November 24, 2020

Volume X, Number 329

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COVID-19 and Lab Testing: What’s the Story Behind the Story?

Recently, newspapers and television news programs have been full of stories about laboratory testing and the important role it will play in containing the spread of COVID-19 and reopening U.S. economic activity. But these stories have told a mixed tale. The Washington Post and The New York Times both ran front page stories on April 19, 2020 about how the Centers for Disease Control and Prevention (CDC) had bungled production of the first U.S. test kits for detecting the presence of the novel coronavirus by manufacturing them in a lab contaminated with the virus, according to the Food and Drug Administration (FDA). The FDA, which regulates test kits, testing materials, and testing instruments, had investigated the causes of its sister agency’s failure, which delayed by weeks the nation’s fight against the virus.

Only days before those stories ran, news outlets reported that Great Britain had paid $20 million to purchase antibody tests from China but, upon their arrival in Great Britain, those tests were found not to work. On April 26, 2020, the front page story in The New York Times headlined that “Testing Remains Scarce as States Weigh Reopening.” 

Day after day, we have read conflicting stories about lab testing: do we have sufficient capacity and capability or do we not? If we do not, why don’t we? We have seen an alphabet soup of federal agencies named as being involved with clinical labs and working towards a solution to the many issues that have been raised. Having worked with labs for decades, we thought we would explore these really important questions. Which agency is responsible for what, and what are they doing? Every day we receive questions like these, and we thought that we would share what we have learned.

What Are the Tests?

In general, there are two types of tests related to COVID-19: (1) molecular tests used to detect the presence of the novel coronavirus, named SARS-CoV-2, and (2) serology tests used to detect the presence of antibodies, which the body creates after it has been exposed to and mounts an immune response to the virus.

Testing for the virus is indispensable in diagnosing COVID-19 and in seeking to follow and contain its spread. Antibody testing will be indispensable in getting people back to work and hopefully doing so in as safe a manner as possible. Businesses are already thinking about how to design back-to-work antibody testing programs. (Of note, the Mintz Employment, Labor, and Benefits Practice has kicked off a blog series exploring the intricacies of returning to work and is hosting a webinar on May 1, 2020 for those who are interested in joining us.)

Tests to detect the presence of the virus became available weeks before tests to detect the antibodies. In fact, it is only in the very recent past that we have begun to read stories in the popular press about the availability and probable benefits of antibody testing. We have also heard that there have been persistent problems with some of these antibody tests.

Who Makes the Tests?

Wholly new tests had to be developed to detect the novel coronavirus that causes COVID-19 disease, which (as we have all heard countless times) is a wholly new virus.  

In normal times, tests are generally developed both by diagnostics manufacturers that produce test kits to sell to clinical labs for use in testing and by laboratories themselves that develop and use such tests in their own facilities (the latter are called “laboratory developed tests,” also known as LDTs). The FDA regulates the manufacturing of test kits by diagnostics manufacturers under its medical device authorities, but it has exercised regulatory discretion for decades to allow labs to use their own LDTs pursuant to rules established under the Clinical Laboratory Improvement Amendments of 1988 (CLIA). The Centers for Medicare and Medicaid Services (CMS), in consultation with FDA, CDC, and state laboratory agencies, implement and enforce CLIA.

When CDC was initially unable to produce reliable test kits, the government decided to permit the country’s diagnostics manufacturers to develop COVID-19 test kits to sell to labs and independent and hospital laboratories to develop LDTs to use themselves. The government also permitted labs to purchase test kits manufactured outside the U.S.

What Are the Test Kits We Have Heard So Much About?

There are several different types of test kits currently on the market. Some are diagnostic kits that are used to conduct the molecular testing on instruments in various settings, including in labs, hospitals, clinics, and wherever the patient is (the latter often called point-of-care or POC testing). Others are collection kits that enable the collection of the patient’s specimen that is subsequently sent to and tested by a laboratory.

In our review of the reporting on the testing story, we found that the press sometimes conflates these two different types of kits. In very recent days, we have heard about kits that permit at-home testing. Here, too, there has been some lack of precision as these kits are actually specimen collection kits, not actual testing kits. At-home collection kits enable the individual to collect the specimen at home and then send it to a lab for testing. There is little doubt that development of home collection solutions for viral and antibody testing would be a significant advance to continue social distancing and potentially to increase the number of individuals who are tested.

At present, there is only one kit that the FDA has authorized for home collection of nasal specimens for subsequent molecular testing in a lab. The FDA did not permit this self-collection kit to be marketed until April 21, 2020, when it issued the kit’s manufacturer an Emergency Use Authorization (also known as an EUA, about which we have been hearing so much). This particular EUA announcement followed a stern March 20 warning from the FDA that it had not authorized any home tests for the coronavirus and that advised consumers to be wary of “unauthorized fraudulent COVID-19 test kits.” Press coverage reported that on April 10, the FDA also confirmed that it had not authorized any kits for home collection of saliva for coronavirus testing.

Accordingly, to date the FDA has not authorized any test kits to diagnose COVID-19 that can be used fully at home (that is, for both collection and processing).

What Are the Specimens?

Currently, most lawfully-marketed tests for SARS-CoV-2 use patient specimens that are collected from the nasal cavity with specially designed cotton swabs. The specimen collector needs to be covered with personal protective equipment (PPE) (e.g., gown, gloves and N-95 mask) to protect him or herself and should be trained in how to collect the specimen. If the specimen is not collected properly, the test result may not be accurate. This technical challenge is the reason that the FDA has to date only authorized one specimen collection kit for at-home use. Moreover, to date only one high-complexity clinical lab has received emergency authorization to perform molecular testing for SARS-CoV-2 using saliva specimens. The expansion of such capabilities would further enable at-home specimen collections and could be a significant advance in the fight against COVID-19.

In contrast, serological or antibody testing is performed on blood. Blood is generally collected in one of two ways:

  1. Through a venipuncture in which a phlebotomist, properly protected with PPE, inserts a needle into the patient’s arm to draw blood into a specimen collection tube. Venipunctures can only be performed at home when a properly trained and equipped phlebotomist travels to the individual’s home to collect the specimen.

  2. With a finger stick in which a sharp instrument is used to draw a small amount of blood from a patient’s finger. There are collection kits being marketed for home collection of blood for COVID-19 antibody testing using this finger-stick blood collection method.

The blood is then put in a container that is sent to a laboratory for antibody detection.

What Are the Instruments?

At present, both the testing for the SARS-CoV-2 virus itself and for its antibodies require instrumentation that must either already be in place in the lab or be acquired. We have heard and read a lot about the development of various instruments that will permit quick POC testing for both the virus and its antibodies, which means that the testing can occur in patient settings and while the patient waits a few minutes following the collection of the specimen.

Thus far, the FDA has only issued a few EUAs for POC coronavirus tests. Manufacturers are also rushing to develop POC instrumentation for antibody testing. The testing that is performed using FDA-authorized POC instrumentation will be deemed CLIA waived for so long as the national health emergency continues. Thus, physicians hoping to test patients in their clinics or in their offices may find the POC tests helpful.

What Are the Shortages We Have Been Hearing About and How Do They Affect Lab Testing?

There are shortages across the entire COVID-19 test delivery system that have impeded the widespread testing that public health experts are recommending.

At the beginning of the pandemic, we understand that there were only two companies that manufactured the types of cotton swabs that were used to collect the specimens to test for coronavirus. One was in a small town in the U.S., and the other was in Northern Italy where the pandemic hit early with ferocity. Thus, a shortage of cotton swabs for specimen collection quickly developed. To address these shortages, companies began working to develop cotton swabs that meet the FDA’s EUA requirements for purposes of nasal specimen collection. Most recently, on April 16, 2020, FDA announced it had recognized that spun synthetic swabs (that is, polyester-based swabs) could be used for collecting nasal specimens from COVID-19 patients.

In addition to the cotton swab shortages, those collecting specimens and performing testing competed for PPE with all other front line health care providers, exacerbating already significant shortages in critical PPE products. Media in which to store and transport patient specimens to the lab for testing have reportedly also been beset by shortages. Testing cannot occur without the required reagents (chemicals) and test kits and here, too, we hear that supplies have been strained.

We remain uncertain as to what policymakers and government officials are referring to when they discuss and debate the shortage of tests. Are they talking about the collection supplies, or reagents and test kits, or all of these essential supplies? We believe that shortages exist for all of these indispensable supplies, but precision in the public discourse would be helpful in order for citizens to understand and for industry to address the magnitude of the problem.

What Safeguards Are In Place to Regulate Quality?

The primary federal statutes that govern lab testing are the Federal Food, Drug, and Cosmetic Act (FD&C Act) and CLIA. FDA implements and enforces the FD&C Act, while CMS implements and enforces CLIA.

What Does FDA Regulate?

FDA regulates the kits and materials that are used to test diagnostic specimens pursuant to the medical device provisions of FD&C Act. FDA Commissioner Dr. Stephen Hahn has said that: “Throughout this pandemic we have been facilitating test development to ensure patients access to accurate diagnostics, which include supporting the development of reliable and accurate at-home sample collection options.” As of April 27, 2020, FDA’s “around-the-clock work since this outbreak began” has resulted in the authorization of 70 diagnostic tests and engagement with over 380 test developers. FDA also reports that it has been notified by more than 225 clinical laboratories that they have begun testing for COVID-19.

In addition, FDA has stated that it will not seek to enforce its COVID-19-related rules in states that choose to authorize labs within their borders to develop and perform such testing under state laws and processes. Connecticut, Maryland, Mississippi, Nevada, New Jersey, New York, and Washington have notified the FDA that they will be taking advantage of this regulatory flexibility to expedite the availability of COVID-19 testing for their citizens.

However, FDA has taken a different policy approach with respect to antibody testing. Because of the nature of the pandemic, the agency took the unusual step of stating early on in the emergency response that it would not object to the development and distribution by commercial manufacturers (or the development and use by clinical labs) of serology tests used to identify antibodies to the novel coronavirus. The requirements for such regulatory flexibility include that the test must have been validated, the developer notifies the FDA, and information is provided in the test report stating that:

  •  the test has not been reviewed by FDA;

  •  negative results do not rule out COVID-19;

  •  follow up molecular testing should be considered;

  •  serology test results should not be used as the sole basis for diagnosing, excluding, or informing infection status; and

  •  positive results may be due to past or present infection with non-novel coronavirus strains.

As of April 27, 2020, FDA had issued at least 7 EUAs for serology tests developed by commercial manufacturers and none for serology tests developed by clinical labs. All of these tests, however, must be performed in labs that are high complexity or moderate complexity under the CLIA regulations (which are described further below). The many serology tests that are currently being offered without EUAs must be performed in laboratories that have high complexity CLIA certificates. To date, labs and manufacturers have notified the FDA that they have validated and are now offering, in the aggregate, more than 150 serology tests for the novel coronavirus. None of those other tests are the subject of granted EUAs.

The FDA’s decision regarding how handle serology testing has been controversial, to say the least. In an April 27 article entitled “Unreliable Antibody Tests Flood the Market as FDA Waives Quality Reviews,” the news organization Politico suggested that many of the antibody tests that are being offered are not accurate enough to inform discussions about when people can return to work and school. Reportedly, some of these marketed tests provide too many false positives, leading people to erroneously believe that they have developed immunity to the novel coronavirus when they, in fact, have not. Politico also reported that the New York City Department of Health had, in the week preceding publication of the story, warned against using the tests to determine whether someone has developed immunity through previous exposure to the virus.

Notably, on April 24, a House of Representatives oversight subcommittee released a report on antibody testing finding that “numerous companies appear to be marketing fraudulent tests.”

What Does CMS Regulate?

Acting in parallel to FDA, sister agency CMS, in partnership with the CDC, regulates the clinical labs that conduct diagnostic testing. CMS derives this jurisdictional authority from CLIA. CLIA mandates the use of a complexity-based system that imposes more comprehensive quality assurance regulations on high complexity labs and somewhat lesser quality assurance regulations on moderate complexity laboratories. Laboratories that perform simple, specifically delineated tests are not subject to the quality assurance regulations but must maintain a CLIA certificate of waiver.

All labs that perform testing on human specimens to diagnose disease or assess the health of the patients whose specimens are tested, therefore, must hold either a CLIA high complexity or moderate complexity certificate or a CLIA certificate of waiver.

What Are the Technical Nuances Between Diagnostic Tests and Antibody Tests?

Negative results from a molecular test for the novel coronavirus do not rule out COVID-19. Most of the PCR-based molecular tests that are used to detect the presence of the virus have high specificity, which in lab-speak means few false positives. However, because there is some variation in the stated sensitivity (false negatives) of the various tests that are being performed and sensitivity is highly dependent on the stage of the disease, CDC is advising physicians to interpret negative results in the context of the patient’s exposure history and symptoms. With regard to tests used to diagnose the SARS-CoV-2 virus, false negatives are of most concern to public health officials, as they permit patients with COVID-19 to believe that they do not have the disease.

CDC and FDA are both advising that serology testing for antibodies not be used as the sole basis for either positively diagnosing or excluding COVID-19 diagnoses. Negative results from serology tests do not rule out COVID-19 infections, particularly for patients who have been exposed to the virus and are still within the estimated incubation period. Regarding antibody tests, false positives cause public health officials the most concern as they falsely lead the patient and others to believe that the patient has developed some level of immunity to the novel coronavirus when that may not be the case.

What Next?

Testing capacity has increased significantly in recent weeks, but the nation is still far from where it needs to be at this stage of the pandemic (as was observed during and in response to a White House testing-related press conference held on April 27, 2020). Developers and labs are all feverishly working on rapid antigen tests for the COVID-19 virus that would act much like rapid strep tests, and at-home tests would be helpful to the public health response as well.

©1994-2020 Mintz, Levin, Cohn, Ferris, Glovsky and Popeo, P.C. All Rights Reserved.National Law Review, Volume X, Number 120
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Hope S. Foster, Member. Chair, Health Care Enforcement Defense Practice,Life Sciences Laboratories Diagnostics Hospitals & Health Systems
Member / Chair, Health Care Enforcement Defense Practice

Hope has a national reputation as a health care enforcement defense lawyer and chairs the firm’s Health Care Enforcement Practice. She regularly defends health care companies in governmental investigations and ensuing cases, conducts internal investigations, and advises health care providers and manufacturers regarding enforcement issues. She has in-depth knowledge of laboratory regulations. Many of Hope’s engagements are the result of qui tam cases initiated by whistleblowers under federal and state false claims acts. She often works with companies to develop and implement policies and...

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Joanna Hawana, Mintz Levin, FDA Lawyer, Clinical Trials & Research Consumer Product Safety FDA Regulatory Health Care Compliance, Fraud & Abuse, and Regulatory Counseling Health Care Transactional Due Diligence
Of Counsel

Joanne counsels global clients on regulatory and distribution-related considerations to bringing a new FDA-regulated product to market and how to ensure continued compliance after a product is commercialized. She also advises on the business impact of new US federal and state actions that affect those regulated products, such as drugs, foods, cosmetics, electronic nicotine delivery systems, and medical devices, including in vitro diagnostics, lab tests, and mobile medical applications. In recent years she has been advising clients in different industries regarding FDA’s approaches to...

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