On March 15, 2023, the European Parliament amended the original Medical Device Regulation (MDR) to lengthen the compliance period for certain medical devices and in vitro diagnostic devices. The move provides device manufacturers with additional time to prepare their products for market and offers a buffer for those trying to navigate the EU’s “state-of-the-art” designation.
The amended timeline proposes staggering submission deadlines to prioritize submissions based on patient risk. Conformity assessments for devices with the highest risk (i.e., class IIb and class III) would be due in 2027, with low-risk devices (i.e., classes IIa and I) due in 2028.
The extension provides a much-needed regulatory respite and will allow new European notified bodies (NBs) more time to gain certification, train new/additional reviewers, and begin chipping away at the growing backlog of device submissions.
Ostensibly, the deadline extension gives everyone a bit of breathing room and ensures that the most needed products are available to the sickest patients first. However, device manufacturers may also see these new deadlines as an opportunity to take their collective feet off the gas. But slowing down or pausing a device’s testing program could still jeopardize a successful transition and exacerbate the problem the deadline extension was designed to fix.
To benefit from the extension, certain conditions must be met. For example, manufacturers must ensure their devices continue to comply with MDR’s predecessors, the Medical Device Directive (MDD) and the Active Implantable Medical Device Directive (AIMDD). Those devices must not contain significant changes in design or intended purpose and they must not pose unacceptable risk to patient health and safety.
Moreover, devices eligible for the deadline extension still have important 2024 milestones to meet. Specifically, the amendment requires manufacturers to formally apply for the extension with a notified body and implement a quality management system (QMS) no later than May 26, 2024. It also states that a device manufacturer—or an authorized representative—must have a written agreement with the NB in place by September 26, 2024.
The Current State of NBs
European health ministers have seen a regulatory “perfect storm” on the horizon since MDR took effect in May 2021 and, the following year, initiated an urgent meeting to explore the issue. The number of certified NBs in Europe decreased from 125 before MDR to around 20 after its implementation. That number has increased to 38 (as of April 2023) but is still only a fraction of what is needed to help manufacturers take this crucial regulatory step.
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Complicating matters, the number of device applications these bodies have received is overwhelming. By October 2022, NBs had received 8,120 applications and certified 1,990 under MDR—and they will continue to receive new applications right up to the May 26, 2024 deadline. A survey of NBs estimated that, at the current pace, as many as 7,000 devices could be certified by the original MDR compliance deadline, which clearly would not have eliminated the backlog.
According to the amendment: “Despite the steady increase in the number of notified bodies designated in accordance with [MDR], the overall capacity of notified bodies is still not sufficient to ensure the conformity assessment of the large number of devices covered by certificates … before May 26, 2024. It appears that a large number of manufacturers, especially small and medium-sized enterprises, are not sufficiently prepared to demonstrate compliance with the requirements of [MDR], in particular when the complexity of those new requirements is taken into account.”
Just as manufacturers should avoid taking their collective feet off the gas, NBs cannot afford to pause. They are still obligated to continue appropriate surveillance per MDD guidelines. They must also assess and audit manufacturers’ QMS and process applications for extension by the May 2024 deadline. And, of course, NBs must be prepared to issue agreement contracts by September 2024 and assess technical documentation for each device to meet the 2027/2028 deadlines.
Clearly, extending MDR’s compliance deadline was a necessary step. But there is cause for optimism.
Team-NB is a European trade group aimed at pursuing transparency for NBs and providing guidance around MDR implementation. In an April 2023 statement, Team-NB estimated that the 38 designated NBs currently operating in Europe could issue 3,200 MDR certificates annually. The group also noted that the number of NBs may increase and the efficiency with which certificates can be issued may also improve—both factors that would speed up MDR certification. Team-NB concluded by saying the latest MDR deadline extension (Amendment EU 2023/607) makes certifying all remaining devices achievable as long as manufacturers do not delay their applications.
State-of-the-art & MDR
From its inception in 2021, MDR sought to remove ambiguity in medical device manufacturing, alleviate subjective regulatory approvals and prioritize patient safety. To achieve these goals, the regulation required any medical device in the European market to be designated “state-of-the-art.” But despite including the phrase “state-of-the-art” 12 times in the original MDR guidance, the concept is not defined anywhere. Not only is the phrase undefined in the regulation but it’s included in a list of terms that are explicitly not defined.
Instead, the EU’s Medical Device Coordination Group (MDCG) defines state-of-the-art devices as those in a “developed stage of current technical capability and/or accepted clinical practice in regard to products, processes, and patient management, based on the relevant consolidated findings of science, technology, and experience.” Simply put, “state-of-the-art” refers to whatever the industry accepts as good practices.
It is not clear from the MDCG’s definition whether state-of-the-art means the devices themselves, the techniques or analytical methods used, or the clinical trials used to gain regulatory approval. That uncertainty creates challenges for device manufacturers and notified bodies, especially when considering a transformative shift in risk assessment for medical devices (i.e., the updated version of 10993-17) is anticipated soon.
Meanwhile, manufacturers are caught in limbo as their designated NB navigates the 174-page MDR document (including its 17 annexes), gains clarity on any amendments and carefully applies EU regulatory law. And it is important to note that the MDR deadline extension does not reorder the queue; it just lengthens it. High-risk devices will still compete with all the others—low-risk submissions already in line will retain their place. However, it does allow NBs to focus on higher-risk devices without interruptions.
The MDR deadline extension is not necessarily a gift. However, it is a chance for manufacturers to choose a notified body if they do not have one, complete applications, submit new applications, fill any data or testing gaps, organize their device submission and get in line.
The Impact of ISO/FDIS 10993-17
A crucial part of considering a medical device state-of-the-art is the thorough evaluation of its potential risks. Manufacturers must conduct a comprehensive risk assessment of their devices, considering its intended use as well as potential misuse. MDR Article 10 requires manufacturers to establish, document and maintain a risk management system but does little to define what that looks like. It outlines an iterative, long-term process that includes:
- Any risks associated with the device must be reduced as far as possible.
- Manufacturers must implement a risk management system and apply it to each device.
- Risk controls measures must be state-of-the-art.
- Risks related to human factors must also be addressed.
- Risk mitigation measures must remain effective throughout the life of the device.
- Risk mitigation measures must not be affected by transporting or storing the device.
- All foreseeable residual risks must be outweighed by the benefits which result from using the device.
Article 10’s list of requirements provides useful information, but it does not address state-of-the-art risk management other than to say it is a necessary inclusion. NBs will often request physical and chemical information as outlined in ISO 10993-1:2018 to meet these goals. Chemical characterization data gathered according to ISO 10993-18:2020 is often instrumental in these analyses.
The days of relying upon literature reviews to demonstrate risk management are indeed over. ISO/FDIS 10993-17 promises to change that by introducing a “systematic approach” that identifies hazards and estimates risk in unprecedented ways.
While ISO 10993-18:2020 provided guidance for manufacturers to investigate the materials in their devices rigorously, ISO/FDIS 10993-17 clarifies when a TRA is needed, how to calculate worst-case estimated exposure, and when potential harm to health should be addressed by other means. Some of the concepts introduced or further developed in the revised standard include:
- Tolerable intake (TI): Expressed as micrograms per kilogram of body weight per day (µg/kg/day), TI is an estimate of the daily exposure of an identified constituent over a specified period—based on body weight—that is considered to be without appreciable harm to health.
- Tolerable contact level (TCL): Represented in micrograms per centimeter squared of tissue at the contact site (µg/cm2), TCL estimates the surface-contact exposure to an identified constituent that is without appreciable irritation.
- Worst-case estimated exposure dose (EEDmax): Represents an exposure dose that is the maximum value for a specific intended clinical-use scenario. EEDmax is expressed in micrograms per kilogram body weight per day (µg/kg/day).
- Margin of safety (MOS): A unitless ratio of the TI to the EEDmax.
- Identified constituent: An identified constituent is one for which molecular structure information is complete. The identity of a constituent can be obtained via targeted or nontargeted analytical approaches, as described in ISO 10993-18.
- Total quantity (TQ): Expressed as micrograms (µg), TQ is the amount of a constituent present in or that can be extracted from a medical device.
- Toxicological screening limit (TSL): The cumulative exposure dose to an identified constituent over a specified period that will be without appreciable harm to health.
- Release kinetics: Refers to the quantity of a constituent released from a medical device over time. Experimental release kinetics are usually generated in a leachables or simulated use chemical characterization study with multiple time points. ISO/FDIS 10993-17 also provides guidance around calculating assumed release kinetics based on the TQ of a constituent.
Final Words on MDR Deadlines, State-of-the-art & NBs
The MDR deadline extension was a welcome announcement to regulators and manufacturers alike. The sheer number of applications for MDR certification combined with a new and redefined group of designated NBs across Europe made the original deadlines untenable. But now is not the time to procrastinate.
Device manufacturers still must demonstrate an MDR compliant QMS and submit their MDR applications by May 2024. The proposed changes in ISO/FDIS 10993-17 promise a more rigorous toxicological risk assessment process, but that will take time to implement and become familiar. The dynamic state-of-the-art concept in the MDR aims to keep cutting-edge science at the forefront of regulatory decisions, but it can also require extra time and testing. Something that is state-of-the-art today, may not be in 12 months or even sooner. And let’s not forget, the number of designated NBs in Europe is increasing, but slowly. Their queues are already long, and some specialize only in certain device classes.
The bottom line is time. Device manufacturers in Europe have been given a bit more of it to ensure the safest products are available. Let’s hope they use that time wisely. Manufacturers who find MDR confusing or lack experience navigating European regulatory expectations would do well to find a lab testing partner they can trust with their product success.