In Vitro Diagnostics manufactured and used within EU Health Institutions - In-House Devices (IH-IVD)

Diagnostic results from laboratory tests conducted on human patient samples often contribute significantly to the diagnosis and to the decision regarding the clinical management of patients. For patients, it is irrelevant whether a result is obtained using a CE-certified, commercial laboratory test or by using an in vitro diagnostic device manufactured within the health institution (in-house IVD, IH-IVD). In both cases, the patient expects the devices used to be safe, reliable and state-of-the-art. Also, devices are expected to be maintained or removed from the market immediately following any incident. In recent years, the requirements for the approval of commercial in vitro diagnostic medical devices have become more stringent, with existing legislation being revised or entirely new regulations introduced. These regulations outline general safety and performance requirements (GSPR), and compliance is mandatory. Manufacturers must adhere to these regulations and demonstrate compliance by providing a declaration of conformity (DoC) for their products. The devices carry a CE mark, often followed by the identification number of the Notified Body. However, surveys indicate that almost half of all diagnostic examinations are performed using in-vitro diagnostics produced in-house, so-called in-house IVDs (IH-IVDs).

Chapter

IH-IVDs are of high relevance
IH-IVDs have been established for years
Regulatory requirements to be fulfilled by IH-IVD
Helpful guidance: MDCG 2023-1 Guidance
Summary

IH-IVDs are of high relevance

On January 23, 2020, an article published by an international working group led by Victor M. Cormann described an in vitro diagnostic laboratory test that became highly important in the context of the coronavirus pandemic (Corman, et al., 2020). The test was a real-time RT-PCR assay developed in collaboration with public and scientific laboratories. The assay was able to identify the RNA of the SARS-CoV-2 coronavirus from human sample materials such as nasal/throat swabs or stool samples, enabling the detection or exclusion of infections with this virus, which was novel at the time. In their publication, the working group disclosed both the protocols and the results obtained, enabling other laboratories and commercial manufacturers worldwide to develop, manufacture and use reagents based on their research findings. The protocol was successfully used in many laboratories for routine diagnostics of patient samples until commercially produced tests became available, thus contributing very quickly and comprehensively to viral surveillance, breaking chains of infection, and protecting many people by identifying and isolating infected individuals.

IH-IVDs have been established for years

Even though the SARS-CoV-2 PCR test developed in Berlin is certainly one of the most famous IH-IVDs, or "Laboratory developed tests" (LDT), the use of devices that are developed, manufactured and used within medical laboratories has been established for decades and is a part of laboratories’ daily routine. In July 2021, the BioMed Alliance, a non-profit association representing leading biomedical societies in the European Union (EU), launched a survey for medical laboratories (Biomedical Alliance in Europe, 2021). A total of 203 laboratories from different European countries responded, providing a comprehensive picture of the frequency of IH-IVD use and their fields of application. In summary, 48% of the test systems used in the laboratories were non-CE marked tests. These included either CE-marked devices that were slightly modified, CE-IVDs that were used outside their intended purpose, products that were marketed for research purposes only, or products that were fully developed, manufactured and used within the health institution. A publication from 2022 presented data from Labor Berlin (as of 2020) that showed that out of 1,336 different laboratory methods used, approximately 49% were IH-IVDs (Spitzenberger, et al., 2022). Given the widespread use and importance of these diagnostics, the question arises: What is the regulatory framework regarding IH-IVD?

Regulatory requirements to be fulfilled by IH-IVD

In vitro diagnostic medical devices in Europe are regulated by the “Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices (IVDR)”. The legal basis for in-vitro diagnostic medical devices produced within health institutions can be found in Article 5 "Placing on the market and putting into service". Paragraph 5 states that “with the exception of the relevant general safety and performance requirements set out in Annex I, the requirements of the Regulation shall not apply to devices that are manufactured and used within health institutions established in the Union”. Nevertheless, there are several conditions specified that must be met by health institutions, to qualify for this derogation:

the devices are not transferred to another legal entity,
manufacture and use of the devices occur under appropriate quality management systems,
the laboratory of the health institution is compliant with standard EN ISO 15189 or where applicable national provisions, including national provisions regarding accreditation,
the health institution justifies in its documentation that the target patient group's specific needs cannot be met, or cannot be met at the appropriate level of performance by an equivalent device available on the market,
the health institution provides information upon request on the use of such devices to its competent authority, which shall include a justification of their manufacturing, modification and use,
the health institution draws up a declaration which it shall make publicly available, including:
1. the name and address of the manufacturing health institution,
2. the details necessary to identify the devices,
3. a declaration that the devices meet the general safety and performance requirements set out in Annex I to this Regulation and, where applicable, information on which requirements are not fully met with a reasoned justification therefor,
as regards class D devices in accordance with the rules set out in Annex VIII, the health institution draws up documentation that makes it possible to have an understanding of the manufacturing facility, the manufacturing process, the design and performance data of the devices, including the intended purpose, and that is sufficiently detailed to enable the competent authority to ascertain that the general safety and performance requirements set out in Annex I to this Regulation are met. Member States may apply this provision also to class A, B or C devices in accordance with the rules set out in Annex VIII,
the health institution takes all necessary measures to ensure that all devices are manufactured in accordance with the documentation referred to in point (g),
the health institution reviews experience gained from clinical use of the devices and takes all necessary corrective actions.

Member States may require that such health institutions submit to the competent authority any further relevant information about such devices which have been manufactured and used on their territory. Member States shall retain the right to restrict the manufacture and use of any specific type of such devices and shall be permitted access to inspect the activities of the health institutions.

Helpful guidance: MDCG 2023-1 Guidance on the health institution exemption under Article 5(5) of Regulation (EU) 2017/745 and Regulation (EU) 2017/746

In January 2023, the European Commission's Medical Device Coordination Group (MDCG) published an MDCG document to further explain Article 5(5). The MDCG document is divided into three sections and includes two annexes. After explaining the scope and target group, the document clarifies terminology and provides a detailed explanation of the requirements of the IVDR according to Article 5(5) in section 3.

Annex A contains a template that healthcare institutions can use for the public declaration regarding the manufacturing and use of its in-vitro diagnostic medical devices produced in-house.

Annex B contains a timeline outlining when the various subsections of Article 5 IVDR must be fulfilled. This timeline was slightly modified as part of the amending ordinance of September 2024.

The guideline introduces the term "in-house devices" for products manufactured exclusively within the EU area and on a non-industrial scale to meet specific patient group requirements that cannot be met by an equivalent CE-marked device.

IH-IVDs are exempt from many regulations by the IVDR, with the exception of Annex I, and must comply with the conditions set out in Article 5(5). These conditions are explained in detail in the document and form the basis for the control and supervision of these products.

The guideline is helpful for understanding the requirements set out in Article 5(5) and incudes common examples. In addition to the definition of the terms health institution and manufacturing, explicit reference is made to meeting the general safety and performance requirements (GSPR). This includes requirements for an appropriate risk management and quality management system, information related to design, manufacturing, and performance, as well as the requirements for the information provided along with the IVD.

A process must be in place to ensure the identification and evaluation of commercial and CE marked equivalent products that may become available on the market. According to the IVDR, the use of IH-IVD must be justified, and this justification must be documented. Further explanations are provided in Section 3.6 of the guideline.

All information must be made available in a searchable, well-structured form. Section 3.9 outlines the technical documentation requirements according to Annex II, IVDR. Section 3.10 of the guideline provides further information on vigilance requirements, including incident documentation and corrective actions. Documented processes should be established within the framework of a quality management system (QMS). Finally, the guideline also states that manufacturing on an industrial scale is excluded, though it does not provide an exact definition. However, analysing a large number of patient samples does not contradict the use of an IH-IVD and does not automatically classify a product as "manufactured on an industrial scale".

Annex B of the guideline provides an overview of when individual sub-sections of Article 5 become binding. With the exception of the reason for why no CE-marked product available on the market can be used, all requirements must already be met since 26 May 2024. The distribution of IH-IVD to other institutions has been prohibited since 26 May 2022. The essential safety and performance requirements of Annex I IVDR have also been mandatory since that date. As part of the amending Regulation (EU) 2024/1860, the deadline for fulfilling the requirement under Art. 5(5)d (documentation of a justification) was extended in July 2024 to 31 December 2030.

The MDCG guideline is not legally binding, but competent authorities generally use it as a reference. Notified bodies are not involved in the assessment of medical laboratories QMS or IH-IVD documentation. There are no requirements for the assignment of a UDI (Unique Device Identifier) and/or entries in the EUDAMED, as required for commercial IVDs.

Summary

With their CE-certified commercial tests, manufacturers provide a huge and powerful diagnostic tool box. This is meaningfully and significantly complemented by the IH-IVDs. IH-IVDs are not only used to assist in diagnosing rare diseases or to serve relatively small patient groups, such as children, but also ensure fast and decentralized diagnostics, and drive innovations. Diagnostic laboratories operate at a high level of quality and also meet the requirements of IVDR Article 5(5).

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Literature sources:

Biomedical Alliance in Europe. (December 2021). Main findings IVDR Questionnaire BioMed Alliance.
Corman, V. M., Landt, O., Kaiser, M., Molenkamp, R., Meljer, A., Chu, D. K., . . . Drosten, C. (2020). Detection of 2019 novel coronavirus (2019-nCoV) by. Eurosurveillance, 23-30.
DIN EN ISO 15189:2022. Medical laboratories - Requirements for quality and competence.
EU Commission. (April 5, 2017). REGULATION (EU) 2017/746 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 5 April 2017 on in vitro diagnostic medical devices. (Rev. 09.07.2024).
MDCG 2023-1. (January 2023). Guidance on the health institution exemption under Article 5(5) of Regulation (EU) 2017/745 and Regulation (EU) 2017/746.
Spitzenberger, F., Patel, J., Gebühren, I., Kruttwig, K., Safi, A., & Meisel, C. (2022). Laboratory-Developed Tests: Design of a Regulatory Strategy in Compliance with the International State-of-the-Art and the Regulation (EU) 2017/746 (EU IVDR). Therapeutic Innovation & Regulatory Science, pp. 47-64.