NEW YORK – As the European Union's In Vitro Diagnostic Medical Device Regulation (IVDR) continues to roll out, clinical laboratories and IVD test makers are beginning to assess its implications.
For labs at so-called health institutions that have been using in-house assays, also known as homebrew tests or laboratory-developed tests (LDTs), IVDR represents a paradigm shift that some say has led to arduous paperwork on top of existing quality control workflows.
Meanwhile, on the commercial side, small and medium-sized companies feel they are getting the short end of the stick as they have limited resources to devote to the stringent regulatory process required under the new law.
Enacted in 2017, IVDR initially asked manufacturers to become fully compliant with the regulation by May 26, 2022. However, as its rollout experienced multiple delays, European legislators extended the grace periods for various classes of existing devices based on their risk profile.
While it remains to be seen what benefits or impact IVDR will have on the European in vitro diagnostics landscape as a whole, many stakeholders fear that the current framework will hold back innovation and potentially limit IVD products available to European patients, especially those developed by smaller companies or for rare diseases.
'A lot of paperwork'
Under Europe's old In Vitro Diagnostic Medical Device Directive (IVDD), in-house-developed assays were effectively not regulated at the EU level. IVDR, on the other hand, introduced uniform requirements for health institutions, requiring those labs to justify the use of their homebrew tests while imposing rules to ensure their safety and performance.
While clinical lab professionals agree that the law is well intentioned, many believe the extra requirements imposed by IVDR are somewhat excessive, especially for labs in member states where checks and balances are already in place.
"For the Netherlands, I think they tried to solve a problem where there is no problem," said Bastiaan Tops, head of the diagnostic lab at Princess Máxima Center, a pediatric oncology research hospital based in Utrecht. "That said, I'm not sure how that goes for the rest of Europe."
According to Tops, all pathology labs in the Netherlands are already required to be accredited according to ISO 15189, an international quality management standard for medical laboratories. IVDR entails additional compliance work for Dutch laboratories, which he believes are already "quite well regulated."
"Patient safety, sure, [it is] a very good argument," he said. "I think the question is, 'Did we have a problem?' And my honest opinion is, I don't think we had a problem."
"Validation was part of our daily routine, I can say, even before the IVDR," said Albrecht Stenzinger, head of the Center for Molecular Pathology at University Hospital Heidelberg in Germany.
Similar to the Netherlands, clinical and medical laboratories in Germany are also required to be accredited according to the ISO 15189 standard, by Deutsche Akkreditierungsstelle (DAkkS), the country's national accreditation authority.
Andy Kahles, quality control manager in Stenzinger's team, said that currently, one significant difference between IVDR and the existing German accreditation framework is that the former requires assay-specific risk management as part of its general safety and performance requirements.
To comply with this, Stenzinger said the team had to create "tons of documents" for each in-house assay in order to assess its individual risk.
"It is time-consuming, it is a lot of paperwork," said Kahles, noting that all these efforts are in addition to the existing German regulatory requirements the lab has to satisfy.
Besides new rules for quality and safety, IVDR also imposes restrictions on the transfer of tests between health institutions.
"I think that the worst thing about [IVDR], particularly from a bioinformatics point of view, is that you are not allowed to share your tests," said Hanneke van Deutekom, head of bioinformatics at the Department of Genetics at UMC Utrecht in the Netherlands.
Labs sometimes collaborate and share informatics pipelines with each other, she noted, which can be especially beneficial to smaller hospitals that do not have a lot of in-house bioinformatics resources. In addition, van Deutekom said most bioinformaticians "have no clue" on how to do proper documentation for IVDR.
As IVDR continues to roll out, by May 26, 2028, the law will also require health institutions to justify the use of their in-house assays by demonstrating that the "target patient group's specific needs cannot be met, or cannot be met at the appropriate level of performance, by an equivalent device available on the market."
However, it is unclear what labs need to do to prove that their in-house tests perform as well as commercial assays. "How do we define equivalence?" said Elizabeth Macintyre, a diagnostic hematologist at Necker-Enfants-Malades Hospital at Université Paris Cité in France. Macintyre is the past president of the European Hematology Association and the president-elect of the Biomedical Alliance in Europe (BioMed Alliance), a federation of 36 European medical societies.
"The IVDR is using the term 'equivalent' without specifying what it actually means," Stenzinger agreed. "That [gap] needs to be filled by professional societies and experts stepping up together and saying, 'Based on our experience, we think that equivalency should be defined as follows.'"
'Grave shortage' of notified bodies
One hallmark of the IVDR is its use of organizations called notified bodies to certify that moderate- and high-risk tests meet the new requirements before they can be marketed and sold. Around 20 percent of all in vitro diagnostic devices in the European market, namely those categorized as class A non-sterile devices and considered to be the lowest risk to patients, do not require the involvement of a notified body under the new regulation, leaving 80 percent in need of assessment by such an organization.
This number pretty much flip-flopped from that of the IVDD, where only 15 to 20 percent of all IVD devices were required to be assessed by notified bodies.
"What that means is, you have this huge bolus of work that needs to be done by a smaller number of notified bodies, because after the [rollout] of IVDR, a lot of notified bodies left the market," said Seamus Kearney, founder and CEO of ARC Regulatory, a Northern Ireland-based consulting firm that helps in vitro diagnostic companies achieve regulatory compliance.
"We have become quite busy," said Alex Laan, head of IVD Notified Body at BSI, a designated notified body based in the Netherlands. "With every change in regulations, it requires attention not only from manufacturers but also very much from notified bodies. More specifically to IVDR, the regulation places many more requirements on the notified bodies," he said, explaining why some have left the market.
Acknowledging the "grave shortage" of notified bodies, the European Commission in 2021 extended the grace periods for certain classes of devices under IVDR in order to minimize the risk of "significant disruption in the supply of various essential in vitro diagnostic medical devices on the market, affecting the diagnosis of patients and their access to relevant healthcare."
By the European Commission's own account, at that time, Europe only had six notified bodies designated under IVDR. Since then, that number has inched up to 10, according to the commission's database, still short of what the market needs, according to some.
"Finding a notified body is a major challenge, especially for small companies," Torsten Kiesner, a spokesperson for Verband der Diagnostica-Industrie (VDGH), wrote in an email. Based in Berlin, VDGH is an in vitro diagnostics industry lobby group that represents more than 120 companies that manufacture or distribute diagnostics and life science research products in Germany.
"During the transition from IVDD to IVDR, large companies were at an advantage as they often had a business relationship with a notified body. Small companies are still waiting to sign a contract with a notified body under the IVDR," Kiesner added.
"What is true is that large manufacturers tend to already have a relationship with a notified body from the past," said Laan. This, he said, gives them a head start "because they have already hit their head on a few stones during earlier processes, so they have already taken on the lessons learned."
However, regardless of their size, all companies are "held against the same bar" during the process, Laan emphasized. In addition, the recent improvement in the capacity of notified bodies and the extended grace period for devices also leave notified bodies a bit more time to accommodate applications.
"We now do have capacity, but the situation will probably be different in a year or two, when all of these transitional timelines are ending," he said. "I think it takes two to tango. As long as we are able to take on all the projects and have capacity, then the manufacturers should also submit [their applications] now."
"I do think being already registered [with a notified body] under the IVDD helped us a lot," said Erica Kremer, director of compliance at GenDx, a medium-sized company based in the Netherlands that produces kits and analysis software for transplant diagnostics.
Their existing "good relationship" with notified body TÜV SÜD, Kremer said, helped her team to master the learning curve during the early days of IVDR. The company also interacted with its notified body early, she said — roughly four and half years ago. By now, GenDx has four reagent kits and one software that are approved under the new regulation, making it one of the first companies to become IVDR compliant.
However, not all companies' IVDR journeys went as smoothly, even with an existing connection with a notified body.
"There were some hiccups indeed," said Paul van Vught, head of quality assurance and regulatory affairs at MRC Holland, also based in the Netherlands, which develops diagnostic tests to detect DNA copy number changes and methylation patterns associated with diseases.
According to van Vught, under IVDD, MRC had already been working with a notified body to certify its products. However, as IVDR started taking effect, the notified body ceased to continue its service as it was not sure whether it had sufficient expertise to evaluate MRC's products, he said.
As a result, the company had to switch to a different notified body, which later withdrew from the IVDR process, forcing the company to find a third one.
After several rounds of questions, the company is currently "at the final stage" of the notified body assessment process, van Vught noted. "We're almost there," he said. "It took some time and some annoyance, to be honest."
Meanwhile, it appears that big players in the IVD industry are in better shape when it comes to becoming IVDR compliant.
At the International Federation of Clinical Chemistry and Laboratory Medicine WorldLab/EuroMedLab conference in May, Ann Costello, global head of Roche Diagnostics Solutions, said the company got ahead of the game and started to prepare for the IVDR transition in 2018. Roche chose TÜV SÜD as its notified body and is about 90 percent done in terms of getting its existing products certified with IVDR, she said.
Similarly, Alexander Antonio Socarrás, executive VP and head of global commercial operations at Siemens Healthineers, noted that the company was ready to go and had no delays in making its products IVDR compliant by the time the law started getting implemented.
Socarrás, who is also a board member of MedTech Europe, a trade association representing the medical technology industries in Europe, also acknowledged that IVDR transition has been the biggest challenge for small firms.
Nevertheless, larger players have seen some challenges, too, according to Fernand Goldblat, VP and general manager of integrated diagnostic solutions at Becton Dickinson.
"In some instances, if you're a company with a very narrow portfolio, you can put all your efforts on that particular small portfolio, get it through the notified bodies," he said. "The breadth of our portfolio is sometimes a challenge."
Goldblat said BD has not been immune to the lack of notified bodies, either. "Everyone has been affected by the limited number of notified bodies, and the notified bodies themselves have been struggling with the amount of work that they simply could not cope with," he pointed out, adding that the problem was exacerbated by the COVID-19 pandemic for more than a year, putting the brakes on the certifications of IVD products during that period.
Gaps to be filled
One of the challenges that MRC experienced during the IVDR review process, van Vught said, is that the law was not written with multiplexed assays or next-generation sequencing-based tests in mind.
His company's conventional multiplex ligation-dependent probe amplification (MLPA) assays, for instance, can have more than 50 targets, and the notified body considers each of these as a single analyte.
"They want to see data for every single analyte," he said. "That was why [the review process] took so long." In the case of their digital MLBA assay, which contains thousands of targets, gathering enough data for the review process has become nearly "impossible," van Vught added.
ARC Regulatory's Kearney also contended that IVDR has little consideration for pharmaceutical clinical studies. Specifically, the law contains a "distance selling" provision, he said, stipulating that regardless of where testing is done, if a sample from a European subject is involved, the requirements of the IVDR must be followed.
Typically, all samples collected for pharmaceutical studies are tested in CLIA labs outside of Europe, Kearney said. However, "we now have a lot of CLIA labs go, 'Well, we don't know anything about IVDR, and we have no interest in complying with IVDR, so we can no longer do this testing for European patients,'" he noted.
Even for notified bodies, there are still gaps to be filled in the IVDR infrastructure. For instance, the regulation requires a batch-verification process carried out independently by European reference labs for class D devices, such as for tests to screen blood and tissue donations for syphilis, Laan said, which the law considers "high individual risk and high public health risk."
However, such European reference labs have not been set up yet. "They should have been set up for quite a few years now," Laan said. "That's a bit of a headache."
Given the lack of reference labs, the European Commission has made an exemption for now, so notified bodies can still issue a certificate for class D devices until European reference labs are designated, Laan said.
With the increase in resources devoted to IVDR certification, many stakeholders fear that the law will hamper innovation, especially at smaller companies developing so-called orphan diagnostic tests for rare disease patients.
"I always say legislation is designed for the worst kids in the class," Kremer said. "So, I do think that companies like ours, that have the quality of [tests] in mind, see the importance of this [law]."
"On the other hand, I do see that it hampers innovation," she noted, adding that her own company's timelines for innovation are "becoming longer," and every time the company makes a change or updates its IVD products, this comes with "a whole circle of paperwork."
"One of our worries is that the small and medium enterprises are going to stop putting out the market niche tests," said BioMed Alliance’s Macintyre.
"We have seen small and medium-sized enterprises that take the course of not going to Europe, but instead going to the US, because it's perhaps easier to access that market," Laan said. "Now, that is a concern."
"Costs are also high, especially when it comes to innovation or diagnostics for rare diseases or niche products," said Kiesner, the VDGH spokesperson. "This leads to companies reducing their product range or going out of business."
In fact, some clinical lab professionals are already starting to notice products coming off the shelf as a result of IVDR.
"Some products like FISH probes, for instance, are from smaller companies, and they say, 'We're not going to deliver anymore because we cannot comply with the new rules of the IVDR, so you have to look for an alternative,'" said Claudia Ruivenkamp, a clinical laboratory geneticist at Leiden University Medical Center in the Netherlands.
In another instance, Ruivenkamp said, a commercial analysis software package that her labs had been using for diagnostic exome sequencing also became unavailable because the company decided not to undergo the IVDR process.
Finding a path forward
While the long-term impact of IVDR on the EU diagnostic landscape remains to be seen, the law is here to stay. With that in mind, many manufacturers and clinical labs are working to find the best way forward to comply with the new regulation.
"We stepped away from doing a lot of documentation in the end," GenDx's Kremer said, and instead integrated the paperwork with the development processes. "If one of the scientists [conducts] a project, we make a template in which they need to document what they do, and by filling all these lines, they are [ready to be] IVDR compliant in the end," she explained.
Medical professionals in some member states are also joining forces to help labs navigate the new regulatory landscape. Stenzinger, Ruivenkamp, van Deutekom, and Tops, for instance, are all members of the IVDR task force within their respective countries.
"I think in the Netherlands, we're doing a really good job [implementing IVDR]," said van Deutekom. "We have this task force that includes members from all the different laboratories within the Netherlands, and we decided to interpret IVDR together and create one document for the whole Netherlands."
The shifting legal paradigm also spurred the development of new commercial services to help diagnostic labs become IVDR compliant, such as from Vienna-based Platomics.
A spinout from the Austrian Institute of Technology, Platomics was initially founded to develop and commercialize a bioinformatics analysis platform for genetic testing. As the company realized its need to go through the IVDR regulatory pathway, it also started to develop software to help it compile technical documents for its potential products.
"The original reason [for us developing the IVDR compliance platform] more or less was because we ourselves had a problem, we ourselves had a challenge in how to create technical documentation for potentially hundreds of products maybe in the future," said Andreas Oberleitner, head of regulatory affairs and quality management at Platomics.
Now the company has completely pivoted to become a compliance software provider and is offering a product called PlatoX IVD Assistant, an automated platform developed to help labs compile IVDR technical documentation for their in-house tests.
On a larger scale, international medical professional organizations, such as BioMed Alliance, are also engaging with stakeholders to help ensure a positive IVDR outcome.
"At BioMed Alliance, we've taken the position that we want to help make [the IVDR transition] as good as possible," said Macintyre. "That means talking to the different stakeholders, including trade associations that represent big industry, trade associations that represent [small and medium-sized enterprises], and startups. It also means talking to our national competent authorities."
"I think the bottom line is, if we communicate between the different stakeholders, we will find the right solution," she added. "If everybody is prepared to go the extra mile to find the right solution, then we will find it."
Tony Fong contributed reporting to this article from the WorldLab-EuroMedLab Congress in Rome.