Gap Analysis Report MedDev 2.7/1 rev.4 Guideline: Equivalence and Risk/Benefit Profile

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2 Gap Analysis Report MedDev 2.7/1 rev.4 Guideline: Equivalence and Risk/Benefit Profile OVERVIEW Introduction: This gap analysis will cover important changes to the topics of equivalence and risk/benefit profile from the revised Clinical Evaluation (CE) MEDDEV 2.7/1 guideline and the Quality Management Systems (QMS) ISO standard. 1,2 With respect to these 2 topics, the goals of this report are to clarify the modifications and to help develop strategies for compliance. Overall, these changes suggest the need for more clinical investigations, but fewer investigations may be acceptable in special cases. These cases will be highlighted. As defined in MEDDEV 2.7/1 revision 4, CE is a procedure to collect, appraise and analyze clinical data pertaining to a medical device and to evaluate whether there is sufficient clinical evidence to confirm compliance with relevant essential requirements for safety and performance when using the device according to the manufacturer s Instructions for Use. 1 In general, the MEDDEV 2.7/1 rev. 4 is widely rewritten and significantly more prescriptive. The revised QMS ISO rd edition also includes numerous additions and clarifications on existing requirements. In a series of gap analyses, CEI will select critical changes from these guidelines and examine them. Background: In the early half of 2016, the requirements in the CE MEDDEV guideline and the ISO standard changed. These revisions were generated in part to medical device safety issues, such as those with Poly Implant Prothese breast implants manufactured with inadequate quality silicone. 3 Multiple authorities are involved with authoring and managing these 2 documents and are defined here. The national competent authorities are entities in each Member State that approve medical devices in the EU that are not approved through the centralized EU procedure. Notified Bodies (NB) are 3rd parties accredited by Member States to determine if a device candidate meets certain standards. The EC is the administrative authority of the EU that proposes legislation, enforces treaties and manages business for the EU. ISO is a non-governmental, voluntary organization comprised of standards organizations from its member countries. The revised MEDDEV 2.7/1 was produced by a task force comprised of representatives from the national competent authorities, notified bodies, the medical device industry, patient groups, and consultants, with oversight from the EC. 1 The new version of the MEDDEV guideline goes into effect immediately, while the 3 rd edition of the ISO standard transitions into effect over a 3-year period. Manufacturers are currently reevaluating their CE processes to ensure compliance. Page 1 of 5

3 ANALYSIS RESULTS Summary Statements: 1. Changes to these guidelines and standards further define and increase the requirements needed to demonstrate medical device equivalence. See Table 1 for additional analysis. 2. Revisions to the CE MEDDEV guideline further clarify how to evaluate the risk/benefit profile to meet the Essential Requirements and provide guidance for special cases. See Table 2 for more details. 3. Changes to the QMS ISO standard require the use of a risk-focused approach to QMS processes. See Table 2 for additional analysis. Gap Analysis Results: Table 1. Gap Analysis of Equivalence Guideline Language Gaps Implications Solution Strategies ISO 2 nd edition: For each type or model of medical device, the organization shall maintain a file containing or identifying documents defining product specifications and quality management system requirements [and] define the complete manufacturing process and, if applicable, installation and servicing. 4,a ISO 3 rd edition: Medical device file shall include labelling instructions for use specifications for product or procedures for manufacturing measuring and monitoring.. b More comprehensive technical dossier needed for each device Manufacturers must document and organize technical information per medical device type or family in 1 or more grouped files. Create a procedure to periodically check and maintain medical device files with relevant information. MEDDEV Revision 3: Gives broad description of criteria to demonstrate equivalence. are there gaps in equivalence that needs addressing through clinical investigation(s)? c if there are differences identified, an assessment and demonstration of the significance these might have on safety and performance must be set out. 5,d MEDDEV Revision 4: The notified body should challenge the ability of the manufacturer to access information that are relevant to the demonstration of equivalence. Demonstration of equivalence might be difficult or impossible in case of limited access to the technical documentation of the devices. e Technical documentation and specifications are required to demonstrate equivalence. If the manufacturer does not have the right to reference the technical documentation for the comparator device, then clinical testing will be necessary to demonstrate equivalence. Factor pre-market clinical testing into device development Can use risk analysis in certain scenarios, to cover use of similar, but not identical materials. If device contacts intact skin or is a minor component of the device, risk analysis may be acceptable. Page 2 of 5

4 Table 1. Gap Analysis of Equivalence Guideline Language Gaps Implications Solution Strategies MEDDEV Revision 3: Describes the general requirements for clinical, technical, and biological equivalence. d MEDDEV Revision 4: Stipulates if evaluators compare the device under evaluation to multiple devices, then equivalence of every single device to the device under evaluation should be fully investigated, demonstrated, and described in the clinical evaluation report. f a Section b Section c Appendix F, d Appendix F, e Appendix f Appendix 1 Equivalence of each device to the one in question must be fully investigated. Evaluators should weigh the benefits of comparing the device to multiple comparators, since the full profile of each comparator will be required for demonstration of equivalence. Weigh the benefit of each comparator added to the CE against the cost when deciding how many devices to compare. Page 3 of 5

5 Table 2. Gap Analysis of Risk/Benefit Guideline Language Gaps Implications MEDDEV Revision 3: any risks associated with the use of the device are acceptable when weighed against the benefits to the patient. The evaluators should weigh the available clinical evidence, the adequacy of estimated risk for identified hazards, the severity of the condition to be treated, and the present standard of care and alternative treatments. a MEDDEV Revision 4: Adds more prescriptive language for how to evaluate risk/benefit profile. Evaluate if the clinical data support all medical conditions and target populations covered by the intended purpose when compared with the current state of the art and whether limitations need to be considered for some populations and/or medical conditions The literature review should demonstrate if the device addresses a significant gap in healthcare provision. Where there is no such clinical need, the design solution needs to show an improved or at least equivalent benefit/risk profile b ISO 2 nd edition: No mention of a risk-based approach for QMS requirements. d ISO 3 rd edition: Need to use risk-based method to support internal and external QMS processes. apply a risk based approach to the control of the appropriate processes needed for the quality management system.. and controls shall be proportionate to the risk involved and the ability of the external party to meet the requirements e,f More stringent guidance included in the section weighing risk/benefit profile. Risk-based development should be used for QMS processes. In the EU, approvals of new devices will be slower and may have limitations, eg to the target population that can be treated. Manufacturers should add more checks and resources to parts of the process where risk is greater Solution Strategies Early in the CE process, ensure that the intended purpose and target population for the device is supported by known data; if not, revise purpose or target. In certain cases, if the device fulfills an unmet medical need and has major benefits, there may be a path to expedited approval. c Develop a lifecycle approach to systematically obtaining feedback from device users and patients and other sources to measure and adjust device quality/safety. a Section 8 b Appendix 7.2 c MEDDEV Revision 4, Appendix 8 d Section 4.1 e Section f Section CONCLUSION The changes to the CE MEDDEV 2.7/1 guideline and the QMS ISO standard on the topics of equivalence and risk/benefit profile imply generally, more clinical investigations and other work will be required to demonstrate conformity. This gap analysis discusses what type of additional work will be required and in select cases, when it may not be required. As regulatory guidelines become more complex, it is vital to work with experienced, well-trained evaluators who are knowledgeable about navigating the new regulations. Page 4 of 5

6 References 1. European Commission. Guidelines on Medical Devices Clinical Evaluation: A Guide for Manufacturers and Notified Bodies under Directives 93/42/EEC and 90/385/EEC. MEDDEV 2.7/1 revision 4. Revised June Accessed October 3, International Organization for Standardization. Medical devices - Quality management systems - Requirements for regulatory purposes. ISO rd edition. Revised March 1, Accessed October 3, Heneghan C. The Saga of Poly Implant Prosthese Breast Implants. BMJ. 2012;344:e International Organization for Standardization. Medical devices - Quality management systems - Requirements for regulatory purposes. ISO nd edition. Revised July 15, Accessed October 3, European Commission. Guidelines on Medical Devices Clinical Evaluation: A Guide for Manufacturers and Notified Bodies under Directives 93/42/EEC and 90/385/EEC. MEDDEV 2.7/1 revision 3. Revised December Accessed October 3, Page 5 of 5