The U.S. FDA has posted an immediately-in-effect policy document regarding clinical laboratory development of diagnostics for the pathogen responsible for COVID-19 disease. The agency said the policy allows a lab to use any diagnostic before the FDA has completed an exhaustive review of the test.

The agency noted in a Feb. 29 statement that the Secretary of Health and Human Service had declared a public health emergency Feb. 4 in connection with the coronavirus outbreak, a development that authorizes the issuance of an emergency use authorization (EUA). FDA Commissioner Stephen Hahn said the agency sees the policy as striking “the right balance during this public health emergency.” Hahn said the FDA is not changing its standards for issuance of EUAs, but that the agency “will continue to help ensure sound science prior to clinical testing and follow-up” with a critical independent review from the agency.

Test ramp-up to reach 10,000 per day

The pathogen has been reported in three eastern U.S. states, Florida, New York and Rhode Island, and the states of Florida and Washington have issued emergency declarations. Public health labs have typically not been included in the scope of EUAs, and the Association of Public Health Laboratories issued a Feb. 29 statement noting that public health labs would be able to ramp up testing to 10,000 tests per day by the end of the first week of March.

The FDA said in a Feb. 27 update on supply chain considerations that 63 device manufacturers are operating more than 70 establishments in China producing essential medical devices. Several of those sites are experiencing staff shortages due to employee absences, although no impact was seen at the time with regard to drug availability.

The problems with the test developed by the U.S. Centers for Disease Control and Prevention have surfaced, and Nancy Messonnier, director of the CDC’s National Center for Immunization and Respiratory Diseases, said on a Feb. 28 briefing, “this has not gone as smoothly as we would have liked.” FDA commissioner Stephen Hahn said the FDA had collaborated with the CDC upon learning of the issues with the CDC tests, and that the determination was that a manufacturing issue was at the root of the issues with the tests.

Tim Stenzel of the FDA’s Center for Devices and Radiological Health said on the March 2 webinar that while the guidance/policy is in immediate effect, it remains subject to comment in concordance with good guidance practices. The policy is limited to labs that are certified to perform high-complexity tests per the Clinical Laboratory Improvement Amendments Act of 1998, and to molecular diagnostics.

Stenzel said the guidance does not affect existing policies regarding who should be tested. The lab in question should validate the test prior to clinical use, and should notify the FDA when clinical use of a validated test begins. Minimal test validation requirements under this policy includes limit of detection testing, for which the guidance suggests a dilution of three replicates per concentration. This would be followed by confirmation of the final concentration with 20 replicates.

For clinical evaluation, the agency recommends testing of at least 30 contrived, reactive specimens and 30 non-reactive specimens. Contrived, reactive specimens can be achieved by spiking viral RNA or inactivated virus into leftover clinical specimens, and 20 of these should be spiked at concentrations of one to two times the limits of detection. The remaining 10 should be spiked to cover the assay testing range, Stenzel said. An acceptable performance level is 95% agreement at one to two times LoD and 100% agreement at all other concentrations and for negative specimens.

For inclusivity, Stenzel said the FDA recommends conducting an in silico analysis of the percent identity matches against publicly available sequences. All the published sequences should be detectable with the selected primers and probes. He said the New York State Department of Health’s Wadsworth Center was granted an EUA authorization, and that the FDA, the CDC, and the office that handles the Biomedical Advanced Research and Development Authority program are working with several makers of in vitro diagnostics and labs to enable additional EUAs as quickly as possible.

The agency encourages labs to be familiar with state regulations as well, given that several states have their own clinical lab requirements. The primer sequence by Integrated DNA Technologies Inc., of Coralville, Iowa, is commercially available and is the same as the CDC primer. Stenzel said the EUA can be updated and amended as circumstances require. FDA commissioner Stephen Hahn was finally added to the federal government’s coronavirus task force according to a March 1 statement by the Trump administration.

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