key: cord-0779624-1jwrzvn5
authors: Kepczynski, Casey M.; Genigeski, Jaelin A.; Koski, Renee R.; Bernknopf, Allison C.; Konieczny, Alison M.; Klepser, Michael E.
title: A Systematic Review Comparing At-Home Diagnostic Tests for SARS-CoV-2: Key Points for Pharmacy Practice, Including Regulatory Information
date: 2021-06-12
journal: J Am Pharm Assoc (2003)
DOI: 10.1016/j.japh.2021.06.012
sha: d6c9f0ca205917966e23bce308eb1332e7021d9c
doc_id: 779624
cord_uid: 1jwrzvn5

Objectives Home-based rapid diagnostic testing can play an integral role in controlling the spread of COVID-19. This review aimed to identify and compare at-home diagnostic tests that have been granted Emergency Use Authorizations (EUA) and convey details about COVID-19 diagnostic tests, including regulatory information, pertinent to pharmacy practice. Methods Food and Drug Administration (FDA) online resources pertaining to COVID-19 tests, EUAs, and medical devices were consulted, as well as linked resources from the FDA’s webpages. Homepages of the 9 COVID-19 home tests with EUAs were comprehensively reviewed. PubMed literature searches were performed, most recently in May 2021, to locate literature about the identified home tests, as were searches of Google Scholar, medRxiv, and bioRxiv. Literature Selection Studies were included if they were performed at home or were self-collected (or collected by a parent or guardian for patients under 18 years of age), and evaluated the positive percent agreement (PPA) and negative percent agreement (NPA) for the clinical diagnosis of SARS-CoV-2 virus. Results Limited data has been published for these home tests given that they are available through EUAs that do not require clinical trials. Fifteen studies were located from searching the literature, but only 2 met the inclusion criteria. Review of the home-tests' websites yielded a single study for each test with the 3 BinaxNow platforms using the same study for their EUAs. The 9 COVID-19 home tests with EUAs as of May 7, 2021 include 3 molecular tests and 6 antigen tests. These tests had similar performance based on positive percent agreement ranging from 83.5% to 97.4% and negative percent agreement ranging from 97% to 100%. Conclusions The 9 SARS-CoV-2 home tests demonstrated satisfactory performance in comparison to laboratory real time reverse-transcription polymerase chain reaction (RT-PCR) tests. The convenience and ease of use of these tests make them well-suited for home-based rapid SARS-CoV-2 testing.

In addition to understanding the regulatory matters surrounding SARS-CoV-2 testing, a 139 basic understanding of SARS-CoV-2 test types and performance parameters is important for 140 pharmacists that may be involved in test administration, distribution, and patient counseling. The Testing during the first few days of infection when viral loads may be small, or inadequate 147 specimens, can lead to false negatives because there is inadequate SARS-CoV-2 genetic material 148 for tests to detect. 29 A meta-analysis found an average test sensitivity of 95% for the studied 149 rapid molecular assays. 30 The same meta-analysis found an average test specificity of 98.9%, 30 150 with specificity being the probability that a negative test result is truly negative [low false 151 positive rate]. 27, 28 Although PCR-based tests have excellent sensitivity and specificity, they 152 require expensive equipment and are prone to contamination. 31 Additionally, these tests are 153 sometimes criticized as being too sensitive because they do not discriminate between viable 154 pathogens and residual genetic fragments from non-viable virus. 32 In other words, these tests can 155 determine if the disease is present in a patient but cannot determine if they are contagious or not. 156 Antigen diagnostic tests detect proteins such as the spike protein, nucleocapsid protein, or meta-analysis found a wide range of test sensitivities for the studied antigen tests, with an 162 average sensitivity of 56.2%. This same meta-analysis found good test specificity, with an 163 average of 99.5% for the antigen tests studied. 30 Even with low sensitivities, Larremore, an 164 infectious disease modeler and proponent of frequent rapid testing for SARS-CoV-2 infection 165 indicated, "Even low-sensitivity tests, which only catch people at the early and most-contagious 175 With the use of rapid diagnostic tests, it is essential to understand the impact of their 176 performance characteristics as the intended use and pretest probability of disease fluctuation. 177 When the sensitivity of a test is low and the pre-test probability of disease is high, the test may 178 return a higher rate of false negative results. This correlates with the negative predictive value 179 (NPV) of a test or how good it is at ruling out a disease. In 

Since all of the tests have been made available through EUA, the data used to obtain the 217 EUAs were from interim analyses; 51-59 therefore, the sample sizes were smaller leading to issues 218 with selection bias and potential issues with the ability to extrapolate the data to expanded 219 populations. Additionally, the clinical data have only been published in the manufacturers' 220 literature, so while the FDA has reviewed it, it has not gone through the rigorous peer-review 221 process that occurs when studies are published in medical journals. Additionally, many of the 222 details needed to fully assess bias are missing (e.g. missing demographic data makes it difficult 223 to know which patient populations are represented in the studies). Therefore, there is a high risk 224 of bias in the studies included in this systematic review.

There are 9 COVID-19 home tests at the time this article was written, some of which are 227 the same testing platform with different availabilities and/or indications. 5, [51] [52] [53] [54] [55] [56] [57] [58] [59] Three of the tests 228 are molecular (2 Lucira and 1 Cue) 55-57 and 6 are antigen (Ellume, 3 BinaxNOW, and 2 QuickVue) . [51] [52] [53] [54] 58, 59 A full comparison of the molecular tests can be found in Table 1 , and a full 230 comparison of the antigen tests can be found in Table 2 show that the tests were evaluated using comparable tests rather than a true reference standard. In 262 this scenario, sensitivity is replaced with PPA, and specificity is replaced with NPA.

All manufacturers' studies of the home test kits' performances were prospective 264 studies. 51-59 The PPA for the 9 home tests ranged from 83.5% (QuickVue At-Home) to 97.4% 265 (Cue COVID-19), while the NPA ranged from 97% (Ellume) to 100% (BinaxNOW) It is 266 important to note that all 3 at home BinaxNOW tests use the same platform, so the same data 267 sets were utilized to receive their EUA. See Table 3 Perfection is defined as "an unsurpassable degree of accuracy or excellence." 61 In 287 medicine and science, we are trained to seek perfection in our instruments, analytical approach, 288 and solutions. Unfortunately, we can become obsessed with striving for perfection and lose sight 289 of our true goals. During World War II, Sir Robert Alexander Watson-Watt, developer of the 290 early warning radar system used in Britain, was a believer in the "cult of the imperfect." 62 He 291 was often quoted as saying "Give them the third best to go on with; the second best comes too 292 late, the best never comes." 62 This suggests that rather than waiting for perfect, which may never 293 come, we can succeed using an imperfect option. This idea holds true now, as we grapple with 294 controlling the spread of SARS-CoV-2. If we wait for development of the perfect SARS-CoV-2 295 test, the loss of life and prevention of spread would be horrific. Therefore, we need to embrace 296 the technologies we have at our disposal and use them to optimize their value.

Many in vitro SARS-CoV-2 diagnostic tests have received EUA since the beginning of 298 the pandemic. These tests employ methods including PCR and antigen detection using a variety 299 of platforms requiring a range of technical expertise, equipment, and expense. If we seek 300 perfection, the question should be asked as to what makes a test perfect. Is perfection based on 301 sensitivity and specificity of the assay? What if, in order to obtain analytical perfection, the 302 procedures use an expensive analyzer and take 3 days to get results? Would that test still be 303 considered perfect? If a comparator test had lower sensitivity and specificity but only cost $5 to 304 perform and gave results within 15 minutes, would that test be imperfect? A companion 305 philosophy to the cult of the imperfect that we as clinicians should embrace is the concept of 306 situational relevancy. 63 Simply put, situational relevancy is the realization that there is not a 307 single correct solution to a problem with multiple variables. Rather, the correct solution for a 308 given problem changes as the variables change. As an example, think about two SARS-CoV-2 309 testing scenarios. In the first scenario, we wish to detect SARS-CoV-2 in a limited number of 310 hospitalized patients exhibiting symptoms of COVID-19. The goal for this scenario is to identify 311 infected individuals for quarantine. Given these conditions, it seems that a test with high 312 sensitivity and specificity would be important, and we may be willing to sacrifice turnaround 313 time to improve these characteristics. Additionally, since we would only be using this test on a 314 relatively small population and given that the cost of a patient in an isolation room would be 315 high, we may find that using a more expensive test would be cost-effective if performance 316 characteristics were maximized. In the second scenario, we wish to screen asymptomatic 317 individuals for SARS-CoV-2 to minimize the chance that they would infect co-workers. In this 318 scenario, we understand that the pre-test probability of having SARS-CoV-2 is low and the 319 likelihood of detecting an individual with infection is low. Additionally, people are to be screened 3 times a week before they may enter a building. Under this set of variables, being able 321 to rule out the presence of the virus would seem more important that detecting the actual virus.

Since the pre-test probability of being infected with SARS-CoV-2 is low, any positive test result 323 would likely need confirmation to rule out a false positive. Furthermore, since individuals are 324 being tested 3 times a week, cost would be an appreciable consideration regarding the long-term 325 application of a test system. Lastly, if a negative result is needed prior to a worker being allowed 326 to go into a workspace, then speed is a critical factor in determining the utility of a test. So even 327 though the underpinning goal of detecting SARS-CoV-2 is the same in the two scenarios, the 328 desirable characteristics of the "perfect" test is highly situational.

The best indicator of situational value is likely to be the PPV and NPV associated with Since some at-home tests require a prescription while others can be purchased OTC at 372 local pharmacies, it is important that pharmacists be familiar with these tests. Table 4 lists 373 common questions pharmacists may be asked regarding these tests. Since only BinaxNOW 374 requires the user to be supervised by a telehealth proctor, many questions related to specimen 375 collection, test interpretation, and post-test actions may arise. Pharmacists should be able to 376 address these questions for the currently authorized tests and be prepared for the marketplace 377 entry of more SARS-CoV-2 home-tests. Additionally, pharmacists should be aware of the 378 regulatory stipulations, particularly CLIA regulations, and understand them prior to physically 379 assisting with specimen collection and test interpretation. A CLIA Certificate of Waiver may be 380 necessary to perform or assist with performing these tests, and physically assisting with these 381 tests may be precluded, even in CLIA-waived settings, since tests authorized for home use are 382 not automatically authorized for use in CLIA-waived settings. Lastly, the pharmacist must be 383 able help patients understand when confirmatory testing is required and where that can be 384 completed. (4) 

PPV: 97.5% (84.7% -99.6%) NPV: 94.2% (89.2% -97%)

Overall NPV: 96% (93.2% -97.7%)

Sx PPV: 98% (87.3% -99.7%)

Sx NPV: 94.2% (90.2% -98.9%)

Overall PPV: 94.9% (82.3% -98.7%) Overall NPV: 99.6% (97.1% -99.94%)

Sx PPV: 93.1% (77.3% -98.2%)

Asx NPV: 96.5% (93.4% -98.1%)

Asx PPV: 100% (95% CI not calculated)

CI = Confidence Interval; LR-= Likelihood Ratio for Negative Test Result

Ratio for Positive Test Result; NPV = Negative Predictive Value

Since all BianaxNow diagnostic test are the same platform with different EU authorizations, the same data sets were utilized to support each test's EU authorization

Pharmacy Care Model 51-59 , 2019-nCoV Infection" or "COVID-19 Diagnostic Testing" or

Diagnostic Testings" or "Diagnostic Testing, COVID-19" or "Severe Acute Respiratory Syndrome Coronavirus 2

Testing" or "Coronavirus Disease-19 Testing" or "Coronavirus Disease 19 Testing" or

Testing, Coronavirus Disease-19" or "2019-nCoV Testing" or "2019 nCoV Testing" or "2019-nCoV Testings" or "Testing, 2019-nCoV") AND ("home test

Lucira COVID-19 All-in-One

Implementation of rapid and frequent SARS-CoV2 antigen testing and response in congregate homeless shelters. medRxiv

Evaluation of the Cue Health point-of-care COVID-19 (SARS-CoV-2 nucleic acid amplification) test at a community drive through collection center

Quantification of the tradeoff between test sensitivity and test frequency in a COVID-19 epidemic-a multiscale modeling approach

Antigen Card test relative to the severe acute respiratory coronavirus virus 2 (SARS-CoV-2) real-time reverse transcriptase reaction (rRT-PCR) assay among symptomatic and asymptomatic healthcare employees

Comparison of two nucleic acid amplification tests (NAATs) and two antigen tests for detection of SARS-CoV-2 from upper respiratory specimens

Performance characteristics of BinaxNOW COVID-19 antigen card for screening asymptomatic individuals in a University setting

Estimation of secondary household attack rates for emergent SARS-CoV-2 variants detected by genomic surveillance at a community-based testing site in San Francisco. medRxiv

Analytical sensitivity of the Abbott BinaxNOW COVID-19 Ag Card

Performance characteristics of a rapid severe acute respiratory syndrome coronavirus 2 antigen detection assay at a public plaza testing site in San Francisco

Field performance and public health response using the BinaxNOW rapid severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen detection assay during community-based testing

Performance and implementation evaluation of the Abbott BinaxNOW Rapid Antigen Test in a high-throughput drive-through community testing site in Massachusetts

Evaluation of Abbott BinaxNOW Rapid Antigen Test for SARS-CoV-2 infection at two community-based testing sites

Strategies for antigen testing: an alternative approach to widespread PCR testing. medRxiv

Performance of repeat BinaxNOW SARS-CoV-2 antigen testing in a community setting

Evaluation of the Abbott BinaxNOW rapid antigen test for SARS-CoV-2 infection in children: implications for screening in a school setting

PubMed 5/5/2021 (PCR or "polymerase chain reaction" or "nucleic acid amplification" or "SARS-CoV-2 nucleocapsid protein" or "molecular diagnostic" or "molecular diagnostics" or "molecular diagnosis" or "Pathology, Molecular" or antigen or nucleocapsid or "lateral flow immunoassay" or immunoassay or "RT-LAMP" or LAMP assay or viable or "non-viable" or "COVID-19 Testing" or "Diagnostic Techniques and Procedures" or "rapid diagnostic tests" or "rapid diagnostic testing") AND (" or "SARS Coronavirus 2 Testing" or "COVID-19 Virus Testing" or "COVID 19 Virus Testing" or "COVID-19 Virus Testings" or "Testing, COVID-19 Virus" or "Virus Testing, COVID-19" or "COVID19 Testing" or "COVID19 Testings" or "Testing, COVID19" or "COVID19 Virus Testing" or "COVID19 Virus Testings" or "Testing, COVID19 Virus" or "Virus Testing, COVID19" or "SARS-CoV-2 Testing" or "SARS CoV 2 Testing" or "SARS-CoV-2 Testings" or "Testing, SARS-CoV-2" or "Coronavirus Disease 2019 Testing" or "2019 Novel Coronavirus Disease Testing" or "2019 Novel Coronavirus Testing" or "2019-nCoV Disease Testing" or "2019 nCoV Disease Testing" or "2019-nCoV Disease Testings" or "Disease Testing, 2019-nCoV" or "Testing, 2019-nCoV Disease" or "2019-nCoV Infection Testing" or "2019 nCoV Infection Testing" or "2019-nCoV Infection Testings" or "Infection Testing, 2019-nCoV" or