Proposal for IVDR extension also impacts MDR, EUDAMED
As many have been expecting, the Commission just proposed a second extension to the transitional period of the European IVD regulation, in response to manufacturer data showing marked unpreparedness, along with continued delays in rolling out tools like EUDAMED that are needed to implement the regulation. But medical device manufacturers also need to take a look at the proposal, since it would affect them, too.
Quick background on why a second extension to the IVD regulation transition might be needed
- AgencyIQ has talked before about the bumps in the road to full implementation of the European in vitro diagnostics regulation (IVDR), but in short: The IVDR introduced significantly more robust testing and documentation requirements for IVDs, as well as a new risk classification scheme, the need for E.U. Reference Laboratories to test high-risk IVDs, and a performance evaluation consultation process with designated expert panels, also set up by the IVDR.
- The new risk classification system had a big impact on how many IVDs need Notified Body oversight. Under the IVD directive (IVDD; Directive 98/79/EC), only a few types of IVDs required Notified Body oversight, while the rest could be self-certified by the manufacturer. The directive used a list-based system – List A and List B outlined what E.U. regulators considered the highest-risk IVD devices, and these and devices for self-test by the patient required Notified Body oversight. The remainder were “general” IVDs self-certified by manufacturers. According to the Commission, under this system around 8% of all IVDs required Notified Body oversight. But the IVDR introduced a risk-based system, with class D being the highest risk (encompassing some List A and B tests along with others not previously on those lists). Class A represents both the lowest risk and the only risk class not requiring Notified Body oversight; under the new scheme, somewhere around 80% of all IVDs will require a Notified Body certificate.
- The IVDR originally gave stakeholders 5 years to comply with the regulation (May 26, 2022). But the pandemic and other causes, most notably a lack of designated Notified Bodies to review applications, prompted the Commission in late 2021 to propose an amendment to the IVDR to convert the compliance deadline to a “progressive rollout” of compliance dates, based on device risk class. Class A devices needed to be IVDR-ready on the original date (May 26, 2022), but class D had until May 2025, class C until May 2026, and class B and sterile class A until May 2027. In-house tests (in the U.S. called laboratory-developed tests manufactured and used in a single lab) had until May 26, 2024. This gave all stakeholders more time to put processes in place, which for manufacturers including gathering new clinical data and completing product technical documentation.
- Other issues with implementation included slow roll-out of the integrated registration and vigilance database, EUDAMED. The database integrates device and economic operator registration with vigilance reports and field safety actions, clinical investigation and performance studies application and approvals, and product certificates. When all modules are complete, the database will offer more transparency to the public and smoother, automated communication among Member States; additionally, firms will no longer have to register with and submit applications to individual Member States. But the database has suffered a number of development delays; to date, three modules are live and functioning on a voluntary basis, two are nearly ready, and the development team is struggling with the sixth, the clinical module. Recently, the Commission updated its full implementation timeline for the database to account for this. However, the regulations are written so that use of the database can’t be made mandatory until all modules are functioning and have passed an audit – a situation that is starting to cause consternation among some stakeholders. [Read AgencyIQ’s complete analysis of EUDAMED and its status here.]
- One of the benefits of EUDAMED ultimately will be Member State coordinated assessment of clinical investigation and performance study applications. Described in MDR Article 78 and IVDR Article 74, the coordinated procedure allows sponsors to submit a single application for a clinical investigation (medical device) or performance study (IVD), rather than an application to each Member State. The database will automatically transmit applications to all Member States where the studies are to be conducted, with the sponsor proposing which member state should coordinate review activities. The Member States then coordinate their review of the application under the direction of the coordinating Member State. The MDR and IVDR set out processes for application questions and refusals, as well as statutory timeframes for Member States to review and respond. MDR Article 78(14) sets out the original transition deadline in going from voluntary use of the coordinated assessment process to mandatory use as May 25, 2027; for IVDs, use of the coordinated procedure becomes mandatory in May 26, 2029 for all Member States, as set out in IVDR Article 74(14).
- But even after the progressive rollout, stakeholders continued to register concerns with implementation of the regulations. Once the E.U. regulator pushed the MDR extension over the finish line in March 2023, stakeholders began raising significant concerns with the rollout of the IVDR. For example, the European pharmaceutical trade association EFPIA expressed concern over the delays the IVDR had been causing in drug clinical application approvals. At that time, EFPIA proposed a voluntary use of the coordinated procedure among Member States and a delay of application of the IVDR. EMA regulators themselves published an article discussing the review process for companion diagnostics and the lack of opportunity to use a single submission for the drug clinical trial under the Clinical Trial Regulation and the performance study application according to the IVDR. In an open letter to STELLA KYRIAKIDES in late June of 2023, medical professionals urgently recommended special processes to get orphan devices and IVDs certified.
- A survey of IVD manufacturers by the Dutch regulator in mid-2023 found an alarming lack of preparation for the IVDR and a high number of high-risk devices manufacturers planned to discontinue due to the increased regulatory and costs burdens of the IVDR, as well as missing tools that the Commission hadn’t yet put in place (e.g., E.U. Reference Laboratories, guidance on clinical evidence for IVDs). In the late November 2023 EPSCO meeting, German regulators observed that, at that point, class D IVDs couldn’t make the technical documentation review timelines and be certified by the deadline, especially given the low number of IVDR certificates issued, a concern shared in a public Biomedical Alliance statement in mid-January 2024. That trade association offered several possible solutions, including extending IVDR transition timelines, immediate deployment of the completed portions of EUDAMED, new regulatory options for orphan IVDs, the use of conditional certificates, and required reporting by manufacturers when they intend to remove an IVD from the European market.
This week, the Commission released a proposal for an extension that would move out the deadline for certain IVDs, make EUDAMED usage mandatory prior to all modules being released, and introduce a new requirement for device and IVD manufacturers to report on device availability
- The proposal, in the explanatory memorandum section, acknowledges the heavy lift the IVDR represents for manufacturers and Notified Bodies, given the new risk classification system and substantially increased involvement of Notified Bodies in IVD conformity assessment – going from 8% of the 40,000 IVDs being surveilled under the IVDD to an estimated 80% under the IVDR. Given the 1,551 certificates issued under the IVDD for List A, List B and self-tests, there should ultimately be around 15,000 Notified Body-issued certificates under the IVDR. But the Commission’s new implementation dashboard shows 1,295 applications (as of August 2023) and 306 product certificates issued, with 683 agreements signed between manufacturers and Notified Bodies. This sets the stage for the four-part proposal the Commission published this week.
- The Commission is proposing to amend both the MDR and the IVDR in four major ways, though only the IVDR would have a change in its transitional period
- The first proposed change in the proposal is to add a requirement to both regulations to require device manufacturers to notify regulators, health institutions, and other affected economic operators, of any interruptions in the supply of critical devices and IVDs, (new Article 10a to both regulations). Similarly, affected economic operators should pass the information along the rest of the supply chain. These requirements are similar to what is already required for critical pharmaceutical products. The Commission is required to complete an assessment of the regulations themselves (MDR Article 121, IVDR Article 111) by May 27, 2027, but given the “multiple challenges related to the implementation of the two Regulations, the Commission will start [has in fact already started] preparatory works for a targeted evaluation already in 2024. The targeted evaluation will assess in particular whether the legislation has delivered results as intended, and whether it is (still) fit for purpose or underperforming in ensuring availability of devices for small patient populations (i.e., ‘orphan devices’) and fostering the development and availability of innovative devices in the EU.”
- Second, the new proposal modifies MDR Article 34 (1) and (2) by removing the requirement that EUDAMED usage becomes mandatory only once all modules are fully functional. This affects the timeline for coordinated assessment, necessitating a change to MDR Article 78(14), adding a voluntary opt-in phase for 5 years before mandatory usage. EUDAMED transition timeframes have been modified to “enable a smooth progressive transfer from multiple registrations in national databases to a single registration in Eudamed” (MDR Article 120(8), Article 122, Article 123(3)). The same two changes would be made to the IVDR, with respect to the timing of coordinated assessment of performance studies (IVDR Article 74(14)) and the EUDAMED transitional period (IVDR Article 110(8), Article 112, Article 113(3)).
- Third, the Commission is required to complete an assessment of the regulations themselves (MDR Article 121, IVDR Article 111) by May 27, 2027, but given the “multiple challenges related to the implementation of the two Regulations, the Commission will start [has in fact already started] preparatory works for a targeted evaluation already in 2024. The targeted evaluation will assess in particular whether the legislation has delivered results as intended, and whether it is (still) fit for purpose or underperforming in ensuring availability of devices for small patient populations (i.e., ‘orphan devices’) and fostering the development and availability of innovative devices in the EU.”
The fourth, and largest, change would be to the IVDR transitional period, lengthening it for IVDs meeting certain requirements
- This would be similar to what was done in early 2023 for medical devices under the MDR with Regulation (EU) 2023/607. That amendment allowed medical devices meeting certain conditions to extend the time for the transition to the MDR to 2027 or 2028, depending on the risk classification of the device. [Read AgencyIQ’s analysis of that regulation and its impact here and here.] The current IVDR proposal would affect IVDR Article 110(3) by replacing paragraph 3 with new paragraphs 3 to 3e.
It would apply only to certain IVDs under certain conditions. For IVDs with valid certificates on May 26, 2022 that have not been withdrawn by the Notified Body, the extension would apply directly (i.e., Notified Bodies do not need to update certificates). Where certificates expired after that date but before the proposal takes effect, the extension would apply if the manufacturer had a signed contract with a Notified Body to conduct conformity assessment at the time of expiry, or where a national competent authority had issued a derogation. For “legacy devices” (those with a certificate or a declaration of conformity under the IVDD before May 26, 2022), the draft regulation would extend timelines for those devices meeting the conditions as follows:
– For Class D IVDs and those with a valid IVDD certificate, the transition is extended to December 31, 2027
– Class C devices: December 31, 2028
– Class B and sterile class A devices: December 31, 2029
- Other conditions to use the extended time period: The devices must continue to comply with the IVDD, they can’t undergo any significant design or use changes, and they can’t present “an unacceptable risk to health or safety.” Additionally, the manufacturer has to have an IVDR-compliant quality management system (QMS) in place by May 26, 2025; notably, this does not require a certificate from a Notified Body or self-certification. Finally, the manufacturer (or its authorized representative) must lodge an application for IVDR conformity assessment for all legacy devices it plans to transition to the IVDR by May 26 of certain years (2025 for class D, 2026 for class C, 2027 for class B and sterile class A) and the manufacturer and Notified Body have to sign an agreement within four months (September 26 of the appropriate year based on risk class). Notably, “legacy device” means either a device planning to transition to the IVDR or one where the manufacturer plans to replace it with a new device and the manufacturer applies for conformity assessment of the new device by the above timeframes.
- Notified Bodies and appropriate surveillance: During the transitional period, Notified Bodies that issued the IVDD certificates remain responsible for surveillance of the device and manufacturer, unless the manufacturer and another Notified Body sign an agreement transferring that responsibility.
- The regulation will enter into force the day it’s published in the Official Journal of the European Union, though Article 1(1) and Article 2(1) on reporting of supply interruptions won’t apply until 6 months after that date.
The Commission published several documents to help with the proposed update to the regulations, including a press release, a fact sheet and a question-and-answer document
- Improving availability in vitro diagnostic medical devices: According to the Commission press release, the proposal gives more time for companies, under certain conditions, to comply with the IVDR, and will provide all stakeholders in the device sector more transparency by launching some elements of the registration and vigilance database, EUDAMED, early. Next will be adoption by the European Parliament and Council if they agree with the proposal. Regulators have already started plans to evaluate the effect of the regulations on device and IVD availability on the European market and the cost and administrative impact on small and medium-sized manufacturers (SMEs). “Going forward, we are determined to analyse the root causes that slow the transition and committed to take appropriate action,” said STELLA KYRIAKIDES, Commissioner for Health and Food Safety, in the press release.
- The Fact Sheet provides a timeline of implementation milestones for the regulations and an overview of non-legislative actions to assist in that effort. Highlights of the timeline include adoption of the regulations in 2017, the MDR one year delay in 2020 due to the pandemic, the two staggered transition periods introduced in 2022 (IVDR) and 2023 (MDR), and the current proposal in 2024. Non-legislative actions largely focus around the 19-point plan introduced in 2022 to increase Notified Body numbers and capacity, with special focus on support of SMEs, scientific advice for high-risk devices and new regulatory solutions for orphan devices. Other activities include, but aren’t limited to, the study to monitor device availability and the Joint Action on market surveillance.
- The new Q&A document summarizes the regulatory improvements put forward by the MDR and IVDR and why the new proposal is necessary. It shows the current IVDR transition deadlines by risk class and what it is proposing to replace them, as well as the conditions devices must meet to make use of the new deadlines. Explaining other actions the Commission is taking, the Commission mentioned increasing Notified Body capacity and helping manufacturers prepare for the regulations, as well as financial support to the MDCG. Other actions are developing a guidance to “significantly help the certification of existing orphan devices” and the evaluation of the impact of the regulations on device availability and on SMEs. Question/responses also address what EUDAMED is and why and how the Commission is proposing to alter its roll-out of the database.
- This proposed extension is similar to the MDR one, where if a certificate expired prior to the extension proposal going into effect, the extension would be subject to several conditions. The main difference between these extensions is that the IVDR extension needs to account for the fact that most IVDs didn’t have certificates under the IVDD but will under the IVDR (approximately 10-fold increase in that number), so the conditions to use the IVDR extension can’t rely solely on manufacturers having certificates that hadn’t been withdrawn. Nonetheless, the conditions for using the extension are highly similar – the device remains safe, it can’t undergo significant changes, and the manufacture needs to get its QMS upgraded within a specified timeframe. Where the MDR extension had just a single deadline for manufacturers to submit applications to a designated Notified Body (May 26, 2024) and a single deadline to have a signed contract with a Notified Body (September 26, 2024), the IVDR extension application and contract deadlines would be staggered by risk class, as described above.
- It proposes relief to manufacturers and other stakeholders but also brings a new requirement not originally in the regulations. For manufacturers and Notified Bodies, it would offer more time to bring quality systems and technical documentation into compliance with the new regulations, especially for the highest-risk IVDs, which were already pushing against the 2025 deadline with less than 18 months to go. For Member State regulators, it would offer more transparency by requiring EUDAMED use as soon as possible, so that they can see what manufacturers and devices are registered. This will provide more definitive data on what products are on the market. Another new requirement will bolster that transparency by requiring manufacturers to notify affected stakeholders of plans to remove critical products from the market; notably, this will require manufacturers to put new reporting systems and processes into place. EUDAMED becoming available sooner would also impact the timelines for the mandatory use of coordinated assessment of clinical applications, which should be a big time-saver for sponsors, since they would no longer need to juggle independent clinical investigation and performance study applications in every Member State where the studies will take place.
- Getting the results of the “targeted evaluation” of the regulations before the statutory deadline of 2027 should be welcomed by all. The proposal notes that the Commission is already working on a plan for this evaluation as to whether the regulations are fit for purpose or “underperforming,” especially with respect to orphan devices and impact on innovation.
- The new plan doesn’t directly address some of the recent concerns, specifically modifications to how in-house devices are regulated under IVDR and the ability for Notified Bodies to issue conditional certificates for IVDs that may not meet every IVDR requirements but don’t raise any safety or performance concerns. This latter provision was called for most recently by the Biomedical Alliance but will likely be dealt with by issuing guidance rather than law-making, as outlined in the recently-updated IVD joint implementation plan.
- What’s the plan to get manufacturers that have never had a Notified Body to transition to the IVDR – and do we need more Notified Bodies designated? Right now, the number of Notified Bodies that have applied for IVDR designation is about the same as those designated under the IVDD (on the order of 21). Are these numbers enough to address a projected ten-fold increase in the number of IVD certificates issued by Notified Bodies? And what about reaching the manufacturers that have never interacted with a Notified Body before? This proposal won’t address this potentially huge issue – huge in the sense that there should be about 10 times more certificate applications than the 1,500-odd that were certified under the IVDD. It’s hard to see how the same number of Notified Bodies as there were under the IVDD can cover the 10-fold increase in products, in addition to the much more stringent clinical, data and documentation requirements outlined in the IVDR.
- The proposal states it has no budgetary implications, but that may not be true for the device reportability requirement, which may require new infrastructure and process for manufacturers and a new requirement to audit by Notified Bodies and regulators.
- A first, and generally supportive, response from industry came from Medtech Europe, focusing on the new EUDAMED roll-out and the notification requirements for critical device discontinuations. The group focused on the impact of these two proposals will impact device and IVD manufacturers, pointing to a recent publication on the five conditions that need to be met before the Commission should make any EUDAMED modules mandatory to use: Each module needs to be user-tested and validated, and manufacturers need to have two years to implement processes to use the released modules.
- A reminder to stakeholders: This proposal impacts the MDR, too. Medical device manufacturers and other stakeholders would have new obligations when this proposal becomes law, including reporting on the removal of critical devices, adopting EUDAMED earlier than the current public timeline states.
- The proposal will be discussed at the Council of the EU Working Party on Pharmaceuticals and Medical Devices, taking place January 30, 2024.
- Exceptional circumstances: Due to the exceptional circumstances on the imminent risk of shortages of critical IVDs and potential to impact public health, the Commission is urging the amending regulation “enter into force as a matter of urgency,” and is invoking an exception to the eight-week period of review for national Parliaments as described in the Treaty on European Union (Recital 17 of the proposed regulation).
Key Documents and Dates
- Proposal for a REGULATION OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL amending Regulations (EU) 2017/745 and (EU) 2017/746 as regards a gradual roll-out of Eudamed, information obligation in case of interruption of supply and the transitional provisions for certain in vitro diagnostic medical devices, published January 23, 2024.
- News announcement: Commission proposes to extend transition periods for certain IVDs, gradual roll-out of Eudamed and an information obligation in case of interruption of supply, published January 23, 2024.
- Press release: Commission proposes measures to improve the availability of in vitro diagnostics, published January 23, 2024.
- Questions and Answers on in vitro diagnostics and the European database on Medical Devices (EUDAMED), published January 23, 2024.
- Factsheet: European Health Union: Helping the transition to the new rules on medical devices and in vitro diagnostics, published January 23, 2024.