Implementation of the new EU IVD regulation – urgent initiatives are needed to avert impending crisis

Introduction

Laboratory testing has an acknowledged widespread role in clinical decision-making, and therefore a direct significance in determining patient management and clinical outcomes. As the famous nephrologist Franz Vollhard said: “Before therapy, the gods have put diagnosis”. Consequently, the value of laboratory testing should be considered in the context of its role in setting the course for beneficial actions and patient outcomes. It is vital that physicians can trust that they are able to choose the best medical test available to help them in their clinical decision-making [1]. An essential precondition is the guaranteed and unrestricted availability of both conventional and innovative medical testing -including companion diagnostics- if “personalized diagnostics” and “precision medicine” are to be promoted.

Laboratory medicine is capable of responding to health care challenges in a timely manner, as can be seen in the current COVID pandemic that has put laboratory medicine and medical testing into the spotlight and amply demonstrated the relevance of medical testing in maintaining public health. Multiple academic laboratories and IVD-manufacturers have invested in the development of different types of COVID tests at short notice to allow market access under the current European IVD Directive 98/79/EC. Unfortunately, as pandemic cases were increasing, the initial focus was mostly on test efficiency rather than test effectiveness as assessment of the latter demands more scrutiny and time [2]. It is important to note that the COVID-19 pandemic has also demonstrated that regulatory systems must be flexible and adaptable, taking into account levels of global risk. Therefore, the FDA in the USA introduced an Emergency Use Authorization (EUA) procedure to speed up the regulatory process as the public health burden caused by COVID-19 required that the regulatory process was “contextualized”.

At the introduction of new tests, medical labs routinely give attention to analytical and clinical performance. There are quasi-standard validation procedures adhered to by national scientific societies, which have proved their value over the years for hundreds of new candidate parameters. Indeed, the field of laboratory medicine is one of the most strictly quality-regulated areas in the whole of medicine, and rightly so, because errors in laboratory diagnostics or assessments can have serious to fatal consequences for patients due to erroneous clinical decision-making that they may initiate. Over the past decades, laboratory medicine has invested enormously in comprehensive quality management systems and diagnostic stewardship in most European countries. As such, the diagnostic sector has regulated itself in a very professional and effective way.

In the past, insufficient testing policies have also revealed tragedies with grave implications for patients leading to e.g. HIV being transmitted to hemophiliacs who routinely injected themselves with concentrate made from large pools of donated plasma, much of which was collected by commercial paid-donor plasmapheresis prior to introduction of routine HIV testing of donor plasma [3].

Transitioning from IVDD to IVDR

To maximize patient safety in the EU the new In Vitro Diagnostic Medical Devices Regulation (IVDR 2017/746) for diagnostic tests (known as in vitro diagnostic medical devices or IVDs) entered into force on 26 May 2017, with a five-year transition period. The IVDR requires IVD-manufacturers to certify their existing diagnostic tests to comply with the new regulation after the necessary regulatory processes have been installed by the EU Commission and its MDCG. After 26 May 2022, the majority of established commercial CE-marked IVDs can only continue to be marketed if conformity with the IVDR can be declared (for the exception, see “Sell-off Provision” and “Grace Period” below).

As there is no grandfathering for established commercial CE-marked IVDs, routinely used tests all fall under the scope of the IVDR.

1. According to IVDR Article 110 [2] and the so called “Sell-off Provision”, CE-marked IVDs that were approved under the IVDD and which have already entered the supply chain before 26 May 2022 may continue to be sold on until they reach the final user (e.g. the clinical laboratory which purchases the IVD) up until 27 May 2025. The usefulness of this provision depends on the shelf-life of the IVDs which are being supplied.

2. Only the restricted number of tests included in IVDD Annex II Lists A and B, as well as self-tests with a valid Notified Body Certificate, can take advantage of the “Grace Period” (IVDR Article 110 (2) and (3)): these IVDs can continue to be manufactured and placed on the market for a limited period up until 27 May 2024 at the latest. After the Date of Application of the IVDR, there can be no significant changes in the design and intended purpose of said devices, and they must meet several other requirements of the new Regulation (such as with regards to surveillance, vigilance and registration). After the 26th May 2024, the devices can take advantage of the “Sell-off Provision” if they are already in the supply chain. See Figure 1.

Figure 1:

Transitioning from IVDD to IVDR and consequences for commercial test availability on the EU market.

Opportunities

The main aim of the new IVDR is to increase transparency, traceability and effectiveness of testing and to maximize patients’ safety. The IVD Regulation should be considered as a legislative tool for better documentation of the safety and performance of tests in the real world during their entire lifecycle. The key aim is to have a set of rules that are less open to interpretation, and which focus on the entire lifecycle of a medical test rather than up to the point of approval.

May 2022 is imminent and (re)certification under the new IVDR should have been accomplished by now, to make sure that medical tests get their approval according to the IVDR before the end of the transition period. While many of the requirements of the IVDR are the same as under the IVDD [1, 4], a considerable number of new requirements have been added [5]. The IVDR not only governs the medical test and its manufacturer, but also distributors, importers, and authorised representatives (individuals or business entities that act as an authorised point of contact on behalf of an IVD-manufacturer which is based outside of the EU), who all carry legal responsibilities for their activities. The regulation stipulates how manufacturers’ quality management systems are to be designed and what they must include for stricter requirements on technical documentation and post-market surveillance – all adding to the emphasis on the test lifecycle. Another change is that all manufacturers, as well as authorised representatives, are required to have a dedicated Person Responsible for Regulatory Compliance with a specified level of relevant training or else work experience corresponding to the training required.

One of the most important changes in the new IVDR is the risk-based test classification system (Figure 2) and the stringent EU Regulatory System (Figure 3). What used to be two limited lists of tests (Annex II, lists A and B) under the IVDD is now a risk-based classification system where approximately 19,000 medical tests with higher risk require assessment and certification by notified bodies. Medical tests which do not clearly fit into a specific class are automatically classified as class B [5].

Figure 2:

Risk-based classification system for medical tests under the IVDR 2017/746.

Medical tests are classified depending on the intended use and the risk that test results bring to patients and/or public health. Non-sterile class A devices are exempted from Notified Body assessment and can be brought on the EU market by self-declaration whereas class A sterile, B, C and D tests all demand Notified Body assessment to check compliance with the IVDR [5].

Figure 3:

Envisioned conformity assessment process of commercial medical tests by the European Commission.

Manufacturers propose medical test classification based on intended purpose and patient or population risk. For test classes A sterile, B, C, D, the claims are verified by a Notified Body which issues the relevant certificate(s). For class D tests, i.e., the highest risk class, more scrutiny is needed and to that end IVD Expert Panels and European Reference Laboratories additionally are involved during the conformity assessment. For companion diagnostics, additional scrutiny of the suitability of the test by a medicines authority is required (not shown). Note that the functions of the competent authority (which is a single agency in each EU member state, although it appears twice in this Figure) include designation and supervision of both reference laboratories and notified bodies within their country.

I Facts and figures on IVDR readiness as of May 2021

During the April 2021 workshop on “The need for better EU Policies for health” [6], organised by the Panel for the Future of Science and Technology (STOA) of the European Parliament, representatives of the IVD working group of the BioMedical Alliance in Europe, a unique initiative of 36 leading European medical societies which, in combination, include more than 400,000 researchers and health professionals (https://www.biomedeurope.org/), stressed that without critical infrastructure, guidance documents and contingency plans, there will be disruption to the availability of essential diagnostic tests, i.e. CE-marked IVDs. To be operational, medical laboratories depend completely on guaranteed diagnostic supply chains that deliver tests in barcoded, tailor-made kits to be run in a fully automated way for a majority of the diagnostic tests provided. The equipment used in core labs often only works with CE-marked tests on closed instruments, allowing only manufacturer-specific formulations and applications to be run, for liability reasons.

Clear and appropriate guidance is needed for in-house developed tests, also known as laboratory developed tests (LDTs), to help laboratories prepare in time for the new legislation and to support the development of innovative solutions for (niche) emerging applications, rare diseases and rapid responses to health crises. Policymakers should realize that once the guidance is available, enough time is needed to allow laboratories to update their procedures.

The diagnostic sector will be thoroughly transformed by the new regulation. It is up to policy makers and all stakeholders to address the risks that inappropriate implementation of IVDR poses for the entirety of the therapeutic medical sector in Europe. The unreadiness of the EU regulatory infrastructure (insufficient number of active Notified Bodies, unavailability of the EUDAMED database, non-operational expert panels and/or reference labs to evaluate the highest risk tests, lack of contingency plans, delayed guidance documents, poor communication structures to allow for efficient dissemination of strategies) is threatening the EU diagnostic sector and will undoubtedly have serious consequences for patients’ lives across Europe in many areas, from emergency medicine to monitoring of therapy.

The main consequences that could be expected are:

1. established CE-marked tests face shortages on the European market and/or will disappear with little pre-notification;

2. specialty CE-marked tests (for genetics, virology, molecular diagnostics, cancer) will be particularly vulnerable;

3. personalised diagnostics and tests for rare diseases will not be developed;

4. a polarization towards monopolies in CE-marked tests will reduce diagnostic portfolios and endanger precision medicine and diagnostic innovation;

5. the development of new and dynamic solutions for rare diseases and acute health crises such as COVID-19 will be hampered; imagine a 9–12 month certification time lapse during an ensuing pandemic;

6. diagnostic laboratories will be unable to re-budget and bear the burden of fulfilling requirements for all their in-house IVD devices/LDTs so may abandon part of their current test portfolio.

7. Specialised reference laboratories will be discouraged from using specifically adapted LDTs by the embargo from existing, more generic, CE-marked tests, particularly if the bureaucracy involved in justification of use is prohibitive.

Based on the presentations given during the STOA workshop, the various facets of unreadiness of the EU Regulatory System became crystal clear to the medical experts in the group of attendees (see Table 1). The group rejected the notion that implementation was well on its way. There is serious concern that the European Commission and Medical Devices Coordination Group have not been able to meet their time goals and required legal framework to implement their own regulation.

II Testimonies from key stakeholders (June 2021)

In preparation of this statement and to collect opinions for discussion with EU regulators, we asked laboratory specialists and manufacturers for their experience of preparing for the IVDR. We reproduce individual anonymized testimonies from selected stakeholders below; these statements confirm the widespread impression that the EU regulatory system is not ready to implement the IVDR.

III Reflections on the looming shortages and/or disappearance of CE-IVDs and in-house tests (status in the second half of 2021)

Less than nine months before the date of application of the IVDR, the above facts and testimonies demonstrate that the EC and MDCG have not succeeded in putting in place the EU regulatory system in time to safely implement the IVDR (Table 1) [7–10]. We consider the current state flawed in such a way that we recommend postponement as the only logical consequence. What is the alternative? No regulatory approval for thousands of tests without which health care would not function in a pandemic situation. No EU politician or administrator will dare to take the responsibility of dismantling a working health care system. It is in the interest of the EU to maintain its healthcare industry and IVD-companies and their market. It is inconceivable that tests will not be allowed in the EU and that countries around the globe which trust in the CE-marking would also suffer since they rely on EU-sourced medical tests. Indeed, the IVD sector is one of the only European manufacturing sectors left with a positive trade relationship with China. If there is a shortage of EU IVDs then this would definitely impact many other countries around the globe. Dismantling will have consequences for customers in addition to the effects it has on patients.

Today, the infrastructure for the very high-risk tests (“class D”) is almost entirely missing. These include tests which are of critical importance to healthcare systems because they are needed to screen the European blood supply, check cells and organs for transplantation or manage outbreaks of infectious disease, such as the COVID-19 pandemic. Aside from the six notified bodies designated so far, common specifications, the IVD expert panel and appropriate EU Reference Laboratories are lacking. Because of this, the EC allows NBs to evaluate class D tests without the guidance of the IVD expert panel/EURLs. Yet, NBs are hesitant about this situation and refused so far to evaluate class D tests without being backed up by the expert panel/EURLs (Figure 3). This is understandable, as NBs are risk averse and do not like to give non-binding guidance on medical tests for the obvious reason of liability. Therefore, if nothing happens, the IVDR may be in place only for the lowest risk devices (e.g., instrumentation, general culture media, etc.) with an uneven, incomplete spread of reagent kits in other classes.

At a meeting of the European Council (of health ministers, EPSCO) on June 15th 2021, 15 ministers of health brought the critical IVD-situation to the attention of the EC and the MDCG. This provides the EC with a formal mandate to find solutions and/or make contingency plans. Due to this intervention, transition measures will be taken to ensure the continuity of commercial tests, however it is not guaranteed that the same prolongation will be given for in-house developed tests. There is a risk that laboratories might still have to be compliant per May 2022 for in-house developed tests. A grace period and/or postponement for in-house developed tests is as crucial as for CE-IVDs, particularly if there is no EUDAMED database and if there is an impact on availability of CE-IVD kits. The time gained should be used in a sensible manner. Specifically and from our perspective appropriate diagnostic experts should be prominently involved and their views given priority, even when they take positions straying from the fixed process governed by non-experts, as we have witnessed up to now. The EU regulatory infrastructure should first be made operational, since implementing the IVDR while the regulatory infrastructure is still being built is disruptive for the diagnostic community and for individual patient management.

Laboratory professionals need to bring in sound arguments and draw attention to the issues around in-house tests, in order to create a similar ground for sustainable solutions as for the CE-IVDs manufactured by the IVD-industry. Possibilities for in-house testing should be protected during transition of the CE-marked sector, both as a safety net and to avoid additional gaps in the diagnostic portfolio. Recognition of diagnostic reference laboratory expertise should also be integrated, in order to avoid monopolies in rare disease and personalised diagnostics which may stifle further improvement.

The preparedness of the medical laboratories in the EU is currently surveyed by BioMed Alliance and EFLM as the awareness regarding the impact of the IVDR for both CE-IVDs and LDTs apparently differs among EU member states. The survey data are not yet available. In other parts of the world such as Australia, the Australian regulatory authority TGA has done nothing to increase regulation of IVD tests. While in-house IVDs are catalogued, they do not have enough expert resources to evaluate them, not even through the accreditation system. As the infrastructure and resources needed to meet the motivation of global regulatory directives are simply not established, and the COVID pandemic is still a priority, it will take many more years to prepare the EU regulatory system for the IVDR.

Laboratory medicine is one of the most strictly quality-regulated areas in all of medicine, enabling state-of-the-art clinical decisions based on objective, reproducible, safe, and effective lab test results. From EQA report sheets, every lab can see how its own performance is in comparison to other (anonymized) participants with respect to all benchmarked EQA parameters within a given EQA scheme. Therefore, besides their value for transparent quality reporting, EQA programs also can be seen as efficient regulators of the market, because test methods that are inferior and at the origin of repeated EQA failures, are easily identified amongst the plethora of methods available for a given biomarker. As passing EQA rounds is mandatory for the right to practise, quality will rule and the lack of it will lead to inferior tests being identified and retracted from the market. There is certainly leverage in using this quality instrument to warrant patient safety in diagnostics.

It is generally recognized that about 70% of clinical decisions made by caregivers in peripheral and academic hospitals are based on diagnostic test results. Therefore, the supportive tools -i.e., medical tests, including CE-IVDs and in-house developed tests- are crucial and should remain unabatedly available and accessible on the European market in their current formulations till the new EU regulatory system is in place and adequate implementation of the IVDR is feasible.

IV In search of solutions for the medical laboratory sector

After the June EPSCO meeting, where ministers of health expressed their concerns regarding the issues around IVDR implementation, the EU Council Conclusions on Access to medicines and medical devices for a Stronger and Resilient EU became publicly available (https://data.consilium.europa.eu/doc/document/ST-9750-2021-INIT/en/pdf).

The EC now needs to reflect on the next steps to take. Guidance from and dialogue with lab professionals is needed to find solutions on how to preserve and support diagnostic laboratory medicine and the test supply chains for creating actionable test results in patients across healthcare systems. Essential starting points for proper IVDR implementation are (a) having in place a minimum acceptable regulatory infrastructure; (b) encompassing all IVDs which need a NB certificate; and (c) ensuring that all IVDs can be certified and transition in a timely way which ensures that full test menus remain available to diagnostic laboratory medicine.

Which scenarios might be considered by the EC for commercial CE-IVDs after the successful awareness campaign in the June EU council meeting? Firstly, there is the one-year postponement precedent from the MDR 2017/745 although one year postponement is nowhere near sufficient for the complex IVDR. Ideally, the test (re)certification process should start after the complete infrastructure is in place, so a longer postponement with undefined date of application is needed. Alternatively, one could consider extending the grace period for all IVDs that need to undergo NB assessment. At least three to four years expansion should be the aim to avoid bottlenecks such as the end of the MDR grace period in May 2024 and because class D tests and companion diagnostics need 16–18 months to be certified. As MDR got an extended grace period, why not give the very impactful and new IVDR a later expansion date? The drawback of extending the grace period is that the grace period option freezes innovation and medical test improvement. Freezing of test improvements must be avoided by an opening clause to allow further development of established tests to achieve the best possible performance. Finally, a mixture of the above scenarios, i.e., postponement with an expanded grace period, is also a possibility, as long as the timelines are similar and parallel for CE-IVDs and LDTs.

Alternatively, the EC could produce and legally implement a Common Specification for certain IVDs (in analogy to similar procedures for the MDR), for example stating that meeting certain EQA-standards would be sufficient. That would make a long NB review and expert panel review unnecessary if there is a published EU Common Specification, and the medical test meets all of its requirements.

Professional societies and lab specialists should map the preparedness of medical laboratories and the issues that they encounter in relation to the implementation of the IVDR per May 2022 for in-house developed tests, according to the requirements of Art 5.5. in the IVDR [5, 11, 12]. To that end, the BioMedical Alliance in Europe conducted a survey in summer 2021 with a representative sample of medical labs serving different diagnostic disciplines. The outputs of the survey should help to provide insight into the current degree of preparedness and the issues that medical laboratories encounter. Secondly, the survey results will help to establish solid arguments for postponement and/or other solutions to safeguard the continuation of in-house developed tests. Moreover, it is anticipated that the outputs are likely to reveal the parallel need for preparation of the EU regulatory infrastructure ahead of the implementation of Art 5.5 for in-house developed tests. The EU should take advantage of the excellent professional infrastructure and concepts available within the BioMedical Alliance in Europe, which represents a broad spectrum of today´s medical societies. Speaking for laboratory medicine, TF-ERA is the operational arm of EFLM within the BioMedical Alliance in Europe and has developed strategies to support improving the steps to be taken for the IVDR implementation.

In conclusion, we value the efforts of the EU Commission to further increase patient safety and clinical effectiveness of diagnostic services but the goal will not be met by imposing blanket regulatory requirements which mean potential disruption of all medical tests indiscriminately. Until now, the process has not involved enough professional laboratory expertise to ensure success and the EC does not appear to be aware of the long-lasting high degree of safety, effectiveness and quality assurance in the diagnostic sector. A failed start and baseless bureaucratic burden will not only harm patients, hurt medical laboratories, but also impede laboratory medicine development for years to come, increase diagnostic costs, and erode diagnostic innovation in Europe. Until the EU Regulatory System is comprehensively reworked and operational, patient safety must be considered to be in danger far beyond the transition time. Sustainable accommodations must be made to the IVDR to prevent collapse of a well-functioning diagnostic sector. Also, the IVDR should be interpreted against the background of already guaranteed quality of diagnostic services in ISO-accredited labs (often ISO 15189:2012) by EC4 registered laboratory specialists, with active participation and guidance of professional societies, who are fully aware of the interest in optimising the whole diagnostic chain.