In March 2023, the European Parliament handed medical device manufacturers some breathing room when it amended the Medical Device Regulation (MDR) to allow for a longer compliance period for certain medical devices and in vitro diagnostic devices. The move was welcomed by device manufacturers, who were given additional time to prepare products for market and to properly consider some of the recent changes in European regulation.
The news may prompt manufacturers to slow down or pause submissions, with some of the time pressure alleviated. But this could put programs in jeopardy and worsen the same backlog the new timeline seeks to fix.
What is the New Timeline?
The amended process will stagger the submission deadlines for devices, prioritizing those with greater potential patient risk. Conformity assessments for devices with the highest risk (class IIb and III) would be due in 2027 under the new timeline, and lower-risk devices in 2028.
Manufacturers must meet certain conditions to benefit from the extension. These include ensuring devices comply with MDR’s predecessors, the Medical Device Directive (MDD) and the Active Implantable Medical Device Directive. They must not have any significant changes in design or purpose and cannot pose an unacceptable risk to patient health and safety.
Device manufacturers also need to meet 2024 milestones. They must formally apply for an extension by May 26, 2024, and must have a written agreement in place with one of Europe’s notified bodies (NBs) by September 26, 2024.
Potential Relief for NBs
Device manufacturers are not the only ones breathing a sigh of relief following the new timeline. European health ministers have described a regulatory “perfect storm” on the horizon since MDR was introduced in May 2021. Prior to MDR, there were 125 certified NBs in Europe. After it took effect, that number fell to around 20. As of September 2023, the figure had risen to 40, but that is still too few to handle the submissions from medical device manufacturers.
By October 2023, NBs had received 17,846 applications and certified 5,599 of those. Submissions will continue to pour in right up until the May 26, 2024, deadline, and an early survey of NBs estimated that only 7,000 devices could be certified by then. That number will likely be exceeded, but still, existing NBs are overwhelmed, and at the current pace will be unable to clear the backlog.
Like manufacturers, NBs are unable to relax despite the new timeline. They must continue appropriate surveillance per MDD guidelines and assess and audit applications for extension by the May 2024 deadline.
Choosing an NB and understanding ‘state-of-the-art’
When MDR was first conceived in 2021, it required any medical device on the European market to be designated “state-of-the-art.” The phrase is mentioned 12 times in the original MDR guidance but is never properly defined. The E.U.’s Medical Device Coordination Group (MDCG) definition of state-of-the-art devices refers to best practices but does not make it clear whether it refers to the devices themselves, the techniques or analytical methods used, or the clinical trials for regulatory approval.
The uncertainty surrounding this language has and will continue to create challenges for device manufacturers and NBs. All parties could find themselves in limbo as they collectively navigate MDR, gain clarity on amendments, and grapple with new expectations.
The deadline extension also gives manufacturers a chance to choose a NB if they don’t have one. These trusted partners can help manufacturers complete applications, submit new applications, fill any gaps in testing data and organize their device’s submission. It also gives manufacturers more time to consult with their NB and come to a consensus on elements of MDR such as defining “state-of-the-art” for their product(s).
The Effect of ISO 10993-17:2023
Evaluating potential risks will certainly play a crucial part in considering if a medical device is state-of-the-art or not. MDR Article 10 specifically addressed risk management systems and outlines a long-term process but doesn’t provide significant detail.
While ISO 10993-18:2020 provided guidance for manufacturers to investigate the materials in their devices, ISO 10993-17:2023 specifies the process and requirements for the toxicological risk assessment (TRA) of medical device constituents. The methods and criteria used to assess whether exposure to a constituent is without appreciable harm are also specified. Some of the concepts introduced or further developed in the updated 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) or or μg/cm2.
- 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 non-targeted or targeted analytical approaches, as described in ISO 10993-18.
- Total quantity (TQ): Expressed as micrograms (µg), total quantity, in μg, present in or on, or extracted from the medical device (e.g. from an exaggerated or exhaustive extraction study)
- Toxicological screening limit (TSL): The cumulative exposure dose to an identified constituent over a specified period that will be without appreciable harm to health. However, the TSL is not applicable to neonates, metals, VOCs, and unknown or incompletely identified constituents.
- Release kinetics: Refers to the quantity of a constituent that is released from a medical device as a function of time. Experimental release kinetics are usually generated in a leachables or simulated-use chemical characterization study with multiple time points. ISO 10993-17:2023 also provides guidance around calculating assumed release based on the TQ of a constituent.
Final Thoughts
The extension to the MDR deadline is a welcome relief to both regulators and manufacturers, but there is still much work to be done on both sides. The ISO 10993-17 updates provide additional detail and direction to the toxicological risk assessment process, but it may take time to understand the extent of recognition for some of the new concepts. Meanwhile, the state-of-the-art concept raised in MDR will also require extra time and testing. The number of NBs may be increasing, but slowly, meaning there are still limited resources and long queues. The new timeline gives breathing space, but manufacturers will still need to work at full speed to avoid long delays. For manufacturers who, justifiably, find the entire process confusing, finding a trusted lab partner can ease the burden of navigating the new regulatory horizon.
