We are almost three years into the public health emergency as a result of the COVID-19 pandemic, and still only have 19 rapid antigen tests authorized for at-home use in the United States. The primary barrier to bringing new antigen tests to market has been FDA’s minimum requirement of 80% sensitivity for authorization. The 80% sensitivity requirement for antigen tests has yet to be explained either scientifically or clinically by the Agency.
It is clearly rooted in fear that less sensitive tests may have too many false negatives. But the question is, is 80% sensitivity the right place to set the bar? By doing so, FDA has limited the number of tests that have reached the market, thereby reducing available supply and increasing prices. Right now, the demand is not particularly high, but last winter had a severe shortage in which it was hard to find antigen tests at any price. That could happen again.
As FDA would acknowledge, the antigen tests are the fastest and most practical method for distributing testing in the general population. These practical benefits are in marked contrast to molecular COVID-19 tests that are used for definitive diagnosis and are generally expected to detect the SARS-CoV-2 virus at least 95% of the time when someone is infected. The molecular tests must be run in a laboratory and usually take several days due to the need to ship the sample and the constraints on laboratory availability and supplies.
Everyone understands that antigen tests are less sensitive and could miss someone who is asymptomatic with an early infection or a low viral load. But on the flip side, they are very specific, i.e., if a positive result is obtained, the result is typically very accurate in the range of 95% of the time or better. The question is whether requiring 80% sensitivity is too high for this tool and keeping too many of them from the market.
Ironically, a recent FDA safety communication points to a potential way out of this dilemma. In this safety communication, FDA advises the public as follows: If you test negative and have COVID-19 symptoms, you test again 48 hours later for a total of two tests. After two negative tests, you should consider a molecular test, or call your healthcare provider. If you test negative and do not have COVID-19 symptoms, you should test again 48 hours later. If the second test is negative, you should test again 48 hours after the second test. If the third test is negative, you should test again with an antigen test, or get a laboratory molecular-based test, or call your healthcare provider. If you get a positive result on any repeat test with an at-home COVID-19 antigen test, you most likely have COVID-19.
These recommendations come based on the latest National Institutes for Health (NIH) and University of Massachusetts Chan Medical School study which was funded by the NIH Rapid Acceleration of Diagnostics (RADx) program. This prospective cohort study recruited participants who were asymptomatic to investigate the performance of serial testing using COVID-19 rapid antigen tests compared to molecular tests. The study represents the most robust attempt at understanding the performance of serial use of rapid antigen tests for SARS-CoV-2 detection among asymptomatic individuals in the U.S. The study demonstrates that serial testing does optimize the ability to detect SARS-CoV-2 infections when using at-home rapid antigen tests.
This testing scheme calls into question whether it is really necessary to require at least 80% sensitivity when comparing an initial at-home antigen test result to the more sensitive molecular tests. One can use serial testing to make up for the sensitivity shortfall in most antigen tests.
In fact, FDA recently authorized several antigen tests that did not meet the sensitivity threshold of 80% for symptomatic individuals when the study population had more than 20% of individuals with low viral loads. The low viral loads were most likely due to individuals infected with the Omicron variant. Instead of simply denying authorization, FDA responded by authorizing these tests with a requirement in the labeling for serial testing. For example, labeling stated: This test is authorized “when tested twice over three days with at least 24 hours (and no more than 48 hours) between tests.”
While this was a step in the right direction, only the tests whose clinical studies occurred during the Omicron surge had this stipulation included in their labeling. Low viral loads within the population will impact all authorized tests, not just the ones that have been authorized since the emergence of the Omicron variant. However, we have not observed any action on the part of FDA to revise the labeling of products that were authorized in 2020 or 2021 to make the labeling consistent across all tests. Nor has FDA required additional warnings highlighting, to the user, that the clinical performance data on the currently authorized tests were generated primarily on a variant that is no longer circulating in the U.S. This lack of uniformity across manufacturers may place an unfair stigma on the newest entrants to the market as being fundamentally less accurate when that may not be the case.
The NIH RADx-sponsored study mentioned in the safety communication addresses a data gap in FDA’s review of antigen tests. FDA permitted the authorization of tests with at least 80% sensitivity in symptomatic individuals and allowed claims regarding serial screening of asymptomatic individuals without submitting performance data on this population. While companies were required to commit to conducting such studies post-authorization, none have been completed to date based on our knowledge. (This nebulous post-authorization study is not well defined in the public templates. See our previous post on the topic here.) The NIH RADx-funded study is a long-awaited dataset finally made public addressing the question of performance in asymptomatic individuals but also includes performance against the Omicron variant for tests authorized without this challenge.
The study results are not surprising, excluding singleton RT-PCR positives, the first-week sensitivity was only 79.2% (71.0-85.9%) after testing three times with a rapid antigen test at 48-hour intervals. Meaning the tests currently on the market and evaluated in the study do not appear to meet FDA’s minimum requirement of 80% sensitivity, even when tested three times in a serial fashion.
The results of this study referenced in the safety communication could be a signal of a new requirement for antigen test developers to add to their labeling, essentially requiring testing at least 3 times with 48 hours between tests if you are asymptomatic and get a negative test result. Adding this new testing scheme to labeling may provide flexibility to the 80% sensitivity requirement but may also require new clinical study designs from sponsors still vying for EUA authorization.
FDA said they are committed to appropriately accurate and reliable at-home COVID-19 tests. The recent safety communication may be a model for how FDA can more broadly authorize tests that do not meet the 80% sensitivity requirement and in addition level the playing field through consistent labeling of the testing scheme for all EUA holders.