This story has been updated with additional comments.
NEW YORK – The Association of Public Health Laboratories on Monday asked the US Food and Drug Administration to exercise enforcement discretion regarding laboratory-developed tests for the novel coronavirus SARS-CoV-2.
This would allow public health laboratories to develop and implement their own tests for the virus rather than relying on the test developed by the Centers for Disease Control and Prevention.
The request comes in response to problems with certain of the reagents in the rRT-PCR test developed by the CDC for detecting the virus.
These problems have limited rollout of the test in public health laboratories around the country. According to Kelly Wroblewski, director of infectious diseases at APHL, around 100 public health labs have received the test, but the large majority of the facilities have not been able to successfully implement it. On a media call Tuesday, Nancy Messonier, director of the CDC's National Center for Immunization and Respiratory Diseases, said that there were currently 12 public health labs across the country that had verified and were using the CDC assay for SARS-CoV-2, the virus responsible for COVID-19.
The FDA declined to comment on how or when it would respond to APHL's request for enforcement discretion, but provided a statement noting that the agency has to date engaged with more than 70 developers working on tests for SARS-CoV-2.
In response to the SARS-CoV-2 outbreak, the FDA instituted its Emergency Use Authorization provisions. These provisions allow test developers to bring an assay to market based on lower standards of evidence than conventional FDA regulatory processes. However, they also require that entities take laboratory-developed tests through the EUA process, which prevents, for instance, a hospital lab from developing and implementing a SARS-CoV-2 LDT without first taking it through the FDA.
The EUA declaration also means that public health labs are not permitted to use their own locally developed COVID-19 tests or test reagents and must instead use the tests and reagents provided by CDC or take locally developed tests and reagents through the EUA process.
The FDA in its statement said that the EUA provisions are necessary to ensure that test results are accurate, noting that "in the context of a public health emergency, false results can lead to significant adverse public health consequences. That is why the [EUA] statutory provisions were put in place to ensure that FDA has oversight over diagnostic tests and other devices used in an emergency."
"Particularly when you have a novel pathogen, one that hasn't been widely tested for in the US or something that is entirely novel, like [SARS-CoV-2], there is a lot you learn about what specimens types it is transmitted in. … The window in which a diagnostic is sensitive or specific," Wroblewski said, explaining FDA's reasoning. "So if you have a lot of laboratories doing different things on a pathogen that is not very well characterized, that is not very well understood, I think from a regulatory perspective there is a concern that you can have bad tests out there."
However, she added, the ongoing spread of the virus globally is increasing pressure to make testing more widely available.
"I think for public health laboratories, particularly as we are watching what is happening across the globe in Italy and [South] Korea with countries moving from the containment phase to a mitigation phase, there is a sense of urgency in getting testing available outside of CDC, which is part of the reason APHL approached FDA as it did," Wroblewski said.
She noted that CDC has not provided a timeline for when it will be able to release new test reagents.
CDC has not specified what exactly has been the source of problems for public health labs working to implement the SARS-CoV-2 test beyond the fact that the issue lies in a test component, known as the N3 assay, intended for the universal detection of SARS-like coronaviruses. The two other test components, the N1 and N2 assays, are meant for the detection of SARS-CoV-2 specifically.
Wroblewski said that labs that have encountered difficulty with the test have seen reactivity in the normal human specimens used as negative controls for the assay.
"It's not happening in every single specimen, but it's happening with enough frequency to be concerning," she said.
She added that researchers have determined that the problem is not with the negative control specimens themselves but most likely with the primer probe sets used in the N3 assay.
The problem could be caused by a variety of factors, Wroblewski noted. One could be that the primers are reacting with each other at low levels, though she said CDC researchers did not consider this the likeliest scenario given that the agency was having success in house using the same assay with the same primers but from a different batch of reagents.
Between January 18 and February 23, CDC labs have used the assay to test 2,620 specimens from 1,007 people for SARS-CoV-2. Messonier said the agency performed another 400 tests on Monday night.
Another possibility is that there could have been contamination during the manufacturing process, Wroblewski said.
Nathan Ledeboer, professor of pathology and medical director of microbiology at the Medical College of Wisconsin, said it appeared the issue was most likely due to a manufacturing problem.
"It's probably just a [problem] with a primer synthesis lot where one of the primers was either made wrong or had the wrong nucleic acid incorporated into, causing the failures," he said.
On the media call Messonier acknowledged "the frustration of our partners in the healthcare sector, of our partners in health departments," around the delay in getting the test up and running throughout the country.
"In terms of timing, I think at this point what I would say is that we are working as fast as we can," she said regarding when CDC might have new reagents to provide to public health labs.
Messonier added that "commercial labs will be coming online soon with their own tests," which she said "would be a great advancement."
Ledeboer, who is not involved in the CDC effort, said fixing an issue with the test primers would probably take around two weeks between the time required for synthesizing the new primers and the time required to validate them.
He added that one consideration around timing is that the same group at CDC might be in charge of validating the new reagents and running the existing test on patient samples.
"So it could really be a question balancing the patient-based testing with the need to get the new lots out and verified," he said.
Wroblewski said she did not know if EUA enforcement discretion, if granted by FDA, would apply to hospitals and commercial labs outside the public health space.
"Because we represent public health laboratories we asked for this exception only for public health laboratories, so that would be up to FDA," she said.
Assuming FDA does not grant provide enforcement discretion, the agency said that when authorizing tests through the EUA process, it "typically reviews information on a rolling basis such that once the full validation package is received, review can be completed within as little as a single day."
The agency added that it "can also take action to facilitate the rollout of a test, such as through prepositioning of material prior to authorization consistent with provisions in the statute."
Ledeboer said that if case volume continues to rise, it will be necessary to expand testing beyond CDC and public health labs to meet demand.
"The reality is that at some point if we rely entirely on the public health system, it will fail," he said. "That is well established. There aren't enough [public health] labs, and they can't push through that kind of volume."
He cited the example of the H1N1 influenza outbreak in 2009, in which the large majority of states were not ultimately able to meet testing demand.
"They had to say, we can no longer test people and we are telling you to, based on clinical symptoms, presume that they are positive," Ledeboer said. "Or, turnaround time became so long that it wasn't clinically useful anymore."
"It was only those locations that had a diversity of different testing locations that were able to keep up and continue to report results in real time," he said, noting that high volume labs like those at major medical centers and large national labs like Quest Diagnostics and Laboratory Corporation of America would likely need to play a role in testing to keep up with demand if the virus spreads widely in the US.
Ledeboer said he and his colleagues were tracking the situation carefully and developing a plan to implement testing if needed.
The first step, he said, would be to learn whether the issue with the CDC test was in fact due to a manufacturing problem as opposed to something wrong with the primer design itself.
"We all want to hear CDC come out and tell us what was wrong with those primers," he said. "I think that is part one, and I think we should know that in the next few days."
Once that has been established, Ledeboer said his lab would consider preparing to use the CDC assay.
"We'd order it, do all the specificity validations, transport validations, as much as we could ahead of time," he said.
Alternatively, "we have been talking to a number of different manufacturers that are actively looking at submitting EUAs [to FDA], and we're looking at what we could maybe do with one of them, as well," he said.
CDC is also developing various other tests to help manage the outbreak, including a serologic test that it plans to use for surveillance purposes and tests to detect SARS-CoV-2 RNA and proteins in tissue specimens.