Test-Now, Regulate-Later Strategy Generates Robust Dx Test Pipeline in Record Time

Historically, the lag between Public Health Emergency (PHE) declaration and FDA approval of a lab test to diagnose the pathogen has been a minimum of eight weeks. Eight weeks into the coronavirus PHE, 18 different COVID-19 tests have received FDA Emergency Use Authorization (EUA)—tests from not only the CDC but also high-complexity CLIA and commercial labs. And that number grows literally every day. It’s an unprecedented achievement and here’s how it happened and continues to happen:

The Historical Context

This is the fifth time the US has declared a PHE in response to the outbreak of an infectious disease. The previous emergencies were for H7N9 influenza, Middle East Respiratory Syndrome (MERS), Ebola, EV-D68 and Zika virus. In each case, the FDA has relied on its EUA pathway to bring new tests to market on a rapid basis. And in each case, the initial EUA went to either the CDC or US Department of Defense, typically within a week of the emergency’s being declared. The government tests were designed as a stopgap measure offering immediate relief until commercial laboratories could get EUA clearance for their own tests. But that took at least two months, as illustrated by the table below.

Time Lag between PHE Declaration & FDA Approval of Commercial Lab Test

The Initial FDA COVID-19 Response

Initially, the FDA response to COVID-19 followed the same path as the previous outbreaks. Thus, on February 4, within days after the emergency was declared on January 31, the agency issued its first approval for a coronavirus test to the CDC’s reverse transcriptase real-time PCR (rRT-PCR) assay. The so called 2019 Real Time RT-PCR Diagnostic Test Panel was approved for use only by CDC-designated laboratories certified to perform high-complexity testing in accordance with agency protocol.

As before, the strategy was for the CDC assay to hold down the fort until commercial tests arrived. The CDC distributed test kits to state health departments and public health labs around the country. But reagent, instrumentation and lab staff shortages, coupled with questions about the test’s reliability in ruling out infection, made the pace of commercial test development frustratingly slow. Adding to the problem was the fact that unlike in previous outbreaks in which the pathogen was familiar to lab scientists, SARS-CoV-2 was something totally novel.

So, the FDA began to improvise utilizing a totally new tactic: Allow labs to validate and deploy tests first and seek EUA later. And not only that. The agency fashioned a different application of the approach for different kinds of labs, eventually creating four separate pathways for approval. It wasn’t until March 25, that the agency sought to conceptualize all the pieces into a single framework, while providing new guidance on how each of them works. The clarification came during a webinar provided by CDRH associate director Elizabeth Hillebrenner.

Policy A

The pathway the agency calls “Policy A” is for high-complexity CLIA labs seeking to launch validated SARS-CoV-2 laboratory-developed tests, including molecular tests, or antigen or antibody tests. Breaking from previous practice, the FDA is letting labs perform those tests immediately after internal validation without an EUA, as long as they notify the agency and apply for an EUA within 15 days. Policy A tests can be performed only by the lab that develops them. Nearly 100 labs are currently running LDTs, according to Hillebrenner, including those at Yale, Northwestern and Massachusetts General Hospital.

Policy B

First unveiled on March 16, “Policy B” allows states to authorize tests to be performed in high-complexity CLIA labs within their jurisdictions. Again, the tests can be run immediately after internal validation and notification to the FDA with no EUA. But unlike Policy A tests, Policy B tests don’t require labs to seek a subsequent EUA. According to Hillebrenner, four states—New York, Washington, Nevada and Maryland — have notified the FDA of their intent to follow the Policy B pathway.

Policy C

Policy C is the Policy A counterpart for commercial manufacturers of COVID-19 tests, allowing test makers to launch tests upon validation without an EUA, provided that they notify the FDA immediately and submit an EUA application within 15 business days. Policy C covers molecular, antigen and antibody tests that can be used in clinical labs and at the point-of-care, but not tests intended to be used at home. Hillebrenner says that four manufacturers have notified the FDA that they’re distributing kits under the Policy C path so far: Becton Dickinson, Qiagen, BGI and Co-Diagnostics.

Policy D

Policy D covers antibody-based serology tests, whether the source is a commercial manufacturer or a high-complexity lab. These tests can be used on patients immediately after validation without the need to apply for EUA. Over a dozen test developers are pursuing the Policy D pathway. On April 1, North Carolina-based Cellex’s qSARS-CoV-2 IgG/IgM Rapid Test became the first coronavirus serology test to receive FDA EUA clearance.

Takeaway

While significant reagent, instrumentation and staffing bottlenecks remain, the speed and extent of the diagnostic response to COVID-19 has been extraordinary and beyond all historical precedent. But then again, so is the urgency of the situation. Of course, the test-first-and-worry-about-regulatory-approval strategy is not without risk; and it may still not be enough to meet the urgent demand for COVID-19 testing (see related story about continuing test shortages ). But the creativity and energy of both the regulators and test makers in developing tests for detecting a totally novel pathogen in such a small window of time should not go unrecognized. 

COVID-19 LAB TESTS RECEIVING FDA EMERGENCY USE AUTHORIZATION
(As of April 10, 2020)