The European Union’s new In Vitro Diagnostic Regulation (IVDR) May 2022 implementation date is fast approaching. If you sell IVDs in multiple markets, it may be challenging to determine the differences between the IVD regulations in the U.S., the existing IVDD, and the new IVDR. It’s not surprising that global IVD manufacturers are finding it challenging to keep it all straight.
We’re here to help! In this post, RQM+ IVD regulatory experts have created a tool to compare IVD regulations based on regulatory oversight, device classification, post-market surveillance, labeling, and clinical evidence requirements.
FDA IVD Regulations
The United States Food and Drug Administration (FDA) considers IVDs to be medical devices and they are therefore subject to the relevant regulations for medical devices in the CFR, including the same pre-market and post-market controls. However, IVDs might also be considered biological products that are subject to section 351 of the Public Health Service Act. Determining the various classifications of your IVDs early in the product development process will help inform the appropriate regulatory path.
Advancements in laboratory-developed tests (LDTs) have led to increased scrutiny of these diagnostic tests that aren’t technically considered IVDs at this point. FDA has issued draft guidance and a discussion paper that describes the enforcement discretion for certain regulatory requirements and certain types of LDTs. This naturally creates a gray area for manufacturers and laboratories that develop LDTs when it comes to compliance with IVD regulations in the U.S.
EU IVD Regulations
The implementation of IVDR is a major shift in the EU regulatory landscape, and many manufacturers are finding that they aren’t prepared for all it entails. If you are an IVD manufacturer, here are some of the major changes to be aware of as we head toward the IVDR date of application:
- One of the most significant changes is that the scope has been expanded so many products that were previously self-certified IVDs will need notified body certification under IVDR. The limited number of notified bodies with IVDR designation combined with the sheer volume of IVD companies needing notified body assistance is making it challenging to get on their schedules, especially if you need to change notified bodies.
- New risk-based classification rules apply to all IVDs in lieu of the previous list system.
- Notified body involvement is new to most IVD manufacturers and requires a huge shift in thinking. Don’t underestimate the increased NB scrutiny and stringent documentation that’s required. Discuss any product changes with your notified body and make sure you are clear on what constitutes a significant change that would require the move from IVDD to IVDR sooner than you had planned.
- There will be no grandfathering. All IVDs that fall into a category for notified body inspection will need to comply with the IVDR.
- The application of state of the art to standards is causing some confusion. The expectation is that you are compliant with the current standards. However, not every standard is harmonized. For example, ISO 14971: 2019 hasn’t yet been harmonized, but we are seeing that notified bodies are requiring it because it is considered state of the art.
- The person responsible for regulatory compliance (PRRC) is a new requirement under MDR. You must identify qualified employees for this role and document the individuals responsible for regulatory compliance.
- Economic operator is also a new term in the IVDR and the entities in this role must meet certain requirements. This could be an importer, authorized representative, manufacturer, or distributor. Virtual manufacturing and distribution relationships are common in the IVD industry, resulting in many economic operator agreements and processes to be established for IVDR compliance.
These are just a few of the most significant changes IVD manufacturers must be aware of as you transition from IVDD to IVDR. The distinctions between U.S. and EU regulations are outlined in the table below.
In Vitro Diagnostic Products: Comparison of IVDR to FDA IVD Requirements
Comparison of In Vitro Diagnostic Product Regulations
Post-Market Surveillance (PMS)
IVDs go through registration and listing, 510(k)s, or PMA submissions with the FDA.*
*LDT and RUO are handled differently
Class I (low risk), Class II (moderate risk), Class III (high risk)
Reactive PMS system
UDI already implemented
Clinical evidence is almost always required for class III devices and may be required for Class II based on risk (approx. 10%).
Clinical performance testing is required for all IVDs.
Only 10-20% of IVDs were subject to NB oversight; many devices were self-certified, and therefore required minimal NB involvement.
General IVD, Self-Testing IVD, List B IVD, List A IVDLess risk-based than FDA. Fixed system leaves little room for interpretation.
Not directly mentioned in the directive, but it is expected that manufacturers would have a PMS system.
Vigilance reporting required.
UDI not required
Level of clinical evidence required is based on classification.
No formal report required.
80-90% of IVDs are required to have a certificate; NBs will now have to review the technical files of IVDs based on risk class.
Class A (lowest risk), B, C, D (highest risk)
Based on rules and risk level for patients and population.
International Harmonization utilizes CND codes.
PMS requirements clearly defined in regulation. Requires formal plans and reports.
Information is stored in EUDAMED.
New requirement for periodic safety update reports (PSURs) for Classes C & D and post-market safety reports (PMSRs) for Classes A & B.
Requirement is similar to FDA UDI with a different format.
Requires a basic UDI.
Information stored in FDA database will be different than info stored in EUDAMED, which requires a more in-depth upload.
Performance evidence reports (PERs) are required for analytical performance, clinical performance, and scientific validity.
State of the art analysis required.
Post-market performance follow-up activities (PMPF) are required and enforced.
Key Differences in Regulations
As you prepare regulatory submissions in one market, it’s helpful to know how they differ from the other markets where your products are sold.
In the U.S., a 510(k) submission demonstrates that your IVD is substantially equivalent to another product on the market. FDA reviews it and responds with a letter indicating whether the device is deemed substantially equivalent. If "cleared" by FDA, it is a one-time process, and the manufacturer isn’t required to demonstrate continuous improvement with state-of-the-art unless there are design changes requiring a new submission.
In the EU, IVD manufacturers must now submit to a notified body review of technical documentation. Under IVDD, only a small percentage of devices had regulatory oversight while the rest were self-certified. With the implementation of IVDR, the majority of manufacturers must now submit to technical documentation review by a notified body.
IVD classification in the U.S. and EU aren’t the same, and there is no one-to-one correlation. Manufacturers must follow the risk-based system in each market to classify devices. This is new in the EU because IVDD followed a list system. The scope has expanded under IVDR to include all of the following: reagents, reagent products, calibrators, control materials, kits, instruments, apparatuses, pieces of equipment, software or systems, and specimen receptacles. This system is like the FDA IVD classification because they are both risk-based.
Post-Market Surveillance (PMS)
U.S. IVD regulations require device malfunctions that could lead to a serious adverse event (death or serious injury) be reported. However, in the EU, this is a challenging area for IVD companies transitioning from IVDD to IVDR. The IVDR requires a much more defined and stringent plan for PMS activities. While having this clarity gives manufacturers a clear path to conformity, it’s causing some challenges for manufacturers with legacy devices.
Labeling and IFU
Labeling and instructions for use (IFU) requirements vary in all markets, including the U.S. and EU, and must comply with the relevant regulations. Changes under IVDR include having an NB number and an EU UDI included on labeling.
In the U.S., the requirement for clinical evidence for IVDs depends on the classification, but there is no reporting requirement. For the FDA, the emphasis is on the manufacturer’s verification and validation studies to support safety and performance. Under the IVDR, the requirement is for sufficient clinical evidence for your own device and/or an equivalent device if duly justified. This is a big challenge for many manufacturers with legacy devices where sufficient data is not available or compliant with IVDR requirements. The EU requirements also include ongoing reporting.
Tips for Efficient IVDR Implementation
With the IVDR implementation deadline looming, there’s a lot changing for IVD manufacturers that produce or distribute their devices in the EU, especially for those that were previously allowed to self-certify. Hopefully, you are already well on your way through the transition, but no matter where you are in the process, you are likely ready for some good news. Some of the work you are already doing in other markets or for other products may be applicable to IVDR compliance in the EU. Here are some ways that you can make your hard work go further:
- If you have filed a 510(k) on your in vitro diagnostic (IVD) device, you may already have some of the documentation and clinical evidence needed for a notified body review.
- If you have global submissions, you may be able to leverage existing submission data from markets such as Canada and Australia.
- If you have a quality system certified by a NB, your QMS is well on its way to IVDR compliance. You will need to implement requirements that are new to IVDR and not covered by IVDD and ISO 13485, for example the new requirements for performance evaluation reports and post market surveillance reporting. If you do not have a 13485 certificate, start mapping out your quality system is soon as possible.
- If you have already implemented UDI per FDA regulations, there are only a couple additional steps needed for compliance in the EU.
- You may already have the required performance data, which will allow you to reassess and repurpose existing documentation and package it in a way that meets IVDR requirements. Think outside of the box here. This data might have been called something different in the past or perhaps it wasn’t looked at as an input for this deliverable.
Ways RQM+ Helps
RQM+ has a large team of experts working on multiple IVDR implementations. Whether you need a technical file gap analysis, support with economic operators, or an experienced team to compile clinical and performance data for legacy devices, we have the expertise you need.
We have been involved with IVDR from the beginning and have already received notified body feedback. In fact, some members of our team have been involved in developing guidance documents.
From business-balanced strategy to expert implementation, the RQM+ team is here for you. If you’re not sure how prepared you are, take our IVDR Readiness Assessment to find out.