In vitro diagnostic (IVD) medical device manufacturers are scrambling to meet the In Vitro Diagnostic Regulation (IVDR) 2017/746 requirements imposed by the European Union (EU). Changes in IVD classification will require the majority of IVDs currently marketed in the EU to undergo notified body scrutiny under IVDR and obtain CE marking, yet few guidance documents have been released. Lessons learned from meeting Medical Device Regulation (MDR) 2017/745 can help pave the way.
Here we share our insights learned from writing many MDR-compliant Clinical Evaluation Reports (CERs) in the context of IVD medical devices and the looming IVDR deadline.
Act With Urgency
One thing is clear, if you have not yet started, time is running out. The May 26, 2022 Date of Application is a hard deadline. Applicable IVDs that are not certified under either the In Vitro Diagnostic Directive (IVDD) or IVDR by this deadline cannot be sold on the EU market.
Currently, approximately 20% of IVDs are certified in the EU through IVDD. The remaining 80% are self-declared and not required to comply with IVDD or work with a notified body. These percentages flip under IVDR. It is estimated that 80% of IVDs will require CE marking under IVDR. And, unlike the case for medical devices, experts indicate that most IVDs will need to be submitted as stand-alone devices, not as device groupings in large part because of unique intended uses.
Getting all these IVDs certified over the next year is already straining the system. The capacity of notified bodies is limited. We stress that you should not underestimate the time and resources needed to prepare all the documents required for obtaining CE marking under IVDR.
Perform a Gap Analysis
Start by performing a gap analysis at the project level to identify and assess integral elements needed to support the evaluation process. Critical to this process is clearly defining the devices intended purpose and determining the devices classification. The device’s intended purpose is the basis of the clinical evaluation. The IVD classification will likely change, and this will impact IVDR requirements.
Asses the gaps in the existing technical files against new technical files. It is likely that the technical files will require significant remediation for compliance with IVDR. The technical documents must develop robust arguments to justify the types, quality, and sufficiency of evidence that are used to determine that the IVD is safe to use and performs as expected in a clinical setting. However, the definition of “sufficient” is ambiguous, and you will need to find clues from past experience with MDR.
The gap analysis should encompass at minimum:
- Devices intended purpose
- New classification rules*
- Technical files
- Benefit-risk analysis
- Performance evaluation, including post-market performance follow-up
- Post-market surveillance plan
- New recall requirements (incidences and field safety corrective actions)
- Quality management system criteria
- Authorized representative requirements
* Use the Guidance on Classification Rules of In Vitro Diagnostic Medical Devices Under Regulation (EU) 2017/746 to determine classification of the device. This document has explicit examples of many IVDs and their classification under IVDR. It also provides clarification for classifying combination IVDs with accessories and IVD instruments as well as how IVD software is treated.
Have Good Document Templates
Having a template that has been pressure tested by going through notified body review is a big advantage. Since IVDR is a new regulation, utilizing MDR preparations will be extremely helpful in developing templates, especially since the structure of both regulations are similar by design.
IVDR documents required:
- Performance Evaluation Plan
- Performance Evaluation Report
- Scientific Validity Report
- Analytical Performance Report
- Clinical Performance Report
- Post-Market Surveillance / Post-Market Clinical Follow-up
- Summary of Safety and Clinical Performance
The Performance Evaluation Plan (PEP) is similar to the MDR Clinical Evaluation Plan (CEP) in that they are both the road map for conducting the clinical evaluation process. Of course, the contents of the PEP will be specific for IVD medical devices as outlined in Annex XIII paragraph 1.1 of IVDR.
The Performance Evaluation Report (PER) is a critical part of the IVDR technical documentation in that its job is to determine if there is sufficient clinical evidence to support the manufacturers intended purpose. The PER is the IVDR’s equivalent of the CER for MDR.
IVDR Article 56 and Part A of Annex XIII clearly states the performance evaluation must demonstrate scientific validity, analytical performance, and clinical performance evaluation with assessment in relationship to the device. Each of these three reports are presented as part of the PER and are briefly described below.
- The Scientific Validity Report (SVR) documents the analyte / technology to the clinical condition or physiological state described in the intended purpose. The SVR is similar to the State of the Art section in the MDR CER and will require a similar approach. The SVR requires formal literature searches, expert opinions, and studies as objective evidence to set the device safety and performance criteria.
- The Analytical Performance Report (APR) presents the ability of the device to correctly detect or measure a particular analyte as necessary to meet the intended purpose. Objective evidence that analytical performance has been achieved must be documented. For example, the test should have appropriate sensitivity and specificity to meet the intended purpose, which could be different for the same analyte depending on how it is intended to be used. The APR should also include a summary of the data with discussion and conclusion about how this meets the specific IVDR requirements for the devices intended use.
- The Clinical Performance Report (CPR) presents the ability of the device to yield results for the target population and user. Clinical performance includes diagnostic sensitivity and specificity, as well as positive and negative predictive values. The CPR should support the populations described in the intended purpose and expected normal values.
Post-Marketing Surveillance (PMS) and Post-Market Clinical Follow-up (PMCF) are some of the new requirements under IVDR. Experience with MDR-compliant PMS and PMCF will be valuable in determining how to best approach these documents.