Table of Contents
- Understanding Clinical Evaluation
- What is a Clinical Evaluation Report (CER)?
- Clinical Evaluation Plan (CEP)
- Regulatory Requirements for Clinical Evaluation
- Best Practices, Common Pitfalls, and Challenges
- Benefits of a Comprehensive CER
- Summary
Understanding Clinical Evaluation
According to Article 2(44) of the European Medical Device Regulation (MDR) 2017/745, clinical evaluation is “a systematic and planned process to continuously generate, collect, analyze and assess the clinical data pertaining to a device in order to verify the safety and performance, including clinical benefits, of the device when used as intended by the manufacturer.”
The clinical evaluation should provide evidence that a medical device is safe and performs as intended, which is essential for protecting patient health and ensuring that the device meets regulatory standards. In fact, the clinical evaluation is crucial in several regions. In the European Union (EU), manufacturers must submit a Clinical Evaluation Plan (CEP) and Clinical Evaluation Report (CER) to demonstrate compliance with EU MDR 2017/745 and eventually obtain market approval of their medical devices. However, the clinical evaluation is not only mandatory for market approval, nor is it a one-time requirement: it must be updated regularly to reflect new clinical data and post-market surveillance findings. This ongoing process helps identify and mitigate any emerging risks associated with the device to ensure continued compliance with the EU MDR 2017/745.
The clinical evaluation is also closely linked to other parts of your technical documentation, such as your risk management file. It helps identify potential risks and ensure that appropriate measures are in place to address them, thereby enhancing the overall safety profile of the device.
Some countries outside the EU, such as Turkey, Switzerland, and countries in Asia and the Middle East, also recognize CE-certificates as part of their approval process or as relevant to simplify the approval process.
The Clinical Evaluation Report (CER) is the document that summarizes the results of the clinical evaluation for a medical device with the aim of demonstrating that this medical device is safe and effective for its intended use. The CER helps Notified Bodies assess and decide whether the manufacturer can receive a CE-certificate allowing the device to be sold in the European market.
What is a Clinical Evaluation Report (CER)?
In practice, Annex XIV Part A of the MDR defines the Clinical Evaluation as a continuous process, and the manufacturers shall:
- Establish and update a Clinical Evaluation Plan
- Identify available relevant clinical data and any gaps
- Appraise all relevant clinical data
- Generate any new or additional clinical data required
- Analyze all relevant clinical data
- Document the evaluation.
The MEDDEV 2.7/1 revision 4 also defined the different stages of the clinical evaluation as follows:
- Stage 0: Definition of the scope of Clinical Evaluation
- Stage 1: Identification of pertinent data
- Stage 2: Appraisal of pertinent data
- Stage 3: Analysis of the clinical data
- Stage 4: Clinical Evaluation Report (CER).
The CER presents Stages 1, 2 and 3 as defined in the MEDDEV 2.7/1 revision 4. The key components of the CER include:
- The identification of pertinent data from the literature as well as those held by the manufacturer, such as manufacturer-sponsored studies, collected post-market surveillance data, etc. Pertinent data is usually identified as relevant to the device under evaluation (hereinafter referred to as “subject device”), or to the state of the art. In the context of CERs, the state of the art refers to the current, generally accepted, best practices and standards in medical technology and treatment. Establishing the state of the art helps to compare the subject device against existing treatments and technologies and helps to demonstrate that the subject device is at least as safe and effective as current alternative options.The appraisal of the identified pertinent data to objectively evaluate the scientific validity and relevance of the included data according to the methodology defined in the Clinical Evaluation Plan (CEP).
- The analysis of the data and the conclusions about the subject device’s safety and effectiveness.
- The discussion and assessment of the benefit/risk ratio.
- Conclusion on the sufficiency of clinical evidence, possible gaps in the evidence, and need to generate additional clinical data.
- Conclusion on the alignment between the CER and the device’s documentation (i.e., risk management file, instructions for use, marketing materials, etc.).
- Conclusion on compliance with the MDR and relevant general safety and performance requirements (GSPRs).
Where Does the Clinical Evaluation Plan (CEP) Fit into this Process?
A Clinical Evaluation Plan (CEP) is a document that defines the strategyfor assessing the clinical safety and performance of a medical device. It includes the identification of GSPRs supported by relevant clinical data. The CEP also details the intended purpose of the device, the target groups with clear indications and contraindications, and the intended clinical benefits to patients. It specifies clinical outcome parameters and describes methods for examining qualitative and quantitative aspects of clinical safety, including residual risks and side effects. Importantly, the CEP lists parameters to determine the acceptability of the benefit-risk ratio and addresses benefit-risk issues related to specific components like pharmaceuticals or non-viable tissues. Additionally, the CEP includes a clinical development plan that outlines the progression from early exploratory investigations to confirmatory studies and post-market clinical follow-up (PMCF), with milestones and acceptance criteria.
The CEP holds a tremendous role in the clinical evaluation process. It is the roadmap of the clinical evaluation, ensuring a structured approach is followed to gather necessary evidence and comply with regulatory requirements of the EU MDR. In other words, it defines the scope and objectives of the clinical evaluation.
The definition of the clinical claims associated with the subject device is an important aspect of the CEP. Clinical claims relevant to clinical performance, safety, and benefits of the device are defined in the CEP, along with specific thresholds associated with these clinical claims, which will serve as acceptance criteria that the subject device must meet to be considered clinically acceptable. The CEP must also identify the data sources (such as literature reviews, manufacturer-sponsored clinical studies, post-market surveillance reports, registries, etc.) for obtaining relevant clinical data. As part of the identification of pertinent data sources, the literature search protocol must be defined and detailed to ensure that a systematic review of the literature is conducted at the CER phase. Objective, non-biased, systematic search and review methods should be used. Finally, the CEP defines the strategy chosen to demonstrate compliance with the MDR, which can rely solely on clinical data pertaining to the device under evaluation and/or other approaches, such as equivalence, usage of a lower level of clinical evidence in specific cases of low-risk standard of care devices, or demonstration of conformity with GSPRs based on non-clinical data.
A well-structured CEP is crucial because it ensures the clinical evaluation is thorough, reliable, and compliant with regulatory requirements, ultimately demonstrating the safety and effectiveness of the device under evaluation. It is also important in terms of scientific rigor, as a mean to enhance the scientific validity of the evaluation, as well as for transparency and reproducibility. In other more practical aspects, having a well-structured CEP allows the evaluators to easily follow the methodology, thereby allowing for a smooth and comprehensive CER writing process. Finally, the CEP is equally as important as the CER for a successful MDR submission. Having a clear and structured CEP will help the notified body conduct its review, ultimately resulting in a successful submission.
CER Writing Services
What are the Regulatory Requirements for the Clinical Evaluation?
The regulatory requirements for Clinical Evaluation include:
- Outline the scope and strategy in the CEP as explained above
- Document the results of the identification, appraisal, and analysis of relevant data in the CER
- Discuss the benefit/risk ratio of the device
- Conclude on the device’s safety and performance
- Conclude on the alignment between the CER and the device’s documentation (i.e., risk management file, instructions for use, marketing materials, etc.)
- Conclude on compliance with relevant GSPRs
- Plan regular updates of the CER
- Ensure that the individuals conducting the Clinical Evaluation are qualified and have the necessary expertise.
Overall, the structure and content of the CER must comply with Article 61 as well as Annex XIV, Part A of the MDR. Additional pointers are provided by several guidance documents produced by the Medical Device Coordination Group (MDCG), including but not limited to MDCG 2020-1, 2020-5, 2020-6, 2020-13, 2023-6, and 2024-10.
Stricter Data Requirements Under the EU MDR
Prior to the MDR 2017/745, the European Medical Device Directive (MDD) and the European Active Implantable Medical Device Directive (AIMDD) were the two regulatory frameworks that governed medical devices in the EU. Requirements were less stringent under the MDD/AIMDD. Under the MDR, there is an emphasis on collecting or generating stronger clinical evidence, including via post-market clinical follow-up (PMCF). New or stricter requirements introduced under the MDR and related to the clinical evaluation include, but are not limited to:
- Mandatory PMCF as part of the clinical evaluation process
- Mandatory CEP
- Clarification or introduction of regulatory routes for compliance with the MDR
- Stricter criteria for demonstrating equivalence
- More robust clinical evidence (introduction of the concept of sufficient clinical evidence)
- Separation of intended purpose versus indications of the device
The MDR states that confirmation of conformity with relevant GSPRs shall be based on clinical data providing sufficient clinical evidence. Although the term “sufficient clinical evidence” is not defined in the MDR, MDCG 2020-6states that it should be understood as “the present result of the qualified assessment which has reached the conclusion that the device is safe and achieves the intended benefits”. It also provides pointers to determine if a body of evidence can be considered sufficient.
Because the MDR requires manufacturers to provide more robust clinical evidence than in the past under MDD, it is of upmost importance to demonstrate, in the CER, that there is sufficient clinical evidence to support relevant GSPRs. The ranking defined in Appendix III of MDCG 2020-6, is a valuable tool to determine, from the CEP phase, the relevant types of clinical data and evidence that would allow to support GSPRs, depending on the considerations such as device classification, risks associated with the device, or novelty.
Other best practices for MDR-compliant clinical evaluations include ensuring alignment between CEP and CER, a clear and coherent structure of the CER, a state-of-the-art section developed following a systematic methodology and properly used for the benefit-risk analysis, defined claims and acceptance criteria, adequate equivalence assessment, as detailed in a separate blog post.
What are the Best Practices, Common Pitfalls, and Challenges in the Preparation of a CER?
Some best practices and common pitfalls to avoid when preparing a Clinical Evaluation are listed below:
- Choose an appropriate strategy: Ensure the strategy is well thought out and thoroughly described in the CEP. An unclear or poorly defined CEP can lead to frequent updates and revisions.
- Adhere to your CEP: Stick to the CEP as much as possible. If changes to the strategy are necessary, document them as deviations from the CEP. Inconsistencies between the CEP and the CER will likely result in non-conformities.
- Include all data: Include all relevant data, even if it is not favorable, to maintain transparency and credibility.
- Collect sufficient evidence: Provide sufficient evidence to support all populations, indications, and device variants. Gaps in clinical evidence may be challenged by the notified body and could result in non-conformities.
- Structure your CER clearly: Ensure the CER is clear, comprehensive, and qualitative. Pay close attention to the structure and format.
- Make it easy for your Notified Body: Help your Notified Body reviewer find the information they need efficiently by organizing the document well and follow appropriate MDCG guidance documents.
- Ensure your evaluators are qualified: Make sure that the individuals conducting the Clinical Evaluation are qualified and have the necessary expertise. MEDDEV 2.7/1 rev. 4, section 6.4, provides guidance for this.
- Plan for PMCF: Ensure the CER will provide the necessary information to develop and implement a robust PMCF plan and gather relevant clinical data.
Additionally, common challenges faced for preparing a CER include the time needed to compile data, especially when there are many relevant data or multiple indications to cover. To ensure a comprehensive and compliant CER, it is crucial to allocate sufficient time for a thorough analysis.
Another common challenge arises when the CEP and CER preparation begin before the technical documentation is fully compliant with the MDR. In such cases, it should be ensured that at least the intended purpose, indications, target population, and clinical claims are already defined.
What are the Benefits of a Comprehensive CER?
Successful and comprehensive CERs lead to many different benefits, such as smooth regulatory approval, allowing the device to enter the market quickly, or ensuring continued regulatory compliance. This builds trust between manufacturers and their notified bodies, and, most importantly, enhances patient safety.
A thorough CER benefits medical device manufacturers as it impacts many other aspects of the technical documentation. First, it allows manufacturer to develop and revise their PMCF strategy. It also plays a crucial role in the risk management process, as it helps identify potential risks associated with the device and assess their severity, likelihood, and potential impact on patients and users. The findings from the CER can lead to the implementation of risk mitigation strategies, which can include design changes, additional safety features, or instructions for use updates.
Overall, successful and comprehensive CERs help manufacturers enhance the overall success and reliability of their medical devices.
Summary
The CER is essential in demonstrating that a medical device is safe and performs as intended, which is crucial for protecting patient health and ensuring regulatory compliance. In the EU, the CER, along with the CEP, is a mandatory requirement under the EU MDR 2017/745 for market approval. The Clinical Evaluation must be regularly updated to reflect new clinical data and post-market surveillance findings, which helps identify and mitigate emerging risks, ensuring continued compliance with the EU MDR 2017/745. Besides, the CER is closely linked to other parts of the technical documentation, such as the risk management file, helping to identify potential risks and ensure appropriate measures are in place to address them. In addition, many countries outside the EU recognize CE-certificates as part of their approval process or to simplify it.
Successful and comprehensive CERs lead to smooth regulatory approval, and continued compliance. Ultimately, CERs help manufacturers enhance the success and reliability of their medical devices.
How can NAMSA help?
Regularly updating CERs to reflect new clinical data and post-market surveillance findings is necessary but can be resource-intensive. Additionally, the MDR has stringent and detailed requirements, which can be difficult to navigate and comply with. Conducting thorough and systematic literature reviews is time-consuming and requires careful documentation. Specific aspects of the CER strategy can be challenging and complex to justify, such as demonstrating equivalence or demonstrating that a device is a well-established technology (WET).
At NAMSA, our team understands the complexities and requirements related to the clinical evaluation process. Our team of medical writers is comprised of seasoned MDR professionals with extensive experience in guiding medical device manufacturers through the preparation and remediation of technical documentation, including the CEP and CER. Our writers partner with our EU regulatory consultants, many of whom are former Notified Body employees, on CEP and CER development.
