By Marcelo Trevino, Senior VP, Regulatory Affairs and Quality Systems, Applied Medical
The MEDDEV guidance document 2.71 revised and released by the European Commission this year instructs manufacturers how to properly conduct a clinical evaluation, including demonstration of the scientific validity of data and conclusions. The document also covers requirements specifically for postmarket surveillance and postmarket clinical follow-up.
This article summarizes the most significant differences between this and the previous guidance. Because the changes focus mainly on clarification of certain concepts, it is expected that manufacturers will follow the guidance immediately.
Frequency Of Clinical Evaluation Report Updates
This revision provides more detailed guidance on requirements for the frequency of evaluation report updates. The guidance indicates a need to update at regular intervals, with that frequency defined and justified. In addition, the report must be updated when new postmarket surveillance information could affect the conclusion of the clinical evaluation report (CER). Typically, for devices that pose very low risk, are established, and have undergone no changes, updates would be necessary every two to five years. Devices carrying significant risks, devices used in high-risk patient populations, or novel devices must be updated at least annually. Additionally, when postmarket surveillance data is received that has the potential to change the current evaluation, manufacturers must assess the need to update the report.
Manufacturers should take into account Medical Device Reporting (MDR) requirements for the periodic safety update report and the summary of clinical performance. Article 60c of the MDR states that, for all devices in classes IIa and above, manufacturers should create a periodic safety update report (PSUR) that must be maintained throughout the lifetime of the device, addressing conclusions of the postmarket surveillance data and associated corrective and preventive actions (CAPAs). Sales data should be included, along with an estimate of the population using the device and usage frequency, where practical. Class IIa device manufacturers must update the report at least every two years; Class IIb and Class III device manufacturers must update the report at least annually, and Class III device manufacturers must submit the report for review by their notified body, through EUDAMED.
The summary of safety and clinical performance is described in article 26 of the MDR; it is required for Class II and class III implantable devices and must be updated at least annually. Some requirements include information related to the device, unique device identification (UDI) information, intended purpose, indications, descriptions of differences from previous models, harmonized standards, training for users, residual risks, and summaries of the clinical evaluation report and postmarket clinical follow-up.
Report Author And Evaluator Qualifications
Under section 6.4 of the guide, there is clarification regarding required qualifications for team members involved in clinical evaluation activities. Knowledge prerequisites include regulatory requirements, research methodologies, medical writing, and information management. Evaluators should have a degree plus five years of relevant professional experience or, absent a degree, 10 years of relevant experience. Not all members need to have these qualifications and experience, but the skill sets should somehow be represented within the team.
Manufacturers will have to define requirements and justify personnel choices through CVs and declarations of interest from each individual. A declaration of interest is intended to prevent bias, and states whether the person involved owns shares in the company, as well as other factors that might influence their conclusions. A stated interest would not disqualify an individual from clinical evaluation team membership, but the potential conflict should be documented.
Clarifying CER Objectives
The revised guidance requires that CER objectives be more clearly linked to specific safety, performance, and risk/benefit endpoints. Appendix A5 defines key elements of the literature search-and-review protocols, which should be objective, non-biased, and systematic. Literature review questions to be addressed must be specified, and should define the population for whom the device is intended, intervention, controls, and outcomes (mortality, qualify of life, pain scores, etc.). For example: For (patient population) should (intervention) or (control) be performed to achieve (outcome)?
Manufacturers have to start with the device specification, identify related essential requirements in need of supporting clinical evidence, define the scope of the clinical evaluation and, finally, define specific and measurable objectives (this remains unchanged from version 3).
This section of the guidance dictates how to establish and document state-of-the-art (i.e., standards and guidance documents, data from benchmark and equivalent devices, safety/performance data from other available treatments). This data should be used to establish clinical safety and performance endpoints, as well as clinically acceptable vs. avoidable risks. In general, referring to state-of-the-art implies use of the most common harmonized standards. Additionally, device features (inputs) should be easily correlated with outcome and expectations.
Identifying state-of-the-art is important in the context that devices used for comparison should be relevant. In other words, it is not acceptable for a manufacturer to compare performance of its device to devices exhibiting historically poor performance, just to claim superiority. To claim its device is better, a manufacturer needs to identify a device that represents state-of-the-art for a particular condition or treatment/therapy. Manufacturers will benefit here by having a team member with relevant clinical experience.
Clarifying Scientific Validity Of Data
The updated guidance clarifies the requirement to obtain sufficient clinical evidence (amount and quality) in order to guarantee the scientific validity of the conclusions. The guidance details how to evaluate methodogical quality and scientific validity, and maps out each stage of the clinical evaluation process to ensure completeness and objectivity. This section of the guidance also clarifies literature search, retrieval methods, data analysis, and demonstration of conformity.
Evaluators should examine the methods used to generate data and then evaluate the extent to which the safety or performance outcomes can be attributed to intervention with the device. Pertinent factors in this evaluation include bias, random errors, inadequate disclosure of information, misinterpretation, or other confounding factors. Overall, though, the clinical evaluation process remains much the same.
Equivalence And Access To Data For Equivalent Devices
This section has been expanded from the previous version and the requirements are described in Appendix 1. Equivalence still is assessed in terms of clinical, technological, and biological parameters, but the revised guidance requires more documented information for each device in order to demonstrate equivalence to those parameters.
Evaluators may wish to compare several equivalent devices, and in such cases, each device compared to the device under evaluation should be fully investigated, demonstrated, and described in the CER. Populations should be equivalent to European Union, as well, so manufacturers need to determine if existing data is relevant; it could be a struggle to justify equivalence if there are significant differences in patient size, weight, etc., in data gleaned from populations outside of the EU.
A significant level of detail must be provided to demonstrate equivalence; the guidance indicates that the differences between the device under evaluation and equivalent devices be identified, fully disclosed, and evaluated. It should be clearly explained how any differences do not affect the performance or clinical safety of the device under evaluation. This process includes analysis of design differences, specifications, comparative drawings and diagrams, descriptions of differences in physical and chemical properties, material characterization and comparative testing in accordance with ISO 10993, and a look at the impact of the devices’ manufacturing processes. All of this information should be summarized in the CER to support information in the technical file, and the technical file should refer to the location of all the supporting documentation.
Furthermore, equivalent devices must be CE marked and used in accordance with their intended purpose, as documented in instructions for use (IFU). Exceptions can be considered when the equivalent device is not CE marked, but a thorough justification with a gap analysis must be included in the CER.
Finally, a contract must be in place with equivalent device manufacturers, allowing full access to their data on an ongoing basis. This is particularly challenging for manufacturers, as such information might be confidential, sensitive, or unavailable to the manufacturer. Notified Bodies are encouraged in the guidance to ensure that manufacturers make every attempt to obtain this information and, if collecting said information is not feasible, manufacturers should at least provide physical, mechanical, and chemical characterization requirements through comparative testing.
When Is Clinical Investigation Required?
Considerations were added to Appendix 2 describing how to assess whether clinical investigation is needed. In general, sufficient clinical evidence should be in place to demonstrate that all essential requirements have been addressed. In making this determination, manufacturers should consider all indications and conditions of intended use, all patient populations, all device variants, models sizes, whether the data is scientifically sound, and whether the device demonstrates compliance with state-of-the-art. If gaps are found that can’t be addressed by other means, then a clinical investigation should be carried out.
Implantable, high-risk, and Class III devices always require clinical investigation, unless a strong, risk-based justification exists to rely on clinical data alone. Additionally, devices with new or unproven technologies, and those that extend the intended purpose of an existing technology (new clinical use), require a clinical investigation. Special attention should be given to new materials, design features, intended purposes, indications, target populations, risks recognized, and types of users or claims. In addition, manufacturers should take into account incorporation of medicinal substances, use of animal tissues, and invasiveness to make this determination.
A quantification of the benefit and risk, as well as an evaluation of the overall risk/benefit profile, is required under Appendix 7.2. Quantifiable benefits for the patient include measurable improvements in the clinical outcome, the probability of the patient experiencing one of these benefits, and the average duration of these benefits. These benefits should be weighed against a similar evaluation of the device’s clinical risks, including the severity, number, and rates of harmful events; the probability of a harmful event; and the duration of a harmful event. The ISO 14971 Standard is a valuable tool for manufacturers developing a risk/benefit plan.
Postmarket Surveillance And Postmarket Clinical Follow-Up
The revised guidance reinforces the links between clinical evaluation, postmarket surveillance, and postmarket clinical follow-up. Appendix 12 requires Notified Bodies to ensure that the postmarket clinical follow-up process is planned, and that conclusions are documented in the CER. Notified Bodies are responsible for confirming the plan’s adequacy, and ensuring that the postmarket clinical follow-up report is aligned with gaps identified in the clinical evaluation.
In addition, Notified Bodies are required to assess manufacturers’ procedures for clinical evaluation, postmarket surveillance, and postmarket surveillance follow-up. They are required to take a representative sample of Class IIa and IIb devices based on risk and novelty. Finally, Notified Bodies must assess the data presented in the CER, the validity of the conclusions drawn by the manufacturer, and the conformity of the device to relevant essential requirements. Review teams structured by the Notified Bodies must include individuals with relevant clinical experience, as well, such as doctors, nurses, clinicians, etc.
Since this is a guidance document, an implementation period has not been defined. Notified Bodies might still accept a CER based on the previous version, but the expectation is that manufacturers will use Version 4 (the revised guidance) for any new reports. In general, most principles remain the same, indicating that manufacturers should use clinical data based on pre-market investigations, data from other devices, and data from postmarket activities to justify compliance with the relevant essential requirements. The revision provides more explicit guidance to manufacturers on how to manage a robust clinical evaluation, as well as how to demonstrate scientific validity of their data and conclusions.
While most requirements are similar to the previous guidance version, there are differences in the acceptable methodology used to analyze data, which now includes more prescriptive expectations from the European Commision. The MDR changes highlight the need for high-quality clinical evaluations, and this guidance will be an excellent tool in assisting manufacturers preparing for the new legislation.