What Led to Reagent Shortages for Coronavirus Testing in the US?
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Countries that take aggressive actions against the COVID-19 outbreaks can make robust progress in halting the spread of the deadly virus and help "flatten the curve." In the initial stages of an outbreak like coronavirus, quarantines, contact tracing, and social distancing are deployed to control its spread; however, these measures are of limited use if suspected cases cannot be tested and identified.
The World Health Organization (WHO) has urged countries to ramp up testing for COVID-19. Tedros Adhanom Ghebreyesus, the director-general of WHO, said: "The most effective way to prevent infections and save lives is breaking the chains of transmission. And to do that, you must test and isolate. You cannot fight a fire blindfolded, and we cannot stop this pandemic if we don't know who is infected. We have a simple message for all countries: test, test, test, test."
Testing the right person is a crucial aspect in any pandemic. Apart from saving lives, widespread testing can provide important data required to model the course of the outbreak. Reagents are a critical component of testing. Unfortunately, many US labs have struggled to procure the reagents needed to perform large batches of coronavirus diagnostic testing.
COVID-19 TESTING IN THE US
In the US, the CDC provides the test kits for public health laboratories (PHLs) to perform real-time RT-polymerase chain reaction (rRT-PCR) detection of the novel coronavirus. The CDC received Emergency Use Authorization (EUA) from the Food and Drug Administration (FDA) for use of its rRT-PCR test on February 4.
The CDC test kits are available through the International Reagent Resource (IRR), which is a special unit established by the CDC to provide registered users with reagents, tools and information for studying and detecting pathogens, such as the virus causing COVID-19. The purpose of centralizing these functions within the IRR is to ensure that use and access of the reagents is monitored and quality control assured. The FDA specifies that clinical and commercial laboratories conducting coronavirus testing can access test reagents from commercial reagent manufacturers which have received EUA from the FDA.
Public health laboratories in the US performing the test receive the following reagents from the CDC’s International Reagent Resource (IRR):
- Equipment and extraction kits used in the preparation of specimens, including kits from QIAGEN and Roche
- rRT-PCR test kits, which include vials of test reagents that detect the virus that causes COVID-19
- Master mix kits from Thermo Fisher that contain the enzymes and other components needed to run the PCR test
- Human specimen control
- EUA positive control
SHORTAGE OF RNA EXTRACTION KITS
In the US, as the number of confirmed coronavirus cases rises, there have been widespread reports of shortages of reagents used to isolate the virus's RNA. RNA extraction is the first step to conduct a coronavirus test. According to a statement made by the American Society of Microbiology on March 10, "One challenge that has come to light is the supply shortage for SARS-CoV-2 PCR reagents. We are deeply concerned that as the number of tests increases dramatically over the coming weeks, clinical labs will be unable to deploy them without these critical components."
COVID-19 test kits developed by the Centers for Disease Control and Prevention (CDC) involve the use of reverse transcriptase-polymerase chain reaction. RNA extraction kits and procedures from QIAGEN and Roche are recommended by the FDA for recovery and purity of RNA for use with the CDC 2019-nCoV Real-Time RT-PCR Diagnostic Panel. The kits in shortage include varieties of the QIAGEN QIAamp Viral Mini Kit and the QIAGEN EZ1 Virus Mini-Kit and the Roche MagNA Pure nucleic acid kit. The supply shortage of the RNA extraction reagents has prevented labs from preparing samples for testing, which, in turn, is delaying test results.
WHAT LED TO THE SHORTAGE?
Problems with testing kits from the CDC
Initially, the US Food and Drug Administration (FDA) provided exclusive authorization to the CDC to conduct COVID-19 tests.
In February, the CDC rolled out a three-step diagnostic test for COVID-19 and distributed the testing kits to nearly one hundred state and local laboratories. But the majority of the laboratories faced issues such as negative controls failing and inconclusive results. On February 12, the CDC officially announced that the problem was the result of a faulty reagent. The agency assured to solve the problem and to re-manufacture the faulty component and distribute that to the public health labs; however, the lack of CDC test kits at this crucial time prevented wider-scale testing early on in the outbreak.
Criteria to determine who to test
Initially, the CDC recommended testing only for those who had a fever and/or lower respiratory symptoms, and had traveled to Wuhan, China or had been in contact with a suspected or confirmed coronavirus case. However, in late February, after a patient was infected despite a lack of travel history or known exposure, the CDC modified its guideline to include anyone with a fever who was hospitalized with a respiratory illness. This change increased the number of patients being tested, which quickly ramped up demand for reagents.
The CDC initially recommended collecting two specimen swabs for testing, which meant greater use of the reagents than was necessary.
ACTIONS TAKEN TO BOOST TESTING
Given the public health emergency, on February 29, the FDA issued the Emergency Use Authorization (EUA). Through the EUA, the FDA commissioner may allow unapproved medical products or unapproved uses of approved medical products to be used in an emergency to diagnose, treat, or prevent serious or life-threatening diseases or conditions caused by chemical, biological, radiological, and nuclear (CBRN) threats when there are no adequate, approved, and available alternatives.
Under the guidance issued on February 29 by the FDA, laboratories certified to perform high-complexity testing under CLIA were allowed to use their own COVID-19 lab-developed tests after validating them but before receiving FDA authorization. The labs would have 15 days to submit a completed emergency use authorization request. If authorized, the EUA means that this COVID-19 diagnostic is temporarily authorized for use until the public health emergency is terminated or the EUA is revoked by the FDA.
On March 16, the FDA updated its policy issued on Feb. 29. While the policy leading to an EUA for CLIA-certified labs remains unchanged, there is a new policy for state authorization of laboratories certified under CLIA. As per the update, when the test is developed under the authorities of the state in which the lab resides and the state takes responsibility for COVID-19 testing by laboratories in its state, the FDA does not intend to object to the use of such tests for specimen testing where the laboratory does not submit an EUA request to FDA.
Below is the latest (as of March 20) list of EUAs issued by the FDA of in vitro diagnostics for testing the virus that causes COVID-19.
- CDC 2019-nCoV Real-Time RT-PCR Diagnostic Panel (CDC)
- New York SARS-CoV-2 Real-time Reverse Transcriptase (RT)-PCR Diagnostic Panel (Wadsworth Center, NYSDOH)
- cobas SARS-CoV-2 (Roche Molecular Systems, Inc.)
- TaqPath COVID-19 Combo Kit (Thermo Fisher Scientific, Inc.)
- Panther Fusion SARS-CoV-2 (Hologic, Inc.)
- COVID-19 RT-PCR Test (Laboratory Corporation of America)
- Lyra SARS-CoV-2 Assay (Quidel Corp.)
- Quest SARS-CoV-2 rRT-PCR (Quest Diagnostics Infectious Disease, Inc.)
- Abbott RealTime SARS-CoV-2 assay (Abbott Molecular)
- Simplexa COVID-19 Direct (DiaSorin Molecular LLC)
- ePlex SARS-CoV-2 Test (GenMark Diagnostics, Inc.)
- Primerdesign Ltd COVID-19 genesig Real-Time PCR assay (Primerdesign Ltd)
- Xpert Xpress SARS-CoV-2 test (Cepheid)
The FDA has also posted an FAQ page on coronavirus diagnostic testing that lists potential alternative reagents, extraction methods, and alternative platforms to those required for the CDC test.
On March 13, the CDC revised its specimen collection recommendation for testing and now recommends collecting just one swab (a single upper respiratory nasopharyngeal) instead of two. This revision will cut the amount of reagents required for testing by almost 50 percent.
With alternative tests and reagent quickly coming available, and with streamlined specimen collection, reagent shortages are expected to become less of a hindrance to testing in the coming weeks. However, labs are now also struggling with shortages of essential supplies such as personal protective gear and testing swabs.