Clinical laboratories in the U.S. over the past weeks have been working to develop and ramp up testing for the 2019 coronavirus disease (COVID-19). More laboratories now are able to do so because of a Food and Drug Administration (FDA) rule change that until a few weeks ago hamstrung clinical laboratories that were prepared to develop tests.

Normally, CLIA-certified clinical laboratories can develop and validate tests for their hospital’s patients without waiting on FDA. But in a twist that has haunted U.S. public health officials, FDA’s Emergency Use Authorization (EUA) power—first enabled by the Project Bioshield Act of 2004—required that laboratories instead stop and wait for FDA review to develop tests like ones for SARS-CoV-2, the virus that causes COVID-19.

Such red tape takes time, which many health experts felt the U.S. didn’t have, especially when the test kits the Centers for Disease Control and Prevention (CDC) developed initially had a faulty reagent that rendered inconclusive results for some public health labs when they were verifying this test.

“With most of these emerging or novel infectious disease outbreaks like SARS and MERS, the majority of the testing has been done at the CDC or state public health labs,” said Matthew Binnicker, PhD, a professor of laboratory medicine and pathology at the Mayo Clinic in Rochester, Minnesota. “Testing was brought up in the public health infrastructure and centralized there as much as possible.”

That was the case at the start of the COVID-19 outbreak, but as the number of cases started to multiply, and the disease reached pandemic stage, it became obvious that this system wouldn’t work. “Our public health infrastructure is not really designed to handle the large testing volume,” said Binnicker. “We need the clinical laboratories throughout the U.S. to carry a good portion of the burden of testing.” 

In a February 28 letter to FDA, AACC President Carmen L. Wiley, PhD, DABCC, FADLM, called on the agency to change its rules to allow clinical laboratories to create and implement their own tests without going through this kind of FDA review. That’s because these clinical laboratories, while not part of the public health system, are already subject to stringent regulations under the Centers for Medicare and Medicaid Services, and they have successfully developed, validated, and performed in-house tests for other serious public health conditions (such as HIV when it first emerged).

On February 29, FDA moved to start loosening restrictions, updating its COVID-19 policy to enable labs already CLIA-certified for high-complexity testing to develop and validate their own tests, then submit an EUA application to FDA within 15 days. Clinical laboratories around the county were off and running. Two that fast-tracked development of COVID-19 tests, including Mayo Clinic and UNC Medical Center in Chapel Hill, North Carolina, shared their experiences with CLN.

On the Frontlines of Coronavirus Test Development

These tests need to do three things, according to Binnicker. First, they need to determine the limit of detection i.e. how little of the virus can be present in the sample for the test to “pick it up,” he said. Tests also need to be accurate, and not produce false positives in the presence of another kind of infection. “If a patient has influenza, we have to make sure that the test isn’t going to be positive because of that,” added Binnicker.

Developing, validating, and seeking an EUA for a COVID-19 test is not for the faint of heart. “It’s a very intense process and we have quite a bit of resources here at the Mayo Clinic in terms of people who can help out, but even with those resources, it’s still taken a lot of time and energy,” said Binnicker. He doesn’t think smaller labs will be able to follow suit on their own. Instead, they’re “going to have to wait until companies come out with more simple tests that they can purchase and implement in their labs,” he said, adding that even the Mayo Clinic pulled resources from outside its clinical microbiology group to work on the test.

At UNC Medical Center efforts were delayed because FDA recommended that labs use viral RNA or viral lysate to validate their studies, which UNC didn’t have at the time—a common problem, according to Melissa B. Miller, PhD, D(ABMM), F(AAM), director of the clinical microbiology and the clinical molecular microbiology labs. “That did create a significant delay for us. The test was otherwise in my opinion ready to go,” she said.

Since February 29 FDA twice has updated its COVID-19 testing policies. On March 12, the agency announced it would exercise enforcement discretion for the New York State Department of Health (NYSDOH) to authorize certain labs in the state to begin COVID-19 testing after validating their tests and notifying the NYSDOH. Labs would then have 15 days to submit validation data to NYSDOH rather than preparing an EUA for FDA. Four days later (March 16) FDA enabled states to oversee tests developed and used by labs in their states. The agency also said it would not object to manufacturers distributing and labs using new commercial tests before EUAs for them have been granted. At the same, FDA gave recommendations to test developers about serological tests.

FDA also has fast-tracked EUA kits from several manufacturers in recent days, including Roche, Thermo Fisher, and Hologic. According to FDA, more than 80 developers have sought the agency’s help so far with tests they plan to bring through the EUA process. Currently, the Roche assay runs on the company’s automated cobas 6800 and cobas 8800 systems, the Thermo Fisher assay on the company's Applied Biosystems 7500 Fast Dx Real-time PCR instrument, and the Hologic assay on the company’s Panther Fusion system.

Once these faster testing systems are in place next week, commercial reference laboratories expect to be able to offer 20,000 tests a day, according to the American Clinical Laboratory Association. “Assuming there are no delays or shortages of necessary materials and supplies, commercial capacity is expected to exceed 280,000 tests per week by April 1,” the association said.

A Public Health System Reimagined

The COVID-19 pandemic has shown multiple weak spots in the U.S. public health system, especially when it comes to testing. “I very much respect the need to safeguard public health and make sure we have accurate and safe testing for people, but it’s really handicapped many of our CLIA-certified labs and delayed us in going live, sometimes close to a month,” said Miller. “Lab testing needed to be available earlier. Capacity needed to be built earlier. When the dust settles from this pandemic, we really need as a nation to go back and look at the process. How can we more effectively enable CLIA labs to have widespread testing of a new infectious agent available more quickly but still safely?”

Binnicker recently wrote a paper about just that, recommending a much more streamlined process (Clin Chem 2020; During the early stages of an outbreak, national (CDC) and international agencies (the World Health Organization) are in the best position to rapidly develop new diagnostic tests. Once an assay has been developed and shown to meet established performance characteristics, he proposed that the national/international public health agency partner with a contracted test manufacturer(s) to initiate the process of mass producing test reagents and submitting performance data to FDA. As is currently the process, FDA would then review a test’s performance characteristics, and if the test passes, would issue an EUA.

This EUA would allow the test manufacturer to distribute kits to qualified laboratories, which in the proposed model, would be expanded to include not only state and local public health laboratories but also clinical laboratories that have participated in a thorough vetting and credentialing process.

“Most clinical laboratories in the U.S. are accredited and approved to perform routine clinical testing,” Binnicker said. The process to be approved to do such tests in the case of an outbreak would involve each clinical lab applying or registering, in which the lab would confirm that it has the required equipment, safety infrastructure, and personnel to complete testing. Each lab also would undergo a site visit from an existing CDC-qualified laboratory representative and would have to successfully complete required validation studies and a blinded verification panel sent from CDC and/or the test manufacturer. Ideally, the first two steps would be done before an outbreak and would serve as accreditation that a lab is qualified to be a testing site for a specified period of time.

Binnicker said that ensuring a path to rapid testing is critical because he thinks something like COVID-19 will happen again. “It may be a while until we have one that’s impacted the globe as much as this outbreak has, but we’ve learned over the last 15 to 20 years that these viruses tend to pop up, and we need to not consider this is a done situation,” he said. “We all need to get on the same page and figure out how do we approach this in a way we don’t have to recreate the wheel every time one of these viral outbreaks occur.”

Miller also thinks this pandemic is going to educate the public about what labs actually do. “For better or for worse, at the end of the day, it’s better the spotlight has been on labs and lab testing and the need for lab testing and the complexity of lab testing,” she said. “We’re finally being recognized for our profession, unlike healthcare providers right in front of patients. You never see the lab. We have shown the world how important lab testing is.”

AACC COVID-19 Resources

The AACC coronavirus resource page gathers AACC’s global laboratory medicine expertise on the topic. Resources include free educational materials from AACC Learning Lab, the latest science from AACC journals, regulatory guidance and news, AACC advocacy work, and more.

In order to expedite access to testing services for healthcare providers, AACC also is gathering data for a COVID-19 testing directory of U.S. laboratories expected to launch March 19. More information is on the AACC coronavirus resource page.

Jen A. Miller is a freelance journalist who lives in Audubon, New Jersey. @byJenAMiller