Brice Ezzouaouy, senior product manager at Beckman Coulter Life Sciences, looks at the journey of the 2017 IVD Regulation and how it affects different aspects of the industry.
The 2017 IVD Regulation (IVDR) undoubtedly aims to raise the safety and quality standards of in vitro diagnostics. However, it introduces various complications not only for manufacturers, but also for laboratories conducting studies with homebrew assays or Laboratory Developed Tests (LDTs). While we were in the latter half of the five-year transition period, many companies and labs had not yet managed to commit to IVDR compliance. Although the May 2022 deadline has been extended, the European Union did not compromise on the strenuous certification and documentation tasks. The more companies and laboratories utilise the transition period to prepare for IVDR compliance, the less hindrance there will be in medical device supply in Europe when the regulations are in full effect.
With that in mind, it helps to take an overview of the IVDR marathon and discuss its implications on different components of the IVD sector.
Notable Changes in IVDR
To account for the technological advancements and growing concerns for safety, the European Union proposed IVDR 2017/246 as a replacement of the previous IVD-Directive (IVDD) from 1998. The main reasons for this upgrade included the limited oversight of the previous IVD legislation on most IVD products and individual laboratory tests, and the increased need for objective quality and safety assessment.
The notable changes in IVDR can be summarised as tackling these concerns:
- Compulsory certification by third parties - notified bodies - according to the risk level of the IVD devices.
- Additional requirements for proving scientific validity and clinical relevance.
- New requirements for performance evaluation after product launch.
- Increased control over Laboratory Developed Tests (LDTs)
IVDR compliance is a marathon, not a sprint. As we approach the end of the initially proposed five-year transition period, some manufacturers and clinical laboratories are still not fully aware of what these changes mean for them.
Implications on IVD Manufacturers
One of the fundamental shifts with IVDR is the re-classification of IVD risk levels. With the new risk definitions, a significant portion of IVDs under IVDD’s self-certification class now require certification by notified bodies. However, this process comprises several steps, as the notified bodies will now assess IVDs on a multitude of criteria. While they were only concerned with the analytical performance of the devices according to the IVDD, they will now evaluate devices based on analytical performance, clinical evidence, supply management, technical documentation, and post-market surveillance.
How could this impact manufacturers? According to the IVDR, except low-risk class A products, which account for less than 20% of the IVDs marketed, an IVD cannot be put on the market without approval from a notified body. In other words, the increased need for data and documentation is non-negotiable. This is true not only for new products but also for legacy IVDs that must be remediated to continue being marketed. For many companies, this points to a substantial investment of time and financial resources. A manufacturer needs to conduct a wide range of studies on its devices to demonstrate their analytical and clinical performance, which can be time-consuming. These studies also require an upgrade to the manufacturer’s quality management capabilities due to the complexity of evaluation and the increased number of IVDs subject to the IVDR. Furthermore, because such quality assessments can be performed only by qualified people, manufacturers need to hire staff members to undertake regulatory compliance roles.
It is also important to note that applying to notified bodies may not always go smoothly. First, the manufacturer needs to inquire about fees to the notified bodies. More importantly, the list of suitable notified bodies has been narrowed down by IVDR. As of 2022, especially after Brexit, there are few notified bodies in Europe to deal with a pile of applications. That’s why a timely application is crucial for avoiding a backlog.
The documentation journey does not end at the launch of the product. IVDR demands a “cradle to grave” performance evaluation, and a significant part of it involves post-market surveillance. By the product launch date, the manufacturer must have constructed a concrete post-market performance follow-up plan, with periodic updates to risk management and performance evaluation.
The increased complexity of documentation and its associated costs will dramatically extend the time needed to get approvals and licences for IVDs, potentially delaying product launches and return on investment. Prior to IVDR, IVD manufacturers were often launching their products first in the EU, while they obtained regulatory clearance in more complex regulatory frameworks such as in the US and China. This probably won’t be the case anymore. In dealing with IVDs for more niche markets (e.g., rare diseases), the manufacturers may find challenges ensuring a project’s viability. Either way, risk management, quality assessment, and budget plans will consume an enormous amount of time and resources. That’s why, despite extended deadlines, manufacturers should not underestimate the difficulty of IVDR compliance.
Lesser-known Impact of IVDR on Clinical Laboratories
IVDR implementation will perhaps have the highest toll on clinical laboratories that once made their homebrew tests to study rare diseases or substitute for commercially available tests they could not afford.
When it comes to LDTs, there are a few scenarios. The first question is whether there is a suitable CE-marked IVD alternative in the market. If so, the laboratory has the choice to use that alternative or continue to make their LDT. However, articles 5.1 and 5.4 indicate that an LDT manufactured and used within health institutions, despite available CE-marked tests, is subject to all the requirements of the IVDR regulations. In other words, the laboratory has to carry out all the steps mentioned in the previous section, as they will be deemed the manufacturer of that LDT.
Indeed, there are exceptions to these situations, as mentioned in Article 5.5. If there is no CE-marked alternative for the test that the laboratory research team intends to study, they can continue to use their own LDT. Nevertheless, that does not grant absolute freedom to the laboratory, as Article 5.5 highlights a set of eligibility criteria to be partially exempted from IVDR compliance such as:
The laboratory must be a European health institution.
It must still comply with the General Safety and Performance Requirements (GSPR), as indicated in Annex I.
It must have a Quality Management System compliant with ISO-15189 or, where applicable, national provisions, including national provisions regarding accreditation.
Most importantly, the laboratory must justify why they need to use their own LDTs by demonstrating that there is no substitute test on the market that delivers the performance necessary to meet the target patient group's specific needs.
IVDR is, for lack of a better term, a double-edged sword for laboratories. If a lab can find CE-IVD reagents, those will be safer.
If a laboratory wishes to continue producing LDTs, they need to invest valuable time and resources to accurately determine if there is a CE-marked IVD alternative. To manufacture LDTs despite equivalent IVD alternatives, a laboratory will have to take on the role of a manufacturer. However, many laboratories have neither the skill set nor the resources to perform these operations on their own. Complying with IVDR is already a major challenge for global IVD manufacturers supplying their assays to hundreds of labs across the globe. The core expertise of clinical laboratories is to produce diagnostic results, not to produce diagnostic assays, and the vast majority will not have the expertise and resources to achieve and sustain compliance with the full IVDR for each individual LDT.
Some laboratories strictly have to produce their own LDTs. This is particularly true for rare diseases. For example, some leukemias require combinations of dyes and conjugated antibodies to be diagnosed by flow cytometry, and these combinations are not commercially available with a CE mark. The validation effort might be reduced using individual CE-marked conjugated antibodies intended to be used in combination to diagnose the target disease. Nevertheless, such flow cytometry laboratories still have to upgrade their quality management systems, laboratory equipment, and protocols.
From this perspective, it becomes clear that access of small-scale independent laboratories to European markets will be significantly hindered.
So, how should laboratories approach the situation? A critical decision process lies ahead for laboratories that will need to determine if it is feasible to invest in LDTs for small-scale studies. This decision requires comprehensive inquiry and market research to determine which tests they must strictly continue producing, which ones they can replace with CE-alternatives, and how to reach out to IVD manufacturers that can provide devices within their budget. Even this initial inquiry stage is a long period of market research, inquiry, budgeting, and overall assessment.
The Importance of Manufacturers in IVDR Compliance for Laboratories
To increase overall IVDR compliance awareness, experienced manufacturers must rise to the occasion, fulfilling their initial IVDR compliance, and guiding EU laboratories. The most urgent task for manufacturers is to convert products to CE-marked IVDs available to laboratories so they can meet the broadest range of clinical needs possible. Furthermore, manufacturers need to assist their customers (especially clinical laboratories) in their own compliance journeys by raising awareness and providing IVDR-compliant workflows.
Beckman Coulter Life Sciences is a good example of a company demonstrating the positive impact of early manufacturer compliance on laboratories. When the IVDR transition period began in May 2017, Beckman Coulter had already been working on compliance for a year. In 2021 alone, the company obtained notified body certification for more than 200 clinical flow cytometry reagents. The plan is to raise that number to more than 300 by the initial May 2022 deadline. By continuously expanding its CE-marked IVD portfolio, Beckman Coulter Life Sciences can ensure that laboratories using flow cytometry for diagnostic studies can continue operating with minimum changes. Throughout the five-year IVDR marathon, we’ve been working around the clock to help laboratories go the distance.
Conclusions
IVDR will reduce safety concerns for diagnostic tools by raising the standards for quality and risk management in the EU. Further, the world is watching, as countries including the United States may consider implementing a version of IVDR.
While this new regulatory environment can improve patient satisfaction and the accuracy of treatment decisions in the long run, the development of IVDs will not be as seamless as before. From the stricter documentation process to the involvement of notified bodies, and the additional costs involved, stricter compliance guidelines create a significant burden for IVD manufacturers and clinical laboratories, both of which have an equal share of responsibilities.
Despite the deadline extension, manufacturers and laboratories need to continue (or begin) their compliance journey without hesitation. Doing so can help ensure a continuous supply of IVD products for health institutions, without the complication of delivery backlogs—which many of us faced due to pandemic-related supply chain issues. Laboratories can start with assessing their test portfolios to determine which CE-marked devices are needed by class, and whether specific LDTs can continue to be used. IVD manufacturers must start by assessing their current and future product portfolios.
To be sure, time is precious for both groups, neither of which can afford to postpone their adoption of new IVDR regulations to the last minute.