(51 days)
The CEDIA Heroin Metabolite (6-Acetylmorphine, or 6-AM) Assay is a homogeneous enzyme immunoassay for the in vitro qualitative and/or semi-quantitative determination of the presence of heroin metabolite (6-AM) in human urine at a cut-off concentration of 10 ng/mL. The assay is intended to be used in laboratories and provides a rapid analytical screening procedure to detect 6-Acetylmorphine in human urine. The assay is designed for use with a number of clinical chemistry analyzers. This product is intended to be used by trained professionals only.
The semi-quantitative mode is for the purpose of enabling laboratories to determine an appropriate dilution of the specimen for confirmation by a confirmatory method such as Liquid Chromatography/tandem mass spectrometry (LC-MS/MS) or permitting laboratories to establish quality control procedures.
The assay provides only a preliminary analytical test result. A more specific alternative chemical must be used to obtain a confirmed analytical result. Gas chromatography/ mass spectrometry (GC/MS) or Liquid chromatography/ mass spectrometry (LC-MS/MS) is the preferred confirmatory method.
Clinical and professional judgment should be applied to any drug of abuse test result, particularly when preliminary results are used. For In Vitro Diagnostic Use Only.
The assay consists of buffers (1 and 2) and Ivophilized reagents (1a and 2a). The components include mouse monoclonal antibodies to 6-Acetylmorphine, recombinant microbial enzyme donor (ED) – 6-Acetylmorphine conjugate: enzyme acceptor (EA), chlorophenol red 3-D-galactopyranoside; stabilizers and preservatives. Calibrators and controls are sold separately.
The document describes the analytical performance of the CEDIA Heroin Metabolite (6-AM) Assay for detecting 6-Acetylmorphine in human urine. Here's a breakdown of the acceptance criteria and the study that proves the device meets them:
1. Table of Acceptance Criteria and Reported Device Performance
The acceptance criteria are not explicitly stated as a target range for each metric, but rather implied by the successful demonstration of performance in each analytical study. The reported device performance is provided in detailed tables for each study.
| Acceptance Criteria (Implied by study objective) | Reported Device Performance (Summary) |
|---|---|
| Precision | Qualitative: |
| - Ability to correctly classify samples at varying concentrations. | - 100% agreement for negative samples from 0 to 7.5 ng/mL (n=80 each). |
| - Low variability in results. | - 100% agreement for positive samples from 12.5 to 21.5 ng/mL (n=80 each). |
| - At 10 ng/mL cutoff: 56 Negative / 24 Positive (n=80), indicating some variability near the cutoff. | |
| Semi-Quantitative: | |
| - 100% agreement for negative samples from 0 to 7.5 ng/mL (n=80 each). | |
| - 100% agreement for positive samples from 12.5 to 21.5 ng/mL (n=80 each). | |
| - At 10 ng/mL cutoff: 42 Negative / 38 Positive (n=80), indicating some variability near the cutoff. | |
| Spike Recovery | Qualitative: |
| - Accurate differentiation of concentrations around the cutoff. | - 7.5 ng/mL (below cutoff): All 20 replicates negative. |
| - 12.5 ng/mL (above cutoff): All 20 replicates positive. | |
| Semi-Quantitative: | |
| - 7.5 ng/mL (below cutoff): All 20 replicates negative. | |
| - 12.5 ng/mL (above cutoff): All 20 replicates positive. | |
| Analytical Recovery and Linearity | - Percent recovery between 97.0% and 113.0% for various concentrations (2 ng/mL to 20 ng/mL). |
| - Consistent performance across the assay range. | |
| Method Comparison and Accuracy (Concordance with LC-MS/MS) | Overall Concordance with LC-MS/MS: 99% |
| - High agreement with a confirmatory method (LC-MS/MS). | Qualitative & Semi-Quantitative Results: |
| - Agreement among Positives: 50/50 = 100%. | |
| - Agreement among Negatives: 49/50 = 98%. | |
| - One discordant sample (Positive by immunoassay, 9.61 ng/mL by LC-MS/MS, attributable to cross-reactivity with high morphine concentration). | |
| Specificity (Cross-Reactivity) | Heroin Metabolite (6-AM) and its metabolites: |
| - Low cross-reactivity to other substances, especially structurally related or unrelated compounds. | - 6-Acetylmorphine: 100% cross-reactivity. |
| - Heroin: 6% cross-reactivity. | |
| Structurally Related or Unrelated Opiate Compounds: | |
| - Generally very low cross-reactivity (<0.01% to 0.10%) for a wide range of common opiates and related compounds (e.g., Codeine, Fentanyl, Morphine, Naloxone, Oxycodone) at very high tested concentrations (e.g., 20,000 ng/mL to 100,000 ng/mL). Morphine showed 0.07% at 13,500 ng/mL. Hydromorphone and Levorphanol showed 0.05% at 20,000 ng/mL. | |
| Structurally Unrelated Compounds: | |
| - No interference observed for a wide range of common drugs and substances tested at high concentrations (e.g., Acetaminophen, Amphetamine, Ibuprofen, Caffeine, Phencyclidine, etc.), maintaining the correct classification (Negative for Low Control, Positive for High Control). | |
| Interference (pH and Endogenous Substances) | - No interference observed from various endogenous compounds (e.g., Creatinine, Glucose, Hemoglobin, Urea) and pH levels ranging from 3 to 10. |
| - Robustness to common sample variations. | - pH 11 urine was noted to interfere with the assay. |
| Specific Gravity | - No interference observed across clinically relevant specific gravity ranges (1.002 to 1.030). |
| - Consistent performance across urine density. |
2. Sample Sizes Used for the Test Set and Data Provenance
- Precision Study: 80 replicates (2 runs/day, 2 times a day for 20 days) for each of the 9 spiked concentrations (total 720 tests per mode, Qualitative and Semi-Quantitative).
- Spike Recovery: 20 replicates for each of the 3 spiked concentrations (total 60 tests per mode, Qualitative and Semi-Quantitative).
- Analytical Recovery and Linearity: Replicates of five for each of the 11 intermediate levels created from dilutions. Total 55 tests.
- Method Comparison and Accuracy: 100 unaltered patient samples.
- Specificity (Cross-Reactivity): Varies per substance, but single concentrations were tested for each compound.
- Interference (pH and Endogenous Substances): Single concentrations were tested for each compound, at both Low and High Control levels.
- Specific Gravity: Unspecified number of samples across the range of 1.002 to 1.030, tested at both Low and High Control levels.
Data Provenance: The studies were performed at the manufacturer's site (Microgenics Corporation, Thermo Fisher Scientific, Fremont, CA). The data appears to be prospective as it involves controlled spiking of samples and testing in a laboratory setting to evaluate the device's performance characteristics. The specific country of origin for the patient samples in the method comparison study is not mentioned, but given the manufacturer's location, it is likely the United States. The term "unaltered patient samples" implies a retrospective collection of samples if they were banked, but the testing itself was prospective.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications
For the CEDIA Heroin Metabolite (6-AM) Assay, the "ground truth" for the test set (primarily for method comparison and accuracy) was established by Liquid Chromatography/tandem mass spectrometry (LC-MS/MS). This is an analytical chemical method, not human expert interpretation. Therefore, the concept of "number of experts" and their "qualifications" in the traditional sense of medical image or clinical diagnosis interpretation does not directly apply here. LC-MS/MS is considered the definitive confirmatory method for drug concentration.
4. Adjudication Method for the Test Set
Not applicable, as the ground truth is established by a definitive analytical method (LC-MS/MS), not by human interpretation requiring adjudication. Any discrepancies between the assay and LC-MS/MS are analyzed and explained (e.g., the one discordant sample in the method comparison was attributed to cross-reactivity with morphine).
5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done, and if so, what was the effect size of how much human readers improve with AI vs without AI assistance
Not applicable. This device is an in vitro diagnostic immunoassay, not an AI-assisted diagnostic tool that aids human readers (e.g., radiologists interpreting images). The study focuses on the assay's analytical performance against a gold standard chemical method, not on human interpretive performance.
6. If a standalone (i.e., algorithm only without human-in-the-loop performance) was done
This is fundamentally a "standalone" or "algorithm only" study in the context of IVD devices. The CEDIA Immunoassay operates as an automated system on clinical chemistry analyzers, generating a result without direct human interpretation of a visual output that would then be further modified by a human. While trained professionals operate the analyzer, the core measurement and qualitative/semi-quantitative determination are performed by the device itself based on the chemical reaction. The performance metrics reported are for the device's output compared to a reference method.
7. The Type of Ground Truth Used (expert consensus, pathology, outcomes data, etc.)
The primary ground truth used is confirmatory analytical methods, specifically Liquid Chromatography/tandem mass spectrometry (LC-MS/MS). This is considered the "gold standard" for precise and accurate quantification of drug metabolites in biological samples. For other studies like precision or linearity, the ground truth is the known spiked concentrations of 6-acetylmorphine into drug-free urine.
8. The Sample Size for the Training Set
Not applicable. This device is an immunoassay, not an AI/machine learning model that requires a distinct "training set" in the computational sense. The "development" or "training" of such assays involves chemical formulation and optimization, followed by rigorous analytical validation studies as described.
9. How the Ground Truth for the Training Set Was Established
Not applicable (as explained in point 8). The assay's chemical reagents and methodology are developed and optimized based on chemical principles and prior knowledge of enzyme immunoassays, rather than learning from a labeled training dataset in the AI sense.
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Image /page/0/Picture/0 description: The image contains the logo of the U.S. Food and Drug Administration (FDA). On the left is the Department of Health & Human Services logo. To the right of that is the FDA logo, which is a blue square with the letters "FDA" in white. To the right of the blue square is the text "U.S. FOOD & DRUG ADMINISTRATION" in blue.
November 22, 2017
Microgenics Corporation Minoti Patel Manager, Regulatory Affairs 46500 Kato Road Fremont, California 94538
Re: K173183
Trade/Device Name: CEDIA Heroin Metabolite (6-AM) Assay Regulation Number: 21 CFR 862.3650 Regulation Name: Opiate test system Regulatory Class: Class II Product Code: DJG Dated: September 28, 2017 Received: October 2, 2017
Dear Minoti Patel:
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food. Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR
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Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.
For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/) and CDRH Learn (http://www.fda.gov/Training/CDRHLearn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (http://www.fda.gov/DICE) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely,
Stayce Beck -A
For: Courtney H. Lias, Ph.D. Director Division of Chemistry and Toxicology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known) K173183
Device Name CEDIA Heroin Metabolite (6-AM) Assay
Indications for Use (Describe)
CEDIA Heroin Metabolite (6-AM) Assay:
The CEDIA Heroin Metabolite (6-Acetylmorphine, or 6-AM) Assay is a homogeneous enzyme immunoassay for the in vitro qualitative and/or semi-quantitative determination of the presence of heroin metabolite (6-AM) in human urine at a cut-off concentration of 10 ng/mL. The assay is intended to be used in laboratories and provides a rapid analytical screening procedure to detect 6-Acetylmorphine in human urine. The assay is designed for use with a number of clinical chemistry analyzers. This product is intended to be used by trained professionals only.
The semi-quantitative mode is for the purpose of enabling laboratories to determine an appropriate dilution of the specimen for confirmation by a confirmatory method such as Liquid Chromatography/tandem mass spectrometry (LC-MS/MS) or permitting laboratories to establish quality control procedures.
The assay provides only a preliminary analytical test result. A more specific alternative chemical must be used to obtain a confirmed analytical result. Gas chromatography/ mass spectrometry (GC/MS) or Liquid chromatography/ mass spectrometry (LC-MS/MS) is the preferred confirmatory method.
Clinical and professional judgment should be applied to any drug of abuse test result, particularly when preliminary results are used. For In Vitro Diagnostic Use Only.
| Type of Use (Select one or both, as applicable) | |
|---|---|
| Prescription Use (Part 21 CFR 801 Subpart D) | Over-The-Counter Use (21 CFR 801 Subpart C) |
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K173183
510(k) Summary
This 510(k) Summary of Safety and Effectiveness is being submitted in accordance with the requirements of Safe Medical Device Act of 1990 and 21 CFR 807.92.
A. Device Information
| Category | Comments |
|---|---|
| Sponsor: | Microgenics CorporationThermo Fisher Scientific46500 Kato RoadFremont, CA 94538Phone: 510-979-5000FAX: 510-979-5002 |
| Correspondent ContactInformation: | Minoti Patel, RACManager, Regulatory AffairsEmail: Minoti.patel@thermofisher.comPhone: 510-979-5000FAX: 510-979-5002 |
| Device Common Name: | 6-Acetylmorphine Immunoassay Test System |
| Trade or Proprietary Name | CEDIA Heroin Metabolite (6-AM) Assay |
| Candidate Device ProductCode, Classification,Classification,Name & Panel | DJG, Class II, 21 CFR 862.3650 – Opiate testsystem, 91 – Toxicology |
Predicate Device Information:
| Predicate Device: | CEDIA DAU 6-AcetylmorphineAssay |
|---|---|
| Predicate Device Manufacturer: | Microgenics Corporation |
| Predicate Device PremarketNotification #: | K001178 |
B. Date Summary Prepared
November 21, 2017
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C. Description of Device
The assay consists of buffers (1 and 2) and Ivophilized reagents (1a and 2a). The components include mouse monoclonal antibodies to 6-Acetylmorphine, recombinant microbial enzyme donor (ED) – 6-Acetylmorphine conjugate: enzyme acceptor (EA), chlorophenol red 3-D-galactopyranoside; stabilizers and preservatives. Calibrators and controls are sold separately.
D. Intended Use
CEDIA Heroin Metabolite (6-AM) Assay
The CEDIA Heroin Metabolite (6-Acetylmorphine, or 6-AM) Assay is a homogeneous enzyme immunoassay for the in vitro qualitative and/or semi-quantitative determination of the presence of heroin metabolite (6-AM) in human urine at a cut-off concentration of 10 ng/mL. The assay is intended to be used in laboratories and provides a rapid analytical screening procedure to detect 6-Acetylmorphine in human urine. The assay is designed for use with a number of clinical chemistry analyzers. This product is intended to be used by trained professionals only.
The semi-quantitative mode is for the purpose of enabling laboratories to determine an appropriate dilution of the specimen for confirmation by a confirmatory method such as Liquid Chromatography/tandem mass spectrometry (LC-MS/MS) or permitting laboratories to establish quality control procedures.
The assay provides only a preliminary analytical test result. A more specific alternative chemical method must be used to obtain a confirmed analytical result. Gas chromatography/ mass spectrometry (GC/MS) or Liquid chromatography/ mass spectrometry (LC-MS/MS) is the preferred confirmatory method.
Clinical and professional judgment should be applied to any drug of abuse test result, particularly when preliminary results are used. For In Vitro Diagnostic Use Only.
| Characteristic | Predicate Device:CEDIA DAU 6-AcetylmorphineAssay (K001178) | Candidate Device:CEDIA Heroin Metabolite(6-AM) Assay |
|---|---|---|
| Intended Use | A homogeneous enzymeimmunoassay for the in vitroqualitative or semi-quantitativedetermination of 6-Acetylmorphine in human urine ata cut-off concentration of 10ng/mL | Same |
| Operating | CEDIA | Same |
E. Comparison to Predicate Device
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| Characteristic | Predicate Device:CEDIA DAU 6-AcetylmorphineAssay (K001178) | Candidate Device:CEDIA Heroin Metabolite(6-AM) Assay |
|---|---|---|
| Principle(Technology) | ||
| Measured Analyte | Heroin and 6-Acetylmorphine | Same |
| Test Matrix | Urine | Same |
| Cutoff Levels | 10 ng/mL | Same |
| Methodology | Homogeneous EnzymeImmunoassay | Same |
| Reagents Form | EA and ED: liquid ready-to-use. | EA and ED: Lyophilized(Reconstitution Required)EARB and EDRB liquidready-to-use. |
| Antibody | Mouse Monoclonal antibody | Same |
| Storage | 2-8°C until expiration date. | Same |
| PrincipalOperator | Trained professionals | Same |
F. Test Principle
The CEDIA Heroin Metabolite Assay uses recombinant DNA technology to produce a homogeneous enzyme immunoassay system. This assay is based on the bacterial enzyme ß-galactosidase, which has been genetically engineered into two inactive fragments. These fragments, termed Enzyme Acceptor (EA) and Enzyme Donor (ED) spontaneously re-associate to form a fully active enzyme that, in the assay format, cleaves a substrate, generating a color change that can be measured spectrophotometrically.
G. Summary of Supporting Data
1. Analytical Performance:
Performance was evaluated at the manufacturer's site on Beckman Coulter AU 680 Analyzer.
a) Precision
Precision studies were performed in accordance with CLSI Guideline EP05-A3. The study was performed for two runs per day, twice a day, for 20 days (total n=80). Samples were prepared by spiking 6-Acetylmorphine methanol stock solution into drug free urine at the cutoff, 25%, 50%, 75% & 100% above and below the cutoff and tested in both qualitative and semi-quantitative modes. The results are summarized in the tables below.
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| % of Cutoff | Spiked Conc.(ng/mL) | GC/MS(ng/mL) | Within Run (n=80) | |
|---|---|---|---|---|
| Number ofdeterminants | ImmunoassayResults | |||
| -100% | 0 | N/A | 80 | 80 Negative |
| -75% | 2.5 | 2.67 | 80 | 80 Negative |
| -50% | 5 | 5.17 | 80 | 80 Negative |
| -25% | 7.5 | 7.82 | 80 | 80 Negative |
| 100% | 10 | 10.2 | 80 | 56 Negative/24 Positive |
| +25% | 12.5 | 12.8 | 80 | 80 Positive |
| +50% | 15 | 15.2 | 80 | 80 Positive |
| +75% | 17.5 | 18.0 | 80 | 80 Positive |
| +100% | 20 | 21.5 | 80 | 80 Positive |
Qualitative Results:
Semi-Quantitative Results:
| % of Cutoff | SpikedConc.(ng/mL) | GC/MS(ng/mL) | Within Run (n=80) | |
|---|---|---|---|---|
| Number ofdeterminants | ImmunoassayResults | |||
| -100% | 0 | N/A | 80 | 80 Negative |
| -75% | 2.5 | 2.67 | 80 | 80 Negative |
| -50% | 5 | 5.17 | 80 | 80 Negative |
| -25% | 7.5 | 7.82 | 80 | 80 Negative |
| 100% | 10 | 10.2 | 80 | 42 Negative/38 Positive |
| +25% | 12.5 | 12.8 | 80 | 80 Positive |
| +50% | 15 | 15.2 | 80 | 80 Positive |
| +75% | 17.5 | 18.0 | 80 | 80 Positive |
| +100% | 20 | 21.5 | 80 | 80 Positive |
b) Spike Recovery
The study was performed for 20 replicates using reagents, calibrators and controls. This study was carried out by testing spiked samples containing 6-Acetylmorphine at the cutoff calibrator and controls levels. The spiked samples were prepared by spiking 6-Acetylmorphine into drug free negative urine. Samples were tested in both Qualitative and Semi-Quantitative mode. The qualitative and semi-quantitative results are summarized in the table below.
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| Replicate | 7.5 ng/mL(n=20) | 10 ng/mL(n=20)(Rate mA/min) | 12.5 ng/mL(n=20) |
|---|---|---|---|
| 1 | Negative | 515 | Positive |
| 2 | Negative | 513 | Positive |
| 3 | Negative | 515 | Positive |
| 4 | Negative | 515 | Positive |
| 5 | Negative | 516 | Positive |
| 6 | Negative | 513 | Positive |
| 7 | Negative | 512 | Positive |
| 8 | Negative | 519 | Positive |
| 9 | Negative | 515 | Positive |
| 10 | Negative | 517 | Positive |
| 11 | Negative | 517 | Positive |
| 12 | Negative | 518 | Positive |
| 13 | Negative | 518 | Positive |
| 14 | Negative | 517 | Positive |
| 15 | Negative | 515 | Positive |
| 16 | Negative | 516 | Positive |
| 17 | Negative | 520 | Positive |
| 18 | Negative | 515 | Positive |
| 19 | Negative | 516 | Positive |
| 20 | Negative | 518 | Positive |
| Overlap | No | No | No |
| Relative to C/O | All 20 below C/O | N/A | All 20 above C/O |
c) Analytical Recovery and Linearity
Linearity studies were performed in accordance with CLSI Guideline EP06-A. To demonstrate the linearity of the entire assay range, drug free urine was spiked to the high calibrator level (20ng/mL) by using 6-AM methanol solution and diluted with drug free urine to generate 10 intermediate levels.
Each sample was run in replicates of five in semi-quantitative mode and the average was used to determine percent recovery compared to the expected target value. The percent recovery is summarized in the table below.
| Level | TargetConcentration(ng/mL) | ObservedConcentration(ng/mL) | Recovery (%) |
|---|---|---|---|
| 1 | 0 | 0.18 | N/A |
| 2 | 2 | 2.26 | 113.0 |
| 3 | 4 | 4.02 | 100.5 |
| 4 | 6 | 6.10 | 101.7 |
| 5 | 8 | 7.86 | 98.3 |
| 6 | 10 | 9.88 | 98.8 |
| 7 | 12 | 11.90 | 99.2 |
| 8 | 14 | 13.72 | 98.0 |
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| 9 | 16 | 15.52 | 97.0 |
|---|---|---|---|
| 10 | 18 | 18.04 | 100.2 |
| 11 | 20 | 19.64 | 98.2 |
d) Method Comparison and Accuracy
The method comparison study was performed in accordance with CLSI Guideline EP09-A3. One hundred unaltered patient samples were analyzed by the CEDIA Heroin Metabolite (6-Acetylmorphine) Assay in both qualitative and semi-quantitative modes and the results are compared to LC-MS/MS. The overall concordance between LC-MS/MS and CEDIA Heroin Metabolite (6-Acetylmorphine) Assay is 99%. The qualitative and semi-quantitative results are summarized in the tables below.
Qualitative Results
| CandidateDeviceResults | Negative | < 50% ofCutoffconcentrationby LC-MS/MS(<5ng/mL) | Near CutoffNegative(Between 50%below the cutoffand the cutoffconcentration asdetermined byLC-MS/MS)(5 – 9.9 ng/mL) | Near CutoffPositive(Between thecutoff and 50%above the cutoffconcentration asdetermined byLC-MS/MS)(10 – 15.0ng/mL) | High Positives(Greater than50% abovecutoffconcentration(> 15.0ng/mL) |
|---|---|---|---|---|---|
| Positive | 0 | 0 | 1* | 5 | 45 |
| Negative | 43 | 2 | 4 | 0 | 0 |
- Discordant sample
Agreement among Positives: 50/50 =100% Agreement among Negative: 49/50=98%
Semi-Quantitative Results
| CandidateDeviceResults | Negative | < 50% ofCutoffconcentrationby LC-MS/MS(< 5ng/mL) | Near CutoffNegative(Between 50%below the cutoffand the cutoffconcentration asdetermined byLC-MS/MS)(5 - 9.9 ng/mL) | Near CutoffPositive(Between thecutoff and 50%above the cutoffconcentration asdetermined byLC-MS/MS)(10 - 15.0ng/mL) | High Positives(Greater than50% abovecutoffconcentration(> 15.0ng/mL) |
|---|---|---|---|---|---|
| Positive | 0 | 0 | 1* | 5 | 45 |
| Negative | 43 | 2 | 4 | 0 | 0 |
- Discordant sample
Agreement among Positives: 50/50 =100% Agreement among Negative: 49/50=98%
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* Discordant Result Summary
| Sample ID | CEDIA 6-AM Urine Assay | LC-MS/MS (ng/mL) | |
|---|---|---|---|
| Qualitative mode | Semi-Quantitative mode | 6-Acetylmorphine | |
| CA170418-025 | Positive | Positive | 9.61 |
Sample showed 13.8 ng/mL in semi-quantitative mode, and is discordant due to cross reactivity to morphine present in the sample at a concentration of 4449 ng/mL as measured by LC-MS/MS
e) Specificity
The cross-reactivity of Heroin Metabolite (6-AM) and its metabolites is evaluated by adding known amounts of each analyte to drug-free negative urine. As indicated by the results in the table below, 6-Acetylmorphine showed 100% cross-reactivity. Heroin showed 6% cross-reactivity.
| Heroin Metabolite (6-AM) and itsmetabolites | Tested Concentration(ng/mL) | Cross-reactivity(%) |
|---|---|---|
| 6-Acetylmorphine | 10 | 100 |
| Heroin | 160 | 6 |
Cross Reactivity of Structurally Related or Unrelated Opiate Compounds
| Opiates and Structurally RelatedCompounds | Tested Concentration(ng/mL) | Cross-reactivity (%) |
|---|---|---|
| 6-Acetylcodeine | 100,000 | 0.01 |
| Buprenorphine | 100,000 | <0.01 |
| Buprenorphine-3β-D-glucuronide | 100,000 | <0.01 |
| Codeine | 100,000 | <0.01 |
| Dextromethorphan | 100,000 | <0.01 |
| Dihydrocodeine | 100,000 | <0.01 |
| EDDP | 100,000 | <0.01 |
| EMDP | 100,000 | <0.01 |
| Ethylmorphine | 100,000 | <0.01 |
| Fentanyl | 100,000 | <0.01 |
| Hydrocodone | 100,000 | <0.01 |
| Hydromorphone | 20,000 | 0.05 |
| Hydromorphone-3β-D-glucuronide | 100,000 | <0.01 |
| LAAM | 100,000 | <0.01 |
| Levorphanol | 20,000 | 0.05 |
| Methadone | 100,000 | <0.01 |
| Meperidine | 100,000 | <0.01 |
| Mitragynine | 100,000 | <0.01 |
| 7-Hydroxymitragynine | 100,000 | <0.01 |
| Morphine | 13,500 | 0.07 |
| Morphine-3β-D-Glucuronide | 100,000 | <0.01 |
| Morphine-6β-D-Glucuronide | 100,000 | <0.01 |
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| Nalorphine | 10,500 | 0.10 |
|---|---|---|
| Naloxone | 100,000 | <0.01 |
| Naltrexone | 100,000 | <0.01 |
| Norbuprenorphine | 100,000 | <0.01 |
| Norbuprenorphine glucuronide | 100,000 | <0.01 |
| Opiates and Structurally RelatedCompounds | Tested Concentration(ng/mL) | Cross-reactivity (%) |
| Norcodeine | 100,000 | <0.01 |
| Norhydrocodone | 100,000 | <0.01 |
| Normorphine | 50,000 | 0.02 |
| Norpropoxyphene | 100,000 | <0.01 |
| Noroxycodone | 100,000 | <0.01 |
| Noroxymorphone | 100,000 | <0.01 |
| Oxycodone | 100,000 | <0.01 |
| Oxymorphone | 100,000 | <0.01 |
| Oxymorphone-3β-D-glucuronide | 100,000 | <0.01 |
| Tapentadol HCl | 100,000 | <0.01 |
| Tramadol | 100,000 | <0.01 |
The potential cross-reactivity posed by drugs commonly co-administered with Heroin Metabolite (6-AM) was evaluated by adding each substance to Heroin Metabolite (6-AM) spiked at Low Control, 7.5 ng/mL (-25% of the cutoff concentration) and the High Control, 12.5 ng/mL (+25% of the cutoff concentration) levels at the concentrations indicated. A drug is considered to cross-react if the observed Heroin Metabolite (6-AM) concentrations result exceed 10 ng/mL. As shown in the table below, all the pharmacologic compounds evaluated exhibited negligible cross reactivity at the concentrations tested.
| Structurally Unrelated Compounds Spiked at the Concentration Listed Below | |
|---|---|
| into Low Control and High Control |
| Structurally UnrelatedCompounds | Tested Conc.(ng/mL) | Spiked 6-Acetylmorphine level | |
|---|---|---|---|
| Low ControlPositive/Negative | High ControlPositive/Negative | ||
| 10,11Dihydrocarbamazepine | 85,000 | Negative | Positive |
| 11-nor-delta9-THC-COOH | 10,000 | Negative | Positive |
| Acetaminophen | 500,000 | Negative | Positive |
| Acetylsalicylic Acid | 500,000 | Negative | Positive |
| Amitriptyline | 125,000 | Negative | Positive |
| Amoxicillin | 500,000 | Negative | Positive |
| Amphetamine | 100,000 | Negative | Positive |
| Amisulpride | 100,000 | Negative | Positive |
| Benzotropine Mesylate | 125,000 | Negative | Positive |
| Benzoylecgonine | 100,000 | Negative | Positive |
| Brompheniramine | 75,000 | Negative | Positive |
| Caffeine | 500,000 | Negative | Positive |
| Captopril | 500,000 | Negative | Positive |
| Chlordiazepoxide | 100,000 | Negative | Positive |
| Structurally UnrelatedCompounds | Tested Conc.(ng/mL) | Spiked 6-Acetylmorphine level | |
| Low ControlPositive/Negative | High ControlPositive/Negative | ||
| Chlorpromazine | 10,000 | Negative | Positive |
| Clomipramine | 250,000 | Negative | Positive |
| Chloroquine | 500,000 | Negative | Positive |
| Cimetidine | 500,000 | Negative | Positive |
| Desipramine | 125,000 | Negative | Positive |
| Diazepam | 100,000 | Negative | Positive |
| Digoxin | 100,000 | Negative | Positive |
| Diphenhydramine | 50,000 | Negative | Positive |
| Doxepine HCl | 50,000 | Negative | Positive |
| Enalapril | 500,000 | Negative | Positive |
| Fluoxetine | 500,000 | Negative | Positive |
| Fluophenazine | 500,000 | Negative | Positive |
| Haloperidol | 50,000 | Negative | Positive |
| Hydroxychlroquine | 100,000 | Negative | Positive |
| Hydroxyzine | 250,000 | Negative | Positive |
| Ibuprofen | 500,000 | Negative | Positive |
| Imipramine | 50,000 | Negative | Positive |
| Levothyroxine | 50,000 | Negative | Positive |
| Methamphentamine | 100,000 | Negative | Positive |
| Maprotiline | 500,000 | Negative | Positive |
| Nalbuphine | 100,000 | Negative | Positive |
| Naproxen | 500,000 | Negative | Positive |
| Nortryptiline | 250,000 | Negative | Positive |
| Nifedipine | 500,000 | Negative | Positive |
| Nordiazepam | 100,000 | Negative | Positive |
| Oxazepam | 100,000 | Negative | Positive |
| Perphenazine | 150,000 | Negative | Positive |
| Phencyclidine | 7,500 | Negative | Positive |
| Phenobarbital | 100,000 | Negative | Positive |
| Procyclidine | 400,000 | Negative | Positive |
| Propoxyphene | 25,000 | Negative | Positive |
| Protriptyline | 50,000 | Negative | Positive |
| Ranitidine | 500,000 | Negative | Positive |
| Salicyluric Acid | 500,000 | Negative | Positive |
| Secobarbital | 100,000 | Negative | Positive |
| Sulpiride | 500,000 | Negative | Positive |
| Thioridazine | 250,000 | Negative | Positive |
| Triprolidine | 125,000 | Negative | Positive |
| Verapamil | 500,000 | Negative | Positive |
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f)
The interference studies were performed in accordance with CLSI Guideline EP07-A2. The potential interference of pH and endogenous physiologic substances on recovery of 6-AM using CEDIA Heroin Metabolite (6-AM) Urine Assay was assessed by spiking known compounds of potentially interfering substances into the Low Control, 7.5 ng/mL (-25% of the cutoff concentration) and the High Control, 12.5 ng/mL (+25% of the cutoff concentration). In the presence of the compounds listed below, the controls were detected accurately, indicating that these compounds did not show interference in the assay.
| Compound | TestedConcentration(mg/dL) | Spiked 6-Acetylmorphine level | |
|---|---|---|---|
| Low Control-25% of cutoff(7.5 ng/mL) | High Control+25% cutoff(12.5 ng/mL) | ||
| Acetone | 1000 | Negative | Positive |
| Ascorbic acid | 1500 | Negative | Positive |
| Creatinine | 500 | Negative | Positive |
| Ethanol | 1000 | Negative | Positive |
| Galactose | 10 | Negative | Positive |
| Y-globulin | 500 | Negative | Positive |
| Glucose | 1000 | Negative | Positive |
| Hemoglobin | 300 | Negative | Positive |
| Human serum albumin | 500 | Negative | Positive |
| Oxalic acid | 100 | Negative | Positive |
| Riboflavin | 7.5 | Negative | Positive |
| Sodium Chloride | 6000 | Negative | Positive |
| Urea | 2000 | Negative | Positive |
| pH | |||
| pH | 3 | Negative | Positive |
| pH | 4 | Negative | Positive |
| pH | 5 | Negative | Positive |
| pH | 6 | Negative | Positive |
| pH | 7 | Negative | Positive |
| pH | 8 | Negative | Positive |
| pH | 9 | Negative | Positive |
| pH | 10 | Negative | Positive |
| pH | 11* | Negative | Negative |
- pH 11 urine interferes CEDIA 6-AM urine assay.
Specific Gravity
Drug free urine samples with specific gravity ranging in value within 1.002 to 1.030 were split and spiked to a final concentration of either 7.5 ng/mL or 12.5 ng/mL (the
{13}------------------------------------------------
Low Control and High Control concentrations, respectively). These samples were then evaluated in both qualitative and semi-quantitative modes. No interference was observed.
| Specific Gravity | Spiked 6-Acetylmorphine Concentration | |
|---|---|---|
| Low Control | High Control | |
| 1.004 | Negative | Positive |
| 1.005 | Negative | Positive |
| 1.007 | Negative | Positive |
| 1.010 | Negative | Positive |
| 1.011 | Negative | Positive |
| 1.013 | Negative | Positive |
| 1.019 | Negative | Positive |
| 1.023 | Negative | Positive |
| 1.025 | Negative | Positive |
| 1.029 | Negative | Positive |
g) Clinical cutoff
SAMHSA guideline for 6-Acetylmorphine is 10 ng/mL cutoff.
H. Conclusion
The information supports a determination of substantial equivalence between CEDIA Heroin Metabolite (6-AM) Assay and the predicate device CEDIA DAU 6-Acetylmorphine Assay (K001178).
§ 862.3650 Opiate test system.
(a)
Identification. An opiate test system is a device intended to measure any of the addictive narcotic pain-relieving opiate drugs in blood, serum, urine, gastric contents, and saliva. An opiate is any natural or synthetic drug that has morphine-like pharmocological actions. The opiates include drugs such as morphine, morphine glucoronide, heroin, codeine, nalorphine, and meperedine. Measurements obtained by this device are used in the diagnosis and treatment of opiate use or overdose and in monitoring the levels of opiate administration to ensure appropriate therapy.(b)
Classification. Class II (special controls). An opiate test system is not exempt if it is intended for any use other than employment or insurance testing or is intended for Federal drug testing programs. The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 862.9, provided the test system is intended for employment and insurance testing and includes a statement in the labeling that the device is intended solely for use in employment and insurance testing, and does not include devices intended for Federal drug testing programs (e.g., programs run by the Substance Abuse and Mental Health Services Administration (SAMHSA), the Department of Transportation (DOT), and the U.S. military).