Some typical gaps require significant effort when reviewing individual CERs. More detail is needed throughout—for example, the device description should contain the suggested content listed in Appendix 3 of Rev 4, which includes model numbers in the CER’s scope. The literature search analysis tables must be more thorough and cumulative so the amount of available subject device clinical data is clear.
The Device Under Evaluation literature search typically must be redone to focus on the subject and/or equivalent device. Searches conducted to Rev 3 typically were more general and included multiple comparable devices instead of just the subject device.
More detail must also be added to establish equivalence. Rev 3 CERs typically did not have enough detail to establish equivalence and included multiple devices. Create tables comparing the subject device’s clinical, technical, and biological aspects to the equivalent device, a discussion of the differences, and conclude that the differences don’t impact safety or performance. Also ensure the appropriate equivalent device is similar enough to the subject device, with enough clinical literature.
A State of the Art section must be added to the CER. This is typically done via a separate literature search for alternative treatments and other devices available for the intended use. Provide a clear clinical background, describe the alternative treatments and risk-benefits, and discuss the subject device’s comparison to the state of the art.
Other typical gaps that must be addressed, and usually require less effort: Summarizing complaints, MDRs, and recalls; stating qualifications of those involved in the CER, particularly the evaluator; including the evaluator’s CV and having a Declaration of Interest on file; and stating when the CER will be updated next.
When it’s time to update individual CERs, outline the CER’s strategy using the CEP template. At this stage, define the CER’s scope, determine whether equivalence is needed, and specify literature searches’ timeframes and strategies. Separate literature search protocols can be created or included. Once literature searches are completed and the CER is written, it may be necessary to plan proactive Post-Market Clinical Follow-up (PMCF) studies for additional subject device safety and performance data, which will depend on the amount and quality of data available and the device’s risk. Regardless of whether a PMCF study will be conducted, the Post-Market Surveillance (PMS) and PMCF plan, if applicable, should be mentioned in the CER. Justify the reason why no PMCF will be conducted, especially for novel or high-risk devices.
R&Q has helped many clients evaluate the state of their CERs and provide CEPs to address their gaps. R&Q has also been speaking with the notified bodies to understand their expectations moving forward to save medical device companies money and time. Plan to address any gaps immediately; it’s very difficult to collect clinical data at the last minute. This is especially true when preparing for EU MDR submissions, where these will be considered new submissions and a cumulative data assessment will be needed.
R&Q has developed five steps—the “DMAIC” process—for EU CERs, based on Six Sigma principles. They include:
Define: Engage with key stakeholders. The CER is a group effort; ensure the right people are involved and everybody understands their respective roles. You may specify some of the updates in your template and quality systems management (QMS) procedure. Define the CER’s scope and strategy in the clinical evaluation plan.
Measure: Gather and appraise the relevant clinical data, for example the subject or equivalent device’s literature data, clinical investigations conducted on the subject device, and post-market data, such as complaints.
Analyze: Analyze the clinical data to provide a cumulative assessment of the device’s safety and performance. Review this against labeling and risk management documents to ensure sufficient data is available to support the device when used as indicated and all risks are appropriately addressed. Also determine what sort of PMS/PMCF the subject device will need.
Improve: Implement PMS/PMCF plans to assess and monitor the clinical evaluation process and modify the templates and quality system to improve it. In some cases, it may be helpful to bring in an outside expert to examine the CER process and templates.
Control: Ensure stakeholder alignment and work with the notified body to understand their expectations.
The Medical Device Regulation’s Impact on CERs
Article 32 – Summary of Safety and Clinical Performance for implantable and Class III devices: This is in addition to and separate from the CER. The notified body will review and validate this; it will then be publicly available via EUDAMED.
Article 86 – Post-Market Surveillance (PMS) Report for Class I and Periodic Safety Update Report (PSUR) for Class IIa, IIb, and III devices: This is also in addition to and separate from the CER. The PMS report is for Class I devices, is updated when necessary, and must be available when requested. The PSUR is for Class II and III devices. It must be updated at least every two years for Class IIa devices and annually for Class IIb and Class III devices. This contains many of the CER’s elements and can be used as CER input.
Annex XIV – Clinical Evaluation Plan and Post-Market Clinical Follow-up Plan: Part A of Annex XIV goes over the clinical evaluation and discusses elements that must be included in the CEP. Part B covers the PMCF and discusses elements necessary in its plan.
Key changes to make clinical evaluation updates compliant with MEDDEV Revision 4 include:
Frequency of updating the clinical evaluation (section 6.2.3): It’s always up to the manufacturer to define and justify the frequency. Yearly updates are recommended for a significant risk device that’s not well understood. The update ranges between two to five years for a significant risk device that’s a well-established technology. As with revision 3, you would need to update it based on new post-market information or device changes. The frequency of evaluation should align with the notified body audits and renewals.
Evaluator qualifications (section 6.4): There is a section on who should perform the clinical evaluation, with specific expectations for evaluators’ experience. Evaluators or teams involved in the CER must be knowledgeable about the device technology, research methodology, information management (scientific or librarianship background), regulatory requirements, medical writing (post-graduate and medical writing experience), and the intended condition’s diagnosis and management. The role of the people involved and how each requirement is met should be clear in the CER. Document and justify exceptions to these requirements.
Additionally, there are expectations for experience—a degree and at least five years of experience, or 10 years of professional experience without a degree prerequisite. Exceptions must be documented. In section A11, the requirement for a declaration of interest establishes a conflict of interest and the ability to perform the evaluation.
Clinical evaluation plan (section 7): There is now an expanded section to include a CEP and its suggested components, which include the device description; any design features and how you will evaluate equivalence; how you will review risk management documents; how you will employ current knowledge or state of the art; data sources (internal and external) examined in evaluation (which could include a clinical investigation or literature search); device changes; new clinical concerns; and anything new (updating and planning) that post-market surveillance reveals.
State of the Art (sections 7 and 8.2): There is a significant amount of detail added here. State of the art includes applicable standards and guidance documents, data for benchmark devices (other devices’ critical components) or medical alternatives, and specific medical conditions and patient populations the device intends to manage.
This is meant to establish the baseline for your device’s risk perspective. It’s typically needed to describe the clinical background, identify alternative treatments and their risk-benefits, and establishing your device within the state of the art.
Demonstration of equivalence (appendix 1): Biological, clinical, and technical equivalence must be fulfilled. Demonstration can only be based on a single device, however an added asterisk can indicate it can be used on several. In either case, sufficient data must be available for the comparative device to establish equivalence. The guidance instructs the notified body to challenge the manufacturer’s ability to access information relevant to demonstration of equivalence. This may be difficult or impossible in cases of limited access and technical documentation.
To apply the CER requirements from the MDR and MEDDEV 2.7.1 for initial reports vs. updates, there are a number of steps to consider. Be sure to follow the frequency requirements per MEDDEV 2.7/1 Rev 4. Initial reports and updates may not have much PMS data on the subject device, and may rely on data based on equivalency. Often, companies will compare their device to a similar legacy device to show equivalency. Updates on established devices should also focus more on specific device-related data, including post-market surveillance. Notified bodies would expect to see more information on your device.
MDR Annex XIV
MDR Article 32
MDR Article 61
MDR Article 86
MEDDEV 2.7/1 rev. 4, Clinical Evaluation: A Guide for Manufacturers and Notified Bodies Under Directives 93/42/EEC and 90/385/EEC, 2016
Jonathan Gimbel is director at R&Q, a regulatory and quality consulting firm that helps medical device and combination product companies bring safe and effective products to market and keep them there. A nearly 20-year veteran of the biomedical and medical device areas, he has been a key member in a medical device startup, a consultant, and a researcher on academic and industrial projects. Jon leads R&Q’s CER business unit and has implemented regulations at multinational medical device companies. Jon oversees clinical evaluations completed at R&Q and helps ensure compliance to MEDDEV 2.7/1 Rev. 4. Jon also works with companies to develop strategies and plans to meet the new EU MDR requirements pertaining to clinical evaluations and post-market activities.