Point-of-Care Instrument-Read SARS-CoV-2 Antigen Test

Among about 100 symptomatic subjects, sensitivity (PPA) was about 85% and specificity (NPA) was 100%, with a small number of false negatives and no false positives.

Cumulative PPA by days from symptom onset was 100% at day 0, about 90% for days 0-1, about 80% for days 0-2 and 0-3, about 82% for days 0-4 and about 85% for days 0-5 and 0-6. The initial invalid rate for symptomatic subjects was about 4%, and all initial invalids were resolved on retest with residual processed sample.

FDA issued the Emergency Use Authorization for CLIA-certified laboratories meeting the requirements for moderate or high complexity testing. A reissued letter of authorization added use at the point of care under a CLIA Certificate of Waiver, Compliance or Accreditation, and testing of individuals without symptoms. It also added a condition requiring a post-authorization clinical evaluation to support the serial screening claim. The current labeling reflects FDA's repeat-testing framework: twice over three days for symptomatic individuals and three times over five days for those without symptoms, with at least 48 hours between tests.

FDA's antigen template asks for a minimum sensitivity of 80% or more. The roughly 85% point estimate meets it. The template text we reviewed does not set a confidence-interval lower bound for antigen tests, and with about 40 RT-PCR positives the 95% interval is wide. With the template's minimum of 30 positives, the interval is necessarily wide, and adding positives is the only way to narrow it. Specificity of 100% also carries uncertainty: a negative set of this size cannot rule out a false-positive rate of a few percent.

The days-from-onset table should be read as cumulative, not daily. The dip to about 80% in days 0-2 and 0-3 rests on only a couple of dozen positives, so one or two misses move the estimate by several points. The labeling also notes that only symptomatic results are presented, although about 400 patients were tested. That limits what the published data say about asymptomatic performance, which FDA addressed through the post-authorization serial-testing condition rather than single-test accuracy.

The test detects SARS-CoV-2 nucleocapsid antigen in direct anterior nasal swabs collected by a healthcare provider, without transport media, and a benchtop biosensor instrument reads the cartridge. The original authorization covered individuals suspected of COVID-19 within the first six days of symptom onset, tested in CLIA-certified laboratories that meet the requirements for moderate or high complexity testing.

Extending the authorization to the point of care, in patient care settings operating under a CLIA Certificate of Waiver, Compliance or Accreditation, required clinical performance data from point-of-care settings. The reissued authorization letter lists updated clinical performance data that include clinical evaluation in POC settings. The evidence therefore had to show acceptable agreement with a high-sensitivity RT-PCR when swabs were collected and tested immediately where patients were seen, stratified by days since symptom onset.

Because the test uses a direct swab with no transport medium, the device swab could not be split. A second swab had to be collected at the same visit for the comparator, and both swabs had to come from the same anatomical site so that sampling differences would not bias agreement.

SARS-CoV-2 antigen tests reached the U.S. market mainly through Emergency Use Authorizations under section 564 of the Federal Food, Drug, and Cosmetic Act. These followed the HHS Secretary's determination of a public health emergency and the declaration that circumstances justified emergency use of COVID-19 diagnostics. An EUA is not a clearance: FDA authorizes use when it is reasonable to believe the product may be effective and its known and potential benefits outweigh its risks. The authorization comes with Conditions of Authorization that can require post-authorization studies and labeling updates.

FDA set out its clinical expectations in a series of downloadable EUA templates, revised several times during 2020 and 2021. The antigen template we reviewed recommends prospective, blinded, randomized clinical agreement studies with at least 30 positive and 30 negative natural clinical samples from the intended-use population, with days since symptom onset recorded for every subject. The comparator should be one of the more sensitive authorized RT-PCR assays using chemical lysis and solid-phase extraction, and a discordant-analysis plan should be fixed in advance. Candidate tests should show a minimum sensitivity of 80% or more for each sample type. For a point-of-care claim, the whole clinical evaluation should run at CLIA-waived sites with four to six non-laboratory-trained operators using only the quick reference instructions, supplemented by blinded near-LoD contrived samples and flex studies.

Serial testing changed what an antigen authorization means. FDA later revised the authorized uses of all authorized SARS-CoV-2 antigen tests to require repeat testing. Tests authorized for symptomatic people are now for use at least twice over three days with at least 48 hours between tests. Tests authorized for asymptomatic people are now for use at least three times over five days. FDA based this on data showing that repeat testing after a negative antigen result increases the chance of an accurate result. Antigen tests are less sensitive than laboratory RT-PCR, so single-test sensitivity near the 80% expectation and strong dependence on days since symptom onset are what make the category hard.

• Testing the direct swab immediately after collection matches the authorized workflow and avoids frozen or transported specimens, which FDA's template treats as needing separate fresh-versus-frozen justification.
• A concurrently collected nasal swab in VTM for the comparator keeps the device and comparator at the same anatomical site and visit. That limits discordance from biological variability, a point FDA's template stresses.
• Using a high-sensitivity EUA RT-PCR as comparator follows the template's recommendation. It also makes agreement with positives a conservative estimate, because the comparator detects low viral loads that antigen tests miss.
• Recording days since symptom onset made it possible to report cumulative agreement from day 0 to day 6, which supports the six-day symptomatic claim and shows where sensitivity is weakest.