Abbott sends the SARS-CoV-2 test results directly to patients’ smartphones, which can be displayed to gain entrance into areas requiring proof of COVID-19 testing
There is no greater example that COVID-19 is a major force for change in the clinical laboratory industry than the fact that—though the US federal government pays 50% of the nation’s total annual healthcare spend of $3.5 trillion—it recently spent $760 million to purchase 150 million COVID-19 tests from Abbott Laboratories (NYSE:ABT), an American multinational medical devices and healthcare company headquartered in Abbott Park, Ill., “to expand strategic, evidence-based testing in the United States,” according to the company’s website.
In August, the federal Food and Drug Administration (FDA) granted an emergency use authorization (EUA) to Abbott for its BinaxNOW portable rapid-response COVID-19 antigen (Ag) test. The credit-card sized test costs $5 and can return clinical laboratory test results in minutes, rather than hours, days, or in some cases, weeks, the Wall Street Journal (WSJ) reported.
The test includes a free smartphone app called NAVICA, which enables those tested to receive their test results directly on their mobile devices—bypassing the patient’s primary care physicians.
According to Abbott’s website, the app “allows people who test negative to get an encrypted temporary digital NAVICA Pass, similar to an airline boarding pass. NAVICA-enabled organizations will be able to verify an individual’s negative COVID-19 test results by scanning the individual’s digital NAVICA Pass to facilitate entry into facilities.”
This feature of Abbott’s new COVID-19 test is a good example of how quickly innovation in the medical laboratory testing profession is bringing new features and new capabilities to the marketplace. By marrying the SARS-CoV-2 test with the NAVICA Pass feature, Abbott hopes to deliver increased value—not just to physicians and their patients—but also to employers with employee screening programs and federal government programs designed to screen federal employees, as well as being used for screening travelers at airports and other transportation hubs.
Abbott appears to be banking that in the future such identification will be required to “enter organizations and other places where people gather,” as the company’s website states.
Testing Limited to CLIA-Certified Clinical Laboratories
An HHS news release announcing the government’s planned distribution of the BinaxNOW tests stated that “Testing will be potentially deployed to schools and to assist with serving other special needs populations.”
In the news release, Alex Azar, HHS Secretary, said, “By strategically distributing 150 million of these tests to where they’re needed most, we can track the virus like never before and protect millions of Americans at risk in especially vulnerable situations.”
The EUA adds that “Testing of nasal swab specimens using [BinaxNOW] … is limited to laboratories certified under CLIA that meet the requirements to perform high, moderate, or waived complexity tests. This test is authorized for use at the [point of care], i.e., in patient care settings operating under a CLIA Certificate of Waiver, Certificate of Compliance, or Certificate of Accreditation.”
The FDA’s EUA describes the BinaxNOW portable rapid-response COVID-19 antigen test (above) as “a lateral flow immunoassay intended for the qualitative detection of nucleocapsid protein antigen from SARS-CoV-2 in direct nasal swabs from individuals suspected of COVID-19 by their healthcare provider within the first seven days of symptom onset.” The test costs $5 and Abbott sends results directly to the patient’s smartphone using the free NAVICA app included with the test. (Photo copyright: Abbott Laboratories.)
IVD Companies See Boom in COVID-19 Test Sales
Demand for COVID-19 testing has created opportunities for in vitro diagnostics (IVD) companies that can develop and bring tests to market quickly.
Recent issues of Dark Daily’s sister print publication—The Dark Report (TDR)—covered IVD companies’ second quarter (Q2) boom in sales of COVID-19 instruments and tests, while also noting a fall-off in routine clinical laboratory testing during the COVID-19 pandemic.
Abbott Laboratories saw molecular diagnostics sales increase 241% in Q2 driven by $283 million in sales of COVID-19 testing, while rapid diagnostic COVID-19 testing rose 11% on $180 million in sales in Q2, TDR reported, based on Abbott data.
“There is huge economic incentive for diagnostic companies to develop technologies that can be used to create rapid tests that are cheap to perform,” said Robert Michel, Publisher and Editor-in-Chief of TDR and Dark Daily. “In this sense, COVID is a major force for change.”
“This new COVID-19 antigen test is an important addition to available tests because the results can be read in minutes, right off the testing card,” said Jeff Shuren, MD, JD (above), Director of the FDA’s Center for Devices and Radiological Health (CDRH), in an FDA news release announcing the federal government’s $760 million purchase of 150 million Abbott BinaxNOW rapid-response antigen COVID-19 tests. “This means people will know if they have the virus in almost real-time. Due to its simpler design and the large number of tests the company anticipates making in the coming months, this new antigen test is an important advancement in our fight against the pandemic.” (Photo copyright: The New York Times.)
Thus, Abbott is determined to ensure this product launch is successful and that the test works as promised. According to a news release, “In data submitted to the FDA from a clinical study conducted by Abbott with several leading US research universities, the BinaxNOW COVID-19 Ag Card demonstrated sensitivity of 97.1% (positive percent agreement) and specificity of 98.5% (negative percent agreement) in patients suspected of COVID-19 by their healthcare provider within the first seven days of symptom onset.”
“The massive scale of this test and app will allow tens of millions of people to have access to rapid and reliable testing,” said Joseph Petrosino, PhD, professor and chairman, Molecular Virology and Microbiology, Baylor College of Medicine, in the Abbott news release. “With lab-based tests, you get excellent sensitivity but might have to wait days or longer to get the results. With a rapid antigen test, you get a result right away, getting infectious people off the streets and into quarantine so they don’t spread the virus.”
Abbott has invested hundreds of millions of dollars in two manufacturing facilities where the tests will be made, John Hackett Jr, PhD, an immunologist and Abbott’s Divisional Vice President Applied Research and Technology, and lead scientist on the BinaxNOW project, told The Atlantic.
“Our nation’s frontline healthcare workers and clinical laboratory personnel have been under siege since the onset of this pandemic,” said Charles Chiu, MD, PhD, professor of Laboratory Medicine at University of California, San Francisco, in the Abbott news release. “The availability of rapid testing for COVID-19 will help support overburdened laboratories, accelerate turnaround times, and greatly expand access to people who need it.”
However, other experts are not so sure. In the Atlantic article, Michael Mina MD, PhD, Assistant Professor Epidemiology at Harvard’s T.H. Chan School of Public Health, voiced the need to test both asymptomatic and pre-symptomatic people. “This is the type of [COVID-19] test we have been waiting for—but may not be the test.”
Nevertheless, the federal government’s investment is significant. Abbott plans to start shipping tens of millions of tests in September and produce 50 million tests per month starting in October, Forbes reported.
Shifting Clinical Laboratory Paradigms
BinaxNOW will be performed without doctors’ orders, in a variety of locations, and results go directly to patients’ smartphone—without a pathologist’s interpretation and medical laboratory report. This is new ground and the impact on non-CLIA labs, and on healthcare in general, is yet to be seen.
Clinical laboratory managers will want to monitor the rise of rapid-response tests that can be easily accessed, conducted, and reported on without physician input.
Though the test initially drew ‘raves’ from Trump administration, the FDA now suggests negative results should be confirmed with an additional ‘high-sensitivity authorized SARS-CoV-2 molecular test’
This spring, as the United States attempted to jump-start a national response to the SARS-CoV-2 coronavirus pandemic, the Trump administration heralded Abbott Laboratories’ five-minute test for COVID-19 as a major breakthrough. But even as the federal Food and Drug Administration (FDA) issued dozens of Emergency Use Authorizations (EUAs) to quickly get COVID-19 diagnostic tests into clinical use, the accuracy of some of those tests came into question—including Abbott’s ID NOW COVID-19 rapid molecular test.
The continuing controversy over Abbott’s ID NOW COVID-19 test shows how the national spotlight can be a double-edged sword, bringing both widespread favorable attention to a breakthrough technology, followed by heightened public scrutiny if deficiencies emerge. At the same time, from the first news stories about the Abbott ID NOW COVID-19 test, pathologists and clinical laboratory managers understood that this test always had certain performance parameters, as is true of every diagnostic test.
“Everybody was raving about it,” a former administration official, speaking on the condition of anonymity to discuss internal deliberations, said of ID NOW in an interview with Kaiser Health News (KHN). “It’s an amazing test, but it has limitations which are now being better understood.”
In a White House ceremony on March 29, 2020, President Trump praised his administration’s role in speeding up development “on both testing and treatment that will help us win our war against the coronavirus.” Among the moves highlighted was the FDA’s approval two days earlier of Abbott’s ID-NOW COVID-19 rapid molecular test (above), which the President stated, “delivers lightning-fast results in as little as five minutes,” adding, “Normally, this approval process from the FDA would take 10 months, and even longer, but we did it in four weeks.” (Photo copyright: Washington Post.)
FDA Warns Public about Inaccurate Test Results
On May 14, the FDA issued a public warning about the point-of-care test’s accuracy after receiving 15 “adverse event reports” indicating some patients were receiving “false negative results.”
“Regardless of method of collection and sample type, Abbott ID NOW COVID-19 had negative results in a third of the samples that tested positive by Cepheid Xpert Xpress when using nasopharyngeal swabs in viral transport media and 45% when using dry nasal swabs,” the NYU study authors stated.
Abbott Rebuts Criticism
In a statement following the FDA’s warning, Abbott said, “We’re seeing studies being conducted to understand the role of ID NOW in ways that it was not designed to be used. In particular, the NYU study results are not consistent with other studies. While we’ve seen a few studies with sensitivity performance percentages in the 80s, we’ve also seen other studies with sensitivity at or above 90%, and one as high as 94%.
“While we understand no test is perfect, test outcomes depend on a number of factors including patient selection, specimen type, collection, handling, storage, transport and conformity to the way the test was designed to be run. ID NOW is intended to be used near the patient with a direct swab test method,” Abbott’s statement added, noting the company would be “further clarifying our product information to provide better guidance” and “reinforcing proper sample collection and handling instructions.”
Then, on May 21, Abbott issued another statement highlighting an interim analysis of an ongoing multisite clinical study demonstrating ID NOW COVID-19 test performance is ≥94.7% in positive agreement (sensitivity) and ≥98.6% negative agreement (specificity) when compared to two different lab-based molecular PCR reference methods.
“We’re pleased ID NOW is delivering on what it was designed to do—quickly detect the virus in people who need to know now if they’re infected,” said Philip Ginsburg, MD, SAIM, Senior Medical Director, Infectious Disease, Rapid Diagnostics at Abbott, in the statement. “This is great news for people who are experiencing symptoms and want to take action before they infect others, reducing the spread of infection in society.”
Nonetheless, KHN reported on June 22 that the FDA had “received a total of 106 reports of adverse events for the Abbott test, a staggering increase. The agency has not received a single adverse event report for any other point-of-care tests meant to diagnose COVID-19.”
Second Comparison Study Results for Abbott’s ID NOW
The Abbott ID NOW test correctly identified 74% of positive samples. In comparison, Cepheid’s Xpert Xpress SARS CoV-2 test correctly identified 99% of positives. Negative agreement was 100% and 92.0% for ID NOW and Xpert, respectively.
The FDA’s testing policy for clinical laboratories and commercial manufacturers recommends diagnostic tests correctly identify at least 95% of positive samples. However, KHN pointed out, a senior FDA official in late May said coronavirus tests that were administered outside lab settings would be considered useful in fighting the pandemic even if they miss 20% of positive cases.
“There’s no way I would be comfortable missing two out of 10 patients,” Whittier told KHN.
Abbott ID-NOW’s Role in the Global Fight to Stop COVID-19
Abbott’s ID NOW COVID-19 test is promoted as delivering positive test results in five minutes and negative results in about 13 minutes. On its website and in news releases, Abbott maintains its test “performs best in patients tested earlier post symptom onset.”
In a July 17 statement, Abbott said, “ We have shipped 5.3 million of our rapid ID NOW tests to all 50 states, Washington DC, Puerto Rico and the Pacific Islands. The majority of these tests have been sent to outbreak hotspots and we’ve asked that customers prioritize frontline healthcare workers and first responders.”
It is common for a new diagnostic instrument and a new clinical laboratory test to be continually improved after initial launch. Thus, the performance of such devices at the time they are given clearance from the FDA to be used in clinical care can be much improved several months or years later.
Given the importance of a reliable point-of-care SARS-CoV-2 test during the pandemic, it can be assumed that Abbott Laboratories is working closely with its medical laboratory customers specifically to improve the accuracy, reliability, and reproducibility of both the instrument and the test kit.
In the absence of a “gold standard,” researchers are finding a high frequency of false negatives among SARS-CoV-2 RT-PCR tests
Serology tests designed to detect antibodies to the SARS-CoV-2 coronavirus that causes the COVID-19 illness have been dogged by well-publicized questions about accuracy. However, researchers also are raising concerns about the accuracy of molecular diagnostics which claim to detect the actual presence of the coronavirus itself.
“Diagnostic tests, typically involving a nasopharyngeal swab, can be inaccurate in two ways,” said Steven Woloshin, MD, MS, in a news release announcing a new report that “examines challenges and implications of false-negative COVID-19 tests.” Woloshin is an internist, a professor at Dartmouth Institute, and co-director of the Geisel School of Medicine at Dartmouth.
“A false-positive result mistakenly labels a person infected, with consequences including unnecessary quarantine and contact tracing,” he stated in the news release. “False-negative results are far more consequential, because infected persons who might be asymptomatic may not be isolated and can infect others.”
Woloshin led a team of Dartmouth researchers who analyzed two studies from Wuhan, China, and a literature review by researchers in Europe and South America that indicated diagnostic tests for COVID-19 are frequently generating false negatives. The team published their results in the June 5 New England Journal of Medicine (NEJM).
For example, one research team in Wuhan collected samples from 213 hospitalized COVID-19 patients and found that an approved RT-PCR test produced false negatives in 11% of sputum samples, 27% of nasal samples, and 40% of throat samples. Their research was published on the medRxiv preprint server and has not been peer-reviewed.
The literature review Woloshin’s team studied was also published on medRxiv, titled, “False-Negative Results of Initial Rt-PCR Assays for COVID-19: A Systematic Review.” It indicated that the rate of false negatives could be as high as 29%. The authors of the review looked at five studies that had enrolled a total of 957 patients. “The collected evidence has several limitations, including risk of bias issues, high heterogeneity, and concerns about its applicability,” they wrote. “Nonetheless, our findings reinforce the need for repeated testing in patients with suspicion of SARS-Cov-2 infection.”
Another literature review, published in the Annals of Internal Medicine, titled, “Variation in False-Negative Rate of Reverse Transcriptase Polymerase Chain Reaction–Based SARS-CoV-2 Tests by Time Since Exposure,” estimated the probability of false negatives in RT-PCR tests at varying intervals from the time of exposure and symptom onset. For example, the authors found that the median false-negative rate was 38% if a test was performed on the day of symptom onset, versus 20% three days after onset. Their analysis was based on seven studies, five of which were peer-reviewed, with a total of 1330 test samples.
Doctors also are seeing anecdotal evidence of false negatives. For example, clinicians at UC San Diego Health medical center treated a patient with obvious symptoms of COVID-19, but two tests performed on throat samples were negative. However, a third test, using a sample from a bronchial wash, identified the virus, reported Medscape.
Sensitivity and Specificity of COVID-19 Clinical Laboratory Tests
The key measures of test accuracy are sensitivity, which refers to the ability to detect the presence of the virus, and specificity, the ability to determine that the targeted pathogen is not present. “So, a sensitive test is less likely to provide a false-negative result and a specific test is less likely to provide a false-positive result,” wrote Kirsten Meek, PhD, medical writer and editor, in an article for ARUP Laboratories.
“Analytic” sensitivity and specificity “represent the accuracy of a test under ideal conditions in which specimens have been collected from patients with either high viral loads or a complete absence of exposure,” she wrote. However, “sensitivity and specificity under real-world conditions, in which patients are more variable and specimen collection may not be ideal, can often be lower than reported numbers.”
In a statement defending its ID Now molecular point-of-care test, which came under scrutiny during a study of COVID-19 molecular tests by NYU Langone Health, Northwell Health, and Cleveland Clinic, according to MedTech Dive, Abbott Laboratories blamed improper sample collection and handling for highly-publicized false negatives produced by its rapid test. An FDA issued alert about the test on May 14 noted that Abbott had agreed to conduct post-market studies to identify the cause of the false negatives and suggest remedial actions.
Issues with Emergency Use Authorizations
In their NEJM analysis, Woloshin et al point to issues with the FDA’s process for issuing Emergency Use Authorizations (EUAs). For example, they noted variations in how manufacturers are conducting clinical evaluations to determine test performance. “The FDA prefers the use of ‘natural clinical specimens’ but has permitted the use of ‘contrived specimens’ produced by adding viral RNA or inactivated virus to leftover clinical material,” they wrote.
When evaluating clinical performance, manufacturers ordinarily conduct an index test of patients and compare the results with reference-standard test, according to the Dartmouth researchers. For people showing symptoms, the reference standard should be a clinical diagnosis performed by an independent adjudication panel. However, they wrote, “it is unclear whether the sensitivity of any FDA-authorized commercial test has been assessed in this way.” Additionally, a reference standard for determining sensitivity in asymptomatic people “is an unsolved problem that needs urgent attention to increase confidence in test results for contact-tracing or screening purposes.”
“To truly determine false negatives, you need a gold standard test, which is essentially as close to perfect as we can get,” Stephen Rawlings, MD, PhD, (above), a resident physician of internal medicine and infectious diseases fellow at UC San Diego’s Center for AIDS Research (CFAR), who has been working on SARS-CoV-2 test validation since March. “But there just isn’t one yet for coronavirus,” he told Medscape. (Photo copyright: University of California, San Diego.)
Continued adherence to current measures, such as physical distancing and surface disinfection.
Development of highly sensitive and specific tests or combinations of tests to minimize the risk of false-negative results and ongoing transmission based on a false sense of security.
Improved RT-PCR tests and serological assays.
Development and communication of clear risk-stratified protocols for management of negative COVID-19 test results.
“These protocols must evolve as diagnostic test, transmission, and outcome statistics become more available,” they wrote.
Meanwhile, clinical laboratories remain somewhat on their own at selecting which COVID-19 molecular and serology tests they want to purchase and run in their labs. Complicating such decisions is the fact that many of the nation’s most reputable in vitro diagnostics manufacturers cannot produce enough of their COVID-19 tests to meet demand.
Consequently, when looking to purchase tests for SARS-CoV-2, smaller medical laboratory organizations find themselves evaluating COVID-19 kits developed by little-known or even brand-new companies.
As federal and state officials ease many regulatory requirements to speed new COVID-19 serology tests to market with minimum data about performance, labs are left with important questions to answer on their own
Every day, elected officials at all levels of government call for a huge expansion of COVID-19 serology testing. But, as most clinical laboratory managers and pathologists know, it is a complex undertaking for a lab to select any serological test, validate it, then run it daily in support of patient care, and have confidence that the results are accurate and reproducible.
Clinical laboratories across the United States understand the volume of testing will be in the tens of millions—even hundreds of millions—of COVID-19 serology tests. That is an important financial opportunity because it gives clinical labs the opportunity to generate some cash flow to offset the 60% decline in daily routine specimens they have experienced since most states enacted shelter-in-place orders in early March.
But this big opportunity to serve physicians and patients with COVID-19 serology testing also comes with equally big risks. There are three major risks a COVID-19 serology testing program that clinical labs must successfully address, otherwise the consequences can be devastating.
Three Major Serology Testing Risks for Clinical Laboratories
Risk one comes during the time when medical laboratories shop for COVID-19 serology tests. As of this writing, about 20 such tests have an emergency use authorization (EUA) with the Food and Drug Administration (FDA) and more are expected to obtain an EUA. As is true with everything in life, not all of these tests will perform equally. The risk to the lab is that it purchases a COVID-19 assay that later proves to be unreliable, despite the lab’s rigorous validation process.
Risk two derives from the fact that new diagnostic methods are being incorporated into the serology tests that companies are submitting to the FDA for an EUA. Although the data submitted to the FDA may indicate acceptable performance to the federal agency, in actual clinical use many unexpected or unknown factors could be recognized which lower confidence that the new method utilized by this particular assay is producing accurate results. That risk would only be recognized downstream from validation and the lab would find itself dealing with unhappy physicians, patients, and employers (who were using the test to check the health of their employees).
Risk three is supply chain risk. Will the manufacturer of the COVID-19 serology test be capable of supplying all of its clinical lab customers with adequate supplies to meet each lab’s demand for this testing? New manufacturers have an unknown track record in their ability to supply their lab customers. But even the largest in vitro diagnostics (IVD) manufacturers may need to ration kits, reagents, and other consumables to the large number of medical laboratories they serve. This happened with the rapid molecular tests for COVID-19. Community laboratories capable of performing these tests could not obtain adequate supplies to serve their client physicians.
Millions Lost on Faulty COVID-19 Serology Test Kits
If there is a fourth major risk to clinical labs performing COVID-19 serology tests for physicians, patients, and employers (who are screening employees in their workplace) it is the negative publicity that can result if a lab’s choice of a COVID-19 serology test ends up generating inaccurate or unreliable test results.
The most recent example is here in the United States. On March 27, Abbott Laboratories announced that the FDA had issued an EUA for its Abbott ID NOW platform and its point-of-care rapid molecular test for COVID-19 that could produce results in less than 15 minutes. This made national news and was hailed regularly during the daily White House COVID-19 Task Force briefings.
What is important with the examples of Spain, United Kingdom, and a major IVD manufacturer is that news outlets are ready to pounce on any evidence that COVID-19 tests are returning inaccurate or unreliable results. This is a source of risk which every clinical laboratory wants to avoid.
How Clinical Laboratories Can Minimize Risk When Buying COVID-19 Serology Tests
During their upcoming webinar, James Westgard, PhD (above), and Sten Westgard of Westgard QC will address how clinical laboratory leaders can evaluate different serology COVID-19 tests by: understanding the testing architecture and intended medical use of COVID-19 testing, taking inventory of lab resources; navigating EUA, LDT, and non-EUA regulatory approval; assessing the expected performance of test methods; understanding the critical performance characteristics for COVID-19 testing; and much more. (Photo copyright: Dark Daily.)
This is an exceptional opportunity to gain an inside perspective of how your lab can address the three major risks identified above when selecting a COVID-19 serology test for use in patient care. You’ll gain essential insights about how to assess the public data on tests with an EUA.
This webinar presentation will also discuss how your lab should view all of its COVID-19 testing as a single program. That’s because your lab may test the same patient with a rapid molecular test, then later do serology tests in the days after the patient may have cleared the infection.
Register now for this critical educational opportunity by clicking here or by entering this URL in your web browser (https://www.darkdaily.com/webinar/quality-issues-your-clinical-laboratory-should-know-before-you-buy-or-select-covid-19-serology-tests/).
