Point of Care Devices for Drugs of Abuse Testing

Chapter 11

Point of Care Devices for Drugs of Abuse Testing: Limitations and Pitfalls Veronica Luzzi Providence Saint Joseph’s Health and Services, Providence Regional Core Laboratory, Portland, OR, United States

INTRODUCTION In the last 20 years, point of care testing (POCT), also known as on-site or near-patient testing, has evolved into a new discipline within laboratory medicine. Some of the contributing factors in this evolution have been easy and fast access to tests results, ease-of-use, cost, and advances on instrument connectivity. Drug of abuse testing has been performed using POCT devices for a while. Since the first waived POCT device was approved by the US Food and Drug Administration (FDA), there has been a steady increase in the number of devices being approved [1]. This data is summarized in Fig. 11.1. However there are controversies about testing for drugs of abuse using POCT devices depending on the assay performed, where and who uses the device, and whether or not using POCT contributes to increase cost due to inadequate test utilization. In this chapter, several of the factors contributing to the expansion of POCT for drugs of abuse and the controversies arising from their use will be covered. Whether POCT devices are used in a clinical laboratory, emergency department, or a pain management clinic, understanding their performance and the nuances that can lead to serious errors is paramount for successful patient management.

DESIGN OF POCT DEVICES Current devices use a solid-phase competitive immunoassay in a lateral flow format. They are often available as strips, cup, or a cassette that can be read manually or using a reader [2,3]. A diagram of a lateral flow immunoassay strip is shown in Fig. 11.2. Close to the sample application line, there are a labeled conjugate and a labeled control antigen pads. Up in the strip, further away from the application line, there are a test and control lines. The test line contains detection antibodies against the target drug or labeled conjugate. The control line contains antibodies against the control antigens. As the sample migrates from the application line to the labeled conjugate and control antigen pads, it carries its contents to the test and control lines. If the concentration of the target drug in the sample is below the cutoff, a color line will appear because the labeled conjugate will bind to the immobilized detection antibodies. On the contrary, if the target drug is above the cutoff, it will compete with the labeled conjugate and inhibit color formation (Fig. 11.3). Result from strips, cups, and cassettes can be evaluated visually by inspecting the presence or absence of color. Testing can be done for a single drug or as a panel. Some strips and cassettes can also be read by semiautomated or automated end point [4] readers. In general, all these devices are easy to use, easy to read, and many times, Clinical Laboratory Improvement Amendments (CLIA) waived. Some users have found difficulty in reading and interpreting competitive immunoassays in the POCT settings and reported unacceptable to use these devices at their institutions [5].

RELIABILITY AND EFFECTIVENESS OF POCT DEVICES The reliability and effectiveness of drugs of abuse POCT devices has been challenged by several studies [4 11]. The main issues described in the literature are due to the specificity of the antibodies used in manufacturing POCT devices, the inconsistency of cutoffs among reagent lots of the same device, the nomenclature used to name drugs or drug classes, and the difficulty of interpreting the device reporting lines depending on the read time used on the device [12]. Critical Issues in Alcohol and Drugs of Abuse Testing. DOI: https://doi.org/10.1016/B978-0-12-815607-0.00011-3 Copyright © 2019 Elsevier Inc. All rights reserved.

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FIGURE 11.1 Drug of abuse waived POCT devices approved by the FDA since 2005.

Test line

Application line

FIGURE 11.2 Diagram of a lateral flow immunoassay strip.

Control line

Backing

Sample pad

Conjugate pad

Nitrocellulose membrane

Absorbent pad

Accuracy issues reported due to antibody specificity is not inherent to POCT devices but rather a characteristic of immunoassays. Results obtained with immunoassays whether they are from a laboratory instrument or a POCT device; often need confirmation with a more specific chemical method. Good laboratory practice recommends that before a patient management decision is made, confirmation of the presence of the drug should be performed [13]. Immunoassays in general use the binding properties of antibodies to capture or detect a molecule, but because antibodies used in clinical assays may be different, drug of abuse POCT devices may cross-react or not with a drug.

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FIGURE 11.3 Diagram of a negative and a positive reaction in a lateral flow immunoassay strip.

In 2002, George and Braithwaite [14] eloquently described some of the potential risks of using POCT devices to measure drugs of abuse. Some of the issues they described then still persist today despite the tremendous growth we have seen in this industry. One of the first methods described in the literature in 1988 used paper chromatography to detect cocaine. It was reported that, three trained individuals read 100 urine tests results, and only correctly identified the presence of cocaine 50% of the time [7]. Several studies performed in the 1990 listed different sensitivity and specificity for POCT drug of abuse assays when compared with other laboratory methods such as Syva EMIT, or gas chromatography/mass spectrometry [8,14]. In all these studies the performance of the assays was highly impacted by factors such as the use of incorrect nomenclature, turbidity of the specimen, reading time, testing settings, and personnel training. For example, a cartridge using latex agglutination inhibition method intended to detect morphine, and also detected other opiates such as codeine and dihydrocodeine [4]. A competitive immunoassay for cannabinoids (accuPINCH) provided negative result in cannabinoid positive turbid specimens. Moreover, if reading time is longer than recommended 5 min, it may increase the rate of false positive test results [7]. Testing settings may also impact accuracy if the personnel reading the device were multitasking, trying to perform patient care at the same time. In one particular report, an essential buffer bead used in a device was prone to loss if personnel not properly trained used the device [8]. Evaluation studies performed on a patient care setting where personnel are not formally trained in laboratory medicine are very valuable. In 2002, Mastrovitch [15] presented evidence that a POCT device used in the emergency department of a tertiary care in the urban medical center (On Trak) performed equivalent to a screening laboratory device used in the central laboratory (Triage). The authors evaluated 170 urine specimens from adult patients (including 34 pediatric patients) analyzed by seven trained nonlaboratory technicians. The drugs evaluated were classified in four groups: cocaine, marijuana, opiates, and amphetamines. The concordance was 97% and 99% for cocaine, and the rest of the drugs respectively. In this study, no confirmation testing was performed. The authors claimed a faster turnaround time and did not elaborate whether or not they encountered specificity issues. A false negative or false positive outcome in a pediatric patient may have implications beyond clinical toxicology, but this fact was not addressed [16,17]. In 2012, a team composed of emergency department and pharmacy personnel in the Netherlands evaluated three POCT devices against a laboratory-based screening method [18]. The POCT devices investigated were TestCard9 (Varina, Middleburg, The Netherlands), Syva RapidTest (SRT) d.a.u. 10 (Dade Behring; Leusden, The Netherlands), and Triage TOX Drug Screen (Biosite; Bunnik, The Netherlands) against the Syva EMIT II immunoassay and chromatographic confirmation. The team tested 80 urine specimens and learned that the sensitivity and specificity for all the devices were at least 93% for amphetamines, cocaine, cannabis, benzodiazepines, and opiates. There were exceptions: for cannabis, the TestCard device sensitivity was 88%, for benzodiazepines, the sensitivities for the SRT and the TestCard were 88% and 80%, respectively. The team concluded favoring the Triage device because it was easy to use and had the option to use an automated reader rather than subjective interpretation used in a manual reading mode. False negative and false positive findings have been previously described in the literature when drugs of abuse are measured using immunoassays in automated analyzers. Several reviews list the names of different substances interfering with immunoassays, and even the concentrations at which these substances may interfere [6,19,20]. Since POCT devices use immunoassay methodology and the format of the assay in the device may be similar to that of the laboratory immunoassay, interpreting results when using POCT devices for drugs of abuse is just as important as when immunoassays are used in the laboratory. Providing interference information to ordering providers is important for understanding what may be the cause of discrepancies between expected results and findings. The National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Recommendations for the Use of Laboratory Tests to Support Poisoned Patients Who Present to the Emergency Department, published in 2003, emphasized the importance

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of providing assay limitation information to ordering providers [21]. Ideally, this information is also available when drugs of abuse are measured at the POCT. The untrained user may contribute to inaccurate results, and in particular this issue becomes very evident when the personnel using the POCT devices are also tasked with other nontechnical duties such as patient care. Training personnel and validating the devices in similar setting to those that are going to be routinely used is very important and have been cited in the literature as contributing to decrease errors [22]. POCT devices report qualitative results, positive or negative, based on a preestablished cutoff (Table 11.1). In comparison with automated chemistry assays, the cutoffs used in POCT devices are very similar. However, during evaluation of a POCT device, the consistency of the cutoff among lot numbers of reagents should be determined. In a recent evaluation, a reference laboratory learned that a commonly used POCT device detects drugs at a different cutoff than those claimed by the manufacturer. For some drugs, the device detected concentrations 20 times smaller than the claimed cutoff, while for other drugs, the amount of drug to be measured needed to be 5% 10% higher than the cutoff to be detected [23]. The study performed as part of the evaluation of this device also showed that the detection of a positive specimen changed to negative if the reading time was extended beyond recommended time. For methadone, extending the reading time to 15 min could possibly lead to false negative results. Knowing the true positive and false positive rate of the screening tests used in the laboratory or elsewhere is important to understand the limitations of the devices. There are studies describing this rate in POCT devices. One study performed by a reference laboratory in the United States analyzed 8825 urine specimens tested by immunoassay screen (Syva and Microgenics) in a Beckman AU 5810. Positive results were later confirmed using a higher chemical method (gas or liquid chromatography with mass spectrometry or tandem mass spectrometry detection, or flame ionization detection). This group reported that the Beckman AU 5810 immunoassay screening for benzodiazepines, opiates, oxycodone, tetrahydrocannabinol, and amphetamines had a positive rate higher than 5%. 3,4-Methylenedioxymethamphetamine, phencyclidine, and propoxyphene had the lowest number of true positives [24].

TABLE 11.1 Example of Urine Cutoff Used in a POCT Device and an Automated Immunoassay, and Its Corresponding Confirmation Cutoff Drug or Drug Class

SAMSHA Cutoff

Chemistry Automated Analyzer Example

POCT Detection Devices Cutoff

Confirmation Cutoff (ng/mL)

AU 5400 EMIT Reagents

NexScreen

RapidCup

GC/MS or LC MS/MS

D-Amphetamine/Dmethamphetamine

500

500

1000

500

200

Barbiturates

200/300

200

300

300

50

Benzodiazepines

200

200

300

300

5 20a

Cocaine metabolite (benzoylecgonine)

300

150

300

150

50

Methadone

300

150

300

300

10

Buprenorphine glucuronide

n/a

n/a

n/a

10

2, 5, or 100a

Opiates

2000/300

300

300

300

10 or 20a

Oxycodone

100

100

100

100

50

Phencyclidine

25

25

25

25

10

Marijuana metabolite (11nor-Δ9-THC-COOH)

50

50

50

50

5

MDMA

500

500

500

500

200

Tricyclic antidepressants

500

500

1000

1000

100, or 200a

GC, gas chromatography; LC, liquid chromatography; MDMA, 3,4-methylenedioxymethamphetamine; MS, mass spectrometry; THC, tetrahydrocannabinol. a It depends on the drug.

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Cutoff concentrations are designed to mimic the Substance Abuse and Mental Health Services Administration (SAMHSA). However, in a clinical setting, these cutoff concentrations may be different than cutoff concentrations that are used in forensic drug testing or for preemployment screening. For some patient populations such as pediatric patients, it may be more relevant to know whether or not the substance is present, even if it is below the federally mandated cutoff [25]. The imprecision below the cutoff concentration has been demonstrated to be within 20%. Using a cutoff concentration based on the precision of an assay rather than a cutoff concentration artificially imposed may be more relevant in the pediatric population.

Oral Fluid Testing Using POCT Devices When performing drugs of abuse testing using POCT devices, body fluids other than urine may be an attractive alternative. For example, oral fluid can be easily available and the presence of a drug may indicate recent drug use [26]. Toennes et al. [27] evaluated the correlation between serum, urine, and oral fluid concentration in drivers suspected of drunk driving. Results from the study demonstrated that impairment symptoms correlated better with alcohol serum and oral fluid concentration than urine. Some countries have incorporated POCT devices that use oral fluid to test for suspected drunk drivers [28 32]. In 2015, SAMHSA, an agency under the Department of Human and Health Services (HHS) has defined oral fluid as an acceptable specimen type to be used in the workplace drug testing program [33]. The HHS has also defined cutoffs for screening and confirmation that are much lower than those of urine specimens (Table 11.2). Alternate methodologies to immunoassays are included as part of the screening in order to reach these lower thresholds. But only HHS-certified laboratories are allowed to test oral fluid specimens for federal agency workplace drug testing programs. Studies have shown that POCT devices are not adequate to meet the HHS cutoff requirements. There are limitations on using oral fluid in drug of abuse testing when using POCT devices. Oral fluid is usually collected on a device that contains a buffer as preservative. The ratio between the buffer and the oral fluid is not necessarily constant and may preclude from accurate drug concentration measurements [34]. The distribution of a drug in the body will vary and cross-studies comparing different body fluids are needed to interpret oral fluid results accordingly [35]. When evaluating whether or not using oral fluids as an acceptable specimen, rigorous studies need to be performed to demonstrate contaminants, environmental conditions, or collection methods do not alter the drug concentration. Crouch [36] has described the use of oral fluid to replace urine or blood specimens and concluded that collecting a valid and representative specimen is intimately related to the collection device. A more recent systematic meta-analysis of previously published TABLE 11.2 SAMSHA Oral Fluid Screening and Confirmation Cutoffs Drug Tested

Screening Cutoff (ng/mL)

Confirmation Cutoff (ng/mL)

Δ -Tetrahydrocannabinol

4

2

Cocaine/benzoylecgonine

15

8

Codeine

30

15

Morphine

30

15

Hydrocodone

30

15

Hydromorphone

30

15

Oxycodone

30

15

Oxymorphone

30

15

6-Acetylmorphine

3

2

Phencyclidine

3

2

Amphetamine/methamphetamine

25

15

MDMA/MDA/MDEA

15

15

9

MDA, 3,4-Methylenedioxyamphetamine; MDEA, 3,4-methylenedioxy-N-ethylamphetamine; MDMA, 3,4-methylenedioxymethamphetamine.

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studies evaluating the reliability of detecting five commonly monitored drugs in oral fluid using POCT devices also warns about the variability in specificity and sensitivity of POCT devices. The authors also point out that a standardized study comparing devices, specimen types, and cutoffs may be needed in order to accurately appreciate the differences in devices, when oral fluid is used [37].

GUIDELINES FOR USING POCT DEVICES The Executive Summary of the National Academy of Clinical Biochemistry: Evidence Based Practice for Point of Care, published in 2004 [13], strongly recommends that POCT device training includes quality monitoring and limitations. Users must be familiar with the devices analytical specifications, and the common interferences or other limitations to prevent misinterpretation errors. If a result from a POCT device is going to trigger a penal or legal decision, confirmation of the results must be mandatory. The Clinical and Laboratory Standard Institute (CLSI) created several guidelines related to POCT [38 41]. These guidelines describe connectivity for engineers and users (POCT01 and POCT02, respectively), approaches and quality practices to reducing errors at the POCT (POCT07-A, POCT08-A), and a selection criteria for POCT devices (POCT09-A). Guidelines POCT01 and POCT02 were created to address connectivity standardization, and follow the Connectivity Industry Consortium vision to “develop, pilot, and transfer the foundation for a set of seamless ‘plug-andplay’ POCT communication standard”. . . These guidelines have helped curved the development of better instrument connectivity, and therefore decreased errors due to manual data entry. However, when POCT devices are used outside a data framework of a university or hospital system, the compliance with these guidelines may not take place. In particular, for pain management monitoring, where the use of POCT devices has been implemented outside the clinical laboratory oversight, data entry errors may still need addressing. Immediate care and primary care clinics where manual entry is often performed may have similar data entry issues. This type of errors will continue to exist unless incorporation of results in the patient medical record is completely automated. Some devices created for monitoring glucose concentration are capable of connecting to a software application via wireless communication. The clinical need of adopting wireless technology for drugs of abuse testing in the POCT setting may not necessarily exist. However, the development of a process free of manual data entry for those locations that are not included in the centralized laboratory network will improve data flow. Guidelines POCT07-A, POCT08-A, and POCT09-A are all related to error reduction but cover the topic from different perspective. POCT07-A provides information on quality indicators for analytical processes and emphasizes the importance of creating indicators to identify common causes of errors. It also provides guidance for creating error tracking processes. POCT08-A translates good laboratory practices into terms usable by testing personnel that is not trained in the laboratory. Sometimes personnel using POCT devices consist of medical personnel that are required to attend to patients at the same time they perform testing. These are not ideal circumstances and avoiding multitasking may be the only way to prevent common operator errors. Finally, POCT09-A describes important criteria for the selection of POCT devices based on the clinical setting and clinical needs. It also provides information on regulatory and accreditation requirements referring to POCT devices and their use. In addition to the CLSI guidelines described earlier, the Center for Medicare Services has recently approved a new plan for laboratories aiming at assessing risk of failure and allowing laboratories to customize a quality control plan according to the method and its use, the environment, and personnel competency. This plan is called “individualized quality control plan” or IQCP. One of the reasons why the use of POCT devices has grown steadily in the last few years is because they appear to provide fast and accurate results without the hassle of sending the specimens to a central laboratory. The perception is that laboratory results correlate really well with POCT device results. As described earlier, there are serious caveats with this perception. Laboratory personnel can be of valuable assistance in implementing, training, and monitoring POCT devices. Laboratory personnel expertise as part of an integrated health care team has value added to the use of POCT devices. POCT devices CLIA defined complexity are waived or non-waived. In general, the nonwaived devices are moderately complex. A waived or nonwaived device may become high complexity if manufacturer’s instructions are not followed. Waived devices are believed to be more reliable and less error prone than high complexity laboratory assays. However, that is hardly the case. Evaluating and monitoring the performance of a waived device is important to understand the limitations of the device and the concomitant implications of those limitations [42].

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CONCLUSIONS Laboratory personnel should be involved in the early adoption of a POCT solution. The activities where the laboratory personnel should be involved are initial evaluation of the analytical specifications of the POCT device, implementing policies, procedures, and training manuals to minimize misinterpretation and operator errors; training and competency assessments to meet regulatory requirements; monitoring device and personnel performance using quality control materials; identifying errors and creating process improvements; and creating an IQCP plan to assess risk and prevent errors. However, it is important to incorporate the routine user of the device in all these activities to be aware of workflows, cognitive errors, or unintended misuse of the device in use [22].

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