With recent updates to ISO 10993-1 and the Medical Device Regulation (MDR) on track to replace Europe’s current Medical Device Directive (MDD) next year, European medical device requirements present greater regulatory hurdles. The impending updates aim to minimize regional regulatory differences and establish a set of uniform compliance standards that uphold quality of care and ensure patient safety. With less than a year until the MDR takes effect (May 26, 2020) and a shrinking number of notified bodies, time is of the essence. Planning and partnership will help companies stay ahead of the curve, but one misstep could result in an avalanche of consequences, so organizations must be sure to dot their I’s and cross their T’s.
MDR will apply to devices being introduced to the market for the first time as well as legacy products. The MDD has historically allowed “grandfathering” devices or approving submissions with supplemental data from biocompatibility tests alone, but this will no longer be the case. OEMs will be required to have updated clinical data and technical documentation that supports the device’s conformity with the new standards.
Although it will be a gradual transition and devices with a valid certificate will still be permitted on the market after May 2020, there will be strict deadlines regarding Quality System and Post Market Surveillance requirements when MDR takes effect.
Let’s dive deeper into how medtech organizations can prepare for and navigate these changes.
Currently, OEMs are looking at MDR through many different lenses, some from a regulatory standpoint, others from a financial impact perspective, or worse, they haven’t started planning. Of course, financial and business viewpoints are critical to consider when the survival of healthcare products is on the line, but if those are the only concerns or the internal teamwork model is siloed, companies may be missing the mark. Every stakeholder and department throughout the organization will feel the impact, which is why it is crucial to build a cross-functional team to tackle MDR.
To build such a team, companies should include internal people from quality, R&D, finance, product management, procurement, and other departments to gain a well-rounded understanding of how the new regulation affects their products. Together the cross-functional team can determine where gaps lie, how to prioritize products, and choose a testing laboratory or contract research organization (CRO) that meets the organization’s needs.
Once assembled, the team can begin gathering existing information on devices to perform a gap analysis. The gap analysis evaluates current product portfolios against new regulatory standards to identify holes that need to be rectified to ensure compliance. A bulletproof submission relies on robust data that is in alignment with current regulatory expectations.
Invest in Testing
MDR will place greater emphasis on the importance of performing complete biological evaluations on all medical devices. A complete biological evaluation must address three sequential stages of testing: a chemical characterization, which is followed by a toxicological risk assessment and biocompatibility tests.
Chemical characterization: Since updates to ISO 10993-1 place greater emphasis on chemical information, extractables and leachables (E/L) studies may be required. E/L studies are the most reliable way to identify the chemicals in the device and the concentration at which each exists. They challenge the device and its constituents by using aggressive solvents and extreme temperature manipulations. Regulators want to see proof a device has been challenged under harsh conditions and its chemistry report shows it is free of unknown chemicals. If unknown chemicals appear on a report, it is very likely a retest will be required, which will inevitably increase the costs, resources, and time required to commercialize a product.
Toxicological risk assessments: Risk assessments are performed to determine if the chemicals found in an E/L report pose a safety risk. This means toxicologists analyze chemistry information collected through chemical characterization to establish a margin of safety for each constituent. They then determine if additional biocompatibility tests are needed to further mitigate safety concerns.
Biocompatibility testing: The final step of a biological evaluation involves exposing living cells to the device to see if a negative reaction occurs. For this reason, the sequence of testing matters, and while beginning with biocompatibility may seem like a shortcut, it could create a number of setbacks down the road. Chemical characterization studies might meet some biocompatibility systemic endpoints (e.g., carcinogenicity), which may eliminate the need to conduct those particular tests altogether. Using chemistry data and risk assessment to drive a biocompatibility test plan can also help organizations avoid unnecessary animal testing and save expensive test article.
Collectively, these evaluations generate data on the physical and chemical makeup of the device to support and prove its safety.
New Subclass for Class I Reusable Devices
MDR will also introduce a new subclass for Class I reusable devices (Class Ir) such as surgical instruments and endoscopes. Extensions will not be granted for any devices that fall into this category. If a Class Ir device does not have an updated CE mark by the May 26, 2020, deadline, it will not be permitted in the market.
To obtain a new CE mark for a Class Ir device, medtech firms will be required to submit detailed technical files to their notified bodies that support safety and efficacy of the cleaning, disinfection, and sterilization processes outlined in the device’s Instructions for Use (IFU). Since there is no universal definition of “clean,” it is a company’s responsibility to define and validate “clean” for its device(s) in a way that complies with the new standards. To have the best chances of getting regulatory approval, organizations should work with their testing laboratory to develop studies and validation test plans that challenge the device in “worst-case scenarios.” The technical files for newer products may require less legwork, therefore it is recommended to focus on older devices first.
Testing Partner Selection Criteria
Before inking an agreement with a testing partner, companies should ask questions to determine if their collaborators have the capabilities necessary to keep them (device firms) ahead of the curve. Be sure to pose the following questions:
Q: Do you have the capabilities to conduct chemical characterization, toxicological risk assessments, and biocompatibility testing in-house?
Partnering with an organization that has all three capabilities in-house increases efficiency, allows required endpoints to be addressed, and helps prevent information gaps. Companies may have to piecemeal their testing if they don’t have all three capabilities, which can result in longer timelines, increased cost, miscommunication between parties, loss of information, and unknown impurities getting missed in chemical reports.
Q: How do you ensure complete identification of compounds in your E/L studies?
Working with a laboratory that reports unknowns will be problematic for a risk assessment and, ultimately, a submission. Reporting unknowns can indicate it doesn’t have the expertise, instrumentation, and/or the commitment to perform complete chemical characterization. This may cause regulators to reject a submission or issue requests for additional information (AIs). On average, repeat testing costs more than $75,000 and 27 weeks of time.
Q: Are your analytical methods sensitive enough to detect constituents at a level low enough to be properly evaluated in a risk assessment?
Analytical method sensitivities illustrate the precision and accuracy of a testing laboratory’s equipment and its team’s expertise and experience. Additionally, the concept of the Analytical Evaluation Threshold (AET) introduced in the upcoming ISO 10993-18 will require analytical labs to determine the sensitivity required of the test methods and require them to achieve those levels in the study.
Q: Do you provide support after submission?
If a partner doesn’t provide follow-up support on their testing, companies will be responsible for answering regulators’ questions or fulfilling additional requests.
Q: How do you stay apprised of regulatory changes and know your advice is in line with how regulators are thinking?
It’s important to stay on top of regulatory changes, but it’s also critical to understand how regulations are being interpreted by regulators. Choose a partner that spends time watching and interacting with regulators to understand their expectations on how testing is conducted. CROs or testing laboratories with international delegation on ISO committees and that collaborate with ISO by writing standards, participating in round robins, or offering other technical expertise may demonstrate a commitment to getting to know what regulators want on a deeper level. Ask if they have international delegates on ISO committees, as this is an indication they may not only know the standards, but also the “why” behind the standards. Organizations may also want to ask if they keep a database of regulatory feedback and questions to track how interpretations change and influence expectations.
In addition to selecting an experienced CRO or testing laboratory, medtech firms should communicate with their chosen notified bodies as soon as possible. MDR is requiring that all notified bodies go through a designation process in order to be qualified to perform assessments, so there will be a smaller number available to evaluate products. For Class Ir devices, organizations may need to consult a specific notified body approved for that type of device because specialization of notified bodies is expected, and this could further limit options.
The regulatory changes may feel daunting, but the process can be made less cumbersome with the right partner. The survival of a product line relies on the ability to be proactive now. Conducting due diligence and asking critical questions will save time and money in the long run.