Rapid Expert Consultation

AUGUST 2022

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Copyright 2022 by the National Academy of Sciences. All rights reserved.

Executive Summary

The coronavirus disease (COVID-19) pandemic self-testing experience has shown some great successes, which are a tribute to the hard work of individuals at all stages in the development, manufacture, regulation, distribution, and uptake processes. However, it has also demonstrated notable challenges, many arising from the lack of a proactive and comprehensive strategy, with the feedback and flexibility needed for adaptive management as the disease, diagnostic tests, and public opinion evolved.

This rapid expert consultation summarizes lessons learned from the COVID-19 pandemic for the future development and usage of self-tests for circulating infectious diseases and future outbreaks and pandemics. It draws from expert input and published research from previous public health emergencies, as well as the ongoing COVID-19 pandemic. The authors organized their discussion for future planning around critical elements described in Box 1.

Introduction

The COVID-19 pandemic has been transformational in accelerating progress in infectious disease diagnostics, including self-administered diagnostic tests, or self-tests, as a potentially critical public health tool. Prior to the availability of self-tests, diagnostic testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was primarily conducted on health care personnel-collected specimens that were obtained in settings such as mass testing sites, point-of-care in medical settings, or in clinical laboratories. This often resulted in lengthy wait times, for both getting tested and receiving results, which limited the practical value of tests for individuals and organizations, especially when demand was high. Today, self-tests are widely available over the counter (OTC). When properly administered and interpreted, self-tests can help people quickly identify whether they are infected with SARS-CoV-2 and take appropriate action, and testing can be conducted without visiting a health care provider or facility, which can reduce costs and the burden on the health care system and lead to more rapid treatment and disease control during an outbreak or pandemic.

The public’s familiarity with technological advances in infectious disease self-tests resulting from the COVID-19 pandemic can facilitate rapid self-testing for other pathogens, such as influenza, sexually transmitted diseases, childhood illnesses, and future emerging pathogens. Careful planning now is crucial to ensuring efficient, equitable access to testing, and to the health care that test results warrant (Gronvall, 2021). At the request of the Centers for Disease Control and Prevention (CDC) Center for Preparedness and Response (CPR), the National Academies of Sciences, Engineering, and Medicine (the National Academies) was asked to produce a rapid expert consultation using lessons learned from the COVID-19 response globally to analyze self-tests for seasonal illness and future pandemics. Specifically, this expert consultation aims to:

• Provide an overview of self-testing trends, including the availability, access, and use of tests.
• Describe the impact of self-testing on COVID-19, the role in meeting surge testing demand, the impact as a community transmission mitigation strategy, the role in linking to treatment, and the potential role in surveillance.
• Discuss the utility of self-testing for seasonal illness, current and future pandemics; for example, how to leverage self-testing going forward, and what are the limitations or issues of doing so.

Box 2 defines key terms and descriptions of self-tests used within the context of this rapid expert consultation, which focuses on self-tests administered by individuals primarily in the home and in other nonmedical settings (e.g., school, workplace, congregate facilities).

To carry out the rapid expert consultation, the National Academies convened a group of subject-matter experts with expertise in communicable disease surveillance, laboratory capabilities, behavioral health, and public health. To supplement their own expertise, the authors consulted published literature and received input from several external sources, whose willingness to share their perspectives and expertise was essential to this work (see Acknowledgments).

Trends in Self-Testing for Infectious Diseases

PRE–COVID-19 PRECEDENT FOR SELF-TESTING: HUMAN IMMUNODEFICIENCY VIRUS (HIV)

Prior to SARS-CoV-2 self-testing, HIV was the only infectious disease for which an FDA-approved or Emergency Use Authorized (EUA) diagnostic self-test had been developed. In 1996, FDA approved a test for HIV that required users to prepare dried blood samples and send them to a central laboratory for processing (Hurt and Powers, 2014). In 2012, FDA approved an OTC rapid HIV self-test (HIVST) (Hurt and Powers, 2014). The HIVST had limitations, compared to the 1996 test, such as lower

sensitivity when administered by users versus clinicians, higher false negative rates, and greater challenges for self-testers in navigating and accessing HIV treatment (Hurt and Powers, 2014). Studies have found that most self-testers perform HIVST reliably and accurately (Figueroa et al., 2018; Ibitoye et al., 2014), with benefits in convenience, privacy, and cost, compared to conventional tests. These self-tests have also proven valuable in public health outreach to community settings as testing could take place in nontraditional venues hence removing barriers (Adalja et al., 2020).

In 2015, Unitaid and Population Services International (PSI) created the HIV Self-Testing Africa (STAR) Initiative to assess the feasibility and uptake of HIVST programs in Africa, in terms of effective, ethical, and efficient delivery, as well as post-test medical and counseling support. To date, it is the largest evaluation of HIVST in Africa and could serve as a model for other self-testing programs (see Box 3) (Unitaid, 2020; Wong et al., 2019), building on its procedures, experience, and public-private partnerships (Gupta-Wright et al., 2021).⁶

OTHER RAPID DIAGNOSTICS FOR INFECTIOUS DISEASES

FDA has approved rapid diagnostic tests for malaria (BinaxNOW) and Ebola (OraQuick) that are authorized for use by laboratory professionals and health care workers (CDC, 2020; FDA, 2019). Multiplex self-tests have been developed to detect infectious diseases including hepatitis C and syphilis (Arnold, 2022). However, the COVID-19 pandemic has been the first instance of widespread

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distribution, promotion, and use of self-testing at a large population scale.

Impact of Self-Testing on the COVID-19 Pandemic

SELF-TESTING FOR SARS-COV-2

The need to develop simple self-tests to detect SARS-CoV-2 was recognized early in the pandemic and led to public-private partnerships encouraging their development. Support for self-testing development was provided by the federal government, with review and authorization under FDA’s jurisdiction. In November 2020, FDA issued its first EUA for a SARS-CoV-2 rapid self-testing kit, available by prescription (FDA, 2020b). The following month, FDA granted the first EUA for an OTC self-testing kit (FDA, 2020a). Molecular self-tests were first approved in November 2020 by prescription and March 2022 for OTC. As of July 2022, FDA had issued EUAs for 20 OTC self-test SARS-CoV-2 diagnostic tests—including 17 antigen tests and 3 molecular tests.⁷ By early 2022, the number of self-tests performed per day in the United States was estimated to be 2–4 times greater than the number of laboratory tests (Juluru et al., 2022). Further research is needed to better understand who used self-tests during the COVID-19 pandemic and for what purposes to ensure that development and implementation of self-tests for future diseases will be used and are able to be accessed by all persons.

COMPARATIVE PERFORMANCE OF SARS-COV-2 DIAGNOSTIC TESTS

Decisions about development, authorization, distribution, and use of self-tests, such as antigen tests for SARS-CoV-2, require comparing their performance with that of other testing modalities, especially RT-PCR and viral culture, within the constraints of specific settings (e.g., considering the end users, the availability of labs and professional staff, the need for results within a specified time frame) and goals (e.g., detect infection or infectiousness). Those comparisons must extrapolate evidence gathered in controlled experimental settings and real-world use studies in which people self-administer tests and interpret their results. Following initial FDA EUA approval, it is important to assess test performance in the real-world setting in order to inform and support decision making. For example, a prospective cohort study (“Test Us At Home”) evaluated the performance of serial use of rapid antigen tests for SARS-CoV-2 in relation to the course of infection for symptomatic and asymptomatic participants (Soni et al., 2022a).

Compared to RT-PCR, antigen tests are typically not as sensitive in detecting virus. As a result, positive test results are believed to correlate with infectiousness given the higher viral loads needed to produce them. However, a negative antigen self-test does not necessarily mean that a person is not infected (even if they do or do not have symptoms), depending on when the test was taken during the course of infection as well as other application considerations like whether the test was performed properly, thus highlighting the value of serial self-testing (Soni et al., 2022b). In contrast, RT-PCR tests can be extremely sensitive and yield positive results in individuals who were infected but are no longer infectious (Crozier et al., 2021).

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Antigen test performance appears to depend on when tests are administered relative to symptom onset, and corresponding viral load. For instance, a systematic review of antigen tests for SARSCoV-2 found substantial variation in sensitivity across studies, but with a consistent pattern of higher average sensitivity among symptomatic participants compared to asymptomatic participants, in the first week after symptom onset compared to the second week after symptom onset, and among asymptomatic individuals with suspected epidemiological exposure to SARS-CoV-2 compared to where testing was available to anyone presenting for testing (Dinnes et al., 2022). Early studies of the real-world performance of SARS-CoV-2 antigen tests found that antigen tests were 30–40 percent sensitive at detecting infections identified by RT-PCR asymptomatic persons, but 60–80 percent sensitive with symptomatic persons (Pray et al., 2021; Prince-Guerra et al., 2021). Subsequent studies have confirmed this pattern, possibly due to differences in viral load in persons infected with SARS-CoV-2.

In addition to their relative insensitivity to low viral loads, antigen self-tests can produce false negatives through errors in improper test storage, specimen collection, processing, or interpretation of results by the user. These problems are not exclusive to antigen self-tests, but are likely greater for self-tests due to fact that the end users may not be medically trained or have experience in conducting medical tests, resulting in error from an inability to understand or follow technical or complex instructions that are poorly written, at too high a reading level, in unfamiliar languages, or impractical given users’ circumstances. For example, people may not realize the need for the serial testing, based on a recent study and guidance (CDC, 2022d; FDA, 2022a), and the necessity for frequent testing especially when a person may be at increased risk for infection but an initial test is negative because it is conducted before viral antigen is detectable by the self-test (Crozier et al., 2021). Untrained individuals may repeatedly collect improper samples (Crozier et al., 2021). People may also choose not test or to repeat tests because they do not want to receive results that restrict their ability to work, travel, or tend to others. This, too, is a place where behavioral research is needed. There are conflicting psychological theories, which can only be resolved with evidence.

As with any kind of diagnostic test, a false negative antigen test result may result in a false sense of security that makes individuals less likely to adhere to infection control practices such as masking and social distancing, thus increasing the risk of transmission (Crozier et al., 2021, Woloshin et al., 2022). In a pilot study investigating self-testing performance among asymptomatic individuals in Liverpool, around 56 percent of survey respondents who tested negative indicated that a negative test result would make them more likely to go outdoors, visit friends and family, or go to work. Comparatively, 95 percent of those who tested positive reported that they immediately self-isolated and informed family, friends, or an employer (University of Liverpool, 2020).

Several studies have suggested that antigen tests track more closely with virus culture positivity and hence potential infectiousness than RT-PCR tests (Chu et al., 2022; Kirby et al., 2021; Lohse et al., 2022; Pekosz et al., 2021). However, people can be infectious even if not culture positive, and the correlation between infectivity and antigen or culture positivity remains unclear. One study found that the antigen test showed a 96 percent sensitivity compared with this viral-culture metric (and ~100 percent specificity) (Lopera et al., 2022).

In clinical performance evaluations comparing antigen tests with RT-PCR, sensitivity varies widely, while specificity is generally very high. A systematic review of studies found that the pooled sensitivity and specificity of rapid antigen detection tests (RADTs), including those that were self-administered, were 69 percent and 99 percent, respectively, when compared to RT-PCR results as the standard (Arshadi et al., 2022).

FDA EUA/APPROVAL PROCESSES

In the United States, antigen and molecular tests have been made available by EUA. FDA can exercise EUA authority in circumstances deemed appropriate by the Secretary of the U.S. Department of Health and Human Services (FDA, 2022c), under section 564 of the Federal Food, Drug, and Cosmetic Act. An EUA is meant to expedite the availability of medical products when a public health emergency is present, no approved alternatives exist, and potential benefits of use outweigh potential risks (MacMillan, 2022a). Once the public health emergency is over, EUAs are revised or revoked. Manufacturers can request full authorization while a public health emergency is still in effect.

The process for FDA full approval for diagnostic tests typically takes 3–7 years (Kepczynski et al., 2021). To accelerate this process, criteria for EUAs differ from those for full FDA approval. Whereas full approval normally applies an “effectiveness” standard, the EUA process applies “may be effective” standard, requiring less evidence (FDA, 2018). Whereas clinical trials are typically required to establish sensitivity and specificity for full approval, they are not required for EUA (Mitchell et al., 2020). Before issuing an EUA, FDA conducts a risk-benefit assessment that must conclude that the known and potential benefits of a product outweigh its known and potential risks (FDA, 2018). All products available by virtue of EUA are posted on the FDA website.⁸

Although antigen tests made available under EUA during the COVID-19 pandemic have aided mitigation efforts, they have not been tested as rigorously as other types of diagnostic tests with full FDA approval. As a result, providers, patients, and caregivers may not have data to compare the performances of among the many SARS-CoV-2 antigen tests (MacMillan, 2022b). For this reason, real-world evaluation and study of self-tests is important, but takes additional time for the science to develop.

In spring 2022, FDA encouraged SARS-CoV-2 diagnostic test manufacturers to seek full approval of their products to prepare for future COVID-19 surges. FDA proposed the standard de novo submission process and 510(k) clearance as the appropriate pathway. FDA has informed manufacturers of tests with EUAs for SARS-CoV-2 diagnostics that they will receive a minimum 180 days’ notice ahead of FDA’s intent to end those authorizations after the end of the current public health emergency declaration. As of April 2022, only molecular tests for SARS-CoV-2 have received full approval, but not antigen or serology tests (Slabodkin, 2022).

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AVAILABILITY AND SCALABILITY OF SARS-COV-2 SELF-TESTS

Over the course of the pandemic, the availability of self-tests has varied. Initial availability of tests in the United States may have been limited by lack of federal prioritization and advance purchasing; delays and lack of clarity in FDA review process and EUA guidelines; lack of a guaranteed market; and the lack of consensus on the utility of these tests (NASEM, 2021).

After self-tests were authorized, shortages arose due to manufacturing delays and supply chain challenges (Fink, 2021; Noguchi, 2021) and surges and subsequent declines in cases with corresponding rises and falls in demand and supply. For example, while there was a rapid increase in at-home testing during Delta and Omicron case surges between August 2021 to March 2022, at-home test use was found to be lower among those who were aged 75 years or older, had lower incomes, had a high school level education or less, and identified as Black (Rader et al., 2022b). Additional infrastructure in manufacturing capacity was required for test production. Increasing the capacity was challenged by initial lack of federal investment and procurement procedures that struggled to match surge demand to supply (Noguchi, 2021). The National Institutes of Health (NIH) Rapid Acceleration of Diagnostics (RADx) initiative supported test developers focusing primarily on technical development, and RADx Advanced Technology Platforms considered the capabilities of test developers to scale production (NIH, n.d.). A 2021 National Academies consensus study concluded that medical countermeasure manufacturers will not have surge capacity in the absence of a sustained financial commitment, especially for those who feel like they have been abandoned, suffering economic losses, after rising to meet a national need (NASEM, 2021).

Strategic Planning Considerations to Optimize Utility of Self-Testing Beyond COVID-19

Self-tests emerged as a critical public health tool in combatting the COVID-19 pandemic, providing individuals with greater ability to track their health status and mitigate the spread of an infectious disease (Crozier et al., 2021). Self-tests provided benefits to health care and public health systems by reducing pressure on those systems and in some cases, allowed for re-opening of schools, businesses, and workplaces. However, as described above, challenges remain. There are difficulties with ensuring equitable access to self-tests and linking positive results to health care quickly, including equitable access to treatment options. There are difficulties ensuring that individuals can administer self-tests and interpret their results. Additionally, there are barriers (e.g., lack of plans, processes, and funding) in conveying test results to public health officials, and with supporting the manufacturing bases needed to provide self-tests for a pandemic or infectious disease event with fluctuating demand and an evolving pathogen. The authors believe that formal evaluations and research (and specifically social science research) are needed to address many of these challenges and inform future self-testing strategies (see Table 1 at the end of this consultation).

Based on experiences with SARS-CoV-2 self-tests, the authors have identified the following considerations as critical to strategic planning for self-tests for infectious diseases and future outbreaks and pandemics. Planning is needed to take full advantage of the expected progress in diagnostic technologies for self-tests, including antigen, molecular, and multi-pathogen tests, in terms

of the performance, timeliness, simplicity, scalability, costs, and availability of self-tests (ECDC, 2021). Planning should consider the interdependent needs of individuals, communities, and health care systems for effective, equitable, and efficient delivery (Wong et al., 2019).

The following considerations are critical to incorporate into future self-testing planning strategies:

• Goals and benefits of self-testing
• Use of self-testing in other settings beyond at-home testing
• Disease-specific considerations and pathogen dynamics
• Manufacturing and regulatory considerations
• Implementation and human component considerations
• Research and evidence gaps

GOALS AND BENEFITS OF SELF-TESTING

Before self-tests are deployed for future events, decisions will need to be made about the outcomes the program is intended to achieve—are the goals to prevent further spread of infection, seek out early treatment and care, meet testing demand in outbreaks or surge events, and/or contribute to disease surveillance efforts?

Prevention and Mitigation

Self-tests are generally faster at turning around a test result and, as observed in the COVID-19 pandemic, can be useful in breaking chains of transmission (CDC, 2022b; Larremore et al., 2021). Early detection of infection helps prevent further spread of infection through case investigation, contact tracing, isolation of the infected person, and potential quarantine or monitoring of close contacts. Even if quarantine is not necessary or enacted (based on disease-specific considerations), early detection of infection can directly impact actions of close contacts of infected persons, such as monitoring for symptoms of infection, seeking out testing, or post-exposure prophylaxis (e.g., influenza, monkeypox). Early diagnosis is also important to seeking care quickly and initiating treatment to mitigate potentially severe impacts of disease (see below discussion on the test-to-treatment gap) (CDC, 2022b). During the COVID-19 pandemic, self-testing was observed in efforts to reduce risks of gathering together with family and friends, determine length of isolation, or allow people in quarantine to return to work or school early to minimize loss of work or education. When combined with other layers of prevention, testing can have an impactful role on preventing disease spread and protect communities. Additionally, the use of self-testing with linkages to telehealth and treatment avoids the need for individuals to present in person at a point-of-care, thereby improving infection control in these settings.

Self-tests are also important to consider implementing for diseases where people may be hesitant to seek testing or care because the diseases might be prone to stigmatization, such as for sexually transmitted infections (STIs). Rates of STI have been increasing for years across the country (CDC, 2022e), and control efforts are hindered by lack of funding and availability of medical clinics focused on STI screening and diagnosis.

The Test-to-Treatment Gap

Compared to typical point-of-care testing, self-testing can allow for earlier detection of infection. Self-testing can facilitate a person to seek medical care, especially if there are outpatient therapies that can be utilized to prevent a person from progressing to more severe disease. During the COVID-19 pandemic, self-tests were important for test-to-treat programs, as new outpatient therapeutics became available. When combined with increasing utilization of telehealth, home self-testing becomes increasingly important for diagnosing a person with an infectious disease. This opportunity is present for self-testing during outbreaks and pandemics, and for routinely occurring diseases, such as influenza and STIs, where outpatient therapies are available that can prevent more severe disease (e.g., neuraminidase inhibitors). However, self-testing requires that the person who is performing a self-test have instruction about how to act on the results, and be informed about available treatment options. Self-testing necessitates information and instructions about how and where someone who tests positive for a specific disease should seek follow-up care. Securing needed treatment may be challenging for those without access to prompt health care. Strategic planning can build on evidence regarding current test-to-treat programs and develop systems to guide future self-testing programs (Wroe et al., 2022). Test manufacturers and public health agencies could partner to develop and deploy self-tests with test-to-treatment linkages and strategies in mind.

Surge Testing Demand

Self-testing continues to play a critical role in meeting the demand for COVID-19 testing during surges, and alleviating the pressure on health care systems observed during the pandemic (Stone, 2022). One of the lessons learned during the current pandemic is just how difficult it is to predict future surges. Thus, strategic planning for future surge events could benefit from modeling future demand, to determine the manufacturing capacity, stockpiles, and supply chain considerations, as well as workforce, needed to meet anticipated demand.

Disease Surveillance

It is important for future strategic planning to consider ways to address disease surveillance challenges that may arise as a result of large-scale self-testing. In the COVID-19 pandemic, an advantage of self-tests was their ease of use during surge events, allowing for more testing and improving the timeliness of results. However, since a proportion of positive self-tests may not be reported to public health agencies, laboratory-based surveillance systems may underestimate the true incidence (Rader et. al, 2022b). Preliminary results from a self-reported survey administered in New England suggest there are five positive at-home SARS-CoV-2 tests for every two positive RT-PCR tests that are lab-reported (Nirappil et al., 2022). A descriptive analysis of COVID-19 cases from March to May 2022, during which there was an increase of home testing, estimates that potentially over 2 million cases of COVID-19 were missed by official case counts due to unreported self-tests (Rader et. al, 2022a).

Early results from the "Say Yes! COVID Test” (SYCT) large-scale home-testing pilot program suggest that it is technically possible to create a system where users can report self-test results to state and federal authorities, should they wish, to inform public health surveillance without privacy concerns (Juluru et al., 2022). As discussed later in the section on reporting results, individual motivations to report self-test results may depend on a number of factors including trust in and perceptions of health

agencies that will use this information.

For surveillance purposes, it may be possible to create representative samples, perhaps using ethically appropriate incentives for reporting self-test results, or to use samples from mandated testing (e.g., in academic or work settings), adjusting for non-representativeness. This reinforces the notion that a combination of clinical testing, self-testing, syndromic surveillance, wastewater surveillance, and development of random sampling strategies may be the best path forward for general surveillance efforts (Dean, 2022).

USE OF SELF-TESTING IN SETTINGS BEYOND AT-HOME TESTING

The most common setting for the use of self-tests have been at home. However, self-tests can reach people in other places, a situation which requires its own strategic planning. Strategic planning efforts for determining the appropriate settings for deploying self-tests include conducting a review the evidence on the costs and benefits of such strategies, considering the goals of testing (described above), and understanding the implementation considerations (described below)—such as number of people requiring testing, the ability for the persons or populations to self-test and interpret their tests, required frequency of testing, and how well users and authorities trust one another (Johns Hopkins Center for Health Security, n.d.).

Some of the settings, in addition to homes, where self-testing was successfully implemented during the COVID-19 pandemic are highlighted below. In many of these settings, self-testing was often implemented through mandatory or encouraged targeted programs. Given some of the limitations of self-testing, the potential benefits need to be weighed against the logistical challenges of implementation in various settings, and the risk tolerance for missing an infection (when compared to more sensitive molecular-based tests), particularly if self-testing is conducted in a setting that is high-risk for transmission (e.g., congregate living) and/or in a population that is at high-risk for severe outcomes from missing an infection.

Schools

Despite considerable variability in the use of self-tests in schools, self-testing became important during the COVID-19 pandemic to identify infection in symptomatic persons, screening for asymptomatic infection, and as a tool to allow exposed students and staff to attend school and avoid loss of education and social development. Many schools distributed self-tests to students and their families, along with test use instructions. Students who tested positive were isolated; students who tested negative could stay in school (CDC, 2021). In some school districts, students performed tests before returning to schools at the start of the school year and/or after school breaks and vacations, or before sporting events and other activities. A United Kingdom study, which administered antigen tests to school children twice a week, found that more than 80 percent of positive self-tests result were confirmed by positive RT-PCR (Hughes et al., 2022). A German study found that high-frequency self-tests by school teachers reduced school-based transmission, especially in settings with high local incidence of infection and for individuals with mild or atypical symptoms (Hoehl et al., 2020). Self-tests thus have proven utility in test-to-stay programs and identifying students and staff with COVID-19, providing an important, local infection control measure for schools and allowing people to return to school and minimizing lost educational opportunity. A study evaluating a test-to-stay program across

K-12 schools in Illinois, found a secondary transmission rate among program participants of 1.5%, tertiary transmission among household contacts, but not school-based contacts, and preservation of 8,152 in-person learning days (Nemoto et al., 2021).

Workplaces

Workplaces used self-tests to screen employees to prevent transmission (Papenburg et al., 2022). A Massachusetts study demonstrated the feasibility of having employees use antigen self-tests twice weekly to reduce COVID-19 transmission and workplace disruption (Harmon et al., 2021). A study of twice-weekly self-testing program in hundreds of Canadian organizations, from January to June, 2021 (Rosella et al., 2022) detected asymptomatic and infectious cases that were confirmed by RT-PCR and initiated prompt isolation and tracing. These findings indicate the value of strategic plans that implement and concurrently evaluate evidence-based programs for workplace-based self-testing.

Congregate Settings

The COVID-19 pandemic revealed the vulnerability of individuals in congregate settings, such as nursing homes, long-term care facilities, prisons, and in facilities with frequent staff contact and high turnover. These vulnerabilities were especially apparent in those with risk factors for severe disease (CDC, 2022c; Nuzzo and Gronvall, 2021). Therefore, self-tests were used in such settings, especially when molecular testing has been unavailable and appropriate antigen testing-algorithms can be implemented to help increase accuracy and minimize the chance for false-negative results (CDC, 2022a; McKay et al., 2021; Nuzzo and Gronvall, 2021). Some programs included testing of symptomatic residents and health care personnel (HCP), testing of asymptomatic residents and HCP in response to local outbreaks or following close contact with someone with SARS-CoV-2 infection, and routine testing of asymptomatic HCP. A prospective evaluation, conducted in October and November 2020, testing all staff and residents of a nursing home during an ongoing SARS-CoV-2 outbreak found that the BinaxNOW RADT, compared with virus culture and RT-PCR, performed well during early infection, when viral load is highest and individuals are more likely to be contagious (McKay et al., 2021). Approaches to address the costs, risks, and benefits of such programs in different congregate living settings can be addressed in strategic planning. Such planning could include consideration of the risks, benefits, and limitations of self-testing and the need for more frequent testing to increase accuracy in high-risk congregate settings.

Communities

The use of self-testing for community-based screening had value for people who have difficulty accessing health facilities or limited local availability of testing sites, distrust the health care system, or are reluctant to seek care (Juluru et al., 2022). For instance, a drive-through SARS-CoV-2 self-testing site in rural South Carolina boosted testing in an area with limited access to testing centers (Plumb et al., 2022). A similar program offering free BinaxNOW tests in Massachusetts had similar success (Pollock et al., 2021). Community-based testing programs can improve access to testing, especially when access to health care facilities or pharmacies may be challenging.

DISEASE-SPECIFIC CONSIDERATIONS AND PATHOGEN DYNAMICS

Looking beyond COVID-19, the potential usefulness of self-tests is immense. The type of test (e.g., antigen, molecular, multi-pathogen) will depend on disease-specific considerations relative to the

pathogen being tested for. Not all pathogens are respiratory viruses, so self-tests may require collection of a person’s specimens other than upper respiratory specimens, such as stool (e.g., GI pathogens), genitourinary (e.g., for STI screening), or rectal swabs (e.g., for gonorrhea or chlamydia testing). Because of this limitation, not all self-tests may be as easy to develop or implement, and will need different approaches to specimen collections.

When to self-test for an infection will also likely vary by the pathogen’s infectious period (if testing is to prevent further spread of infection), ability of the test to detect the pathogen (e.g., predictive value, sensitivity, and specificity), and importance of diagnosis for connecting a person to medical care or treatment within a specific timeframe. Some infections will cause asymptomatic infection whereas others may not be detectable until symptoms develop. Instructions for when to test will vary based purpose of testing and whether testing is for diagnostic purposes (e.g., testing because of the presence of symptoms, or due to known exposure) or for asymptomatic screening without identified risk factors for exposure (CDC, 2022b). These, and other, disease-specific considerations will need to be considered when developing and implementing new self-tests, but ultimately it remains important for there to be clear messaging for people about how and when to test and what actions to take based on the test results—especially if the test is positive.

MANUFACTURING AND REGULATORY CONSIDERATIONS

Meeting demand for self-tests requires biomedical and academic infrastructure for test development, the regulatory structure for evaluation and quality control, the industrial capacity and market incentives for manufacturing (especially when there is a lack of or uncertain demand), and the supply chain and distribution networks. As COVID-19 has shown, strategic planning is important for each element. Novel pathogens needing innovative self-tests are likely to be made available through EUA. Strategic planning can help to ensure that FDA has the surge capacity to evaluate tests quickly and carefully as well as to consider the transition of self-tests from EUA to full FDA approval status. The plans may include pre-approval of generic test instructions that can be adapted to specific settings and preferred methods for specimen collection, processing, and reading. Preferred swabs and other test materials may also need to be stockpiled in advance. However, EUA pathways may not apply to all situations and infectious diseases, and it will be important to understand how this might affect approval for future self-tests.

IMPLEMENTATION AND HUMAN COMPONENT CONSIDERATIONS

Accessibility of Self-Tests

An advantage of self-tests, specifically antigen tests, is greater accessibility and lower cost than laboratory-based RT-PCR testing. To ensure broad and equitable access, it is important to consider routes of distribution, depending on priority populations (e.g., direct to consumer, workplace, through commercial partners vs. state/local government partners, schools). The current pandemic has also shown the challenges of self-test acceptance and use in areas of high social vulnerability.

Cost

Self-tests that are widely available and relatively low cost or free of cost can be used more effectively

as public health tools, especially in communities with disparities in access. The direct, out-of-pocket cost of SARS-CoV-2 self-tests available in the United States can range from $7 to nearly $40 per test. Self-testing will need to be performed many times during a pandemic, which can be financially challenging. For example, testing just twice per week with the least expensive test, if available, would total $728 per year (Dawson and Jennifer, 2021). In December 2021, the Biden Administration announced that private insurers would be required to cover the cost of OTC SARS-CoV-2 self-tests (Dawson et al., 2022). Under this regulation, health insurance companies can cover eight free OTC SARS-CoV-2 self-tests monthly for each person that has coverage (CMS, 2022). In January 2022, the Biden Administration launched an initiative that offered and distributed SARS-CoV-2 antigen tests free of charge to each U.S. household (Artiga and Rae, 2022; The White House, 2022b). The program was supported by communication outreach to individuals who did not or could not follow these procedures. The program was met with modest demand (Associated Press, 2022), though issues did arise (discussed below).

The federal government announced in April 2022 that it may not have sufficient funding to purchase additional COVID-19 supplies without additional congressional allocation (The White House, 2022c). This change may impact self-test accessibility, as many uninsured people could need to pay out-of-pocket for testing, and privately insured people could potentially be subject to cost-sharing for SARSCoV-2 testing when the public health emergency concludes. To promote self-testing in the future, no-cost or low-cost programs are needed to reach people of all financial means.

Health Equity

SARS-CoV-2 self-tests have highlighted existing inequities and disparities in access to health care services. Recent survey data find that SARS-CoV-2 rapid antigen tests are used most commonly by people who are White, high-income (>$150,000), and have a post-secondary education; they are used least frequently among people who are Black/African American, low-income, and have a high school education or less (Rader et al., 2022b). A qualitative study examining barriers and facilitators to SARS-CoV-2 self-testing among Black/African American populations found that self-testing was seen as a valuable tool because it encouraged individuals to test for the virus. However, the cost and perception of potential for inaccurate results were barriers. Participants recommended engaging community members (e.g., barbers and religious leaders) in providing information about self-testing and developing culturally tailored education communications and instructions (Nwaozuru et al., 2022).

The Biden Administration’s plan to provide four COVID-19 tests to each household in the country (upon request) was intended to increase accessibility among people who cannot afford testing, with a greater priority toward disproportionately affected areas (Artiga and Rae, 2022). However, it was criticized for providing an equal number to each home, regardless of household size or risk level (though second and third orders can be requested, but this was not possible when the program was initiated). The program also required access to a computer and a mailing address for test ordering. Challenges were also related to access to information about the program in multiple languages, and the lack of broader communication strategies.

Self-testing can pose accessibility challenges for people with disabilities. People who are colorblind may have difficulty with tests that rely on colors to convey information. People with limited vision may

have difficulty with written instructions, as may people with limited literacy, given the high reading level of many instructions, and people who are literate in languages other than those used in the instructions or who cannot readily access online supplements. People with limited physical dexterity may have difficulty self-administering tests (Alcántara, 2022). They may also struggle to order or receive tests for various practical reasons.

In addition to ensuring that the cost of self-tests is not a barrier to access such tests, there are other considerations for planning for future self-test use that include identifying disadvantaged persons and communities who may need focused outreach; engaging and communicating specifically to those communities; developing mechanisms to distribute self-tests to priority communities; and ensuring that persons with disabilities are accounted for when developing self-tests, instructions, and guidance (The White House, 2022a). Equity in perceived or actual benefits of testing is also an important consideration for implementation, as individuals equating the potential for a positive test with missed participation in day-to-day activities (e.g., school, work, recreation) or financial implications (e.g., missed wages) may be deterred from self-testing.

Interventions to Broaden Accessibility

To broaden the availability of SARS-CoV-2 testing services, including access to self-tests, CDC initiated the following programs: the Increasing Community Access to Testing (ICATT) program supports no-cost COVID-19 testing for persons who are symptomatic, exposed, or at high-risk of severe disease by partnering with pharmacies and other testing facilities across the country; and the Operation Expanded Testing (OpET) program which provides no-cost testing to child care centers, K-12 schools, historically Black colleges and universities, under-resourced communities, and congregate settings, such as homeless shelters, domestic violence and abuse shelters, non-federal correctional facilities, and other qualified sites. Evaluation of the effectiveness of these programs can help identify those programs and strategies that were the most effective and could be helpful in the development of self-testing strategies beyond COVID-19. For example, it was anecdotally reported that while testing may have been covered, the actual implementation often required more resources than certain settings, like schools and child care center could devote.

Another attempt to improve and understand accessibility is the COVID-19 Self-Testing through Rapid Network Distribution (C-STRAND), a current randomized controlled trial evaluating secondary distribution of self-test kits, whereby individuals distribute tests to their social network contacts, to encourage them to self-test. This decentralized approach aims to reduce the stigma, fear, and mistrust associated with the conventional health care system.

Experience with a rural South Carolina program found that such access required balancing “simplicity, accessibility, and community trust” (Plumb et al., 2022). Allocating self-tests may require setting priorities among users. Those priorities will affect where the stockpiles are located, transportation logistics, how inventories are tracked, and program management. Consideration is needed for self-test distribution to areas of social vulnerability and areas disproportionately affected by the pathogen.

In addition to what has already been undertaken during the COVID-19 pandemic to broaden

accessibility, steps in future self-testing strategic planning include identifying lessons learned from these most recent partnerships, improving upon existing partnerships, identifying other strategic partnerships to broaden accessibility, and incorporating health equity considerations mentioned above. Furthermore, it is clear that local action, along with state and/or federal support, is critical for pandemic management. As such, local distribution networks may need to be developed in order for these networks to have access to a steady supply of self-tests. Also, implementation of testing in certain settings outside of the home may require additional personnel, staffing, or other infrastructure and funding support beyond just supplying testing resources.

Usage of Self-Tests

The accuracy of self-tests depends on a variety of factors, but the usefulness of even accurate test results depends on how well individuals can translate them into action and how well they inform medical and public health systems. Therefore, individuals will need resources and clear, timely information and guidance about how and when (i.e., the best situations) to use self-tests to protect themselves and others.

Understanding When to Test

As the COVID-19 pandemic and testing capabilities evolved, so did the government’s guidance on how and when to use self-tests. However, it appeared confusing and inconsistent to the public (Dawson and Jennifer, 2021). In part this was influenced by test availability. For example, in August 2020, CDC recommended that people exposed to COVID-19 not test unless they were symptomatic, older, or medically vulnerable (Edwards, 2020). Two days later, CDC’s director released a statement indicating that testing may be considered by all close contacts of confirmed or probable COVID-19 patients. Although that change may have been medically sound, rapid changes, without accompanying explanations create an impossible burden on the public. In this case, matters were further complicated by the old guidance remaining on CDC’s website (Dawson and Jennifer, 2021). Later in the pandemic, CDC provided recommendations for quarantining after a negative antigen test in various clinical scenarios that were hard to interpret and difficult to access due to information that was spread across multiple webpages, was poorly summarized, and not entirely consistent (Woloshin et al., 2022). Throughout the COVID-19 pandemic, state and local public health agencies as well as other experts also developed different recommendations from CDC for how to use antigen and other self-tests. This has led to significant public confusion about how and when to use self-tests.

Therefore, clear instructions and guidance about when and how to use self-tests can be provided by recognizing that messaging may change based upon test availability and changes in the pandemic, and refining messaging using lessons learned from self-tests during the COVID-19 pandemic. Because there have been differences in recommendations for how to use self-tests, it is important for planning for future guidance and recommendations on use to involve engagement with the public and community members as well as health care partners and other state and local public health partners.

Administering the Test

Improper or suboptimal usage might include testing too early for detection, not performing serial testing, not understanding manufacturer instructions, not following (or being able to follow) instructions, not understanding the practical implications of test results, and being unable or unwilling to take action based on the results (Crozier et al., 2021; Woloshin et al., 2022). FDA does not require

that the SARS-CoV-2 self-test kit instructions be empirically evaluated, nor does FDA require manufacturers to provide evidence that users can follow test kit instructions or properly interpret test results. Whereas review of these issue is viewed as important and FDA could consider such requirements, the time it takes for additional review needs to be balanced against the need for rapid EUA approval. Poor instructions on how to administer tests can reduce their sensitivity. Inadequate instructions on interpreting tests results can lead to incorrect interpretation of the test, even if the test itself is accurate (e.g., reading control and sample lines, no presence of control line, faint positive results, etc.). Self-tests have limited value unless users can read and follow the instructions for administration of the test and interpretation of the results.

Test Storage

Self-test stability may be affected by climate and ambient heat (Parker-Pope, 2022). In January 2022, for example, when the federal government began to ship self-tests to homes during the winter months, there were reports of packages being left out for extended periods of time in cold temperatures and concern about the impact on test validity. Differences in test expiration dates or updates to expiration dates make appropriate use more difficult, especially when the date on the box no longer corresponds to the official expiration date and since users do not routinely follow changes on official websites (Parker-Pope, 2022). While FDA typically authorizes SARS-CoV-2 self-tests with a shelf-life of 4–6 months based on initial data, they may extend the official shelf-life based on additional, real-world data (FDA, 2022b).

Interpreting Test Results and Taking Action

For a test result to be useful, the user must be able to use the results to guide action. These actions include understanding (1) test sensitivity, or the proportion of individuals with infection who test positive; (2) test specificity, or the proportion of individuals without infection who test negative; (3) the individual’s pretest probability of infection, which depends on population prevalence and individual circumstances and risk factors; and (4) the individual’s decision threshold, reflecting relative aversion to false negatives and false positives (Crozier et al., 2021). These factors are important for guidance development that will impact a person’s ability to understand the likelihood they may or may not have the infection being tested for even in the setting of a negative antigen test and whether additional action may be needed or recommended (e.g., repeat testing). The user needs instructions that synthesize these concerns for their personal circumstances. One study found that potential test users with some suspicion of infection (due to symptoms or exposure) were more likely to interpret test results appropriately with no instructions at all than with the FDA-approved instructions. They did much better with instructions based on decision science principles (Woloshin et al., 2022). A study of self-performed serial SARS-CoV-2 tests in a workplace found that test results were often interpreted poorly when relying on the manufacturer’s instructions, but significantly better using a modified quick reference guide (Papenburg et al., 2022). The authors know of no studies of how interpretation of test results affects users’ actual behavior (e.g., masking, socializing, travel, work) or that of people who observe or interact with them. When planning for future self-testing, there is a need for developing clear messaging and instructions for interpreting test results, and also incorporating guidance on follow-up actions that may be necessary depending on whether a test result is positive or negative or inconclusive.

Reporting Test Results

Reporting of self-test results to public health authorities or providers is entirely voluntary (Blauer and Nuzzo, 2022; McLaughlin, 2021). In contrast, samples from at-home specimen collection RT-PCR kits are sent to a laboratory that must report positive results to public health authorities. Individuals who wish to report self-test results need assurances of privacy and easy reporting pathways (Mueller-Hsia and Hecht-Felella, 2021). Box 4 describes one attempt to increase such reporting.

As mentioned previously in this consultation, the limited reporting of at-home test results has led to substantial underestimates of new cases of the disease. The authors know of no studies examining how the change in these estimates has affected the perceptions or behavior of individuals (e.g., those who follow charts of prevalence, perhaps not realizing that the reporting regimes have changed over time). Lack of reporting self-testing results to public health agencies could be based on a variety of reasons such as the lack of reporting system or lack of communication from or lack of trust in the

public agencies. Additional research into understanding why individuals may not report, what motivates them to report, and other facilitators and barriers for reporting is critical to informing future strategic planning regarding the use of self-tests. For individuals to be willing to report their self-test results, the system will not only need to protect their data and privacy, but also convince them about the reliability of that protection. Building such trust will require understanding community perspectives on this issue and then developing processes, including a dedicated communication strategy, that are supported by evidence of efficacy.

Both molecular laboratory tests and point-of-care tests are subject to the reporting standards specified in the Clinical Laboratory Improvement Amendments of 1988 (CLIA). The Coronavirus Aid, Relief, and Economic Security (CARES) Act, additionally, requires any CLIA-certified SARS-CoV-2 testing site to report some test results used for diagnosis or screening purposes to public health departments (Juluru et al., 2022).⁹ In contrast, CLIA applies only to self-tests administered or interpreted by individuals or facilities other than the test recipient. Thus, people who administer tests to themselves or other household members are not required to report test results (Juluru et al., 2022). SARS-CoV-2 self-testing programs implemented in educational settings may allow schools to obtain a CLIA waiver to administer tests. Secure and confidential reporting (or even aggregate, anonymous reporting in some settings) of self-test results to both health care providers and public health authorities can be improved by exploring and developing mechanisms to facilitate connecting individuals with medical care, so that self-testing can be incorporated into future surveillance strategies. However, it needs to be recognized that, due to practical and privacy related issues, there will not be global reporting of self-test results. As such, numbers of new cases will be underestimated due to self-testing—a limitation that has to be balanced against the considerable benefits from having self-testing widely available. Other strategies for assessing disease burden in the community are therefore needed.

Improving Self-Test Guidance

The COVID-19 pandemic has posed challenges in communicating when and how people should test and what the test results mean. Without effective communications, public trust will be lost and, with it, the full potential value of self-tests. Strategic planning can create scientifically sound, evidence-based communications, with appropriate content, delivery methods (e.g., video, telemedicine support), and channel and distribution network (e.g., community partners) (Juluru et al., 2022). Planning would ensure that communications are evaluated before they are disseminated, and not rushed into service, risking needless confusion and frustration. That planning should take advantage of research into communicating health and risk information (Fischhoff, 2013; Fischhoff and Davis, 2014). For example, in redesigning self-test instructions, Woloshin et al. addressed the well-known tendencies to ignore a priori probabilities (2022) and imperfect diagnostic value (Tversky and Kahneman, 1974). They also applied decision science principles that included, “(1) using simple and familiar wording; (2) enhancing users’ intuitive mental models of the disease and test; (3) providing an easily navigable visual design; (4) spelling out the implications of different scenarios in comparable terms; and (5) explicitly recognizing uncertainty without suggesting ignorance” (Woloshin et al., 2022). Any communication is limited by the quality of the technical information supporting it, such as variation in

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self-test sensitivity (Dinnes et al., 2022).

RESEARCH AND EVIDENCE GAPS

Self-testing has been identified as a critical public health tool during the COVID-19 pandemic and for other infectious diseases, like HIV. However, many questions remain and research and evidence is still developing to inform best practices moving forward for both the ongoing COVID-19 pandemic as well as known and unknown pathogenic threats. Table 1 lists examples of author-identified research and evidence gaps relevant to this rapid expert consultation.

Table 1 Examples of Research and Evidence Gaps for Self-Tests

Concluding Remarks

Self-testing holds great promise for helping individuals, communities, and health care and public health systems manage infectious diseases and limit morbidity and mortality. Strategic planning to determine the goals and benefits of self-testing and to identify the appropriate setting(s) for self-testing based on disease-specific considerations, pathogen dynamics, and community values will provide the elements needed to realize that potential. A robust industrial and logistical infrastructure for developing manufacturing and deploying self-tests is necessary—along with the regulatory infrastructure needed to evaluate tests and monitor their performance. The social infrastructure is needed to ensure that people get affordable tests and test results can be linked to interventions or treatment, and the communication infrastructure is needed to ensure that individuals can understand the need for tests and respond effectively to test results. Finally, the public health and health care systems will need surveillance strategies for a world in which most test results are not reported to them. One lesson from the COVID-19 pandemic is that successful public health strategies require systematic evaluation of self-test uptake, usage, and impact, along with the authority and resources for adaptive management. As reviewed here, the COVID-19 experience has revealed both creative solutions and unsolved challenges.

REFERENCES

ACKNOWLEDGMENTS

We thank the sponsor of the Standing Committee for CDC Center for Preparedness and Response (SCPR)—the Centers for Disease Control and Prevention—and its committee members. To supplement the group’s expertise, we received input from several external sources, whose willingness to share their perspectives and expertise is appreciated. We thank Donald Klepser, University of Nebraska Medical Center; Tener Veenema, Johns Hopkins Bloomberg School of Public Health; David Walt, Harvard Medical School; and Kelly Wroblewski, Association of Public Health Laboratories.

We extend gratitude to the staff of the National Academies who contributed to the research, writing, and editing of this rapid expert consultation, in particular Lisa Brown, Matthew Masiello, Shalini Singaravelu, and Margaret McCarthy, and to our science writer, Anna Nicholson.

The following individuals served as reviewers: Rick Bright, The Rockefeller Foundation; Emily Brunson, Texas State University; Andrew C. Cannons, Florida Department of Health; Jeffrey Duchin, Public Health–Seattle & King County; Mark Smolinski, Ending Pandemics. Monitor, Paul A. Volberding, University of California, San Francisco, and Coordinator, Linda C. Degutis, Yale University School of Public Health, reviewed and approved this document on behalf of the National Academies’ Report Review Committee. Responsibility for the final content rests entirely with the authors and has been reviewed and approved for release by the National Academies

This activity was supported by a contract between the National Academy of Sciences and the U.S. Centers for Disease Control and Prevention (200-2011-38807/75D30121F00100). Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project.

Copyright 2022 by the National Academy of Sciences. All rights reserved.