After some delays, Revision 4 of Clinical Evaluation MEDDEV guidance document 2.7.1 was released by the European Commission on July 1, 2016. Although the new revision is slightly larger in content (65 pages vs. 46 pages) and more detailed with 12 chapters and 23 appendices, it provides needed regulatory guidance including examples to clarify already existing requirements as well as providing new ones.
More concise language is provided to manufacturers on how to implement a robust and systematic clinical evaluation process and compile scientifically valid clinical evaluation reports (CERs).
|MEDDEV 2.7.1 Rev 4: Key Changes and Clarifications|
|Stricter Qualifications of Report Authors and Evaluators.
Clause 6.4 introduces specific requirements for the expertise and experience of CER authors and evaluators, including a relevant higher education degree and five (5) years’ related professional experience or ten (10) years’ professional experience in case a degree is not considered a prerequisite for the task.
Deviations from these requirements should be documented and duly justified.
All evaluators must now make a declaration of interest.
Stricter Requirements for Demonstration of Device Equivalency.
Merely a footnote in Appendix F of MEDDEV 2.7.1 Revision 3 is now expanded considerably in Revision 4 with details provided in Appendix 1.
Manufacturers may use only one (1) single device against which to demonstrate equivalency and all three (3) equivalency criteria must be met.
Though all device equivalency criteria (clinical, technological, biological) remain unchanged, more detailed information on how this should be documented and factors which could affect the demonstration of equivalency are provided. In particular, Revision 4 requires that design differences and their impacts on clinical safety and performance are described in detail, including provision of comparative design drawings and diagrams and supporting non-clinical information (e.g. pre-clinical reports).
Equivalent devices (Predicates) being compared should have the same material and should be for the same intended use and clinical indication as compared with the subject device.
If non-CE marked devices are to be claimed equivalent, differences in patient population or clinical practice between the jurisdictions where the product is approved and the EU must be justified.
Access to Data for Equivalent Devices.
Revision 4 also requires the Notified Body to challenge the manufacturer’s access to credible information to substantiate the validity for device(s) claimed equivalent to the subject device (Appendix A12.2.3).
This is considered a transition point for the regulation, which will require a manufacturer to have a contract in place allowing access to data for competitor devices with which equivalence is claimed.
Scientific Validity of Data.
The new revision places much greater emphasis on demonstrating the scientific validity of clinical data, including statistical considerations on sample size and randomization (Section 9.3.1).
The section titled “How to evaluate methodological quality and scientific validity” addresses factors which can affect the scientific validity of different types of clinical datasets.
In addition, clarification is provided in extensive detail throughout the guidance document for each stage of the clinical evaluation process:
|Frequency of Updates to the CER is More Prescriptive.
Clause 6.2.3 requires the CER to be updated at least annually for high risk or new devices and every 2 to 5 years for lower risk, well-established devices. A justification rationale for the frequency of updates will be required.
A CER update is generally required for all device risk classifications whenever new information from the Post Market Surveillance (PMS) affects the evaluation or its conclusions.
Specific and Measurable Objectives for the CER to Meet Essential Requirements.
Revision 3 of MEDDEV 2.7.1 required the manufacturer to document the objectives and scope of the CER and to define these in terms of safety, performance and risk endpoints related to the Essential Requirements. However, the connection between scope and endpoints was somewhat buried in Appendix F, the Clinical Evaluation Checklist for Notified Bodies.
Annex 7 now provides additional guidance on how to analyze clinical data to demonstrate compliance with the ERs.
For example, compliance with MDD (M5) ER 6—evaluation of undesirable side effects now requires a reasonably large enough investigational study population to ensure a reasonable probability to detect such side effects for evaluation.
More detailed guidance is provided in Section 7 and Appendix 5.
Establishing the State of the Art.
Clause 8.2 provides more detail with respect to establishing and documenting state-of-the-art and other available treatment options.
This includes establishing the safety and performance of the device, its claimed equivalent(s) and any benchmark or other similar devices, as well as the risks and clinical benefits of other available treatment options.
When is a Clinical Investigation Required?
Appendix 2 describes key considerations relating to device risk and how manufacturers should determine if they have sufficient clinical evidence.
In case the design includes novel technical technology or there are gaps in the clinical data with regard to the identification of the benefits, risks, claims or side effects of the use of the requirement for a clinical investigation, new or different intended uses for an existing technology is clearly suggested in Revision 4.
Appendix 7 provides detailed guidance on the analysis of data to demonstrate device safety and performance.
Appendix 7.2 discusses the risk-benefit profile in particular, including the evaluation and quantification of benefits and risks, and the evaluation of the overall risk-benefit profile.
The value of post-market data, and factors which could affect the statistical validity of the evaluation of this data, are addressed in some detail.
Post Market Surveillance (PMS) and Post Market Clinical Follow-up (PMCF).
Throughout Revision 4 of the guidance document, the links between clinical evaluations, PMS and PMCF are reinforced.
Appendix 12 highlights the requirement for Notified Bodies to ensure PMCF is indeed a planned objective and appropriately justified in light of the clinical data retrieved and conclusions documented in the CER.
Conclusion and Next Steps
The new MEDDEV revision 2.7.1 revision 4 can be considered more instructive, but also more prescriptive. The clinical evaluation process follows a product lifecycle approach and should include review of clinical usability claims for the intended users. However, the most significant change in this revision, the demonstration of “equivalence” between predicate and subject device, is much stricter and may lead to more clinical investigational trials with larger patient populations, in conjunction with higher expectations for the scientific validity of clinical data and evaluation of state-of-the-art treatment options.
As no transition period is typically being provided for published MEDDEV guidance documents, medical device manufacturers are best advised to start discussing with their Notified Bodies about how they will start implementing these new MEDDEV requirements and to start performing gap assessments including the need for additional and new resources now.