Serology Testing Critical to COVID-19 Survival & Post-Crisis Transition

There are two kinds of people who have SARS-CoV-2 antibodies in their systems: Those who are currently infected with COVID-19 (both symptomatic and asymptomatic), and those who were infected but have recovered. Being able to identify and distinguish between these two groups will go a long way in determining how and how soon people can emerge from self-isolation and the world can go back to normal. That is why so many are investing so much hope and energy in serology testing. Here is an overview of the FDA’s strategy to promote serology testing for COVID-19.

Importance of Serology COVID-19 Testing

Antibodies remain in the body long after the infection they were created to fight disappears. The principle method being used to diagnose COVID-19, reverse transcriptase polymerase chain reaction (RT-PCR) testing, detects viral material that is present during a current infection. By contrast, blood-based serology tests indicate whether a person had COVID-19 but since recovered. In addition to furnishing invaluable data about particular populations, the capability to identify healthy individuals who carry COVID-19 antibodies and are thus presumably safe to “let out” is integral to the coming challenge of gradually peeling back social distancing.

FDA Regulation of Serology Testing

Not surprisingly, fostering the development of safe and reliable serology tests is one of the key elements of the US Food and Drug Administration’s (FDA) COVID-19 emergency response strategy. After initially resisting the idea, the agency agreed to loosen its regulatory control over new diagnostic tests for COVID-19, allowing high-complexity and commercial laboratories to develop and provide their own tests immediately after validating them without waiting for FDA Emergency Use Authorization (EUA). The agency organized the four different regulatory pathways into separate “Policies.” Among these, the least rigorous is “Policy D,” which allows commercial manufacturers and high-complexity laboratories to provide validated tests without having to apply for an EUA at all.

Serology tests can also be cleared via Policy C, a slightly more rigorous pathway requiring the manufacturer or laboratory to launch tests intended for use at the point of care, upon validation without an EUA, provided that it notifies the FDA immediately and submits an EUA application within 15 business days.

Are Manufacturers Taking Advantage of Policy D?

Of the 74 COVID-19 serology tests that have passed or are currently in these pathways (as of April 17, 2020), only four have received EUA. That leaves 70 assays without FDA clearance. While getting serology tests immediately to the front lines is of critical importance, the FDA is also wondering if it might have gone a bit too far in lowering its guard.

COVID-19 Serology Tests with FDA Emergency Clearance

As of April 17, four COVID-19 serology tests have received EUA clearance from the FDA (listed in chronological order of approval date):

• Cellex’s qSARS-CoV-2 IgG/IgM Rapid Test, a lateral flow immunoassay detecting IgG and IgM in blood serum, plasma, or venipuncture whole blood specimens in 15 minutes;
• Chembio Diagnostics’ DPP COVID-19 serological point-of-care test and analyzer providing numerical readings for IgM and IgG antibody levels from a finger stick blood drop in 15 minutes;
• Ortho Clinical Diagnostics’ high-throughput Vitros Immunodiagnostic Products Anti-SARS-CoV-2 Total Reagent Pack and Calibrators capable of processing up to 150 tests per hour;
• Mount Sinai Laboratory’s COVID-19 ELISA IgG Antibody Test detecting human IgG antibodies in serum and plasma.

The source of the concern are the claims being made by some firms that the serology tests they are providing under Policy D, the EUA-less pathway: i. have FDA approval; or ii. can diagnose COVID-19. On April 7, FDA Commissioner Steven Hahn issued a statement warning against such false claims and indicating that “the FDA will take appropriate action against firms making false claims or marketing tests that are not accurate and reliable.”

A week later, the agency once more cited the false claims issue. “We continue to see problematic claims and uses of serology tests, particularly those . . . under pathway D,” noted Timothy Stenzel, director of FDA’s Office of In Vitro Diagnostics and Radiological Health during the agency’s weekly town hall. “These devices are only for high-complexity labs; they are not to be used in moderate complexity labs or in point-of-care, near-patient settings, nor in the home.”

The Accuracy Challenge

 The other big concern is with the sensitivity and specificity COVID-19 serology tests that have passed through Policy D. The problem is that serology tests are especially vulnerable to specificity issues that can produce false positive results, leading people who are still susceptible to COVID-19 into falsely believing they are immune.

Thus, the FDA finds itself in the very strange position of having to assess whether the results of tests it allowed into the US market “can be relied upon and can have a level of accuracy that indicates that they are fit for use in the United States,” according to Stenzel. In response, the agency has formed a voluntary interagency validation protocol that is open to all developers of serology tests in the Policy D pipeline. The agency is asking developers to send their point-of-care test kits and any instrumentation that might be needed to a central laboratory for validation. Meanwhile, the agencies are creating a panel of sera and plasma to independently evaluate test performance. “We have been receiving test kits from some of these developers and we believe testing will begin in the very near future,” Stenzel noted.

CLIA Categorization of Serology Tests

The other element of the test regulation strategy that the FDA has to create on the fly due to the emergency is CLIA categorization of serology tests that go through the different pathways. In the recent town hall, Stenzel offered some clarification.

Tests with EUA clearance: Stenzel noted that tests that receive EUA are authorized for use in specific environments. Thus, for example, the Cellex serology test can be used by laboratories with CLIA authorization to perform moderately complex testing. EUA-cleared tests for use at the point of care are deemed to be CLIA-waived tests.

Non-EUA Policy D tests: Stenzel also clarified that tests that go through Policy D have not undergone FDA review and thus have not received a CLIA categorization. Result: By default, these tests revert to highly-complex test status.

Takeaway

These are extraordinary times and, like everybody else, the FDA has to make its strategy on the fly. The agency’s test-now-and-regulate-later approach helps satisfy the desperate need for COVID-19 testing but also carries significant risks, including false claims by test makers and, more significantly, accuracy and reliability of test results. It remains to be seen how the FDA catches up with the runaway train of its own making.