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FDA Issues New Guidance on SARS-CoV-2 Variants for Test Developers

NEW YORK – The US Food and Drug Administration on Monday issued new guidance for SARS-CoV-2 test developers to evaluate the potential impact of viral mutations on the tests.

The impact of mutations on a test's performance can be influenced by the sequence of the variant, the design of the test, and the prevalence of the variant in the patient population, the agency said in a statement. The guidance pertains to makers of molecular tests and rapid antigen tests that detect the coronavirus, and serology tests that detect antibodies against SARS-CoV-2, the FDA noted. 

In the guidance, which went into effect immediately, the agency recommends molecular diagnostic test developers design their tests to minimize the impact of viral mutations on test performance, routinely monitor for viral mutations that may impact test performance, and clearly convey any test limitations in the test's labeling. 

For developers that are submitting tests to the agency for Emergency Use Authorization, the FDA said they should address in their submission whether the labeling should include statements or limitations indicating when the specimens used in clinical evaluations were collected and noting that performance may vary depending on the variants. For those that have already received EUA, the agency said it will work with those developers to determine whether those updates are needed for the labeling.

The agency recommended test developers consider the performance of their test across all known variants at the time of validation and also the potential impact of future variants when developing the test design. It also said developers should include in their EUA submissions a description of how they evaluated performance across the variants and how their design mitigates the risk of future variants.

For tests with multiple targets, developers could include a "highly conserved pan-SARS-CoV target" not specific to SARS-CoV-2 to improve performance with a new genetic variant. If this is used, there may be a need for more information on appropriate result interpretation, the agency said. 

The agency also noted that developers should conduct sequence alignment of their primer and probe sequences with available SARS-CoV-2 genomes to determine whether the mutations will impact performance. If there is an impact from a mutation, developers should determine whether the mutations could reduce performance by 5 percent or more from the previously established performance and if so, notify the agency with a supplemental EUA request.

The FDA also said developers should evaluate hybridization changes if there is a mutation expected to result in a mismatch within the target primer and probe binding sites. The developers should provide the FDA with information on the results from melting temperature calculations with the primers and probes, an analysis on how the melting temperature changes as the salt and primer concentration changes, analysis of the likelihood the mutation will impact performance, and an evaluation of that impact on benefits and risks for the tests. It should also provide a justification for any actions taken based on the analysis outcomes. 

For antigen and serology tests, the FDA said developers should connect with the agency early in test development to make sure they hear about new recommendations to evaluate the impact of variants on these tests. Currently the agency is "considering how to best assess the impact" of mutations on these tests. Developers of antigen and serology tests should make a plan to monitor for new mutations and assess the impact as needed.

Since the original SARS-CoV-2 virus was first detected and identified more than a year ago, variants of it, notably the B117 variant first isolated in the UK; the South African variant, or B1351; and the Brazilian variant, or P1, have been identified and found in the US.

In the FDA's statement, Acting FDA Commissioner Janet Woodcock said that emergence of the variants has raised concerns about whether existing and COVID-19 tests in development would be able to detect them. 

"By issuing these guidances, we want the American public to know that we are using every tool in our toolbox to fight this pandemic, including pivoting as the virus adapts," Woodcock said. "We need to arm health care providers with the best available diagnostics, therapeutics and vaccines to fight this virus.