The U.S. FDA continues to modify its emergency use authorization (EUA) policy for testing for the SARS-CoV-2 virus, although workplace testing is still on the agency’s to-do list. The FDA’s Tim Stenzel noted on a May 6 briefing that serological tests for antibodies must now demonstrate an overall sensitivity of 90% and overall specificity of 95%, a set of standards that might challenge some tests that are available under the EUA policy.

The FDA’s device center has posted a webpage listing the serology tests that are administered under the EUA policy, some of which are directed toward a single antibody while others capture multiple antibodies. The list includes data on sensitivity and specificity along with positive and negative predictive values (PPV and NPV, respectively), and the agency advised that the PPV and NPV values are still based on an assumed prevalence of 5% in the area where a given serological test is administered.

More specific expectations regarding antibody isotopes

Stenzel, who is the director of the Office of In Vitro Diagnostics and Radiological Health, said the agency’s performance expectations for serological tests are that overall sensitivity is 90%, and overall specificity is at least 95%. The specificity level of 95% is applicable to each antibody isotype, assuming results for each isotype are broken out, and sensitivity should be 90% for IgG if reported. If IgM is reported separately, sensitivity should be at least 70%, but the list of tests suggests that not all the tests currently operating under the EAU meet those benchmarks.

Stenzel made note of the May 4 policy update for serological tests for antibodies, highlighting that commercial tests developers must now notify the FDA within 10 days of validation of an antibody test or within 10 days after publication of the policy, whichever is later. He emphasized that serological tests are not for diagnosis, but said a second serological test should be considered if a first one comes back positive if the prescribing entity deems it important to know whether the first result was accurate. The combination of two serological tests offers greater specificity than a single test, and possibly improved PPV as well, Stenzel said, adding that the resulting information might be useful “if that’s important for a given patient.”

The results of the FDA/NIH/CDC collaboration for evaluation of serological testing will be made public, Stenzel said, assuming the FDA makes a regulatory decision for authorization on the basis of those results. He noted that the listing of test performance parameters also lists confidence intervals, awareness of which is important given the differences in sample sizes used to validate the listed tests.

Stenzel said home collection and home testing require the FDA to accumulate data to affirm accurate use, which in part revolves around human use factors. Those factors will have to be aligned under the EUA paradigm, and the FDA is concerned in part that home test users might not follow test instructions with sufficient fidelity to ensure the validity of the results. “We feel it’s important to assess the performance … with actual or simulated patients,” Stenzel said, adding that user competence is also a consideration.

Template for home sample collection on near horizon

The agency is working on a template for home sample collection, which Stenzel said should be available in “the not-too-distant future.” The FDA is also working on an antigen testing template, after which the agency will commence working on EUA templates for home test EUA applications.

The agency’s pre-EUA advisory process is intended in part to advise a test developer on validation methods, and Stenzel said this was a more important consideration for serological tests before the templates were made available in the May 4 policy update. These templates should provide some answer about the more widely used test types, although tests for antigens and those that rely on saliva samples might not be exhaustively addressed in the templates. Still, he said developers should go through the templates before going to the agency for advice as FDA employees “are very busy” dealing with the pandemic. Stenzel also said the three-agency serological test validation protocol is limited to tests that rely on serum and plasma as samples.

Addressing a question regarding workplace testing, Stenzel said the FDA has operated under the expectation that a physician would be involved in ordering the test as a means of ensuring accurate interpretation of results to the patient or that patient’s other health care professionals. He said the FDA is open to authorizing a test for use on asymptomatic individuals, although the FDA is concerned about the likelihood of false positives. Studies that would clarify such an eventuality “are not necessarily easy studies to carry out,” Stenzel said, noting that the listing of such a test under the EUA paradigm “would require some discussion with our team.”

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