By: Anand Shah, M.D., Deputy Commissioner for Medical and Scientific Affairs, and Jeff Shuren, M.D., Director, Center for Devices and Radiological Health
As we at the FDA have said before, every step we have taken in our approach to COVID-19 testing has been a careful balancing of risks and benefits – all done to anticipate and meet continuing and evolving public health needs as we combat this virus. That’s why today the FDA issued an update to a policy from March 16, 2020 on antibody tests for COVID-19.
High-quality antibody tests (a type of serological test) can help us understand a person’s and population’s exposure to COVID-19. A person who has been exposed to, and recovered from, COVID-19 will likely have antibodies to the SARS-CoV-2 virus in their blood. These tests may be important for guiding our next steps in the fight against this pandemic, such as by providing information on disease prevalence and the frequency of asymptomatic infection, and also by identifying potential donors of “convalescent plasma,” an approach in which blood plasma containing antibodies from a recovered individual serves as a therapy for an infected patient with severe or immediately life-threatening disease.
At the time we issued our March 16 policy, a higher level of flexibility was appropriate for antibody tests than for molecular tests that detect the presence of the virus that causes COVID-19, since antibody tests are not meant for use to diagnose active SARS-CoV-2 infection. The flexibility in our March 16 policy allowed for early use of antibody tests to begin to answer critical population-level questions about the prevalence of COVID-19 infections in different communities, and whether the presence of antibodies conveys immunity, and, if so, for how long. Early availability of serology tests has helped generate important information that can inform the future use of serology tests.
To help mitigate the trade-off of helping to ensure early availability and having time to obtain a good understanding of test performance, the FDA’s March 16 policy was intended to limit antibody testing to laboratories certified under the Clinical Laboratory Improvement Amendments (CLIA) by the Centers for Medicare and Medicaid Services (CMS) to perform testing in high-complexity and point-of-care settings when covered by such certificates – that is, labs with special clinical and technical expertise – as long as the tests were properly validated and labeled as outlined in our policy, and the developer notified the FDA. Under CLIA, only those laboratories are permitted to perform tests that have not been FDA authorized. The FDA is aware that several of these labs have conducted their own validation of commercial manufacturers’ tests they were interested in and then used those tests that were fit for purpose. Notably, use of antibody tests in other settings, including at home, prior to issuance of an emergency use authorization (EUA) authorizing such use is not permitted under CLIA, and our March 16 policy did not change that. Moreover, as we have said before, it is not accurate for developers to claim their test was authorized by the FDA if an EUA was not granted for the tests, nor should they be distributing their test if it has not been properly validated.
To be clear, the March 16 policy did not change that an EUA is a key tool to making critical products for COVID-19, including antibody tests, available in a public health emergency. We continue to encourage all developers to submit EUA requests, so the FDA is able to examine data on the test’s performance and make a formal determination of whether to authorize it for emergency use, because EUAs give labs and health care professionals the confidence that the FDA has reviewed a particular test. In fact, almost half of the tests offered by commercial manufacturers are already the subject of an EUA review or a pre-EUA, a pre-submission that provides an opportunity for the developer to begin to share data with or seek advice from the FDA. To date, 12 antibody tests have been authorized under an individual EUA, most within just the past few days, and over 200 antibody tests are currently the subject of a pre-EUA or EUA review.
In addition to reviewing data submitted in the form of EUA requests, we also worked with the National Institutes of Health, the Centers for Disease Controls and Prevention, and the Biomedical Advanced Research and Development Authority to help establish a capability at the National Cancer Institute (NCI) for the U.S. Government to independently validate certain antibody tests, including antibody tests that were not the subject of an EUA or pre-EUA, as well as those that were under FDA review. The FDA can use the NCI data to inform future decision making, such as whether to authorize the test, guide us in engaging the test developer for additional information to support its test remaining on the market, or take other action regarding tests that do not perform adequately, including to stop their marketing in the U.S. NCI has shared validation data from 13 test kits so far with the FDA. We will make the NCI results available once the FDA has reviewed and determined if any further actions are appropriate for those test kits prior to publication.
We are continuing to adapt based on real-world experience and data and so, as the FDA has authorized more antibody tests and validation data have become available, including through the capability at NCI, the careful balancing of risks and benefits has shifted from where it was in mid-March. Therefore, the FDA is making an important change to the March 16 policy regarding the FDA review for commercial manufacturers’ serology tests.
Under this revised policy, the FDA has outlined the following expectations for antibody test developers:
Commercial manufacturers will submit EUA requests, with their validation data, within 10 business days from the date they notified the FDA of their validation testing OR from the date of this policy, whichever is later.
Furthermore, the FDA has provided specific performance threshold recommendations for specificity and sensitivity for all serology test developers.
High-complexity laboratories developing their own tests, also called Laboratory Developed Tests or LDTs, must still have a CLIA certificate (provided by CMS) to legally develop a serology test. In addition, under the policy outlined by the FDA, they are performing their own validation and providing notification to the FDA, as well as following other labeling recommendations described in the March 16 policy. Developers of LDTs are still encouraged to seek authorization through an EUA.
In addition to updating the policy, we are introducing a more streamlined process to support EUA submissions and review. Two voluntary EUA templates for antibody tests have been made available – one for commercial manufacturers, and one for CLIA certified high-complexity labs who decide to seek FDA authorization. These templates will facilitate the preparation and submission of an EUA request and can be used by any interested developer. Last week the FDA issued an umbrella EUA for certain antibody tests that undergo validation at NCI, or another government agency designated by the FDA. Tests that the FDA confirms meet the performance and labeling criteria included in that EUA may be added under the umbrella EUA, streamlining the submission and review of these important tests.
In mid-March, it was critical for the FDA to provide regulatory flexibility for serology test developers, given the nature of this public health emergency and an understanding that the tests were not to be used as the sole basis for COVID-19 diagnosis, a fact that remains true today. However, flexibility never meant we would allow fraud. We unfortunately see unscrupulous actors marketing fraudulent test kits and using the pandemic as an opportunity to take advantage of Americans’ anxiety. Some test developers have falsely claimed their serological tests are FDA approved or authorized. Others have falsely claimed that their tests can diagnose COVID-19 or that they are for at-home testing, which would fall outside of the policies outlined in our March 16 guidance, as well as the updated guidance. Also, since that time, the FDA has become aware that a concerning number of commercial serology tests are being promoted inappropriately, including for diagnostic use, or are performing poorly based on an independent evaluation by the NIH.
When we become aware of these issues, we have and will continue to take appropriate action against firms unlawfully marketing their tests, for example, by detaining and refusing illegitimate test kits at the border. The FDA is continuing to provide updated information and educational materials to states and health care partners. If particular commercial manufacturers that are currently marketing tests under our March 16 policy fail to submit an EUA within 10 business days, we intend to share this information publicly. We will keep up our work to stop illicit tests from entering the U.S., and we encourage states, hospitals and consumers to be on high alert and to make informed purchasing decisions regarding these tests.
As important, those who use an antibody test need to understand its limitations and use test results as just one piece of data to inform decision making. All tests can provide at least some false results. Even a high-performing antibody test when used on individuals in a population that does not have many cases of COVID-19 infection – a population with low prevalence – may produce as many or more false results as true results because the likelihood of finding someone who has been infected is very small. This doesn’t mean the test is bad, but rather recognizes the inherent limitations of these kinds of tests. Therefore, it may be necessary for some individuals to have two serology tests performed to generate reliable results. That is why antibody tests should only be used as part of a well-conceived testing plan and why the results should always be interpreted by appropriate experts.
The FDA will continue to take steps to appropriately balance assurances that an antibody test is accurate and reliable with timely access to such tests as the continually evolving circumstances and public health needs warrant.
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