On February 2020, FDA issued a Policy that allows CLIA certified high-complexity testing laboratories to use their validated diagnostic tests to detect the SARS-CoV-2 virus in specimen while they are preparing for EUA submission to FDA.
The goal of this policy is to increase the testing capacity of laboratories and rapid detection of COVID-19 cases in the United States to control the emergence of this rapidly spreading, severe illness.
After test validation, laboratories have to notify FDA about completion of validation, report their test results, submit the application for the Emergency Use Authorization (EUA) to FDA and perform clinical testing as summarized here below.
FDA Emergency notification steps for LABORATORIEs:
STEP 1: TEST VALIDATION
Tests need to be validated before being used use and comply with the following minimum requirements:
Limit of Detection (LoD)
LoD as the lowest concentration at which 19/20 replicates are positive.
§ Laboratories shall document the limit of detection (LoD) of their SARS-CoV-2 assay.
§ Laboratories shall test a dilution series of three replicates per concentration, and then confirm the final concentration with 20 replicates.
§ Laboratories shall submit in their EUA requests the results from the most challenging clinical matrix if they intent to use multiple clinical matrices for clinical testing.
Performance as 95% agreement at 1x-2x LoD, and 100% agreement at all other concentrations and for negative specimens.
§ In the absence of known positive samples for testing, laboratories shall confirm performance of their assay with a series of contrived clinical specimens by testing a minimum of 30 contrived reactive specimens and 30 non-reactive specimens
§ Contrived reactive specimens can be created by spiking RNA or inactivated virus into leftover clinical specimens, of which the majority can be leftover upper respiratory specimens such as NP swabs, or lower respiratory tract specimens such as sputum, etc.
§ Twenty of the contrived clinical specimens should be spiked at a concentration of 1x-2x LoD, with the remainder of specimens spanning the assay testing range.
100% of published SARS-CoV-2 sequences shall be detectable with the selected primers and probes.
§ Laboratories should document the results of an in-silico analysis indicating the percent identity matches against publicly available SARS-CoV-2 sequences that can be detected by the proposed molecular assay.
in silico cross-reactivity as shall be greater than 80% homology between one of the primers/probes and any sequence present in the targeted microorganism
§ At a minimum, FDA believes an in-silico analysis of the assay primer and probes compared to common respiratory flora and other viral pathogens is sufficient for initial clinical use.
§ Laboratories shall follow recognized laboratory procedures in the context of the sample types intended for testing for any additional cross-reactivity testing.
Step 2: FDA Notification
Following completion of assay validation, laboratories should notify FDA that their assay has been validated. This notification should include the name of the laboratory, name of the lab director, address, and contact person in this email. FDA will acknowledge receipt of this notification via auto-reply. Then, laboratories shall submit a completed EUA request within 15 business days of the initial communication to FDA that the assay has been successfully validated.
Step 3: Reporting Results
All test reports shall include a general statement that the test has been validated but FDA’s independent review of this validation is pending.
Step 4: EAU Request
Laboratories shall submit a completed EUA request within 15 business days of the initial communication to FDA that the assay has been successfully validated. They should use the COVID-19 specific EUA template available at FDA website.
Step 5: Clinical Testing
While awaiting FDA feedback on the EUA request, clinical laboratories shall obtain confirmation of the first five positive and the first five negative clinical specimens using an EUA-authorized assay, which may involve sending these ten specimens to another laboratory for confirmation.
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