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EU IVDR Transition Remains Bumpy Ride for Smaller Firms, Labs

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NEW YORK – Concerns continue to swirl around the implementation of the European Union's In Vitro Diagnostic Regulation even two years after it came into effect, with new developments, such as the recent extension of transitional periods for certain classes of IVDs, creating fresh uncertainties.

One IVDR-connected issue is the drop-off in applications for certification, as some companies wait and see if the regulation will be further tinkered with by policymakers, while other firms grapple with the increased costs, a particular burden for small- and medium-sized firms.

Another is that European clinical laboratories need to meet certain requirements to use in-house devices (IHDs), laboratory-developed tests that often rely in part on commercially available components, conditions that some argue should be delayed.

These concerns and others are reshaping the European diagnostics landscape on an almost daily basis, as newer diagnostics firms increasingly see the US as a safer bet for market entry, and laboratories have started to lobby policymakers for the same kinds of extensions that companies have received. So far, nobody can say how the market will shake out.

"Nobody knows the endgame," remarked Gert Bos, executive director, partner, and CSO at QServe, a medical device consultancy group based in Amsterdam.

Device certification

Under the old IVD Directive (IVDD), enacted in 1998, Bos noted, most IVDs could be placed on the market following a self-certification process. But under the IVDR, the majority of tests must undergo an assessment by an independent entity known as a notified body, or NB. For years, industry observers were alarmed by a lack of such NBs to manage the conformity assessment of what was expected to be a deluge of submissions. During the COVID-19 pandemic, it was decided that devices that already held CE-IVD certificates would not require an IVDR certificate until well beyond the May 26, 2022, enactment date, with higher-risk Class D and C IVDs requiring IVDR certification by May 26, 2025, and May 26, 2026, respectively, and lower-risk Class A and B devices requiring certification by May 26, 2027.

This year, the European Commission extended the transitional period yet again. High individual and public health risk Class D devices will now need to obtain an IVDR certificate by December 2027, while high individual and moderate public health risk Class C devices will require such a certificate by December 2028. Lower-risk devices will need one by the end of 2029. The extensions apply to IVDs with existing CE-IVD marks and are designed to ensure access to tests during the transition period.

According to Bos, it's unclear how many of those IVDs that were CE-IVD-marked under the IVDD will undergo assessment by an NB for IVDR certification. Currently, applications to NBs have trailed off for numerous reasons, leaving an inverted situation from what observers had previously warned about: auditors with time on their hands.

"The vast majority of products historically were not conformity-assessed by the notified bodies, but rather placed on the market and at a high level supervised by the healthcare authorities separately per EU country," said Bos. "It is clear that the amount of submission for assessment currently received by the joint notified bodies is at the very low end of what has been expected to come in."

According to Bos, there now is sufficient capacity in the system to assess IVDs, and NBs are actually asking for work and reminding their customers to submit dossiers and to request audits because they have, in fact, the time. "Closer to the deadlines this might become tighter," as many manufacturers may wait until the last minute to submit products to NBs for certification, Bos speculated.

There are various theories as to why submissions have trailed off, but "I think that it's mainly linked to the postponement of the dates within the amended regulations," said Françoise Schlemmer, director of Team-NB, the European Association of Medical Devices Notified Bodies.

Schlemmer added that NBs are currently able to handle most requests from IVD manufacturers. She said that 12 NBs have been designated under the IVDR.

There are other factors at work. The EU, when the UK was still a member, was once considered an ideal place to launch a new test for small- and medium-sized enterprises (SMEs), given the self-certification process under the IVDD.

Those days are over now, according to Mark Street-Docherty, CEO of Bedford, UK-based Global Access Diagnostics, a social enterprise company that is looking to meet the diagnostics needs of low- and middle-income countries. Street-Docherty, who also led other UK diagnostics firms like Elucigene Diagnostics, MicrosensDx, and Rosa Biotech, said that GADx has about 25 tests in development at any single time and a global footprint of intended end users.

"Aligning our developments with international changes in regulation is of particular importance to the business," he stressed.

In general, said Street-Docherty, the IVD industry is struggling with increased development, manufacturing, and distribution costs, and the IVDR has just added another layer of complexity to those smaller companies that want to sell in the market. Here, both the time it takes to gain compliance as well as the cost have been added factors.

Profitable SMEs, he said, have likely trimmed their lists of innovative products, focusing on a smaller number of tests to ready for certification, while they try to bring their existing catalog current, Street-Docherty said. Early-stage, highly innovative firms have needed to source higher levels of venture capital funding, as it might take them nine months to a year while an NB assesses their product for compliance with the IVDR.

And within the process of obtaining an IVDR certificate, there can be numerous other hitches. "The EU notified bodies currently lack a mechanism for agreeing [on] expectations around IVDR validation processes," said Street-Docherty. This puts an "increasing burden" on SMEs, he said, noting that such a mechanism exists during pre-submission negotiations with the US Food and Drug Administration.

The result has been that companies with "highly innovative technologies" are turning to the US for a first launch, he said.

In addition, when companies do pursue IVDR certification, they also need to take time to prepare their submissions as well as better understand the way their NB interprets various provisions in the IVDR, too, affecting the length of the approval process, Street-Docherty added. The UK is in the process of setting up its own regulatory pathway for IVDs, which will require assessment by state-designated approved bodies to obtain a UK Conformity Assessed (UKCA) mark.

The UK "could eventually offer an alternative" market for EU firms to initially launch their IVD tests, Street-Docherty offered, "but at present, [it] also lacks the much-needed pre-submission consultative approach taken by the FDA."

One European company that is looking to launch a test first in the US is Geneva-based ABCDx. CEO Jean-Charles Sanchez said ABCDx decided to prioritize an FDA path for LVOCheck, a blood-based, point-of-care test that can be used in ambulances to triage large vessel occlusion patients prior to sending them to the closest reference stroke center for thrombectomy.

"The FDA process is significantly more transparent, with clear guidelines and efficient interactions," said Sanchez, noting that ABCDx is discussing breakthrough device designation for LVOCheck and is also engaged in the FDA's Q-Submission Program for its de novo Class II system.

Sanchez cited the "small number of European notified bodies available to handle the IVDR requirements" as a reason for the company's decision to prioritize the US. "This scarcity has resulted in a long backlog of startup requests, complicating and delaying the process for companies trying to bring innovative tests to the market in Europe," he said.

Erik Vollebregt, a life sciences and IP lawyer and partner at Amsterdam-based Axon Lawyers, said that SMEs, given their limited sources of funding, have to make such decisions, leading them to trim their menus to focus on specific IVDs or launching elsewhere, such as in the US.

"If you can choose between markets of roughly similar size where you can sell at more or less the same price, the EU and US, but the US offers a faster, cheaper, and more predictable path to market, where do you go to market first?" said Vollebregt.

He also called into question the narrative that NBs are now able to accept any application and that manufacturers are sitting on their hands given the dearth of new submissions. "Acceptance of an application is one thing, but they omit that it is still not certain that they can actually process any IVDR applications timely and predictably and at a reasonable cost," Vollebregt said. "This is why manufacturers delay their submissions or apply elsewhere first." 

Even if SMEs manage to get a new test through the FDA before they get their hands on an IVDR certificate, they will still need to navigate the new regulation, even with its extensions for legacy devices and even with its surfeit of complexities for companies.

Simona Varrella, an expert consultant in regulatory intelligence and innovation at Obelis, a Brussels-based company that offers representation and consultancy services to IVD manufacturers that wish to sell devices in the EU, UK, and Switzerland, noted that IVDR requirements are "more stringent" than requirements under the IVDD. Varrella cited surveys published by the European Commission that show it could take a year to two years to obtain an IVDR certificate, depending on the route a device is subject to.

Varrella noted that an incomplete application is among the main reasons for application refusals. Because of this, manufacturers "need to take into account the time necessary to reach the certification and, ideally, submitting their application precisely and with the required information," she said.

And even with the recent extensions, Varrella urged manufacturers to "act promptly" with their submissions. She noted that the extensions for legacy devices only applies to IVD manufacturers that have applied to an NB for IVDR conformity assessment by certain deadlines: by May 26, 2025, for Class D devices and devices covered by IVDD Certificate; by May 26, 2026, for Class C devices, and by May 26, 2027, for Class B and Class A sterile devices and have an agreement in place with an NB within four months after these deadlines. Companies also need to have an IVDR-compliant quality management system in place by May 26, 2025, for all classes.

As such, she said that involving IVDR experts could be "crucial" for obtaining compliance. "For both EU and non-EU manufacturers, being prepared, aware, and supported towards the EU market access are aspects which manufacturers sometimes underestimate and later result in major obstacles," she said.

IHDs

While companies have been granted two extensions for legacy devices by policymakers, European laboratories that use in-house devices are still dealing with a now-passed May 26, 2024, deadline to become compliant with certain IVDR requirements that some have characterized previously as excessive and creating unnecessary bureaucracy.

The situation is dire enough that seven professional German medical organizations, including the Federal Association of German Pathologists, the German Society for Pathology, and the Society of German Laboratory Doctors, this month released a position paper calling for an extension of the deadlines related to labs until January 2027.

In its joint statement, the German organizations noted that while commercial manufacturers had received extensions to close potential supply gaps, deadlines for medical diagnostic facilities remain unchanged. Considering that labs are now required under the IVDR to either adopt commercial kits with IVDR certificates or demonstrate how their in-house devices perform better than existing kits, the organizations argued in the position paper that "implementation is not achievable."

They also pointed out that IHDs enable the diagnosis of rare diseases, particularly in genetics, and are at risk of losing compliance given the expense needed to validate them in line with IVDR requirements, which could have a negative impact on healthcare. Obtaining access to large cohorts for validating tests for rare diseases is not achievable, they stated, adding such a situation would make other markets, such as the US, a preferable avenue for introducing new, innovative tests compared to Europe.

The organizations called for a reassessment of the regulations governing laboratories and said that labs should not be forced to adopt commercial kits over IHDs, for instance.

Axon Lawyers' Vollebregt said that health institutions have "consistently reported that they are unable to meet the IVDR requirements for in-house devices." He said this is why, to his knowledge, no member state has yet started serious enforcement despite the widespread noncompliance with IHD requirements — the new regulation began to apply to IHDs May 26, 2022, and nearly all but one were applicable by this past May.

Qserve's Bos said that he was surprised that the position papers were released at such a late stage. He noted that the IVDR has been the law since it was enacted in 2017, and that discussions had gone on for seven years prior to that.

"It will be interesting to see how powerful the current lobby is going to be, and on the other hand if there is any willingness from authorities to supervise and take action," he said.