At-Home COVID-19 Testing and Pandemic Surveillance: A Regulatory Perspective
- October 09, 2020
- Clint Hermes , Bass Berry & Sims PLC
- Angelique Salib , Bass Berry & Sims PLC
Imagine waking up for work or school, and in addition to your usual morning routine of brushing your teeth and brewing a cup of coffee, you self-administer a COVID-19 test, confirming that you are virus-free before heading out the door. Or, you test positive and stay home. You repeat this process every morning to ascertain your health status. This type of test—one that allows for self-collection of a specimen and also immediately runs the analysis without having to send it out to a laboratory—can allow for a more effective public health response to a pandemic. There are currently no such COVID-19 tests available on the market today. The reason is likely based on the way the Food and Drug Administration (FDA) has imposed a high bar for clinical diagnostic tests, with an eye to confirm their validity and accuracy. However, considering the widespread impact of COVID-19 on day-to-day activities, the availability of a test that individuals can cheaply and independently use to obtain immediate results on their current health status, would be immensely effective from a public health perspective, especially for a virus such as COVID-19 where asymptomatic spread is prevalent. This test might not meet the same specificity and sensitivity rates as traditional clinical diagnostic tests but with an accuracy rate that is “good enough” (and at a low-cost point), the trade-offs may be well worth it. To that end, the FDA could approve rapid diagnostic tests during an infectious disease outbreak through a new categorical standard that is less demanding than the standard used for tests whose primary function is for clinical diagnosis. A number of public health experts have advocated this position as essential to properly address a pandemic and as a means to mitigate future outbreaks as we approach the fall and winter seasons.
This article broadly summarizes the current regulatory regime applicable to clinical diagnostic products, the FDA’s deployment of emergency use authorizations during this pandemic, and challenges to bringing rapid, direct-to-consumer (DTC) tests to market.
FDA Regulation of IVDs
The FDA regulates devices under Section 201(h) of the Federal Food, Drug, and Cosmetic Act (FFDCA). In-vitro diagnostic products (IVDs) are a type of device. IVDs are defined as “those reagents, instruments, and systems intended for use in the diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, mitigate, treat, or prevent disease or its sequelae. Such products are intended for use in the collection, preparation, and examination of specimens taken from the human body.” In simpler terms, IVDs are tests performed on specimens taken from the human body such as blood drawn from a fingerstick or saliva swabbed from the mouth. IVDs must be manufactured in accordance with the good manufacturing practices requirement.
Laboratory-developed tests (LDTs) are a type of IVD that are designed, manufactured, and used within a single laboratory. Since the 1970’s, the FDA has taken the position that it had authority to regulate LDTs but the agency in fact rarely used that authority except in high-risk situations. The FDA considered the COVID-19 pandemic to be one such high-risk situation. In August of 2020, the Department of Health and Human Services (HHS), in an unprecedented move, effectively rescinded the requirement that laboratories with LDTs submit validation data or seek an emergency use authorization from the FDA absent notice-and-comment rulemaking. As a result, it is now unclear whether LDTs that are IVDs still need to comply with FDA quality control standards such as good manufacturing processes.
Devices are categorized into different classes, so IVDs also can be characterized as a class I, class II or class III device. Devices are placed in a classification depending on the associated risk level, thereby dictating what pre-market approval process and the extent of regulatory control that is required. Non-exempt class I and class II devices must complete what is known as the 510(k) submission process. For this submission, the sponsor must demonstrate that the new device is “substantially equivalent” to a predicate device with respect to its intended use, technological characteristics, and performance testing, as needed. Some class I and class II devices are exempt from the 510(k) process if the FDA determines that such submission is not required to provide reasonable assurance of safety and effectiveness. Devices that may be exempt include pre-amendments devices and class I and class II devices that are specifically exempted. Class III devices require a pre-market approval application, unless it is a pre-amendments device or is substantially similar to a pre-amendments device. The Premarket Approval Application (PMA) is an application to request approval based on a determination by the FDA that there is sufficient valid scientific evidence that provides reasonable assurance that the device is safe and effective for its intended use(s). All devices regardless of class are subject to the current good manufacturing practices specified in 21 C.F.R. Part 820, unless there is an exception or exemption noted in the regulation.
General and Special Controls
All devices (unless exempted) must maintain certain quality standards called general controls. General controls include standards related to labeling, reporting injuries and deaths, registration with the FDA, device listing, quality controls, and protections against adulteration and misbranding. Specific controls are not common, only apply to class II devices, and are usually device specific. For example, special controls have been established for high permeability hemodialysis systems. Special controls can include specific guidelines for design, testing, labeling or other targeted guidance for the specific device in question. Class III devices require additional oversight and neither general nor specific controls are sufficient to provide reasonable assurance of safety and effectiveness, which necessitates the submission and approval of a PMA.
The following chart provides a visual of the three device classes, risk levels, controls, and submission processes for approval:
Exempt or 510(k)
General and special (if available)
Exempt or 510(k)
General and PMA
Determining Safety and Effectiveness
To bring a device to market, a submission to the FDA must demonstrate valid scientific evidence for safety and effectiveness. The regulatory standard for demonstrating safety and effectiveness is found at 21 C.F.R. § 860.7(b), which requires the FDA Commissioner and classification panels to consider:
(1) The persons for whose use the device is represented or intended;
(2) The conditions of use for the device, including conditions of use prescribed, recommended, or suggested in the labeling or advertising of the device, and other intended conditions of use;
(3) The probable benefit to health from the use of the device weighed against any probable injury or illness from such use; and
(4) The reliability of the device.
With respect to scientific evidence, the FDA permits manufacturers to submit any form of evidence to substantiate the safety and effectiveness of a device. However, the FDA only relies upon valid scientific evidence, which taken as a whole, is adequate to support a determination that there is reasonable assurance that the device is safe and effective for its conditions of use. Specifically, the FDA considers valid scientific evidence to be: evidence from well-controlled investigations, partially controlled studies, studies and objective trials without matched controls, well-documented case histories conducted by qualified experts, and reports of significant human experience with a marketed device, from which it can fairly and responsibly be concluded by qualified experts that there is reasonable assurance of the safety and effectiveness of a device under its conditions of use. The evidence required may vary according to the characteristics of the device, its conditions of use, the existence and adequacy of warnings and other restrictions, and the extent of experience with its use. Isolated case reports, random experience, reports lacking sufficient details to permit scientific evaluation, and unsubstantiated opinions are not regarded as valid scientific evidence to show safety or effectiveness. Such information may be considered, however, in identifying a device with questionable safety or effectiveness.
FDA EUA for COVID-19
While the 510(k) submission and PMA are traditional routes for approving devices, the FDA has the ability to expedite certain uses of new devices during an emergency. The Pandemic and All Hazards Preparedness Reauthorization Act of 2013 (PAHPRA) amended Section 564 of the FFDCA to provide more flexibility to the HHS Secretary to authorize the FDA to issue “emergency use authorizations.” 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 when there are no adequate or approved alternatives available, also known as an emergency use authorization (EUA). One flexibility that PAHPRA introduced was the express permission granted to the FDA, as part of the issuance of an EUA, to categorize the complexity of an IVD to indicate whether the test can be performed in a point-of-care setting or only in a more sophisticated laboratory. The FDA Commissioner can only authorize EUAs after the Secretary has made a declaration of emergency or threat justifying authorization of emergency use. EUAs can be used for any tests, including those performed outside of the laboratory setting, such as at home, schools, or workplaces. Granting an EUA does not constitute clearance by the FDA of the device, but rather facilitates expedited use in the event of an emergency.
On January 31, 2020, Secretary Alex Azar declared a public health emergency related to a novel coronavirus, COVID-19. On that basis, Secretary Azar authorized the emergency use of IVDs for the detection and/or diagnosis of viruses that cause COVID-19. Subsequently, Secretary Azar authorized the use of alternative products for detection and/or diagnosis of COVID-19, which included the use of home-collection kits. EUAs are currently available for COVID-19 diagnostic tests (molecular and antigen tests), serology tests (antibody tests), and tests for management for COVID-19 patients (e.g., biomarker detection).
Criteria for Issuance of an EUA
The FFDCA sets out certain criteria that must be met for the Secretary to issue an EUA. If the criteria are not all met, then an alternative regulatory mechanism would be the appropriate means to approve the product. After the Secretary consults with the Assistant Secretary for Preparedness and Response, the Director of the National Institutes of Health, and the Director of the Centers for Disease Control and Prevention (CDC), an authorization can be issued if the Secretary concludes:
- Serious or life-threatening disease or condition. An agent referred to in an emergency declaration can cause a serious or life-threatening disease or condition;
- Evidence of effectiveness and a risk-based analysis. Based on the totality of scientific evidence available to the Secretary, including data from adequate and well-controlled clinical trials, if available, it is reasonable to believe that (A) the product may be effective in diagnosing, treating, or preventing (i) such disease or condition; or (ii) a serious or life-threatening disease or condition caused by a product authorized under this section, approved or cleared under this chapter, or licensed under Section 351 of the Public Health Service Act [42 U.S.C. 262], for diagnosing, treating, or preventing such a disease or condition caused by such an agent; and (B) the known and potential benefits of the product, when used to diagnose, prevent, or treat such disease or condition, outweigh the known and potential risks of the product; and
- No alternatives. There is no adequate, approved, and available alternative to the product for diagnosing, preventing, or treating such disease or condition.
Given that one of the criteria for issuing an EUA includes allowing “any product that may be effective in diagnosing, treating or preventing” a disease or condition, assuming all other conditions are met, there appears to be no barrier preventing the FDA from granting an EUA for a DTC COVID-19 test with a lower sensitivity or specificity threshold. Therefore, in a situation such as COVID-19, the FDA could issue EUAs for DTC tests.
Challenges to Epidemiological Surveillance Testing
For epidemiological purposes, giving individuals the ability to immediately process their own test results is one method to contain the spread of a contagious virus. Being able to identify, on a daily or on an as-needed basis, would alert individuals of their contagiousness and allow them to make health decisions in a manner that is timely. Waiting several days for laboratory results after taking a traditional molecular test does not provide people with the information they need to know now. Many public health experts have already advocated for a shift in the FDA’s strategy on COVID-19 testing; rather than focusing on a test’s analytic sensitivity, the specific context of testing should be considered. For COVID-19, that means lots of repeated testing, or a testing “regimen,” made available to patients at home and at a low-cost point.
For example, Abbott’s BinaxNOW COVID-19 Ag Card, which was granted an EUA in late August, uses lateral flow technology to produce a test result within 15 minutes at a cost of $5 per test. The test has a 97.1% sensitivity rate and a 98.5% specificity rate. However, under the EUA, this test can only be used by health care professionals or in point-of-care settings that operate under a Clinical Laboratory Improvement Amendments certificate.
Looking to the Zika virus outbreak as a reference point, similar challenges to the current pandemic were at play. Laboratories and other manufacturers scrambled to develop a test, for which EUAs were granted; however, patients faced extremely long wait times for their test results to return from laboratories. Some laboratories developed tests without FDA approval or an EUA. For example, Texas Children’s Hospital and Houston Methodist Hospital jointly developed the “Zika Direct Test.” The FDA issued a letter to both indicating that this was a high-risk test that had not been the subject of premarket clearance, approval, or an EUA. An FDA spokesperson stated: “While FDA encourages laboratories to develop Zika tests, these tests should not be used for clinical diagnoses without the FDA’s approval, clearance, or authorization. Because of the serious public health impact of the Zika virus in certain populations, the FDA is requesting that those with tests for the detection of Zika virus in patient samples submit a request for emergency use authorization (EUA) to the agency. EUA is a streamlined regulatory process by which medical products may enter the marketed in an expedited manner.”
The FDA also explained its reasoning behind requiring developers to follow its guidelines to meet specific analytical sensitivity requirements:
Patients, as well as their physicians, depend on FDA to assure the tests they use to make medical decisions are accurate, reliable, and clinically meaningful. Recently, several developers announced they would be developing and making [laboratory developed tests] LDTs for Zika virus available to patients. Zika virus may have serious implications for certain populations. For example, given the potential association of microcephaly and other poor pregnancy outcomes and Zika virus, a positive Zika test results poses a serious and challenging situation for pregnant women. Thus it is essential that in vitro diagnostic tests for Zika virus provide accurate and reliable results. As such, FDA has requested developers of LDTs for Zika virus to submit information about their tests to help FDA better understand their design, validation, and performance characteristics. While FDA recognizes the need for expanding laboratory testing capacity for Zika virus, and encourages laboratories to develop Zika in vitro diagnostic tests, these tests should not be used for clinical diagnoses without FDA’s approval, clearance, or authorization. FDA is encouraging developers of LDTs for Zika virus to submit a request for an EUA; FDA will work interactively with LDT developers to support such requests.
The FDA’s approach to granting approval or an EUA for Zika tests generally tracks the current approach to the COVID-19 pandemic: that all IVDs must be approved for clinical diagnostic purposes for which a high sensitivity bar is required. That approach, however, does not address unique concerns in the context of testing for purposes of a public health response, even more so for a pandemic such as COVID-19 that impacts a larger population than the Zika virus did.
To date, there is no FDA-approved DTC COVID-19 test likely for several reasons. First, the FDA likely views these products as having a diagnostic or treatment-based use, rather than a product that merely provides health information (e.g., the 23andME Genetic Health Risk test). Second, another factor may be based on the FDA’s skepticism of the public to properly self-administer, run, and interpret their own tests. Third, to some extent, lack of a purely at-home test might be due to technological limitations; if the technology is currently limited such that it requires technical training to administer and analyze, then the FDA may have a legitimate concern. That said, as tests have begun to develop over the course of this pandemic, the potential for new technologies such as Abbott’s BinaxNOW have emerged that can continue to evolve.
While EUAs provide for an expedited track for use, they are not without their own set of requirements. For the COVID-19 emergency, the FDA prepared optional EUA templates for developers to reference. The templates reflect the FDA’s current thinking on the data and information that developers should submit. The process for obtaining a COVID-19 EUA is by no means easy, and FDA policy reflects a certain level of skepticism about individuals collecting and interpreting their own tests: “Tests that are also interpreted in the home require demonstration of the ability of a lay user to collect their specimen, run the test, and interpret their results accurately.”
According to the FDA’s Policy for Coronavirus Disease-2019 Tests During the Public Health Emergency (Revised) (Policy Document), all clinical tests for COVID-19 must be validated prior to use—both analytically and clinically—especially in the context of a public health emergency because false results can negatively impact an individual and the broader public. The Policy Document sets out parameters that molecular tests must be within to assure validation including metrics on limits of detection, clinical evaluation, inclusivity and cross-reactivity. The Policy Documents includes thresholds for these parameters based on what FDA believes are reasonable, acceptable, or recommended metrics.
While the protocols set out in the Policy Document address thresholds typically required of a clinical diagnostic product such as IVDs, these metrics are not necessarily geared towards the widespread use of a product that is meant for public health surveillance purposes. To address the public health needs of a contagious virus such as COVID-19, there should be a product that individuals can self-administer and immediately determine their results. The purpose of the test is not so much to determine a clinical diagnosis, but rather, to give the individual information about their health status in a timely manner. In that sense, it may be more acceptable from a validation standpoint not to require an as stringent set of metrics for approval, if that is a necessary trade-off to bringing a faster and cheaper product to market. The FDA’s tolerance for less sensitive tests is evidenced to a degree in its approach to pooled testing. Pooled testing is beneficial from a public health standpoint because it allows for the testing of multiple individuals using less resources. However, because individual samples are diluted in the pool, there is a higher likelihood of false negatives. The FDA states: “since sample pooling will greatly increase the number of individuals that can be tested using existing resources, a small reduction in sensitivity may be acceptable depending on the pooling efficiency and other mitigations in place.” Additionally, in addressing repeated screening protocols for asymptomatic individuals for COVID-19, the FDA states: “If highly sensitive tests are not feasible, or if turnaround times are prolonged, health care providers may consider use of less sensitive point of care tests, even if they are not specifically authorized for this indication (commonly referred to as “off label”). For congregate care settings, like nursing homes or similar settings, repeated use of rapid point of care testing may be superior for overall infection control compared to less frequent, highly sensitive tests with prolonged turnaround times.” Thus, there is an indication that the FDA is to some degree comfortable with less sensitive tests so long as there is some alternative benefit in return. In the context of COVID-19, the benefits of a DTC test are paramount to containment.
The FDA’s “safe and effective” standard used in its regular approval process and the “may be effective” standard applicable to EUAs both could, in theory, be read broadly enough to allow the agency to set a sensitivity requirement of a COVID-19 test at a lower level. Since reviewing the effectiveness of a test in the context of repeated testing (a testing regimen), as opposed to a single diagnostic test, is not how the FDA typically evaluates IVDs, if the agency desires to create a pathway for public health testing, it could do so by approving a DTC COVID-19 test and seeking joint input from a public-health oriented agency such as the CDC to develop and publish guidance for use by the public.
About the Authors
Clint Hermes is Counsel with Bass, Berry & Sims PLC. Clint advises research institutions and life sciences companies regarding biomedical research regulation, funding, contracting, and product development. From 2007-2019, Clint was Chief Legal Officer at two academic medical centers, where he also had operational responsibility for technology transfer, compliance, enterprise risk management, clinical trial regulatory affairs, and Institutional Review Board offices.
Angelique Salib provides health care regulatory counsel as it relates to compliance, operational, and transactional matters through applicable components of the Stark Law, Anti-Kickback Statute, HIPAA, CMS guidance on reimbursement, and other relevant guidance. In addition, she works with hospital and health system clients on contractual arrangements, corporate governance, and a broad range of compliance matters.
 Menachem Fromer, Paul Varghese, and Robert M. Califf, Fast, low-cost testing is essential for averting a second wave of Covid-19, STAT News (Sept. 23, 2020), https://www.statnews.com/2020/09/23/fast-low-cost-coronavirus-testing-avert-new-wave-covid-19/; Alvin Powell, Cheap, frequent COVID tests could be ‘akin to vaccine,’ professor says, The Harvard Gazette (Aug. 11, 2020), https://news.harvard.edu/gazette/story/2020/08/cheap-daily-covid-tests-could-be-akin-to-vaccine/; Michael J. Mina, M.D., Ph.D., Roy Parker, Ph.D., and Daniel B. Larremore, Ph.D., Rethinking Covid-19 Test Sensitivity—A Strategy for Containment, New Eng. J. Med. (Sept. 30, 2020), https://www.nejm.org/doi/full/10.1056/NEJMp2025631
 A “device” means an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory, which is (1) recognized in the official National Formulary, or the United States Pharmacopeia, or any supplement to them; (2) intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals; or (3) intended to affect the structure or any function of the body of man or other animals, and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of its primary intended purposes. 21 U.S.C. § 321(h).
 21 C.F.R. § 809.3(a).
 21 C.F.R. § 809.20(b).
 FDA, How to Study and Market Your Device, https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-assistance/how-study-and-market-your-device.
 Food and Drug. Admin., Class I / II Exemptions, https://www.fda.gov/medical-devices/classify-your-medical-device/class-i-ii-exemptions#:~:text=A%20device%20may%20be%20exempt,510(k)%20requirements%20are%3A&text=Class%20I%20and%20Class%20II%20devices%20specifically%20exempted%20by%20the%20FDA.
 21 C.F.R. pt. 814.
 Food and Drug. Admin., Class I / II Exemptions, https://www.fda.gov/medical-devices/classify-your-medical-device/class-i-ii-exemptions#:~:text=A%20device%20may%20be%20exempt,Preamendments%20devices%3B%20and.
 21 C.F.R. § 800 et seq.
 21 C.F.R. § 876.5860(b).
 21 C.F.R. § 860.7(c).
 U.S. Dep’t of Health and Human Servs., Food and Drug. Admin., Emergency Use Authorization of Medical Products and Related Authorities, Guidance for Industry and Other Stakeholders (Jan. 2017), https://www.fda.gov/media/97321/download.
 See Section 564(m) of the FFDCA; Food and Drug. Admin., Pandemic and All-Hazards Preparedness Reauthorization Act of 2013 (PAHPRA) Medical Countermeasure (MCM) Authorities: FDA Questions and Answers for Public Health Preparedness and Response for Stakeholders (Jan. 2014), https://www.fda.gov/media/87718/download.
 U.S. Dep’t of Health and Human Servs., Determination that a Public Health Emergency Exists (Jan. 31, 2020), https://www.phe.gov/emergency/news/healthactions/phe/Pages/2019-nCoV.aspx. The declaration was renewed on April 21, 2020, effective April 26, 2020; and subsequently renewed on July 23, 2020, effective July 25, 2020, and October 2, 2020, effective October 23, 2020.
 85 Fed. Reg. 7316, https://www.govinfo.gov/content/pkg/FR-2020-02-07/pdf/2020-02496.pdf.
 85 Fed. Reg. 17335, https://www.govinfo.gov/content/pkg/FR-2020-03-27/pdf/2020-06541.pdf.
 21 U.S.C. § 360bbb-3(c).
 Michael J. Mina, M.D., Ph.D., Roy Parker, Ph.D., and Daniel B. Larremore, Ph.D., Rethinking Covid-19 Test Sensitivity—A Strategy for Containment, New. Eng. J. Med. (Sept. 30, 2020), https://www.nejm.org/doi/full/10.1056/NEJMp2025631 (“Clinical tests are designed for use with symptomatic people, do not need to be low-cost, and require high analytic sensitivity to return a definitive clinical diagnosis given a single opportunity to test. In contrast, tests used in effective surveillance regimens intended to reduce the population prevalence of a respiratory virus need to return results quickly to limit asymptomatic spread and should be sufficiently inexpensive and easy to execute to allow frequent testing—multiple times per week. Transmission of SARS-CoV-2 appears to occur days after exposure, when the viral load peaks. This timing increases the importance of high test frequency, because the test must be used at the beginning of an infection to stop onward spread, and reduces the importance of achieving the very low molecular limits of detection of the standard tests.”).
 Abbott, Press Release, Abbott’s fast, $5, 15-minute, easy-to-use COVID-19 antigen test receives FDA emergency use authorization (Aug. 26, 2020), https://abbott.mediaroom.com/2020-08-26-Abbotts-Fast-5-15-Minute-Easy-to-Use-COVID-19-Antigen-Test-Receives-FDA-Emergency-Use-Authorization-Mobile-App-Displays-Test-Results-to-Help-Our-Return-to-Daily-Life-Ramping-Production-to-50-Million-Tests-a-Month.
 Texas Children’s Hospital, Press Release, First rapid detection Zika test now available through collaboration with Texas Children’s Hospital and Houston Methodist Hospital (Feb. 23, 2016),
 Michael Mezher, FDA Sends Three Letters Over Unapproved Zika Diagnostics (Mar. 14, 2016), Regulatory Focus, https://www.raps.org/regulatory-focus%E2%84%A2/news-articles/2016/3/fda-sends-three-letters-over-unapproved-zika-diagnostics.
 Food and Drug. Admin., Zika Virus Diagnostic Development, https://www.fda.gov/emergency-preparedness-and-response/mcm-issues/zika-virus-diagnostic-development.
 Food and Drug. Admin., FDA allows marketing of first direct-to-consumer tests that provide genetic risk information for certain conditions (Apr. 6, 2017), https://www.fda.gov/news-events/press-announcements/fda-allows-marketing-first-direct-consumer-tests-provide-genetic-risk-information-certain-conditions (The 23andMe Genetic Health Risk test provides consumers with information on genetic predispositions to certain medical diseases or conditions. The test was approved by the FDA through a de novo premarket review pathway, which is used for low to moderate risk devices that are not substantially equivalent to an already legally marketed device. The test specifically excludes authorization to market any diagnostic function. In other words, the results cannot be used for diagnostic purposes or to inform treatment decisions).
 Food and Drug. Admin., In Vitro Diagnostics EUAs, https://www.fda.gov/medical-devices/coronavirus-disease-2019-covid-19-emergency-use-authorizations-medical-devices/vitro-diagnostics-euas.
 Food and Drug. Admin., Pooled Sample Testing and Screening Testing for COVID-19, https://www.fda.gov/medical-devices/coronavirus-covid-19-and-medical-devices/pooled-sample-testing-and-screening-testing-covid-19 (last accessed October 2, 2020).