Amid mounting scrutiny, FDA overhauls antibody testing guidance

Serological (or “antibody”) tests are used to identify if an individual has had an immune response to a pathogen. A new FDA guidance document overturns existing FDA policy and requires that most marketed tests undergo the agency’s Emergency Use Authorization review procedure.


By Laura DiAngelo, MPH


Executive IQ Brief

  • How Things Work Now: A March 16 guidance from the FDA allowed manufacturers two options to market their serological tests. Manufacturers could either submit their test to the FDA for an Emergency Use Authorization (EUA) or notify the FDA that they had completed validation of the test and market it without review. This policy led to the marketing of hundreds of serological tests without substantive review by the FDA, concerning policymakers. By contrast, just twelve tests were authorized for use by FDA on an emergency basis.

  • What’s New: On May 4, the FDA issued new guidance rolling back the policy allowing manufacturers to bring serological tests to market without an EUA. All tests currently marketed under the previously available pathway, also known as “Pathway D,” will have to submit an EUA request to the agency within 10 days. The guidance doesn’t update the types of validation testing that should be submitted as part of an EUA submission, but does note that the policy could further evolve as the agency’s thinking and scientific evidence on serological testing advances.
  • Impact: The agency’s tighter requirements on serological test market entry could help increase public trust in the tests available. However, new research on what level of antibody response could confer functional immunity, and how long that immunity can last, is still needed and will still be a key factor when policymakers (including state governors) decide which tests purchase.

  • What’s Next: Manufacturers that have a serological test marketed through Pathway D (i.e., without an EUA) have 10 days to submit a request to the agency, including all of their validation data. While the FDA states that “almost half” of those currently on the market are either in EUA review or pre-EUA, at least 100 more tests will either need to be submitted to the FDA or be pulled off the market. Going forward, every manufacturer will need to submit a serological test for EUA consideration. However, serological tests that are developed and used within Clinical Laboratories are only “encouraged” to submit an EUA to the FDA for their tests, rather than required.

Regulatory Background and Context

In March 2020, the FDA issued comprehensive guidance for diagnostic developers of both molecular diagnostics and serologic tests. Under that guidance, serologic test developers could pursue two pathways to market access:


  • Pathway C: A serological test developer can submit an Emergency Use Authorization (EUA) to the agency for formal authorization.
  • Pathway D: A serological test developer can submit notification to the agency that they have completed validation of a test.

As of May 4, twelve manufacturers had their serological tests authorized by the FDA under an EUA. However, an estimated 200 have bypassed agency review via Pathway D and are marketed without significant oversight from the FDA.

That policy has raised significant concerns recently. The preliminary report from an investigation opened in the House of Representatives found that “a lack of enforcement by FDA has allowed manufacturers to make fraudulent claims” about tests, and that “companies are ignoring requests from [HHS] to voluntarily submit their tests for validation.”


[Read AgencyIQ’s extensive explainer “How the FDA does—and doesn’t—regulate serological tests for COVID-19” here.]


With increasing calls from federal and state lawmakers to re-open the economy, there is an acute need for reliable, accurate serological testing. Plans to re-open, including that from Former FDA Commissioners Scott Gottlieb and Mark McClellan, highlight serological testing as an opportunity to establish a risk-based reintroduction plan by loosening restrictions for individuals who have been determined to be immune to the virus via antibody testing.


However, without validated research on what titer of antibodies to the virus would establish functional immunity, and an understanding how long that immunity would last, widespread serological testing could be limited to use in epidemiological research for now.


What’s New

On May 4, the FDA issued new guidance eliminating Pathway D for manufacturers, stating that the “policy succeeded in encouraging development of serology tests” and was no longer needed.


Under the updated policy, all serological tests will need to be submitted to the FDA for an EUA. Those that are already on the market have 10 days to submit an EUA to the agency.


In a statement, FDA Commissioner Stephen Hahn said that “when the March 16 policy was issued, flexibility was appropriate since antibody tests are not meant to diagnose active [COVID-19] infection, and early availability and use could help answer critical questions about COVID-19 prevalence and immunity.” Now that several tests had been cleared through the EUA process, the FDA said that flexibility was no longer needed.


The updated policy maintains that developers can market and distribute their tests to laboratories following the test’s validation, but only for up to 10 days after validation and before the submission of an EUA. The policy is shorter than the 15 days of pre-submission marketing granted to molecular diagnostics in the FDA’s March 16 guidance document.


However, clinical laboratories that develop and use their own tests are still not subject to the requirement to submit an EUA. Under the new guidance, the policy for serological tests developed and used by laboratories that are certified to conduct high-complexity testing under CLIA has not changed from the March 16, 2020 guidance. In effect, these laboratories may continue developing serological tests in-house and use them after submitting validation information the FDA and without submitting an EUA. Although FDA continues to “encourage” such laboratories to submit EUAs for their laboratory developed tests, the agency notes that reviewing these types of tests are not it’s priority:


“At this time, we believe it is most beneficial to focus our EUA review and authorization efforts on tests from commercial manufacturers, which have the potential to be distributed more broadly, rather than laboratory-developed serology tests that are not for diagnostic purposes, are being performed at one laboratory that is CLIA-certified to perform high-complexity testing, and that are validated in-house.”

The FDA arguably does not have authority to compel clinical laboratories to submit their tests, called laboratory developed tests (LDTs), for formal review by the agency. However, in times of public health emergency, the agency has taken the stance that the increased risk profile associated with the emergency situation does grant it authority over LDTs.


[AgencyIQ subscribers can read an analysis on the interaction, and challenges, CLIA creates for the FDA and CMS.]


The FDA’s guidance states that if it “becomes aware” of any issues with an LDT serology tests, it will take action. However, the agency’s ability in this area is fairly limited. The guidance states that if issues with a test aren’t addressed in a timely manner, it will “remove the laboratory from the website of listing notifications and may take additional actions as appropriate.” What those actions could be, however, remains unclear, as it doesn’t have the authority to compel the withdrawal of these devices—a significant issue for the FDA in recent years.


What’s Next

The guidance is immediately in effect, meaning that all manufacturers currently marketing a test under Pathway D will have to submit an EUA request, including all their validation data, within 10 days. While “almost half” of all tests marketed by manufacturers under Pathway D are either in active EUA review or a pre-EUA process, this still means that a significant number will need to be submitted to the agency or withdrawn in the next few days. The FDA says that “over 200 antibody tests” are currently under investigation in some part of the EUA process.
Going forward, manufacturers will have 10 days from the time of their validation data notification to the agency to submit their EUA.


Capacity is still likely to be an issue. The FDA cannot compel clinical laboratories to report on their testing capacity, but states in the guidance that “it would be helpful to FDA if laboratories provide information on testing capacity.”


Another issue is whether the FDA’s approach to testing regulation is equitable. Laboratories are generally exempt from FDA oversight, while manufacturers are subject to FDA oversight like premarket review. As a result, tests originating from laboratories may not be held to the same standards of quality or effectiveness.


While laboratories may be able to develop tests more quickly, concern about the accuracy of serological tests could actually be a boon for the diagnostics industry. Because diagnostics are most stringently regulated, those tests are more likely to obtain market recognition and favorable payments if they are authorized, cleared or approved by the FDA.


Additionally, public awareness of and concern over serological testing regulation could lead to legislative diagnostic policy reform, already under consideration in Congress.


For the FDA, a significant short-term concern is its capacity to review the now un-authorized serology tests quickly. There are approximately 200 such tests on the market, and many of them may soon seek authorization. That could overwhelm FDA review resources, or potentially slow the review of other diagnostic products under review.


So far it doesn’t appear that expected clearances have been impacted, as the FDA cleared 275 510(k)s in March (up from 224 in February and 232 in January). Although the FDA has taken some actions to focus its resources on certain tests (i.e., those from traditional developers), and recently initiated a blanket EUA for developers that submit their products for validation by the NIH, the impact on April and May clearance numbers could be significant.


To contact the author of this analysis, please email Laura DiAngelo.
To contact the editor of this analysis, please email Alec Gaffney.


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