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Laboratory-Developed Tests in the New European Union 2017/746 Regulation: Opportunities and Risks

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Vogeser, Michael, Brüggemann, Monika, Lennerz, Jochen, Stenzinger, Albrecht, Gassner, Ulrich M·2021·Clinical Chemistry
DOI 10.1093/clinchem/hvab215
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Abstract

In vitro diagnostics (IVD) in the European Union (EU) is facing fundamental change with the implementation of a new regulation termed in vitro diagnostic medical device regulation (IVDR) (1). Going into full effect in May 2022, IVDR will affect 447 million people in 27 countries. There is substantial concern that IVDR will result in over-regulation and potentially result in “the end of the laboratory-developed tests as we know it” (2). In this context, it should be noted that in the USA, the topic of regulation of in-house procedures—and in particular potential regulation of medical practice—has been a subject of controversy for a considerable time and a definitive conclusion is still pending (3–6). Here, we provide practical interpretations and aim to facilitate a focused debate that will support meaningful local implementation of IVDR. In our view, IVDR will primarily affect commercially manufactured diagnostic products whereas the impact on laboratories performing in-house testing may be more nuanced than previously portrayed. So far in-house testing was exclusively addressed by law of the Member States. An overview of the definitions given in IVDR is provided in Table 1. It is important to note that the IVDR does not apply to products of general laboratory use [Art. 1 (3 a)]. A guidance document by the European Commission (7) specifies that, for example, a generic mass spectrometer does not constitute an IVD device. Definitions provided in Regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR). Definitions provided in Regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR). The IVDR lays down rules concerning (i) placing on the market, (ii) making available on the market, or (iii) putting into service in vitro diagnostic medical devices and accessories for such devices (Article 1) (1). The definition of IVD according to IVDR is formulated in rem, in other words concerns exclusively devices applied in the context of laboratory testing, and, in our opinion, does not extend to laboratory testing operations as a whole or to protocols applied in testing. Since this cannot be recognized in the present legal text, it is reasonable to assume that if regulation of processes and protocols within the context of measurement and analysis procedures had been the intention of the EU legislator, it would have been specified. The IVDR exclusively uses the terminology “in vitro diagnostic medical device … manufactured and used only within health institutions established in the Union”; the term laboratory-developed test (LDT) or test is not used. Common testing procedures, for example the microscopic investigation of a Gram-stained smear, or the quantitative determination of nucleated cells in a cerebrospinal fluid sample (probably referred to as an in-house test in many laboratories), or microscopy-guided evaluation of immunohistochemical stains used for tumor typing, are performed as a diagnostic process and should not fall under the IVDR because the procedure is not a device per se (8). Similarly, the determination of drug concentrations in the blood using a generic mass spectrometry system might not be considered an IVD. However, for the standardization of these procedures, laboratories may use in-house–manufactured calibration materials. These will fall under the IVDR pursuant to the definition in Article 2 (IVDR) and must be treated accordingly. Concretely, compliance with Annex I of the IVDR has to be demonstrated. Except for the general safety and performance requirements (Annex I), in-house procedures are excluded from the IVDR provisions [Article 5 (5)]. However, to manufacture in vitro diagnostics in health institutions an up-to-date quality management system (QMS) is required. Notably, the IVDR does not exclusively specify the type of QMS [although ISO 15189 is mentioned (9)] and explicitly leaves room for the application of national QMS provisions. The approach to separate regulatory oversight of laboratory operations from oversight of in vitro diagnostic devices is thereby similar to the US framework where IVD devices oversight resides with the Food and Drug Administration whereas laboratory testing operations are governed by the Clinical Laboratory Improvement Amendments (i.e., Centers for Medicare and Medicaid Services). The IVDR contains relevant ambiguities with respect to in-house IVDs. First, in-house IVDs are exempt from most provisions of the IVDR only if they are not manufactured on an “industrial scale” (1); however, this term is not specified. Process automation, as currently applied in many laboratories, does not qualify as production on an industrial scale in our opinion. Arguably the most problematic point of the IVDR with respect to in-house diagnostic devices is subparagraph (d) of Article 5 (5) IVDR. The section outlines that in-house diagnostic devices may only be used when the target patient group’s specific needs cannot be met by an equivalent marketed produ

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  1. Evans BJ, Clayton EW. The Yale Law Journal -Forum: Deadly Delay: The FDA's Role in America's COVID-testing debacle. Yale Law J 2021. Part one, Title XIV.

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Authors
Vogeser, M., Brüggemann, M., Lennerz, J., Stenzinger, A., & Gassner, U. M.
Affiliations
  • Institut für Laboratoriumsmedizin (DE)
  • University Hospital Schleswig-Holstein (DE)
  • Harvard University (US)
  • University Hospital Heidelberg (DE)
  • University of Augsburg (DE)
Corresponding author
Vogeser, Michael
ORCID
Venue
Clinical Chemistry
Publisher
Oxford University Press (OUP)
Published
2021-12-30
Volume
68
Issue
1
Pages
40-42
ISSN
  • 0009-9147 (ISSN-L)
  • 1530-8561
DOI
10.1093/clinchem/hvab215
OpenAlex
W4206450393
Cited by
22
References
8
Citations by year
2026: 2 · 2025: 4 · 2024: 6 · 2023: 5 · 2022: 5
FWCI
3.50
Type
journal article
Language
en
Open access
Licence
academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations
  • Clinical Chemistry (publishedVersion)
  • PubMed (publishedVersion)
  • OPUS (Augsburg University) (submittedVersion)
Funders
  • A. Stenzinger
  • Bayer
  • Incyte
Topics
  • Health Sciences › Health Professions › Health Information Management › Healthcare Regulation
  • Health Sciences › Medicine › Physiology › Clinical Laboratory Practices and Quality Control
  • Health Sciences › Medicine › Physiology › Biomedical Ethics and Regulation
Keywords
IVDR, laboratory-developed tests, in-house testing, overregulation, medical practice regulation, clinical laboratory, quality management systems
MeSH terms
European Union, Humans

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