Jonathan Gimbel, Director, Regulatory and Quality Solutions LLC (R&Q)05.29.18
The latest revision of MEDDEV 2.7/1 was published June 2016 and calls for substantial changes from revision 3. Updating clinical evaluation reports (CER) to meet the new requirements will require a major effort for most manufacturers selling in the EU market. Revision 4 is more prescriptive and requires manufacturers to provide greater quantity and quality of information for clinical evaluations. The guideline now includes additional expectations in terms of equivalence and data used to establish equivalence, and adds increased requirements for evaluators’ expertise.
Revision 3 is similar to revision 4, but has been expanded and includes multiple content enhancements. Revision 3 included three stages—Stage 1: Identifying the Clinical Data, Stage 2: Appraising the Clinical Data, Stage 3: Analyzing the Clinical Data, culminating in a written CER. Scoping and writing the CER were previously part of the same document, but a clinical evaluation plan (CEP) and a list of aspects to include in it are now mentioned. The clinical evaluation’s stages have also been updated to add the plan in Stage 0 and represent the clinical evaluation as a cyclical process updated at a predefined frequency. The stages included in revision 4 are:
As these stages outline, the clinical evaluation’s purpose is to collect, appraise, and analyze the device’s clinical data and evaluate its safety and performance according to the instructions for use (IFU). It is applicable to all classes. This process is not necessarily new to revision 4, but it has expanded on the process. Following is a closer look at the five stages.
Stage 0—Defining the Scope
The Scope of the clinical investigation must be defined in the CEP. As part of the CEP, you must consider how to justify equivalence when using clinical data from your device or a competitive device. Ensure you collect data to support all claims and patient populations your device is intended for (e.g. pediatric and adult populations). The appropriate people must be included in the clinical evaluation, evaluators qualified per the guidance’s considerations. Similar to a protocol, the CEP is the clinical evaluation’s starting point and helps ensure evaluation is done properly to limit future issues.
Stage 1 – Identifying Pertinent Data
This stage determines what data will be used for clinical evaluation:
Stage 2—Appraisal of the Data
This stage stresses the importance of scientific validity. Revision 3 provided a potential method for potential clinical data appraisal, which can still be used in the clinical evaluation. Revision 4 now has additional details and examples pertaining to clinical data appraisal. An appendix has been added to provide “examples of studies that lack scientific validity for demonstration of adequate clinical performance and/or clinical safety.” Per guidance specifications, clinical data generated through randomized controlled clinical trials conducted on the actual device should be weighted highest. Device registries, case series, and retrospective analyses of patient dossiers may be incomplete and would likely be weighted lower. Lower quality data, such as opinions or single case studies, may not be adequate to support the device’s safety and performance, but may be used to identify unexpected risks.
Stage 3—Analysis of the Data
A thorough summary and analysis of the clinical data must be performed during evaluation to establish conformity to essential requirements. The applicable essential requirements (ER) include ER1 (Safety), ER3 (Performance), and ER6 (undesirable side effects). Further details are provided in Appendix 7 of the guidance: “Analysis of the clinical data—compliance to specific Essential Requirements.” Address each of the relevant essential requirements and determine if additional data needs to be generated through clinical investigations or Post-market Clinical Follow-up (PMCF), considering:
The intended purpose for all models and sizes must also be included with all patient populations. If sufficient information is not available, additional clinical investigations may be needed or the labeling may need to be revised to limit indications and claims.
Implants, high-risk devices, novel technology with limited clinical data, and lower class devices with gaps in clinical data are likely to require a clinical investigation. MDD Annex X requires a clinical investigation for Class III and implantable devices unless sufficient clinical data exists. The notified body will determine if the manufacturer has provided sufficient clinical evidence regarding safety and performance.
Stage 4—Clinical Evaluation Report
Revision 4 provides an appendix with a detailed proposed table of contents for the CER with examples of information to include within each section. It also provides a proposed checklist for the CER’s release. The report must be reviewed and approved by the manufacturer and an appropriately qualified medical professional. The report needs to provide the frequency of updates with a justification, the evaluation of qualifications, and a declaration of interest for each evaluator.
Additional Changes Required
There are additional details on various aspects of the clinical evaluation throughout the newest revision of MEDDEV 2.7/1 (for example post-market surveillance, risk benefits, and literature search process) but two of the biggest differences impacting clinical evaluation include:
Appendix 1 contains more details on aspects that must be considered for demonstrating equivalence. A detailed comparison of the clinical, technical, and biological characteristics of the subject device and proposed equivalent device must be included in the CER using the information in this appendix. Equivalence is also expected to only be based on a single device, although the option to use multiple devices is mentioned. Notified bodies are also expected to “challenge the ability of the manufacturer to access information that are relevant to the demonstration of equivalence.” Ultimately, use of an equivalent device will now require a robust justification supported by sufficient information.
While no specific appendix has been added regarding the State of the Art literature search, State of the Art is mentioned throughout and is included within the proposed table of contents. Therefore, a separate State of the Art literature search is recommended to provide information pertaining to current knowledge, standards, guidance documents, a description of medical conditions and patient population treated by the device, and alternative therapies with a summary of advantages, disadvantages, risks, and benefits.
Common Areas of Noncompliance
The guidelines provide a roadmap for achieving the applicable essential requirements; however, they can be overwhelming and there are some common areas of non-compliance.
Device equivalency: There is often insufficient information or an incomplete analysis provided in the clinical evaluation to demonstrate equivalence. Notified bodies also review these analyses with more scrutiny. There is no set requirement for how much data is enough to establish equivalency, but all criteria in the device equivalence appendix should be considered and addressed.
Data on competitive products: It can be challenging to obtain enough data to establish equivalence from another manufacturer’s device. Potential information sources include literature articles or websites, product brochures, IFUs, and trade show information companies make available online for customers.
Competency of Clinical Evaluators and Reviewers
Reviewers of the clinical evaluation may lack required knowledge or skill sets. Ensure clinical evaluation is conducted by appropriately qualified personnel. The guidance provides specific requirements that must be met for people involved in the clinical evaluation—including knowledge of research methodology, information managements, regulatory requirements, and medical writing. Product experts and medical professionals with knowledge of the device and medical condition must also be included. A Declaration of Interest must be on file for each evaluator (see Appendix 11) with maintained resumes or CVs.
Post-Market Surveillance
Only collecting passive post-market surveillance data is another potential area of non-compliance. Passive data may be valuable, but notified bodies expect active collection of post-market data for many devices to specifically support safety and performance data.
Most companies find it challenging to keep up with and understand changing standards or regulations, how their quality management system (QMS) is impacted, and impact on products, CER, etc. It is crucial new or revised standards and regulations are understood to apply them to product certification and QMS.
R&Q helps clients with questions surrounding equivalence, how to establish it to determine best use of current clinical data, and whether a clinical investigation is needed.
References
1 MDR Annex X
2 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 area, 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 by 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. Jon holds a Ph.D. in mechanical engineering and bioengineering, and a master’s degree in mechanical engineering from the University of Pennsylvania.
Revision 3 is similar to revision 4, but has been expanded and includes multiple content enhancements. Revision 3 included three stages—Stage 1: Identifying the Clinical Data, Stage 2: Appraising the Clinical Data, Stage 3: Analyzing the Clinical Data, culminating in a written CER. Scoping and writing the CER were previously part of the same document, but a clinical evaluation plan (CEP) and a list of aspects to include in it are now mentioned. The clinical evaluation’s stages have also been updated to add the plan in Stage 0 and represent the clinical evaluation as a cyclical process updated at a predefined frequency. The stages included in revision 4 are:
- Stage 0-Scoping, Plan (Section 7 App. A3)
- Stage 1-Identification of pertinent data (Section 8, App. A4-A5)
- Stage 2-Appraisal of pertinent data (Section 9, App. A6)
- Stage 3-Analysis of the clinical data (Section 10, App. A7-A8)
- Stage 4-CER, includes PMS/PMCF plan (Section 11, App. A9-A10)
As these stages outline, the clinical evaluation’s purpose is to collect, appraise, and analyze the device’s clinical data and evaluate its safety and performance according to the instructions for use (IFU). It is applicable to all classes. This process is not necessarily new to revision 4, but it has expanded on the process. Following is a closer look at the five stages.
Stage 0—Defining the Scope
The Scope of the clinical investigation must be defined in the CEP. As part of the CEP, you must consider how to justify equivalence when using clinical data from your device or a competitive device. Ensure you collect data to support all claims and patient populations your device is intended for (e.g. pediatric and adult populations). The appropriate people must be included in the clinical evaluation, evaluators qualified per the guidance’s considerations. Similar to a protocol, the CEP is the clinical evaluation’s starting point and helps ensure evaluation is done properly to limit future issues.
Stage 1 – Identifying Pertinent Data
This stage determines what data will be used for clinical evaluation:
- Data held by the manufacturer (complaints, MDRs, recalls, field safety corrective actions, corrective and preventative actions, etc.)
- Data from the literature (for the device itself, equivalent devices, or benchmark devices)
- Multiple databases to ensure coverage
- Favorable and unfavorable data must be included. The notified body will confirm the data is relevant and a systematic search strategy has been used.
Stage 2—Appraisal of the Data
This stage stresses the importance of scientific validity. Revision 3 provided a potential method for potential clinical data appraisal, which can still be used in the clinical evaluation. Revision 4 now has additional details and examples pertaining to clinical data appraisal. An appendix has been added to provide “examples of studies that lack scientific validity for demonstration of adequate clinical performance and/or clinical safety.” Per guidance specifications, clinical data generated through randomized controlled clinical trials conducted on the actual device should be weighted highest. Device registries, case series, and retrospective analyses of patient dossiers may be incomplete and would likely be weighted lower. Lower quality data, such as opinions or single case studies, may not be adequate to support the device’s safety and performance, but may be used to identify unexpected risks.
Stage 3—Analysis of the Data
A thorough summary and analysis of the clinical data must be performed during evaluation to establish conformity to essential requirements. The applicable essential requirements (ER) include ER1 (Safety), ER3 (Performance), and ER6 (undesirable side effects). Further details are provided in Appendix 7 of the guidance: “Analysis of the clinical data—compliance to specific Essential Requirements.” Address each of the relevant essential requirements and determine if additional data needs to be generated through clinical investigations or Post-market Clinical Follow-up (PMCF), considering:
- Are the data in line with current knowledge and state of the art?
- Are the data scientifically sound?
- Can a conclusion be drawn that the essential requirements have been met?
The intended purpose for all models and sizes must also be included with all patient populations. If sufficient information is not available, additional clinical investigations may be needed or the labeling may need to be revised to limit indications and claims.
Implants, high-risk devices, novel technology with limited clinical data, and lower class devices with gaps in clinical data are likely to require a clinical investigation. MDD Annex X requires a clinical investigation for Class III and implantable devices unless sufficient clinical data exists. The notified body will determine if the manufacturer has provided sufficient clinical evidence regarding safety and performance.
Stage 4—Clinical Evaluation Report
Revision 4 provides an appendix with a detailed proposed table of contents for the CER with examples of information to include within each section. It also provides a proposed checklist for the CER’s release. The report must be reviewed and approved by the manufacturer and an appropriately qualified medical professional. The report needs to provide the frequency of updates with a justification, the evaluation of qualifications, and a declaration of interest for each evaluator.
Additional Changes Required
There are additional details on various aspects of the clinical evaluation throughout the newest revision of MEDDEV 2.7/1 (for example post-market surveillance, risk benefits, and literature search process) but two of the biggest differences impacting clinical evaluation include:
- An appendix has been added for the demonstration of equivalence and the clinical literature section has been expanded.
- More details throughout the document regarding the State of the Art literature search
Appendix 1 contains more details on aspects that must be considered for demonstrating equivalence. A detailed comparison of the clinical, technical, and biological characteristics of the subject device and proposed equivalent device must be included in the CER using the information in this appendix. Equivalence is also expected to only be based on a single device, although the option to use multiple devices is mentioned. Notified bodies are also expected to “challenge the ability of the manufacturer to access information that are relevant to the demonstration of equivalence.” Ultimately, use of an equivalent device will now require a robust justification supported by sufficient information.
While no specific appendix has been added regarding the State of the Art literature search, State of the Art is mentioned throughout and is included within the proposed table of contents. Therefore, a separate State of the Art literature search is recommended to provide information pertaining to current knowledge, standards, guidance documents, a description of medical conditions and patient population treated by the device, and alternative therapies with a summary of advantages, disadvantages, risks, and benefits.
Common Areas of Noncompliance
The guidelines provide a roadmap for achieving the applicable essential requirements; however, they can be overwhelming and there are some common areas of non-compliance.
Device equivalency: There is often insufficient information or an incomplete analysis provided in the clinical evaluation to demonstrate equivalence. Notified bodies also review these analyses with more scrutiny. There is no set requirement for how much data is enough to establish equivalency, but all criteria in the device equivalence appendix should be considered and addressed.
Data on competitive products: It can be challenging to obtain enough data to establish equivalence from another manufacturer’s device. Potential information sources include literature articles or websites, product brochures, IFUs, and trade show information companies make available online for customers.
Competency of Clinical Evaluators and Reviewers
Reviewers of the clinical evaluation may lack required knowledge or skill sets. Ensure clinical evaluation is conducted by appropriately qualified personnel. The guidance provides specific requirements that must be met for people involved in the clinical evaluation—including knowledge of research methodology, information managements, regulatory requirements, and medical writing. Product experts and medical professionals with knowledge of the device and medical condition must also be included. A Declaration of Interest must be on file for each evaluator (see Appendix 11) with maintained resumes or CVs.
Post-Market Surveillance
Only collecting passive post-market surveillance data is another potential area of non-compliance. Passive data may be valuable, but notified bodies expect active collection of post-market data for many devices to specifically support safety and performance data.
Most companies find it challenging to keep up with and understand changing standards or regulations, how their quality management system (QMS) is impacted, and impact on products, CER, etc. It is crucial new or revised standards and regulations are understood to apply them to product certification and QMS.
R&Q helps clients with questions surrounding equivalence, how to establish it to determine best use of current clinical data, and whether a clinical investigation is needed.
References
1 MDR Annex X
2 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 area, 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 by 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. Jon holds a Ph.D. in mechanical engineering and bioengineering, and a master’s degree in mechanical engineering from the University of Pennsylvania.