Once discussions began earlier this year about postponing the European Union’s Medical Device Regulation, it was clear that the COVID-19 pandemic would have an impact on medical device regulation. Even the U.S. FDA felt like a different agency, as it demonstrated its own agility through emergency guidance and Emergency Use Authorizations (EUAs). FDA has since rescinded a few such authorizations (and has even been criticized for one) so it seems as though regulatory oversight is unfolding in real-time, based on real-world data.
Will crisis-time collaboration forever change regulator-industry relationships? Will steps taken to expedite authorization and reviews lead to faster approvals in the future? Will real-time data from the field on products marketed through EUAs influence the type of clinical data relied on for future regulatory decisions? We have a lot of questions, so we turned to some of the experts who spoke in two of MD+DI’s webinar series, How the Medtech Industry Can Respond to Crisis and EU Medical Device Regulation: What Does Postponement Mean for Medtech? now available on demand.
EUAs Are Providing Emergency Solutions
In the June webinar, “Respond and Restore: Best Practices for Responding to a Pandemic (and Other Crises),” Pat Shafer, managing director, regulatory risk and quality effectiveness, Grant Thornton, said at the time that “perhaps the most interesting impact we’ve seen in the life sciences is the flurry of activity that has been happening at FDA, with CDRH, CDER, and CBER. Looking at the number of EUAs, they have been growing rapidly. Every time we check there are another few. What’s interesting is that some have been rescinded almost as rapidly as these authorizations have been happening. FDA has been watching for their effectiveness and safety and the reliability of the tests and a good number have been rescinded or removed over the last few weeks.”
MD+DI has shared news of a number of these EUAs as well as a few that have been rescinded. Many authorizations have been for diagnostics tests, such as the recent EUA for Abbott’s BinaxNOW COVID-19 Ag Card for rapid detection of COVID-19 infection, the saliva-based test SalivaDirect COVID-19 developed by researchers at the Yale School of Public Health, and many more tests for infection or the presence of antibodies. FDA authorized devices for treating COVID-19 patients. For instance, Abiomed received two EUAs, one for its Impella RP heart pump for COVID-19 patients with right side ventricular failure and a second for Impella heart pumps for left ventricular unloading and support for COVID-19 patients who are undergoing ECMO treatment and develop pulmonary edema or myocarditis. FitBit received an EU for its low-cost ventilator FitBit flow. (Click here for more EUAs.)
FDA also authorized the emergency use of convalescent plasma to treat COVID-19 patients, but FDA Commissioner Stephen Hahn was criticized “for overstating the benefits of the therapy for COVID-19 patients,” MD+DI reported.
FDA did revoke Chembio Diagnostics’s emergency use authorization for a SARS-CoV-2 antibody test as well as Autobio Diagnostics Co.'s EUA for Anti-SARS-CoV-2 rapid tests for the qualitative detection and differentiation of IgM and IgG antibodies to SARS-CoV-2 in human plasma from anticoagulated blood (Heparin / EDTA / sodium citrate) or serum 2.
With these reversals, FDA has demonstrated its quick response to emerging data from the field. When the agency revoked Chembio's EUA, Jeff Shuren, MD, director of FDA’s Center for Devices and Radiological Health, said in a statement: “By continuing to monitor authorized tests and emerging scientific evidence, we are able to make changes when appropriate—including taking action when a test’s benefits no longer outweigh its risks. Through these efforts, we are able to help assure that FDA-authorized tests meet the needs of the American public.”
Alpa Patel, B.S., RM (NRCM), principal scientist for Nelson Laboratories, who spoke in the MD+DI webinar, “Method Development for Decontamination and Sterile Processing of Personal Protective Equipment (PPE),” believes that real-time data from the field on products marketed through EUAs “will help design better studies and validation plans to accurately represent and capture the practices and procedures in the field.”
Regulator Collaboration Key to Developing Quick Solutions
Regulator collaboration played a key role in the search for emergency solutions for medical products in short supply, such as ventilators and personal protective equipment.
Regarding quickly identifying PPE decontamination methods, Patel from Nelson and Aaron DeMent, vice president of technical services for Sterigenics U.S., spoke in the webinar, “Method Development for Decontamination and Sterile Processing of Personal Protective Equipment (PPE),” now available on demand. They shared learnings as industry and regulators worked to identify effective decontamination approaches. After Sterigenics was initially contacted by the Chinese government to sterilize containers of PPE and subsequently by dozens more interested parties, DeMent led the team’s response to the crisis and called it one of the “more rewarding moments” of his career. “We are in a highly regulated industry, and the concept of new process development on a very accelerated time frame was sort of a new muscle for everyone involved to flex,” he told the webinar audience. “We defined the necessary information for new process development and that was a huge challenge and one that fraught with frustration and a relatively high level of disappointment at times.”
Collaboration with regulators was key. “One of the most rewarding parts of this journey was working with regulators with around the world,” he explained. “The regulatory landscape had to rapidly evolve to address growing needs for PPE and the collaboration [among] regulators, end-users, and industry was very high. One of the things we did learn is there was no one person, no one company, and no one regulatory agency had all the answers to unlock the mystery of how to decontaminate PPE. It took a team comprised of many people,” he said.
“This was one of the most difficult times in my career, and I’ve been doing reprocessing for 17 years,” added Patel during the webinar. The challenge was “trying to figure out a test plan for decontaminating single-use PPE,” she said, and “we needed a whole team.
“A validation plans takes a lot of people and takes a lot of effort to put together, and collaboration between all the parties is huge,” she added. “You need to have regulatory, QA, face masks experts, decontamination experts, sterilizations experts—without this collaboration, we cannot move forward in anything.”
Regulations didn’t exist for such reprocessing of N95 masks, for instance, so industry and regulators weren’t really prepared for the urgent demand from the crisis. The Sterigenics team members found themselves in some countries in “a dual role—working with stakeholders to gain approval of processing while also acting as consultants for regulators at the same time,” said DeMent. Multidisciplinary experience was needed for the accelerated projects, and regulators were a part of the multifunctional team. (In no case, however, did any Sterigenics customers bypass appropriate testing for the sake of responding quickly, DeMent said. There may have been limited quantities of testing, but “key elements of functionality, sterility and decontamination, and biocompatibility were required to be tested,” he said.)
Working in the “fast-paced environment,” Patel said the team was “grateful” that FDA issued two documents that offered recommendations. She said the working relationships that developed among agencies such as FDA and NIOSH (the National Institute for Occupational Safety and Health) “worked really well because we were working together to figure out a process.” Patel said that FDA indicated that it would expedite its evaluation of decontamination processes if provided measurable data that all process steps were working.
DeMent said that “the interaction with regulators across the globe in some ways has been the high point of the crisis for me. The level of collaboration with regulatory bodies was outstanding, and the relationships formed will have long-lasting and positive benefits outside the COVID-19 crisis.”
Risk-Based Approach to Regulation
The pandemic has put “special stresses on the medical device market and on regulators,” Matthew Jorgensen, PhD, DABT, senior chemist and toxicologist for Nelson Laboratories, told MD+DI. The “time stress forced regulators to use a risk-based approach that the agency has aspired to for some time but hadn’t really transitioned to. FDA and notified bodies were essentially forced to fast-track use of a risk-based approach so they could ensure that life-saving devices needed for treatment of COVID-19 could make it to the market in a timely manner.” Jorgensen spoke in the July webinar, “A Year of MDR Remediation: Strategies and Lessons Learned,” now available on demand.
“We always think about risks and benefits when it comes to a particular medical device, such as whether we would feel comfortable having a loved one use that device, even if all the check boxes aren’t checked,” he added. “I think we all hope that this rough push of regulators into this full risk-based mentality is permanent.”
In terms of materials science and chemistry, such a risk-based approach means that regulators could be relying on existing material and clinical use data. For instance, if the known risks for a certain material are low and the potential benefit to patients is high, a regulator is more likely to support that material for a ventilator part, he said. They are “more open to scientific explanations,” Jorgensen said. He has even seen such a mindset during a few pre-submission calls unrelated to COVID, in which the agency pointed out that only a “pen-and-paper material review” was needed for a few projects rather than extensive testing.
Jorgensen points out that FDA was already on this path given the February 2019 guidance, “The Least Burdensome Provisions: Concept and Principles,” which stated that the agency defines "‘least burdensome’ to be the minimum amount of information necessary to adequately address a relevant regulatory question or issue through the most efficient manner at the right time.”
Risk-based language is also embedded in its emergency use guidances, Jorgensen said. For example, in their criteria for emergency use authorization for ventilators, the FDA authorization is “Based on the totality of scientific evidence available to FDA, it is reasonable to believe that authorized ventilators, ventilator tubing connectors, and ventilator accessories may be effective in treating patients during the COVID-19 pandemic, and that the known and potential benefits of such products, when used to treat patients during the COVID-19 pandemic, outweigh the known and potential risks of such products.” He also points to FDA policies for IVDs, PPE, ventilators, and other products as well as for 3D printing of medical devices and components.
“I can’t help but think that the people writing the language of these guidances will continue to do so after the pandemic. I hope this language will be recycled,” Jorgensen said.
Jorgensen also believes there may have been faster regulatory decisions given the need for emergency response. He said he has seen quicker turnaround times for regulatory responses, and less formal ones. “There’s been more communication between reviewers and companies and faster timelines, such as days rather than weeks or months,” he said.
“After this crisis, I hope both industry and regulators can find a way to meet in the middle, having gone through the EUA process and flexing the risk-based-approach muscle,” he added. “It has allowed a clearer understanding about where FDA is comfortable when it comes to testing, such as being OK with material data from a scientific review or a pen-and-paper review.”
Shafer also noted during the webinar that FDA had announced that it would “continue to adopt some of the pandemic practices such as rapid assessment post pandemic. They are going to be relying on real-world evidence and require companies that have received rapid approval to provide post-market evidence and data as far as safety and what they’ll do is they will adjust approvals or rescind them altogether based on that real-world evidence. It appears as though they are eager to get devices and therapeutics to market, but there will be of course increased risks related to that.”
When asked about the emerging importance of real-time data in regulatory decisions, Jorgensen said that he doubts such data would play a role in material decisions. “I don’t think we can leverage real-time data to support a device application in terms of biocompatibility,” he said. “When a device is used in a patient, only acute adverse event information is relatable to the device, but it is imperative that we safeguard people from chronic adverse effects as well. [For instance,] 20 years after a person receives an implant, if they get cancer, it is impossible to know whether that is from the device or if the cancer is due to other environmental factors or if it is simply naturally occurring. You need to consider long-term biocompatibility.”
So, will crisis-time collaboration forever change regulator-industry relationships? It is difficult to generalize, of course. But the industry and regulator response to the pandemic has certainly demonstrated that quick collaboration can help meet emergency needs. A “regulatory agency has always been in the forefront of any crisis that has come across in the medical device industry and has encouraged the industry to come up with innovation towards the crisis with their support. I believe FDA took a great lead in COVID-19 pandemic discussion and has helped and guide the manufacturers of face masks to take the right approaches,” said Patel.
And she believes that steps taken to expedite authorization and reviews could lead to faster approvals in the future. “I believe so; the response that we have seen with COVID-19 with the regulatory is very promising and hopeful,” she said. “Regulatory agencies are very open to novel and new ideas and encourage an environment of collaboration and innovation with the manufacturers. However, discussions should be established with the regulatory agency before implementation of an idea outlining all the criteria’s and probable study plans.”