NEW YORK – As the US Food and Drug Administration (FDA) moves forward with its plan to regulate laboratory-developed tests, some have questioned the agency's ability to manage the increased workload involved in LDT oversight.
The FDA has expressed confidence that it will be able to manage this challenge, but labs and vendors remain concerned given the experience of the COVID-19 pandemic as well as the general lack of clarity around the expected volume of LDT submissions.
"We just saw during COVID that FDA could not handle the influx of tests that came in," Allyson Mullen, a director at law firm Hyman, Phelps & McNamara, said. "It wasn't just the backlog of EUAs [Emergency Use Authorizations], the deprioritization of EUAs. Non-COVID tests saw at times very significant delays, too."
A report by medical device and diagnostics consulting firm RQM+ found that the COVID-19 pandemic led to a "significant increase" in the number of 510(k) submissions that the FDA failed to review within the 90-day target established by the current Medical Device User Fee Agreement (MDUFA). According to the report, the agency missed this goal for 90 and 71 510(k) submissions in 2020 and 2021, respectively. By comparison, it missed the goal for 29 and 33 510(k) submissions in 2018 and 2019, respectively.
Eric Konnick, assistant professor of laboratory medicine at the University of Washington and chair of the professional relations committee at the Association for Molecular Pathology, which opposes the FDA proposed rule, likewise suggested that the COVID-19 pandemic raised questions about how prepared the FDA is to tackle LDT regulation.
"If you look at just genetic testing … there were about 75,000 genetic tests on the market as of 2018," he said. "Assume most of those are at least moderate risk and would have to be reviewed. Look at COVID — it took two years to get through 3,200 relatively simple applications. It's really challenging to imagine how this would function."
Konnick also raised the question of where the agency will get the personnel for reviewing the increased number of submissions, particularly if it is competing with increased demand for such personnel from industry as labs and vendors add staff to help them comply with new regulatory requirements.
Others have made similar arguments. In a statement released this week opposing the proposed rule, ARUP Laboratories said that the agency "simply does not have the staff to support a hundred- or thousandfold increase in regulatory submissions, nor is it likely that such professional expertise could be reasonably hired."
One difficulty in assessing how well prepared the FDA is to tackle oversight of LDTs is a lack of information around how many such tests are currently in use and how many LDT submissions the agency might expect to see.
This month, at the New York State Department of Health, which requires that LDTs offered for use on specimens collected in the state be approved by its public health laboratory, the Wadsworth Center, released information on its program that could help shed light on the broader LDT picture.
Since the program launched in 1991, the NYDOH has received more than 15,000 LDT submissions, though some of those represent modifications to previously approved LDTs as opposed to new, unique tests. Since 2010, the Wadsworth Center has typically received in the range of 700 to 900 LDT submissions per year.
The center also provided data on the percentage of tests coming from in-state versus out-of-state providers in recent years, noting that of the 2,665 LDT submissions received during 2018, 2019, and 2020, 23 percent came from within the state and 77 percent came from out-of-state labs.
That indicates that New York labs have in recent years submitted around 200 LDTs, or modifications to existing LDTs, per year. Assuming every state averaged a similar number of LDT submissions per year, that would put the expected annual submissions at around 10,000 tests, not counting review of existing LDTs in the case that the FDA decides not to grandfather these tests. The actual number could be lower as some labs would likely stop offering tests duplicated elsewhere. Additionally, as home to a number of major academic medical centers and research institutions, New York likely sits at the higher end of LDT development activity.
In its proposed rule, the FDA used data from the NYSDOH LDT program to project the nationwide impact of its plan, estimating based on that data that its rule would impact between 40,200 and 160,800 existing LDTs and that it would see between 3,888 and 15,552 new LDT submissions per year.
The FDA currently averages around 3,000 510(k) clearances per year along with 20 to 40 PMA approvals and a similar number of de novo classifications.
During a recent FDA presentation on its proposed rule, Elizabeth Hillebrenner, associate director for scientific and regulatory programs in the office of the center director within the Center for Devices and Radiological Health (CDRH), addressed the question of how the agency would handle an "influx of submissions from laboratories," saying that it would look to expand its third-party review program and that it "generally would not intend to enforce premarket review requirements" for LDTs submitted to the agency until after it had completed its review of the submission.
Review by third parties like the Wadsworth Center is an approach the agency has been promoting for some time. Mullen noted, however, that the third-party review program remains limited.
"FDA has estimated that a very large proportion of LDTs could be eligible for the third-party review program, but it is unclear how they come to that determination, particularly given how limited the scope is of 510(k) [submissions] that can go through third-party review now," she said. "It's something that as this continues to move forward, and with the resource question, the framework for the third-party review program and its applicability needs to be considered in greater detail."
Kim Trautman, managing director and VP at regulatory consulting firm Medicept, said that the FDA has struggled to expand its third-party review program in part due to a lack of interest from industry, which, she said, has been reluctant to pay additional fees for third-party review. She added that past cases in which the FDA demanded additional scrutiny even after devices passed muster with third-party reviewers soured some vendors on the process.
Trautman said, however, that she believes the agency has improved its processes to reduce such instances of double review and that it is "very open to exploring how to utilize [third-party review] in this LDT area."
Trautman, who worked at the CDRH from 1991 to 2016, is more sanguine than many lab stakeholders regarding the FDA's ability to handle the workload involved in LDT oversight. She suggested that the COVID-19 pandemic strengthened the agency's processes in ways that would position it to better handle LDT regulation.
"They became much more efficient in the consult process," she said. "Whether it is within the [FDA] center or from center to center, if you need expertise that is outside of a particular review decision, there is a consult that goes to another portion of the center, and [FDA] became much more efficient at looking at the work, dividing it up, and bringing it back together under the review division while utilizing technical experts throughout the center."
As the pandemic has wound down, "the urgency has diminished," Trautman said. "But the process efficiencies and the consultation process and those learnings from COVID have not gone away."
Also notable, final implementation of the FDA's proposed rule on LDTs is timed to the next MDUFA renewal, during which time the agency and industry will have a chance to establish user fee levels and expectations around timelines for the review of submissions.
Other aspects of Trautman's expectations for how the FDA might deal with LDT submissions will likely be more concerning for laboratories. For instance, she suggested that the agency might have less time for the pre-submission consultations to which many in the industry have become accustomed.
Trautman also suggested that increased regulation could drive a number of providers out of the LDT business, thereby reducing the number of submissions to the agency. She analogized to her experience at the agency in the late 1990s when it established guidelines for providers around the reuse of single-use devices. Following the release of those guidelines, "tons of hospitals chose not to [reuse devices any longer] and take on that extra [regulatory] burden," she said.
She also cited her more recent work as a consultant to diagnostics and device companies working to comply with Europe's new In Vitro Diagnostic Regulation and Medical Device Regulation.
"With most of the clients that I have had, one of the first things is going through the SKUs and having the manufacturers make business decisions as to what is worth continuing and what isn't," she said. "It's the same thing with the hospitals. Is running these little LDTs worth the regulatory burden for what money they may be bringing in?"
While this prediction would seem to vindicate the fears of many in the lab industry, Robert Boorstein, medical director of Brooklyn-based Lenco Diagnostic Laboratory, suggested that such an outcome could be for the best.
"It's not clear that having hundreds of labs doing the same lab-developed test is, in fact, efficient or reliable," he said. "Would it be better for society if those lab-developed tests were done in a small number of labs where the labs or the manufacturer got FDA approval for the test? The tests would then be run under one set of guidelines to make sure it is done the right way as opposed to 100 different labs doing the test in many different ways under 50 different state laws."
Trautman said that despite the dire predictions coming from some in industry, she believes that "as long as the regulators are working with industry to solve problems as they come up," labs will be able to adapt successfully.