Commission designates first E.U. Reference Laboratories for class D IVDs
This week, the Commission announced the designation of the first group of E.U. Reference Laboratories with publication of the implementing regulation in the Official Journal. The regulation designated laboratories in Germany, Spain and Sweden to test four categories of high-risk diagnostics, though Notified Bodies and affected manufacturers will have until October 1, 2024 to adopt the new processes.
The requirement and need for E.U. Reference Laboratories are codified in the European IVD regulation
- Class D (High-Risk) IVDs have specific requirements for conformity assessment. Manufacturers have several options for demonstrating conformity of the device against IVDR requirements, outlined in Article 48 of the IVD Regulation (IVDR; Regulation (EC) 2017/746). Class D IVDs also must be tested by E.U Reference Laboratories (EURLs) against specific requirements known as “common specifications” (CS). These are defined in Article 2(74) of the IVDR as “a set of technical and/or clinical requirements, other than a standard, that provides a means of complying with the legal obligations applicable to a device, process or system.” The Commission has published CSs for certain class D IVDs in Commission Implementing Regulation (EU) 2022/1107, which cover tests for certain blood grouping antigens, HIV, HTLV, hepatitis C, B and D, variant Creutzfeldt-Jakob disease, cytomegalovirus, Epstein Barr virus, Treponema pallidum and Trypanosoma cruzi. [Read AgencyIQ’s analysis of these CSs here.]
- The requirements for EURLs are codified in two implementing regulations that describe the tasks, structure and fee requirements for the EURLs. The final regulations require that Member States verify the conformity of potential EURLs before nominating that lab for designation; notably, those labs accredited to EN ISO/IEC 17025 General Requirements for the Competence of Testing and Calibration Laboratories will be presumed to conform with most requirements. [Read AgencyIQ’s analysis of the final EURL regulations here.]
- The IVDR requires the involvement of EURLs with class D IVDs in two different ways. IVDR Article 48(5) notes that once EURLs have been designated for a particular device category, Notified Bodies need to request that a designated EURL “verify by laboratory testing the performance claimed by the manufacturer and the compliance of the device with the applicable CS,” or, where a CS is not available, other solutions chosen by the manufacturer as part of the initial conformity assessment of a particular class D IVD. EURLs also test batches of marketed class D devices on a sampling basis, on a schedule currently determined by Notified Bodies but eventually codified via an implementing act (IVDR Article 48(13)(c)). When devices undergo changes, the EURL that initially consulted on the device will again be consulted to confirm it still complies with the CS (IVDR Annex IX Chapter II section 4.11)
- Until this week, the Commission hadn’t yet designated any EURLs. In situations for which there are no CSs for a particular type of class D IVD and it’s the first certification for that type, in the absence of a designated EURL, the Notified Body representing that IVD needs to go before the IVD expert panel. Expert panels are “designated in relevant medical fields to deliver opinions and views on the level of clinical evidence provided for certain high-risk medical devices and in vitro diagnostic medical devices,” according to the European Commission (EC). Largely, these panels weigh in on the performance evaluation consultation procedure (PECP) under Article 48(6) of the IVDR. The panels can also provide ad hoc advice to the EC, Medical Device Coordination Group (MDCG), Member States, Notified Bodies and sponsors. [Read AgencyIQ’s analysis of the guidance for Notified Bodies in determining the need for an expert panel.] [Read more about the IVD expert panel here.]
The designation process for EURLs started in mid-2022
- Procedure for designating the EURLs: According to comitology, the Commission uses implementing acts to designate EURLs. The Commission is assisted by a committee comprised of Member State representatives and chaired by the Commission. The Commission submits the draft act to the committee and the chair convenes a meeting to review the draft act. Until it delivers an opinion, any member can suggest amendments. The examination procedure allows majority opinion to adopt the act, according to Article 238(3) of the Treaty on the Function of the E.U. (TFEU). Where no opinion is issued, the Commission can adopt the draft implementing act.
- Once designated, the Commission will monitor the performance of an EURL via on-site visits and audits ( IVDR Article 100(9)). If the Commission finds non-compliance with the conditions of designation, it “shall take appropriate measures, including the restriction, suspension or withdrawal of the designation” via further implementing acts.
- In July 2022, the Commission called on Member States to nominate laboratories to become EURLs. The announcement also encouraged interested laboratories to “contact their Member State for further information and instructions.” In the information pack for candidate laboratories, the Commission described the selection process and criteria as well as the opportunities to participate in advisory committees and provide scientific advice. EURLs can apply to qualify for one or more of the eight IVD categories – detection or quantification of markers for: hepatitis or retrovirus infection; herpesvirus infection; infection with bacterial agents; arbovirus infection; respiratory virus infection; hemorrhagic fever or other biosafety level 4 viruses; parasite infection; blood grouping markers. [Read AgencyIQ’s analysis of the call and information pack here.]
- Reviews of MDCG agendas and minutes have offered insight into the progress related to EURL designations over time. In October 2022, the MDCG reported that a survey of member states showed 30 or so interested labs that would cover all categories of designation. In March of this year, the Commission offered an update on the state of EURLs as well as a timeline that predicted the first EURLs would be designated in Q3 2023 and become operational in early 2024, following an expected six-month transition. The Commission took that opportunity to remind Notified Bodies that they do not need to wait for EURLs to be designated to certify class D IVDs “as EURLS may eventually not be designated in all fields.” The Commission suggested that Notified Bodies use a risk-based approach to certify class D IVDs while it examines other measures for class D IVDs “in the absence of EURLs.”
- The European Commission website has offered updated estimates on the number of labs that may actually receive designation. Although Member States had estimated around 30 labs would be interested in this designation, as of the deadline on March 31 of this year, national regulators had submitted just eight applications for evaluation. A few months ago, the web page was updated to say that only five laboratories were “shortlisted” for designation, and that “the laboratories are expected to be designated by a European Commission implementing act by the third or fourth quarter of 2023.” The Commission also escalated its anticipated turnaround time to get the labs up and running and ready to participate in device conformity assessment and testing from six months to just “several months.” Finally, the Commission acknowledged that the five “shortlisted” labs would be able to cover only four categories – hepatitis and retroviruses, herpesviruses, bacterial agents and respiratory viruses. For the remaining four categories, “there were either no laboratories that satisfied the criteria or their combined capacity was insufficient to cover the expected volume of requests. Therefore, no EU reference laboratory will be designated for these categories of devices.”
This week, the formal EURL designations were published in the Official Journal
- On December 6, Commission Implementing Regulation (EU) 2023/2713 appeared in the Official Journal (OJEU), designating the first five EURLs. Per the implementing regulation, the selection committee took into account capacity concerns when designating the labs and only designated those that would be able to handle all devices within a category. The implementing regulation enters into force on December 9, three days after publication in the OJEU.
- The implementing regulation gives all parties time to adopt the new regulation into their processes. The designated labs need to create networks to “coordinate and harmonise their working methods as regards testing and assessment,” and affected manufacturers and Notified Bodies need to update their conformity assessment and batch testing processes to account for the availability of the EURLs. For these reasons, the regulation will apply only to those lodging formal applications for conformity assessment after the EURL designation applies on October 1, 2024 (Article 2(2)).
- The designated laboratories (listed in Annex):
- Hepatitis and retrovirus infection: Two labs in Germany and Spain received designation for devices to detect or quantify markers of hepatitis or retrovirus infection: EU Referenzlabor für In-vitro-Diagnostika am Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51–59, 63225, Langen, Germany; Instituto de Salud Carlos III, Carretera de Majadahonda – Pozuelo, Km. 2,200, 28220, Majadahonda, Madrid, Spain.
- Herpesvirus infection: For devices to detect or quantify markers of herpesvirus infection, the Commission designated a consortium and two other labs, all from Spain: The two other labs are Instituto de Salud Carlos III, Carretera de Majadahonda – Pozuelo, Km. 2,200, 28220, Majadahonda, Madrid, Spain; and Consulting Químico Sanitario SLU, Calle Marie Curie 7, 28521, Rivas-Vaciamadrid, Madrid, Spain. The consortium is managed by Servicio Madrileño de Salud (SERMAS), Paseo de la Castellana 280, 28046, Madrid, Spain; and is composed of: Hospital General Universitario Gregorio Marañón, C/Doctor Esquerdo n°46, 28007, Madrid, Spain; Hospital Universitario la Paz, Paseo de la Castellana 261, 28046, Madrid, Spain; and Hospital Universitario Ramón y Cajal, Carretera de Colmenar Viejo Km 9,100, 28034, Madrid, Spain.
- Bacterial agent infection: For devices to detect or quantify markers of infection with bacterial agents, the Commission designated the same consortium and labs as for testing devices detecting or quantifying herpesvirus infection.
- Respiratory virus infection: The Commission designated two labs for detection or quantification of markers of respiratory virus infection, from Germany and Sweden: EU Referenzlabor für In-vitro-Diagnostika am Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51–59, 63225, Langen, Germany; and RISE Research Institutes of Sweden AB, Brinellgatan 4, 504 62, Borås, Sweden.
- Makers of certain class D IVDs, and the Notified Bodies assessing their conformity, need to update their quality management system processes to accommodate EURL testing, both for demonstrating initial performance for CE marking and for ongoing performance verification, according to the new implementing regulation. Each entity has until October 1, 2024 to get those processes in place, although it’s possible that Notified Bodies may look for preparations to comply, or at least a written plan for compliance, during certification and surveillance audits prior to this date.
- Only those companies with devices to detect or quantify the four covered categories discussed above (hepatitis or retrovirus, herpesvirus, bacterial infection, respiratory virus infection) are affected by the new designation. Manufacturers of diagnostics for arboviruses, hemorrhagic fever and other biosafety level 4 viruses, parasites and blood grouping do not yet need to update approval and surveillance testing processes, since there aren’t yet any EURLs designated to those categories.
- The class D deadline to comply fully with the IVDR is May 2025, about seven months after the EURL designation regulation applies (October 1, 2024). However, as the new regulation states, it will only apply to those affected manufacturers lodging an application with a Notified Body on or after October 1, 2024.
- It has been a long implementation process for EURLs. As we all know, the IVDR came into force in May 2017 and applied as of May 2022 (with a risk-based extension for class D devices though May 2025). It took until mid-2022 to publish the implementing acts on EURL tasks and fees, until July 2022 to send out a first call for EURL designations and, finally, until the end of 2023 to actually designate the first labs. In the end, the designated labs will only cover half of the eight class D categories originally called for.
Key Documents and Dates
- News announcement – Designation of EU reference laboratories for high-risk in vitro diagnostic medical devices, published December 6, 2023
- Commission Implementing Regulation (EU) 2023/2713 of 5 December 2023 designating European Union reference laboratories in the field of in vitro diagnostics, published in the Official Journal of the European Union on December 5, 2023