Work

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

Year: 2021

Type: article

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 product. However, what if a commercial IVD exists and an in-house test differs in aspects of performance? Then, the entire section hinges on the interpretation of the term “equivalent” and “the target patient group’s specific needs.” An unduly broad interpretation of this provision would overshoot the legislator’s goal of bringing IVD to a higher, common, and safer standard and result in inadvertent consequences to the intricate interplay between CE-marketed IVDs and in-house tests (10). An embargo of in-house IVDs as soon as there is any corresponding CE-IVD product on the market threatens the ability of laboratories to continuously maintain complete and optimal test portfolios for diagnostic patient care. In addition, such an embargo would prevent optimizing analytical parameters for specific clinical use cases, which many experts regard as a foundation to medical progress in diagnostics. Finally, the lack of a specific definition for equivalence creates a disincentive—namely, that any new in-house IVD must outperform (or at least perform as well as) the preexisting CE-certified IVD. This disincentive will likely encourage monopolies due to the (financial) risk of failure to meet performance requirements for the laboratories and ending up with the entire development cost of a subpar IVD that cannot be legally used. In-house diagnostic procedures also have a particularly important role for special patient groups in the context of rare diseases—where the development of products is not attractive for the diagnostic industry from a business point of view. Article 5 (IVDR) contains an opening clause that demonstrates the intention of the EU legislator to further enable this diagnostic area. The so-called “orphan disease” exemption with a cutoff of <8000 affected individuals per year can also be found in the corresponding US legislation (11). In-house procedures are also a driver of innovation in the field of laboratory medicine and medical diagnostics. The availability of diagnostic tests in the early phase of the COVID pandemic—designed and manufactured in laboratories– illustrates the importance of in-house test development (12). The EU legislator indeed recognizes the need for development and validation of in-house devices, however, demanding a very high level of expertise. Legal concerns may arise as to the compatibility of Article 5 (5) IVDR with EU primary law in that the enactment of this provision significantly affects medical practice in healthcare institutions and their laboratories. It is important to point out that the IVDR was adopted under the EU competence rule [Article 168 (4)(c) Treaty on the Functioning of the European Union (TFEU) (13)], which is limited to measures that set high standards of quality and safety for devices for medical use. Notwithstanding this competence, Article 168 (7) TFEU provides that Member States retain responsibilities for national health policy and healthcare system organization and management, which the Union must respect. Even though this subsidiary clause is a formal manifestation of advocacy for the principle of federalism, healthcare is generally considered to add little sovereignty or formal division of powers between the EU and its Member States. It may well be argued that the EU legislator did not pay sufficient attention to the delicate and sophisticated balance between the EU and national competences in healthcare laid down in Article 168 (7) TFEU when it carved out Article 5 (5) IVDR. The field therefore faces an interesting dilemma: Politically, we are obligated to establish appropriate regulatory mechanisms for compliance with IVDR. However, the final authority resides constitutionally with the Member States who have been overwhelmed with the nuanced aspects of unifying IVD regulation. Thus, we are witnessing a cultural shift in IVD governance that affects stakeholders and regulators alike. In conclusion, IVDR can be regarded as a major step forward with respect to commercial products. The times of self-declaration of devices in the EU are over and a large proportion of industrially manufactured products are now subject to an external certification procedure. Thus, once IVDR is realized, we recognize the opportunities in the industrial sector and accordingly expect a quality boost in laboratory medicine products. For in-house diagnostic processes including those of higher complexity, we emphasize the importance of avoiding sprawling interpretations of the IVDR. IVD, in vitro diagnostics; EU, European Union; IVDR, in vitro diagnostic medical device regulation. All authors confirmed they have contributed to the intellectual content of this paper and have met the following 4 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved. Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest: M. Brüggemann, Board member of EuroFlow and EuroMRD. M. Brüggemann, Advisory Boards (Amgen, Incyte, and Molecular Health); A. Stenzinger, consulting fees (Aignostics, Astra Zeneca, AGCT, Bayer, BMS, Eli Lilly, Illumina, Incyte, Janssen, MSD, Novartis, Pfizer, Roche, Seattle Genetics, Takeda, and Thermo Fisher). None declared. M. Brüggemann, Amgen and Janssen. A. Stenzinger, grants (Bayer, Incyte, BMS, and Chugai). None declared. None declared.

Source: Clinical Chemistry

DOI: 10.1093/clinchem/hvab215

Authors: Michael Vogeser, Monika Brüggemann, Jochen Lennerz, Albrecht Stenzinger, Ulrich M Gassner