Immunalysis EDDP Specific Urine Enzyme Immunoassay, Immunalysis EDDP Urine Calibrators, Immunalysis EDDP Urine Control Sets

{0} 1 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY ASSAY ONLY TEMPLATE A. 510(k) Number: K151395 B. Purpose for Submission: New device C. Measurand: EDDP (2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine) D. Type of Test: Homogenous Enzyme Immunoassay, Qualitative and Semi-quantitative. E. Applicant: Immunalysis Corporation F. Proprietary and Established Names: Immunalysis EDDP Specific Urine Enzyme Immunoassay Immunalysis EDDP Urine Calibrators Immunalysis EDDP Urine Control Sets G. Regulatory Information: 1. Regulation section: 21 CFR 862.3620, Enzyme Immunoassay, Methadone 21 CFR 862.3200, Calibrator, Drug Specific 21 CFR 862.3280, Drug Specific Control Materials 2. Classification: Class II Class I, reserved 3. Product code: DJR DLJ LAS 4. Panel: Toxicology (91) H. Intended Use: 1. Intended use(s): See Indications for use below. 2. Indication(s) for use: {1} 2 Immunalysis EDDP Specific Urine Enzyme Immunoassay The Immunalysis EDDP Specific Urine Enzyme Immunoassay is a homogeneous enzyme immunoassay with cutoffs of 100ng/mL, 300ng/mL and 1000ng/mL. The assay is intended for use in laboratories for the qualitative and semiquantitative analysis of EDDP in human urine with automated clinical chemistry analyzers. The 100ng/mL and 300ng/mL cutoff is for qualitative and semi-quantitative analysis. The 1000ng/mL cutoff is for qualitative analysis only. This assay is calibrated against EDDP. This in-vitro device is for prescription use only. The semi-quantitative mode is for purposes of enabling laboratories to determine an appropriate dilution of the specimen for confirmation by a confirmatory method such as GC-MS or permitting laboratories to establish quality control procedures. The Immunalysis EDDP Specific Urine Enzyme Immunoassay Kit provides only a preliminary analytical test result. A more specific alternate chemical method must be used in order to obtain a confirmed analytical result. Gas Chromatography/ Mass Spectrometry (GC-MS) or Liquid Chromatography/Tandem Mass Spectrometry (LC-MS/MS) is the preferred confirmatory method. Clinical consideration and professional judgment should be applied to any drug of abuse test result, particularly when preliminary positive results are used. Immunalysis EDDP Urine Control Sets The Immunalysis EDDP Urine Control Sets are used as control materials in Immunalysis EDDP Specific Urine Enzyme Immunoassay. Immunalysis EDDP Urine Calibrators The Immunalysis EDDP Urine Calibrators are used as calibrators in the Immunalysis EDDP Specific Urine Enzyme Immunoassay for the qualitative and semi-quantitative determination of EDDP in urine on automated clinical chemistry analyzers. 3. Special conditions for use statement(s): For prescription use only. Not for use in Point of Care settings. 4. Special instrument requirements: Beckman Coulter AU 400e chemistry analyzer was used to generate data for this submission. Automated clinical chemistry analyzers capable of maintaining a constant reaction temperature, pipetting samples and reagents, mixing reagents, timing reactions and measuring enzyme rates at 340nm can be used for the assay. I. Device Description: Immunalysis EDDP Specific Urine Enzyme Immunoassay (EIA) Kit includes antibody/ substrate reagent and enzyme conjugate reagent. - Antibody/ substrate reagent includes recombinant fab antibodies to EDDP, glucose-6-phosphate (G6P) and nicotinamide adenine dinucleotide (NAD) in Tris buffer with {2} Sodium Azide as a preservative. - Enzyme conjugate reagent includes EDDP derivative labeled with glucose-6-phosphate dehydrogenase (G6PDH) in Tris buffer with Sodium Azide as a preservative. Calibrators and controls are sold as individual bottles. The EDDP calibrators and control sets consist of: - Negative Calibrator – a processed, drug-free synthetic urine matrix with sodium azide as a preservative. - Immunalysis EDDP Urine Calibrator – Level 1 containing 100ng/mL of EDDP - Immunalysis EDDP Urine Calibrator – Level 2 containing 300ng/mL of EDDP - Immunalysis EDDP Urine Calibrator – Level 3 containing 500ng/mL of EDDP - Immunalysis EDDP Urine Calibrator – Level 4 containing 1000ng/mL of EDDP - Immunalysis EDDP Urine Control Set 1 containing LOW (75ng/mL) and HIGH (125ng/mL) controls for a cutoff of 100ng/mL of EDDP - Immunalysis EDDP Urine Control Set 2 containing LOW (225ng/mL) and HIGH (375ng/mL) controls for a cutoff of 300ng/mL of EDDP - Immunalysis EDDP Urine Control Set 3 containing LOW (750ng/mL) and HIGH (1250ng/mL) controls for a cutoff of 1000ng/mL of EDDP All calibrator and control solutions are prepared from drug-free synthetic urine matrix and commercially available, DEA exempt, EDDP drug standard obtained from a commercial sources. All reagents are sold in liquid form and ready to use. J. Substantial Equivalence Information: 1. Predicate device name(s): DRI® Methadone Metabolite Enzyme Assay DRI® Methadone Metabolite Urine Calibrators and Controls 2. Predicate 510(k) number(s): K023617 3. Comparison with predicate: {3} | Item | Immunalysis EDDP Specific Urine Enzyme Immunoassay (Candidate Device) | DRI® Methadone Metabolite Enzyme Immunoassay, k023617 (Predicate Device) | | --- | --- | --- | | Intended use | For the qualitative and semi-quantitative determination of the presence of EDDP in human urine. For in vitro diagnostic use. | Same | | Measured analyte(s) | EDDP | Same | | Assay cutoff | 100ng/mL, 300ng/mL and 1000ng/mL of EDDP | 300ng/mL and 1000ng/mL of EDDP | | Assay calibrated against | EDDP | Same | | Test system type | Homogenous enzyme immunoassay | Same | | Antibody type | Recombinant fab antibodies to EDDP | Mouse monoclonal antibodies to EDDP | | Storage conditions | 2 - 8°C until expiration date | Same | | Calibrator form | Liquid | Same | | Calibrator levels | 0, 100, 300, 500 and 1000 ng/mL of EDDP | 0, 150, 300, 500, 1000, 1500 and 2000 ng/mL of EDDP | | Control set levels | For 100 ng/mL cutoff, the set contains 75 ng/mL and 125 ng/mL level of EDDP. For 300 ng/mL cutoff, the set contains 225 ng/mL and 375 ng/mL level of EDDP. For 1000 ng/mL cutoff, the set contains 750 ng/mL and 1250 ng/mL level of EDDP. | For 1000 ng/mL cutoff, the set contains 750 ng/mL and 1250 ng/mL level of EDDP. For 300 ng/mL cutoff, the calibrators at 150 ng/mL and 500 ng/mL levels of EDDP are used as controls. | K. Standard/Guidance Document Referenced (if applicable): - CLSI EP5-A2: Evaluation of Precision Performance of Quantitative Measurement Methods. - CLSI EP7-A2: Interference Testing in Clinical Chemistry {4} 5 L. Test Principle: The assay is based on the competition of EDDP labeled enzyme glucose-6-phosphate dehydrogenase (G6PDH) and the free EDDP in the urine sample for the fixed amount of antibody binding sites. In the absence of the free EDDP in the urine sample, the antibody (recombinant antibody) binds the EDDP enzyme conjugate and enzyme activity is inhibited. This creates a dose response relationship between EDDP concentration in the urine and enzyme activity. The enzyme G6PDH activity is determined at 340 nm spectrophotometrically by the conversion of NAD to NADH. M. Performance Characteristics (if/when applicable): All the performance studies were performed on the Beckman Coulter AU 400e chemistry analyzer. 1. Analytical performance: NOTE: the 1000 ng/mL cutoff is for qualitative analysis only. a. Precision/Reproducibility: A precision study was performed by one experienced operator following the CLSI (EP5-A2) precision guidelines. Drug free negative urine was spiked with EDDP to concentrations representing 0, 25, 50, 75, 100, 125, 150, 175 and 200% of the device cutoff (100ng/mL, 300ng/mL and 1000ng/mL). Each level sample was tested in duplicate per run, two runs per day for twenty days (total N= 80/level) on the Beckman Coulter AU 400e chemistry analyzer. The results are summarized in the table below: Qualitative Precision Result for 100ng/mL cutoff: | Concentration as % of the Cutoff Level | Target EDDP concentration (ng/mL) | Immunalysis EDDP Urine EIA # Neg / # Pos | | --- | --- | --- | | 0 | 0 | 80 Neg / 0 Pos | | 25 | 25 | 80 Neg / 0 Pos | | 50 | 50 | 80 Neg / 0 Pos | | 75 | 75 | 80 Neg / 0 Pos | | 100 | 100 | 43 Neg / 37 Pos | | 125 | 125 | 0 Neg / 80 Pos | | 150 | 150 | 0 Neg / 80 Pos | | 175 | 175 | 0 Neg / 80 Pos | | 200 | 200 | 0 Neg / 80 Pos | {5} Qualitative Precision Result for 300ng/mL cutoff: | Concentration as % of the Cutoff Level | Target EDDP concentration (ng/mL) | Immunalysis EDDP Urine EIA # Neg / # Pos | | --- | --- | --- | | 0 | 0 | 80 Neg / 0 Pos | | 25 | 75 | 80 Neg / 0 Pos | | 50 | 150 | 80 Neg / 0 Pos | | 75 | 225 | 80 Neg / 0 Pos | | 100 | 300 | 40 Neg / 40 Pos | | 125 | 375 | 0 Neg / 80 Pos | | 150 | 450 | 0 Neg / 80 Pos | | 175 | 525 | 0 Neg / 80 Pos | | 200 | 600 | 0 Neg / 80 Pos | Qualitative Precision Result for 1000ng/mL cutoff: | Concentration as % of the Cutoff Level | Target EDDP concentration (ng/mL) | Immunalysis EDDP Urine EIA # Neg / # Pos | | --- | --- | --- | | 0 | 0 | 80 Neg / 0 Pos | | 25 | 250 | 80 Neg / 0 Pos | | 50 | 500 | 80 Neg / 0 Pos | | 75 | 750 | 80 Neg / 0 Pos | | 100 | 1000 | 46 Neg / 34 Pos | | 125 | 1250 | 0 Neg / 80 Pos | | 150 | 1500 | 0 Neg / 80 Pos | | 175 | 1750 | 0 Neg / 80 Pos | | 200 | 2000 | 0 Neg / 80 Pos | {6} Semi-Quantitative Precision Result for 100ng/mL cutoff: | Concentration as % of the Cutoff Level | Target EDDP concentration (ng/mL) | Immunalysis EDDP Urine EIA # Neg / # Pos | | --- | --- | --- | | 0 | 0 | 80 Neg / 0 Pos | | 25 | 25 | 80 Neg / 0 Pos | | 50 | 50 | 80 Neg / 0 Pos | | 75 | 75 | 80 Neg / 0 Pos | | 100 | 100 | 10 Neg / 70 Pos | | 125 | 125 | 0 Neg / 80 Pos | | 150 | 150 | 0 Neg / 80 Pos | | 175 | 175 | 0 Neg / 80 Pos | | 200 | 200 | 0 Neg / 80 Pos | Semi-Quantitative Precision Result for 300ng/mL cutoff: | Concentration as % of the Cutoff Level | Target EDDP concentration (ng/mL) | Immunalysis EDDP Urine EIA # Neg / # Pos | | --- | --- | --- | | 0 | 0 | 80 Neg / 0 Pos | | 25 | 75 | 80 Neg / 0 Pos | | 50 | 150 | 80 Neg / 0 Pos | | 75 | 225 | 80 Neg / 0 Pos | | 100 | 300 | 13 Neg / 67 Pos | | 125 | 375 | 0 Neg / 80 Pos | | 150 | 450 | 0 Neg / 80 Pos | | 175 | 525 | 0 Neg / 80 Pos | | 200 | 600 | 0 Neg / 80 Pos | b. Linearity/assay reportable range: Linearity study in the semi-quantitative mode was conducted by spiking drug free urine pool with EDDP (serial dilutions of a high concentration EDDP in urine in increments of 10%) to achieve concentrations ranging from 0ng/mL to 1100ng/mL, and testing each level in triplicate on the Beckman Coulter AU 400e clinical {7} chemistry analyzer. The results of the linearity/recovery study are summarized below: | Expected Concentration (ng/mL) | Mean Concentration (ng/mL) | Recovery (%) | | --- | --- | --- | | 0 | 2.3 | N/A | | 100 | 109.5 | 109.5 | | 200 | 203.8 | 101.9 | | 300 | 292.7 | 97.6 | | 400 | 413.4 | 103.4 | | 500 | 492.2 | 98.4 | | 600 | 638.0 | 106.3 | | 700 | 746.0 | 106.6 | | 800 | 833.7 | 104.2 | | 900 | 926.1 | 102.9 | | 1000 | 980.0 | 98.0 | | 1100 | 1037.8 | 94.3 | c. Traceability, Stability, Expected values (controls, calibrators, or methods): Traceability Calibrators and controls are prepared from a standard solution of EDDP purchased from a commercial vendor. This standard solution is diluted with drug-free synthetic urine matrix to make the three control sets of low and high controls, and calibrator set (of 5 level calibrators). The concentrations of the prepared solutions are confirmed by GC/MS or LC/MS/MS. Value Assignment - Calibrators and Controls A commercially available standard solution of EDDP is mixed with a commercially available drug-free synthetic urine matrix to the desired calculated concentrations for the LOW and HIGH controls for the three cutoffs and the calibrators. The calibrators and controls are tested by GC/MS or LC/MS/MS. Values are assigned to the controls once the GC/MS or LC/MS/MS results are within acceptable ranges. The negative standard is prepared with the drug-free synthetic urine matrix. The negative standard {8} is compared to a reference negative standard to ensure that it is free of EDDP. Value is assigned when the test result is within the acceptable range. Acceptance criteria for value assignment were reviewed and deemed acceptable. ## Calibrators and Controls Stability Studies Accelerated and real-time stability studies in the qualitative and semi-quantitative modes were conducted on multiple lots of Immunalysis EDDP Urine Controls and Immunalysis EDDP Urine Calibrators. The stability protocols and acceptance criteria for open and closed vial were reviewed and found acceptable. The open vial and closed vial study results support the open vial stability claim of twelve months and closed vial stability claim of twelve months when stored at 2 to 8 °C for the Immunalysis EDDP Urine Controls and Immunalysis EDDP Urine Calibrators. ## d. Detection limit: Not applicable. ## e. Analytical specificity: The sponsor performed studies at all claimed cutoffs in both qualitative and semi-quantitative modes to evaluate the cross-reactivity of compounds that are structurally related to EDDP. Results are summarized below: | Structurally Related Compounds at 100 ng/mL cutoff - Qualitative | | | | --- | --- | --- | | Compound | Concentration Tested (ng/mL) | Cross-reactivity (%) | | EDDP | 100 | 100 | | Methadone | 700,000 | 0.01 | | EMDP | 1,000,000 | <0.01 | | Chlorpromazine | 90,000 | 0.11 | | Diphenhydramine | 1,000,000 | 0.01 | | Methylphenidate | 100,000 | 0.10 | | Doxylamine | 1,000,000 | <0.01 | | LAAM | 1,000,000 | <0.01 | | (±)-alpha methadol | 1,000,000 | 0.01 | | (-)-iso-methadone | 100,000 | <0.1 | | Structurally Related Compounds at 300 ng/mL cutoff - Qualitative | | | | --- | --- | --- | | Compound | Concentration Tested (ng/mL) | Cross-reactivity (%) | | EDDP | 300 | 100 | | Methadone | 1,000,000 | <0.03 | | EMDP | 1,000,000 | <0.03 | | Chlorpromazine | 300,000 | 0.1 | | Diphenhydramine | 1,000,000 | <0.03 | | Methylphenidate | 360,000 | 0.08 | | Doxylamine | 1,000,000 | <0.03 | | LAAM | 1,000,000 | <0.03 | {9} | Structurally Related Compounds at 100 ng/mL cutoff - Semi-quantitative | | | | --- | --- | --- | | Compound | Concentration Tested (ng/mL) | Cross-reactivity (%) | | EDDP | 100 | 100 | | Methadone | 700,000 | 0.01 | | EMDP | 1,000,000 | <0.01 | | Chlorpromazine | 90,000 | 0.11 | | Diphenhydramine | 1,000,000 | 0.01 | | Methylphenidate | 100,000 | 0.10 | | Doxylamine | 1,000,000 | <0.01 | | LAAM | 1,000,000 | <0.01 | | (±)-alpha methadol | 1,000,000 | <0.01 | | (-)-iso-methadone | 100,000 | <1.0 | | Structurally Related Compounds at 300 ng/mL cutoff - Semi-quantitative | | | | --- | --- | --- | | Compound | Concentration Tested (ng/mL) | Cross-reactivity (%) | | EDDP | 300 | 100 | | Methadone | 1,000,000 | <0.03 | | EMDP | 1,000,000 | <0.03 | | Chlorpromazine | 300,000 | 0.1 | | Diphenhydramine | 1,000,000 | <0.03 | | Methylphenidate | 360,000 | 0.08 | | Doxylamine | 1,000,000 | <0.03 | | LAAM | 1,000,000 | <0.03 | | (±)-alpha methadol | 1,000,000 | <0.03 | | (-)-iso-methadone | 100,000 | <0.3 | {10} Potential interference from non-structurally related drugs and metabolites was evaluated in the qualitative and semi-quantitative modes by spiking these compounds into drug free urine containing EDDP at $\pm 25\%$ of the cutoff (75ng/mL and 125ng/mL for the 100ng/mL cutoff, 225ng/mL and 375ng/mL for the 300ng/mL or 750ng/mL and 1,250ng/mL for the 1,000ng/mL cutoff). The results were the same for the qualitative and semi-quantitative modes and are summarized below: | Non - Structurally Related Compounds at 100 ng/mL cutoff | | | | | --- | --- | --- | --- | | Compound | Concentration Tested (ng/mL) | -25% Cutoff | +25% Cutoff | | | | Result | Result | | Acetylsalicylic Acid | 500,000 | Neg | Pos | | 6-Acetylcodeine | 100,000 | Neg | Pos | | 6-Acetylmorphine | 100,000 | Neg | Pos | | Alprazolam | 100,000 | Neg | Pos | | 7-Aminoclonazepam | 100,000 | Neg | Pos | | 7-Aminoflurnitrazepam | 100,000 | Neg | Pos | | 7-Aminonitrazepam | 100,000 | Neg | Pos | | Amitriptyline | 100,000 | Neg | Pos | | Amobarbital | 100,000 | Neg | Pos | | S-(+)-Amphetamine | 100,000 | Neg | Pos | | Benzylpiperazine | 100,000 | Neg | Pos | | Bromazepam | 100,000 | Neg | Pos | | Buprenorphine | 100,000 | Neg | Pos | | Bupropion | 100,000 | Neg | Pos | | Butabarbital | 100,000 | Neg | Pos | | Butalbital | 100,000 | Neg | Pos | | Caffeine | 500,000 | Neg | Pos | | Cannabidiol | 100,000 | Neg | Pos | | Cannabinol | 75,000 | Neg | Pos | | Carbamazepine | 100,000 | Neg | Pos | | Carisoprodol | 100,000 | Neg | Pos | | Chlordiazepoxide | 100,000 | Neg | Pos | | cis-Tramadol | 100,000 | Neg | Pos | | Clobazam | 100,000 | Neg | Pos | | Clomipramine | 50,000 | Neg | Pos | | Clonazepam | 100,000 | Neg | Pos | | Clozapine | 100,000 | Neg | Pos | | Codeine | 100,000 | Neg | Pos | | Cotinine | 100,000 | Neg | Pos | | Cyclobenzaprine | 100,000 | Neg | Pos | | Dehydronorketamine | 100,000 | Neg | Pos | | Demoxepam | 100,000 | Neg | Pos | | Desipramine | 30,000 | Neg | Pos | | Desalkylflurazepam | 100,000 | Neg | Pos | {11} | Dextromethorphan | 100,000 | Neg | Pos | | --- | --- | --- | --- | | Diazepam | 100,000 | Neg | Pos | | Digoxin | 100,000 | Neg | Pos | | Dihydrocodeine | 100,000 | Neg | Pos | | Δ9 THC | 100,000 | Neg | Pos | | Doxepin | 100,000 | Neg | Pos | | 1R,2S (-) Ephedrine | 100,000 | Neg | Pos | | 1S,2R (+) Ephedrine | 100,000 | Neg | Pos | | Ethyl-β-D-Glucuronide | 100,000 | Neg | Pos | | Ethylmorphine | 100,000 | Neg | Pos | | Fenfluramine | 100,000 | Neg | Pos | | Fentanyl | 100,000 | Neg | Pos | | Flunitrazepam | 100,000 | Neg | Pos | | Fluoxetine | 100,000 | Neg | Pos | | Flurazepam | 100,000 | Neg | Pos | | Haloperidol | 100,000 | Neg | Pos | | Heroin | 100,000 | Neg | Pos | | Hexobarbital | 100,000 | Neg | Pos | | Hydrocodone | 100,000 | Neg | Pos | | Hydromorphone | 100,000 | Neg | Pos | | 11-hydroxy- Δ9 THC | 100,000 | Neg | Pos | | Ibuprofen | 500,000 | Neg | Pos | | Imipramine | 50,000 | Neg | Pos | | Ketamine | 100,000 | Neg | Pos | | Lamotrigine | 100,000 | Neg | Pos | | Levorphanol Tartrate | 100,000 | Neg | Pos | | Lidocaine | 100,000 | Neg | Pos | | Lorazepam | 100,000 | Neg | Pos | | Lorazepam Glucuronide | 50,000 | Neg | Pos | | Lormetrazepam | 100,000 | Neg | Pos | | LSD | 100,000 | Neg | Pos | | Maprotiline | 100,000 | Neg | Pos | | (+)-MDA | 100,000 | Neg | Pos | | MDEA | 100,000 | Neg | Pos | | MDMA | 100,000 | Neg | Pos | | Meperidine | 50,000 | Neg | Pos | | Meprobamate | 100,000 | Neg | Pos | | S(+)-Methamphetamine | 100,000 | Neg | Pos | | Methaquolone | 100,000 | Neg | Pos | | Methoxetamine | 100,000 | Neg | Pos | | Methylone | 100,000 | Neg | Pos | | Midazolam | 100,000 | Neg | Pos | | Morphine | 100,000 | Neg | Pos | | Morphine-3β-D-Glucuronide | 100,000 | Neg | Pos | | Morphine-6β-D-Glucuronide | 50,000 | Neg | Pos | 12 {12} | N-Desmethyltentadol | 100,000 | Neg | Pos | | --- | --- | --- | --- | | Nalorphine | 100,000 | Neg | Pos | | Naloxone | 100,000 | Neg | Pos | | Naltrexone | 100,000 | Neg | Pos | | Naproxen | 100,000 | Neg | Pos | | Nitrazepam | 100,000 | Neg | Pos | | 11-nor-9-carboxy -Δ9-THC | 100,000 | Neg | Pos | | Norbuprenorphine | 50,000 | Neg | Pos | | Norcodeine | 100,000 | Neg | Pos | | Nordiazepam | 100,000 | Neg | Pos | | Norketamine | 100,000 | Neg | Pos | | Normorphine | 100,000 | Neg | Pos | | Norproxyphene | 100,000 | Neg | Pos | | Norpseudoephedrine | 100,000 | Neg | Pos | | Nortriptyline | 100,000 | Neg | Pos | | Olanzapine | 100,000 | Neg | Pos | | Oxazepam | 100,000 | Neg | Pos | | Oxycodone | 100,000 | Neg | Pos | | Oxymorphone | 100,000 | Neg | Pos | | PCP | 50,000 | Neg | Pos | | Pentazocine | 100,000 | Neg | Pos | | Pentobarbital | 100,000 | Neg | Pos | | Phenobarbital | 100,000 | Neg | Pos | | Phentermine | 100,000 | Neg | Pos | | Phenylephedrine | 100,000 | Neg | Pos | | Phenylpropanolamine | 100,000 | Neg | Pos | | Phenytoin | 100,000 | Neg | Pos | | PMA | 100,000 | Neg | Pos | | Prazepam | 100,000 | Neg | Pos | | Propoxyphene | 100,000 | Neg | Pos | | Propranolol | 100,000 | Neg | Pos | | Protriptyline | 100,000 | Neg | Pos | | R,R (+)- Pseudoephedrine | 100,000 | Neg | Pos | | S,S (-)- Pseudoephedrine | 100,000 | Neg | Pos | | Ranitidine | 100,000 | Neg | Pos | | Ritalinic Acid | 100,000 | Neg | Pos | | Salicylic Acid | 100,000 | Neg | Pos | | Secobarbital | 100,000 | Neg | Pos | | Sertraline | 100,000 | Neg | Pos | | Sufentanil Citrate | 50,000 | Neg | Pos | | Tapentadol | 100,000 | Neg | Pos | | Temazepam | 100,000 | Neg | Pos | | Theophylline | 100,000 | Neg | Pos | | Thioridazine | 30,000 | Neg | Pos | | Trazodone | 100,000 | Neg | Pos | 13 {13} | Non - Structurally Related Compounds at 300 ng/mL cutoff | | | | | --- | --- | --- | --- | | Compound | Concentration Tested (ng/mL) | -25% Cutoff | +25% Cutoff | | | | Result | Result | | 4-bromo 2-5, dimethoxyphenethylamine | 100,000 | Neg | Pos | | Acetaminophen | 500,000 | Neg | Pos | | Acetylsalicylic Acid | 500,000 | Neg | Pos | | 6-Acetylcodeine | 100,000 | Neg | Pos | | 6-Acetylmorphine | 100,000 | Neg | Pos | | Alprazolam | 100,000 | Neg | Pos | | 7-Aminoclonazepam | 100,000 | Neg | Pos | | 7-Aminoflurnitrazepam | 100,000 | Neg | Pos | | 7-Aminonitrazepam | 100,000 | Neg | Pos | | Amitriptyline | 100,000 | Neg | Pos | | Amobarbital | 100,000 | Neg | Pos | | S-(+)-Amphetamine | 100,000 | Neg | Pos | | Benzylpiperazine | 100,000 | Neg | Pos | | Bromazepam | 100,000 | Neg | Pos | | Buprenorphine | 100,000 | Neg | Pos | | Bupropion | 100,000 | Neg | Pos | | Butabarbital | 100,000 | Neg | Pos | | Butalbital | 100,000 | Neg | Pos | | Caffeine | 500,000 | Neg | Pos | | Cannabidiol | 100,000 | Neg | Pos | | Cannabinol | 100,000 | Neg | Pos | | Carbamazepine | 100,000 | Neg | Pos | | Carisoprodol | 100,000 | Neg | Pos | | Chlordiazepoxide | 100,000 | Neg | Pos | | cis-Tramadol | 100,000 | Neg | Pos | | Clobazam | 100,000 | Neg | Pos | | Clomipramine | 100,000 | Neg | Pos | | Clonazepam | 100,000 | Neg | Pos | | Clozapine | 100,000 | Neg | Pos | | Codeine | 100,000 | Neg | Pos | | Cotinine | 100,000 | Neg | Pos | | Cyclobenzaprine | 100,000 | Neg | Pos | {14} | Dehydronorketamine | 100,000 | Neg | Pos | | --- | --- | --- | --- | | Demoxepam | 100,000 | Neg | Pos | | Desipramine | 100,000 | Neg | Pos | | Desalkylflurazepam | 100,000 | Neg | Pos | | Dextromethorphan | 100,000 | Neg | Pos | | Diazepam | 100,000 | Neg | Pos | | Digoxin | 100,000 | Neg | Pos | | Dihydrocodeine | 100,000 | Neg | Pos | | Δ9 THC | 100,000 | Neg | Pos | | Doxepin | 100,000 | Neg | Pos | | 1R,2S (-) Ephedrine | 100,000 | Neg | Pos | | 1S,2R (+) Ephedrine | 100,000 | Neg | Pos | | Ethyl-β-D-Glucuronide | 100,000 | Neg | Pos | | Ethylmorphine | 100,000 | Neg | Pos | | Fenfluramine | 100,000 | Neg | Pos | | Fentanyl | 100,000 | Neg | Pos | | Flunitrazepam | 100,000 | Neg | Pos | | Fluoxetine | 100,000 | Neg | Pos | | Flurazepam | 100,000 | Neg | Pos | | Haloperidol | 100,000 | Neg | Pos | | Heroin | 100,000 | Neg | Pos | | Hexobarbital | 100,000 | Neg | Pos | | Hydrocodone | 100,000 | Neg | Pos | | Hydromorphone | 100,000 | Neg | Pos | | 11-hydroxy- Δ9 THC | 100,000 | Neg | Pos | | Ibuprofen | 500,000 | Neg | Pos | | Imipramine | 100,000 | Neg | Pos | | Ketamine | 100,000 | Neg | Pos | | Lamotrigine | 100,000 | Neg | Pos | | Levorphanol Tartrate | 100,000 | Neg | Pos | | Lidocaine | 100,000 | Neg | Pos | | Lorazepam | 100,000 | Neg | Pos | | Lorazepam Glucuronide | 50,000 | Neg | Pos | | Lormetrazepam | 100,000 | Neg | Pos | | LSD | 100,000 | Neg | Pos | | Maprotiline | 100,000 | Neg | Pos | | (+)-MDA | 100,000 | Neg | Pos | | MDEA | 100,000 | Neg | Pos | | MDMA | 100,000 | Neg | Pos | | Meperidine | 100,000 | Neg | Pos | | Meprobamate | 100,000 | Neg | Pos | | S(+)-Methamphetamine | 100,000 | Neg | Pos | | Methaquolone | 100,000 | Neg | Pos | | Methoxetamine | 100,000 | Neg | Pos | | Methylone | 100,000 | Neg | Pos | 15 {15} | Midazolam | 100,000 | Neg | Pos | | --- | --- | --- | --- | | Morphine | 100,000 | Neg | Pos | | Morphine-3β-D-Glucuronide | 100,000 | Neg | Pos | | Morphine-6β-D-Glucuronide | 50,000 | Neg | Pos | | N-Desmethyltapentadol | 100,000 | Neg | Pos | | Nalorphine | 100,000 | Neg | Pos | | Naloxone | 100,000 | Neg | Pos | | Naltrexone | 100,000 | Neg | Pos | | Naproxen | 100,000 | Neg | Pos | | Nitrazepam | 100,000 | Neg | Pos | | 11-nor-9-carboxy -Δ9-THC | 100,000 | Neg | Pos | | Norbuprenorphine | 50,000 | Neg | Pos | | Norcodeine | 100,000 | Neg | Pos | | Nordiazepam | 100,000 | Neg | Pos | | Norketamine | 100,000 | Neg | Pos | | Normorphine | 100,000 | Neg | Pos | | Norproxyphene | 100,000 | Neg | Pos | | Norpseudoephedrine | 100,000 | Neg | Pos | | Nortriptyline | 100,000 | Neg | Pos | | Olanzapine | 100,000 | Neg | Pos | | Oxazepam | 100,000 | Neg | Pos | | Oxycodone | 100,000 | Neg | Pos | | Oxymorphone | 100,000 | Neg | Pos | | PCP | 100,000 | Neg | Pos | | Pentazocine | 100,000 | Neg | Pos | | Pentobarbital | 100,000 | Neg | Pos | | Phenobarbital | 100,000 | Neg | Pos | | Phentermine | 100,000 | Neg | Pos | | Phenylephedrine | 100,000 | Neg | Pos | | Phenylpropanolamine | 100,000 | Neg | Pos | | Phenytoin | 100,000 | Neg | Pos | | PMA | 100,000 | Neg | Pos | | Prazepam | 100,000 | Neg | Pos | | Propoxyphene | 100,000 | Neg | Pos | | Propranolol | 100,000 | Neg | Pos | | Protriptyline | 100,000 | Neg | Pos | | R,R (+)- Pseudoephedrine | 100,000 | Neg | Pos | | S,S (-)- Pseudoephedrine | 100,000 | Neg | Pos | | Ranitidine | 100,000 | Neg | Pos | | Ritalinic Acid | 100,000 | Neg | Pos | | Salicylic Acid | 100,000 | Neg | Pos | | Secobarbital | 100,000 | Neg | Pos | | Sertraline | 100,000 | Neg | Pos | | Sufentanil Citrate | 50,000 | Neg | Pos | | Tapentadol | 100,000 | Neg | Pos | 16 {16} | Non - Structurally Related Compounds at 1000 ng/mL cutoff | | | | | --- | --- | --- | --- | | Compound | Concentration Tested (ng/mL) | -25% Cutoff | +25% Cutoff | | | | Result | Result | | 4-bromo 2-5, dimethoxyphenethylamine | 100,000 | Neg | Pos | | Acetaminophen | 500,000 | Neg | Pos | | Acetylsalicylic Acid | 500,000 | Neg | Pos | | 6-Acetylcodeine | 100,000 | Neg | Pos | | 6-Acetylmorphine | 100,000 | Neg | Pos | | Alprazolam | 100,000 | Neg | Pos | | 7-Aminoclonazepam | 100,000 | Neg | Pos | | 7-Aminoflurnitrazepam | 100,000 | Neg | Pos | | 7-Aminonitrazepam | 100,000 | Neg | Pos | | Amitriptyline | 100,000 | Neg | Pos | | Amobarbital | 100,000 | Neg | Pos | | S-(+)-Amphetamine | 100,000 | Neg | Pos | | Benzylpiperazine | 100,000 | Neg | Pos | | Bromazepam | 100,000 | Neg | Pos | | Buprenorphine | 100,000 | Neg | Pos | | Bupropion | 100,000 | Neg | Pos | | Butabarbital | 100,000 | Neg | Pos | | Butalbital | 100,000 | Neg | Pos | | Caffeine | 500,000 | Neg | Pos | | Cannabidiol | 100,000 | Neg | Pos | | Cannabinol | 100,000 | Neg | Pos | | Carbamazepine | 100,000 | Neg | Pos | | Carisoprodol | 100,000 | Neg | Pos | | Chlordiazepoxide | 100,000 | Neg | Pos | | cis-Tramadol | 100,000 | Neg | Pos | | Clobazam | 100,000 | Neg | Pos | | Clomipramine | 100,000 | Neg | Pos | | Clonazepam | 100,000 | Neg | Pos | | Clindacarb | 100,000 | Neg | Pos | | Dexacarb | 100,000 | Neg | Pos | | Dexylphenidate | 100,000 | Neg | Pos | | Dexylphenidate | 100,000 | Neg | Pos | | Dexylphenidate | 100,000 | Neg | Pos | | Diphenhydramine | 100,000 | Neg | Pos | | Diphenhydramine | 100,000 | Neg | Pos | | Diphenhydramine | 100,000 | Neg | Pos | | Diphenhydramine | 100,000 | Neg | Pos | | Diphenhydramine | 100 | Neg | Pos | {17} | Clozapine | 100,000 | Neg | Pos | | --- | --- | --- | --- | | Codeine | 100,000 | Neg | Pos | | Cotinine | 100,000 | Neg | Pos | | Cyclobenzaprine | 100,000 | Neg | Pos | | Dehydronorketamine | 100,000 | Neg | Pos | | Demoxepam | 100,000 | Neg | Pos | | Desipramine | 100,000 | Neg | Pos | | Desalkylflurazepam | 100,000 | Neg | Pos | | Dextromethorphan | 100,000 | Neg | Pos | | Diazepam | 100,000 | Neg | Pos | | Digoxin | 100,000 | Neg | Pos | | Dihydrocodeine | 100,000 | Neg | Pos | | Δ9 THC | 100,000 | Neg | Pos | | Doxepin | 100,000 | Neg | Pos | | 1R,2S (-) Ephedrine | 100,000 | Neg | Pos | | 1S,2R (+) Ephedrine | 100,000 | Neg | Pos | | Ethyl-β-D-Glucuronide | 100,000 | Neg | Pos | | Ethylmorphine | 100,000 | Neg | Pos | | Fenfluramine | 100,000 | Neg | Pos | | Fentanyl | 100,000 | Neg | Pos | | Flunitrazepam | 100,000 | Neg | Pos | | Fluoxetine | 100,000 | Neg | Pos | | Flurazepam | 100,000 | Neg | Pos | | Haloperidol | 100,000 | Neg | Pos | | Heroin | 100,000 | Neg | Pos | | Hexobarbital | 100,000 | Neg | Pos | | Hydrocodone | 100,000 | Neg | Pos | | Hydromorphone | 100,000 | Neg | Pos | | 11-hydroxy- Δ9 THC | 100,000 | Neg | Pos | | Ibuprofen | 500,000 | Neg | Pos | | Imipramine | 100,000 | Neg | Pos | | Ketamine | 100,000 | Neg | Pos | | Lamotrigine | 100,000 | Neg | Pos | | Levorphanol Tartrate | 100,000 | Neg | Pos | | Lidocaine | 100,000 | Neg | Pos | | Lorazepam | 100,000 | Neg | Pos | | Lorazepam Glucuronide | 50,000 | Neg | Pos | | Lormetrazepam | 100,000 | Neg | Pos | | LSD | 100,000 | Neg | Pos | | Maprotiline | 100,000 | Neg | Pos | | (+)-MDA | 100,000 | Neg | Pos | | MDEA | 100,000 | Neg | Pos | | MDMA | 100,000 | Neg | Pos | | Meperidine | 100,000 | Neg | Pos | | Meprobamate | 100,000 | Neg | Pos | 18 {18} | S(+)-Methamphetamine | 100,000 | Neg | Pos | | --- | --- | --- | --- | | Methaquolone | 100,000 | Neg | Pos | | Methoxetamine | 100,000 | Neg | Pos | | Methylone | 100,000 | Neg | Pos | | Midazolam | 100,000 | Neg | Pos | | Morphine | 100,000 | Neg | Pos | | Morphine-3β-D-Glucuronide | 100,000 | Neg | Pos | | Morphine-6β-D-Glucuronide | 50,000 | Neg | Pos | | N-Desmethyltapentadol | 100,000 | Neg | Pos | | Nalorphine | 100,000 | Neg | Pos | | Naloxone | 100,000 | Neg | Pos | | Naltrexone | 100,000 | Neg | Pos | | Naproxen | 100,000 | Neg | Pos | | Nitrazepam | 100,000 | Neg | Pos | | 11-nor-9-carboxy -Δ9-THC | 100,000 | Neg | Pos | | Norbuprenorphine | 50,000 | Neg | Pos | | Norcodeine | 100,000 | Neg | Pos | | Nordiazepam | 100,000 | Neg | Pos | | Norketamine | 100,000 | Neg | Pos | | Normorphine | 100,000 | Neg | Pos | | Norproxyphene | 100,000 | Neg | Pos | | Norpseudoephedrine | 100,000 | Neg | Pos | | Nortriptyline | 100,000 | Neg | Pos | | Olanzapine | 100,000 | Neg | Pos | | Oxazepam | 100,000 | Neg | Pos | | Oxycodone | 100,000 | Neg | Pos | | Oxymorphone | 100,000 | Neg | Pos | | PCP | 100,000 | Neg | Pos | | Pentazocine | 100,000 | Neg | Pos | | Pentobarbital | 100,000 | Neg | Pos | | Phenobarbital | 100,000 | Neg | Pos | | Phentermine | 100,000 | Neg | Pos | | Phenylephedrine | 100,000 | Neg | Pos | | Phenylpropanolamine | 100,000 | Neg | Pos | | Phenytoin | 100,000 | Neg | Pos | | PMA | 100,000 | Neg | Pos | | Prazepam | 100,000 | Neg | Pos | | Propoxyphene | 100,000 | Neg | Pos | | Propranolol | 100,000 | Neg | Pos | | Protriptyline | 100,000 | Neg | Pos | | R,R (+)- Pseudoephedrine | 100,000 | Neg | Pos | | S,S (-)- Pseudoephedrine | 100,000 | Neg | Pos | | Ranitidine | 100,000 | Neg | Pos | | Ritalinic Acid | 100,000 | Neg | Pos | | Salicylic Acid | 100,000 | Neg | Pos | 19 {19} # Endogenous compounds Potential interference from endogenous compounds was evaluated in the qualitative and semi-quantitative modes by spiking these compounds into drug free urine containing EDDP at $\pm 25\%$ of the cutoff (75ng/mL and 125ng/mL for the 100ng/mL cutoff, 225 ng/mL and 375 ng/mL for the 300 ng/mL cutoff or 750 ng/mL and 1,250 ng/mL for the 1,000 ng/mL cutoff). The results were the same for the qualitative and semi-quantitative modes for all cutoffs and are summarized below: | Compound | Concentration Tested | -25% Cutoff | +25% Cutoff | | --- | --- | --- | --- | | Acetone | 1.0 g/dL | Neg | Pos | | Ascorbic Acid | 1.5 g/dL | Neg | Pos | | Bilirubin | 0.002 g/dL | Neg | Pos | | Creatinine | 0.5 g/dL | Neg | Pos | | Ethanol | 1.0 g/dL | Neg | Pos | | Galactose | 0.01 g/dL | Neg | Pos | | γ-Globulin | 0.5 g/dL | Neg | Pos | | Glucose | 2.0 g/dL | Neg | Pos | | Hemoglobin | 0.300 g/dL | Neg | Pos | | Human Serum Albumin | 0.5 g/dL | Neg | Pos | | Oxalic Acid | 0.1 g/dL | Neg | Pos | | Riboflavin | 0.0075 g/dL | Neg | Pos | | Sodium Azide | 1% w/v | Neg | Pos | | Sodium Chloride | 6.0 g/dL | Neg | Pos | | Sodium Fluoride | 1% w/v | Neg | Pos | | Urea | 6.0 g/dL | Neg | Pos | Boric Acid was also evaluated. Boric Acid at a concentration of $1\%$ w/v was found to cause false negative results at $\pm 25\%$ of the $100\mathrm{ng / mL}$ cutoff (75ng/mL and $125\mathrm{ng / mL}$ ), $300\mathrm{ng / mL}$ cutoff (225ng/mL and $375\mathrm{ng / mL}$ ) and $1000\mathrm{ng / mL}$ cutoff {20} (750ng/mL cutoff and 1250ng/mL) in both the qualitative and semiquantitative modes. The following statement is provided in the limitations section of the labeling: "Boric Acid at 1% w/v may cause false negative results. Boric Acid should not be used as a preservative for urine specimens." ## pH and Specific Gravity To evaluate potential interference from the pH of urine, device performance in the qualitative and semi-quantitative modes was tested using a range of urine pH values (3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0 and 11.0). All test samples were prepared in drug free urine containing EDDP at ±25% of the 100 ng/mL cutoff (75 ng/mL and 125 ng/mL), 300 ng/mL cutoff (225 ng/mL and 375 ng/mL) and 1000 ng/mL cutoff (750 ng/mL cutoff and 1250 ng/mL). No positive or negative interference was observed at urine pH values ranging from 3.0 to 11.0 for each test mode. To evaluate potential interference from the specific gravity of urine, device performance in the qualitative and semi-quantitative modes was tested using a range of urine specific gravity values (1.000, 1.002, 1.005, 1.010, 1.015, 1.020, 1.025 and 1.030). All test samples were prepared in drug free urine containing EDDP at ±25% of the 100 ng/mL cutoff (75 ng/mL and 125 ng/mL), 300 ng/mL cutoff (225 ng/mL and 375 ng/mL) and 1000 ng/mL cutoff (750 ng/mL cutoff and 1250 ng/mL). No positive or negative interference was observed at urine specific gravity values ranging from 1.000 to 1.030 for each test mode. ## f. Assay cut-off: Characterization of how the device performs analytically around the claimed cutoff concentration of 100 ng/mL, 300 ng/mL and 1000 ng/mL EDDP is described in the precision section, M.1.a. above. ## 2. Comparison studies: a. Method comparison with predicate device: A total of 80 unaltered urine samples from clinical testing laboratories were analyzed by the candidate device in the qualitative and semi-quantitative modes on the Beckman Coulter AU 400e clinical chemistry analyzer and the comparative mass spectrometry based quantitative method (LC/MS). The results from the study are summarized below: 21 {21} Qualitative Mode for 100ng/mL cutoff: | Candidate Device Results | <50% of cutoff concentration by LC/MS (< 50ng/mL) | Near Cutoff Negative (Between 50% below the cutoff and the cutoff concentration by LC/MS) (50 ~ 99 ng/mL) | Near Cutoff Positive (Between the cutoff and 50% above the cutoff concentration by LC/MS) (100 ~ 150 ng/mL) | High Positive (Greater than 50% above the cutoff concentration by LC/MS) > 150 ng/mL | | --- | --- | --- | --- | --- | | Positive | 0 | 1 | 4 | 36 | | Negative | 36 | 3 | 0 | 0 | % Agreement among positives is 98%. % Agreement among negatives is 100%. Qualitative Discordant Results for 100ng/mL cutoff: | Test Device | LC/MS Result | | --- | --- | | POS | 97.0 ng/mL | Qualitative Mode for 300ng/mL cutoff: | Candidate Device Results | <50% of cutoff concentration by LC/MS (< 150ng/mL) | Near Cutoff Negative (Between 50% below the cutoff and the cutoff concentration by LC/MS) (150 ~ 299 ng/mL) | Near Cutoff Positive (Between the cutoff and 50% above the cutoff concentration by LC/MS) (300 ~ 450 ng/mL) | High Positive (Greater than 50% above the cutoff concentration by LC/MS) > 450 ng/mL | | --- | --- | --- | --- | --- | | Positive | 0 | 0 | 4 | 36 | | Negative | 36 | 4 | 0 | 0 | % Agreement among positives is 100%. % Agreement among negatives is 100%. 22 {22} Qualitative Mode for 1000ng/mL cutoff: | Candidate Device Results | <50% of cutoff concentration by LC/MS (<500ng/mL) | Near Cutoff Negative (Between 50% below the cutoff and the cutoff concentration by LC/MS) (500 ~ 999 ng/mL) | Near Cutoff Positive (Between the cutoff and 50% above the cutoff concentration by LC/MS) (1000 ~ 1500 ng/mL) | High Positive (Greater than 50% above the cutoff concentration by LC/MS) > 1500 ng/mL | | --- | --- | --- | --- | --- | | Positive | 0 | 0 | 4 | 36 | | Negative | 36 | 4 | 0 | 0 | % Agreement among positives is 100%. % Agreement among negatives is 100%. Semi-Quantitative Mode for 100ng/mL cutoff: | Candidate Device Results | <50% of cutoff concentration by LC/MS (< 50ng/mL) | Near Cutoff Negative (Between 50% below the cutoff and the cutoff concentration by LC/MS) (50 ~ 99 ng/mL) | Near Cutoff Positive (Between the cutoff and 50% above the cutoff concentration by LC/MS) (100 ~ 150 ng/mL) | High Positive (Greater than 50% above the cutoff concentration by LC/MS) > 150 ng/mL | | --- | --- | --- | --- | --- | | Positive | 0 | 1 | 4 | 36 | | Negative | 36 | 3 | 0 | 0 | % Agreement among positives is 98%. % Agreement among negatives is 100%. Semi-Quantitative Discordant Results for 100ng/mL cutoff: | Table 41 - Discordant Result Summary – 100ng/mL Cutoff – Semi-Quantitative | | | | | | --- | --- | --- | --- | --- | | Sample ID | In-House ID | Semi-Quantitative Results 100ng Cutoff | | LC/MS Confirmation | | | | Value | Result | EDDP | | JM042877 | 15980 | 149.5 | POS | 97.0 | {23} 24 Semi-Quantitative Mode for 300ng/mL cutoff: | Candidate Device Results | <50% of cutoff concentration by LC/MS (< 150ng/mL) | Near Cutoff Negative (Between 50% below the cutoff and the cutoff concentration by LC/MS) (150 ~ 299 ng/mL) | Near Cutoff Positive (Between the cutoff and 50% above the cutoff concentration by LC/MS) (300 ~ 450 ng/mL) | High Positive (Greater than 50% above the cutoff concentration by LC/MS) > 450 ng/mL | | --- | --- | --- | --- | --- | | Positive | 0 | 0 | 4 | 36 | | Negative | 36 | 4 | 0 | 0 | % Agreement among positives is 100%. % Agreement among negatives is 100%. b. Matrix comparison: Not applicable. Urine is the only claimed matrix for the candidate device. 3. Clinical studies: a. Clinical Sensitivity: Not applicable. b. Clinical specificity: Not applicable. c. Other clinical supportive data (when a. and b. are not applicable): Not applicable. 4. Clinical cut-off: Not applicable. 5. Expected values/Reference range: Not applicable. N. Proposed Labeling: The labeling is sufficient and it satisfies the requirements of 21 CFR Part 809.10. O. Conclusion: The submitted information in this premarket notification is complete and supports a substantial equivalence decision.