2POCT Testing: The Basic Principles Dr Genevieve BoshoffGood afternoon ladies and gentleman. I would like to start this afternoon off by providing you with information on how Point of Care Testing kits work.
3Principles Based on immunoassay Reaction between an antibody and an antigenAntigen = drug of interestAntibody = protein produced by the immune systemPOCT kits are based on immunoassay technology. Immunoassay technology (a hybrid of chemistry and biology) refers to an extremely convenient and quick analytical system that relies on specific antigen - antibody reactions for detecting analytes or compounds of interest.The term antigen refers to any substance that when introduced into the body, stimulates the production of an antibody.An antibody is a protein that is produced by the body in response to the antigen. For example, when your body is exposed to bacteria or viruses, it produces antibodies to these bacteria or viruses. These antibodies bind to the antigens and essentially neutralise them.
4Antigen-Antibody Binding Antibodies bind strongly to a compound with a specific shapeNormally only binds to compound that was used to produce the antibodyAntibody produced using single compound of interest for each testTests kits allow us to visualise and quantify antigen-antibody bindingThe antigen and antibody bind in a number of different ways. There may be a number of weak interactions between the antigen and antibodies in the form of hydrogen bonds, ionic interactions or Van Der Waals forces. These interactions take only take place if the molecules are close enough to each other and if the molecules have complementary shapes. That means that an antibody will only bind to an antigen which has a specific shape. An antibody has a Y-shape with 2 antigen binding sites, one on each arm. The arms are made up of 4 polypeptide chains or proteins – 2 light and 2 heavy which form a Y-shape. Every member of a particular antibody family shares the same constant region but the variable region varies base on the antigen. The affinity of antibody for an antigen is governed by how well the antigen fits into the antigen binding site.This binding is however reversible and the stability of the antibody-antigen complex is determined by affinity of the antibody for the antigen as well as the valency or charge of the molecules. For example, the complex will be much stronger when both antigen binding sites are engaged or when the antigen is more highly charged.The antibodies are produced by injecting an antigen into the body of a mouse. The antibodies used in POCT kits are produced using a single compound of interest for each test. For example, for aAs you can imagine, the drug on its own can not elicit an immune response due to its small size. In order to produce antibodies against specific drugs, the drugs are attached to a larger protein molecule which can elicit an immune response. The drug-protein complex is then injected into the mouse, normally twice (primer and booster dose). The B-cells, which produce the antibodies are then harvested and those that produce the antibody of specific interest are identified. These are then cultured and the antibodies produced, harvested and used in the POCT kits. (monoclonal antibodies).The POCT test kits allow us to visualise the interaction between antigens and antibodies.
5POCT Drug Test Kits Number of different types Dip sticksCassettes-testing of multiple drugs simultaneouslyCups-testing of multiple drugs simultaneouslyGenerally used to test urine samplesDetect use within the last weekOther test matrixes include saliva and bloodPOCT kits come in a number of different forms. Some are simple single use dipsticks where the result is read off . Others comprise casettes or cups which allow you to test for multiple drugs at the same time using only one sample.Generally speaking most POCT test kits are used to test urine samples.
6Elements of immunoassay 3 essential components required:Antigen that you would like to detect e.g. drugSpecific antibody to the drugMethod of quantifying the antigenNumber of immune complexes formedUse detectable labels e.g. enzyme, dye or pigment, radioactive componentThe essential components of antibody-based immunoassay systems are threefold: an antigen that we would like to detect and perhaps quantitate; a specific antibody to this antigen; and a system to measure the amount of antigen in a given sample.The extent of the antibody-antigen bond, i.e. the number of immune complexes formed by the antibodies and immobilized analytes, is an indicationof the concentration of the analyte in the sample. However, the antibody-antigen bond is not directly accessible for analysis in most immunoassays.This problem is solved by coupling one of the two components, either the antigen or the antibody, to an easily detectable “label”. Radioactivecomponents, enzymes (biocatalysts), dyes or fluorophors are examples of possible labels.
7Membrane containing test strip and control strip Lateral Flow AssaysSample pad-adsorbent pad to which sample is appliedConjugate pad- contains antibodies or antigens specific to the drug of interest conjugated with pigment or colour compoundTest strip –contain antibodies/antigenControl strip- contains antibodies to the conjugateWicking pad -absorbent pad to draw sample across the test stripSample padConjugate padMembrane containing test strip and control stripWicking padTest StripControl StripI now want to give you an example of how one of these immunoassay systems is constructed and employed in drug testing. Most dipstick systems are based on what is called a lateral flow assay. Essentially the antibodies to the drug and the detectable labels are immobilised on a thin membrane. The test sample is introduced to one end of the membrane and migrates via capillary action laterally across the capillary, interacting with the antibody and detectable labels as it moves along. A basic test strip is composed of the following elements:A sample pad which is made of an adsorbent material. The sample is introduced onto this pad either by dipping it into the sample or by pipetting the sample onto the pad.A conjugate pad which contains the detectable labels conjugated to either antibodies to the drug or to the antigen itself (drug conjugate)A test stip. This is where antibodies have been immobilised in a specific area of the strip (generally along a line)A control strip. This is where antibodies to the detectable label conjugate are immobilised in a specific area. This control strip is devised to give an indication as too how well the test has worked.A wicking pad which facilitates the flow of the test solution along the membrane by capillary action.
8Assay Methods Direct Assay Competitive Assay Positive result indicated by presence of test lineCompetitive AssayPositive result indicated by absence of a test lineControl line is present in both casesThe antibodies and detectable labels and the configuration in which they are placed on the test strip is determined by the assay method. There are 2 main assay methods:In the direct assay method, the antigen reacts with a colour complex which then reacts with antibodies immobilised on the test strip to produce a coloured line. The presence of the analyte of interest is indicated by the appearance of a coloured line. In the competitive assay method a positive results is indicated by the absence of a coloured line.Due to the small size of the drug molecules, the competitive assay method is normally used for drug detection.
9Competitive AssayCompetition between free drug and immobilised drug (immobilised antigen) for limited antibodiesIn presence of drug, free drug binds to the antibody conjugate, preventing it from binding to immobilised drug. No colour reaction.If no drug present antibody complex binds to the immobilised drug to produce coloured line.1.Antibody conjugated to gold or pigment (conjugate)3.Antibodies to conjugate2.Immobilised DrugPositive ResultNegative ResultTCIn this assay the drug in the samples competes with immobilised drug for a limited number of antibodies. The system comprises 3 main elements:The antibody to the drug which has been bound to a gold particle of pigment.This is called the antibody conjugate.The drug which has been immobilised in the test strip.Antibodies to the antibody conjugate which have been immobilised in the control area.In the test procedure, a sample of urine is placed in the sample well of the device, and the sample is allowed to migrate upward. If any of the applicable drugs is present in the urine sample, it forms a complex with the antibody-dye conjugate specific for that drug, and the complex migrates toward the opposite end of the card, passing the specific locations on the membrane where each of the applicable drug conjugates are immobilized. The drug in the sample competes with the drug conjugate, which is immobilized on the membrane, for the limited antibodies present in the form of antibody-dye conjugate. When a sufficient amount of drug is present, the drug will saturate the antibodies, and the antibody-dye conjugate cannot bind to the drug conjugate on the membrane. Therefore, a drug-positive urine sample will not generate a line at the specific drug position in the result window, indicating a positive result from positive drug competition. Conversely, if a particular drug is absent in the urine specimen, the antibody on the antibody-dye conjugate will bind the membrane-bound drug. In this case, a drug-negative urine sample will generate a line at the specific drug position in the result window, indicating a negative result from an absence of competition with free drug.In addition, the test card has a procedural control built into the system, in the upper control line area. The control line is immobilized with polyclonal anti-mouse antibody; therefore, it will capture monoclonal antibody-dye conjugates that pass the region, showing a colored line in the control (validation) zone. The line works as a procedural control, confirming that proper sample volume was used and the reagent system worked. If insufficient volume is used, there may not be a control line, indicating the test is invalid.
10Positive ResultAny indication of a drug above the cut-off level/thresholdMinimum concentration of the drug or metabolite that must be present in the specimen in order for the test to be reported as positive.Vary from drug to drug and kit to kitNegative result does not mean that the sample is drug freeA positive result provides an indication that the drug or a compound with a similar structure to the drug is present in the urine at a concentration above the cut-off or threshold of the kit that has been used. The cut-off or threshold is the minimum concentration of the drug or metabolite that must be present in the sample to provide a positive result. This values varies from drug to drug and kit to kit. In some cases it is based on regulatory requirements but this is not always the case. Each individual test is calibrated using a test calibrator. This calibrator is normally the compound that has been used to generate the antibodies.The Rapid Exams Multi-Drug Test yields a positive result when Amphetamines in urine exceed 1,000 ng/mL. This is the suggested screening cut-off for positivespecimens set by the Substance Abuse and Mental Health Services Administration (SAMSHA).A negative result does not mean that there is no drug present in the sample but only that it is present below the cut-off level.
11How results from POCT kits are reported True Positive (TP): The result of the test is positive and that drug is present in the sample at or above the threshold concentration of the test.False Positive (FP): The result of the test is positive but the drug is not present in the sample or at concentrations below the threshold of the test.True Negative (TN): The result of the test is negative and the drug is not present in the sample or is below the threshold concentration of the test.False Negative (FN): The result of the test is negative but the drug is present in the sample above the threshold concentration of the test.In a drug testing programme the main objective is to determine if a drug of abuse is present or absent. When considering how to report analytical results, there are four possible outcomes that must be considered:
12Sensitivity Lowest concentration of analyte that can be detected number of positive samples determined by the POCT devicenumber of positive samples determined by the comparison methodComparison method normally GC-MSReasons for poor sensitivity:Antibody affinity for the antigenAmount of antibody or antigen usedMembrane use for producing dipstickStorage conditionsProduction methodologyIn the next talk, you will hear a couple of terms being used. One is sensitivity and us very important when interpreting the results from a POCT kit. Sensitivity relates to the lowest concentration of the drug that can be detected by the POCT. In other words , the kits ability to detect samples that actually do contain the particular drug of abuse. As noted previously, each test kit will have different cut-off l levels below which a negative result is returned. In order to determine the sensitivity of a POCT kit it is necessary to analyse samples via a confirmatory method such as GC-MS and compare the results to those obtained by the POCT kit. The greater number of samples that the POCT identify as containing the drug of interest that actually do contain the drug of interest, the greater the sensitivity of the test kit.Detection of a particular drug by a drug-class-specific immunoassay depends on two factors:The structural similarity of that drug, or its metabolite(s), to the compound used for standardisationThe sample concentration of that drug / metabolite compared with the standardising compound (Yang, 2001).The standardisation compound refers to the material used to generate the antibodies employed in the manufacturing of the devices. The greater the structural similarity, the lower the cut-off limit can be.A PoCT device’s sensitivity is highly variable depending on the panel of drugs it is designed to detect. Also, there is variability between device manufacturers. Concerns have also been raised that there may be variability in sensitivity between batches of devices produced by the same manufacturer (Melanson et al. 2010). This makes any true estimate of sensitivity impossibleAlthough it is sometimes necessary to use a PoCT device to identify a single compound, most kits are used to detect a range or panel of drugs. However, due to their poor sensitivity, PoCT Immunoassays generally lack the ability to identify all drugs present in a given class (Saxon et al., 1990). For example, general opiate / opioid immunoassays are unable to detect the presence of the opioid methadone. An opiate is a drug derived from the poppy seed whilst an opioid is a synthetic or semi-synthetic compound..
13SpecificityThe ability of the kit to detect the analyte of interest and not other compoundsNumber of negative samples determined by the POCT devicesNumber of negative samples determined by the comparison methodAbility to detect true positives and few false positivesVaries between drugse.g. opiate/opiod tests have low specificity while cocaine tests have high specificityAnother term that you will hear and is also important when interpreting the data from POCT kits, is specificity. Assay specificity refers to the ability of an antibody to produce a specific response to the analyte of interest, whilst not showing any response to other compounds. A highly specific test gives few false-positive results. Hence the results from a POCT kit with high specificity will more likely return a positive result with samples which actually contain the drug of interest. They are less likely to give a positive result which contains another compound i.e. a false positive.The specificity of POCT kits varies between drugs. For example, For opiate / opioid immunoassays generally have a low specificity and cannot distinguish between morphine (the urinary metabolite of heroin), codeine and other opioids, including opiates from poppy seeds used in baked goods .Cocaine tests on the other hand have a high specificity.
14Cross-Reactivity Non-specific influence of substances in sample that: Structurally resemble the analyteMolecules have similar cross reacting epitopes or sites which bind to the antibody receptorsE.g. amphetamine assays- ephedrine/pseudoephedrine structurally similar to amphetamineMarijuana – can produce false positives with hemp productsLeads to the production of false positivesSo what causes this low specificity? Cross-reactivity.While assay specificity refers to the ability of an antibody to produce specific response for the analyte of interest, cross – reactivity is a measurement of antibody response to substancesother than the target analyte. Cross-reactivity is the most common interference in immunoassays, but mostly in competitive assays. It is a non-specific influence of substances in a sample that structurallyresemble the analyte (carry similar or the same epitopes as the analyte) and compete for binding site on antibody, resulting in over- or underestimation of analyte concentration.Cross-reaction is a problem in diagnostic immunoassays where endogenous molecules with a similar structure to the measured analyte exist or where metabolites of the analyte havecommon cross-reacting epitopes, and where there is administration of structurally similar medications (Kroll & Elin, 1994).Amphetamine immunoassays are among the most susceptible to analytical interference. Sympathomimetic amines like ephedrine/pseudoephedrine and phenylpropanolamine arestructurally very similar to amphetamine and are readily detected in these screening immunoassays. Ranitidine interference has been noted previously in amphetamine immunoassays.
15ConclusionsPoCT devices offer a inexpensive screening method for drugs of abuse.Due to the underlying method, it is always possible that a PoCT devices will report false positives or false negatives due to cross reactivity and non-specific binding.All results should be validated using GC-MS or a similar technique.False negative results cannot be screened i.e. just because the result is negative does not mean the drug is not present.
16Direct AssayAt conjugate pad, sample mobilises the antibody conjugate which migrates with the analyte towards the test and control strip. As it migrates, the drug reacts with the antibody conjugate to form a drug-antibody conjugateDrug-antibody conjugate reacts with drug antibodies in control strip-forms a coloured line – positive testAntibody conjugate reacts with conjugate antibodies to form a coloured lineAntibodies conjugated to gold or pigment (conjugate)Antibodies to the conjugateAntibodies to the drugPositive ResultNegative ResultTC
18Introduction to ‘real world’ use of PoCT devices Dr Simon Davis
19What to consider before using PoCT devices ! How accurate are PoCT devices?
20Laboratory based performance of PoCT devices Taken from data collected by the College of AmericanPathologists Proficiency Testing Surveys over a 6 year periodModified from Melanson et al.(2010)
21How do PoCTs perform outside a clinical environment ROADSIDE Testing Assessment Project (ROSITA 2) project was carried out between 2003 and With 2046 subjectsObserved sensitivity plots of OF PoCT devices to different classes of drug. Modified from Blencowe et al 2011.
22Driving Under the Influence of Drugs (DRUID) project (2012) 1025 subjectsPoCT sensitivity to Cocaine and Cannabis as reported in Strano-Rossi et al Positivity criteria were based on the kit manufacturer’s recommendation (CUTTOFF KIT) and those used in the DRUID study (CUTOFF DRUID).
23Does a PoCT device conform to your testing program criteria? To ensure good analytical performs and reduce the risk of false positives and negatives, all testing programs have a “Threshold” of concentrations above which a positive is reported and below which a negative is reported.
24Effect of Sample THC concentration on drug detection by a range of immunoassay techniques A range of different immunoassay techniques were compared. These were: enzyme donor immunoassay (diamonds), colloidal metal immunoassay (Triage; squares, &), enzyme immunoassay (Diagnostics Reagents Inc; triangle), enzyme immunoassay (enzyme multiplied immunoassay technique; X-shape), fluorescent immunoassay (asterisk,), fluorescence polarization immunoassay (circle), microparticle immunoassay (kinetic interaction of microparticles in solution; plus sign.Modified from Melanson (2010)
25Why are Thresholds a problem for PoCT devices Threshold concentrations for a range of PoCT Devices commonly used comparedto the SAMHSA threshold concentrationsDrugSAMHSA EMIT (ng/ml)Fastect® II (ng/ml)Reditest (ng/ml)Amphetamines5001000Cocaine150300Marijuana50Opiates2000300/2000Phencyclidine25Substance Abuse and Mental Health Service Administration (SAMHSA)
26Can a PoCT device reliably identify the drugs of abuse you wish to control? There will always be a risk of false positive results with PoCT devices.This risk can be mitigated by a process of screening and confirmation of all positive results by GC-MS or another gold standard technique.There is also a risk of false negatives, this risk cannot be mitigated.
27Sample CollectionCan operatives with minimal training be used to carry out PoCT tests and interpret and record theresults?Operatives must understand and be able to identify false positives due to cross reactivity.Operatives must be able to review a subjects medical, pharmaceutical, dietary and behavioural characteristics to identify false positives and false negatives.Operatives must be able to identify individuals claiming to be taking a legal substance with cross reactivity to an illegal substance in an attempt to mask drug abuse.
28Sample Collection“It is well known that in clinical settings immunoassay tests are more accurate when the results are interpreted by clinicians rather than non-technical staff (Melanson et al., 2010).
29Can a PoCT Device Have a Legally Defensible Chain of Custody? What is a Chain of Custody?US government regulations:“[a]ll urine specimens must be collected using chain of custody procedures to document the integrity and security of the specimen…” (Bush, 2008).The World Anti-Doping Agency (WADA) considers CoC to have been appropriately conducted when:“[t]he external record is initiated at the collection site and ensures that the Samples and the results generated by the Laboratory can be unequivocally linked to the [donor].” (WADA TD2009LCOC).The EWDTS provides similar language requiring that:“…the results reported relate beyond a doubt to that specimen.” (EWDTS (2011)).
30Can a PoCT Device Have a Legally Defensible Chain of Custody? Results from PoCT devices only remain visible as long as the sample remains aqueous.ISO requires a laboratory to:“retain records of original observations, derived data and sufficient information to establish an audit trail…” (ISO ).
31Are you confident that a PoCT devices will provide a consistent analytical performance? PoCT devices are not covered by any formal accreditation.There are no regulations monitoring the manufacture, use or distribution of PoCTs within the UK or Europe.No ISO accreditation exists for occupational testing.Most Devices are not CE marked.Quality, performance and accuracy vary between different providers and even between batches of devices from the same manufacturer.Don’t forget about Thresholds!
32ConclusionsPoCT devices can only be used as a screening method and require confirmation by a gold standard method such as GC-MS.The use of PoCT devices will always run the risk of false negatives, even if used as part of a screening program. Therefore, PoCT devices should never be used in safety critical environments.Positivity criteria (thresholds) are fixed in PoCT devices, if your positivity criteria is different to that of the PoCT, you cannot use the PoCT device.The lack of accreditation means you cannot be confident of the quality of the devices you purchase. Detection limits may vary causing doubt over threshold levels.PoCTs should only be used by trained operatives.A full chain of custody is not possible with PoCT devices.
34Case StudyMichalakis Michael – LGC LtdApril 2013
35LGC historyOrigins dating back to 1842 as customs laboratory protecting excise duty payable on tobacco importation into the UKCompany established in 1996 on privatisation from government agencyGrown organically and through strategic acquisitionsOrganised in to divisions – Health Sciences, Genomics, Forensics, Standards, Science and Technology35
36LGC locations FINLAND N. IRELAND RUSSIA SWEDEN UK IRELAND POLAND CHINA BoråsFINLANDTurkuBerlinLuckenwaldeAlmereWeselCologneLomiankiBrnoSzentendreCluj-NapocaMolsheimGERMANYCZECH REPUBLICPOLANDHUNGARYROMANIAITALYFRANCEBULGARIASofiaMilanBarcelonaSPAINNETHERLANDSRUSSIASt PetersburgCHINABeijingShanghaiTURKEYIstanbulDubaiINDIAUAEDelhiAhmadabadMumbaiGoaBangaloreHyderabadEdinburghWakefieldLeedsBuryRuncornRisleyTamworthUKCulhamExeterSandwichHoddesdonSt NeotsBelfastN. IRELANDIRELANDFordhamTwickenhamTeddingtonBeverlyUSALexingtonDenverManchesterSao PauloSOUTH AMERICAJohannesburgSOUTH AFRICA36
38Drug Testing Dedicated laboratory established for over 16 years Urine, oral fluid, and hairControlled, prescribed, and ‘legal high’ drugsSteroids and supplementsLegal, clinical, employment sectorsExperienced teamBroader scientific network within LGC
39Case Study Customer background Employ over 50,000 people 2000 pre-employment interviews per annumProfessional workforceHigh specification trainingPre-employment drug testingRandom drug testingFor-cause/Incident drug testingTotal cost to recruit, train, staff downtime = £25,000 per successful candidate
40Historic Testing Approach Previously used a combination test approach (even spread)urine testing (random)urine point of care testing (pre-employment/random)oral fluid (pre-employment)oral fluid point of care testing (pre-employment)Instant resultQuickEasyCheap
42Oral Fluid Detection Advantages Disadvantages No specific facility (i.e. toilet) requiredObserved sampleLow to moderate sample costDisadvantagesShort window of detection (12-24hrs)Collection devices are all different (not universally supported)Inconsistent approach between labsTrue A and B samples questionableContested samples can be problematic
43Urine Detection Advantages Disadvantages Industry standard Low initial sample costRobust and proven proceduresNo shortage of sampleDisadvantagesRequires specific collection facilities (toilet)Not observed sampleLonger collection time if ‘shy bladder’
44Hair Detection Advantages Disadvantages Easy to collect Quick to collectObserved sampleEasy to store and sendLong timeframe available (up to 3 months)DisadvantagesInitial costs are highNot suitable for ‘for-cause’
45Point Of Care Test (POCT) AdvantagesGenerally low cost deviceInitial test result available in few minutesDecision can be taken based on screen resultDisadvantagesNo detailed guidelines for performance criteriaHuge variation in performance between test devicesLess analytical flexibility (i.e. harder to change cut offs)
47Trial Period Hair Testing Urine Testing Oral Fluid POCT Best for pre employment testing (longest window)Policy easier to change as it’s pre-employmentMore expensive initial outlay but expecting to be ‘cost efficient’Urine TestingRandom and for-cause (reasonable window)Policy easy to appease as industry standardCost efficientOral FluidHistorically used but dropped in favour of urine and hairPOCT
48Trial Results 3 month trial Findings Comparison to previous methods Both hair an urine run side by side for pre-employmentFindings2.5% positive rate in urine (overlap with hair)5% positive rate in hairComparison to previous methodsPrior methods (POCT and Oral Fluid) found 0.5% over the previous 3 year periodSimilar (some the same) sample population and conditions to historic populous
49Finance Background Overall costs at 100% selection Average of £25,000 to recruit and train2,000 pre-employment interviewsHair = £90 per testUrine = £30 per testOral Fluid = £30 per testPOCT = £20 per testOverall costs at 100% selectionHair (at 5%) = 2000*90 = £180,000Potential of 100 donors being recruited and £2.5M ‘lost’ (+£2.32M)Urine (at 2.5%) = 2000*30 = £60,000Potential of 50 donors being recruited and £1.25M ‘lost’ (+£1.19M)POCT (at 0.5%) = 2000*20 = £40,000Potential of 10 donors being recruited and £250K ‘lost’ (+£210K)Figures are not actual but representative of cost
50Finance 2 (NOT ACTUALS)100% selection not realistic therefore based on 10% selectionHair (at 5%) = 2000*90 = £180,000Potential of 10 donors being recruited and £250,00 ‘lost’ (+£70K)Urine (at 2.5%) = 2000*30 = £60,000Potential of 5 donors being recruited and £125,000 ‘lost’ (+65K)POCT (at 0.5%) = 2000*20 = £40,000Potential of 1 donor being recruited and £25,000 ‘lost’(-£15K)Recruitment and Training figures do not include loss due toAbsenteeismTheftRelated accidentsLoss of productivityDisciplinary actionsDismissal
51Case Conclusion (Historic) POCT/Oral fluid combinationOral fluid gave too short detection time for pre-employmentPOCT and oral fluid gave a very low (confirmed) positive ratePOCT random testing was viewed as unsuitable due to questions over the integrity of test result and on-site POCT result not essentialPOCT did not offer the flexibility of laboratory testingOften slow collections when dealing with larger numbers of peopleCostCheapest initial cost and met budgetary requirements but…After considering all costs easy to show that it works out as the most expensive option (on recruitment and training alone)
52Customer Conclusion (New) Hair - pre-employmentExcellent window of detectionExcellent ‘positive return’ (5%)Quick and easy to collect, store, and sendMost expensive initial cost but excellent overall value (based on recruitment and training costs alone)Urine – random and for-cause and incidentSuitable window of detectionIndustry standardGood ‘positive return’ (2.5%)Good value initial outlay and good overall valueRequires specific collection facilities (i.e. toilet)Successful programmeMore efficient, cheaper overallMore effective, people aware programme is more effective with higher calibre recruitment
53Questions? Teddington, UK Teddington, UK firstname.lastname@example.org Lexington, USA Wesel, GermanyBury, UKTeddington, UKBeijing, ChinaBangalore, IndiaKyalami, South AfricaLuckenwalde, GermanyTeddington, UK53
55Point of Collection Testing – the Legal Issues Peter FeldschreiberFour New Square, Lincolns Inn
56Relevant technical issues Do the validity, reproducibility, precision sensitivity and specificity of the point of collection (POCT) diagnostic tests for drugs provide the degree of accuracy that such testing for both screening and diagnostic purposes requires in order to satisfy the statutory health and safety legislation ?
57Potential for false positive and false negative test results Potential for false positive and false negative test results. This implies very wide confidence intervals for the statistical values of the point of collection evaluations of urine tests. Such wide confidence intervals would amplify the risk of false results in random testing.Technology of POCT analysis for drugs could enhance the risk of contamination and interaction of chemical analytes with potential for spurious results with different drugs.
58Harm from false positive and from false negative tests (1) Examples of indirect harm include misdiagnosis, delayed diagnosis, delayed treatment, inappropriate treatment, absence of treatment, transfusion of inappropriate materials.Indirect harm may be caused by imprecise results, inadequate quality controls, inadequate calibration, false positive or false negative results
59Harm from false positive and from false negative tests Employers could be liable in negligence for taking action regarding employment of examinees on the basis of both false negative and false positive tests.False positive test resulting in a prospective employee being refused employment on the grounds of alcohol or drug misuse, employer liable in negligence.False negative screening test; subsequently operates machinery under the influence and causes injury or death leading to action for substantial damages, and potentially prosecution e.g. corporate manslaughter.
60InsuranceValidity of insurance contract depends on compliance with statutory health and safety legislation. Potential for failure to mitigate against the risk of unreliable and inaccurate testing. If a test result, originally evaluated as negative, is subsequently found to be unreliable or incorrect and the employee causes injury or death and/or damage in the course of his job, questions as to the applicability and validity of the insurance policies, regarding negligence and possibly product liability may arise.
61Insurance (2)Validity of indemnity insurance for negligence when decisions on employment of persons who subsequently cause loss and/or damage are found to have been employed on the basis of false negative tests. Reliance on technologically flawed tests without due care or process to ensure their accuracy could result in void contracts of insurance. This could result from false negative tests, when an employee was subsequently found to be under the influence of drugs and/or alcohol and also from false positive results if an applicant claimed discrimination if not appointed.
62Obligations of Confidentiality Disclosure of confidential and private information regarding the health and welfare status of the examinee could breach employer’s and relevant medical staff’s obligation of confidentiality.Current legal position is that the obligation of confidence applies where a doctor or medical professional receives information other than in connection with a professional relationship, e.g. medical screening in respect of employment.May have implications for training and qualifications of staff undertaking screening.
63Statutory Obligations Type of testing, sample collection and security of the sample from contamination are specifically referred to in the European Workplace Drug Testing Society Guidelines: ‘1.1 Legally defensible workplace drug testing is a three stage process. The specimen has to be collected, analysed and finally the analytical result has to be correctly interpreted. This all has to be done in the context of ‘Chain of Custody’.1.3 If any one of these three stages has flaws, then the whole process may be invalid.’1.4 Where immediate test results are required, Point of Collection Tests (POCT) can be utilised, but the principles and procedures for specimen collection outlined in these guidelines still apply.’BUT : note the appendix referred to was never drafted!
64POCT testing is explicitly approved, with the caveat that privacy and security is ensured at the specimen collecting site, there is proper identification of the examinee, appropriate steps are taken to protect against tampering and adulteration, there is evidence of written informed consent of the individual and that disclosure of recent medication or evidence that the individual was advised of the significance of recent medication is confirmed. .
65Practical Questions (1) POCT test fails to spot a positive and the person is then involved in an incident. If they are then tested by laboratory analysis and found positive (and if, for example there is serious injury or death on a construction site) what legal sanctions could be taken against the contractor and his Occupational Health Company?
66False negatives – negligence and potential criminal issues If employee operates machinery under the influence drugs/alcohol and causes injury, action for substantial damages. Employer could face potential liability for gross negligence manslaughter. Employer owed duty of care, was in breach of that duty and the breach of duty must have caused the death of the victim. The nature of the breach of duty must have been so bad as to amount to gross negligence with criminal consequences. Jury question. In a foreseeably false negative test missing a dangerous drug level the jury would have to consider whether the extent to which employer’s conduct (in failing to ensure that their testing policy was followed) departed from the proper standard of care incumbent upon them, involving a risk of death, was such that it should be judged criminal. Similarly there is a real possibility of prosecution for corporate manslaughter.
67What would be the legal implications where an employee gives a false positive test via POCT and is suspended pending laboratory confirmatory testing?Could be action in breach of confidenceAlthough suspension is a neutral act, the reputational damage suffered by ‘an employee could cause him to feel that there had been a breakdown in trust and confidence in his relationship with his employer, leaving him no choice but to resign – constructive dismissal
68As regards the duty of confidentiality of the company towards employees in relation to drug testing results, what would be the legal situation whereby contractors designate potentially untrained administrative staff to conduct POCT testing?Current operating system contravenes the EWDTS guidelines. Audit trail for chain of custody sampling demands a robust administrative procedure and mechanisms to ensure privacy and security of the collection site, identification of both the individual and the samples, protection against tampering and adulteration, evidence of informed consent and disclosure of recent medication or evidence that the examinee was advised of the significance of recent medication. In the absence of a qualified, trained and competent individual to collect the test sample, analyse and interpret the results and then have a robust administrative system to handle the test sample(s) appropriately, testing process invalid and potentially legally indefensible in actions in negligence and breach of confidence.
69Point of Collection vs Chain of Custody Immediacy of the result and subsequent lack of a tamper proof and auditable ‘chain of custody’ procedure in POCT testing considerably reduces the protection from disclosure of medical information that is inherent in the conventional sampling and laboratory testing.Inadvertent disclosure of confidential information without the written express consent of the examinee may constitute negligent disclosure
70PoC tests as medical devices Regulated under the In Vitro Devices DirectiveMust comply with essential requirements as specified by appropriate Notified BodyObligations to report incidents of defective performanceBoth false and negative test results constitute ‘incidents’ and may cause indirect harm; must be reported to Notified Body and potentially to competent authority such as MHRA
71CORPORATE GOVERNANCE accurate and reliable results are paramount If company fails to apply sufficiently vigorous governance to regime of testing Board of Directors may be held to be negligent
72CONCLUSIONSFalse positives and false negatives, coupled with unqualified staff reading tests and making employment and/or operating decisions could render employer liable in negligence.Potential insurance issuesPotential criminal liabilitySerious doubts over use of PoC tests as employment screening tools