Toxicology Testing Is it a Good Fit for Your Laboratory? Rebecca Kenner, BA, MT, DLM(ASCP) Leigh Ann Smith, BS, MLS(ASCP), CLS

Transcription

1 Thursday April 6, 2017 B16 Toxicology Testing Is it a Good Fit for Your Laboratory? Rebecca Kenner, BA, MT, DLM(ASCP) Leigh Ann Smith, BS, MLS(ASCP), CLS Global Analytical Development DESCRIPTION: Are you considering expanding your lab services into toxicology testing? With the epidemic of overdoses from Opioid abuse and the recommendation by the CDC to screen and monitor patients prescribed opioid pain medication, Urine drug testing is being implemented across the country. Urine drug testing is being utilized by not only pain management and substance abuse clinics but by physician office laboratories to meet the monitoring standards. This presentation will briefly point out the need for drug testing. It will describe how the facilities use urine drug testing to meet best practice standards. The difference between POCT, immunoassay screening and LCMS/MS testing will be discussed. And finally, this presentation will explain the implementation process focusing on the compliance standards from personnel to validation. OBJECTIVES: At the end of the session, participants will be able to: Describe toxicology testing Summarize important needs for drug screening Outline how the lab fits into best practices in pain management and substance abuse monitoring Describe how the testing is done using immunoassay testing and LCMS/MS confirmation testing Focus on compliance when implementing toxicology services CRI and COLA do not endorse, directly or indirectly, the presentations given at this conference or the products or services provided by the exhibiting vendors. Presentations are intended to be free of bias. The use of any particular product is for demonstration purposes only, and does not imply an endorsement of the product by the presenter or the sponsors of the symposium CRI

2 Toxicology Testing Is this a good fit for your laboratory? Presented by Rebecca Kenner BA, MT, DLM(ASCP) and Leigh Ann Smith BS, MLS(ASCP), CLS CRI Symposium 2017 Who We Are Global Analytical Development has a proven track record of establishing and supporting successful licensed laboratories operating within compliance guidelines. We provide consulting services to support sustainable, compliant-driven lab operations. Credentialed technical consultants Application, licensure, and accreditation Laboratory set up Quality control procedures Audit and inspection support Graph created by Alere Toxicology. 1

3 Objectives Define toxicology testing Describe the need for urine drug testing Understand the differences between various testing methodologies Compliance requirements for high complex testing 2 What is Toxicology Testing? It is the measurement and interpretation of concentrations of drugs and other toxic substances in human biological fluids for the purpose of patient care.

4 History History For thousands of years, opiates have been used to relieve pain. It was originally derived from the opium poppy. Morphine is the active substance. It was named after Morpheus, the Greek god of dreams. Papaver somniferum 5

5 History (cont d) During the 16th century, early chemists created laudanum, an opium tincture prepared in an alcoholic solution (brandy). By the 19 th century, it was available in the pharmacy or general store. Graphic: Library of Congress, 6 History (cont d) Infants were introduced to opiates through breast milk. Harassed babysitters and overworked parents found opium-based preparations were a dependable way to keep their children happy and docile. Graphic created by Alere Toxicology. 7

6 History (cont d) In 1830 codeine, a naturally-occurring methylated morphine, was first isolated to replace raw opium for medical purposes. It was primarily used as a cough remedy. Later in the 19th century, morphine was extracted in its pure form. In 1874 chemists also developed heroin in an effort to create something less addictive than morphine but they ended up developing something with twice the addictive qualities. In 1898, heroin was marketed as a non-addictive cough suppressant. The U.S. banned opium in 1905, and the following year the Pure Food and Drug Act was passed, requiring content labeling on all food and drug products. In 1924 the Heroin Act banned the manufacture, importation, and possession of heroin. 8 Recent History By the late 20th century, a new breed of painkillers hit the market synthetic opiates which mimic the body s natural painkillers. Common names include Vicodin (1984), OxyContin (1995), and Percocet (1999). Since 1999, prescriptions for opioid pain medication have quadrupled. This leads us to where we are today 9

7 The Opioid Epidemic Statistics From 2000 to 2015, more than half a million people died from drug overdoses. Since 2000, the rate of deaths from overdoses has increased 137%. Including a 200% increase in the rate of overdose death involving opioids. In 2014, an estimated 1.9 million people had an opioid use disorder related to prescription pain relievers and an estimated 586,000 had an opioid use disorder related to heroin use. 11

8 Statistics 91 Americans die everyday from an opioid overdose (that includes prescription opioids and heroin). Graphic created by Alere Toxicology. 12 Statistics Centers for Diseases Control and Prevention, IMS, National Prescription Audit (NPA ),

9 Overdose Death Rates Centers for Diseases Control and Prevention, National Vital Statistics System Increase in Regulatory Support and Funding Protecting Our Infants Act of 2015 CARA Comprehensive Addiction Recovery Act Medicaid expansion for Substance Use Disorders (SUD) New guidelines for testing and monitoring $ 15

10 Federal Support The Centers for Disease Control and Prevention (CDC) released new opioid guidelines on March 15, This new guideline is for primary care providers who account for prescribing nearly half of all opioid prescriptions treating adult patients for chronic pain in outpatient settings. It is not intended for guiding treatment of patients in active cancer treatment, palliative care, or end-of-life care. Urine Drug Testing (UDT) plays import role in managing prescription opioid use. 16 CDC Recommendations When prescribing opioids for chronic pain, clinicians should use urine drug testing before starting opioid therapy. Consider urine drug testing at least annually to assess for prescribed medications as well as other controlled prescription and illicit drugs. 17

11 New Guidelines Pain management Addiction treatment The National Academy of Clinical Biochemistry Presents LABORATORY MEDICINE PRACTICE GUIDELINES Using Clinical Laboratory Tests to Monitor Drug Therapy in Pain Management Patients Graphic created by Alere Toxicology. 18 Why is Drug Testing Necessary? Statistics National drug epidemic Changing regulations Increased government support National organizations: new guidance and recommendations: CDC 1, ASAM 2, SAMSHA 3, NIDA 4, and AACC 5 1. Centers for Disease Control and Prevention (CDC) 2. American Society of Addiction Medicine (ASAM) 3. Substance Abuse and Mental Health Services Administration (SAMSHA) 4. National Institute on Drug Abuse (NIDA) 5. American Association for Clinical Chemistry (AACC) 19

12 Where is Drug Testing Relevant? Primary care Pain management Substance abuse Rehabilitation Detoxification Addiction medicine Other Rural health clinics Obstetrics (OB) 20 Use of UDT in Primary Care Unexplained symptoms or unexpected response to treatment Evaluating patient in psychiatric care for substance abuse issues before prescribing psychoactive medications Identification of potential substance abuse problems in women who are pregnant or planning on becoming pregnant Identifying patients with possible substance abuse issues Monitoring patients in substance abuse programs Ensuring patient safety prior to surgery or other invasive procedure, to prevent medication interactions Managing patients with prescribed opioids for chronic pain Monitoring potentially addictive prescription use (sedatives, tranquillizers and medication for attention deficient disorders) 21

13 Use of UDT in Pain Management Drug testing in pain management clinics is used to determine: Whether the patient is taking the pain medication as prescribed Whether the patient is abusing other substances Opioids are drugs that produce analgesia through interaction with opioid receptors found in the central nervous system. Benzodiazepines are psychoactive drugs that are often taken by chronic pain patients to improve sleep, relax musculature, and relieve anxiety that may be attributed to or exacerbate the sensation of pain. 22 Substance Use Disorders (SUD) SAMSHA s recommended treatment plan for drug testing in Substance Use Disorders (SUD): Baseline drug levels are a component of the initial assessment of a patient being evaluated for a diagnosis of an SUD Screen to prevent potential adverse effects of pharmacotherapy (e.g., opioid screen prior to starting naltrexone) A way to monitor the patient s use of illicit substances (including illegal drugs and non-medical use of prescription drugs) Adherence to pharmacotherapy treatment for SUDs and a way to assess the efficacy of the treatment plan (i.e., level of care) 23

14 Types of Opioid Pain Medications Natural (derived from the opium poppy): Codeine and Morphine Semi-Synthetic: Hydromorphone, Hydrocodone, Oxycodone, Oxymorphone, and Heroin Synthetic: Fentanyl, Methadone, Tramadol, Propoxyphene, Buprenorphine, and Meperidine 24 Examples of Metabolism of Opioids Codeine Morphine 6-AM Heroin t ½ = mins t ½ = 3-5 mins Hydrocodone Hydromorphone Oxycodone Oxymorphone Not comprehensive pathways, but may explain presence of apparently unprescribed drugs Graphic created by Alere Toxicology. 25

15 Major Opioid Metabolites Opioid Inactive metabolites Acive metabolites indentical to pharmaceutical opioids Active metabolites that are not pharmaceutical opioids Morphine Normorphine Hydromorphone 1 Morphone-3-G glucuronide Morphone-6-G glucuronide Hydromorphone Minor metabollites None Hydromorphone-3-glucuronide Hydrocodone Norhydrocodone Hydromorphone None Codeine Norcodeine Hydrocodone Morphine None Oxycodone None Oxymorphone Noroxycodone Oxymorphone Oxymorphone-3-glucuronide None 6-Hydroxy-oxymorphone Fentanyl Norfentanyl None None Tramadol Nortramadol None O-desmethyltramadol Methadone 2-Ethylidene-1,5-dimethyl-3,3- diphenylpyrrolidine 2-Ethyl-5-methyl-3,3-diphenylpyrroline None None Heroin Normorphine Morphine 6-Monoacetylmorphine 1. Only very low levels are seen in the urine: less than 11% for hydrocodone after codeine administration and less than 2.5% for hydromorphone after morphine administration. Graphic created by Alere Toxicology. 26 Major Benzodiazepines Metabolites Benzodiazepines (generic name) Trade name example Duration of parent drug activity Metabolite examples found in urine Alprazolam Xanax Intermediate Alpha-hydroxyalprazolam Chlordiazepoxide Librium Pro-drug Nordiazepam Clonazepam Klonopin Intermediate 7-aminoclonazepam Diazepam Valium Long-acting Nordiazepam and Temazepam, both of which metabolize into Oxazepam Flunitrazepam Rohypnol Intermediate 7-aminoflunitrazepam Flurazepam Dalmane Short-acting Desalkylflurazepam, 2-hydroxyethylflurazepam Lorazepam Ativan Short-acting Lorazepam glucuronide Midazolam Versed Short-acting Alpha-hydroxymidazolam Nordiazepam Long-acting Oxazepam Oxazepam Serax Short-acting Oxazepam glucuronide (liberated by hydrolysis treatment) Prazepam Centrac Long-acting Nordiazepam Temazepam Restoril Intermediate Oxazepam Triazolam Halcion Short-acting Alpha-hydroxytriazolam Graphic created by Alere Toxicology. 27

16 Use and Detection Marijuana metabolite single use 2-8 days chronic use days Cocaine hours beginning 2-4 days Opioid metabolites heroin 40 mins 6-AM 4-12 hours codeine/ morphine 2-3 days oxycodone 2-4 days methodone 3-6 days Amphetamine amphetamine 1-2 days methamphetamine 3-4 days Benzodiazepines short-acting 3 days long-acting 30 days Barbiturates short-acting 1 day long-acting 21 days Alcohol 7-12 hours Ethyl glucuronide > 72 hours Graphic created by Alere Toxicology. 28 If It Could Only Be This Easy Graphic created by Alere Toxicology. 29

17 Drug Screening Overview of Drug Testing Drug screening Detects chemical classes in a drug sample Qualitative or semi-quantitative Performed using immunoassay principles Screening can be performed as POCT cup or by instrumentation Confirmation and Quantitation Detects and identifies the actual drug compound present in a sample Quantifies the amount of target compound present in the sample Performed using gas chromatography mass spectrometry (GC-MS) or liquid chromatography tandem mass spectrometry (LC-MS/MS) 31

18 Why Bother with Drug Screening? Provides timely results for clinicians. Which improves patient care and communication by managing the misuse and diversion risks associated with select medications. To verify patient self-report of medication history. Is a prescribed drug present? Is anything else unexpectedly present? To encourage or reinforce healthy behavioral change, or sometimes as a requirement of continued treatment. 32 Drug Screening Tests Screening tests are based on immunoassay techniques. The majority of POC screening tests use test strips. Higher incidence of false positives Limited test panel availability Inconsistent interpretation of result Instrument screening tests use liquid reagents. More selective, i.e. fewer false positives Larger number of drug classes available, including newer drugs such as carisoprodol (SOMA ), fentanyl, zolpidem (Ambien ), and Spice/K2 Consistent results 33

19 Point of Care Testing (POCT) Point of Care Testing (POCT) POCT refers to any testing performed outside the traditional laboratory, such as a physician office, rehabilitation facility, emergency department, or urgent care. Many clinical rapid screening devices are categorized as CLIA-Waived and may be used by laboratories with a CLIA certificate. Instrumentation is available and can be considered point of care: It is not considered waived. It follows non-waived compliance criteria. 35

20 Pros and Cons of Using Waived Drug Screening Systems Pros Convenient and portable Reduced wait time and immediate clinician consultation Fast turnaround time No special personnel requirements Minimal CLIA requirements Cons Cost is higher Minimum use of quality assurance and control processes Less sensitive & less specific than analyzer with reagents, resulting in false positive or false negative Some drugs have higher cutoffs on the waived method Limited test panel to 12 drug classes Limited data management systems Graphic created by Alere Toxicology. 36 Screening Instrumentation

21 Advantages of Screening Instrumentation Consistency of patient results. Standardization of testing procedure: Same sample size Instrument monitored timing Daily quality control Higher sensitivity and specificity. Broader test menu. Pertinent patient cutoffs. 38 Test Menu Available Sample Validity ph Chromate Creatinine Oxidant Nitrite Specific Gravity Drug Screening 6-AM Alcohol Amphetamine Barbiturates Benzodiazepines Benzoylecgonine (Cocaine Metabolite) Buprenorphine Cannabinoids (THC) Carisoprodol EDDP (Methadone Metabolite) Ethyl Glucuronide Fentanyl Ketamine Meperidine Methadone Methamphetamine Opiates Oxycodone Phencyclidine (PCP) Propoxyphene Synthetic Cannabinoids Tapentadol Tricyclic Antidepressants (TCA) Tramadol Zolpidem 39

22 Enzyme Immunoassays (EIA) EIAs are biochemical tests that measure the concentration of a substance in a biological liquid (typically serum, plasma, saliva and urine) using the reaction of an antibody or antibodies in the reagent to its antigen (target drug) in the sample. Lock and Key type model reaction. In drug screening, antibodies target a specific analyte (or drug class). 40 Adulteration

23 Adulterants A substance a patient adds to the specimen to mask the presence of the drug or drug metabolite in the specimen. Usually people try to cheat drug testing by three different ways: Substituting their urine with synthetic urine or drug-free urine purchased from a clandestine source. Drinking a commercially available product to flush out drugs (overhydration rapidly fills the bladder with water to dilute the drugs and metabolites). Adding an adulterant in vitro to the urine specimen after collection. 42 Specimen Validity Tests Specimen validity tests determine whether a urine specimen has been diluted, adulterated or substituted to obtain a negative result. It is not required in the clinical settings, but in their recent publication LABORATORY MEDICINE PRACTICE GUIDELINES: Using Clinical Laboratory Tests to Monitor Drug Therapy in Pain Management Patients, The National Academy of Clinical Biochemistry suggests validity testing be performed prior to testing for drugs in the urine sample. Do not test sample if adulteration is suspected. 43

24 Types of Validity Testing ph: specimen adulteration should be suspected if the ph level is less than 3.0 or greater than 11.0 Creatinine: If the creatinine is less than 20 mg/dl, specific gravity testing should be performed Specific gravity: Only specimens whose urine creatinine is less then 20 mg/dl need to be reflexively tested. Specimens with a low creatinine and an abnormal specific gravity may be reported as dilute, invalid or substituted depending on the laboratory s reporting policy Oxidants: detects the presence bleach, nitrite, chromate, iodate and peroxidase. These are common ingredients of commercially available adulterants used to inhibit or mask the screening results Nitrite: a sample is considered adulterated if the nitrite concentration is > 500 mg/l Urine temperature: F 44 Confirmation Instrumentation

25 When to Confirm To detect specific drugs that cannot be identified on standard immunoassays The presence of unexpected urine drug test results, according to the new CDC guidance To be able to identify between drugs in a class 46 Confirmation Testing Generally performed using LC-MS/MS technology Turnaround time is usually 3-5 days from collection Results are specific for the drug and drug metabolite High specificity and sensitivity Results are quantitative, high complex, and considered laboratory-developed testing 47

26 Regulatory Compliance Compliance Requirements Personnel standards High complexity requirements Validation standards Lab developed testing 49

27 Personnel High Complexity Personnel Position Laboratory Director Requirements 1. Licensed MD 1 / DO 2 / DPM 3 AND certified in anatomic or clinical pathology OR 1 year of lab training during medical residency OR 2 years experience directing or supervising high complexity testing 2. Doctoral degree in laboratory science AND certified by an HHS 4 -approved board OR prior to 02/24/2003, served as Lab Director AND 2 years lab training or experience AND 2 years experience supervising or directing high complexity testing 1. Doctor of Medicine (MD) 2. Doctor of Osteopathic Medicine (DO) 3. Doctor of Podiatric Medicine (DPM) 4. U.S. Department of Health & Human Services (HHS) 51

28 High Complexity Personnel Position Technical Supervisor Requirements 1. Licensed MD/DO/DPM or PhD AND certified in clinical pathology OR 1 year lab training or experience in the high complexity testing specialties performed 2. Master s degree in lab science AND 2 years lab training or experience in the high complexity testing specialties performed 3. Bachelor s degree in lab science AND 4 years lab training or experience in the high complexity testing specialties performed 4. Additional COLA requirement: must have 1 year of LC-MS/MS hands-on experience 52 High Complexity Personnel Position General Supervisor Requirements 1. Qualified Lab Director or Technical Supervisor of high complexity testing 2. Licensed MD/DO/DPM, or have a Doctoral, Master s, or Bachelor s degree in lab science AND 1 year laboratory training or experience in high complexity testing 3. Qualified as Testing Personnel for high complexity testing AND at least 2 years laboratory training or experience in high complexity testing 4. Previously qualified as General Supervisor on or before 02/28/

29 High Complexity Personnel Position Testing Personnel Requirements 1. Licensed MD/DO/DPM 2. Doctoral, Master s, Bachelor s or Associate s degree in laboratory science 3. Have education equivalent to an Associate s degree AND graduated from a clinical laboratory training program OR have 3 months experience in each specialty of high complexity testing performed 4. Prior to 04/24/1995, High School graduate or equivalent AND graduated from an HHS-approved lab training program OR completed military Medical Lab Specialist (50 week) course 5. Prior to 04/24/1995, High School graduate or equivalent AND documentation of training for high complexity testing AND if training before 01/19/93, on-site supervision is required when high complexity testing is performed 54 Validation Requirements

30 CLIA 1 Standard D (b)(2) Establishment of performance specifications. Each laboratory that modifies a test system cleared for U.S. market, or introduces a test system not subject to clearance or approval (including methods developed in-house and standardized methods such as text book procedures), or uses a test system in which performance specifications are not provided by the manufacturer must, before reporting patient test results, establish for each test system the performance specifications for the following performance characteristics, as applicable. 1. Clinical Laboratory Improvement Amendments (CLIA) 56 CLIA Validation Requirements Requirements Accuracy Precision Reportable Range Sensitivity Specificity Any other performance characteristics required for verifying test performance Reference Range (not applicable for drug detection) Determination of calibration and QC frequencies COLA Criteria VER 1 5 VER 6 VER 7 VER 9 VER 10 VER 11 VER 8 VER Verification of performance standards (VER) 57

31 CLIA Validation Requirements Must start with a written validation plan 58 Validation Plan A validation plan should include: All experiments required for method validation Detailed instructions describing how the experiments will be performed Supplies and reagents needed Calibrator and QC number and concentrations Acceptability criteria for evaluation of raw data (this should be based on appropriate guidelines) 59

32 Method Validation: High Complexity Testing Qualitative Validation Requirements Qualitative Accuracy Verified by testing samples with known values and comparing results Precision Verifies that results can be repeated on day-to-day, run-to-run, and within runs Analytical sensitivity The lowest concentration that can be differentiated from the cutoff point for a positive result Specificity The ability to find the presence of a target compound in a sample Sample storage stability (room temp, refrigerated, frozen) Interfering substances Carryover assessment 61

33 Method Validation: High Complexity Testing Quantitative LC-MS/MS Specific Components of the LC-MS/MS 1 Method Validation Accuracy Verified by testing samples with known values and comparing results Precision LOQ 2 and LOD 3 Determinations (S/N ratio of the LLOQ 10:1) Linearity Carryover Assessment Matrix Effect (Ion suppression) Cross Talk Evaluation of structurally-related molecules Interference Testing Ion Ratio Monitoring Stability 1. Liquid chromatography tandem mass spectrometry (LC-MS/MS) 2. limit of quantitation (LOQ) 3. limit of detection (LOD) 63

34 Primary References for LC-MS/MS Method Validation CLSI 1 Guidelines Liquid chromatography tandem mass spectrometry (LC-MS/MS) methods Mass spectrometry in the clinical lab Stability of in-vitro diagnostic reagents CLSI Document C62-A C50-A EP25-A 1. Clinical & Laboratory Standards Institute (CLSI) 64 Primary References for LC-MS/MS Method Validation (cont d) CLSI Guidelines Precision Accuracy Analytical measurement range LoB, LoD, LLoQ Total analytical error Interference testing CLSI Document EP05-A3 EP09-A3 EP06-A EP17-A2 EP21-A EP07-A2 65

35 Additional References for Method Validations FDA Guidance for Industry: Bioanalytical Method Validation, May 2001 CLIA-Compliant Analytical Method Validation Plan and Template for LRN-C Laboratories, December 2013 Scientific Working Group for Forensic Toxicology (SWGTOX) Standard Practices for Method Validation in Forensic Toxicology, Evaluation of the Validation Data Once the validation experiments have been completed you must evaluate the data and compile it in a format that demonstrates you have met your acceptability criteria that is stated in your validation plan, for all components of the plan. The validation must be approved by your Technical Supervisor and Lab Director. 67

36 Additional Compliance Requirements Must have detailed procedures for reagent preparation. Include: controls, calibrators, solvents, internal standard working solutions, and hydrolysis reagent. (APM 6, MA 1) Procedure for the validation of new lots of in house prepared reagents, controls, and calibrators. (APM 6) Documentation process to record validations of reagents and standards use. (APM 7) Instructions for performing calibrations. Must include acceptability limits. Criteria for dropping calibration points. (APM 7) 68 Additional Compliance Requirements (cont d) QC procedure defines limit of acceptability, number, type, frequency of performance. Review criteria. (APM 8) Procedure for corrective actions for QC or calibration failure. (APM 9) Establish a maintenance program and documentation process to record required daily function checks and required maintenance. (MA 17) Step by step instructions for performing testing. Must include sample prep and criteria for interpreting test results. (APM 10) 69

37 Additional Compliance Requirements (cont d) Written instruction for specimen collection, labeling and conditions regarding specimen transport available for your clients. (PRE 11) Written policies and procedures for collection, handling, transportation, and storage of specimens. (PRE 12) Proficiency Testing. Enrollment in a module that is consistent with type of testing performed. If performing quantitative testing don t enroll in a qualitative module. Split sample testing procedure to cover drugs not included in PT. (PT 4) 70 Summary The opioid overdose epidemic is real. Pain management and rehabilitation are not the only practices that monitor drug use. Any practitioner who prescribes drugs is required to monitor. The laboratory testing is a integral component in monitoring patient compliance. This can be done through screening and confirmation testing. All testing must follow CLIA guidelines. 71

38 Any questions? 72 References CDC Morbidity and Mortality Weekly Report (MMWR): Increases in Drug and Opioid Overdose Deaths United States, SAMSHA SAMSHA Technical Assistance Publication 32 CDC Guidelines for Prescribing Opioids for Chronic Pain, US American Society of Addiction Medicine pdf AACC: How People Try to Beat Drug Testing The National Academy of Clinical Biochemistry, Laboratory Medicine Practice Guidelines: Using Clinical Laboratory Tests to Monitor Drug Therapy in Pain Management Patients, July

39 Waived Testing References For a list of waived tests sorted by analyte name, visit the FDA website at: For a list of waived tests sorted by the test categorization date and by the test system name, visit the FDA website at: 74 Knowing now matters gadevelop.com 2017 Global Analytical Development. All rights reserved. Global Analytical Development and Knowing now matters are trademarks of the Alere group of companies. All other trademarks referenced are trademarks of their respective owners. Photos are for illustrative purposes only. Any person depicted in photos is a model. MKT50506 REV1 3/17