THERMO SCIENTIFIC CEDIA OPIATE OFT ASSAY

{0} 1 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY ASSAY ONLY TEMPLATE A. 510(k) Number: k101754 B. Purpose for Submission: New device C. Measurand: Opiates in oral fluid D. Type of Test: Qualitative immunoassay E. Applicant: Microgenics Corp. F. Proprietary and Established Names: Thermo Scientific CEDIA Opiate OFT Assay G. Regulatory Information: 1. Regulation section: 21 CFR 862.3650, opiate test system 2. Classification: Class II 3. Product code: DJG, enzyme immunoassay, opiates 4. Panel: Toxicology (91) {1} H. Intended Use: 1. Intended use(s): See indications for use below. 2. Indication(s) for use: The CEDIA® Opiate OFT Assay is intended for use in the qualitative determination of opiates at a cutoff of 30.0 ng/mL in neat oral fluid. The specimen must be collected exclusively with the Oral-Eze™ Saliva Collection System. The assay is calibrated against morphine and performed on the MGC 240. This in vitro diagnostic device is intended for clinical laboratory use only. The CEDIA Opiate OFT Assay provides only a preliminary analytical test result. A more specific alternative method must be used to obtain a confirmed analytical result. Gas Chromatography/Mass Spectrometry (GC/MS) and Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) are the preferred confirmatory methods. Clinical consideration and professional judgment should be applied to any drug of abuse test result particularly when preliminary positive results are used. 3. Special conditions for use statement(s): For prescription use only The assay is not designated for use in point-of-care settings. 4. Special instrument requirements: MGC 240 analyzer I. Device Description: Oral-Eze Saliva Collection System The Oral-Eze Saliva Collection System consists of Oral-Eze saliva collector and collection tube with preservative buffer. Oral-Eze saliva collector consists of an absorbent pad attached to a plastic handle. The saliva collector is provided with a volume adequacy indicator. The plastic handle has a round window where blue color will appear when sufficient volume of oral fluid is collected. Samples are collected by placing the collector pad and plastic shield between lower cheek and gum with the plastic shield facing the cheek. Oral fluid collection is done when blue color appears in the window of the handle. The pad is ejected in to the collection tube by placing thumb on the ridges on the handle and pushing the thumb forward. The collection tube is capped and sent to the laboratory for processing and testing {2} 3 # CEDIA® Opiate OFT Assay Reagents 1. EA Reconstitution Buffer Contains buffer salts, mouse monoclonal anti-amphetamine antibody, stabilizer, and preservative 1a EA Reagent Contains Enzyme Acceptor (microbial), buffer salts and preservative 2. ED Reconstitution Buffer Contains buffer salts, stabilizers, and preservative 2a ED Reagent Contains Enzyme Donor (microbial) conjugated to amphetamine derivative, chlorophenol red- $\beta$ -D-galactopyranoside, stabilizers, detergent and preservative ## Additional Materials Required (sold separately): 10014954 CEDIA Multi-Drug OFT Negative Calibrator 10014955 CEDIA Multi-Drug OFT Cutoff Calibrator 10014956 CEDIA Multi-Drug OFT High Calibrator 10014957 CEDIA Multi-Drug OFT Controls Kit Calibrators are cleared under k101752 ## J. Substantial Equivalence Information: 1. Predicate device name(s): OTI Opiates Micro-Plate EIA 2. Predicate 510(k) number(s): k981341 3. Comparison with predicate: | Items | CEDIA Opiate OFT Assay (Candidate Device) | OTI Opiates Micro-Plate EIA (Predicate Device) | | --- | --- | --- | | Similarity | | | | Intended use /Indication for use | Same | For use in the qualitative determination of opiates in oral fluid samples. For In Vitro Diagnostic Use. | | Sample type | Same | Oral fluid | | Calibrated against | Same | Morphine | | Difference | | | {3} | Cutoff | 30 ng/mL in Neat Oral Fluid | 10 ng/mL when oral fluid collected with the Oral Specimen Collection Device | | --- | --- | --- | | Collection Device | Oral-Eze | OraSure® | | Instrument | MGC 240 analyzer | Micro-plate reader | | Measuring wavelength | 570 nm (primary) 670 (secondary) | 450 nm | ## K. Standard/Guidance Document Referenced (if applicable): None were referenced. ## L. Test Principle: Microgenics CEDIA® Opiate OFT Assay uses recombinant DNA technology to produce a unique homogeneous enzyme immunoassay system. The assay is based on the bacterial enzyme β-galactosidase, which has been genetically engineered into two inactive fragments. These fragments spontaneously re-associate to form fully active enzyme that, in the assay format, cleave a substrate, generating a color change that can be measured spectrophotometrically. In the assay, analyte in the sample competes with analyte conjugated to one inactive fragment (enzyme donor) of β-galactosidase for antibody binding site. If analyte is present in the sample, it binds to antibody, leaving the inactive enzyme fragment free to form active enzyme. If the analyte is not present in the sample, antibody binds to analyte conjugated on the inactive fragment, inhibiting the re-association of inactive β-galactosidase fragments, and no active enzyme is formed. The amount of active enzyme formed and resultant absorbance change are directly proportional to the amount of analyte present in the sample. The Oral-Eze Saliva Collection System consists of Oral-Eze saliva collector and collection tube with preservative buffer. Oral-Eze saliva collector consists of an absorbent pad attached to a plastic handle. The saliva collector is provided with a volume adequacy indicator. The assay result is reported as a positive or negative result relative to the neat oral fluid cutoff of 30 ng/mL ## M. Performance Characteristics (if/when applicable): ### 1. Analytical performance: All analytical performance data was collected on human oral fluid samples collected with the Oral-Eze Saliva Collection System and analyzed on the MGC 240 analyzer. The collection device includes a diluent that results in a dilution of approximately 1/3. The assay cannot be used to measure undiluted (neat) {4} samples. Analyte concentrations refer to the neat oral fluid concentration, unless otherwise noted. # a. Precision/Reproducibility: Negative neat oral fluid samples were collected by spitting into a cup. Testing samples were prepared by spiking morphine into the negative neat oral fluid. The samples were applied onto the pad of Oral-Eze collection device (n=2 pad/level) and eluted following the instruction menu. Precision were evaluated following randomized CLSI (EP5-A2) precision protocol as in study 1. Note: The values obtained in this study were collected from samples containing opiates prior to the collection step. Therefore the results reflect the performance of the entire system including the collection step. The results are summarized in the table below: | Analyte | Concentration of sample | Opiate OFT Assay # Neg / # Pos | | --- | --- | --- | | Morphine | Negative | 50 Neg / 0 Pos | | Morphine | -75% | 50 Neg / 0 Pos | | Morphine | -50% | 50 Neg / 0 Pos | | Morphine | -25% | 50 Neg / 0 Pos | | Morphine | Cutoff | 0 Neg / 50 Pos | | Morphine | 25% | 0 Neg / 50 Pos | | Morphine | 50% | 0 Neg / 50 Pos | | Morphine | 75% | 0 Neg / 50 Pos | # b. Linearity/assay reportable range: Not applicable. This is a qualitative assay. # c. Traceability, Stability, Expected values (controls, calibrators, or methods): See k101752 decision summary for information on calibrators. # Reagent stability: Real time testing is on-going to support the product shelf life of 3 years. The stability protocol was reviewed and found acceptable. The current test results support the stability at $2 - 8^{\circ}\mathrm{C}$ for 24 months. The on board stability of reconstituted reagents is 60 days $(2 - 8^{\circ}\mathrm{C})$ . # Sample storage and stability: {5} The stability of oral fluid samples in the preservative buffer was evaluated in real time. The stability protocol was reviewed and found acceptable. Oral fluid samples in the preservative buffer can be stored at 2-8°C or at room temperature (21-25°C) for 21 days. ## Sample shipment/travel stability: Conditions simulating ground shipping, air shipping and various climate conditions (desert, tropical) were tested. Neat samples spiked at concentrations below the cutoff recovered as negative for both the control and shipped samples. Samples spiked at concentrations above the cutoff recovered as positive for both the control and shipped samples. ## d. Detection limit: Analytical performance of the device around the cutoff is described in the precision section 1.a above. ## e. Analytical specificity: ### Cross-reactivity: Pooled neat drug-free oral fluid samples were collected by spitting into a cup. The cross-reactant solutions were prepared by adding the compounds to neat oral fluid samples at the concentration listed in the table below. The neat oral fluid samples were processed using the Oral-Eze device to obtain diluted oral fluid samples which were tested in the CEDIA Opiate OFT Assay. The table below lists the concentrations of each compound that gave a response approximately equal to the cutoff. Structurally Related Compounds: | Compounds | Tested Concentration in Neat Oral Fluid* (ng/mL) | Response Equivalent to the cutoff | | --- | --- | --- | | Codeine | 24 | Positive | | Diacetylmorphine | 42 | Positive | | Hydrocodone | 36 | Positive | | Hydromorphone | 42 | Positive | | Imipramine | 2,100 | Positive | | Morphine-3-Glucoronide | 37.5 | Positive | | Morphine-6-Glucoronide | 75 | Positive | | 6-Monoacetylmorphine | 37.5 | Positive | | Meperidine | 18,000 | Positive | | Oxymorphone | 1,800 | Positive | | Oxycodone | 1,050 | Positive | {6} *The concentrations listed were the lowest levels yielding positive results in the assay. Potential interference from structurally unrelated compounds and various common over-the-counter medications were tested by spiking the potentially interfering compound into neat oral fluid, and then processed through the oral fluid collection device. | Compounds E | Tested Concentration In Neat Oral Fluid (ng/mL) | Response Equivalent to the cutoff | | --- | --- | --- | | Acetaminophen | 1,800,000 | Negative | | Acetylsalicylic Acid | 1,800,000 | Negative | | Alprazolam | 30,000 | Negative | | Amobarbital | 30,000 | Negative | | Amoxicillin | 240,000 | Negative | | Amphetamine | 240,000 | Negative | | Ampicillin | 30,000 | Negative | | Atropine | 30,000 | Negative | | β-Phenethylamine | 30,000 | Negative | | Buproprion | 30,000 | Negative | | Butabarbital | 30,000 | Negative | | Butalbital | 30,000 | Negative | | Caffeine | 60,000 | Negative | | Captopril | 1,800,000 | Negative | | Chlordiazepoxide | 240,000 | Negative | | Chlorpromazine | 30,000 | Negative | | Cimetidine | 600,000 | Negative | | Clonazepam | 30,000 | Negative | | Clorazepate | 30,000 | Negative | | Codeine | 120,000 | Negative | | Cotinine | 30,000 | Negative | | Cyclizine | 6,000 | Negative | | Dextromethorphan | 30,000 | Negative | | Diazepam | 90,000 | Negative | | Digoxin | 120,000 | Negative | | Diphenhydramine | 30,000 | Negative | | Enalapril | 600,000 | Negative | | Fluoxetine | 600,000 | Negative | | Gentisic Acid | 30,000 | Negative | | Ibuprofen | 600,000 | Negative | | l-Ephedrine | 30,000 | Negative | | Levothyroxine | 600,000 | Negative | | Lidocaine | 30,000 | Negative | | Loperamide | 30,000 | Negative | | Medazepam | 30,000 | Negative | | Methadone | 240,000 | Negative | | Methamphetamine | 240,000 | Negative | | Metoprolol | 30,000 | Negative | | Naproxen | 30,000 | Negative | | Niacinamide | 30,000 | Negative | | Nicotine | 30,000 | Negative | | Nifedipine | 3,000,000 | Negative | | Norchlordiazepoxide | 30,000 | Negative | | Nordiazepam | 30,000 | Negative | {7} # Interference: The potential interference from several endogenous and exogenous substances, and pH on the detection accuracy of samples containing morphine at $+/- 50\%$ of the cutoff concentration were tested in the assay. The interfering substances were added to neat oral fluid at the concentrations listed in the table below. The neat oral fluid samples were processed using the Oral-Eze collection device and tested in the CEDIA Opiate OFT Assay. | Compounds | Tested Conc. in Neat Oral fluid | Opiate OFT Assay | | | --- | --- | --- | --- | | | | -50% Morphine | +50% Morphine | | Cotinine | 0.03 mg/mL | Negative | Positive | | Nicotine | 0.015 mg/mL | Negative | Positive | | Hemoglobin | 0.6 mg/mL | Negative | Positive | | Human serum albumin | 24 mg/mL | Negative | Positive | | Sodium Chloride | 18 mg/mL | Negative | Positive | | Cholesterol | 45 mg/mL | Negative | Positive | | Acetaminophen | 0.3 mg/mL | Negative | Positive | | Acetylsalicylic Acid | 0.3 mg/mL | Negative | Positive | | Caffeine | 0.06 mg/mL | Negative | Positive | | Ibuprofen | 0.12 mg/mL | Negative | Positive | | Coffee | 6% v/v | Negative | Positive | | Milk | 3% v/v | Negative | Positive | | Orange Juice | 6% v/v | Negative | Positive | | Cranberry Juice | 6% v/v | Negative | Positive | | Soft drink (Coke) | 6% v/v | Negative | Positive | | Toothpaste | 6% v/v | Negative | Positive | | Mouthwash | 6% v/v | Negative | Positive | | Tea | 6% v/v | Negative | Positive | | Denture Adhesive | 6% v/v | Negative | Positive | | Alcohol | 6% v/v | Negative | Positive | | Baking Soda | 6% v/v | Negative | Positive | | Cough Syrup | 6% v/v | Negative | Positive | | Whole Blood | 6% v/v | Negative | Positive | | Hydrogen Peroxide | 6% v/v | Negative | Positive | | pH | 5-9 | Negative | Positive | Potential interference from additional food and dental compounds was tested by collecting neat oral fluid from volunteers after use of the following substances: hard candy, chewing gum, chewing tobacco, cigarettes and tooth whitening strips. {8} | Compounds | Tested Concentration in Neat Oral Fluid | Opiates OFT Assay Results | | | --- | --- | --- | --- | | | | -50% Opiates | +50% Opiates | | Water | n/a | Negative | Positive | | Chewing Tobacco | n/a | Negative | Positive | | Cigarettes | n/a | Negative | Positive | | Gum | n/a | Negative | Positive | | Hard Candy | n/a | Negative | Positive | | Tooth Whitening Strips | n/a | Negative | Positive | f. Assay cut-off: Characterization of how the device performs analytically around the claimed cutoff concentration appears in the precision above. 2. Comparison studies: a. Method comparison with predicate device: Study 1: Eighty two unaltered neat oral fluid samples were processed using the Oral-Eze collection device. The diluted oral fluid samples after passing the collection device were tested by the CEDIA Opiate OFT Assay and by the GC-MS method. Note: this study was performed on samples already collected with the Intercept collection device. When the GC-MS values of the diluted samples were compared to the immunoassay values, the following results were obtained. Therefore the results below do not reflect any inaccuracy inherent in the collection process itself. {9} 10 | Candidate Device Result | Negative | Less than half the cutoff concentration by GC-MS analysis | Near Cutoff Negative (Between 50% below the cutoff and the cutoff concentration) | Near Cutoff Positive (Between the cutoff and 50% above the cutoff concentration) | High Positive (greater than 50% above the cutoff concentration) | | --- | --- | --- | --- | --- | --- | | Negative | 33 | 4 | 4 | 0 | 0 | | Positive | 0 | 0 | 1* | 4 | 36 | - Discrepant result – The sample contained 9 ng/mL morphine by GC/MS - * This sample initially tested positive, but was found to be negative when retested The overall concordance between CEDIA Opiate OFT Assay (not including the collection step) and GC-MS in diluted oral fluid is 97.6%. ## Study 2: Forty-two natural (unaltered) neat oral fluid samples from rehabilitation clinics were collected. The neat oral fluid samples were processed using the Oral-Eze collection device. Both the neat and diluted oral fluid samples were tested by LC-MS/MS method while only the diluted samples were tested in the CEDIA Opiate OFT Assay. Note: The values obtained in this study were collected from samples containing opiates prior to the collection step. Therefore the results reflect the performance of the entire system including the collection step. | Candidate Device Result | Less than half the cutoff concentration by LC-MS/MS analysis | Near Cutoff Negative (Between 50% below the cutoff and the cutoff concentration) | Near Cutoff Positive (Between the cutoff and 50% above the cutoff concentration) | High Positive (greater than 50% above the cutoff concentration) | | --- | --- | --- | --- | --- | | Negative | 18 | 2 | 1* | 0 | | Positive | 0 | 0 | 3 | 18 | *Sample was confirmed positive by LC-MS/MS Discrepant sample: | Discrepant Sample # | OFT assay (POS/NEG) | Neat Sample LC/MS value (ng/mL) | | --- | --- | --- | | 21 | Negative | 30.39 | {10} The overall concordance between CEDIA Opiate OFT Assay (including the collection step) and LC-MS/MS using a cutoff of 30 ng/mL in neat oral fluid is 97.6%. b. Matrix comparison: Not applicable. The assay is intended for only one sample matrix. 3. Clinical studies: a. Clinical Sensitivity: Not applicable. Clinical studies are not typically submitted for this device type. b. Clinical specificity: Not applicable. Clinical studies are not typically submitted for this device type. 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. 11