Critical Implications of IVDR for Innovation in Diagnostics: Input From the BioMed Alliance Diagnostics Task Force

Abstract

OVERVIEW AND INTRODUCTION With the implementation of Regulation (European Union [EU]) 2017/746 on in vitro diagnostic medical devices (IVDR), from May 26, 2022, onwards, the development and use of diagnostic tests will be governed by a vastly expanded and upgraded EU regulatory framework. We provide here an overview of the amended transition timelines, the role of notified bodies, EU reference laboratories, expert panels, and the Medical Device Coordination Group (MDCG). We also describe the implications of the IVDR for innovative laboratory medicine by explaining the exemption for in-house devices (IH-IVDs). Two key challenges faced by the academic diagnostic sector are: (1) the stipulation on equivalence of tests (article 5.5d), which poses a new condition for the use of IH-IVDs and (2) the gray area between CE marked in vitro diagnostics (CE-IVDs), modified CE-IVDs, Research Use Only (RUO) tests, and IH-IVDs. Furthermore, the results of a questionnaire on current diagnostic practice conducted by European medical societies collaborating in the BioMed Alliance indicate widespread use of IH-IVDs in diagnostic laboratories across Europe and emphasize the need for support and guidance to comply with the IVDR. Diagnostic equivalents of the European Reference Networks (ERNs) for rare diseases could help ensure affordable and equal access to specialized diagnostics across the EU. Concerted action by clinical and laboratory disciplines, regulators, industry, and patient organizations is needed to support the efficient and effective implementation of the IVDR in a way that preserves innovation and safeguards the quality, safety, and accessibility of innovative diagnostics. Laboratory medicine plays an increasingly important part in medical decision-making at diagnosis and follow-up and evolution towards “Personalized” or “Precision” medicine in Hematology and other disciplines. It is, therefore, not surprising that this has long been an area with strict regulatory surveillance, particularly in specialties generating numerical results. These are more easily subject to evaluation of analytical performance parameters such as trueness (bias) and precision (repeatability and reproducibility), than descriptive, qualitative diagnostic specialties. Within the EU, laboratory or in vitro diagnostic (IVD) tests were regulated by the 1998 Directive 98/79/EC on in vitro diagnostic medical devices (IVDD),1 which mainly governed pre-market production within the manufacturing sector of CE-IVD marked tests. The majority were self-declared by manufacturers, with EU-wide application, and only approximately 10% required certification by notified bodies, appointed by the national competent authorities in Member States. IVDD did not regulate use of laboratory-developed tests (LDT)/in-house devices (IH-IVD, referred to herein as IH-IVD as this is the term used in EU legislation), which are manufactured and used within the same health institution for medical purposes, in keeping with the EU principle of subsidiarity, and consequent national regulation. In 2017, 2 new EU regulations were adopted: the Regulation (EU) 2017/746 on IVDR2 and the Regulation (EU) 2017/745 on medical devices (MDR). In contrast to Directives, Regulations are directly applicable in all Member States and do not need to be transposed into national legislation. This reduces the potential for divergent interpretation in different Member States. The IVDR requires more accurate description of intended use and clinical evidence and has strengthened post-market performance follow-up and post-market surveillance (in conjunction with notified bodies and competent authorities), all of which have been introduced for the benefit of the patient. As described in the guidance on general principles of clinical evidence for IVDs from the MDCG, the clinical evidence, including scientific validity, analytical performance and clinical performance data, needs to verify the safety and performance for all claims in the intended purpose.3,4 The IVDR, like the IVDD, still exempts IH-IVDs from most requirements applicable to CE-marked devices. However, for the first time, it provides a list of conditions for that exemption5 (see below), thereby opening an EU-wide regulatory dimension to development and use of innovative diagnostic tests. The IVDR will have major implications for the latter, some of which seem to have been poorly taken into consideration. This commentary will describe the IVDR regulatory environment and the implementation timelines based on a recent amendment. It will also present results of a questionnaire on current diagnostic practice, disseminated to European medical societies via the Biomed Alliance, with particular attention to the development and use of innovative tests. Appropriate concerted action should allow us to avoid the IVDR complicating innovation and instead support it from its early development steps onwards. THE TRANSLATIONAL DIAGNOSTIC VALUE CHAIN There will always be coexistence of CE-IVD tests provided by the manufacturing sector and IH-IVDs developed and used by the academic diagnostic sector,6 with complementary roles in the translational research value chain illustrated in Figure 1.Figure 1.: The translational research value chain.Ideally, development by academia will lead to transfer to the industrial sector of tests that meet criteria of economic viability for the latter, with appropriate recognition and compensation (eg, via royalties from licensed tests) to the former.3 Industrial transfer is unlikely to be the case for all diagnostic tests, particularly those that are rare and/or complex.3 Factors preventing transfer include, but are not limited to: analytical complexity and dependence on patient-derived material for controls; suitability for automation; algorithm dependence; lack of interest from manufacturers and a variety of national diagnostic and reimbursement practices that affect economic viability. There is also a tendency to maintain within the academic sector tests that lead, directly or indirectly, to establishment of the tissue and data banks that form the basis for future discovery and development. The real-world pertinence and relative clinical effectiveness of IVDR are evaluated by Health Technology Assessment (HTA) agencies. Depending on the country, these also perform the economic appraisal or provide the evidence used for cost-effectiveness and reimbursement decisions by payers. The new EU Regulation on HTA7 will provide a mechanism for harmonized, collaborative clinical assessments as well as joint scientific consultations and horizon scanning. IVDR REGULATORY ENVIRONMENT Succinctly, IVDR legislation2 classifies IVD tests into 4 classes, with increasing personal and public risk. Class A represents low individual and low public health risk, class B moderate individual and/or low public health risk, class C high individual and/or moderate public health risk, and class D high individual and high public health risk. Classes B, C, and D (and sterile class A devices) require notified body certification, thus representing a massive increase (from approximately 10% to 80% of tests) in the proportion of CE-IVD tests to be evaluated by a small number (6 in February 2022) of notified bodies.8,9 IVDD-compliant tests are not considered automatically compliant with the IVDR, that is, all such tests need reevaluation. Class C tests include many used in Hematology, such as screening, diagnosis, or staging of cancer, genetic testing, and companion diagnostics. Class D devices cover essentially high-risk infectious agent testing (such as in blood transfusion or testing for life-threatening diseases) and blood/tissue compatibility testing. In addition to the overall assessment by a notified body, the performance of class D devices is to be verified by independent testing in EU reference laboratories, once those laboratories are designated by the European Commission. For novel class D devices, the performance evaluation has also to be reviewed by an IVD expert panel. Expert panels on MDs and IVDs (EXPAMED)10 have been developed by the Joint Research Centre, the European Commission’s internal scientific service, and will be managed by the European Medicines Agency (Figure 2). A European Database on Medical Devices (EUDAMED)12 containing information on devices on the market under MDR and IVDR is also under development, but few modules are available to date.Figure 2.: The European IVDR regulatory environment with inclusion of the IH-IVD activities of health institutions. For details on CE-IVDs, see Cobbaert et al.11 EU level implementation of the IVDR, adopted by the European Parliament and the Council of the EU in 2017, is executed by the European Commission (DG SANTE) and the Medical Device Coordination Group (MDCG), which is chaired by the European Commission and consists of representatives of the Member State competent authorities. Stakeholders such as the BioMed Alliance and EFLM are invited to advise/comment. Supervision of notified bodies, health institutions, and economic operators such as IVD manufacturers is the primary task of the Member State competent authorities. For all IVDs except class A nonsterile devices, manufacturers need to submit their technical documentation to notified bodies for conformity assessment. For class D devices, consultation of EU reference laboratories and/or expert panels (coordinated by the EMA on behalf of the European Commission) can be part of this procedure (*expert panels are consulted when it is the first certification of that type of device and there are no common specifications; EU reference laboratories are involved when a relevant EU reference laboratory is designated; otherwise, it is not mandatory). For CDx, which are typically class C, consultation of the EMA (or a national medicines agency) is included in the conformity assessment procedure by the notified body. After approval, the notified body issues a certificate of conformity, allowing the manufacturer to CE mark the IVD and place it on the market for use in diagnostic patient care. In addition to such CE-IVD tests, health institution diagnostic laboratories can develop and use in-house devices (IH-IVDs), which need to meet a number of conditions and requirements specified in IVDR Article 5.5. Some IH-IVDs might become available for the broad diagnostic community as CE-IVDs after successful technology transfer. CDx = companion diagnostics; CE-IVDs = CE marked in vitro diagnostics; DG SANTE = Directorate-General for Health and Food Safety; EFLM = European Federation of Clinical Chemistry and Laboratory Medicine; EMA = European Medicines Agency; EU = European Union; EXPAMED = expert panel on medical devices and in vitro diagnostic devices; IH-IVDs = in-house in vitro diagnostics; IVD = in vitro diagnostic; IVDR = Regulation (EU) 2017/746 on in vitro diagnostic medical devices; MDCG = Medical Device Coordination Group.Progress in implementation at the EU level is led by the IVD Working Group of the MDCG,13 which is composed of representatives of Member States and the European Commission. Relevant, representative stakeholders are invited to participate in regular meetings and to comment on consultative documents that are subsequently made public, in order to guide stakeholders on a range of topics.14 Readers interested in the details of IVDR implementation are invited to consult the BioMed Alliance statements15 and the references cited in this commentary.5,14,16,17 Given the very large number of diagnostic medical specialties, particularly within the academic sector, MDCG representation is assured by federative alliances; the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) and the Biomedical Alliance in Europe (BioMed Alliance). EFLM represents many medical laboratory specialties and 40 national associations, particularly Clinical (Bio)Chemistry and Laboratory The BioMed Alliance represents a range of European medical with an interest in medical including many with a diagnostic including Hematology, and and information can be on the of the BioMed Alliance on IVDR The implementation timelines for the MDR were May 26, and May 26, 2022, for the IVDR. The led to the first in timelines, the of of the MDR to May This with of IVDR to development and appropriate of CE-IVD for of development by the academic diagnostic The timelines for IVDR were from the but it increasingly that concerted of the EXPAMED panels, EU reference laboratories and the by May be for to for IVDR are specified in Article of the IVDR. In there and still is, a lack of notified This led to widespread that CE-IVDs from the market Europe in May 2022, with no for the public sector to with regulatory requires increasing the by the Council and the European Parliament in to a European Commission the IVDR implementation timelines, widespread by the manufacturing sector by and by the BioMed Alliance and The implementation timelines are in Figure for IVDR The and specified in as well as Article the of to are not in the and as applicable from May CE-IVDs = CE marked in vitro diagnostics; IH-IVDs = in-house in vitro diagnostics; IVDR = Regulation (EU) 2017/746 on in vitro diagnostic medical is to be that this will allow the MDCG, national competent notified bodies, EXPAMED panels, EU reference laboratories, and to the regulatory required for implementation of with of the of clinical It is also that the and specified in of the IVDR are not in the and are still applicable from May consists of requirements performance evidence, information on the and of the and for As the timelines still require by the diagnostic and manufacturing as the EU are in For the latter, for IVDD CE-IVDs will have to be to of the have a of conformity May 26, 2022, in order to benefit from the and IVDs use of the after that IVDR Article that the of the relevant general safety and performance requirements in the requirements of this Regulation not to devices manufactured and used only within health in the provided that all of the conditions are The conditions for this IH-IVD exemption are in Article Article that IH-IVDs to other is not as did the This not European collaborative from laboratory and information and require diagnostic to comply with the for which requirements for and in medical laboratories, or with applicable national are important as to the of the use of IH-IVDs. tests will only be to be under the IVDR, there is no CE-IVD on the market or when a needs be at the appropriate level of performance by an The for this has been to Appropriate interpretation of and the of such as and is as are the basis that should laboratories to an of CE-IVDs and IH-IVDs. We that such interpretation is part of the of which have a of the basis of laboratory medicine including assessment of diagnostic research in a regulatory in particular at and national are These should be at an and The once is to be the major of information devices available on the the for manufacturers to CE mark class C devices under the IVDR is and will from onwards, Hematology laboratories should have at 2 to for devices for most of their and applicable that will have to be Article requires diagnostic laboratories to a public that IH-IVDs meet the and of requirements for class D devices are in Article Member States this also to class B, or C devices. Article clinical of and by the health the of Article that the IH-IVD exemption is only for devices that are not manufactured on an industrial It is that laboratories should always for national In for Article will also be applicable for class IH-IVDs. of Article not from required documentation for an compliant the of from clinical use will from practice to a regulatory It is of that the IVDR is not an and is not evaluated by the national bodies but by the national competent authorities (Figure 2). The is than the IVDR, but the to the the requirements and within the public, and particularly the diagnostic sector Article 2 (1) Article and viability of innovative diagnostics and (2) of an IH-IVD and the gray area between CE-IVDs, use of modified CE-IVDs, use of tests, and IH-IVDs. In a more general it is that the IVDR diagnostic laboratories it is to diagnostic to this be It is will provide the guidance and support on implementation of these and meet the of regulatory The manufacturing sector will the development and of CE-IVDs, but it will be to the academic and/or public sector to do the same for IH-IVDs. There are some national and to help medical is the a of scientific medical societies in that provides and guidance on to the IVDR in a The European for Laboratory has IVDR the IVDR and such as are available on the The EFLM Working Group on is a of principles and key data requirements needed to or clinical evidence for of the intended diagnostic to use and medical results. AND The the stipulation that the health institution that the needs of a particular of be or be at the appropriate level of by an device available on the is to include a for the intended patient based for clinical effectiveness and and and for of results. clinical effectiveness include, as an rare of or some on equivalence for MDs there is no guidance for equivalence should be evaluated for IVD when needs are considered to be at the appropriate level of This be well in of the implementation by diagnostic with in in an and and in with national competent authorities. at the way to clinical evidence and evaluation of medical and are It is also that at part of the is to help the European sector by academic to and via the manufacturing sector, their in-house developed tests. on the proportion of health sector that are licensed that this could be the IVDR will help the to of innovative and to be be needed to to their or in other to its an IH-IVD is to devices available on the there is, at public health to such a available to a number of are to These are to all diagnostic but tests, by reference such tests are by the academic or the manufacturing sector has implications for tissue and banks for rare genetic and infectious The common here is their It is that the IVDR will provide and for the of Diagnostic Reference These be complementary and the for rare In Hematology, IH-IVDs genetic testing for and referred to as precision diagnostics. Appropriate Hematology diagnostic reference current within the The to Article is that of the on the market of a IVD device will and devices developed by the academic This well be to a of once and to a to very rare is well to mainly access to patient and to new of diagnostic IH-IVD including in with the manufacturing It is that of equivalence will not be by or notified It is to the health to devices are available and to have for their use of IH-IVDs. The competent authorities will the of health with to of Article 5.5. It is also important to for laboratories to when from IH-IVD to CE-IVD tests, this will and assessment with their interpretation of IVDR Article in particular the equivalence of tests, should be as to safety, and principles in academic in with the of the IVDR. DIAGNOSTIC THE EU In order to the of tests by diagnostic laboratories, the Biomed Alliance a questionnaire to its as well as in to It did not to or of or diagnostic specialties, for and to between The can be on the BioMed Alliance were from medical laboratories in the EU and including at from of the EU Member States. representation by Member States to in the and/or of a national medicine the academic The majority of were public or laboratories, but academic research laboratories and and/or laboratories were also activities in a range of diagnostic specialties in in or of these with for this not considered with the of the other than for with laboratories for a of approximately use at the between CE-IVDs and IH-IVDs as when there were not safety or when there were from the intended for use clinical such as use of different or when such were used for diagnostics under the of the diagnostic The relative of the different of IVDs used by laboratories from the diagnostic (Figure the CE-IVDs, CE-IVDs, and IH-IVDs. The diagnostic with the of IH-IVDs were and Hematology laboratories to the with CE-IVDs, CE-IVDs, and it is that some laboratories their tests within the or Succinctly, IH-IVDs are to of Hematology tests, by the proportion of diagnostics of from IVD used by of the questionnaire = diagnostic (1) CE-IVDs used to the (2) CE-IVDs with and devices A of the IVD can be can be in the and the on the BioMed Alliance CE-IVDs = CE marked in vitro diagnostics; = for IH-IVDs = in-house in vitro diagnostics; IVD = in vitro diagnostic; = laboratory-developed = Research Use on a to that CE-IVD tests used as by manufacturers only to of the type of tests used by diagnostic It is, of that this to a proportion of diagnostic the majority of tests are CE-IVD and will This questionnaire also the need for implementation timelines by the of the IVDR in the widespread of increasing of diagnostics and a need for and support to to the IVDR. the amended timelines (Figure there is a of to be May of and in the 2 in order to the regulatory requirements in the amended IVDR. THE IVDR this is it that IVDR will increase the of diagnostics. The IVDR the manufacturer to perform more evaluation and more independent which will (1) the and performance of CE-IVD tests and (2) the manufacturers to devices that have evidence of safety and As the IVDR will the level of safety and performance of devices on the market in the EU and the of these requirements for the manufacturing and diagnostic will be this is by and appropriate of for specialized IH-IVD tests, within reference could be with overall of patient with a from to diagnostic The number of IH-IVDs by a laboratory is to the in to a manufactured In the case of CE-IVDs, IVD manufacturers have a to the clinical evidence and other IVDR from the innovative diagnostic sector to to use and develop IH-IVDs should use the amended transition in order to the benefit and clinical evidence in an appropriate academic of innovative diagnostics is considered it will be to and support for in order to for rare and/or specialized diagnostic tests across the of diagnostic to be to need the that provide such support be the of this of and the potential of concerted diagnostic for rare diseases have in the public health of and as have the increasing number of European and infectious agent reference European diagnostic equivalents could in with these and in with regulators, Europe and the IVD industry, clinical and laboratory medicine patient to ensure access to specialized diagnostics across the EU. be in with national diagnostic medical reference such as the and have the of action in for the IVDR, by between national competent bodies, and It is that the IVDR concerted the regulatory and of more THE the IVDR will patient and and in-house developed tests at There is a clinical need for CE-IVD and IH-IVD tests, as there is for modified CE-IVDs, tests, and as long as their benefit for is or can be the IVD and a joint that innovative diagnostics are first developed and in or diagnostic reference with and taken by IVD manufacturers a production that production and In that access to innovative for of patient and the to the include European for and Clinical by European of by European of Clinical and by European Federation of by European by European Alliance of for by European of by European of by European by and European for the of the by an from and a with all and are not but to Medical to have an for the not but to of to be of the which royalties from licensed which are by the of the These royalties are used for of the and of the personal from and support for reference diagnostics from and and personal from and personal from all the that is of the European Hematology and a BioMed Alliance the other have no of interest to

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