With rapid antigen tests for SARS-CoV-2 slow to come to market, officials at the US Food and Drug Administration have tried to signal via a number of public comments that the agency would be flexible regarding test performance requirements and use models.
These indications of flexibility have largely failed to speed development and commercialization of rapid antigen tests, however, as test vendors, wary of falling short of agency requirements, have instead stuck to the more stringent specifications presented in the FDA's test templates.
Early in the COVID-19 pandemic, rapid antigen tests were identified as a potentially key technology for slowing transmission of SARS-CoV-2 with calls for these tests growing as it became evident that molecular test capacity was not able to keep up with demand and was unlikely to ever reach a level where regular testing at population scale would be possible.
Antigen tests have also been slow to scale, at least to the capacities deemed necessary by advocates of population screening. In particular, the US has yet to see the sort of cheap, relatively low sensitivity rapid antigen tests that researchers like Harvard University epidemiologist Michael Mina have advocated for use in serial screening models where frequent, repeated testing could compensate for such tests' lower sensitivity.
The FDA has often been cited as the key roadblock to the availability of such tests, with supporters of serial testing models claiming that the agency's stated requirements of 80 percent sensitivity and 99 percent specificity for home tests available by prescription and for 90 percent sensitivity and 99 percent specificity for over-the-counter tests have added to product development times and prevented lower performing tests from entering the market.
To date, only 15 rapid antigen tests for COVID-19 have received Emergency Use Authorization from the FDA. In comparison the agency has authorized 219 molecular tests for the virus.
FDA, however, has indicated flexibility on its requirements. Last year, an FDA official told 360Dx on background that these benchmarks are not hard-and-fast cutoffs that tests must hit in order to receive EUA. The official said that the agency was open to considering a variety of SARS-CoV-2 testing approaches including lower sensitivity rapid tests that could be used at home in a serial manner.
On a September call for labs and test developers, Timothy Stenzel, director of the Office of In Vitro Diagnostics and Radiological Health at the FDA's Center for Devices and Radiological Health, entertained a serial testing scenario much like those proposed by Mina.
"Where our recommended levels of sensitivity may not be achieved with a single test result in a home situation, maybe with the paper strip test, strategies utilizing serial testing, for less sensitive tests, could be deployed," he said, noting that in the case of a test with, for instance, 70 percent sensitivity, "perhaps with a two-pack, two test results you can achieve a greater sensitivity together."
More recently, an FDA official, speaking to 360Dx on background, reiterated these remarks, noting that the agency has made a conscious effort to communicate its openness to different models of testing including speaking with some of its critics about this openness. The official said, however, that the agency has not received any submissions for SARS-CoV-2 rapid antigen tests that feature sensitivity below that specified in the agency's templates and are intended to be used in serial fashion to compensate for that lower sensitivity.
One reason for that lack of submissions appears to be that while FDA has said it is open to such tests, vendors nonetheless consider submitting tests that don't meet the agency's template too risky a prospect from a regulatory perspective.
Prashant Chouta, CEO of Cambridge, Massasachusetts-based E25Bio said that he was aware of FDA's stated flexibility around SARS-CoV-2 rapid antigen test requirements but questioned what that flexibility actually meant.
"Obviously, any application will be considered," he said. "It's not the consideration that matters, it is the approval that matters. There's a big difference between, yes, I will consider, and yes, I will approve."
E25Bio has submitted for EUA a rapid antigen test to be available by prescription and is in the process of supplementing that submission with a submission for over-the-counter use. Chouta said that the test meets the performance requirements for home testing set out in the FDA template. He also said that E25Bio would probably have been able to bring a home test to market sooner if it had aimed at less stringent performance requirements.
"Obviously, to get to a higher level [of performance] it takes time, it takes validation, it takes research," he said. "If you are asking, would you have had a product out there if the sensitivity [requirement] was lower, probably, yes."
But, he said, "we would not waste our time with a submission that does not meet the minimum requirements that the FDA mentioned in its template."
Stephen Tang, president and CEO of OraSure Technologies – which plans to submit a rapid antigen test for EUA for professional use and prescription-use, self-test indications by the end of March with a submission for an over-the-counter at-home self-test to follow – similarly said that the company considered the FDA template the authoritative statement on its test performance requirements, regardless of any other comments coming from the agency.
"We have had a long relationship working with FDA," he said. "We take them at face value. The templates are the templates. And that is what we are targeting and abiding by. That is the way we are playing the submission that we are about to make."
Australian diagnostics firm Ellume, the first company to receive EUA for an over-the-counter at-home SARS-CoV-2 rapid antigen test, similarly worked to maximize its test's performance, as opposed to adopting a serial testing approach like those advocated by Mina and others.
"We certainly took to trying to make the most accurate test we possibly could," said Sean Parsons, Ellume's founder and CEO.
In a study of the test in 198 subjects ranging from 2 years to 82 years of age, it correctly identified 96 percent of positive samples and 100 percent of negative samples in symptomatic individuals and 91 percent of positive samples and 96 percent of negative samples in people without symptoms, placing it above the FDA's template requirements for sensitivity but below the stated requirements for specificity in the asymptomatic population.
While Ellume's success getting an OTC home test through FDA shows that vendors can meet FDA's stated performance requirements, advocates of the serial model argue that the requirements have not only slowed the progress of such tests to market but also that home tests, like Ellume's, that do make it through the EUA process, are too expensive and/or not available in the quantities needed for frequent population scale testing.
Many say that for these tests to have use for mass testing purposes, they need to be in the $10 to $15 range per test. Abbott's BinaxNow COVID-19 Ag Card test, by comparison, which received FDA EUA in December, costs about $25. The firm said it anticipates delivering about 30 million of the tests in Q1 2021, ramping up to 90 million in Q2.
Parsons said Ellume's test will start in the $30 range and that the company expects to bring that down into at least the $20 range as it scales production. It has thus far produced on the order of hundreds of thousands of tests for the US market and aims to produce tens of millions of tests for the US market this year.
Orasure's Tang said the company had not determined pricing for its planned OTC home test. The company's OTC home HIV test sells for around $40 to $50, but he noted that buyer behavior for this test is different than he would anticipate for an at-home SARS-CoV-2 test.
E25Bio's Chouta said that company hoped to offer its test for under $10, though he added that whether it could bring the price down to this level would depend on the scale it produced and sold at.
The experience of Pasadena, California-based Innova Medical Group suggests that test vendors were perhaps prudent in not taking FDA's offers of flexibility at face value. The company has produced the kind of cheap (around $5), scalable, but lower performing SARS-CoV-2 rapid antigen tests for which proponents of serial testing have advocated but have not yet been able to get them through FDA.
Daniel Elliott, president and CEO of Innova, said that FDA turned down the company's first two EUA submissions for OTC at-home use of the test. He said it is now preparing an EUA submission for point-of-care use and will then add on submissions for prescription home use and OTC home use.
Elliot said that he believed Innova had run up against the fact that a serial testing model didn't fit well within FDA's traditional approach to evaluating tests in which it is mainly concerned about the performance of a test when used in a single individual at a single time point.
"On the one side, we are advocating to do [serial testing], but on the other side, we have to fit into the very narrow cracks that FDA has defined as how you go through the approval process," he said.
FDA did not respond to a request for comment on Innova's SARS-CoV-2 submissions.
While modeling studies suggest that frequent and consistent testing can significantly reduce transmission of SARS-CoV-2 even when using lower performance tests, it remains something of an open question how feasible and effective such approaches are when applied in the real world.
Liverpool, England, has been running a COVID-19 testing pilot using the Innova assay to test around 40 percent of the city's population. That followed an initial plan to test the entire population that was ultimately deemed unfeasible.
In data published in an interim analysis, 897 individuals tested positive for COVID-19 via lateral flow while 2,902 positive individuals were identified by PCR. As of Jan. 21, 359,606 lateral flow tests had been performed on 205,836 residents (41 percent of the Liverpool population) and had identified 4,421 positive individuals.
The Innova test demonstrated sensitivity of 40 percent, which was well below the 77 percent accuracy the test showed in validation studies collected by Public Health England and Oxford University in which trained staff performed the test. The test identified roughly two-thirds of individuals with high viral loads (as determined by a PCR cycle threshold of less than 25). Test specificity was 99.9 percent.
While the testing program identified several thousand COVID-19 positive individuals who might otherwise have gone undetected, Alex Crozier, a researcher in the division of biosciences at University College London, said that Liverpool did little better than nearby Manchester, which did not undertake a similar testing program.
"It seemed for a while that Liverpool might have been holding off that second wave more than comparable cities, but in the end it basically got hit as badly as everywhere else," he said. "It doesn't seem from the initial analysis that it was able to prevent the second wave or keep society more open, which I think is probably quite an important finding."
Crozier suggested that targeted use of rapid antigen testing would probably prove more feasible and more useful than a true mass screening campaign.
Data from a collaboration between the US National Institutes of Health and the University of Illinois could soon provide additional information on how effective serial rapid antigen testing could be at suppressing SARS-CoV-2.
Bruce Tromberg, director of the National Institute of Biomedical Imaging and Bioengineering, said that results from the study so far indicate that "if you do these [rapid antigen tests] multiple times per week, you can actually begin to approach the sensitivity of PCR."
The study isn't, however, currently evaluating how well rapid antigen tests with performance levels below those stated in the FDA template detect infections when used serially. Like the majority of test vendors, the NIH and Illinois researchers chose to take the agency's template as the definitive statement on acceptable test sensitivity and specificity.
"We haven't really explored the performers that are below 80 percent, you know, say 70 percent," Tromberg said. "That's in part because the FDA has a bar. The FDA wants you to have 90 percent [sensitivity] in order to get over-the-counter approval for their test."
He said the researchers plan to look at lower sensitivity tests in the future, but he expressed sympathy for test vendors who have decided to stick to the FDA template as opposed to pursuing a lower sensitivity, serial route.
"Remember, this has never been done before," he said. "So, if you're a company with shareholders and you are trying to get testing into people's homes, that's exploring the great unknown."
This story first appeared in our sister publication, Genomeweb.