requires that manufacturers:

• establish and regularly update a Clinical Evaluation Plan (CEP)
• identify all available clinical data (favourable or unfavourable) relevant to the device according to a documented search protocol
• identify any gaps in clinical evidence through a literature review
• appraise all relevant clinical data by evaluating the quality and relevance of each data source to the clinical evaluation
• generate any necessary new or additional clinical data required in order to address any identified gaps
• analyse all relevant clinical data in order to reach conclusions about the safety and performance of the device

Correct performance of a medical device Clinical Evaluation comprises three principal steps, best conducted in strict order:

1. State-of-the-art (SOTA) literature review
2. Clinical Evaluation Plan (CEP)
3. Clinical Evaluation Report (CER)

Following this sequence helps ensure that outputs of one process form an input into the next. Let’s take a look at each in turn.

1. State-of-the-art (SOTA) literature review

The foundation of any successful medical device Clinical Evaluation is a well-conducted SOTA literature review. Often overlooked, the SOTA review defines a ‘line in the sand’ that will be used in the CER to determine whether safety and performance of the subject device is acceptable when compared with alternatives.

The purpose of the SOTA literature review is to conduct a detailed analysis of evidence relating to devices that are similar to, or form comparable alternatives to, the subject device. This involves a comprehensive systematic literature review conducted according to a documented protocol. Principles guiding appropriate conduct of a SOTA review include:

• Objectivity – the review should include both positive and negative data, as available, with no artificial selectivity
• Impartiality – it should ideally be conducted by an independent professional with appropriate experience in the clinical field, ensuring that the review isn’t swayed by an interest in the subject device
• Reproducibility – the method of the review outlined in the Protocol should enable another person to replicate the review and achieve the same outcomes
• Use of a documented process for identification, appraisal and analysis of sources
• Use of a validated method, such as PICO, for construction of research questions and search terms
• Providing a full record of all excluded sources against each search term
• Use of at least two literature databases, helping avoid accidental exclusion of relevant sources.

The SOTA review should comprise both a Protocol and a Report, although it is acceptable to combine both within a single document.

The SOTA review forms a vital part of the Clinical Evaluation process because it defines clinical outcome parameters and safety & performance objectives that will be used as a means of comparison during the analysis of subject device data.

• Clinical outcome parameters are qualitative “types of output” that the SOTA review reveals to be commonly-reported outcomes. Examples might include “improvement in walking distance” or “change in frequency of arrhythmia episodes per day”.
• Safety & performance objectives are numerical values relating to identified clinical outcome parameters, such that the array of results for each parameter across the literature is reduced to a single value. Calculating this value requires calculation of a weighted mean, wherein the contribution of each source is weighted according to factors such as study quality and sample size.

Further objectives of the SOTA review are to:

• Place the subject device into its clinical context
• Enable the determination of a qualitative state-of-the-art statement, setting out a justification for concluding that the subject device reflects a recognised and accepted approach to a clinical problem.

Please see the dedicated Literature Search & Review guide for greater detail on this subject.

Clinical Evaluation Plan (CEP)

The Clinical Evaluation Plan (CEP) sets out a method for ensuring conduct of the Clinical Evaluation in alignment with MDR Article 61 and Annex XIV Part A. Informed by the SOTA review, it should also describe how the subject device will be evaluated against the four major Clinical Evaluation objectives described above, including alignment with safety & performance objectives.

Please see the dedicated Clinical Evaluation Plan guide for greater detail on requirements for producing an effective CEP.

Clinical Evaluation Report (CER)

The Clinical Evaluation Report (CER) forms the culmination of the Clinical Evaluation process. A CER is a detailed and complex document requiring expertise in technical regulatory writing alongside relevant clinical experience.

The CER incorporates outputs from the SOTA review process and reports on the results of a Clinical Evaluation conducted according to the CEP. Written correctly, the CER will include an analysis of subject device data derived from an array of inputs, including:

• Outcomes relating to any previous versions of the device
• Pre-clinical testing
• Clinical investigations conducted by the manufacturer
• Outcomes of Post-Market Surveillance and PMCF activities
• Searches of adverse events databases such as MAUDE, MHRA and DAEN
• Results of a systematic literature review designed to identify device-specific safety & performance outcomes

Risk Management also forms a vital input into each Clinical Evaluation. Risk Management concerns processes for identifying, analysing, monitoring and controlling risk, alongside consideration and evaluation of clinical benefits resulting from use of a device. The MDR accepts that risks cannot be eliminated from the use of medical devices, and instead requires that manufacturers provide evidence that individual risks are appropriately controlled, overall residual risk is acceptable and that the benefit-risk profile of the device is favourable. ISO 14971:2019 outlines an internationally recognised standard for medical device risk management.

Demonstrating an acceptable benefit-risk profile is a major objective of medical device Clinical Evaluation. Requirements extend beyond a simple qualitative comparison of benefits and risks, calling for determination of a quantitative benefit-risk ratio, appropriately weighted by rate of observed occurrence of benefits and risks.

Once all relevant data sources have been assimilated, the Clinical Evaluation Report can begin to take shape. In terms of structure and content, valuable sources of guidance include:

• MDCG 2020-13 – sets out a scheme for Notified Bodies to use when conducting reviews of CERs
• MDCG 2020-5 – provides guidance on including a claim of equivalence, wherein evidence relating to another device may be used to represent safety and performance of the subject device
• MDCG 2020-6 – guidance of specific aspects of clinical evaluation for legacy devices previously approved under MDD
• MDCG 2020-1 – specific information relating to clinical evaluation of Software As A Medical Device (SaMD) products
• MedDev 2.7/1 Rev 4 – while now outdated, this was the primary guidance source for Clinical Evaluation under MDD and still contains valuable principles.
• Free CER templates

Please see the dedicated Clinical Evaluation Report guide for greater detail on requirements for producing an effective CER.

How often should a Clinical Evaluation be performed?

The EU MDR requires that Clinical Evaluation is a constant process that is conducted throughout the entire lifetime of every medical device, summarised periodically in a Clinical Evaluation Report (CER). The required periodicity is determined by the risk class of the device.

The CER should also be updated in the event of one or more of the following:

• New evidence from PMS or other sources suggests that previous conclusions on safety, suitability for intended purpose or overall benefit-risk ratio may need to be revisited
• Non-minor changes have been made to the design of the device or its interaction with users
• The intended purpose or use population of the device has altered
• Other triggering information

How has the introduction of EU MDR impacted Clinical Evaluation?

When the Medical Device Regulation (MDR) 2017/745 replaced the Medical Device Directive MDD 93/42/EC, it represented the most significant overhaul of medical device regulation in a generation. All medical devices and medical device manufacturers within the EU need to comply with the MDR regulations (with transitional arrangements in place) in order to trade and sell in the EU market.

As a consequence of the enhanced requirements imposed by the MDR, many medical device Clinical Evaluations that were acceptable under MDD are now failing to meet conformity under MDR.

Specific changes to Clinical Evaluation introduced by the MDR include:

• Replacing the MDD Essential Requirements with the Annex I General Safety and Performance Requirements (GSPRs). The GSPRs are more extensive and specific than the Essential Requirements and raise the required evidence burden for manufacturers.
• Thoroughly overhauling rules on equivalence, making it much more difficult for manufacturers to successfully claim equivalence under the MDR. In many cases, manufacturers who previously claimed equivalence will need to completely re-engineer the Clinical Evaluation for their devices.
• Assigning a new risk classification to some devices, increasing the complexity of Clinical Evaluation required for devices that have been allocated a higher risk category.
• Introducing enhanced requirements for Post-Market Clinical Follow-up (PMCF), detailed in MDR Annex XIV Part B, that require manufacturers to establish more robust PMCF systems and include outputs of PMCF into the Clinical Evaluation for each device.
• Mandating a higher level of detail and structure in CERs, including calling for granularity of evidence across all components of a device’s intended purpose and user population (especially any ‘special interest’ populations).

Is a Clinical Investigation mandatory for MDR Clinical Evaluation?

MDR Article 61 sets out requirements for conduct of a clinical investigation in preparation for Clinical Evaluation. The Article is important to study in detail as its drafting style makes its comprehension challenging, although its vital to avoid any misinterpretation as the consequences could be highly problematic.

Article 61(1) defines the basic position, which is that Clinical Evaluation shall be based on ‘sufficient clinical evidence’, with the manufacturer responsible for justifying the level of evidence required. While this appears to offer relatively free rein to the manufacturer, this is constrained by the requirement that the level of evidence “shall be appropriate in view of the characteristics of the device and its intended purpose”.

Article 61(4) determines that the ability of the manufacturer to define the level of evidence required does not apply to implantable or Class III devices, for which a clinical investigation is normally mandatory. Articles 61(4), 61(5) and 61(6) then set out exceptions to this general position, and it is these that are especially prone to misinterpretation. In summary, clinical investigations are not required for a Class III / implantable device if:

• It is a development of a predicate device from the same manufacturer, the predicate is equivalent to the subject device, and there is sufficient evidence on the predicate device (Article 61(4))
• It is equivalent to a device from another manufacturer, there is a contract in place granting access to the equivalent device’s technical files, and investigations performed on the equivalent device complied with MDR requirements (Article 61(5))
• It is a legacy device previously approved under Directives 90/385/EEC or 93/42/EEC, its Clinical Evaluation is based on ‘sufficient clinical data’, and it complies with relevant product-specific Common Specifications, where available (Article 61(6a))
• It is a Well-Established Technology ‘similar’ to those listed in Article 61(6b), there is ‘sufficient’ clinical evidence, and (where applicable) the device conforms with product-specific Common Specifications (Articles 61(6a) and 61(8)).

While not applicable to Class III or implantable devices, a further exception to the requirement for clinical evidence is provided by Article 61(10), which applies to circumstances in which conformity on the basis of clinical evidence would be ‘inappropriate’. This route to conformity allows Clinical Evaluation to be based on non-clinical testing methods alone, including performance evaluation, bench testing and pre-clinical evaluation – however, it only applies in specific circumstances and its use must be carefully justified.

Of note, Article 61(10) is not intended for use when clinical data is unavailable and it does not relieve manufacturers of the responsibility to generate evidence where relevant; it only applies to device types, such as oxygen gas taps or blood unit fridges, where it would not be appropriate to evaluate safety or performance using clinical data.

Clinical Evaluation support services

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