OBJECTIVES

After completing this chapter, the reader should be able to

  • Identify resources for Clinical Laboratory Improvement Amendments–waived point-of-care testing options

  • Interpret the performance characteristics of common point-of-care tests

  • Describe clinical opportunities for point-of-care testing in an outpatient pharmacy setting for both population- and patient-specific applications

  • Identify potential resources for maintaining good laboratory practices

  • Discuss the limitations for Clinical Laboratory Improvement Amendments–waived point-of-care testing

The pharmacist’s role in the healthcare system is continually evolving. Over time, the pharmacist’s role has shifted from being product focused to delivering patient-oriented pharmaceutical care. Today, pharmacists are on the frontline of providing patient-centered care and wellness, and their role in delivering care as a member of the healthcare team is essential. Pharmacists are highly trained, accessible healthcare professionals who are second only to registered nurses in terms of the number of practicing professionals. They are also underutilized in the U.S. healthcare delivery system.1 However, when working in collaboration with physicians and other healthcare professionals, pharmacists’ roles and their ability can be expanded to deliver quality patient-centered care and improve public health.1

Working in collaboration with other providers and public health officials, pharmacists can leverage their knowledge and accessibility to offer point-of-care testing (POCT) services that are waived under the Clinical Laboratory Improvement Amendments of 1988 (CLIA-88) (CLIA-waived POCT).2 Such services are offered to manage chronic diseases, improve access to healthcare services, rapidly initiate appropriate therapy, and screen for diseases of public health significance.2 Chapter 1 defines POCT, differentiates it from home testing, and provides an overview of the advantages and disadvantages of these testing paradigms. The objective of this chapter is to describe and illustrate opportunities to perform CLIA-waived POCT in outpatient pharmacy settings. This chapter focuses on POC tests and POCT by expanding on the overview of common CLIA-waived POC tests provided in Chapter 1; in addition, this chapter discusses available tests, reviews their performance measures and practical limitations, discusses their use in current practice, and identifies potential future applications for their use in practice.

FEDERAL AGENCIES INVOLVED WITH CLINICAL LABORATORY IMPROVEMENT AMENDMENTS–WAIVED POINT-OF-CARE TESTS AND TESTING

The U.S. Food and Drug Administration (FDA) and the Centers for Medicare and Medicaid Services (CMS) are the federal agencies charged with oversight of CLIA. The Centers for Disease Control and Prevention (CDC) supports the CLIA program by serving as a resource for analytical, research, and technical information on CLIA and POCT.

The FDA regulates test manufacturers and classifies their tests by a premarket authorization process. During this authorization process, the FDA uses criteria in the CLIA regulations to classify tests according to their level of complexity (high, moderate, or waived) and potential for risk to public health. Waived tests are low-complexity methods that are simple to use, and their risk of producing erroneous results is negligible or poses no reasonable risk of harm to the patient if performed incorrectly.3 In public health emergencies, like the COVID-19 pandemic, the FDA commissioner can authorize the use of medical products, including diagnostic tests, before they undergo the normal review and classification process using an Emergency Use Authorization (EUA).4 Since an EUA allows use of a diagnostic test before it has been classified according to its complexity, the authorization must specify the test can be performed in a patient care setting (ie, at the POC), or else it must be performed in a laboratory capable of carrying out moderate to high complexity tests.4

CMS regulates facilities that conduct laboratory testing, including all POC tests, on human specimens for health assessment, diagnosis, prevention, or treatment of disease. Waived laboratories, such as community pharmacies or ambulatory care clinics, can only perform waived tests and are not subject to regular inspections, personnel requirements, or proficiency testing. To perform such tests, these sites must obtain a CLIA Certificate of Waiver from CMS, pay applicable fees biannually, and follow the manufacturers’ testing instructions. In most states, the process is similar; however, CMS has exempted New York and Washington from CLIA so some of the processes and regulations to perform CLIA-waived tests are different. More information on how to apply for a CLIA Certificate of Waiver can be found at the CMS website (https://www.cms.gov/Regulations-and-Guidance/Legislation/CLIA/How_to_Apply_for_a_CLIA_Certificate_International_Laboratories.html).

Resources

The market for CLIA-waived POC tests continually and rapidly grows and changes. Therefore, a pharmacist who has a CLIA waiver must be aware of the most current information on the available tests. The FDA, CMS, and CDC websites provide useful and current information on CLIA-waived tests (Table 4-1).5,6

TABLE 4-1.

Resources for CLIA-Waived POCT

AGENCY

RESOURCE

SITE

COMMENTS

FDA

Searchable list of analytes used in waived laboratory test systems

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfClia/analyteswaived.cfm

  • Select an analyte to display a list of waived test systems for it, with hyperlinks to regulatory information and documentation

  • Updated frequently

  • Contains more regulatory information than clinicians need

Website with information on EUAs issued for emergencies (eg, COVID-19, H1N1)

https://www.fda.gov/medical-devices/emergency-situations-medical-devices/emergency-use-authorizations

  • Information on EUAs for diagnostic, nondiagnostic, and therapeutic medical devices

  • Information on diagnostics tests for a given disease includes date EUA was issued, manufacturer, hyperlink to authorizing letter, technology, authorized setting, hyperlinks to authorizing documents

CMS

A listing of tests that have been granted a waived status under CLIA

https://www.cms.gov/Regulations-and-Guidance/Legislation/CLIA/Downloads/waivetbl.pdf

  • List is organized by CPT code

  • Contains less information than the U.S. FDA website

  • Provides basic information (eg, CPT code, test name, and manufacturer) in an easy-to-read tabular format, which clinicians may find useful

CDC

CLIA website

https://www.cdc.gov/clia/default.aspx

  • Good resource with professional information and educational resources regarding the analytical and technical aspects of a test for a given analyte

Website for CLIA-waived POC tests

https://www.cdc.gov/labquality/waived-tests.html

  • Contains hyperlinks to documents that outline good laboratory practices for sites performing waived tests and a booklet detailing the practical considerations for performing CLIA-waived POCT or developing CLIA-waived POCT services5,6

CPT = current procedural terminology; FDA = Food and Drug Administration.

PERFORMANCE CHARACTERISTICS OF CLINICAL LABORATORY IMPROVEMENT AMENDMENTS–WAIVED POINT-OF-CARE TESTS AND THEIR APPLICATION

Like any test, CLIA-waived POC tests have random and systemic error associated with their use. Thus, pharmacists should be aware of the variability of POC tests when interpreting their results. A given test’s performance characteristics will be included in the manufacturer’s test literature. In addition, such information may be gleaned from the literature or the manufacturers’ websites.

Most CLIA-waived POC tests for chronic disease management that are applicable to outpatient pharmacy settings are either qualitative or quantitative. All CLIA-waived POC tests for infectious diseases that are applicable to outpatient pharmacy settings are qualitative. CLIA-waived POC tests can be described in terms of several performance characteristics introduced in Chapter 1, including accuracy/bias, precision, specificity, sensitivity, negative predictive value (NPV), and positive predictive value (PPV).

Accuracy and Bias

The terms accuracy and bias are often used synonymously. Accuracy, the percentage of true results, is a performance measure of qualitative CLIA-waived POC tests. In contrast, bias, how close the mean test measurement is to the true value, is a performance measure for quantitative CLIA-waived POC tests. The accuracy of a qualitative CLIA-waived POC test can be affected by many variables, including errors in sample collection, environmental conditions (eg, temperature, humidity), operator error (ie, not following test manufacturer instructions), improper instrument operation, and maintenance. Likewise, depending on the analyte, negative or positive bias associated with a quantitative CLIA-waived POC test may necessitate confirmatory lab-based testing for values that exceed a certain acceptable threshold.

Precision

For a CLIA-waived POC test, precision characterizes test reproducibility (ie, the degree to which the test performed under constant conditions produces the same measurement each time). For qualitative CLIA-waived POC tests, precision is characterized by PPV, which is the proportion of true positive results relative to all (ie, true and false) positive results. A CLIA-waived POC qualitative test with high precision regularly returns truly positive results. For quantitative CLIA-waived POC tests, precision is characterized by values such as standard deviation, relative standard deviation (coefficient of variance), or standard error of the mean. A CLIA-waived POC quantitative test with high precision regularly produces results that are in close agreement.

Application of Accuracy/Bias and Precision

Accuracy/bias and precision characterize the quality of a CLIA-waived POC test. These quality measures help the clinician choose the test, by comparing the expected performance of a test across different manufacturers. In addition, using these measures clinicians can evaluate the validity of a test’s result, and assess whether it is performing within its expected error limits. These quality measures are determined in studies for regulatory approval, the results of which are included in the manufacturer’s provided package insert for the test.

Specificity and Sensitivity

CLIA-waived POC tests for chronic disease management in an outpatient pharmacy setting evaluate the need for therapy and medication adjustments at a certain treatment threshold. In the case of infectious diseases, they confirm the presence of an infectious disease and aid in its diagnosis. A perfect CLIA-waived POC test for a chronic disease would return the exact value above or below the threshold, whereas one for an infectious disease would produce a positive result in all patients with the infection and a negative result in all patients without it. Unfortunately, like laboratory-based tests, no CLIA-waived POC test is perfect.7 Thus, when choosing a CLIA-waived POC test, clinicians must consider a test’s specificity and sensitivity, when there is a referenced laboratory standard for comparison, or the analogous respective terms negative percent agreement and positive percent agreement, in the absence of one.8

The specificity, or negative percent agreement, of a qualitative CLIA-waived POC test represents its ability to not detect the analyte when it is indeed absent (ie, a true negative). The specificity of a quantitative test is dependent on a cutoff value, which is also known as the limit of detection.

A qualitative CLIA-waived POC test with 90% specificity will incorrectly detect the presence of the analyte in 10% of those tested when they do not have the analyte of interest (ie, false positives). Thus, when screening for the presence of an infectious disease, using a CLIA-waived POC test with high specificity is desired because it means the test is rarely positive in the absence of the infection. The sensitivity, or positive percent agreement, of a qualitative CLIA-waived POC test represents its ability to detect the analyte when it is indeed present (ie, a true positive). The sensitivity of a quantitative test is dependent on a predefined cutoff or threshold value so that a diagnosis or therapeutic management decision can be made. A qualitative CLIA-waived POC test with 80% sensitivity will positively detect 80% of those tested who have the analyte of interest, but it will not detect the other 20% who also have it (ie, false negatives). Thus, when screening for an infectious disease that carries a poor prognosis or is highly contagious, using a CLIA-waived POC test with high sensitivity is desired because a false negative result cannot be tolerated.

Application of Specificity and Sensitivity

Specificity and sensitivity are performance characteristics that are independent of the population of interest being tested and are considered fixed characteristics of the test.7 Therefore, without further improvements in the methodology or analytical techniques, their values do not significantly change. Choosing the CLIA-waived POC test with the highest specificity minimizes the chance that someone without the condition or disease will be misidentified as having it. Thus, when using a CLIA-waived POC test to screen for a condition or disease that many of those tested will not have, choose the method with the highest sensitivity to optimize the testing efforts. A highly sensitive test does not often produce a false negative result. By doing so, the chance that someone with the condition or disease goes undetected will be minimized. To assess the value of specificity and sensitivity and relate them to patients in one’s clinical setting, the test’s NPV and PPV must be considered.7 By calculating either of these values, clinicians can apply a test’s performance to their own clinical setting.

Negative Predictive and Positive Predictive Value

For a qualitative CLIA-waived POC test, the NPV addresses the likelihood that a given patient does not have the condition or disease of interest when the test result is negative. Similarly, for a qualitative CLIA-waived POC, the PPV addresses the likelihood that a given patient has the condition or disease of interest when the test result is positive.

Application of Negative Predictive Values and Positive Predictive Values

The application of these values provides useful insight into how to interpret test results. Unlike specificity and sensitivity, NPVs and PPVs are not fixed characteristics of the test, but they are dependent on the population being tested and are influenced by the prevalence of the disease. Understanding how these values are influenced by disease prevalence can help clinicians use strategies to optimize test performance and mitigate overtesting and thereby improve the usefulness of a CLIA-waived POC test.

The NPV allows the clinician to determine how reassuring to be when answering the question from the patient who tested negative (“How likely is it that I do not have this condition?”), whereas the PPV allows the clinician to answer the question from the concerned patient who tested positive (“How likely is it that I have this condition?”).7

Interferences

Interferences are a performance characteristic that is not statistically based. Rather, interferences are medical conditions, medications, or other substances that might influence test results positively or negatively. For qualitative tests, interference can cause false negative or false positive results, whereas for quantitative tests, it can obscure the limit of detection. Interferences with CLIA-waived POC tests can occur and often involve cross-reactivity, microbial, or other interfering substances, such as chemicals or certain foods. Information on interferences is included in the manufacturer information included with the tests, which personnel performing the test must read to ensure they have the most up-to-date information.

SPECIMENS USED IN CLINICAL LABORATORY IMPROVEMENT AMENDMENTS–WAIVED POINT OF CARE

Waived tests are approved for use only with unprocessed specimens that require no manipulation (eg, centrifugation, precipitation, dilution, and extraction). Serum or plasma specimens require manipulation during sample preparation or training in their handling; thus they are not suitable for use in CLIA-waived POC tests.9 Clinicians should be aware that some test systems provide instructions for processed and unprocessed specimen types, but waived use is intended only for the testing of unprocessed specimens.

Specimens Used in Common Clinical Laboratory Improvement Amendments–Waived Point-of-Care Tests for Chronic Disease State Management

In addition, depending on the type of specimen the test analyzes, not all CLIA-waived POC tests used for disease state management are suitable or feasible for use in an outpatient pharmacy setting. The most commonly obtainable specimen types for POCT in disease state management are urine and whole blood.

Urine

The urine dipstick and tablet reagent urinalysis are common CLIA-waived POC tests found in many outpatient settings. Urine testing may involve a tabletop POC testing device or may be a manually read test kit. The determination of what type of POC testing device to use may factor in cost, time to test, and efficiency to document results.10 It is important to consider the specificity and sensitivity, and the NPV and PPV, for the POC urine test used at the practice site due to variability between devices.11 Subsequent therapy or treatment recommendations based on data collected from a POC urine test should be based on the specific device and analyte sampled. Typically, a sample is obtained in a clean container and analyzed promptly. If the time between collection and analysis is delayed more than 4 hours, the sample may be able to be refrigerated.12 Depending upon the test, an average of 1 to 2 oz may be needed for an accurate analysis. In addition, patients may be asked to obtain a sample in the morning in order for more concentrated urine to be collected.13 Often, a clean catch urine is necessary, requiring the patient to clean the genital area before collecting the sample to avoid contamination. Patients may be asked to alter sampling technique to obtain a first-void urine or a midstream urine sample.11 Menstrual period or vaginal secretion effect on certain test results may impact the timing of a test or ability to obtain a clean sample.

Whole Blood

Pharmacists obtain whole blood samples through a finger stick method for a variety of CLIA-waived POC tests. Blood conservation is one advantage of POC tests; as such, tests analyze whole blood analytes using volumes typically measured in drops of blood rather than milliliters. Each testing device may require varying amounts of a blood sample for a given analyte, making it critical for pharmacists to follow the manufacturer’s guidelines for blood sample collection as required by CLIA-waived testing regulations. The minimal amount of blood required by POC tests may also reduce the chance of errors that can occur when using larger volumes. As described in Chapter 1, a quick turnaround time (TAT) is also a major advantage to POCT. The TAT is the time interval from sample collection to test performance, and it is a critical step in ensuring test accuracy for some CLIA-waived POC tests. Outpatient pharmacy settings are often very busy; thus, pharmacists performing CLIA-waived POCT services in these settings must be cognizant of proper sample collection technique and timing information. This information is also found in the manufacturer’s guidelines.

Specimens and Types of Tests Used for Common Clinical Laboratory Improvement Amendments–Waived Point-of-Care Tests for Infectious Diseases Screening and Management

Currently, there are CLIA-waived tests for 17 infectious diseases analytes, but not all these tests have POC applications or are suitable for testing in the outpatient pharmacy setting. The most common obtainable specimen types for POCT for screening or management of infectious diseases are swabbed secretions from nose, nasopharynx, oropharynx, oral mucosal transudate, and whole blood.

Secretions From the Nose, Nasopharynx, and Oropharynx

Several infectious disease analytes, such as group A streptococci (GAS), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and influenza A and B, cause acute respiratory illnesses. The upper respiratory tract—the nasopharynx, oropharynx, and laryngopharynx—is easily accessible to airborne microorganisms and is colonized throughout life by commensal organisms and potential bacterial pathogens, including GAS, but not by viruses. Collecting lower respiratory tract specimens, such as sputum for diagnostic purposes, often requires invasive procedures, and for this reason, CLIA-waived POC tests for GAS, SARS-CoV-2, and influenza A and B rely on obtaining secretions from the more readily accessible upper respiratory tract. With minimal training, pharmacists can perform nasopharyngeal, nasal, or oropharyngeal swabs to collect specimens that would be suitable for the available CLIA-waived POC tests. Such samples can also be collected by nasopharyngeal aspiration or nasal wash, but these collection methods are technically difficult and not practical for a pharmacist to perform in an outpatient setting.14,15

Oral Mucosal Transudate

To date, human immunodeficiency virus (HIV) -1 and -2 are the only infectious disease analytes measured from oral mucosal transudate specimens for CLIA-waived tests. In 2004, the FDA approved a rapid HIV antibody–based, CLIA-waived POC test—which it had initially approved for finger stick, whole blood, and plasma specimens—for use with specimens of oral mucosal transudate. In 2012, the FDA approved an identical version of the test for sale directly to consumers for in-home use, which cannot be used in clinical outpatient settings. Oral mucosal transudate is more acceptable to patients because of its noninvasive, pain-free specimen collection and its rapid TAT. Moreover, the test enabled the expansion of testing efforts from laboratory-based facilities to outpatient settings, community health and nonclinical outreach testing sites, thereby increasing the availability of HIV testing and allowing more people to get tested and learn their results in a timely manner. The test also enables individuals to get tested at least once as part of routine healthcare.16 With minimal training, pharmacists can swab a person’s oral cavity to obtain oral mucosal transudate and perform the professional version of the CLIA-waived test. In general, POC tests for HIV-1 or HIV-2 using oral mucosal transudate specimens are less technically demanding than methods using blood and minimize the concern for biohazard disposal. Methods using oral mucosal transudate have low sensitivity and may miss more acute HIV infections than CLIA-waived tests that use whole blood specimens.

Whole Blood

HIV-1, HIV-2, and hepatitis C virus (HCV) are among the common infectious disease analytes measured from whole blood for CLIA-waived POC tests. Like POC tests for chronic disease state management, many pharmacists are comfortable with obtaining whole blood samples through a finger stick method for these CLIA-waived POC tests.17,18 Unlike the CLIA-waived oral tests for HIV-1 and HIV-2, the CLIA-waived whole blood tests for HIV-1 and HIV-2 require more equipment (eg, lancets) and biohazard waste precautions (eg, sharps containers and gloves). Although a blood sample for HIV-1, HIV-2, and HCV CLIA-waived tests that use whole blood can be obtained by venipuncture, it is easier to obtain the sample via finger stick for POCT purposes in outpatient pharmacy settings. However, HIV-1 and HIV-2 antibodies and p24 antigen concentrations are generally lower in whole blood finger stick samples than from plasma.

Types of Point-of-Care Tests for Infectious Diseases

The types of tests that exist to detect pathogens are antigen, molecular, and antibody-based methods. These methods differ in what is measured and their role in testing for a given pathogen. Antigen tests detect protein fragments of the pathogen that elicit an immune response; therefore, they may serve as a marker for infection. However, the tests do not distinguish between antigen from a viable pathogen and antigen from a nonviable pathogen, so a positive antigen test does not necessarily mean the patient has an active infection. Antigen tests target protein fragments that are large enough to detect without the use of amplification reactions, often through lateral flow chromatographic enzyme immunoassays or latex agglutination techniques. Such techniques can be performed with little or no training and typically produce a visual readout. However, despite its convenience, visual readouts may be unreliable; thus, for some pathogens, many contemporary antigen tests use an automated reader.19 Antigen tests typically have lower sensitivity than molecular tests and provide a qualitative result.19 These tests can be used to detect exposure that may necessitate therapy, and screen for potential outbreaks in institutions or environments with close quarters to develop further preventative strategies.

Molecular methods for detecting pathogens amplify nucleic acids in the viral genome using real-time reverse transcription polymerase chain reaction (rtRT-PCR) or reverse transcription isothermal amplification. The amplification reaction in rtRT-PCR methods requires a series of alternating temperature cycles, which makes their application to a POC platform challenging. However, technological advances such as the advent of reverse transcription isothermal amplification (ie, RT-loop-mediated isothermal amplification [RT-LAMP]), in which amplification reaction occurs at a constant temperature, have enabled molecular diagnostic tests to be applied to a POC testing platform.19 Molecular tests are typically highly sensitive, provide a qualitative result or a semiquantitative measure of pathogen burden, and are useful for detecting active infections.

Serological methods detect the presence of immunoglobulin M (IgM) or immunoglobulin G (IgG) antibodies directed against the virus in a whole blood, plasma, or serum sample. These methods typically use enzyme-linked immunosorbent assays (ELISA) techniques. Performing serological tests involve applying a small sample of blood from a finger stick (ie, drops) to a cartridge containing the immunoassay, followed by a couple of drops of a buffer solution. The qualitative results should then be readily displayed within minutes. The initial antibody response to an infection varies for each pathogen and among individuals. The response is comprised of IgM antibodies followed, in time, by IgG antibodies. Thus, a test that detects IgM antibodies would indicate a recently acquired infection, whereas one detecting IgG antibodies would signify that some time had elapsed since acquisition of infection. Serologic methods do not detect active acute infection, and are typically used for diagnosis of chronic infections or public health disease surveillance and epidemiology efforts (ie, HIV, HCV, and COVID-19).

USES AND APPLICATION OF COMMON CLINICAL LABORATORY IMPROVEMENT AMENDMENTS–WAIVED POINT-OF-CARE TESTS

The use of CLIA-waived POC tests provides another tool for pharmacists practicing in patient-centered, team-based environments to contribute to the appropriate management of chronic diseases. CLIA-waived POCT services are also used in outpatient pharmacy settings to monitor the safety and efficacy of medications as well as provide measurable clinical outcome data consistent with evidence-based guidelines. CLIA-waived POC tests are used in the screening of at-risk patients for certain disease states (eg, diabetes, dyslipidemia) and in their long-term management. Direct pharmacist involvement using CLIA-waived POCT in conjunction with medication therapy services, collaborative practice agreements (CPAs), or collaborative drug therapy management (CDTM) agreements can assist patients in reaching their chronic disease management goals as well as build strong patient and pharmacist relationships demonstrating positive clinical outcomes and return on investment.1,20 Pharmacists also perform CLIA-waived POC tests to screen for infections of public health interest (eg, HCV, SARS-CoV-2, and influenza), or to aid in the diagnosis and management of an acute infection in an individual patient (eg, influenza, GAS). This section explores common CLIA-waived POCT services provided by pharmacists in the outpatient setting; however, it is not an all-inclusive representation of the pharmacist’s role in POCT.

HgbA1c

Use in Pharmacy

An estimated 34.2 million Americans have been diagnosed with diabetes mellitus, with an additional 7.3 million remaining undiagnosed.21 In 2015, it was estimated that 88 million Americans age 18 or older had prediabetes.21 Measurement of the percent concentration of glycated hemoglobin (HgbA1c) in blood is a useful CLIA-waived POC test for identifying patients with prediabetes and monitoring patients with diabetes during routine follow-up visits. Pharmacists can perform screening for diabetes as part of large community or corporate health and wellness efforts. Individuals identified as being at risk can then be offered counseling on nonpharmacologic lifestyle changes (eg, exercise, dietary adjustments, and smoking cessation) or referred to their provider for additional follow-up. It is important that pharmacists reference national diabetes guidelines when discussing results and determining the appropriate time to refer patients to their primary care provider.

Determining Appropriate Testing Candidates

Patients at risk for diabetes that do not have current diagnostic testing for diabetes should obtain an initial laboratory-based HgbA1c to determine glycemic status; however, if a validated and regularly monitored CLIA-waived POC test is used for the HgbA1c, it may be acceptable to use that test for diagnosis when associated signs and symptoms are present.22 For patients with a current diagnosis, CLIA-waived POCT of HgbA1c for monitoring allows for more timely disease management.23 Immediate feedback from CLIA-waived POCT has demonstrated increased likelihood of medical or pharmaceutical intervention, as well as greater HgbA1c lowering as compared with commercial laboratory testing.24

Application of HgbA1c Point-of-Care Testing in Practice

As part of enhanced pharmacy services, pharmacists in an outpatient setting can build CLIA-waived POCT services into their workflow. Depending on the state board of pharmacy’s statutes, the pharmacist engaged in a CPA/CDTM agreement can then follow the protocol to adjust medication dosages, recommend nonpharmacological therapies, or schedule additional testing or physician follow-up (Minicase 1).

Performance Characteristics

Prior to the early 1990s, measurement of HgbA1c was not standardized, so it was used only as a surrogate marker of glycemic control. In the early 1990s, the landmark Diabetes Control and Complications Trial (DCCT) established the correlation between HgbA1c measurement and the risk of developing complications from diabetes; subsequently, target values were created to lower patients’ risk of poor outcomes.25-27 Rigorous standardization was needed because in the DCCT a very small difference, such as 2%, in mean HgbA1c values between treatment groups translated into a significant decrease in the risk for a variety of complications from diabetes.25 The National Glycohemoglobin Standardization Program (NGSP) was initiated to standardize HgbA1c test results so laboratory results were comparable to those in the DCCT.27 As part of the NGSP, a network of laboratories works with test manufacturers to standardize their methods.27 Over the years, the rigorous standardization efforts have facilitated the monitoring of HgbA1c with rapid reporting of results, which has demonstrated improved glycemic control in type 1 and insulin-treated type 2 patients with diabetes.28,29

Type 2 Diabetes Mellitus and HgbA1C

Stuart M., a 60-year-old man with a 5-year history of type 2 diabetes mellitus, presents to his primary care clinic for a follow-up visit. Although he was diagnosed 5 years earlier, he exhibited symptoms of diabetes for at least 2 years before diagnosis, including nocturia. He reports increased physical activity but has gained 10 lb over the past year with little success in weight loss (weight 190 lb; height 5′10″; BMI 27.3 kg/m2). He reports eating a high-carbohydrate diet with pasta or bread at every dinner. Stuart M.’s medications for diabetes include metformin 500-mg tablets, one tablet twice a day for the past 4 years, and various nutritional supplements that he has tried with no noticeable improvement. His personal blood glucose logs over the past 3 months indicate values ranging throughout the day from 108 to 264 mg/dL. His previous A1C level, tested with the POCT device 3 months ago at the clinic, was 7.8%. The pharmacist performs POC A1C testing based on a CPA. Stuart M.’s vital signs include blood pressure (BP), 128/78 mm Hg; heart rate (HR), 84 beats/min; respiration rate (RR), 20 breaths/min; and HgbA1C, 8.3%.

QUESTION: What does this A1C level indicate?

DISCUSSION: The rise in A1C level of 0.5% over 3 months indicates that the patient’s average blood glucose level is increased, and he is at increased risk for diabetes complications. In addition to the A1C level, the patient’s weight gain and report of a high-carbohydrate diet would contribute to the pharmacist’s decision to modify therapy. According to the CPA and following therapeutic guidelines, the pharmacist may decide to maximize the metformin therapy and educate the patient on dietary strategies to reduce the amount of carbohydrates consumed and increase physical activity with the goal of weight loss. The pharmacist would also recommend a follow-up visit with a repeat A1C level in 3 months.

The American Diabetes Association recommends that the HgbA1c methods used be NGSP certified.30 NGSP requires annual manufacturer certification of POC instruments against a secondary reference laboratory with a HgbA1c range of 4% to 10%. The HgbA1c reporting range for certain devices may exceed the NGSP certification of accuracy up to 10%, thus requiring the end user to assess a manufacturer’s documentation of calibration at the upper limit of their reportable range.24 Although the same quality standards apply for laboratory and POC HgbA1c systems, a concern regarding the lack of required proficiency testing for end users performing CLIA-waived POC HgbA1c tests exists.25,26 Few data characterize how these methods truly perform when conducted in the setting of a CLIA-waived laboratory; thus, their real analytical performance is not known.25,26 Nonetheless, data indicate that CLIA-waived POC methods for HgbA1c perform no worse than many laboratory-based HgbA1c methods.25 Moreover, in a series of studies, investigators have demonstrated that the analytical performance of POC instruments for HgbA1c have improved considerably in the last decade.31,32 Measurement of HgbA1c via CLIA-waived POC tests are based on structural differences among the various types of hemoglobin (Hgb) molecules, using either affinity separation or more specific immunoassays.26 Affinity separation methods use a boronate matrix to measure “total” glycation and distinguish glycated Hgb from nonglycated Hgb.26 Based on affinity separation, the analyzers of the CLIA-waived POC tests measure the percentage of HgbA1c. An advantage to affinity separation methods is a lack of interference by nearly all Hgb variants or derivatives.26 Immunoassay methods use specific antibodies directed toward the first several amino acids and the glucose molecule of the N-terminal of the β-chain of the Hgb molecule.26 These methods measure total Hgb through methods including turbidimetric measurement and latex agglutination inhibition.26 Although most immunoassays do not interfere with common Hgb variants (eg, HbAS, HbAC, HbAD, and HbAE), they are subject to interference with rare Hgb variants resulting from amino acid substitutions.25 Overestimation of HgbA1c due to variants could result in overly aggressive treatment; thus, it is important for the user to factor in this potential influence.24

In evaluating the performance characteristics of CLIA-waived POC, HgbA1c tests bias and measures of imprecision are important.25 Acceptable levels of accuracy and precision for HgbA1c POCT devices have been suggested by some authors at within 0.2 points of true value and a coefficient of variation <3%.32 As the measurement of HgbA1c can result in therapy adjustments, consistency between POCT devices, TAT, and methods are important components of a laboratory’s policies and procedures. Therefore, using devices meeting NGSP quality measures that are subject to regular monitoring for accuracy will help ensure accurate and standardized results.

Hemoglobin

Use in Pharmacy

Anemia is caused by the impaired production or increased destruction of red blood cells, blood loss, or fluid overload. Several CLIA-waived POC tests for Hgb and hematocrit (Hct) using capillary blood samples have been used in critical care settings as well as in outpatient settings to assist with the diagnosis of anemia or its associated morbidities.

Determining Appropriate Testing Candidates

Patients at risk for anemia include those who have deficiencies in their diet, intestinal disorders, chronic conditions, or genetic disorders as well as those who are menstruating or pregnant. Pharmacists using POC tests for Hgb in outpatient settings can screen for anemia as well as monitor therapies.

Application of Hemoglobin Point-of-Care Testing in Practice

Hemoglobin POCT devices use relatively small amounts of finger stick blood, allowing for ease of use for trained pharmacists, and quick results. Pharmacists may use results to manage or monitor anemia, providing recommendations to the patient and communicating results or recommendations to the provider. Sickle cell disease is a common genetic disorder worldwide that has used POCT devices for the screening and early diagnosis of the disease. However, a detailed discussion of application to sickle cell disease is outside the scope of this chapter.

Performance Characteristics

The CLIA-waived POC tests to determine an Hgb level are typically based on either the conductometric method or the spectrophotometric method.33 The commonly used spectrophotometric method measures the azide-methemoglobin formed by the test reagent mixed with a drop-size sample of capillary, venous, or arterial blood. The conductometric POCT device uses optical absorption photometry to obtain Hgb and Hct from a single drop of blood in less than 1 minute.

In addition to the POCT devices described previously, a noninvasive, multi-wavelength sensor exists that uses a spectrophotometric method to determine Hgb concentration.34 Another device also uses a sensor that emits wavelengths of light to measure Hgb concentration data based on light absorption through the finger. In a similar manner as conventional pulse oximetry, it uses signal processing algorithms and adaptive filters to translate the absorption data. The proposed advantages of a noninvasive testing device would be no risk of exposure to bloodborne pathogens for the pharmacist and a painless process for the patient.

Physiologic factors can affect Hgb measurement, emphasizing the need for consistency in laboratory procedures and documentation. Identified causes of variation include capillary blood versus venous blood, tourniquet use for longer than 30 seconds, patient position (standing, sitting, or supine), time of day, whether the right or left hand is used, and even which finger is used for a capillary sample.35

Cholesterol

Use in Pharmacy

Heart disease has a profound effect on the United States population as the leading cause of death among men and women and affects all races and ethnic groups.36 In 2018, it was estimated that atherosclerotic cardiovascular disease (ASCVD) caused nearly one of every three deaths in the United States.36 Elevated cholesterol is one of the leading causes of ASCVD. Hyperlipidemia, defined as a total serum cholesterol >200 mg/dL, affects an estimated 95 million adults, although only an estimated 43 million are taking medication(s) to reduce their risk.37

Pharmacists perform screening for ASCVD risk as part of large community or corporate health and wellness efforts. Individuals identified as at risk are offered counseling on nonpharmacologic lifestyle changes (eg, exercise, dietary adjustments, blood pressure management, and smoking cessation) or referred to their provider for additional follow-up. Additionally, under a CPA/CDTM agreement, pharmacists can initiate or modify medications to minimize a patient’s ASCVD risk.

Determining Appropriate Testing Candidates

While many workplace health and wellness plans offer annual cholesterol screenings, current clinical guidelines recommend screening adult patients every 4 to 6 years to assess a patient’s ASCVD risk.38 Patients on therapy are often monitored on a routine basis.38

Application of Cholesterol Point-of-Care Testing in Practice

Trained pharmacists applying and properly using CLIA-waived POC tests for the management of chronic diseases provides significant benefits to community health. Chronic disease management for cardiovascular disease and hyperlipidemia, specifically, are areas in which pharmacists have demonstrated a positive impact on outcomes.1 Managing ASCVD and lowering ASCVD risk often require prescription medication therapies in addition to nonpharmacological lifestyle changes. In addition, clinical management guidelines for ASCVD and the medications used in its treatment recommend regular monitoring of laboratory values to determine appropriate drug dosing. It is important for pharmacists to reference national disease state guidelines when discussing results and determining the appropriate time to refer patients to their primary care provider.

As part of enhanced pharmacy services, pharmacists in an outpatient setting can build CLIA-waived POCT services into their workflow. As described previously, common CLIA-waived POC tests for chronic disease state management require the collection of a small blood sample for the monitoring of cholesterol. Depending on the state board of pharmacy’s statutes, the pharmacist engaged in a CPA/CDTM agreement could then follow the protocol to adjust medication dosages, recommend nonpharmacological therapies, or schedule additional testing or physician follow-up. The accessibility of pharmacists enables them to reach large numbers of adults at risk for ASCVD with appropriate cholesterol testing, which may benefit prevention and treatment efforts in a community.

Performance Characteristics

Historically, the National Cholesterol Education Program’s goal to reduce morbidity and mortality caused by ASCVD relied on accurate and precise measurement of the lipid profile. In response to the need to improve cholesterol measurement, the CDC created the Cholesterol Reference Method Laboratory Network to ensure that manufacturers of diagnostic products in meeting the criteria of the National Reference System for Cholesterol (NRS/CHOL).39 The NRS/CHOL determines the methods and materials for cholesterol testing that are used by research laboratories, which may determine the American College of Cardiology and American Heart Association prevention guidelines for healthcare professionals on the treatment and management of blood cholesterol to reduce ASCVD risk.

Several of the CLIA-waived tests have demonstrated acceptable ranges of specificity and sensitivity when compared with test methods from the Clinical and Laboratory Standards Institute (CLSI).40 Many waived tests and devices are available for the testing of cholesterol that report results ranging from only total cholesterol to an entire standard lipid panel (eg, total cholesterol, high-density lipoprotein, low-density lipoprotein-calculated, and triglycerides). These tests and devices typically use finger stick capillary or venous blood samples and produce results within a few minutes. There are two common CLIA-waived POC test methodologies, one using combined enzymatic methodology and solid-phase technology and the other using reflectance photometry to produce results in minutes. The procedure manuals for each test provide guidance on proper specimen collection, handling, and quality control (QC) measures. Variants, including day-to-day or seasonal variations, can contribute to the accuracy of a cholesterol level.41,42 Common variants to consider in interrupting the POC test results include age, gender, diet and alcohol, exercise, medications, fasting, and pregnancy.41,42

Blood Chemistries

Use in Pharmacy

A wide variety of CLIA-waived POCT devices measure blood chemistry in an outpatient setting. A blood chemistry analyzer uses a whole blood sample and can measure analytes, including ionized calcium, carbon dioxide, chloride, creatinine, glucose, potassium, sodium, and urea nitrogen. In addition, some CLIA-waived blood chemistry analyzers measure other analytes, including alanine amino transferase, aspartate amino transferase, albumin, total bilirubin, alkaline phosphatase, and total protein. Blood chemistry analyzers with these analytical capabilities can be used by a pharmacist practicing under a CPA or CDTM provisions in state regulations or statutes to determine liver and renal function values and assist with any appropriate medication dosing adjustments for chronic conditions, such as diabetes or cardiovascular disease.

Many medications are used in the management of chronic diseases that can lead to electrolyte imbalances. Additionally, most medications’ pharmacokinetics are impacted by renal and/or liver function. Blood chemistry panels, such as a complete metabolic panel, can assist pharmacists in understanding a patient’s renal and liver function to adjust or monitor the safety of these medications. CLIA-waived POC platforms for blood chemistries have multiple panels, not all of which are CLIA-waived. Measuring blood chemistries in real time can enable the pharmacist to adjust the medications accordingly. It is important that pharmacists understand the performance characteristics of these tests, reference guidelines, and ranges when discussing results and determining the appropriate time to refer patients to their primary care provider.

Determining Appropriate Testing Candidates

Patients under the supervision of a pharmacist for chronic disease management (eg, hypertension, diabetes) require routine blood chemistry monitoring to ensure the safety and efficacy of their medications. Pharmacists should consult relevant national guidelines and perform necessary basic assessments to determine when to use these tests in the appropriate patient.

Application of Blood Chemistries Point-of-Care Testing in Practice

Many medications on the market require renal or hepatic dosing adjustments as a patient’s renal or liver function declines. Assessing a patient’s renal and hepatic function at the POC allows a pharmacist with a CPA/CDTM agreement to adjust the medication dose or modify a patient’s treatment to provide safe pharmacological treatment.43 Several chronic disease medications (eg, diuretics, angiotensin converting enzyme inhibitors) can impact a patient’s electrolytes. To safely start and modify these medications, it is essential to assess the patient’s electrolytes before and after. Using POCT to monitor the electrolytes allows the pharmacist to make real-time decisions and adjust medications accordingly.

Performance Characteristics

CLIA-waived POC tests for blood chemistries analyze whole blood samples collected through venipuncture or finger stick, depending on the analyzer and analytes being tested. Analyzers can provide results within minutes from a few drops of blood. To produce readable results, the analyzer conducts chemical reactions between the whole blood and the chemical reagents provided to produce chromophores, which are then measured through photometry. Using absorbed wavelengths, the analyzer can determine the concentration of the desired analyte. In general CLIA-waived POC tests for blood chemistries meet established thresholds for total allowable error for most analytes.44 However, in different settings, analytes such as sodium, glucose, calcium, and others may demonstrate significant bias, compared with reference methods.44 Reasons for the bias include differences in analytical methods used by the CLIA-waived POC test and the comparator or improper sample collection technique (eg, failure to properly clean the fingertip prior to obtaining capillary blood).44,45

Urinalysis

Use in Pharmacy

The urine dipstick and tablet reagent urinalysis are common CLIA-waived POC tests found in many outpatient settings. Urinalysis screens for a variety of different diagnostics (eg, urinary tract infection, pregnancy) and assists in the management of chronic diseases (eg, glucose, ketones, albumin to creatinine ratio). With a CPA/CDTM agreement, pharmacists provide nonpharmacological treatment and antibiotic treatment for a urinary tract infection identified through a CLIA-waived POC urinalysis. Additionally, pharmacists use urinalysis to assess patients with diabetes through monitoring glucose, albumin, and ketones in the urine, providing guidance on adherences and efficacy of medication(s).

Determining Appropriate Testing Candidates

When considering incorporating urinalysis into the pharmacy workflow, the location for obtaining a urine sample will determine the site’s ability to use these POC tests. The site needs to ensure a private area to obtain a urine specimen while ensuring the accuracy of the sample.

Application of Urinalysis Point-of-Care Testing in Practice

A variety of urinalysis POC tests allow pharmacists to screen for and manage a variety of conditions and disease states. The urinalysis test provides pharmacists with values for bilirubin, glucose, Hgb, ketone, leukocytes, nitrite, pH, protein, and specific gravity. This test can be used to detect an acute urinary tract infection. Additional POC testing for urine albumin concentration or albumin to creatinine ratio for identification of microalbuminuria can assist the pharmacist in the management of diabetes or hypertension.24 Pharmacists involved with prescribing or administering birth control may benefit from urine human chorionic gonadotropin (hCG) testing to determine a patient’s pregnancy status. Outpatient monitoring for proteinuria for pregnant patients during routine prenatal care may aid in identifying patients at risk for preeclampsia.24,46 The pharmacist involved in a smoking cessation program might use a nicotine detection test. This test detects nicotine and its metabolites in urine and could indicate the smoking status of an individual as a low or high nicotine consumer. Additionally, urine POC tests can also be used for a variety of other screening and diagnostic purposes; however, these uses are beyond the scope of this chapter. It is important that pharmacists reference national disease state guidelines when discussing results and determining the appropriate time to refer patients to their primary care provider.

Performance Characteristics

Urine POCT studies are limited and, of those available, there is considerable variation in how the urine screening tests are performed: such testing is often in conjunction with other physical assessments, the review of symptoms, and laboratory testing. The interpretation of results depends on proper collection procedures and testing methods. Additionally, it is important to consider specificity and sensitivity and the NPV and PPV for the POC urine test used at the practice site because of variability between devices.11

Hepatitis C Virus

Use in Pharmacy

An estimated 2.4 million people in the United States are infected with HCV, and nearly half of infected individuals are unaware of their infection because they are asymptomatic.47-49 The CDC estimates suggest there were nearly 44,700 new infections in 2017.50 Studies demonstrate that testing adults for HCV is cost effective in a variety of outpatient pharmacy settings and can facilitate linkage to care.51

Clinic models that are led by pharmacists or models in which they assist in care provide accessible and effective alternatives for providing outpatient HCV care.52 Given the accessibility of pharmacists, training pharmacists on the application and proper use of screening for HCV with CLIA-waived POC tests can have a significant impact on public health efforts, increasing the number of people getting tested, especially those at high risk (eg, younger patients using illicit intravenous drugs) who are not receiving care.17,53 Pharmacist-directed CLIA-waived POCT efforts can increase the linkage to care (eg, follow-up assessment with providers, medicine distribution, and access to medication assistance programs) and expand access to appropriate counseling services and community resources.17,53 Such efforts can also enhance collection of prevalence and surveillance data to help resources reach targeted at-risk populations.

Determining Appropriate Testing Candidates

Guidelines for HCV testing have evolved as HCV shifted from a chronic infection to a curable disease. Current guidelines recommend routine, one-time testing for all adults and risk-based testing for patients younger than 18 years. Periodic repeat testing can be performed in all individuals who are at increased risk of or have been exposed to HCV. Pharmacists can identify individuals for testing based upon risk behaviors or exposures and other conditions or circumstances outlined in the national guidelines.54

Application of Hepatitis C Virus Point-of-Care Testing in Practice

In 2013, the CDC recommended that the testing sequence for current active hepatitis C infection begin with testing for the HCV antibody, including use of the rapid POC assay prior to further HCV RNA testing and linkage to care. A positive HCV antibody test does not distinguish whether the patient currently has acute or chronic active HCV infection or a past infection that has resolved. Therefore, to confirm active infection, individuals testing positive must have a follow-up HCV RNA PCR test to detect HCV viremia, which informs management and treatment decisions.54 Persons with a negative screening are considered not infected and do not need further evaluation unless they have a known risk factor.54 Thus, CLIA-waived POCT for HCV offers potential savings in healthcare expense as well as the opportunity to educate patients on risk factors.

Performance Characteristics

Currently, there is one FDA-approved CLIA-waived POC rapid immunoassay test that detects antibodies to HCV from whole blood samples obtained either by venipuncture or finger stick.55 The results from it can be read between 20 to 40 minutes after the analysis is started, which enables a patient to receive pretest and posttest counseling within a single visit. This test is a noninstrumented, indirect lateral flow immunoassay, and its performance characteristics are summarized in Table 4-2. It has excellent sensitivity and specificity using whole blood from a finger stick.56 In a multicenter study of individuals at risk for HCV infection, the test demonstrated a clinical performance equivalent to laboratory-based tests across all specimen types.57 In addition, several studies have observed that the specificity of the HCV rapid test with all specimen types is similar to that reported for anti-HCV enzyme immunoassay (EIA).58 The CLIA-waived POC test to detect antibodies to HCV also has a high degree of interoperator agreement in result interpretation.59 For these reasons, the initial testing for HCV antibody screening with POC rapid immunoassay is an effective alternative to the third-generation EIA methods.56

TABLE 4-2.
Summary of CLIA-Waived POC Tests for HIV and HCVa

TEST

MANUFACTURER

CLIA WAIVER GRANTED

METHOD

ANALYTE(S) (TYPE OF ABS)

SPECIMEN TYPE

TIME TO RESULTS (MIN)

OVERALL CLINICAL SENSITIVITY (%)b

OVERALL CLINICAL SPECIFICITY (%)b

HIV

OraQuick Advance Rapid HIV-1/2 antibody test

OraSure Technologies

June 2004

Lateral flow

HIV-1/2 Abs (IgG)

OMT, FSWB, VPWB

20

HIV-1 Abs

99.3 (OMT)

99.6 (FSWB)

99.8 (OMT)

100 (VPWB)

Uni-Gold Recombigen HIV test

Trinity Biotech

November 2004

Sandwich

HIV-1/2 Abs (IgG + IgM)

FSWB, VPWB

10

100

99.7

Clearview HIV-1/2 Stat-Pak

Chembio

May 2006

Lateral flow

HIV-1/2 Abs (IgG)

FSWB, VPWB

15

HIV-1 Abs = 99.7

HIV-2 Abs = 100

HIV-1 Abs = 99.9

Sure Check HIV-1/2

Chembio

March 2011

Lateral flow

HIV-1/2 Abs (IgG)

FSWB, VPWB

15

HIV-1 Abs = 99.7

HIV-2 Abs = 100

99.9

DPP HIV-1/2

Chembio

December 2012

Dual path flow

HIV-1/2 Abs (IgG)

OMT

FSWB

VPWB

25–40 (OMT)

10–25 (FSWB)

10–25 (VPWB)

98.9 (OMT)

99.8 (FSWB)

99.9 (VPWB)

99.9 (OMT)

100 (FSWB)

99.9 (VPWB)

Determine HIV-1/2 Ag/Ab combo test43

Abbott Laboratories

December 2014

Lateral flow

HIV-1 p24 Ag

HIV-1/2 Abs

(IgG + IgM)

FSWB

20

HIV-1 Abs = 99.9

HIV-2 Abs = 100

Low risk 100 High risk 98.9

Overall 99.6

INSTI HIV-1/2 antibody test44

bioLytical Laboratories

July 2012

Flow through

HIV-1/2 Abs (IgG + IgM)

FSWB

<2

99.8c

99.5

HCV

OraQuick rapid antibody HCV test

OraSure Technologies

February 2011

Lateral flow

HCV Abs

FSWB

VPWB

20–40

100

100

Abs = antibodies; Ag = antigen; FSWB = whole blood via finger stick; OMT = Oral mucosa transudate; VPWB = whole blood via venipuncture.

aValues obtained from product package inserts and/or from manufacturers websites, except where noted.43,44

bData for whole blood via finger stick unless otherwise noted, data for whole blood via venipuncture not provided.

cOnly HIV-1 Abs data provided.

Human Immunodeficiency Virus

Use in Pharmacy

Estimates suggest that nearly 1.2 million individuals in the United States are living with an HIV infection, of whom 161,800, or one in eight (13%), are unaware of their infection.60 Testing is important because individuals who are unaware of their HIV infection status cannot take advantage of treatments to reduce viral loads and maintain their health; thus, they pose a risk of transmitting the infection to others.16

Given the accessibility of pharmacists and a less stigmatizing setting, pharmacies can be effective for the delivery of HIV testing, even though they are underutilized. Data demonstrate that by training pharmacists to perform CLIA-waived POC tests for the screening of HIV, pharmacies can be an effective setting for those who have not previously been tested and increase access to testing, particularly in underserved areas.61 HIV screening in pharmacies can have significant impact on public health efforts to increase the number of people getting tested, especially those who engage in high-risk behaviors. Pharmacist-directed CLIA-waived POCT efforts could increase the linkage to medical treatment (eg, facilitate medicine distribution and access to medication assistance programs); expand access to appropriate counseling services, community resources, and care; and aid in risk-mitigation efforts (eg, needle exchange programs). Such efforts can also enhance the collection of prevalence and surveillance data to help resources reach targeted at-risk populations quicker. Recognizing these public health benefits, the CDC offers a training program on HIV testing in community pharmacies (https://www.cdc.gov/hiv/effective-interventions/diagnose/hiv-testing-in-retail-pharmacies?Sort=Title%3A%3Aasc&Intervention%20Name=HIV%20Testing%20in%20Retail%20Pharmacies).

Determining Appropriate Testing Candidates

The CDC recommends that individuals aged 13 to 64 years be tested for HIV at least once as part of routine care and that individuals with risk factors be tested annually.16 When performing CLIA-waived POCT for HIV, refer to national guidelines to determine who should be tested.16

Application of Human Immunodeficiency Virus Point-of-Care Testing in Practice

Studies show that the accessibility of community pharmacies can be leveraged to successfully offer CLIA-waived POCT services for HIV infection.18,61-66 Moreover, establishing CLIA-waived POCT services for HIV in a pharmacy practice setting requires a modest amount of staff training, and the costs are similar to other services offered in these settings.18,63,64,66 Collectively, studies indicate pharmacies can serve as an alternate, highly accessible, and less stigmatizing healthcare facility to perform HIV testing services.18,62-66 Approximately 1 week is needed for viral infection and replication to produce detectable p24 antigen, which is the first viral protein that can be measured after HIV infection. This antigen is then detectable for approximately 1 to 8 weeks (average within 2 weeks), until there is sufficient antibody production to bind and neutralize it. On average, the onset of symptoms occurs within 1 to 3 weeks of infection and corresponds to seroconversion (ie, the development of antibodies). Seroconversion occurs in most individuals within 4 weeks of potential exposure (ie, infection). Individuals who have not seroconverted by 4 weeks should do so by 12 weeks postexposure. At that point, if seroconversion has not occurred (ie, the test result is negative), the individual is considered HIV negative.

Performance Characteristics

There are several CLIA-waived POC tests to detect antibodies to HIV-1 and HIV-2 and one test that detects those antibodies plus HIV-1 p24 antigens. Following specimen collection, the time to test results for HIV POC tests ranges from 1 minute to 20 minutes, which enables a patient to receive pretest and posttest counseling within a single visit. These test devices are typically based on a capillary lateral flow design and use whole blood from a finger stick or oral mucosal transudate. The performance characteristics of these tests are summarized in Table 4-2.

The performance characteristics of the CLIA-waived POC tests for HIV are sufficient to detect HIV infection or its absence. In general, the CLIA-waived POC tests for HIV have specificity and sensitivity equivalent to nonwaived HIV screening test kits (eg, ELISA) approved for laboratory use.67 The performance characteristics of CLIA-waived POC tests for HIV vary depending on the type of test (eg, antigen or antibody-based), whether it detects only one type of immunoglobulin (ie, IgG) or more (ie, IgM and IgG) antibodies, the stage of infection, whether the analyte has achieved measurable concentrations to give a positive result (ie, the window period), and the type of specimen (eg, whole blood or oral mucosal transudate) being analyzed. Acute HIV infection (ie, the period from infection to seroconversion) is difficult to detect with CLIA-waived POC tests because HIV antibody titers are typically low in this stage of HIV infection. Thus, these tests have lower sensitivity than the nonwaived laboratory-based ELISAs and automated systems for detecting seroconversion.67 This means the window period may be longer for CLIA-waived POC tests for HIV compared with a nonwaived test performed in a laboratory. According to the CDC, laboratory-based antigen/antibody tests can detect HIV infection from venous blood within 18 to 45 days postexposure; the CLIA-waived POC counterpart does so within 18 to 90 days.68 Tests using oral mucosal transudate are highly accurate but have even lower sensitivity for detecting seroconversion than those using serum, plasma from venous blood, or whole blood from a finger stick because the antibody concentration found in oral mucosal transudate is lower.69,70 Thus, CLIA-waived POC tests that measure HIV antibody in oral mucosal transudate often fail to detect acute HIV.67,70 By measuring p24 antigen in addition to antibodies for HIV-1 and HIV-2, the marketed combination CLIA-waived POC test should allow for the detection of acute infection.71 However, to date, the test does not detect p24 antigen with a high sensitivity; thus its accuracy for detecting acute infection is poor as well.72,73 In addition to stage of infection, HIV prevalence in the population being tested can impact the oral tests.69 In high-prevalence settings, the PPVs for either whole blood or oral mucosal transudate are similar; however, in low-prevalence settings, PPVs are much higher for whole blood than oral mucosal transudate specimens.70 CLIA-waived POC HIV testing will involve an initial HIV test and, if it is reactive, a follow-up HIV test in a moderate to high complexity laboratory. A negative test result in someone after a potential HIV exposure should be repeated after the window period, approximately 12 weeks after the potential exposure.68

Influenza A and B

Use in Pharmacy

The annual burden of influenza in the United States fluctuates markedly depending on a variety of variables. According to CDC estimates, each year since 2010, influenza infects between 9 and 45 million individuals and results in 140,000 to 810,000 hospitalizations and up to 61,000 deaths.74 Influenza occurs seasonally and produces symptoms that are often indistinguishable from bacterial respiratory infections. Moreover, the prompt initiation of appropriate cost-effective antiviral therapy is key to hastening the resolution of the infection and limiting its severity.

Using CLIA-waived POC tests to screen for influenza represents a collaborative opportunity for pharmacy and local health departments to improve data sharing that informs disease surveillance efforts.75 In some cases, such efforts can be combined with technological solutions to improve vaccine and antiviral distribution and perhaps even curtail inappropriate antibacterial use. In addition, POCT for influenza can assist with efforts to distinguish between influenza and COVID-19.

Determining Appropriate Testing Candidates

The CDC has published useful algorithms to guide interpretation of CLIA-waived POC tests for influenza and clinical decision-making when influenza activity in the community is high (https://www.cdc.gov/flu/professionals/diagnosis/algorithm-results-circulating.htm) or low (https://www.cdc.gov/flu/professionals/diagnosis/algorithm-results-not-circulating.htm).76 To determine if a patient is an appropriate candidate for testing, pharmacists should perform an appropriate physical assessment to determine if the patient has symptoms consistent with an acute respiratory disease that began within several days of patient presentation. Accordingly, CLIA-waived POCT for influenza should be performed using a highly sensitive and specific test during the influenza season when the disease prevalence is high.76 Pharmacy researchers developed a physician–pharmacist collaborative management model for influenza based largely on the CDC principles.77 In that model, pharmacists in a community practice setting provided CLIA-waived POCT services for influenza by screening adult patients for symptoms of an influenza-like illness and using proper nasal swab specimen collection technique to obtain a sample.77 The PPV of the tests was maximized by performing these activities only when local influenza activity had been documented by state or federal surveillance and by performing a physical assessment and assessing vital signs (eg, heart rate, blood pressure, respiratory rate, temperature, and oxygen saturation).77 Only 11% of patients with an influenza-like illness had a positive result. Moreover, because the CPA prevented pharmacists from dispensing oseltamivir or antibacterial therapy to patients who tested negative, the study demonstrated that this practice model can lead to rational use of antivirals and avoid the overuse of unnecessary antimicrobial therapy.77

To determine whether influenza is present in a specific patient population and assist providers in diagnosing and treating acute respiratory illnesses, the CDC also recommends that CLIA-waived POCT be done during an acute outbreak of a respiratory disease and in patients with clinical signs and symptoms of influenza during the influenza season.76

Application of Influenza A and B Point-of-Care Testing in Practice

Studies demonstrate that protocol driven CLIA-waived POCT for influenza using antigen or molecular tests can be successfully implemented in the outpatient setting, particularly in community pharmacies.77-80 These services increase access to care outside of normal clinic hours for patients regardless of their insurance status or whether they have a primary care provider.77-80 In addition, such services provide patients appropriate therapy without promoting the overuse of antibiotics.78 By offering CLIA-waived POCT services for influenza in the outpatient setting, pharmacists can also collaborate with public health agencies to improve seasonal surveillance efforts and reduce inappropriate antibacterial use in respiratory illnesses during the influenza season.2,75,81

Performance Characteristics

The results of antigen or molecular CLIA-waived POC tests for influenza depend on viral load, which is influenced by several variables, including patient age and the timing of sample collection relative to symptom onset. Pharmacists should recognize that viral loads are higher in samples obtained from infected children than those obtained from infected adults. Thus, when evaluating literature to select a test with appropriate performance data for their patients, pharmacists should be aware that performance data are typically better when the tests are performed using samples from infected children than samples from infected adults.19 In addition, viral shedding peaks 24 to 72 hours after symptoms begin. This time interval represents the ideal window to achieve optimal test performance. Therefore, when assessing whether a patient is an appropriate test candidate, pharmacists should establish when symptom onset began. Other variables that pharmacists cannot mitigate that influence viral load (and therefore may affect test performance) include the viral strain, materials used to collect the sample, type of specimen, and, in the case of antigen tests, the volume of viral transport media used in test.19 In addition, regardless of method, the performance characteristics of these tests can be affected by annual genomic drifts or a shift when it occurs.82,83

Historically, CLIA-waived POC tests for influenza virus nucleoprotein antigen have been chromatographic lateral flow immunoassays. Such tests often lacked sensitivity for a variety of reasons, including being based upon immunochromatographic methodology that did not amplify the target antigen and relying on visual detection.19 However, since 2015, several technological and regulatory developments have led to improvements in the sensitivity of CLIA-waived POC tests for influenza in general. First, with the advent of isothermal nucleic acid amplification methods that enable rapid detection of DNA/RNA, the first molecular test for influenza was authorized by the FDA in 2015.84 Then, in 2017, the FDA reclassified these tests from class I to class II devices.85 This reclassification enabled the FDA to impose more rigorous performance thresholds for the antigen tests in 2018. According to the new thresholds, existing and new antigen tests must achieve sensitivity of at least 80% compared with a molecular test and 80% to 90% when compared with viral culture.85 Tests that could not meet the performance standards are no longer available in the United States.

The performance characteristics of marketed antigen and molecular CLIA-waived POC influenza tests are summarized in Table 4-3. The antigen CLIA-waived POC influenza tests are simple to use and provide results within 15 minutes. The tests differ in terms of simple sample processing prior to test, incubation and run times, and throughput capacity.86 Most tests now use automated, rather than visual, detection to improve sensitivity and performance to meet the FDA thresholds. As stated previously, antigen tests have lower sensitivities to detect influenza viruses in respiratory specimens than molecular tests.82,83 Thus, negative results of antigen CLIA-waived POC influenza tests should not be used to exclude a diagnosis of influenza.82,83 For this reason, the Infectious Diseases Society of America (IDSA) recommends the use of molecular CLIA-waived POC influenza tests rather than antigen CLIA-waived POC influenza tests for the detection of influenza viruses in respiratory specimens of outpatients.

TABLE 4-3.
Summary of Performance Characteristics for CLIA-Waived POC Tests for Influenza A and/or Ba,b

TEST (MANUFACTURER)

SPECIMEN TYPE

TIME TO RESULTS (MIN)

OVERALL CLINICAL SENSITIVITY (%) A/B

OVERALL CLINICAL SPECIFICITY (%) A/B

PPV (%) A/B

NPV (%) A/B

OVERALL ACCURACY (%) A/B

Antigen-Based Tests

BD Veritor System for Rapid Detection of Flu A+B (Becton Dickinson)c

NPS

10

81.3/77.8f

95.6/100g

89.7/100h

91.7/99.0h

91/99h

BinaxNOW Influenza A&B Card with Digival 2 (Abbott Laboratories)

NS, NPS

15

84.3/89.5i

94.7/99.4i

83/94.4i

95.1/98.9i

92.2/98.2i

QuickVue Influenza A+B Test (Quidel Corporation)d

NS, NPS

≤10

81.5/80.9f,i

97.8/99.1g,i

90/89.9h,i

95.6/98.0h,i

94.5/97.3h,i

Sofia Influenza A+B (Quidel Corporation)c,e

NS, NPS

3–15

NS

90/89

NPS

97/90

NS

95/96

NPS

95/97

NSh

82/81

NPSh

75/84

NSh

97/98

NPSh

99/98

NSh

94/95

NPSh

95/96

Acucy Influenza A&B Test (Sekisui Diagnostics, LLC)

NPS, NS

15

96.4/82.3i

96.0/98.1i

87.4/89.0h,i

77.7/84.2h,i

96.1/95.6h,i

Molecular Testsj

ID NOW Influenza A & B 2 (Abbott)

NPS, NS

<15

92.8/100i

98.5/97.7i

95.3/81.5h,i

97.6/100h,j

97.0//97.9h,i

Xpert Xpress Flu (Cephid)

NPS, NS

20–30

NS

98.9/

98.4

NPS

97.6/

97.3

NS

97.6/

99.3

NPS

98.2/

99.6

Data not provided

AcculaTM Flu (Mesa Biotech)

NS

<30

97/94

94/99

83/90

76.3/89.3

95/98

Cobas RInfluenza A/B Assay (Roche)

NPS

<30

100/100

96.8/94.1

Data not provided

Silaris Influenza A/B (Sekisui Diagnostics, LLC)

NS

<30

97/94

94/99

82/90

99/99

94.5/98.2

A = influenza virus A; B = influenza virus B; NPS = nasopharyngeal swab; NS = nasal swab.

aValues obtained from product package inserts and/or from manufacturers websites.

bData for nasal aspirate/nasal wash not included.

cRequires separate analyzer or reader device.

dDoes not distinguish between influenza A and B virus infections when used alone.

eImmunofluorescence assay.

fValues represent positive percent agreement.

gValues represent negative percent agreement.

hValues taken from 2 × 2 table of results in package insert.

iClinical study included both specimen types.

jIncludes only tests that detect influenza A and/or B, not other respiratory pathogens.

Molecular CLIA-waived POC influenza tests use different amplification methods, including isothermic nucleic acid amplification, RT-PCR, and one that uses RT-PCR followed by hybridization to allow for qualitative to be read visually.19 Unlike antigen CLIA-waived POC influenza tests, molecular tests use samples that require no manipulation (ie, addition of buffers). Molecular tests produce results within 15 to 30 minutes depending on the amplification method. In general, sensitivities of available molecular CLIA-waived POC tests range from 66% to 100%.82

Group A Streptococci

Use in Pharmacy

Pharmacists can use POC tests for GAS to assist in the acute management of infected patients.78-80,87-89 GAS causes 5% to 10% of adult acute pharyngitis and 15% to 30% of acute pharyngitis among children.90 Epidemiologically, GAS pharyngitis occurs primarily in the winter and early spring and afflicts individuals in a narrow age range. Clinically, GAS pharyngitis has a well-recognized presentation and rarely requires confirmation by culture, but its symptoms are often indistinguishable from viral respiratory tract infections. Data from the United States, Canada, and the United Kingdom demonstrate that CLIA-waived POC tests for GAS improve access to care and help ensure that appropriate antibiotic therapy is initiated if warranted, which could hasten infection resolution by 1 to 2 days.78-80,87-89

Determining Appropriate Testing Candidates

GAS is the most common bacterial cause of acute sore throat, but it is difficult to accurately diagnose it as a cause of pharyngitis.91 On the basis of clinical manifestations alone, GAS pharyngitis is often indistinguishable from viral respiratory tract infections.91,92 In contrast, to adults, GAS pharyngitis is more common than viral etiologies among children and adolescents (Minicase 2). Therefore, to aid in the identification of patients with pharyngitis who have a high likelihood of GAS infection, additional strategies are needed. Performing an appropriate physical exam and applying its results using a validated, age-based clinical prediction rule, such as the Modified Centor Criteria Score, can further assist in identifying patients with pharyngitis who would benefit most from CLIA-waived POCT for GAS.93 Originally developed in 1981, the Modified Centor Criteria Score was based on the presence of tonsillar exudates, swollen tender anterior cervical nodes, fever, and the lack of cough and was used to estimate the probability of acute GAS pharyngitis in adults with a sore throat.93 The score was later modified by adding age to the criteria and validated in a large study of adults and children.94 The Modified Centor Criteria Score ranges from −1 to 5, with testing for GAS recommended in patients with a score of 2 or higher.92 However, even when using this clinical prediction rule, there is limited success in accurately diagnosing GAS pharyngitis because at the highest Modified Centor Criteria Scores (eg, ≥4), it only helps identify 53% of patients with GAS pharyngitis.91-95 The Modified Centor Criteria and their interpretation are summarized in Table 4-4. In a pilot study, pharmacy researchers developed a physician–pharmacist collaborative management model for GAS based largely on these principles.87 In that model, pharmacists in a community practice setting used the Modified Centor Criteria to screen 316 patients, of whom 273 were eligible for testing. Only 48 patients (17.5%) had a positive test result and received amoxicillin or azithromycin per their CPA. This pilot project demonstrated that such a practice model can dramatically reduce inappropriate antimicrobial use in the community practice setting.87 Like influenza, these results were validated by several studies, including one that used a molecular test, in a variety of community pharmacy settings, in multiple states, and several countries.78-80,87-89

TABLE 4-4.
Modified Centor Score Criteria and Interpretation88-91

TOTAL SCORE

RISK OF GAS INFECTION (%)

  • Absence of cough (+1)

  • Swollen and tender anterior cervical lymph nodes (+1)

  • Temperature >100.4°F (+1)

  • Tonsillar exudate or swelling (+1)

  • Age (yr):

    3–14 (+1)

    15–44 (0)

    ≥45 (−1)

≥4

51–53

3

28–35

2

11–17

1

5–10

≤0

1–2.5

Application of Group A Streptococci Point-of-Care in Practice

Performance characteristics of current CLIA-waived POC tests for GAS are sufficiently robust: the current guidelines do not recommend any additional confirmatory tests for adults when results are negative. Although confirmatory testing is currently recommended when CLIA-waived POC test results are negative in children and adolescents, data suggest that such follow-up testing may not be necessary.91,96

Group A Streptococcal Pharyngitis and Point-of-Care Testing

Maya B., a 10-year-old girl, presents to the community pharmacy in November with her mother. The mother states that Maya B. reported a sore throat, mild cough, and headache after attending a slumber party 2 days earlier. In addition, one of the other girls attending the slumber party tested positive for GAS yesterday. Maya B.’s physical findings include a red throat and tender cervical lymph nodes.

QUESTION: What additional information should the pharmacist obtain to determine if CLIA-waived POCT for GAS would be appropriate in this patient?

DISCUSSION: The pharmacist should obtain vital signs and calculate a Modified Centor Criteria Score as part of the CPA to determine the likelihood of GAS pharyngitis.

Maya’s vital signs are as follows: BP 120/70 mm Hg, HR 80 beats/min, RR 20 breaths/min, temperature 101°F, and weight 90 lb.

Modified Centor Criteria Score92-95

Patient’s Calculated Score

  • Absence of cough (+1)

  • (0)

  • Swollen and tender anterior cervical lymph nodes (+1)

  • (+1)

  • Temperature >100.4°F (+1)

  • (+1)

  • Tonsillar exudate or swelling (+1)

  • (0)

  • Age (years):

    3 to 14 (+1)

    15 to 44 (0)

    >45 (−1)

  • (+1)

  • Score = 3; probability of GAS ∼28% to 35%

QUESTION: Based on the pharmacist’s findings, how should the pharmacist proceed under CPA?

DISCUSSION: The pharmacist should perform a throat swab and CLIA-waived POCT to verify the presence of GAS. The recommended management of GAS according to the patient’s Modified Centor Criteria score would be antibiotics based on the result of the CLIA-waived POC test. In addition, the pharmacist should recommend an analgesic/antipyretic for symptom management.

Performance Characteristics

CLIA-waived POC tests that detect GAS antigens have been marketed for years and have evolved and improved through several generations. The tests use a variety of antigen detection methods (eg, latex agglutination, ELISAs, lateral flow immunochromatographic assays, and optical immunoassays). In addition, several molecular methods to detect GAS exist that use either rt-PCR or isothermal nucleic acid amplification are now CLIA-waived. The use of antigen POC tests is addressed in the IDSA guideline for the diagnosis and management of GAS pharyngitis.96 However, the guideline was published before the advent of the CLIA-waived molecular tests, so their use is not addressed. The antigen CLIA-waived POC tests for GAS infection have limited sensitivity; therefore, the IDSA guideline recommends confirming negative results in populations at high risk of developing pharyngitis because of GAS or viral etiologies with a throat culture to reduce the chance of missing a positive case.96 The specificity associated with CLIA-waived antigen POC tests for GAS infection is high; therefore, positive results do not require a backup culture in a patient, regardless of age.96 A comprehensive meta-analysis of 48 studies found that sensitivity and specificity across all studies analyzed were 86% and 96%, respectively.91 Investigators also found that although there was marked variability in sensitivity, specificity varied little across studies.91 In contrast to the IDSA guideline, overall, the study demonstrated that the sensitivity of POC tests for GAS is sufficiently high and a backup culture is not needed, particularly given the low risk of complications such as acute rheumatic fever in the United States.91 Moreover, investigators concluded that the high overall specificity of POC tests for GAS could minimize the overdiagnosis of GAS pharyngitis and prevent unnecessary antibiotic use in such cases.91 Molecular CLIA-waived POC tests for GAS have much higher sensitivity than the antigen-based tests, which lowers the chance of missing a positive case.96

COVID-19

Use in Pharmacy

Discovered in late 2019, the novel SARS-CoV-2 is associated with a constellation of mild to life-threatening symptoms, known as COVID-19, and has rapidly spread as a worldwide pandemic. Early in the course of the pandemic, using the EUA provisions, the FDA commissioner accelerated the marketing of POC tests to detect SARS-CoV-2 (COVID-19 POC tests). Shortly thereafter, the Department of Health and Human Services issued a policy permitting licensed pharmacists to order and administer FDA-authorized COVID-19 POC tests.97 This policy illustrates the important role pharmacists performing POCT can have in providing services that contribute to the health and well-being of their community. The policy extended the legal protections under the Public Readiness and Emergency Preparedness Act to pharmacists performing COVID-19 POC tests so they could collect nasopharyngeal, throat, or nasal swabs from patients with suspected infection and perform assays that have EUA.97 By leveraging the accessibility of pharmacists, the policy sought to expand the nation’s testing capacity, so that if necessary, public health mitigation strategies, including contact tracing and isolation, could be employed. Under the policy, pharmacists can also perform FDA-authorized serological COVID-19 tests. However, for a pharmacist to perform a serological COVID-19 test marketed under an EUA, it would need to be CLIA-waived. Such tests that are not CLIA-waived or lack a CLIA classification are considered moderate- or high-complexity tests and are not allowed to be performed outside an appropriately CLIA-certified laboratory.98 Thus, pharmacists’ POCT efforts for COVID-19 entail testing patients for active infection using molecular or antigen-based tests so that they may be linked to care or public health professionals.

Determining Appropriate Testing Candidates

Decisions regarding who qualifies for testing rest with state and local health departments or healthcare providers. Individuals are encouraged to visit their state or local health department’s website for the latest local information on testing in their locale.

Application of COVID-19 Point-of-Care Testing in Practice

Many antigen or molecular COVID-19 POC tests have been marketed under an EUA, but not all of them are considered waived. Antigen or molecular tests have a variety of uses. They are recommended for diagnosis of acute infection in persons with signs or symptoms of infection.99 To control transmission, testing is performed with antigen or molecular tests in asymptomatic individuals with recent known or suspected exposure to SARS-CoV-2.99 In addition, such tests are used for asymptomatic individuals without known or suspected exposure to SARS-CoV-2 to assist in early detection in institutional settings.99 Antigen and molecular tests are also used to detect the resolution of infection to determine when individuals can end isolation.99 Lastly, antigen or molecular tests can be used in public health surveillance efforts for SARS-CoV-2.99

Serological COVID-19 tests have also been marketed under an EUA, but to date, all but one of them are considered moderate- or high-complexity tests and are not allowed to be performed outside an appropriately CLIA-certified laboratory. These tests are not authorized for diagnosis of COVID-19; rather they are recommended for situations in which it is necessary to determine whether the individual being tested was previously infected.

Performance Characteristics

Having EUA status means tests can be used in the declared emergency, but the FDA has not thoroughly evaluated them to grant approval. Gaining FDA EUA status requires minimal performance data, and at the time of authorization, typically tests only have data regarding limits of detection from contrived samples. As experience is gained with tests during the evolving pandemic, emerging clinical data, often from small samples, provide estimates of their negative percent agreement and positive percent agreement (ie, specificity and sensitivity, respectively) as well as their NPV and PPV. Initial data contained in the package inserts of the individual tests suggest the specificity COVID-19 that could be performed outside an appropriately CLIA-certified laboratory are similar (98.8% to 98.9%), regardless of the type (eg, antigen, molecular, or serological) test.100-110 In addition, the overall sensitivity of such tests is high (93.9% to 100%).100-110 However, though high, the sensitivity of antigen tests varies by test (84% to 98%) and appears to be slightly less sensitive (mean 93.9%) than molecular (99.5%) or serological (100%) tests.100-110 These initial findings are consistent with other POC tests for respiratory viruses in that molecular tests are typically highly specific and more sensitive than antigen tests. Like other respiratory viruses, the performance characteristics such as NPV and PPV of these tests will likely be influenced by viral load, when and how viral shedding occurs, patient characteristics, and sample type. The effects of annual genomic drifts or a shift should it occur on these tests is unknown.

GOOD LABORATORY PRACTICES

To provide consistency in the patient care process, it is vital to develop appropriate policies and procedures specific to each CLIA-waived POC test to optimize the ability of the test to produce results that aid in chronic disease state management or detect the analyte of interest without overtesting. For CLIA-waived POC tests in chronic disease state management, pharmacists should specify the frequency of testing as part of the patient-specific care plan in accordance with relevant national clinical guidelines. In addition, frequency of monitoring should be driven by the patient’s disease progression and achievement of treatment goals. Although CLIA-waived tests are determined to be simple for the user, it is necessary for a pharmacist to be properly trained on each CLIA-waived device and for the laboratory to follow “good laboratory practices” for waived testing sites per CDC guidelines.5 These practices include steps that should be taken before initiating or expanding CLIA-waived POCT services and include actions taken during and after the actual performance of test (Figure 4-1).5

FIGURE 4-1.
FIGURE 4-1.

Steps of Good Laboratory Practices

Before Initiating Services (Preparation Phase)

Recommended practices prior to initiating POCT services involve regulatory, logistic, procedural, and personnel considerations. An initial step toward initiating CLIA-waived POCT services is to identify a qualified individual who will be responsible and accountable for testing operations.5,9 As described previously, some states have additional requirements that must be met to fulfill this role. Individuals leading and working in a waived laboratory must be familiar with local, state, and federal regulatory requirements. In addition to the CLIA requirements and state pharmacy practice acts, practitioners need to be familiar with state and local regulations governing laboratory operations, federal laws governing privacy (eg, Health Insurance Portability and Accountability Act), Occupational Safety and Health Administration (OSHA) work place safety standards (eg, OSHA standards related to workplace hazards and bloodborne pathogens standards), and information from the CDC and CLSI regarding biosafety and precautions for preventing the transmission of bloodborne pathogens in the workplace.5,9 Having familiarity with these regulations and resources will help ensure that any CLIA-waived POCT services protect patient confidentiality and are safe for both the patient and testing personnel.5

Many factors must be considered prior to initiating services to create a testing space that meets the needs of the practice setting, employees, patients, and the environmental requirements specified in the test manufacturers’ package insert. Additional considerations that are addressed include a fiscal assessment of the proposed POCT services and an analysis of offered tests so that all factors required to properly conduct the test(s) of interest can be determined (eg, advantages and disadvantages of the available devices, any additional equipment, and access to ancillary care services).5

Developing written policies and procedures that clearly outline the responsibilities and testing instructions for testing personnel and facility directors is a critical process that must occur before testing begins. Procedures should be based on the manufacturer’s instructions and be used to train testing personnel.5 In addition to test performance, the policies and procedures should outline and standardize specimen collection techniques, QC procedures, proper handling and storage of tests and reagents, and documenting and reporting results.5

Testing personnel are a critical component to any CLIA-waived POCT service. Because personnel at waived testing sites are not subject to proficiency testing, it is essential that they be trained by a qualified person and be competent in any test they will perform before performing the test.5 Training should include an observed performance of the trainee performing the test. Many training resources are available through test manufacturers and distributors, professional organizations, and governmental agencies. Training should be documented and reviewed on a regular basis to ensure that all updates or changes are noted. Although proficiency testing is not mandated, including such assessments is recommended as part of any quality assurance program.5

Test Ordering and Sample Collection (Preanalytical Phase)

Considering all aspects in the planning phase helps ensure personnel have the resources, understanding, and skills needed to perform a CLIA-waived POC test properly during the preanalytical phase. Good laboratory practices in this phase include confirming the test has been properly ordered, identifying the patient, labeling the sample collection device to avoid any confusion with other patients, providing the patient with pretest education or information, reviewing the complete test procedure, and preparing the test area and materials.5

During Testing (Analytical Phase)

Good laboratory practices in the analytical phase involve QC, test performance, and result interpretation and documentation.5 The QC measures are important to ensure proper training of the user’s technique, the integrity of the testing device, and the overall performance of the POCT analytical device. It is a process that consists of two components: internal QC and external QA. Internal QC requires the analysis of manufacturer-provided QC materials. These materials are imbedded in the test in known concentrations and produce a result that indicates whether the analytical method and the reading device are functioning properly. The purpose of internal QC is to monitor the precision and function of the analytical method over time. In contrast, external QA monitors the testing process from specimen application to result interpretation. External QA requires analyzing patient-like samples comprised of liquid or other materials similar to patient specimens provided by the manufacturer or purchased separately. These patient-like samples can be run before or concurrent with patient samples, and their results are compared across testing personnel to monitor the accuracy of reporting. QC test results should be documented, and any action taken in response to QC tests should be recorded. The CLIA-waived laboratory director should incorporate a QC plan in the site’s policy and procedures.5 The POC test and device manufacturer provides QC materials, which often include internal and external controls. A test site should determine QC testing frequency that fits its operations for each test system, but at a minimum, QC testing should be performed as often as the product insert recommends.5

Each CLIA-waived POC test and device can require different techniques for acquiring or testing a sample. Therefore, CLIA requirements stipulate that when personnel perform the tests, they must strictly adhere to the manufacturer’s guidelines and follow specific storage conditions for the test and test materials (eg, testing strips, cartridges, cassettes, and reagent). Temperature and humidity may also be critical factors in providing a successful test result. The CLIA-waived POC test results should be interpreted within the manufacturer’s specified time period, and the test should be repeated if the results conflict with the available clinical information or are invalid.5 Once valid test results are obtained, they should be documented according to established policy and procedures in a timely fashion.

After Testing (Postanalytical Phase)

Good laboratory practices in the postanalytical phase involve issuing test reports, performing supplemental or confirmatory testing, testing area cleanup, disposing biohazard waste, and documenting testing activities. The pharmacist’s appropriate interpretation of the test results is a critical part of the postanalytical phase, along with communicating the results to the patient and provider. The pharmacist’s discussion of a laboratory result with the patient should be well planned and considerate of the patient’s response. When a pharmacist encounters a test result that requires follow-up with a physician for further evaluation, it is important to communicate with the patient’s physician and have referral resources ready and available as needed. In some cases, good laboratory practices and state or local statutes mandate that test results for certain infectious diseases also be reported to local or state public health agencies.5 For all postanalytical phase activities, the testing site should have specific policies and procedures clearly defined and in place.

LIMITATIONS OF POINT-OF-CARE TESTING

Legal and Regulatory Barriers to Pharmacists Performing Clinical Laboratory Improvement Amendments–Waived Point-of-Care Tests

Under CLIA requirements, there are no minimum educational or training requirements needed for the director or testing personnel.3,5 Therefore, in nearly all states, pharmacists can serve in either of these roles and perform a CLIA-waived POC test. However, the ability of pharmacists to use the result of a CLIA-waived POC test to make a therapeutic decision for the management of chronic diseases or acute infections falls under the scope of practice, which is regulated by state agencies and boards of pharmacy.2 However, studies have identified that legislative and regulatory variability across states may produce confusion among practitioners and represent a barrier to pharmacists’ efforts to perform POCT.2,111 Although performing CLIA-waived POCT may not be explicitly addressed in many pharmacy practice acts, such activities may be permissible under CPA/CDTM agreement provisions in state regulations or statutes.2 A few states, however, still do not have these provisions in their pharmacy practice acts. There is variability across states with CPA/CDTM agreement provisions in terms of specificity, scope, and structure.2 For example, some states restrict CPAs/CDTM agreements to written agreements for individual patients, whereby pharmacists can treat a patient for the condition specified in the protocol only if they have advanced authorization from the patient’s primary care provider. Such an approach poses a challenge for patients who do not have a primary care provider.81

Lack of Training/Education

According to their classification, CLIA-waived POC tests are simple to perform with low risk for erroneous results or harm to patients if they are performed incorrectly.3 However, they are not error proof; CLIA regulations explicitly stipulate that individuals who perform the tests must strictly adhere to the manufacturer’s instructions.3 Although CDC and CMS studies indicate that waived laboratories (including pharmacies) generally perform testing correctly, the results of the agencies’ surveys also highlight the need for additional education and training for site directors and testing personnel.5 Because CLIA requirements do not specify any level of education for directors or testing personnel in waived laboratories, lack of education regarding CLIA-waived testing is a gap that exists across all healthcare professional education.5 Two national surveys of academic pharmacy suggest that education on CLIA-waived POC tests for infectious diseases is generally lacking from professional pharmacy degree programs.112,113 This is an opportunity for the expansion of core curricula that would enhance pharmacists’ participation in POCT services. Training for pharmacists is available through an accredited national certificate training program offered by a national pharmacy professional organization that is designed for community pharmacists to implement testing programs for influenza, GAS, HIV, and HCV.114 Data suggest that the program can help improve training and expand POCT services.115

Overtesting

Overtesting is a concern with CLIA-waived POC tests for infectious diseases because they are qualitative and detect seasonal pathogens that produce infections with nonspecific symptoms (eg, GAS and influenza) or produce infections that are most prevalent in specific high-risk populations (eg, HIV and HCV); therefore, overtesting is a concern. To optimize the ability of the test to detect the analyte of interest and avoid overtesting, pharmacists should develop practices that enable them to distinguish patients who could benefit from testing. Because low disease prevalence can negatively impact the PPV of qualitative tests, pharmacists can optimize test performance and minimize overtesting by performing relevant physical assessments and gathering additional information to identify those in need of testing. Taking such steps will also enable them to make referrals to physicians for follow-up or make immediate referrals to emergency medical care.

FUTURE APPLICATIONS FOR CLINICAL LABORATORY IMPROVEMENT AMENDMENTS–WAIVED POINT-OF-CARE TESTS IN OUTPATIENT PHARMACY PRACTICE SETTINGS

With continued transformations in the delivery of healthcare in the United States and advances in technology, there will likely be many more innovative applications of CLIA-waived POC tests for chronic disease state and infectious diseases in outpatient pharmacy practice settings. The growing shortage of primary care providers will lead to an increasing role of pharmacists performing CLIA-waived POC test to screen for and manage chronic diseases. Scientific advances in genetic testing and molecular diagnostics will increase the POC tests on the market. The potential to perform POC pharmacogenomic testing will enable pharmacists to help guide and select therapies based on a patient’s genetic make-up, limiting side effects and increasing efficacy. The development of new molecular-based CLIA-waived POC tests or improved current antibody/antigen-based tests may make it more practical to test infectious disease analytes of public health interest (eg, tuberculosis and pathogens responsible for sexually transmitted infections). In addition, in cases such as sexually transmitted infections, molecular-based CLIA-waived POC tests could allow a pharmacist working under a CPA/CDTM agreement to institute prompt therapy under protocol. Adapting to these changes will be vital for pharmacists to develop workflow processes and financial models to sustain CLIA-waived POCT.

Ongoing reforms to the U.S. healthcare delivery system will continue to raise awareness of pharmacists as ready access points to the healthcare system. To fully realize this potential for POCT services in outpatient pharmacy practice settings, local, state, and federal regulations governing pharmacy practice must continue to evolve so pharmacists can practice to their fullest professional potential. Technological advances in health informatics will ultimately enable the pharmacist to have access to electronic medical records (EMRs) regardless of practice setting. Similarly, pharmacists will transmit CLIA-waived POCT results to a patient’s EMRs, their primary provider, and other relevant public health agencies.

LEARNING POINTS

1. How have the CLIA-88 created opportunities for pharmacists in outpatient settings?

ANSWER: Technology has allowed many laboratory tests useful in the detection and management of chronic diseases and infections to be simplified and classified as CLIA-waived. CLIA-waived POCT represents an opportunity for pharmacists in outpatient settings to expand their patient care services.

2. What must pharmacists know to properly perform CLIA-waived tests in their practice settings?

ANSWER: To properly perform a CLIA-waived test in outpatient settings, pharmacists must understand the basis of the test, how to handle specimens, and how to perform the test. They must also understand all relevant state and federal regulations related to performing such tests and reporting the results.

3. What must pharmacists know to provide useful POCT services in their practice settings?

ANSWER: To provide useful POCT services, pharmacists must understand how to identify patients who would benefit from testing. In addition, they must understand how to evaluate the various performance characteristics and the limitations of the test.

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