Ultimate Guide to Clinical Evaluation of a Medical Device in the EU

To obtain a CE marking and market your medical device in the EU, you’ll first need to perform a clinical evaluation—and report your findings in a Clinical Evaluation Report (CER).

A clinical evaluation is required for every medical device sold in the EU, regardless of risk classification, and it tends to be a lengthy and highly involved process.

At Greenlight Guru, we understand just how difficult the clinical evaluation process can be, which is why we’ve put together this eBook to help manufacturers understand the essentials of clinical evaluation for medical devices.

Create a Clinical Evaluation Process & Establish Equivalency

Clinical evaluation of medical devices is mandated under the EU Medical Device Regulation (EU MDR). However, the clinical evaluation process is laid out in MEDDEV 2.7.1 Rev 4, a guidance document put out by the European Commission. 

MEDDEV 2.7.1 Rev. 4 lists four stages of a clinical evaluation:

• Stage 0 - Scope: The scope and context of the clinical evaluation, including the product being tested and any sizes or settings covered in the evaluation. This also includes an explanation of the technology the device is based on and any claims about its performance or safety.

• Stage 1 - Identification of pertinent data: This may include any data generated by the manufacturer, including premarket clinical investigations, as well as data from literature.

• Stage 2 - Appraisal of data: In this stage the data is appraised and the validity of each data set must be determined, as well as its relevance to the clinical evaluation and how heavily it should be weighed in the overall evaluation.

• Stage 3 - Analysis of clinical data: This is the actual analysis of the clinical data, which should include the benefits and risks of the device, explain the acceptability of the benefit/risk profile, and address any residual risks, uncertainties, or unanswered questions.

Additionally, there is a fifth stage (stage 4) that the guidance document places in its own category: writing the CER. The CER is a living document which demonstrates that your device fulfills its intended purpose without compromising the safety of patients or users.

Your CER is only as good as the clinical data you obtain and your methods for analyzing it, so let’s take a closer look at the first stage of your clinical evaluation.

Define your scope and build a clinical evaluation plan

Clinical evaluation is a systematic process. In practice, this means you need to create a plan for carrying out the evaluation and then document the steps you took in executing that plan. 

MEDDEV 2.7.1 Rev 4 states that your first step should be to define the scope of the evaluation, which should include:

• The device description.

• Any design features, indications, or target populations that need specific attention during the evaluation.

• The information you need for evaluating equivalence, if you intend to claim it.

• Risk management documents such as the hazard identification list and any clinical risks identified from the risk analysis. Your clinical evaluation will be expected to address the significance of any clinical risks that exist after risk mitigation strategies have been applied during design.

• Current knowledge or state of the art. This includes other devices and medical alternatives available to the target population and information about the condition managed by the device and its natural course. This also includes applicable standards and guidance documents. 

• The data sources and types you will use in the clinical evaluation. This may be data generated by the manufacturer (direct) or data from scientific literature (indirect).

Once you’ve addressed the scope of your clinical evaluation, you need to put together the clinical evaluation plan that will guide your data collection, appraisal, and analysis. 

You can find the requirements for a clinical evaluation plan in Annex XIV of MDR, which states that the plan should at least include:

• The general safety and performance requirements that you need to support with relevant clinical data.

• The intended purpose of your device.

• The intended target populations with clear indications and contra-indications. 

• The intended clinical benefits to patients with relevant and specified clinical outcome parameters. 

• The methods you’ll use for examining qualitative and quantitative aspects of clinical safety with clear reference to the determination of residual risks and side-effects. 

• The parameters you’ll use to determine, based on the state of the art in medicine, the acceptability of the benefit-risk ratio for the various indications and for the intended purpose(s) of the device.

• How you will address benefit-risk issues relating to specific components such as use of pharmaceutical, nonviable animal, or human tissues.

• 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.

Establish equivalency with devices already on the market

Though it isn’t listed as one of the discrete stages in clinical evaluation, if you intend to establish equivalency with another device, you should do so before gathering clinical data. 

That’s because if you can establish equivalence with another device, you can use literature and clinical data regarding the equivalent device in your clinical evaluation. It also saves you from potentially having to perform a redundant clinical investigation when there are already studies available on an equivalent device. 

Keep in mind, under EU MDR, you must demonstrate that your device is equivalent in all three of the following ways:

• Clinical

• Technical

• Biological

The full criteria for these characteristics is laid out in Annex I of MEDDEV 2.7.1 Rev 4. However, there are differences between the text in EU MDR and MEDDEV, which the European Commission has addressed in their guidance document on equivalence, MDCG 2020-5.

Identify Relevant Data and Create a Literature Review Protocol

Now that you’ve established the scope for your clinical evaluation, created a plan to carry it out, and identified any equivalent devices, your next step is to begin gathering relevant data. A successful clinical evaluation hinges on your ability to find and appraise the data you’ll need to demonstrate your device’s safety and performance. 

Determine where you’ll obtain clinical data for your clinical evaluation

Your clinical evaluation will be based on both direct and indirect data. 

Direct data is data that has been generated by your device, such as the data obtained from pilot studies or clinical trials. If your device is Class III or a Class IIb implantable, then you will be required to conduct clinical trials on your device and will generate direct data that way. 

Direct data also includes registries and publicly available data on your device. You’ll also generate direct data from your postmarket surveillance activities, though this won’t be available to you during the initial clinical evaluation process.

Indirect clinical data is data that has been generated by an equivalent device, which is why it’s important to establish equivalence early on. The decision to claim equivalence (or not) will be one of the factors that affects your literature review. 

The literature review is the means by which you obtain indirect clinical data. Many companies, especially if they are evaluating a low-risk device, will rely heavily on data from literature searches, as they won’t be carrying out any clinical trials. 

Goals of your literature review

Your literature review will have two outputs:

1. Literature on your device and the equivalent device (if applicable).

2. A review of the “current knowledge/state of the art” necessary for appraising and analyzing the clinical data from the literature on your device and any equivalent devices.
   
   

Let’s talk about the term “state of the art” for a moment. MEDDEV 2.7.1 Rev 4 defines “state of the art” as the:

applicable standards and guidance documents, information relating to the medical condition managed with the device and its natural course, benchmark devices, other devices and medical alternatives available to the target population.

Your device does not live in a vacuum. The benefit-risk assessment of your device in part depends on what alternatives to your device exist, and whether they pose more or less risk to a patient than your device. Put simply, “state of the art” refers to the best practices currently available in the marketplace, and your clinical evaluation must take into account how your device compares to those alternatives. 

Create your clinical evaluation literature review protocol

Once you know the outputs you’re looking for, it’s time to create a plan to obtain them. This means crafting a detailed protocol for your literature review. This isn’t an instance in which a Google search will turn up what you need; the literature review must be a systematic process.

Annex 5.3 of MEDDEV 2.7.1 Rev 4 includes a full list of what should be included in your search protocol, but here are a few pointers to keep in mind as you create your literature review protocol:

• Your protocol will need to clearly define the objectives of your literature evaluation. For instance, if there are particular risks related to your device that have been identified, one of your objectives may be to search for literature containing information on that risk. On the other hand, you might also search for literature pertaining to any clear benefits that have been identified with your device.

• You’ll need to designate specific terms that you’ll use in your search. If your terms are too broad, your search may return thousands of articles, many of which will be irrelevant to your clinical evaluation. 

• Your protocol also needs to establish which sources of information will be used for searches, and you need to be consistent about using those sources. That means applying the same search terms to several databases, such as PubMed, MEDLINE, or Embase. 

• Set up your search so that you get both titles and abstracts for the articles. The abstract will help you better determine whether you should acquire and read the full text of the article. This is what tends to make the literature review process so time-consuming—you need to read all of the relevant literature that your searches turn up.

Keep in mind: you cannot pick literature that will support your device and discard those papers that may be harmful to your cause. This is part of the reason you’re required to create a search protocol in the first place—it allows your Notified Body to retrace your steps if they have concerns about your literature review.

Appraise clinical data from your literature review

Even a literature search with specific, defined terms can turn up hundreds of results. That’s why it’s important to have a systematic approach to appraising which results you should use and which you should discard. Generally, you want to consider four factors:

• Suitability - Is this based on our device or an equivalent device?

• Applicability - Is this about other devices that use the same technology?

• Population - Is the population similar to the population we believe our device will treat?

• Quality - Is this literature published in a peer reviewed journal? Is the data generated from a randomized double-blind trial with a placebo, for instance?
  
  

That last point, quality, is a big one. In MEDDEV 2.7.1 Rev. 4, Annex 6 offers a number of points for concern you should look out for including:

• A lack of information on elementary aspects, such as methods, patient population, side-effects, or clinical outcomes.

• Statistically insignificant data or improper statistical methods.

• A lack of adequate controls leading to bias or confounding.

• The improper collection of mortality and serious adverse events data.

• Misinterpretation of data by the authors, such as when the conclusions they draw are not in line with the results section of the report.

• Any illegal activities, such as clinical investigations that were not conducted in compliance with local regulations. 
  
  

Once you’ve eliminated any results with these types of flaws, you’ll need to weigh the importance of the different data that you’ve obtained from your scientifically valid sources. 

At its most basic level, this means assigning a higher weighting to high-quality data that is most relevant to your device, and assigning a lower weighting to less relevant data. If you’re unsure about how to weight your data sets, Appendix III of MDCG 2020-6 provides a suggested hierarchy for clinical data that should be helpful.

It’s important to note that the appraisal of data may require someone with a specialized skill set, such as a statistician. In fact, it’s highly unlikely that one QA/RA professional can handle an entire clinical evaluation by themselves, and I certainly wouldn’t recommend trying.

Finally, your appraisal of the data must be documented, and it should be presented clearly enough for a third party to review your decisions.

Analyze your Clinical Data

Once you’ve gathered and appraised the data you need, the next step is analyzing it to determine whether or not it demonstrates compliance with clinical performance and safety requirements. 

All of your hard work has been leading up to this. So far in the clinical evaluation process, you’ve made a plan, gathered clinical data, and appraised its relevance and quality. Now, it’s time to analyze that data to determine if your device is compliant with safety and performance requirements in the European Union.

Goal of your data analysis

Ideally, your data analysis will demonstrate that the clinical data you’ve gathered shows your device to be safe and effective for end users and patients. 

Under the previous Medical Device Directive (MDD), this meant demonstrating compliance with the MDD’s Essential Requirements covering safety, performance, and risk-benefit profile. 

However, the MDD has been replaced by the European Union Medical Device Regulation (EU MDR), which has a new set of requirements known as the General Safety and Performance Requirements (GSPRs). 

There are more GSPRs than there were Essential Requirements, but their scope is similar—they are still criteria for safety, performance, and benefit-risk profile that your device must meet to receive its CE marking.

Keep in mind that there is a strong connection between the analysis of your clinical data and risk management. Appendix A7 of MEDDEV 2.7.1 Rev. 4 repeatedly references the use of risk management documents as a means of determining knowledge gaps that need to be covered by clinical data and identifying whether all known risks to patients and users have been minimized. 

This should be a good reminder that risk management is more than a checkbox activity—it’s integral to getting a safe and effective device to the patients who need it most. 

What happens during a comprehensive analysis of clinical data?

“Analysis” is a broad term, which is why it’s important to read all the guidance surrounding clinical evaluation carefully and hew to its recommendations. For instance, MEDDEV 2.7.1 Rev. 4 offers a four-point plan for evaluators during the analysis stage of clinical evaluation:

1. Use sound methods

During the appraisal stage, you weighted your data sets to ensure that the most relevant data from the highest-quality studies would be given the most consideration in your analysis.

MEDDEV 2.7.1 Rev. 4 states that you may use quantitative or qualitative methods to analyze this data. However, it also states that available clinical data should generally be quantitatively assessed in relation to state of the art (STOT), meaning the current best practices on the market. You may use qualitative methods in some cases, but if you do, you must also justify their use. 

Your analysis will also need to include all the data sets you identified and appraised in earlier stages, looking for consistency around device performance and any risks you’ve identified. If there’s conflicting information, the weighting process you performed during appraisal will help you decide how to evaluate the conflicting data. 

2. Make a comprehensive analysis

Remember, the goal of your analysis is to determine compliance with the General Safety and Performance Requirements in Annex I of EU MDR.

According to MEDDEV 2.7.1 Rev. 4, your evaluation of whether your device is compliant with the GSPR should include: 

• An assessment of the adequacy of pre-clinical testing—such as bench tests or animal tests—to verify safety, risks to patients, and benefits to patients.

• Confirmation that the device performs as you claim it does.

• Confirmation of the device’s usability. In other words, the device’s design reduces the risk of error as much as possible and that the design is appropriate for the intended user.

• Assurance that the information supplied by the manufacturer is adequate and that risk mitigation measures are addressed in the instructions for use (IFU).
  
  

You’ll also need to identify any gaps in the evidence you’ve collected, including aspects like your understanding of the interaction between the device and the body and the comprehensiveness of the available data. 

Finally, you’ll need to assess the consistency and alignment between the clinical evaluation, the information supplied by the manufacturer, and your risk management documentation for the device. 

Once you’ve done so, you’ll then assess whether there is consistency between those documents and the STOT. Discrepancies between the documents themselves or between the documents and the STOT should be identified during the analysis.

Did you know Greenlight Guru has a dedicated Risk Management workflow to help you easily execute these steps? You’ll be able to conduct risk analysis evaluation in a traceable system, capturing and recording relevant data throughout the design and development process.

The purpose-built solution makes it easy to keep your risk management file up-to-date and living throughout the entire lifecycle by electronically reviewing, signing, and approving documentation with a single source of truth.

3. Determine if additional clinical investigations are required

It’s possible that the analysis of your clinical data will turn up some gaps. Perhaps the data you have related to the safety or performance of the device isn’t strong enough to determine your device’s compliance with some of the GSPRs. 

In such a case, you would need to generate the missing data required to confidently draw conclusions about your device’s conformity with the GSPRs. This may require a clinical investigation.

4. Determine the post-market clinical follow-up (PMCF) needs

Your postmarket clinical follow-up (PMCF) is a part of your mandated postmarket surveillance activities under EU MDR. The PMCF is a continuous process of updating your medical device’s clinical evaluation once you’ve obtained CE marking. The goal is to ensure the safety and performance of the device over its lifetime, and it should identify any emerging risks through the collection of clinical data. 

The final step in the data analysis stage is to describe any residual risks, uncertainties, or unanswered questions that your PCMF will need to collect data on once the device reaches market.

NOTE: You may notice that MEDDEV 2.7.1 Rev. 4 references “Essential Requirements” rather than “General Safety and Performance Requirements”. This is because MEDDEV 2.7.1 Rev. 4 is actually based on the older MDD. 

However, the European Commission has issued a guidance document, MDCG 2020-6, on Sufficient Clinical Evidence for Legacy Devices. In Appendix I, the document states that the sections of MEDDEV 2.7.1 Rev. 4 related to the analysis of data are still relevant under MDR.

Write your Clinical Evaluation Report (CER)

Your clinical evaluation may be complete, but your findings still need to be documented and delivered to your Notified Body. 

If you plan on selling a medical device in the European Union, then you should plan on writing a clinical evaluation report (CER). Your CER will document the clinical evaluation that is required of every medical device sold in the EU. Its purpose is to prove your device performs as intended without compromising the safety of its end users. 

Even if your device falls into the lowest risk class possible, you’ll still need a CER in your technical file when you submit it to your Notified Body. With so much riding on the CER, it’s essential that you create a well-structured and comprehensive report. 

What do MDR and MEDDEV 2.7.1 Rev 4 say about the clinical evaluation report (CER)?

When you have a question about your medical device’s path to market, it’s always a good idea to start with the regulations and guidance that are readily available. 

In this case, the European Union Medical Device Regulation (EU MDR) is the regulation that covers clinical evaluation. Article 61 of EU MDR requires every medical device manufacturer to document the clinical evaluation of their device in a CER. This requirement is expanded upon in Annex XIV Part A, which states:

The results of the clinical evaluation and the clinical evidence on which it is based shall be documented in a clinical evaluation report which shall support the assessment of the conformity of the device.

However, you may have noticed that EU MDR doesn’t go into much detail about what should actually go into the clinical evaluation report itself. For that, you’ll need MEDDEV 2.7.1 Rev 4. That’s the guidance document put out by the European Commission (EC) that covers clinical evaluation.

MEDDEV 2.7.1 Rev 4 states that your CER should outline the four different stages of clinical evaluation:

• Stage 0 - Scope: The scope and context of the clinical evaluation, including the product being tested and any sizes or settings covered in the evaluation. This also includes an explanation of the technology the device is based on and any claims about its performance or safety.

• Stage 1 - Identification of pertinent data: This may include any data generated by the manufacturer, including premarket clinical investigations, as well as data from literature.

• Stage 2 - Appraisal of data: In this stage the data is appraised and the validity of each data set must be determined, as well as its relevance to the clinical evaluation and how heavily it should be weighed in the overall evaluation. 

• Stage 3 - Analysis of clinical data: This is the actual analysis of the clinical data, which should include the benefits and risks of the device, explain the acceptability of the benefit/risk profile, and address any residual risks, uncertainties, or unanswered questions.

In addition, MEDDEV 2.7.1 Rev 4 notes that your CER should contain sufficient information that external parties can read and understand it, stating:

Therefore, it should provide sufficient detail for understanding the search criteria adopted by the evaluators, data that are available, all assumptions made and all conclusions reached.

How should your CER be structured and written?

This still leaves us with the practical question of how to write a clinical evaluation report. The MEDDEV guidance offers some general rules for writing your CER, saying:

The contents of the clinical evaluation report shall be cross-referenced to the relevant documents that support them. It should be clear which statements are substantiated by which data, and which reflect the conclusions or opinions of the evaluators. The report should include references to literature-based data and the titles and investigational codes (if relevant and available) of any clinical investigation reports, with cross-references to the location in the manufacturer’s technical documentation.

Additionally, in Appendix A9 of MEDDEV 2.7.1 Rev 4, you can find a proposed table of contents along with examples of what information your CER may contain. Keep in mind that every device is different and your CER may not be structured in exactly this manner. 

1. Summary 

2. Scope of the clinical evaluation 

3. Clinical Background, current knowledge, state of the art

4. Device under evaluation 

1. Type of evaluation

2. Demonstration of equivalence (if equivalence is claimed)

3. Clinical data generated and held by the manufacturer

4. Clinical data from literature

5. Summary and appraisal of clinical data

6. Requirement on performance

7. Requirement on acceptability of side effects

5. Conclusions

6. Date of next clinical evaluation

7. Dates and signatures

8. Qualification of the responsible evaluators

9. References

Finally, Annex 10 of MEDDEV 2.7.1 Rev 4 contains a checklist to help ensure you haven’t missed anything before you submit your CER.

How often must your clinical evaluation report be updated?

Although compiling it may take plenty of effort, your work isn’t done once your clinical evaluation report is completed. 

The CER is meant to be a living document, and if at any point you receive new and pertinent information about your device through postmarket surveillance or new clinical evaluations, then the CER must be updated to reflect that. However, even if you don’t receive new information, your clinical evaluation report must still be updated according to a schedule that you, the manufacturer, define and justify. 

For devices that carry significant risk—Class III devices or Class IIb implantables—the CER must be updated every year. For devices without significant risk, the CER must be updated every two to five years. The schedule you choose should reflect the risk classification of your device and how well-established the technology behind the device is.

The guidance document MDCG 2020-6 provides a definition for well-established technologies, stating that they have:

• relatively simple, common and stable designs with little evolution; 

• their generic device group has well-known safety and has not been associated with safety issues in the past; 

• well-known clinical performance characteristics and their generic device group are standard of care devices where there is little evolution in indications and the state of the art; 

• a long history on the market.
  
  

Though the choice of when to update the clinical evaluation report is left up to the manufacturer, you must be sure that you can justify your decision based on the risk classification of your device and the technology behind it.

Manage the entire clinical evaluation process with a purpose-built QMS

When you start working in the medical device industry, it doesn’t take long before you hear that famous phrase:

“If you didn’t document it, it didn’t happen.”

From defining the scope of your clinical evaluation to creating your literature review protocol to analyzing your data, everything you do in the clinical evaluation process must be documented. And because the clinical evaluation is an ongoing process, you’ll also be updating what you’ve previously documented. 

Unfortunately, that means clinical evaluation is an area that’s full of potential pitfalls if you aren’t using the right QMS. To flawlessly manage the clinical evaluation process from start to finish, you need a purpose-built QMS that offers a single source of truth, a streamlined document approval process, and complete revision control. 

What you don’t need is a paper-based QMS or a generic eQMS that tries to fit a round peg in a square hole. 

That’s why at Greenlight Guru, we built our suite of solutions specifically for medical device companies. We understand what it takes to conduct a clinical evaluation.

We know the importance of documenting, maintaining, and sharing everything from your SOPs to your literature search because we’re a team of medical device professionals, just like you. We also understand how hard it can be to keep everything organized and audit-ready without the right tools to help you.

Before you start your clinical evaluation, ask yourself: Am I using the best possible tool for the job? If you aren’t confident the answer is “yes,” then get your free demo of Greenlight Guru today.