The U.S. FDA is actively working on guidance for conversion of emergency use authorizations (EUAs) to conventional premarket review programs, but the FDA’s Tim Stenzel said he does “not perceive a need to rush to convert EUAs” because of the volume of EUA applications, and because he does not expect the public health emergency “to end anytime soon.”
Stenzel, director of the FDA’s Office of In Vitro Diagnostics and Radiological Health (OIR), was addressing the Jan. 6 edition of the weekly town hall for COVID-19 testing, noting that the agency will have some feedback on the EUA conversion question even in the absence of guidance. That feedback will hinge on the characteristics that distinguish the SARS-CoV-2 virus from similar respiratory pathogens, but Stenzel added that the agency is still swamped with requests for EUAs for various types of tests.
Stenzel also referred to the two latest variants of the virus, which have emerged principally in the U.K. and South Africa. The variant reported first in the U.K., dubbed B.1.1.7, features an amino acid deletion that seemed at first blush to aid the virus in evading detection, although other specifics about this variant have not been fully described.
New year, same testing priorities
The FDA’s priorities regarding EUA test applications largely mirror those in place in 2020, Stenzel indicated. These priorities include tests that can exert a significant impact on public health, but also include home tests, home collection kits, point-of-care tests, and tests that can be performed in “super-high” volumes in central labs. Stenzel said that any EUA that can check one of these boxes will be a priority at the agency.
The agency is also keen to see applications for testing that can be produced in high volume for low per-unit costs, but Stenzel reiterated a plea that applicants file EUA submissions that are complete and well written. Some data can be filed in spreadsheet format to expedite review, and applicants should include their protocols for clinical validation studies. Among the information of interest is the methods for selection and collection of test samples, the absence of which might impede the review process.
Stenzel said both new strains seem to be of higher infectivity than the variant that initially swept across the U.S. and the rest of the globe. The working theory behind this increase in infectivity is that these variants are more effective at binding to the receptor on the host cell surface, which when combined with higher viral load translates into greater infectivity and a more dangerous pathogen.
“We do have an interest in sequencing-based tests that provide whole genome sequence,” Stenzel said, one of which has already been authorized. This test, developed by San Diego-based Illumina Inc., was authorized prior to the agency’s understanding of how important sequencing might ultimately prove, and was “a great step forward,” Stenzel said. He added that the agency is asking developers about the impact of these two new variants on the function of test primers and probes.
There is also an interest at the agency in the ability of existing EUA tests to detect the new SARS-CoV variants, which has been the subject of communication with developers and of internal agency research. The Taqpath assay with S gene drop-out by Thermo Fisher Scientific can pick up on whether there is a drop-out of the S gene target in a region of the virus’s RNA where there is a deletion of amino acids 69 and 70. Thermo Fisher said its test hasn’t been particularly affected by the deletion because of the test’s use of multiple targets. The detection of the S gene drop-out is suggestive of the presence of the so-called B.1.1.7 variant (the variant first identified in the U.K.) when the test is otherwise positive, Stenzel said. Developers can reach out to the CDC for technical assistance on this question.
FDA has been asking developers about any problems with primers and probes for variants of the virus, and has interrogated sequence databases to see if there are any obvious problems that could affect test performance. The agency is asking developers for an assessment of the impact of the mutations on the performance of their tests and is working with developers to assess any potential impact. Stenzel said the FDA does not yet have enough information to make any public statements on this point, but will do so expeditiously when a sufficient amount of confirmed information arises.
There are obviously a number of assay design issues caused by the mutations, particularly for tests based on a single-target assay. Multi-gene assays will be less affected by mutations and thus will have an advantage. Some technologies are fundamentally not amenable to multi-gene targets, and Stenzel said there is a “pressing need to understand how the variants might impact the performance of single-gene assays.”
Data not there yet for post-vaccination testing
Stenzel said the data needed to demonstrate that a serology test could be predictive of immunity in any manner would be of interest. The FDA has authorized semi-quantitative serology and neutralizing antibody tests, which may be useful in assessing immunity for those who have been vaccinated, but Stenzel said that using any tests under existing EUAs for this purpose “would be dangerous right now,” given the absence of data to reliable demonstrate such a capability.
Development of such a test would require “significantly large studies” for validation, Stenzel said, adding that it would be dangerous to make any such claims at present, given the paucity of data to back such a claim. There is also some question as to whether a given test would function the same way for those who have been exposed to the SARS-Cov-2 virus and its recent progeny, in no small part because of the lack of data on whether the resulting antibodies are the same as those generated by one or more of the current suite of authorized vaccines.