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Lisa Michels, General Counsel and regulatory affairs expert at Regulatory Compliance Associates^® Inc., discusses regulatory strategies for software as a medical device (SaMD), artificial intelligence and other emerging technologies. She presents insights on working with regulatory bodies on novel devices such as artificial intelligence, machine learning and algorithms.

Artificial Intelligence

When powerful new technologies emerge, unbridled excitement often reigns. The possibilities are endless and markets are undoubtedly huge. Artificial intelligence and machine learning in medicine are at an early stage and the potential to improve medical care is solidifying. Many opportunities are being pursued including enhancing and supporting the decision-making process of physicians, individualizing patient care with precision medicine and using near real-time information to improve care.

AI in Healthcare

Early ideas such as wearables that monitor activity levels or heart rate have been on the market for some time and have mixed results as tools for patient health management. Technology platforms such as Watson from IBM have shown amazing capabilities. AI- related applications have progressed to a point where formal medical device development is occurring, but challenges remain.

Innovators are often fearless and can be blind to the real risks and business difficulties to commercialize emerging technology. On the other hand, the mainstream medical device community can perceive that innovation exposes threat of the long-timelines, high-costs and painful failures. The reality is probably in between both extremes and risk can be mitigated with a deliberate approach to regulatory strategy.

Regulatory Challenges

Regulatory requirements require transparency and regulators need to understand how and why a result came about. Many AI applications are a black box with little transparency and daunting complexities. AI applications can produce valid conclusions that are counter intuitive to those which individuals or even teams of experts derive. Traditionally to gain marketing clearance for a medical device, substantial equivalence to a predicate device needs to be demonstrated.

Artificial Intelligence in Healthcare

Regulators review and clear a device as a system that will not change without considerable deliberation; in fact, manufacturers go to great lengths to ensure that a device manufactured years after initial clearances demonstrates the same performance as the original device. However, one of the more powerful aspects of some AI applications is that the accuracy of output information can continually improve with continued use. This will produce a perpetually dynamic system by design. There are solutions to this dynamic situation.

Making applications as seamless as possible is where the challenges and opportunities are. Independent demonstration of the safety and effectiveness of the dynamic system through the Pre-Market Approval (PMA) process could be necessitated, albeit this regulatory path is much more costly, complex and difficult.

SaMD FDA

The FDA and industry has since finalized a new medical device user fee agreement that lays out the application process and expectations regarding medical devices being submitted for regulatory approval. The agreement calls for:

• A new digital health unit overseeing Software as a Medical Device (SaMD) and software inside of medical devices (SiMD)
• Opportunities to support 510(k), premarket approval and clearance pathways tailored to SaMD, SiMD, and take into account real world evidence
• Participation in international harmonization efforts for digital health initiatives

Regulatory

1. Strategy begins with build your case, if regulators cannot or do not yet understand a technology, they will struggle to establish ways to assess the safety and effectiveness of your product.

• Find clinical and regulatory information throughout the world that is supportive of what you are trying to achieve. If negative information is uncovered, do not ignore it; instead, address it.
• Do not plan on submitting a “black box.” Spend the time to develop ways to communicate how and why a particular result comes about.
• Seek related credible sources, publications, guidance documents and experts, reference them, and utilize them.

2. Plan on early and frequent meetings with regulatory authorities. Gaining regulatory clearances for emerging technologies benefits from building solid working relationships with regulatory bodies. These relationships are built over a series of meetings that begin early in the development process, aiding both parties as they learn together.

Regulatory Communication

These early collaboration meetings provide a venue for industry to explore new ideas through regulatory communication. Based on working with many novel products, we recommend the following considerations, particularly in working with the FDA.

• Start with a solid pre-submission package. Make certain to follow established guidelines for pre-submissions, setting the tone that your organization has done its homework. Additionally, a complete pre-submission package enables regulators to prepare for the meeting and identify the appropriate experts needed.
• Be ready for questions surrounding mechanism of action. In traditional medical devices, a key component of the submission surrounds the mechanism of action, or how the device is perceived to work. Be prepared to explain what your novel technology does and how it does it.
• Prepare for the meeting. Before the meeting or teleconference, identify your question areas and structure your questions to get the specific information needed without using open-ended formats. Avoid introducing new information that the FDA is not prepared to discuss.
• Set an open tone during the meeting. Be transparent about the information you have and the areas that are lacking. In early development cycles, gaps exist and it is important to be candid so you get accurate early feedback. Set aside any fears that your organization is setting precedent by not having complete information and instead, work to close those gaps as you progress through the product development process.
• Set specific but realistic expectations for meetings. Your device is novel and that means regulators have not seen anything like it before. Expect regulators will have questions that will be challenging to answer. Remember, agencies can only provide feedback on what you have presented–what your device is currently– and not what you hope it will be in the future.
• At all times, be professional and seek to understand their questions. Early collaboration around emerging technologies is a two-way street. When you provide information the FDA needs, they will provide direction to guide your product development. And remember, the agency is a resource. Be open to the answers you receive, so your processes can evolve and improve.

Regulatory Assets

There are cultural differences that exist between the Silicon Valley visionaries that are pushing novel technologies forward versus the deliberately cautious, stepwise approach taken by traditional medical device development teams. In advance of nearly any new, disruptive technology being adopted by broader medical establishments and nearly always in advance of solid profitability.

These teams of brilliant visionaries must still possess the regulatory assets needed to receive FDA approval. Data science has been embraced by many regulatory agencies and included in traditional medical device development organizations.

Application Developer

• Build effective multidisciplinary teams by addressing cultural divides. When building regulated medical products based on AI, organizations will benefit from vertical structures. Software engineers must connect with key leaders from the company early in the development cycle.
• Building SaMD medical device products requires deep subject matter expertise. Combining subject matter with technical expertise and embracing the multidisciplinary approach drives innovation, making it possible to accurately model the vision, answer the key questions and realistically hold leaders accountable for results. Team evolution needs to be intentional and designed.
• If you are unable to set the joint domain early, one side dominates, and it becomes a challenge to bring in world-class experts from the other side. Top people recognize such unbalance and the byproduct that they will not achieve the parity in authority and respect.

Regulatory Compliance Software

Creating solid regulatory affairs teams with prior experience in addressing uncertainty surrounding quality systems and regulatory approval, specifically:

• Members who understand quality management system compliance for ISO 13485 & 21 CFR 820.  
• Members with a focused subject matter expertise in the AI/machine learning space and the mindset/ability required to work in a highly complex multidisciplinary environment.
• Regulatory expertise introducing and gaining FDA clearance or approval for new technologies and with the intention and ability to communicate with the developers.
• Direct expertise developing software for medical devices and developing and managing quality systems for software development.
• Where clinical trial work is required, the CRO and strategic regulatory experts need to work closely together to generate the type of clinical data that supports the safety and effectiveness of the underlying product. Also the regulatory team needs to develop and conduct the studies in ways that bring transparency and simplify the “black box” aspects of the product.

Executive Summary

• Embrace and enforce the multidisciplinary approach.
• Break down the problem and bring subject matter experts to the table to solve each.
• Beware of thinking you can do all. Inventors and software developers are uniquely brilliant but not necessarily the best at navigating regulatory challenges.
• Don’t assume the person with the most RA experience should lead the FDA strategy. The RA and especially QA mindset can limit creativity and curiosity that propels novel technologies forward. QA is a support mechanism to the RA strategy.
• Leverage working with RA SMEs experienced in emerging technologies and with prior nontraditional submissions.

To begin the Regulatory Compliance Associates scoping process today, please enter your information in the blue form below and click the submit button at the bottom of the webpage. You may also email us at [email protected].

The MDR Delay’s Impact on Regulatory and Testing—An Orthopedic Innovators Q&A

While the recent MDR delay gives companies some breathing room, it should not stall their effort in ensuring their products remain compliant for the EU.

By Sean Fenske, Editor-in-Chief at Orthopedic Design & Technology

Companies were beginning to get nervous in terms of keeping their products on the market in the EU. With the impending deadline for transition of MDD to MDR for legacy products already in hospitals and doctor’s offices, there would have been a significant shortage of medical devices available, potentially impacting quality of care. As a result, the EU Parliament voted to extend the deadline.
 
To find out the details of the new deadlines for transition and its impact on testing for medical device manufacturers, Jordan Elder, director of regulatory affairs at Regulatory Compliance Associates, and Thor Rollins B.S. RM(NRCM), VP, global market segment leader—Medical Device at Nelson Labs LLC, took time to address a number of questions around this important issue. They provided a comprehensive overview of what considerations medtech firms should keep in mind when looking at the new deadlines and their products they’d like to keep on the EU market.

Sean Fenske: The EU MDR went into effect in May 2021 so can you please explain what was postponed with regard to the latest action involving the MDR?
 
Thor Rollins: One of the latest actions involving the EU MDR that was postponed was the application of the Unique Device Identification (UDI) system for certain low-risk medical devices. The EU has delayed the UDI system’s full implementation for low-risk devices until 2027. Also due to the limited capacity of Notified Bodies, the general need for registration was also pushed back.
 
Jordan Elder: To expand on that second portion, this update does not change any of the current safety and performance requirements under the MDR, nor does it change any of the newly introduced regulations. This extension only amends the transitional provisions to give more time for manufacturers to transition from the previously applicable rules to the new requirements of the Regulation.

This extended transition period applies only to “legacy devices” or those covered by a certificate or declaration of conformity issued under the MDD before May 26, 2021. For medical devices covered by a certificate or a declaration of conformity issued before May 26, 2021, the transition period to the new rules is extended from May 26, 2024 to December 31, 2027 for higher risk devices (Class IIb and Class III), December 31, 2028 for medium and lower risk devices (Class I and Class IIa), and May 26, 2026 for Class III implantable custom-made devices.
 
However, the extension of validity for these devices only applies if one of the following conditions is met:
 

1. The manufacturer has signed a contract with a Notified Body for the conformity assessment of the device in question at the moment of expiry.
2. A national competent authority has granted a derogation in accordance with Article 59 of the MDR.
3. A national competent authority has required the manufacturer to carry out the conformity assessment procedure within a specific time period in accordance with Article 97 of the MDR.

 
The “sell-off” date—the end date after which devices that have already been placed on the market and remain available for purchase—has been withdrawn. Under the original requirements, any previously approved devices that had yet to be recertified but were still available for purchase would have been required to be completely removed from the market by May 26, 2025.

Fenske: What’s the situation in the EU that brought about the reason for this delay?
 
Rollins: There were many factors that went into the reason for the delay, two of the biggest reasons was the COVID-19 pandemic, which has put significant strain on medical device manufacturers, notified bodies, and regulatory authorities, and also the number of notified bodies and their resources. These two factors made it evident that keeping the original date would risk having approved medical devices for the market.
 
Elder: Regarding the number of notified bodies, currently, 36 have been designated under Regulation (EU) 2017/745. As of October 2022, an additional 26 notified body applications were being processed, with three of them at an advanced stage in the application process. At the time, notified bodies reported they had received a total of 8,120 applications from manufacturers for MDR certification.

It was also reported only 1,990 MDR certificates had been issued to manufacturers. According to an estimation presented by the notified bodies, the number of MDR certificates issued to manufacturers by the original deadline (May 2024) would likely only reach around 7,000 with the current issuance rate. In 2022, due to the reduced number of notified bodies and a significantly slower rate of MDR certificate issuance than initially expected, many regulators and government officials began to voice concerns that the current compliance deadline would create a shortage of legally marketed medical devices, putting patient safety at risk.
 
The MDR certificate bottleneck was further exacerbated by COVID-19, as Thor mentioned, and its impact on the global supply chain and clinical investigations. In order to prevent a medical device shortage and reduce the strain on the notified bodies and manufacturers, the European Parliament agreed to adopt the transition delay.

Fenske: What changes come with the MDR with regard to testing?
 
Rollins: The MDR introduces new requirements for testing medical devices, including new rules on clinical data requirements, post-market surveillance, and clinical investigations. The MDR also requires testing to the most current ISO standard; this includes tests like extractable and leachable testing and toxicological risk assessments. These tests were not required when most of these devices were originally approved and, therefore, have gaps when looking to renew their approval under MDR.
 
Elder: Exactly. The MDR requires manufacturers to submit significantly more documentation covering the total product lifecycle than previously under the MDD. A critical change with MDR is the clinical evidence necessary to demonstrate the safety and efficacy of the device. The rules on equivalence have been revised, making it more difficult for manufacturers to use this route in their clinical evaluation.

Under the new regulation, device product classification is expanded with new and revised terms and classification rules. Manufacturers must be aware of how their product is now regulated to fully understand the level of clinical information required for their device and whether clinical testing is required.
 
In addition to the updated clinical requirements, biological evaluations are under more scrutiny by the notified bodies under the MDR. Manufacturers should be careful to ensure all stages of preclinical safety testing, including chemical characterization and evaluation, biocompatibility, and a toxicological risk evaluation, have been completed, as Thor mentioned.
 
In order to facilitate some of the new testing requirements, the MDR officially recognizes harmonized standards as a method for manufacturers to demonstrate conformity to the General Safety and Performance Requirements (GSPR). Demonstrating compliance with applicable harmonized standards allows manufacturers and notified bodies to streamline the conformity assessment process.

Fenske: Might this delay cause some companies to reassess their regulatory strategy in either keeping a medical device on the EU market or getting a new device to replace it certified?
 
Rollins: Yes, it certainly could. Ultimately, the delay provides more time for companies to prepare for compliance, but it also means they may have to continue selling their devices under the older Medical Device Directive (MDD) until the new regulations are fully implemented.
 
Elder: In addition, companies that have struggled to make the transition might want to reassess their strategy if they had considered discontinuing their MDR certification due to the rapidly approaching deadline. However, since the expectation is companies have already demonstrated their intent with their notified body to transition to MDR, most companies would not need to reassess their regulatory strategy beyond accounting for updated timelines.

Fenske: Given the delay for the recertification of MDD devices under the MDR, what timeline should device manufacturers be working under to keep a product on the market?
 
Rollins: Device manufacturers should work under the timeline of the EU MDR’s transitional provisions, which was extended as Jordan explained earlier. High-risk devices are subject to the shorter transition period ending in 2027, while low- and medium-risk devices have until the end of 2028 to complete a conformity assessment.
 
Elder: The MDR delay and subsequent MDD certificate validity extension require that manufacturers have already taken steps with their notified body to transition to MDR. Although the delay provides manufacturers more time to transition to MDR, manufacturers transitioning from MDD to MDR should work with their notified body to ensure an appropriate submission/review timeline and a smooth transition.
 
Manufacturers should avoid delaying their MDR transition more than necessary to ensure the notified body has sufficient time to review and issue the MDR certificates. Currently, notified bodies are scheduling technical file reviews more than 24 months out. Under today’s notified body timelines and bandwidth, a company that chooses to delay its transition for 20 months would be pushing its MDR certificate issuance into 2027, assuming there are no major issues (technical file deficiencies) or unforeseen delays from the notified body.

Fenske: From the testing standpoint, what changes with the MDR are creating the greatest challenges and why? What should device makers be doing in preparation?
 
Elder: The greatest challenge manufacturers face from a testing standpoint is the increased clinical evidence data requirements. Manufacturers should review the updated classification rules to determine whether their product’s device classification has changed under the MDR. A clinical evaluation plan (CEP) must be established. Manufacturers should review the new requirements for claiming equivalence to understand if their device may continue to utilize this pathway as a part of the clinical evaluation (where applicable). Manufacturers must demonstrate their device is “state of the art” as part of their clinical testing/evidence. Manufacturers should be aware that the need to include post-market clinical follow-up (PMCF) data as a part of the technical documentation conformity assessment will depend on the device’s risk classification and available clinical data.
 
Rollins: In addition to the clinical data and evidence challenges, I’d also point to the new rules on post-market surveillance and vigilance, and the stricter requirements for clinical investigations. Device makers should prepare by conducting comprehensive risk assessments and by conducting more extensive clinical studies and collecting more data on their devices’ safety and performance.
 
Elder: One last item to remember is a periodic safety update report (PSUR) is required for Class IIa, IIb, and III devices.
 
Rollins: Keep in mind, the changes are putting more emphasis on the chemical characterization requirements for high-risk devices and, because the industry is limited in capacity of these tests, manufacturers should not wait to start evaluating the biocompatibility requirements under MDR.
 
Elder: Manufacturers should not assume their clinical evaluation under the MDD will provide sufficient clinical evidence under the MDR. Manufacturers should review their existing clinical data and conduct a gap assessment to determine whether the device “conforms with relevant general safety and performance requirements under the normal conditions of the intended use of the device, and the evaluation of the undesirable side-effects and of the acceptability of the benefit-risk-ratio is based on clinical data providing sufficient clinical evidence,” as is stated in Article 61 of the MDR.

Fenske: Do you have any additional comments you’d like to share based on any of the topics we discussed or something you’d like to tell orthopedic device manufacturers?
 
Elder: Don’t delay your MDR transition due to the deadline extension. Notified bodies are already at capacity and are scheduling more than 24 months out for MDR Technical File reviews. Use this extra time to ensure your company can seamlessly transition from the MDD to MDR.
 
Rollins: Well said. Medical device manufacturers should prioritize compliance with the EU MDR and work closely with notified bodies and regulatory authorities to ensure their devices meet the new regulation requirements. They should also stay informed about any new developments or changes to the regulations and be prepared to adapt their strategies accordingly.

To begin the Regulatory Compliance Associates scoping process today, please enter your information in the blue form below and click the submit button at the bottom of the webpage. You may also email us at [email protected].