June 21, 2022 | The pandemic has thrown a spotlight on the Emergency Use Authorization (EUA) process of the U.S. Food and Drug Administration (FDA) whereby the agency can quickly give companies temporary permission to market unapproved medical products or unapproved uses of approved ones. The FDA’s EUA power has been in place a long time, and many such authorizations—including diagnostics specific to the Ebola and Zika viruses—remain open many years after declaration of the public health emergency that invoked it, according to B. Melina Cimler, Ph.D., CEO and founder of PandiaDx, a consultancy specializing in regulatory matters surrounding in vitro diagnostics.
When the FDA will revoke EUAs tied to COVID-19, because the U.S. Department of Health and Human Services Secretary (currently Xavier Becerra) declares an emergency no longer exists, is probably the top question on everyone’s mind, says Cimler. But she suspects it could be a while since variants of the virus keep emerging.
Cimler is one of a trio of experts who will be leading a short course on navigating the EUA process for diagnostics at the upcoming Next Generation Dx Summit. She’ll be joined by regulatory consultants Alberto Gutierrez, Ph.D., partner in NDA Partners and former director of the FDA’s Office of In Vitro Diagnostics and Radiological Health, and Gail Radcliffe, Ph.D., president of Radcliffe Consulting, who has been a regulatory support for companies on RADx (Rapid Acceleration of Diagnostics) initiatives.
Since the pandemic began, the FDA has granted EUAs or traditional marketing authorizations to over 2,300 medical devices for COVID-19, nearly 600 of them in fiscal year 2022 to date, reports Cimler. The agency issued “very specific guidance” for labs and manufacturers (e.g., sample pooling, temporary acceptance of control samples for serology tests, and information on at-home testing versus point-of-care and laboratory high-throughput diagnostics) to try to stay on top of the unprecedented EUA-related workload.
But many companies struggled with how to apply that advice, she continues, including many smaller companies with no prior medical device experience and international ones with no practice in interpreting FDA guidance documents and putting in place systems to validate their test clinically and analytically. They found it particularly tricky to get access to patient samples, since in a public health emergency they initially get routed to the Centers for Disease Control and Prevention (CDC).
It is no coincidence that the CDC had the first assay on the market for COVID-19. At the end of 2021, the CDC withdrew its request for EUA of its RT-PCR Diagnostic Panel introduced nearly two years earlier.
Meanwhile, wait times on FDA review of EUA applications progressively lengthened, Cimler says. “Initially, the turnaround was very quick because there were a lot of FDA staff and very few tests. As more and more players came on the market, the FDA became overwhelmed.”
Finally, the agency “drew a line in the sand,” prioritizing for review only the products that were truly novel—e.g., an at-home test or one based on saliva—and temporarily setting all the other me-too swab tests to the side, she continues. “The timeline for getting a decision on emergency authorization definitely got longer and longer as the pandemic went on.”
On May 31, the FDA signaled that the situation was at least starting to turn back toward pre-pandemic norms with the announcement that it was reopening all non-COVID IVD pre-submissions. Previously, many pre-submissions received through the agency’s document control center were given a number and closed without input, says Cimler, the exceptions being breakthrough designation requests, companion diagnostics, and study risk determinations.
The FDA is still warning people that pre-submissions will initially be reviewed under an extended timeline, Cimler says, meaning greater than the historic 75 days to get input from the agency. And the timeline on EUAs isn’t likely to budge, and could possibly grow longer, at least for the foreseeable future.
The good news is that once companies are granted an EUA, the authorization “stays live” until the end of the public health emergency, provided the test is working as intended and isn’t returning an excessive number of false results, says Cimler. Additionally, any changes made to the test would trigger the need for more validation testing—for example, when late in 2020 Abbott’s BinaxNOW transitioned from being a point-of-care assay to an at-home test involving self-collection of nasal swab samples.
Specimen type introduces yet another set of challenges, Cimler says. Initially, nasopharyngeal swabs were the only allowed means of specimen collection. When they were in short supply, companies began validating other types of nasal swabs for collecting samples from varying depths of the nose, highlighting the need to collect an adequate sample to avoid too many false-negative results.
With saliva-based tests, archived samples are not an option and their preservation and transport come with a fair amount of compliance challenges, continues Cimler. Multi-target testing became the preference of many companies, providing the means to differentiate between SARS-CoV-2 and respiratory infections caused by distinct flu types or respiratory syncytial virus with a single multiplex assay.
But given mandatory social distancing and masking precautions in many places, obtaining positive flu samples has often proved difficult, she says. Flu cases plummeted during the pandemic, requiring companies to “follow flu around the globe to try to get to someone else’s winter during our summer.”
When it comes to clinically validating a sample collection device for at-home testing, usability testing becomes part of the exercise, “to make sure an average person that reads at the sixth-grade level or lower can interpret [the results],” says Cimler. On the other hand, manufacturers of point-of-care tests deemed to be of “moderate complexity” by the FDA would need to formally request a waiver under CLIA (Clinical Laboratory Improvement Amendments), a designation given automatically to at-home tests.
Serological (antigen) tests currently account for 49 of the 436 COVID-19 diagnostics authorized by the FDA under EUAs, as compared to 302 molecular tests and sample collection devices, 84 antibody and other immune response tests, and one diagnostic breath test. The hope early on was that neutralizing antibodies, either from natural immunity or vaccination, would confer some protection but no such correlation has been seen, Cimler says.
The only surefire defense against SARS-CoV-2 is a robust immune system, with which Cimler says she appears to be blessed. Following a recent cruise with seven family members, she was the only one not to test positive for COVID, as confirmed six times in 10 days—despite sitting directly behind the person with the first confirmed case with the air blowing at her for more than four hours on the car ride home.
From the start, the FDA has been remarkably transparent about the EUA process, says Cimler, adding that she sympathizes with the difficult situation the agency is in having Congress as its boss and staying in step with a challenging and unpredictable pandemic. Beyond immediately publishing guidance documents, including separate templates for manufacturers and labs to use for their EUA submissions, the FDA initially held weekly town hall meetings specific to COVID testing (later switching to a biweekly schedule) that also facilitated information-sharing between companies. Moreover, the agency maintains a mailbox dedicated to handling pre-EUA questions.
In terms of metrics and predictability, the FDA is “probably still lagging,” she says. The lengthening wait time on the granting of an EUA—two to six months is now the norm—has been frustrating to companies who have often also been contending with the pandemic’s ripple effects on commercial aspirations for their non-COVID product pipeline. Despite diverting attention from other applications to review only COVID-related ones, the agency found it impossible to keep up with the EUA influx.
“The FDA has basically been telling companies to look at guidance documents and reach out to consultants, and that is about it,” says Cimler. “[Companies] are not going to shut down their development and validation process, but they are going it alone without [direct] FDA input.”
An added irritation emerges when companies receive long-awaited feedback on an EUA request, only to be given a few days to respond. “You can ask for more time, especially if you need to do additional testing, but in certain situations the FDA is asking companies to withdraw their EUA ... and then resubmit [their application], and people worry about losing their place in line,” says Cimler.
However, based on firsthand experience, the agency is often amenable to having EUAs remain open for a long time while companies address any outstanding issues, she notes.
The situation with EUAs remains fluid and new hot topics may be up for discussion by August, when Cimler and her colleagues teach the short course. She, Gutierrez, and Radcliffe have been interacting with the FDA regarding the nuances of the EUA process, including transitioning of an EUA to a true marketing authorization—be it through the 510(k), de novo, or premarket approval pathway—which will unquestionably require many times more patient samples.
Provided the EUA-authorized device hasn’t changed, companies should at least be able to leverage data generated for that regulatory permission, she says. A 510(k) clearance has additional requirements, including a compliant quality management system that has been expected for EUA submissions.
But, as we reported here last fall, many companies may end up abandoning tests because of the requirement for more extensive clinical studies required for a 510(k), especially as government funding for the National Institutes of Health’s RADx program ramps down. Ultimately, the cost of compliance could outweigh the marketing benefits.