Experience With IVDR Implementation in Three Diagnostic Laboratories: Messages to EU Health Institutions, Diagnostic Healthcare Payers, and Authorities.

Regulation (EU) 2017/746 on in vitro diagnostic medical devices1 (IVDR) has been implemented with the aim to safeguard the quality of diagnostic tests in the EU, for example, by requiring robust proof of safety and performance. The IVDR is a product regulation mainly aimed at industry manufacturing and marketing medical devices. While IVDR-compliant diagnostic tests should predominantly be supplied by manufacturers, health institutions have the possibility of manufacturing and using in-house devices (IH-IVDs), provided they meet the Article 5(5) conditions and relevant general safety and performance requirements in Annex I. This “health institution exemption” concerns, for example, their quality management system (QMS), risk management, performance evaluation, and justification of IH-IVD use.2 The first significant task for diagnostic laboratories at health institutions, compliance with Annex I, has been applicable since May 2022, whereas other implementation timelines are shifted based on the December 2021 amendment of the IVDR.3,4 The European Commission published official EU guidance on the health institution exemption under Article 5(5) in January 2023,5 but this document contains limited detail on how to fulfill the IVDR requirements for IH-IVDs. National competent authorities (NCAs), which perform inspections and enforce IVDR compliance in their Member States, can therefore be a valuable source of information on interpretation of this regulation for the diagnostic community. Manufacturing and usage of IH-IVDs is common in most diagnostic disciplines, including hematology. Rare disease diagnostics depend extensively on this category of tests, and many steps of testing in blood transfusion. Data from University Hospitals Leuven and a BioMed Alliance survey of EU diagnostic laboratories both found that roughly 75% of IH-IVDs have no suitable CE-IVD alternative.6,7 IVDR implementation therefore requires a serious effort for many, and particularly for specialized, laboratories, and can benefit from constructive interaction with relevant stakeholders. We here report on the European Hematology Association (EHA)-IVDR session of the EHA2022 Congress (a recording of which is available on the EHA website - https://ehaweb.org/advocacy/ivdr/resources),8 during which laboratory professionals from 3 different EU Member States shared their experiences on IVDR implementation in a diagnostic laboratory setting, after an introduction by a Danish NCA representative (M.S.B.). EXPERIENCE WITH IVDR IMPLEMENTATION BY HEALTH INSTITUTIONS Specialized hematology laboratories rely heavily on IH-IVDs The 3 laboratories (from Germany, Czech Republic, and Belgium) are all part of large university hospitals. They perform specialized hematology diagnostics, predominantly class C tests to diagnose, classify, and monitor leukemias, lymphomas and other immune system disorders. Most of the tests that they perform are IH-IVDs (>83%). Based on market research, the 3 laboratories indicate that up to 10%–20% of these can be replaced with suitable CE-IVDs. Consistent with the high level of specialization of the laboratories and the relatively rare diseases targeted, their percentage of IH-IVDs is far above the average reported by the BioMed Alliance survey respondents from hematology laboratories (27% IH-IVDs, alongside 55% CE-IVDs, 11% modified CE-IVDs and 7% research use only tests [RUOs]), and is closer to those reported by somatic genetic laboratories (51% IH-IVDs, 26% CE-IVDs, 7% modified CE-IVDs, and 16% RUOs).7 Of note, the EU guidance on IH-IVDs5 indicates that devices that are manufactured, combined, or significantly modified are IH-IVDs, and therefore, Article 5(5) applies to them. In contrast, devices solely used without such a “manufacturing step” (eg, CE-IVDs used outside of the indication or contrary to the manufacturer’s instructions) will not be covered by the IVDR. Such use will still have to comply with applicable national regulations. QMS based on ISO 15189 Article 5(5)c, applicable from May 2024 onwards, requires laboratories that manufacture and use IH-IVDs to comply with the ISO 15189 standard on requirements for quality and competence for medical laboratories (or, where applicable, national provisions). The 3 laboratories have been ISO 15189 accredited since 2010–2014, principally to improve and demonstrate the quality of their diagnostic services. National quality guidelines and regulations are also followed, that is, MPBetreibV and RiliBÄK (Germany) and Sciensano (Belgium). The proportion of BioMed Alliance survey respondents compliant with ISO 15189 (with or without accreditation) was reported to increase from 77% to 88%, at least partially in response to the introduction of the IVDR.7 This high proportion is however probably not representative of diagnostic laboratories throughout Europe, particularly those not aware of the IVDR. IVDR compliance: organization, education, and QMS adaptation One laboratory was able to hire a dedicated person for coordinating IVDR compliance, whereas the other two depended on reallocation of existing resources (personnel and budget). Participation in (inter)national IVDR initiatives, contribution to drafting of guidance documents and consultation of available sources9,10 were useful for understanding the IH-IVD requirements. Key actions to reach IVDR compliance were inventorying/classifying IVDs; identifying gaps between the current QMS and Article 5(5)/Annex I; adapting the QMS where necessary by developing/adapting processes; and generating/updating documentation on IH-IVDs. Available templates were helpful to determine laboratory-specific needs for QMS adaptation.11,12 ISO 15189 compliance provided a solid basis, since the laboratories already fulfilled many IVDR requirements. However, a “QMS upgrade” was needed to fulfill all requirements in sufficient depth, in particular regarding manufacturing, performance evaluation (analytical and clinical performance), and risk management. Interaction with national competent authorities Even though NCAs have a central role in overseeing IH-IVD implementation, the laboratories experienced limited activity of their NCA in guiding of the national diagnostic community. State Institute for Drug Control (SUKL, a Czech NCA) participated in one meeting with the Alliance of national societies for IVDR implementation,13 clarifying the legal framework. The same applied for the Belgian NCA, which also provided some indications on national IVDR interpretation (eg, Article 5(5)g will apply to class C IH-IVDs). Due to the federal organization in Germany, different competent authorities are responsible in the 16 federal states. Here, a dialog between the Ad hoc Commission IVD of the Association of the Scientific Medical Societies in Germany (AWMF) and the national working group of the regional competent authority has been initiated. The Danish Medicines Agency has interacted with all relevant national diagnostic specialties and hospital laboratories through approximately 10 meetings since 2019 with focus on the IVDR and Article 5(5). Will the IVDR increase quality? All 3 laboratories agreed that the IVDR has the potential to increase the quality of IVDs. This central goal of the regulation is based on stricter requirements and more extensive oversight for CE-IVDs/manufacturers and compliance to ISO 15189 for IH-IVDs/health institutions. Specifically, the clinical performance data requirement (connected to the intended purpose of the device) and an expected increase of standardized/published methods are mentioned as important parameters for guaranteeing high quality diagnostic patient care. However, several aspects of the IVDR, if not addressed, might adversely impact on diagnostic patient care based on IH-IVDs: rare disease diagnostics, which have relatively high “regulatory compliance costs” per test result, might be discontinued by some laboratories because of insufficient capacity or budget for IVDR compliance; increased regulatory workload and uncertainties concerning how to fulfill IVDR requirements might hamper IH-IVD implementation and innovation (potentially also for Article 5(5)d on justification for IH-IVD use in 2028); insufficient resources for IVDR implementation. MESSAGES FOR IH-IVD STAKEHOLDERS The IVDR was introduced to increase the safety and quality of IVDs in the EU. Based on the recent EHA-IVDR session on IVDR implementation in diagnostic laboratories, we formulate a number of messages for 3 different groups of IH-IVD stakeholders, to emphasize how they can contribute to quality increase under the IVDR (Box 1).BOX 1 Message for diagnostic healthcare management and laboratories at health institutions A QMS according to ISO 15189 is a solid basis for reaching IVDR compliance. Laboratory professionals in laboratories that are not ISO 15189 compliant should realize that this norm covers all elemental quality management processes for diagnostic laboratories, and are advised to promptly work towards compliance (with a focus on IVDR Annex I). A thorough understanding of IVDR Article 5(5) and Annex I is crucial in this process. Hospital and laboratory management are strongly advised to support IVDR implementation in their specialized laboratories (staff and counseling), including establishing the extensive documentation and validation required by ISO 15189 and IVDR Annex I. Without such additional support, the demanding process of reaching IVDR compliance will negatively impact on other diagnostic responsibilities. Message for diagnostic healthcare payers Reaching IVDR compliance is a major burden for diagnostic laboratories. Healthcare system authorities, insurance companies, and other payers should allocate an increased budget for reimbursement of diagnostic testing (estimated 10%–15%), as this will be critical for increasing quality under the IVDR while preserving rare disease diagnostics. Message for EU and national authorities The European Commission and NCAs have a key role in raising awareness of the IVDR among the EU-wide diagnostic community. Importantly, IVDR implementation will result in a major quality increase in laboratories that do not yet comply with ISO 15189 or comparable national QMS. Diagnostic laboratories that manufacture and use IH-IVDs under the health institution exemption have a clear need to interact as a collective with NCAs on how to practically interpret Article 5(5) and relevant Annex I requirements. We strongly encourage all NCAs to be approachable for national and European medical societies and take on an active role in discussing a way forward within the framework of the IVDR with the diagnostic community.Last but not least, ambiguities around requirements for IH-IVDs should soon be cleared up by NCAs (additional national interpretations/requirements, if applicable) and the diagnostic community (detailed framework/guidelines for IVDR compliance) together. To facilitate efficient, harmonized, and adequate IVDR implementation in EU diagnostic laboratories, laboratory professionals should collectively address the need for detailed guidelines based on their unique expertise (eg, on the level of national or international medical societies), taking along input from NCAs on critical elements. This includes, on the longer term, also an appropriate fulfillment of Article 5(5)d on justification of IH-IVD use. AUTHOR CONTRIBUTIONS BRL and JJMvD wrote the manuscript in close collaboration with the other authors. DISCLOSURES MB reports advisory boards and invited speaker for Amgen, BD, Janssen, art tempi communications, Pfizer; research support from Amgen. KD reports research support from Novartis, Celgene/BMS, Astellas and Agios; honoraria from Novartis, Celgene/BMS, Daiichi Sankyo, JAZZ and Roche; advisory board for Novartis, Janssen, Celgene/BMS, Daiichi Sankyo, JAZZ, Roche and Abbvie. EM reports that she is president of the European Hematology Association and a BioMed Alliance board member. JJMvD reports an Educational Services Agreement and a Scientific Advisor Agreement from BD Biosciences (San José, CA); all related fees and honoraria are not received personally but go to University of Salamanca. JJMvD also reports to be chairman of the EuroFlow Consortium, which has jointly owned Intellectual Property (IP) and Patents; the royalties from the licensed IP and Patents are owned by the EuroFlow Foundation. These royalties are exclusively used for continuation of the EuroFlow collaboration and sustainability of the EuroFlow consortium. All the other authors have no conflicts of interest to disclose.