EVA

What is IVD-R and why does it matter

Medical devices* as a term can refer to a range of things: from a reagent or reagent product, to a control material, or piece of equipment, among many others (for a detailed definition please refer tothe *). The intended use of such devices by the manufacturer, academic, industrial or public health institute, is the in vitro examination of specimens, including blood and tissue donations (1, 2). It is nota surprise therefore that medical devices, as well as their use, need a consistent and thorough regulatory framework for safeguarding patient wellbeing. This framework has evolved over the years and is, currently in Europe, known as In Vitro Diagnostic medical device Regulation (IVD-R). IVD-R was approved in 2017 and came into validity in 2022 (1). It aims at implementing tighter criteria for the approval and certification of medical devices, as a response to fraudulent, negligent or insufficient fulfilling of certification requirements for medical devices experienced in Europe in the past.

Examples of medical device misuse in the past include the affair of non-conforming breast implants made of industrial, rather than medical, grade silicone by Poly Implant Prothèse during the 1990s (3). In the U.S., due to the FDA higher regulatory threshold, the manufacturing deficiencies of these devices were identified, while in Europe, where the more lenient IVDD regulation was in place at the time, these implants had been in use for approximately a decade. Repeated reported cases of ruptured implants led to a scandal that came into the public spotlight in the 1990s (4). Other relevant examples include metal on metal hip prostheses that created microparticles causing inflammation of the joint and eventually required replacement (5), as well as the contaminated (HIV and HEP-C) blood transfusions distributed by the French National Center for Blood transfusions in 1984-1985, causing a health and regulatory crisis between 1983-2003 (4, 6).

A regulatory framework in evolution

In this context, the evolution of IVDD to IVD-R aimed at creating uniform and stricter criteria for the evaluation of medical devices. While IVDD required manufacturers of medical devices to certify themselves the conformity of the devices developed, IVD-R requires the Conformité Européenne (CE) status, a label obtained through the competent authorities and notified bodies of EU countries. These agencies are also responsible for surveying how devices are used, monitoring of any potential side effects and reserve the right to withdraw a product from the market. During the IVDD era, more than 50 notified bodies existed, with varying criteria, a situation that encouraged a ‘shopping’ mentality on behalf of the manufacturers who would seek certification from the more ‘flexible’ notified body (4). The IVD-R coming into action resulted in the tightening of the certification criteria and, as a result, a decrease in the number of notified bodies. It is also worth noting that IVD-R also stipulates the need to recertify already validated devices, creating a significant workload for the now fewer notified bodies.

And when it comes to pandemic preparedness and response against a virus outbreak?

While all this may sound distant when we think in terms of virology research, it is not, especially when we place the subject in the context of pandemic preparedness and response. Public health institutions and diagnostic labs often have at hand in vitro diagnostic assays developed for in-house use. These can be particularly useful tools to deploy in case of a pathogen outbreak, where unpredictability and logistical bottlenecks often make response time longer (7). IVD-R allows the use of in-house developed assays as a replacement of CE-assays, only if it can be proven that no other suitable option is available to cover this diagnostic necessity. However, the requirements for justifying this are not clear (7).

Here we discuss with Lance Presser, PhD, a virologist with a strong background in working in public health settings and currently based at the Dutch National Institute for Public Health and the Environment (RIVM), a partner of the EVORA alliance. RIVM is the EU reference laboratory for public health on vector-borne viral pathogens, as well as a WHO collaborating center for laboratory preparedness and response against high threat pathogens and biorisk .

RIVM offers scientific and technical expertise in pandemic preparedness and response against high- risk pathogens at the national, European and international level. By providing scientific expertise, guidelines, reference materials, training and capacity building to EU and international public health actors, RIVM contributes towards facilitating the detection and characterization of viruses, pathogen surveillance and standardization of lab practices across Europe, in order to obtain reliable and comparable data across countries.

Lance Presser’s insights on the implications IVD-R may have in the pandemic response towards a virus outbreak offer a very useful perspective from a public health point of view.

‘The second issue that comes to mind, and again we have seen it play out in numerous pandemics/outbreaks (SARS-CoV-2, Monkeypox virus, Influenza virus, Chikungunya virus, etc.), is when some commercial molecular assays start to fail due to a change in the virus mid-outbreak, or mid- pandemic ’, he adds.

This can happen due to mutations to the original virus strain resulting in virus variants. ‘In that case, existing assays need to be re-formulated. With the implementation of IVD-R, that process will be much more expensive and time-consuming. Mid-pandemic…that seems problematic to me. The above bottlenecks boil down to the increased administrative burden required to conform to IVD-R. Most of those administrative costs are duplicative, as most diagnostic labs already conform to ISO-15189 standard’ explains Lance.

‘At a more fundamental level, the maintenance of in-house tests will be more time-consuming, diagnostic laboratories may opt for commercially available CE-labelled tests, which could result in a decrease of expertise for setting up in-house tests and, as a consequence, reduced availability of open systems necessary to quickly adapt tests for rapidly evolving pathogens’, he concludes.

In the case of industry, the tightening of the certification criteria through IVD-R, together with the reduction of NBs, has resulted in making access to regulatory bodies harder for manufacturers, especially in the case of small start-up companies. Companies with a single product of interest are in great disadvantage when it comes to accessing regulatory bodies, compared to large companies with a large portfolio of products and established relationships with regulatory bodies. Furthermore, accessing regulatory bodies is not only related to obtaining certifications but also to understanding the regulatory requirements that apply to each different device. Getting feedback on the requirements for a specific product is increasingly harder for smaller scale manufacturers (4).

Taken together, these parameters mean that fewer resources are available on the market for responding to a pathogen emergence, impacting EU capacity to adapt to the needs of a potential pandemic.

Where quality control- ISO comes into play and what scientists suggest.

IVDR explicitly references the ISO-15189 standard and scientists, academic and industrial, are advocating that compliance with this quality standard should be sufficient for use of devices and diagnostics. Most manufacturers and clinical or public health labs comply with the ISO-15189 standard and argue that additional regulatory requirements should not be necessary, as they are redundant with the ISO-15189 (7, 8).

An increasing population of scientists are proposing aligning IVDR compliance with ISO-15189 compliance (7, 8).

‘In this context, EVORA work package 10 focuses on finding simple, functional adaptations for laboratories to comply with the IVD-R. In addition, it is a channel for voicing our concerns as scientists to the policy makers working on these regulations’, comments Lance, who is leading this work. EVORA partners, involved in work package 10, have produced a “Pre-validated template protocol for diagnostic assays”; this document offers a set of practical guidelines to facilitate EVORA partner laboratories in validating Laboratory Developed Tests (LDTs) according to IVDR criteria.

‘Furthermore, we are currently working on a report document, reviewing the challenges imposed by the IVDR in relation to public health tasks, as experienced by public health labs and diagnostic labs in health care, and illustrating their implications through examples from the Netherlands and other European countries’, concludes Lance.

Text by Semeli Platsaki, PhD

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*Medical devices:

Article 2 (2) of the IVD-R defines an IVD as: “‘in vitro diagnostic medical device’ means any medical device which is a reagent, reagent product, calibrator, control material, kit, instrument, apparatus, piece of equipment, software or system, whether used alone or in combination, intended by the manufacturer to be used in vitro for the examination of specimens, including blood and tissue donations, derived from the human body, solely or principally for the purpose of providing information on one or more of the following: (a) concerning a physiological or pathological process or state;
(b) concerning congenital physical or mental impairments;
(c) concerning the predisposition to a medical condition or a disease;
(d) to determine the safety and compatibility with potential recipients;
(e) to predict treatment response or reactions;
(f) to define or monitoring therapeutic measures.

1 See Medical Device Coordination Group guidance documents here:
https://health.ec.europa.eu/medical-devices-sector/newregulations/guidance-mdcg-endorsed-documents-and-other-guidance_en#sec1 Medical Devices Medical Device Coordination Group Document MDCG 2024-11 Page 4 of 13

Specimen receptacles shall also be deemed to be in vitro diagnostic medical devices.”

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References

1. REGULATION (EU) 2017/746 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 5 April 2017 on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU

2. MDCG 2024-11 Guidance on qualification of in vitro diagnostic medical devices, Medical Device Coordination group document.

3. Greco, Cinzia. “The Poly Implant Prothèse breast prostheses scandal: Embodied risk and social suffering.” Social science & medicine (1982) vol. 147 (2015): 150-7. doi:10.1016/j.socscimed.2015.10.068

4. Prince, Adam J et al. “The Impact of the Medical Device Directive to Medical Device Regulation Transition on Early Clinical Testing of Cardiovascular Devices.” Journal of the Society for Cardiovascular Angiography & Interventions vol. 1,5 100401. 12 Jul. 2022, doi:10.1016/j.jscai.2022.100401

5. Scientific Committee on Emerging and Newly Identified Health Risks. The Safety of Metal-On- Metal Joint Replacements with a Particular Focus on Hip Implants. Adopted this Opinion at the 7th plenary of 24-25 September; 2014. Accessed July 12, 2022. https://ec.europa.eu/health/scientific_committees/emerging/docs/scenihr_o_ 042.pdf

6. Casteret AM. L’affaire du sang. 1992, 2nd ed. Paris, France: La Découverte; 1992. ISBN/ISSN 978-2-7071-2115-8.

7. Molenkamp, Richard et al. “Despite good intentions, the regulation on in vitro diagnostic medical devices (IVDR) in Europe could impact negatively on preparedness and response for the next pandemic.” Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin vol. 31,2 (2026): 2500553. doi:10.2807/1560-7917.ES.2026.31.2.2500553

8. Vanstapel, Florent J L A et al. “ISO 15189 is a sufficient instrument to guarantee high-quality manufacture of laboratory developed tests for in-house-use conform requirements of the European In-Vitro-Diagnostics Regulation.” Clinical chemistry and laboratory medicine vol. 61,4 608-626. 31 Jan. 2023, doi:10.1515/cclm-2023-0045