NEW YORK – The lack of clarity in the European Parliament's regulation on in vitro diagnostic medical devices slated to take effect next year may significantly disrupt oncologists' ability to access companion diagnostics they rely on to prescribe cancer treatments to patients, industry observers are cautioning.
UK-headquartered health technology firm Diaceutics and industry interest groups have been sounding alarm bells for months that labs, IVD manufacturers, and EU member states' healthcare systems won't be ready to meet the new oversight framework, dubbed the IVDR for short, by May 26, 2021, when it is scheduled to go live. Although the IVDR (EU regulation 2017/746) was adopted in 2017 with a five-year transition period, drug and diagnostic industry groups and cancer patient advocates have asked the European Commission to postpone implementation for another year and phase in requirements, such as audits by third-party compliance organizations, called notified bodies.
The European Commission so far has stuck with its timeline to implement the new regulations in eight months, raising concerns about what that means for cancer patients' ability to receive biomarker testing and treatments based on results from those tests. "As it stands, there is a genuine prospect of a catastrophe in medical management in May of next year," said Dave Smart, director of the scientific operations team at Diaceutics.
The medical technology trade organization MedTech Europe recently projected that if the European Commission doesn't immediately address the lack of IVDR infrastructure and its implementation timeline, between 22 percent and 76 percent of currently marketed IVDs will be lost to patients in the EU and global health services. Diaceutics has also estimated that around 70 percent of IVDs could be unavailable as a result of implementing the IVDR next year.
Most oncologists may not fully appreciate how the IVDR might impact their practice, and those who do describe how most institutional labs are uncertain how to meet regulations in the absence of guidelines and support from the European Commission. "There is little awareness among practicing oncologists about how the new IVDR regulation will impact, if it does, the way we order and interpret test results," said Joaquin Mateo, an oncologist at Vall d'Hebron Institute of Oncology in Barcelona and chair of the European Society for Medical Oncology's translational research and precision medicine working group.
The outstanding regulatory questions have hindered the Istituto Nazionale Tumori – Fondazione Pascale (INT-Pascale), the largest research and clinical cancer center in Southern Italy, from putting a detailed compliance and test access plan in place. In fact, according to Nicola Normanno, chief of the cell biology and biotherapy unit at INT-Pascale, "the majority of laboratories still do not have a plan on how to deal with the new regulation on diagnostic tests, although [IVDR] implementation is imminent."
But regardless of what happens between now and May 2022, patient care must continue, in Normanno's view. If IVD manufacturers are unable to meet IVDR regulations in time, creating a dearth of approved test kits in Italy, Normanno said his institution will continue performing in-house lab tests that have been internally validated and have established performance in external quality assessment programs. "I believe this will be the attitude of the majority of Italian [labs]," he added.
The IVDR is replacing the current IVD Directive 98/79/EC (IVDD), under which most IVD manufacturers can legally market their tests after self-certifying that they conform to EU regulations and affixing a "CE mark" symbol to denote the self-certification. The new IVDR will bring more stringent oversight for the majority of IVDs, including molecular diagnostics, such that test manufacturers that were previously able to launch tests through the self-certification process will have to be audited by designated notified bodies to ensure their tests meet the regulations and obtain a CE mark.
Under the IVDD, around 8 percent of IVDs, approximately 3,300 tests, needed a certificate from 22 notified bodies. Once the IVDR goes into effect, MedTech Europe estimates that nearly 80 percent of IVDs — more than 24,300 tests — will need a certificate from a notified body, but to date, only six such compliance organizations have been designated to clear IVDs for the market.
The IVDR will also impose new regulations on lab-developed tests, which the IVDR defines as "devices manufactured and used only within health institutions established in the Union." Such tests will have to show conformity with general safety and performance requirements, and the health institution performing them must be established in the EU and meet internationally accepted lab standards (ISO 15189). But perhaps the biggest IVDR hurdle for labs will be the lab-developed test/distributed kit equivalence requirements.
Starting next year, the IVDR will require that labs adopt CE-marked IVD tests or "justify" in writing that the needs of a target patient population that would receive a particular in-house test cannot be met by "equivalent" IVD kits already on the market. Diaceutics recently surveyed 116 pathology labs conducting PD-L1 testing for non-small cell lung cancer patients within its DXRX network from January to June 2020 and found that up to 62 percent of labs in four EU countries — France, Germany, Italy, and Spain — may find it difficult to meet the lab test/IVD kit equivalency requirements.
If testing shows NSCLC patients have tumors with high levels of PD-L1 expression, it gives doctors more confidence that they are likely to benefit from expensive immune-oncology drugs, like pembrolizumab (Merck's Keytruda) and nivolumab (Bristol Myers Squibb's Opdivo). Given oncologists' reliance on in-house tests in certain countries, if labs are unable to justify maintaining those tests, it could seriously disrupt access to companion diagnostics like PD-L1 testing, Diaceutics' analysis shows.
In scanning the PD-L1 testing landscape in the UK and the four EU countries, Diaceutics found that oncologists in the UK and Spain largely use IVD kits, while providers in France, Germany, and Italy depend more on lab-developed tests or kits that labs have modified for in-house use. Across the five countries, the most widely used CE-marked PD-L1 CDx kits are Agilent's Dako 22C3 pharmDx test and Roche's Ventana SP263 assay, likely due to their approval as companion tests alongside immunotherapies for NSCLC.
While 71 percent of labs in the five territories have access to a Ventana platform and 46 percent have the Dako assay, 18 percent of labs have implemented immunohistochemistry platforms that aren't compatible with companion IVD kits, and therefore are considered lab-developed tests. These labs will have to justify their continued use of in-house testing, switch to CE-marked IVD kits, or stop testing.
There have been rumors of a fourth alternative, Smart said, which is to keep testing until a competent authority comes calling. "Whether some labs will try this I'm not sure, and we certainly wouldn't suggest it," he said. "The regulation specifically says that sanctions for noncompliance should be 'dissuasive.'"
And even labs that adopt an IVD kit that is CE-marked under the IVDR, common adjustments and alterations, such as using different reagents than the kit manufacturer, would make the test fall out of regulatory compliance and be considered a lab test requiring justification for its use. While labs make these types of changes frequently to IVD kits to save on cost, the regulations don't mention cost as a valid reason for using a lab test in place of a CE-marked IVD kit.
"I am not sure this is as widely appreciated as it needs to be," Smart said. "A lot of places will be thinking they're OK, [because] they're running [a CE-marked] IVD kit. They're not."
In fact, there is not much detail in the IVDR on what acceptable justifications health institutions could give to maintain their in-house tests. For example, if an institution were able to show its lab test is more sensitive in detecting a biomarker than a marketed CE-marked IVD kit, but the institution can't show that this added sensitivity significantly improves cancer patients' outcomes on targeted therapy, would regulators accept that justification?
What if an institution showed that an IVD kit CE-marked under the old regulations hadn't yet been certified under the IVDR? Would regulators allow the institution to continue offering patients its lab test until notified bodies certified the IVD kit? "We don't know," Smart said. "And there's still no guidance from the European Commission."
Moreover, regulators haven't clearly defined key terms. For example, they need to provide more details on when an in-house lab test and a CE-marked IVD kit would be considered "equivalent" for a group of patients and explain how a patient group is delineated.
As recently reported in Precision Oncology News sister publication 360Dx, a significant swath of labs appear to be either unaware of these IVDR requirements or largely unprepared to meet them by the deadline. Based on its PD-L1 NSCLC testing survey, Diaceutics estimates that 50 percent of labs in Germany, France, Italy, and to a lesser extent Spain, won't be able to provide a justification and will have to stop providing lab-developed tests; 15 percent will be able to comply with the requirement, and the rest will switch to a CE-marked IVD if one is available.
"We've had this supposition that if [labs] couldn't use [in-house tests] they can transition to using commercially available tests, or kit tests," Smart said. "But we now see ... that there could be a significant loss of kit availability. If [institutions] are not allowed to use lab-developed tests and there's no kits to backfill, what are they going to do for testing?"
If "equivalent" IVD kits aren't available, then IND-Pascale in Italy, which has ISO-certified labs and procedures, will continue to perform well-validated in-house lab tests. "In the absence of IVD panels, we will continue to use the technologies validated over years of work because we certainly cannot stop the diagnostic activity," Normanno said.
In the Netherlands, oncologists at the Princess Máxima Center for Pediatric Oncology aren't very aware of the test access challenges looming on the horizon as the IVDR deadline inches closer. Bastiaan Tops, head of the diagnostic laboratory at the cancer center, is optimistic that his institution can either justify the continued use of lab-developed tests or switch to CE-marked IVD kits when they're available in a timely fashion, so his colleagues won't "notice any difference" in patient care.
Tops' lab performs mostly lab-developed tests, including molecular tests such as whole-exome and RNA sequencing. In light of the IVDR's test equivalency requirements, he reflected that when CE-marked IVD kits with comparable performance to in-house lab tests are available, then the cancer center has no problem switching to the kit. "However, the pediatric oncology field is developing very rapidly, so the question is if manufacturers will be able to keep pace and adapt their tests in time?" he said.
Impact on NGS panels
Worries about how the IVDR will impact precision treatment for cancer patients come as biomarker test access is already inequitable across EU member states, due to factors like the lack of parallel drug and companion test approval programs as well as a dearth of regional budgets for biomarker testing. While large academic institutions in the EU are adopting in-house next-generation sequencing panels that can identify many therapeutically targetable biomarkers in one go instead of sequential single-gene analysis, the broad availability of these panels depends on government payor coverage. The availability of NGS panels from commercial labs, such as Foundation Medicine and Guardant Health, are similarly limited in many EU member nations by payors' cost-effectiveness considerations.
Despite these barriers, oncologists and cancer researchers in the EU support increasing the use of NGS panels. ESMO, the leading European medical oncology professional organization, last year recommended that doctors routinely test advanced non-squamous NSCLC, prostate cancer, ovarian cancer, and cholangiocarcinoma patients on large multi-gene NGS panels, if the added cost of doing large panels is "acceptable" compared to small panels. Oncologists like Normanno, working on advancing precision oncology efforts on a national and international scale, are wondering how the IVDR regulations will impact the availability of in-house NGS panels.
"The situation is complex because there is still not enough clarity on what the [IVDR] requirements are to be able to continue using non-IVD panels. For some of the NGS panels we use for clinical practice and clinical research there is already a plan by the manufacturing companies to obtain IVD certification," said Normanno, who is one of the authors of ESMO's NGS testing guidelines. "Pending clarification on how to proceed, we will continue to use panels for which we have carried out an internal validation with an adequate number of samples and an external validation through participation in external quality assessment schemes."
Cancer institutions with labs accredited to perform in-house NGS panels will likely be able to show there are no other equivalent IVD kits on the market and continue performing those tests under the new regulatory regime, Diaceutics' Smart predicted. "NGS panels may have the easiest ride as lab-developed tests compared to other IVDs," he reflected. "While there's a lot of overlap on kits and instruments, the analysis pipelines, markers, and depth [of coverage] … all tend to be different." As such, if one interprets the term "equivalent" in the IVDR regulations to mean "identical," Smart said labs likely won't have to justify use of in-house NGS panels since "virtually all NGS [panels] differ in some way from virtually every other NGS test including commercially available ones."
While academic cancer centers with in-house NGS panels can perhaps mitigate some of the IVD CDx kit shortages that MedTech Europe and Diaceutics are predicting will happen due to IVDR implementation challenges, this won't necessarily help non-academic institutions that rely more on single-gene tests from commercial labs. In Catalonia, Spain, for example, five regional university hospitals will receive funding to stand up in-house NGS panel testing within a year or so, Mateo said. However, there isn't a general access program for NGS panel testing on a national scale, he added, and actionable biomarkers are largely identified via single-gene companion tests, which again, will likely be disrupted much more by the IVDR.
The lab test/IVD test kit equivalency requirement suggests to Diaceutics' Smart that European regulators are under the misconception that IVD kits are of a higher quality than lab-developed tests, likely because kits are developed according to specific quality control standards. "We all know cases where kits have been withdrawn from the market because they've had quality issues," Smart said. "The basic concept is flawed, and there's no reason, given appropriate regulation, why a lab test can't be of an equal or possibly higher quality standard [than a kit]."
'There will be consequences'
A June report by the Medical Device Coordination Group, which advises EU member states and the European Commission on IVDR implementation, said that guidance on the new regulatory requirements for companion diagnostics and lab tests are urgently needed if manufacturers and labs are to come into compliance by next year. "While the spirit of IVDR regulations is to be supported, the laboratory community in Europe has not been adequately supported to deal with the deadlines and workloads required to keep critical patient tests flowing," Diaceutics CEO Peter Keeling said, adding that while the company is trying to support its lab and diagnostics partners within its DXRX network, industry players and politicians need to pay more attention to the problem.
Not many IVD manufacturers have publicly detailed the challenges they may be facing in readying their test pipelines for the IVDR deadline, probably due to competitive reasons, and many of the big pharmaceutical companies still appear to be assessing the potential impact of the regulations on their drug pipelines. This makes it even harder to raise awareness and convince regulators to delay IVDR implementation, Smart suggested. Some manufacturers Diaceutics has spoken to have confidentially indicated their test kits, including PD-L1 and other IHC companion tests, will be audited and certified in time. But a lot of the small and medium-sized manufacturers seem to be "struggling to even get in the queue" with notified bodies, Smart said, and haven't even started the certification process.
Given that multiple stakeholders — Diaceutics, the European Federation of Pharmaceutical Industries and Associations, the European Cancer Patient Coalition, and MedTech Europe — have expressed concerns that the healthcare sector isn't ready to meet IVDR regulations by the deadline and asked for delays, EU regulators can't be unaware of the problems, Smart said. In fact, he urged stakeholders to keep making noise. "If [regulators] are completely set against a delay, they've got to be made aware that there will be consequences," he said.
The impact of IVDR implementation, particularly the requirements pushing institutional labs to transition from in-house testing to CE-marked IVD kits, could increase their costs and diminish their ability to launch new, innovative tests, Diaceutics cautioned in a recent white paper.
In the same paper, the company showed that regulatory ambiguities and restrictions on lab test use across 27 EU member countries could mean that 42,544 out of 258,299 metastatic NSCLC patients, or 16 percent of those with alterations in genes such as EGFR, BRAF, ALK, ROS1, and NTRK, as well as PD-L1 high expression, may not receive appropriate treatments. If only 10 percent of lab tests are no longer available due to IVDR regulations, that will impact 4,254 NSCLC patients' ability to receive personalized treatments, resulting in losses of over €329 million ($380 million) in pharmaceutical revenues. The impact on pharma revenues could increase to €823M, Diaceutics estimated, if 25 percent of lab tests are no longer available in the EU, placing 11,636 patients at risk of not receiving the appropriate treatments.
Diaceutics predicts patients with other kinds of tumors, such as ovarian and breast cancer, may face similar difficulties accessing companion tests and molecularly targeted therapy due to IVDR implementation challenges. "Can you imagine … if HER2 testing [for personalizing breast cancer targeted therapy] takes a big hit because a lot of that is lab testing?" Smart said, predicting that implementing the IVDR next May could have dire repercussions not just in cancer but across disease settings.
"That's not hyperbole," he continued. "This could remove a huge amount of the medical management decision-making capacity available to doctors … and affect millions of people across the Union."