RANDOX BARITURATES ASSAY

{0} 1 # 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY ASSAY ONLY TEMPLATE A. 510(k) Number: k092268 B. Purpose for Submission: New assay C. Measurand: Barbiturates D. Type of Test: Homogeneous enzyme immunoassay – qualitative and semi-quantitative E. Applicant: Randox Laboratories Ltd. F. Proprietary and Established Names: Randox Barbiturates assay Randox Multidrug Calibrator Set Randox Multidrug Controls, Levels 1 and 2 G. Regulatory Information: 1. Regulation section: | Product Code | Classification | Regulation Section | Panel | | --- | --- | --- | --- | | DIS | Class II | 21 CFR § 862.3200, Barbiturate test system | 91-Toxicology | | DLJ | Class II | 21 CFR § 862.3200, Calibrators, Drug specific | 91-Toxicology | | LAS | Class I, reserved | 21 CFR 862.3280 Clinical Toxicology control material | 91-Toxicology | {1} H. Intended Use: 1. Intended use(s): See Indications for use below. 2. Indication(s) for use: Randox Barbiturates Assay: The Randox Laboratories Ltd. Barbiturates Assay is an in vitro diagnostic test for the detection of Barbiturates, in human urine on the Rx Imola and Rx Daytona. The cutoff for secobarbital is 200 ng/mL. This in vitro diagnostic device is intended for prescription use only. The semi-quantitative mode is for purpose of (1) enabling laboratories to determine an appropriate dilution of the specimen for confirmation by a confirmatory method such as GCMS Or (2) permitting laboratories to establish quality control procedures. This assay provides only a preliminary analytical result. A more specific alternative chemical method must be used in order to obtain a confirmed analytical result. Gas chromatograph/mass spectrometry (GC/MS) is the preferred confirmatory method. Clinical consideration and professional judgment should be exercised with any drug of abuse test result, particularly when the preliminary result is positive. Randox Multidrug Calibrator Set: Randox Multidrug Calibrator Set consists of liquid calibrators containing Secobarbital, Oxazepam and Methadone. There are 5 levels of calibrator. They have been developed for use in the calibration of Barbiturates, Benzodiazepines and Methadone assays for use on the Rx analysers, which includes the Rx Daytona™ and the Rx Imola. This in vitro diagnostic device is intended for prescription use only. Randox Multidrug Controls, Level 1 and 2: Randox Multidrug Controls, Level 1 &amp; 2 are liquid controls containing Secobarbital, Oxazepam and Methadone. There are 2 levels of controls. They have been developed for use in the quality control of Barbiturates, Benzodiazepines and Methadone assays for use on the Rx analysers, which includes the Rx-Daytona™ and the Rx-Imola. This in vitro diagnostic device is intended for prescription use only. 3. Special conditions for use statement(s): The assay is for prescription use {2} The sponsor includes the following limitations in their labeling: The test is not intended for quantifying barbiturates in patient samples and is not intended for therapeutic drug management. A positive result does not indicate drug abuse. 4. Special instrument requirements: The assay has been developed for use on the Rx Daytona™, and Rx Imola™. I. Device Description: The assay consists of two reagent bottles supplied ready for use. R-1 contains mouse monoclonal anti- secobarbital antibodies, glucose-6-phosphate (G6P), nicotinamide adenine dinucleotide (NAD), stabilizers, and sodium azide &lt;0.1% w/v. R2 contains enzyme-drug conjugate reagent, buffer, secobarbital-labelled G6PDH, and sodium azide &lt;0.1% w/v. The calibrators and controls are ready to use human urine-based liquid (concentrations are listed in the comparison table, below. J. Substantial Equivalence Information: 1. Predicate device name(s): DRI Barbiturates Assay; DRI Multi-Drug Calibrators and controls 2. Predicate 510(k) number(s): k955928 (assay); k983159 (calibrators and controls) 3. Comparison with predicate: The intended use and test principle are the same for both assays. See the table below for further comparison. | ITEM | Randox Barbiturate Assay k092268 | DRI Barbiturates Assay, k955928 | | --- | --- | --- | | Cutoff | 200 ng/mL | Same | | Intended Use | Qualitative and semi-quantitative analysis of Barbiturates in human urine | Same | {3} | Test Principle | A competitive enzyme immunoassay based on competition between drug in the sample and drug labelled with the enzyme glucose-6-phosphate dehydrogenase (G6PDH) for a fixed amount of antibody in the reagent. | Same | | --- | --- | --- | | Sample type | Human urine | Same | | Type of reagent | Liquid Ready to use Two reagent assay | Same | | | Randox Multidrug Calibrator Set | DRI Multi-Drug Calibrators K983159 | | --- | --- | --- | | Indications | Randox Multidrug Calibrator Set consists of liquid calibrators containing Secobarbital, Oxazepam and Methadone. They have been developed for use in the calibration of Barbiturates, Benzodiazepines and Methadone assays for use on the Rx analysers, which includes the Rdaytona™ and the RxImola. This in vitro diagnostic device is intended for prescription use only. | The Multi-Drug Urine Calibrators and Controls are intended to be used for calibration and validation of DRI's drugs of abuse enzyme immunoassays to detect amphetamines, barbiturates, benzodiazepines,cocaine metabolites, methadone, methaqualone, opiates, phencyclidine and propoxyphene in human urine. | | Form and concentrations | Liquid ready to use (0, 100, 200, 1000 ng/mL) | Liquid ready to use (100, 200, 500, 1000ng/mL) | | | Randox Multidrug Controls | DRI Multi-Drug controls K983159 | | Indications | Randox Multidrug Controls have been developed for use in the quality control of Barbiturates, Benzodiazepines and Methadone assays This in vitro diagnostic device is intended for prescription use only. | Same | | Form and concentrations | Liquid ready to use (150, 250ng/mL) | Liquid ready to use (150, 300ng/mL) | {4} 5 K. Standard/Guidance Document Referenced (if applicable): None were referenced. L. Test Principle: The assay is a homogeneous enzyme immunoassay with ready-to-use liquid reagent. The assay is based on competition between drug in the sample and drug labeled with the enzyme glucose-6-phosphate dehydrogenase (G6PDH) for a fixed amount of antibody in the reagent. In the absence of drug in the sample, the antibody binds the conjugated G6PDH-barbiturates thus the enzyme activity is inhibited. When free drug is present on the sample, the antibody will bind to the free drug and the unbound G6PDH-conjugated drug exhibits its maximal enzyme activity. The G6PDH activity is measured spectrophotometrically at 340 nm due to conversion of NAD to NADH by the active enzyme. M. Performance Characteristics (if/when applicable): Performance was evaluated on the Rx Daytona™, and Rx Imola™. 1. Analytical performance: a. Precision/Reproducibility: Secobarbital stock solution and a human urine pool were used to prepare samples. Concentrations were confirmed by GC/MS. These samples were tested for precision in qualitative and semi-quantitative modes. Each sample was assayed two times per run, 2 runs per day, for 20 days on both the Imola and Daytona instruments. Identical results were obtained for semi-quantitative and qualitative results on both the Imola and the Daytona Instruments. | Secobarbital concentration (ng/mL) (cutoff=200 ng/mL) | No. of determinations | Results #Neg/#Pos | | --- | --- | --- | | 0 | 80 | 80 Neg | | 65 | 80 | 80 Neg | | 105 | 80 | 80 Neg | | 144 | 80 | 80 Neg | | 272 | 80 | 80 Pos | | 338 | 80 | 80 Pos | | 399 | 80 | 80 Pos | | 449 | 80 | 80 Pos | b. Linearity/assay reportable range: Drug free urine pool was spiked with pure Secobarbital. A 1000 ng/mL sample was further diluted in increments of 10% to a concentration of {5} 10ng/mL. These samples were tested in a random order in triplicate. Results are shown below. Rx Imola and Daytona Semi-Quantitative Recovery | Expected Concentration | Imola Result (ng/mL) | Percent recovery Rx Imola | Daytona result (ng/mL) | Percent recovery Rx Daytona | | --- | --- | --- | --- | --- | | 0 | 2.2 | N/A | 0.0 | N/A | | 10 | 10.7 | 107 | 16.8 | 168 | | 20 | 28.2 | 141 | 24.6 | 123 | | 30 | 47.9 | 160 | 40.3 | 134 | | 40 | 46.8 | 117 | 28.7 | 72 | | 50 | 69.2 | 138 | 43.7 | 87 | | 60 | 79.4 | 132 | 48.3 | 80 | | 70 | 88.9 | 127 | 71.5 | 102 | | 80 | 87.1 | 109 | 72.5 | 91 | | 90 | 100.6 | 112 | 104.2 | 116 | | 100 | 104.2 | 104 | 107.9 | 108 | | 200 | 187.2 | 94 | 189.6 | 95 | | 300 | 291.7 | 97 | 334.5 | 111 | | 400 | 390.7 | 98 | 410.4 | 103 | | 500 | 437.2 | 87 | 453.0 | 91 | | 700 | 691.6 | 99 | 635.9 | 91 | | 1000 | 1110.5 | 111 | 991.2 | 99 | c. Traceability, Stability, Expected Values (controls, calibrators, or methods) Traceability and value assignment The 4 levels of calibrator and 2 levels of control materials are traceable to master lots that have been GC/MS quantified. The master lots were made by spiking commercially available drug into a human urine matrix. The accuracy of the drug is ensured by spectrophotometric methods and gravimetric preparation using balances calibrated with NIST traceable standards. Each of the Randox calibrator/control level is value assigned using Rx Daytona and Rx Imola. The target value for each level is the median of the observed values. Stability Real time stability testing including shelf-life and on-board stability studies for the assay, controls and calibrators for both instruments. Controls and calibrators are stable for 12 months when stored unopened at $2 - 8^{\circ}\mathrm{C}$ and 28 days at $2 - 8^{\circ}\mathrm{C}$. 6 {6} d. Detection limit: Performance at low drug concentration in the semi-quantitative assay was characterized by determination of the lowest concentration of drug that is capable of producing a positive result. This concentration was sufficiently below the claimed cutoff for both instruments. e. Analytical specificity: Interference and cross-reactivity studies were evaluated in both qualitative and semi-quantitative modes to evaluate potential cross-reactive compounds, potential interfering compounds including structurally related compounds and potentially interfering endogenous compounds. Cross-reactivity for barbiturates: The drugs listed in the table below were tested for cross-reactivity with the assay. Drugs were spiked into urine and concentrations were verified by GC/MS. Each sample was evaluated against the cut-off calibrator (200 ng/mL secobarbital) to determine percent cross-reactivity. Results from both instruments are shown below. Some variations in cross-reactivity were observed depending on the assay mode and instrument. The ranges observed across modes and instruments are included in the table: | Compound | Perents cross-reactivity observed | | | | | --- | --- | --- | --- | --- | | | Daytona qualitative | Daytona semi-quantitative | Imola qualitative | Imola semi-quantitative | | Alphenal | 66 | 73 | 66 | 63 | | Amobarbital | 19 | 18 | 19 | 19 | | Butabarbital | 24 | 33 | 29 | 29 | | Hexobarbital | 2 | 3 | 1 | 3 | | Pentobarbital | 32 | 32 | 43 | 43 | | Phenobarbital | 52 | 73 | 52 | 83 | | Thiopental | <1 | <1 | 1 | 1 | | Butalbital | 52 | 51 | 52 | 53 | | Secobarbital | 100 | 100 | 100 | 100 | Endogenous compounds Potential interference from endogenous compounds pH, and specific gravity was assessed by spiking known amounts of potentially interfering substances into urine containing secobarbital concentrations $+/- 25\%$ of the assay cut-off. No interference was observed (in either semi-quantitative or qualitative mode on either instrument) from the substances below at the concentrations shown. | Compound | Tested Conc. (mg/dL) | | --- | --- | | Total Bilirubin | 15 | | Direct Bilirubin | 5 | {7} | Hemoglobin | 115 | | --- | --- | | Creatinine | 30 | | Urea | 258 | | Glucose | 2000 | | H.S.A. | 500 | | Ethanol | 1000 | | Acetone | 1000 | | Gamma globulin | 500 | | Oxalic acid | 100 | | Riboflavin | 7.5 | | Sodium chloride | 6000 | | Boric acid | 1000 | | Sodium azide | 1000 | | Sodium fluoride | 1000 | Commonly co-administered prescription and OTC compounds The potential effect of other compounds on the recovery of barbiturates using the Randox Barbiturates assay was assessed by spiking known amounts of the compounds into urine containing secobarbital at concentrations +/- 25% of the assay cutoff. Compounds were identified by the manufacturer as non-cross-interfering with the assay if the recovery of the samples containing secobarbital at +/-25% of the cutoff recovered within 10% of a sample containing no cross-reactant. No compounds were shown to interfere. The complete list of co-administered prescription and OTC compounds tested is shown in the package insert. No interference was observed with non-barbiturate compounds. f. Assay cut-off The assay is calibrated to a cutoff of 200 ng/mL with secobarbital. See also precision and detection limit sections, above. 2. Comparison studies: a. Method comparison with predicate device: Urine samples were obtained from a clinical laboratory where they had been tested by GC/MS for the presence or absence of various barbiturates including butabarbital, butalbital, phenobarbital, and secobarbital. Results are shown in the tables below. For purposes of comparison relative to the 200 ng/mL cutoff for secobarbital, the following adjustment was applied to samples containing other barbiturates, based on the cross-reactivity of each barbiturate: (GCMS-determined concentration) X (percent cross-reactivity) = "adjusted concentration" The table below is based on these adjusted concentrations. {8} | Daytona Semi-quantitative | Neg | Less than half the cut-off conc. by GC/MS | Between 50% below the cutoff and the cutoff conc. | Between the cutoff and 50% above the cutoff conc. | Greater than 50% above the cutoff conc. | | --- | --- | --- | --- | --- | --- | | Positive | 0 | 10 | 17 | 24 | 76 | | Negative | 85 | 8 | 7 | 2 | 0 | The list of discrepant results is shown in the table below. Concentrations shown in tables are the actual measured GCMS concentration for each drug listed in parentheses. | Daytona Semi-Quantitative | Drug/ Metabolite GC/MS value (ng/mL) based on cross-reactivity profile (ng/mL) | GCMS value of drug indicated (ng/mL) | | --- | --- | --- | | POS | 65 | 200 (Butabarbital) | | POS | 69 | 210 (Butabarbital) | | POS | 72 | 220 (Butabarbital) | | POS | 75 | 230 (Butabarbital) | | POS | 76 | 150 (Butalbital) | | POS | 78 | 240 (Butabarbital) | | POS | 78 | 240 (Butabarbital) | | POS | 82 | 250 (Butabarbital) | | POS | 86 | 168 (Butalbital) | | POS | 93 | 182 (Butalbital) | | POS | 102 | 312 (Butabarbital) | | POS | 102 | 312 (Butabarbital) | | POS | 116 | 228 (Butalbital) | | POS | 130 | 177 (Phenobarbital) | | POS | 134 | 183 (Phenobarbital) | | POS | 143 | 439 (Butabarbital) | | POS | 147 | 449 (Butabarbital) | | POS | 150 | 150 (Secobarbital) | | POS | 150 | 150 (Secobarbital) | | POS | 150 | 150 (Secobarbital) | | POS | 150 | 460 (Butabarbital) | | POS | 160 | 160 (Secobarbital) | | POS | 164 | 502 (Butabarbital) | | POS | 179 | 245 (Phenobarbital) | {9} | POS | 180 | 180 (Secobarbital) | | --- | --- | --- | | POS | 182 | 559 (Butabarbital) | | POS | 195 | 383 (Butalbital) | | NEG | 260 | 355 (Phenobarbital) | | NEG | 270 | 270 (Secobarbital) | | Daytona Qualitative | Neg | Less than half the cut-off conc. by GC/MS | Between 50% below the cutoff and the cutoff conc. | Between the cutoff and 50% above the cutoff conc. | Greater than 50% above the cutoff conc. | | --- | --- | --- | --- | --- | --- | | Positive | 0 | 12 | 13 | 23 | 72 | | Negative | 85 | 10 | 9 | 5 | 0 | | Daytona Qualitative | Drug/ Metabolite GC/MS value (ng/mL) based on cross-reactivity profile | GCMS value of drug indicated (ng/mL) | | --- | --- | --- | | POS | 49 | 200 (Butabarbital) | | POS | 51 | 210 (Butabarbital) | | POS | 52 | 215 (Butabarbital) | | POS | 56 | 230 (Butabarbital) | | POS | 58 | 240 (Butabarbital) | | POS | 58 | 240 (Butabarbital) | | POS | 61 | 250 (Butabarbital) | | POS | 76 | 312 (Butabarbital) | | POS | 76 | 312 (Butabarbital) | | POS | 78 | 150 (Butalbital) | | POS | 88 | 168 (Butalbital) | | POS | 95 | 183 (Phenobarbital) | | POS | 107 | 439 (Butabarbital) | | POS | 109 | 449 (Butabarbital) | | POS | 112 | 460 (Butabarbital) | | POS | 119 | 228 (Butalbital) | | POS | 122 | 502 (Butabarbital) | | POS | 122 | 502 (Butabarbital) | | POS | 128 | 245 (Phenobarbital) | | POS | 136 | 559 (Butabarbital) | | POS | 150 | 150 (Secobarbital) | | POS | 160 | 160 (Secobarbital) | {10} | Imola Semi-quantitative | Neg | Less than half the cutoff conc. by GC/MS | Between 50% below the cutoff and the cutoff conc. | Between the cutoff and 50% above the cutoff conc. | Greater than 50% above the cutoff conc. | | --- | --- | --- | --- | --- | --- | | Positive | 0 | 11 | 13 | 28 | 76 | | Negative | 85 | 9 | 6 | 1 | 0 | | Imola Semi-quantitative | Drug/ Metabolite GC/MS value (ng/mL) based on cross-reactivity profile | GCMS value of drug indicated (ng/mL) | | --- | --- | --- | | POS | 59 | 200 (butabarbital) | | POS | 62 | 210 (butabarbital) | | POS | 68 | 230 (butabarbital) | | POS | 70 | 240 (butabarbital) | | POS | 70 | 240 (butabarbital) | | POS | 73 | 250 (butabarbital) | | POS | 80 | 150 (Butalbital) | | POS | 89 | 168 (Butalbital) | | POS | 92 | 312 (butabarbital) | | POS | 92 | 312 (butabarbital) | | POS | 97 | 182 (Butalbital) | | POS | 121 | 228 (Butalbital) | | POS | 129 | 439 (butabarbital) | | POS | 132 | 449 (butabarbital) | | POS | 135 | 460 (butabarbital) | | POS | 147 | 177 (Phenobarbital) | | POS | 147 | 502 (butabarbital) | | POS | 147 | 502 (butabarbital) | | POS | 150 | 150 (Secobarbital) | {11} | Imola Qualitative | Neg | Less than half the cutoff conc. by GC/MS | Between 50% below the cutoff and the cutoff conc. | Between the cutoff and 50% above the cutoff conc. | Greater than 50% above the cutoff conc. | | --- | --- | --- | --- | --- | --- | | Positive | 0 | 15 | 13 | 23 | 73 | | Negative | 85 | 8 | 8 | 4 | 0 | | Imola Qualitative | Drug/ Metabolite GC/MS value (ng/mL) based on cross-reactivity profile | GCMS value of drug indicated (ng/mL) | | --- | --- | --- | | POS | 58 | 200 (Butabarbital) | | POS | 61 | 210 (Butabarbital) | | POS | 63 | 220 (Butabarbital) | | POS | 66 | 230 (Butabarbital) | | POS | 69 | 240 (Butabarbital) | | POS | 69 | 240 (Butabarbital) | | POS | 72 | 250 (Butabarbital) | | POS | 77 | 150 (Butalbital) | | POS | 87 | 168 (Butalbital) | | POS | 90 | 312 (Butabarbital) | | POS | 90 | 312 (Butabarbital) | | POS | 91 | 177 (Phenobarbital) | | POS | 94 | 182 (Butalbital) | | POS | 94 | 183 (Phenobarbital) | | POS | 99 | 193 (Phenobarbital) | | POS | 118 | 228 (Butalbital) | | POS | 126 | 245 (Butalbital) | | POS | 126 | 439 (Butabarbital) | | POS | 129 | 449 (Butabarbital) | | POS | 132 | 460 (Butabarbital) | {12} | POS | 145 | 502 (Butabarbital) | | --- | --- | --- | | POS | 145 | 502 (Butabarbital) | | POS | 150 | 150 (Secobarbital) | | POS | 160 | 160 (Secobarbital) | | POS | 161 | 559 (Butabarbital) | | POS | 180 | 180 (Secobarbital) | | POS | 190 | 369 (Butalbital) | | POS | 198 | 383 (Butalbital) | | NEG | 217 | 423 (Phenobarbital) | | NEG | 220 | 220 (Secobarbital) | | NEG | 240 | 240 (Secobarbital) | | NEG | 280 | 280 (Secobarbital) | Additional information was submitted by the sponsor to support that positive results for samples with GCMS values below 100 ng/mL were due to barbiturate metabolites. b. Matrix comparison: Not applicable. The test is only for urine specimens. 3. Clinical studies: a. Clinical Sensitivity: Not typically reviewed for this device type. b. Clinical specificity: Not typically reviewed for this device type. c. Other clinical supportive data (when a. and b. are not applicable): 4. Clinical cut-off: Not typically reviewed for this type of test. The analytical cutoff is 200 ng/mL for secobarbital. 5. Expected values/Reference range: Not applicable. {13} 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. 14