Key Takeaways for IVD manufacturers
Authored By: Karin Hughes, SVP Global Regulatory and Quality
While the European Union (EU), United Kingdom (UK) and Switzerland once presented a largely harmonized and favorable first market for launching diagnostic products, the current era, post-Brexit, post-Swixit and a year post the implementation date of the EU In Vitro Diagnostics Regulation (IVDR) presents in vitro diagnostic (IVD) manufacturers with enormous challenges. Extensive and more stringent conformity assessment requirements have emerged, most notably through the application of the IVDR (Regulation (EU) 2017/746) and, in some regimes (i.e., the UK), new Medical Device Regulations are not yet published.
While the primary aim of the IVDR – which became effective on May 26, 2022– and the future UK Medical Device Regulations is to ensure better protection of public health and patient safety, the resulting costs, and complexities of introducing new products to these markets, as well as maintaining IVD legacy products on market, have increased dramatically.
The June 2023 MedTech Summit in Brussels, Belgium, offered a number of insightful updates on the evolving European and UK regulatory landscapes. Participants included several Notified Bodies (TÜV SÜD, TÜV Rheinland, BSI and DEKRA), and UK representatives from the British In Vitro Diagnostic Association (BVDA) and the Association of British HealthTech Industries (ABHI). Participants also included national competent authorities (NCAs) from Germany (Paul-Ehrlich-Institut), Finland (Finnish Medicines Agency – Fimea), and Ireland (National Standards Authority of Ireland), as well as those of us responsible for the implementation of these requirements.
Here, we report some of the most salient insights for IVD manufacturers, including:
● The Ebb and Flow of Notified Body Capacity
● Updates on Companion Diagnostics
● European Database on Medical Devices (EUDAMED) Update
● The Changing Landscape for Distance Sales
● COVID-19 (SARS CoV and SARS-CoV-2) Classification
● Clinical Performance Data Requirements
The Ebb and Flow of Notified Body Capacity
More than one year after the implementation of the IVDR — replacing the In Vitro Diagnostic Medical Devices Directive 98/79/EC (IVDD) and related legislation of individual EU nations — several issues and challenges have emerged. Yet, despite the shortcomings, positive news reported at the MedTech Summit is that more IVD manufacturers are successfully navigating the process.
One of the larger challenges facing the system has been the lack of sufficient Notified Body (NB) capacity. Under the old directive, the number of IVD devices that required an NB conformity assessment was approximately 20 percent. Now, under the IVDR, that number has grown to roughly 80 to 90 percent.
Notified Bodies have been navigating their own processes under the IVDR to (1) become designated to perform conformity assessments, and (2) to expand the scope of their Product Families, Procedures and Articles/Annexes for which they have demonstrated competence. Additionally, a large number of IVD manufacturers have required extensions of IVDD certificates prior to the 2022 date of application. The combination of these three factors has consumed NB capacity over the past year, and, as recently as six months ago, several NBs were unable to accept new applications.
On the upside, those NBs represented at the MedTech Summit reported that their capacity has greatly improved, and the number of certificates that were issued under the IVDR tripled in the second half of 2022. All summit-participating NBs are currently accepting new applications. As well, two companion diagnostics (CDx) have been issued certificates — one by TÜV SÜD and another by BSI. What’s more, at least six European Medicines Agency (EMA) consultations have been completed, with more in the pipeline.
Notified Bodies are urging manufacturers to continue moving forward with their applications and assessments. With the implementation of the IVDR transitional provisions for IVDs (those previously certified for the European market in compliance with the IVDD), representatives from various NBs noted that they have begun to see application withdrawals and a decline in industry submissions for conformity assessments. As a result, NBs are concerned that as industry delays conformity assessment submissions, a new capacity challenge may result. As transitional provisions bring Class D submissions online (due by May 26, 2025), there is a risk the timing may coincide with a new push by IVD manufacturers to attempt to get their IVDs reviewed under the IVDR.
The timetable for successfully receiving certification does not favor delaying submission for conformity assessments. Prior to review, it may take several months to complete the request-for-quote process, and have an NB subsequently assign appropriate subject matter resources to begin the technical documentation review. Participating NBs noted that, on average, conformity assessments are still taking one year to complete, with an observed range of nine to 24 months. As well, on the back end, there can be as much as another three to six months after a device has been recommended for certification to actually receive the certificate. For those who may have had experience with CE-marked List II A or self-test IVDs under the IVDD, these IVDR review timelines still exceed those six-month reviews common under the IVDD. Dedicated review – NB service wherein IVD manufacturers pay an extra fee (per conformity assessment review) for a focused, dedicated review – may provide shorter timelines, but can be costly. Proper device classification and NBOG code assignment and high-quality submissions, which meet all applicable Technical Documentation requirements and include justifications for those not applicable, remain the best timeline risk mitigations..
Updates on Companion Diagnostics
For companion diagnostics (CDx), two factors — (1) the delay in the availability of the coordinated assessment procedures for the review and approval of CDx performance study applications, and (2) the current lack of harmonization in national legislation requirements for NCA and ethic committee application documentation and reviews — are continuing to negatively impact the ability to initiate clinical trials of investigational medicinal products (CTIMPs) that rely on a CDx for medical management decisions. While the European Medicines Agency (EMA) offers scientific and protocol assistance to developers of medicinal products through multiple pathways — including the Simultaneous National Scientific Advice (SNSA) pilot, which has been successfully used by CDx developers in conjunction with their pharma partners — the MedTech Summit CDx panel noted there is no process for structured dialog among all stakeholders (e.g., medicinal product developer, diagnostics manufacturer, NB and EMA) prior to, or during, the conformity assessment of the CDx and the medicinal product authorization. This lack of guidance puts at risk the simultaneous approval of the medicinal product, alongside certification of the CDx, potentially delaying timely access for patients to both
There was welcome news that the EMA has established a “focus group on provision of scientific advice for medicinal product developments comprising drug-device combinations and drug-CDx combinations.” This is meant to be a broader exchange platform for EMA, Scientific Advice Working Party (SAWP) members, NCA experts, NBs, and industry. The initial goal is to understand the perspectives of the stakeholders through case studies to determine when, where and from whom advice is needed. This group is also exploring the possibility of structured exchanges between stakeholders.
The kickoff meeting occurred two months before the MedTech Summit, and there have been four meetings to date, with the results of these meetings expected to be published by the EMA. It was also noted that there is on-going activity by the EMA’s Methodology Working Party aimed at providing guidance for simultaneous medicines authorization and CDx certification based on the EMA/Committee for Medicinal Products for Human Use 2016 Concept paper on predictive biomarker-based assay development in the context of drug development and lifecycle. The working party is moving to finalize the guideline as soon as possible.
European Database on Medical Devices Update
One year after IVDR implementation, the regulatory infrastructure remains incomplete and continues to pose a challenge. The European Database on Medical Devices (EUDAMED) had been scheduled to go live in May 2020, but, as yet, has achieved only half of its implementation goals. Composed of six modules — actor registration; unique device identification (UDI) and device registration; NBs and certificates; clinical investigations and performance studies; vigilance; and market surveillance — EUDAMED is intended to provide a “living picture” of the lifecycle of medical devices that are made available in the EU.
The EUDAMED production environment currently contains three modules — actor registration, UDI and device registration, and NBs and certificates — containing valid data for devices placed on the EU market. Significant progress continues to be made towards full implementation in Q4 2024, and the European Commission (EC) continues to target Q2 2024 for the remaining modules to be available.
Once EUDAMED has achieved full functionality, and there is publication of an EC notice in the Official Journal of the European Union (OJEU), industry will have six months before use of EUDAMED becomes mandatory with respect to the obligations related to actors, vigilance, clinical investigations and performance studies, and market surveillance modules. Twenty-four months after publication of the notice in OJEU (Q2 2026), the use of EUDAMED becomes mandatory with respect to the obligations related to UDI and device registration, NBs, and certificates.
The Changing Landscape for Distance Sales
Distance sales — non-EU-based clinical laboratories providing services to EU patients — lack guidance under the new IVDR, and many U.S. laboratory-developed test (LDT) providers are unaware of the new requirements. Or, if aware, they may incorrectly believe their testing is exempt under the “in-house” exemption provisions described in Article 5 of the IVDR, which allow healthcare institutions to manufacture, modify, and use in-house tests on a non-industrial scale to meet the specific needs of target patient groups, if an equivalent device available on the market cannot already meet these needs at the appropriate level of performance.
However, this exemption applies only to labs that are part of healthcare institutions established in the EU. All non-EU and most EU-based commercial laboratories will, therefore, be required to CE mark their LDTs. For the subset of labs that meet the in-house exemption, the IVDR will still require them to meet several new standards, including compliance with the IVDR’s Annex I – General Safety and Performance Requirements and quality management system framework.
While the requirements for distance sales are found in Article 6 of the IVDR, they are brief and not straightforward. NBs at the MedTech Summit noted that it has been a challenge for them to interpret those requirements. One NB noted that manufacturers often do not realize they are performing distance sales, and the NB only uncovers this during technical documentation review. Also, from an NCA point of view, Article 6 presents uncertainty. For example, if a U.S. company offers laboratory services via the internet, accessible by anyone in the EU, which country/NCA has responsibility for review?
On a positive note, a distance sales task force has been initiated. However, the Medical Device Coordination Group (MDCG) guidance and/or a Q&A paper is not imminent; any results from the task force will be eagerly awaited by manufacturers, with hope for a clear implementation pathway for distance sales requirements.
COVID-19 (SARS CoV and SARS-CoV-2) Classification
With the World Health Organization downgrading the COVID-19 pandemic, and stating it is no longer qualified as a global emergency in May of this year, IVD manufacturers of SARS-CoV-2 diagnostics are looking for a decision as to whether these products will be down-classified under the IVDR.
These discussions have reached the EC, who is consulting NCAs. Currently, in MDCG 2020-16 rev.2, SARS-CoV and SARS-CoV-2 are listed as examples of products classified as Class D under Rule 1 as a transmissible agent. The MDCG 2020-16 has already undergone revision, and down-classification would minimally require additional changes to guidance. However, some manufacturers are choosing not to wait, and are undertaking a classification dispute with their NB. In accordance with IVDR Article 47, such classification disputes are referred for a decision to the particular NCA. The NCA then notifies the MDCG and the EC of its decision. SARS-CoV-2 tests are currently trending at 42 percent of Class D by application.
Clinical Performance Requirements
Clinical performance requirements for IVD certification remain an issue, particularly for legacy devices. Demonstration of clinical performance for legacy devices is often based on studies conducted under the IVDD, and IVD manufacturers may have difficulty justifying suitability of their products’ performance with that of the generally acknowledged state of the art in medicine. IVD manufacturers may not have the institutional or financial support to conduct new performance studies to fulfill gaps to meet the more burdensome clinical performance requirements.
While the NBs are aware of the challenges of legacy devices, manufacturers must justify whether using previous data, without having to produce any new data, is sufficient to support their intended purpose. It may be possible to augment previously conducted performance evaluation data with literature and/or data from published experience gained by routine diagnostic testing. Otherwise, a change to the intended purpose, resulting in limited and less desirable claims, or market removal may be necessary. Deficiencies in performance evaluation continue to be the number one gap in Technical Documentation cited by the NBs for legacy devices.
Navigating the New IVDR With Beaufort
The transition from the IVDD to the IVDR continues to be challenging. Lack of the expected infrastructure (e.g., EUDAMED, EU Reference Labs, etc.) coupled with the slow pace of available guidance still requires evolutionary steps before solidifying into a cohesive and comprehensive regulatory regime. While not unexpected, the impact to stakeholders remains high, and continues to add risk to commercialization efforts.
Beaufort’s expertise can help you effectively address your IVDR challenges from Covid to Companion Diagnostics. Our team is assisting clients from implementation of quality system requirements and establishment of clinical evidence to technical writing of reports and final Technical Documentation. We are also constantly monitoring the continuously changing regulatory landscape so we can effectively consider near-term and evolving cross-regulatory-regime requirements when developing regulatory strategies to reduce the overall pre-market burden across the US, EU, UK, and ROW markets.
We bring all the pieces together to create a clear and actionable roadmap for legacy and new products to meet the IVDR requirements and adjust that roadmap to meet emerging changes in the IVDR infrastructure and newly published Guidance.
Contact us today to see how we can help you bring your IVD product successfully through the changing regulatory landscape.