(59 days)
The CEDIA Heroin Metabolite (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 with tandem 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 lyophilized reagents (1a and 2a). The components include mouse monoclonal antibodies to 6-Acetylmorphine, recombinant microbial "enzyme donor" - 6-Acetylmorphine conjugate, "enzyme acceptor", chlorophenol red ß-Dgalactopyranoside, stabilizers and preservatives.
Here's a summary of the acceptance criteria and study details for the CEDIA Heroin Metabolite (6-AM) Assay, based on the provided document:
1. Table of Acceptance Criteria and Reported Device Performance
| Acceptance Criteria Category | Specific Criteria (Implicitly Derived) | Reported Device Performance |
|---|---|---|
| Precision | All determinations at concentrations below the cutoff should be negative; all at concentrations above the cutoff should be positive. For cut-off concentration, readings can be mixed. | Qualitative Mode:- 0 to 7.5 ng/mL (below cutoff): 80/0 (Negative/Positive) determinations.- 10 ng/mL (at cutoff): 25/55 (Negative/Positive) determinations.- 12.5 to 20 ng/mL (above cutoff): 0/80 (Negative/Positive) determinations.Semi-Quantitative Mode:- 0 to 7.5 ng/mL (below cutoff): 80/0 (Negative/Positive) determinations.- 10 ng/mL (at cutoff): 46/34 (Negative/Positive) determinations.- 12.5 to 20 ng/mL (above cutoff): 0/80 (Negative/Positive) determinations. |
| Spike Recovery | Qualitative: No ± 2SD overlap between samples below, at, and above the cutoff. All replicates of spiked negative and positive controls should be accurately detected.Semi-quantitative: Spiked samples recover within 80-120% of nominal values. | Qualitative Mode: No ± 2SD overlap between 7.5 ng/mL, 10 ng/mL, and 12.5 ng/mL. All 20 replicates of 7.5 ng/mL were Negative, and all 20 replicates of 12.5 ng/mL were Positive, compared to 10 ng/mL.Semi-Quantitative Mode: Spiked samples recovered within 80-120% of nominal values (as seen in the Analytical Recovery table). |
| Analytical Recovery and Dilution Linearity | Semi-quantitative mode: Demonstrates ability for sample dilution and QC across the assay range, with acceptable percent recovery. | Average Recovery (%) ranged from 97.3% to 115.6% for target concentrations from 0 to 20 ng/mL. Range of Recovery (%) was also provided. |
| Method Comparison and Accuracy | High concordance (suggesting 100%) between the immunoassay and a confirmatory method (LC-MS/MS) for patient samples across various concentration ranges. | Qualitative & Semi-Quantitative Modes: Overall concordance between LC-MS/MS and CEDIA Heroin Metabolite (6-AM) Assay was 100% for the 103 samples tested. |
| Specificity (Cross-reactivity with Metabolites) | 6-Acetylmorphine shows 100% cross-reactivity and heroin shows appropriate cross-reactivity (e.g., in this case, 8.3%). | 6-Acetylmorphine: 100% cross-reactivity at 10 ng/mL.Heroin: 8.3% cross-reactivity at 120 ng/mL. |
| Specificity (Cross-reactivity with Structurally Related/Unrelated Compounds) | Structurally related or unrelated compounds should exhibit minimal cross-reactivity (e.g., <0.01% or as indicated by accurate detection of spiked controls). | Numerous compounds (e.g., 6-Acetylcodeine, Buprenorphine, Codeine, Fentanyl, Oxycodone, etc.) showed cross-reactivity <0.01%, or specific low cross-reactivity (e.g., Dextromethorphan (0.01%), Hydromorphone (0.05%), Levorphanol (0.07%), Morphine (0.07%), Nalorphine (0.1%), Normorphine (0.02%)). Controls in the presence of these compounds were detected accurately (Low Control as negative, High Control as positive), indicating minimal interference. |
| Interference (pH and Endogenous Substances) | Endogenous physiologic substances and varying pH levels should not interfere with the accurate detection of low and high controls. | Compounds like Acetone, Ascorbic acid, Creatinine, Ethanol, Glucose, Hemoglobin, Human serum albumin, Urea, and various pH levels (3.0-11.0) did not interfere with the assay, with both Low and High Controls detected accurately. |
| Interference (Specific Gravity) | Variations in specific gravity of urine samples should not interfere with accurate detection. | Drug-free urine samples across a specific gravity range of 1.002 to 1.029, spiked with Low Control and High Control levels, showed no interference. |
| Stability (Open Vial, Reagent On-Board, Reconstituted Reagent, Real-Time) | The device should demonstrate specified stability periods for open vial, on-board reagents, reconstituted reagents, and overall shelf-life. | Open Vial: 60 days (qualitative and semi-quantitative modes) - data from K173183.Reagent On-Board: 60 days (qualitative and semi-quantitative modes).Reconstituted Reagent: 60 days (qualitative and semi-quantitative modes).Real-Time Stability: 24 months (supported by 26 months of data from K173183). |
2. Sample Sizes and Data Provenance
- Test Set Sample Size:
- Precision Studies: 80 samples for both qualitative and semi-quantitative modes (two replicates per run, twice a day, for 20 days). These samples were spiked at various concentrations relative to the cutoff (0, 2.5, 5, 7.5, 10, 12.5, 15, 17.5, 20 ng/mL).
- Analytical Recovery and Dilution Linearity: Drug-free urine spiked to 20 ng/mL and diluted to generate 10 intermediate levels. Each sample was run in replicates of five.
- Method Comparison and Accuracy: 103 patient samples.
- Specificity (Cross-reactivity): Varies per compound, usually tested at one high concentration for structurally related/unrelated compounds, and two control levels (7.5 ng/mL and 12.5 ng/mL) for "structurally unrelated compounds spiked at the concentration listed below into Low Control and High Control".
- Interference (Endogenous & pH): Low Control (7.5 ng/mL) and High Control (12.5 ng/mL) samples, spiked with various interfering substances.
- Interference (Specific Gravity): Drug-free urine samples separated into 11 specific gravity levels, then each spiked at Low Control (7.5 ng/mL) or High Control (12.5 ng/mL).
- Data Provenance: The document does not explicitly state the country of origin. The studies are described as analytical performance studies conducted by the manufacturer (Microgenics Corporation, Fremont, CA, USA). The studies appear to be prospective for the current submission, though some stability data references previous 510(k) submission (K173183).
3. Number of Experts and Qualifications for Ground Truth
The document does not mention the use of experts to establish ground truth in the traditional sense (e.g., radiologists, clinicians reviewing images). For this type of in vitro diagnostic device (immunoassay), the "ground truth" for the test set is established by a highly accurate and precise reference method.
4. Adjudication Method for the Test Set
Not applicable. For this type of in vitro diagnostic, adjudication by human experts is not typically used for establishing ground truth. The comparison is made against a validated confirmatory laboratory method.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No. This is an in vitro diagnostic assay, not an imaging device or AI-assisted diagnostic tool for human readers. Therefore, an MRMC comparative effectiveness study involving human readers and AI assistance is not applicable.
6. Standalone Performance
Yes. The entire document describes the standalone performance of the CEDIA Heroin Metabolite (6-AM) Assay in both qualitative and semi-quantitative modes. The performance metrics (precision, accuracy, specificity, interference, stability) are all evaluated for the assay itself, without a human-in-the-loop component.
7. Type of Ground Truth Used
The primary ground truth for the test set (method comparison and accuracy, as well as for spiking concentrations in other studies) was established using Liquid Chromatography/tandem mass spectrometry (LC-MS/MS), and potentially Gas chromatography/mass spectrometry (GC/MS), as these are stated as the "preferred confirmatory methods."
8. Sample Size for the Training Set
Not applicable. This is an immunoassay, not a machine learning or AI-based device that would typically have a separate "training set" for model development. The reagents are chemical components that react based on established biochemical principles.
9. How the Ground Truth for the Training Set was Established
Not applicable, as there is no "training set" in the context of an immunoassay. The development of the assay's reagents and methodologies would rely on chemical and biochemical principles and rigorous validation against known standards and reference methods.
{0}------------------------------------------------
Image /page/0/Picture/0 description: The image shows 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 FDA logo is the text "U.S. FOOD & DRUG ADMINISTRATION" in blue.
December 16, 2019
Microgenics Corporation Sharron Penn Senior Regulatory Affairs Specialist 46500 Kato Road Fremont, CA 94538
Re: K192943
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: October 17, 2019 Received: October 18, 2019
Dear Sharron Penn:
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. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. 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.
{1}------------------------------------------------
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) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; 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 https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). 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 (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely,
Marianela Perez-Torres, M.T., Ph.D. Acting Deputy Director Division of Chemistry and Toxicology Devices OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Quality Center for Devices and Radiological Health
Enclosure
{2}------------------------------------------------
Indications for Use
510(k) Number (if known) K192943
Device Name CEDIA Heroin Metabolite (6-AM) Assay
Indications for Use (Describe)
The CEDIA Heroin Metabolite (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 with tandem 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) |
CONTINUE ON A SEPARATE PAGE IF NEEDEDThis section applies only to requirements of the Paperwork Reduction Act of 1995.
DO NOT SEND YOUR COMPLETED FORM TO THE PRA STAFF EMAIL ADDRESS BELOW.
The burden time for this collection of information is estimated to average 79 hours per response, including the time to review instructions, search existing data sources, gather and maintain the data needed and complete and review the collection of information. Send comments regarding this burden estimate or any other aspect of this information collection, including suggestions for reducing this burden, to:
Department of Health and Human Services Food and Drug Administration Office of Chief Information Officer Paperwork Reduction Act (PRA) Staff PRAStaff@fda.hhs.gov
"An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB number."
{3}------------------------------------------------
1. 510(k) Summary
A. Device Information
| Category | Comments |
|---|---|
| Sponsor: | Microgenics CorporationThermo Fisher Scientific46500 Kato RoadFremont, CA 94538Phone: 510-979-5000FAX: 510-979-5002 |
| Correspondent ContactInformation: | Sharron PennSenior Regulatory Affairs SpecialistEmail: Sharron.Penn@thermofisher.comPhone: 510-979-5000FAX: 510-979-5002 |
| Device Common Name: | 6-Acetylmorphine Immunoassay Test |
| Trade or Proprietary Name | CEDIA Heroin Metabolite (6-AM) Assay |
| Predicate Device ProductCode, Classification,Classification Name & Panel | DJG, Class II, 21 CFR 862.3650 – Opiate test system,91 - Toxicology |
Predicate Device Information:
| Predicate Device: | CEDIA Heroin Metabolite (6-AM) Assay |
|---|---|
| Predicate DeviceManufacturer: | Microgenics Corporation |
| Predicate Device CommonName: | 6-Acetylmorphine Immunoassay Test System |
| Predicate Device PremarketNotification #: | K173183 |
| Predicate Device ProductCode, Classification,Classification Name & Panel | DJG, Class II, 21 CFR 862.3650 ">– Opiate test system,91 – Toxicology |
B. Date Summary Prepared December 12, 2019
C. Description of Device
The assay consists of buffers (1 and 2) and lyophilized reagents (1a and 2a). The components include mouse monoclonal antibodies to 6-Acetylmorphine, recombinant microbial "enzyme donor" - 6-Acetylmorphine conjugate, "enzyme acceptor", chlorophenol red ß-Dgalactopyranoside, stabilizers and preservatives.
{4}------------------------------------------------
D. Intended Use
CEDIA Heroin Metabolite (6-AM) Assay
The CEDIA Heroin Metabolite (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 with tandem mass spectrometry (LC-MS/MS) is the preferred confirmatory method.1
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 Heroin Metabolite(6-AM) Assay. K173183. | CEDIA HeroinMetabolite (6-AM)Assay |
|---|---|---|
| Intended Use | The CEDIA Heroin Metabolite (6-AM) Assay is ahomogeneous enzyme immunoassay for the in vitroqualitative and/or semi-quantitative determinationof the presence of heroin metabolite (6-AM) inhuman urine at a cut-off concentration of 10 ng/mL.The assay is intended to be used in laboratories andprovides a rapid analytical screening procedure todetect 6-Acetylmorphine in human urine. The assayis designed for use with a number of clinicalchemistry analyzers. This product is intended to beused by trained professionals only.The semi-quantitative mode is for the purpose ofenabling laboratories to determine an appropriatedilution of the specimen for confirmation by aconfirmatory method such as LiquidChromatography/tandem mass spectrometry (LC-MS/MS) or permitting laboratories to establishquality control procedures. | same |
E. Comparison to Predicate Device
{5}------------------------------------------------
| Characteristic | Predicate Device: CEDIA Heroin Metabolite(6-AM) Assay. K173183. | CEDIA HeroinMetabolite (6-AM)Assay |
|---|---|---|
| The assay provides only a preliminary analyticaltest result. A more specific alternative chemicalmethod must be used to obtain a confirmedanalytical result. Gas chromatography/ massspectrometry (GC/MS) or Liquid chromatographywith tandem mass spectrometry (LC-MS/MS) isthe preferred confirmatory methodClinical and professional judgment should beapplied to any drug of abuse test result, particularlywhen preliminary results are used. For In VitroDiagnostic Use Only. | ||
| Operating Principle(Technology) | CEDIA | Same |
| Measured Analyte | Heroin and 6-Acetylmorphine | Same |
| Test Matrix | Urine | Same |
| Cutoff Levels | 10 ng/mL | Same |
| Methodology | Homogeneous Enzyme Immunoassay | Same |
| Reagents Form | EA and ED: Lyophilized (ReconstitutionRequired)EARB and EDRB liquid ready-to-use. | Same |
| Antibody | Mouse Monoclonal antibody | Same |
| Storage | 2-8°C until expiration date. | Same |
| Principal Operator | Trained professionals | Same |
| Reference Instrument | Beckman AU680 | Horiba Pentra C400 |
F. Test Principle
The CEDIA Heroin Metabolite Assay uses recombinant DNA technology (US Patent No. 4708929) to produce a unique homogeneous enzyme immunoassay system.10 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:
- a) Precision Study is performed for two replicates per run, twice a day, for 20 days (total n=80). Samples are 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, using a Clinical Laboratory and Standards Institute (CLSI) protocol.
{6}------------------------------------------------
Qualitative Results:
| 6-Acetylmorphine | % of Cutoff(10 ng/mL) | LC-MS/MS(ng/mL) | Total Precision (n=80) | |
|---|---|---|---|---|
| SpikedConcentration(ng/mL) | Number ofDeterminations | ImmunoassayResults(Negative/Positive) | ||
| 0 | -100 | N/A | 80 | 80/0 |
| 2.5 | -75 | 2.6 | 80 | 80/0 |
| 5 | -50 | 5.1 | 80 | 80/0 |
| 7.5 | -25 | 7.6 | 80 | 80/0 |
| 10 | 100 | 10.0 | 80 | 25/55 |
| 12.5 | +25 | 12.6 | 80 | 0/80 |
| 15 | +50 | 15.0 | 80 | 0/80 |
| 17.5 | +75 | 17.6 | 80 | 0/80 |
| 20 | +100 | 20.0 | 80 | 0/80 |
Semi-Quantitative Results:
| 6-AcetylmorphineSpikedConcentration(ng/mL) | % of Cutoff(10 ng/mL) | LC-MS/MS(ng/mL) | Total Precision (n=80) | |
|---|---|---|---|---|
| Number ofDeterminations | ImmunoassayResults(Negative/Positive) | |||
| 0 | -100 | N/A | 80 | 80/0 |
| 2.5 | -75 | 2.6 | 80 | 80/0 |
| 5 | -50 | 5.1 | 80 | 80/0 |
| 7.5 | -25 | 7.6 | 80 | 80/0 |
| 10 | 100 | 10.0 | 80 | 46/34 |
| 12.5 | +25 | 12.6 | 80 | 0/80 |
| 15 | +50 | 15.0 | 80 | 0/80 |
| 17.5 | +75 | 17.6 | 80 | 0/80 |
| 20 | +100 | 20.0 | 80 | 0/80 |
- b) Spike Recovery In qualitative mode, there is no ± 2SD overlap between the spiked 10 ng/mL, 7.5ng/mL and 12.5 ng/mL samples.
All 20 replicates of spiked 7.5 ng/mL and 12.5 ng/mL samples detect as Negative and Positive, respectively, when compared to 10 ng/mL spiked sample.
In semi-quantitative mode, the spiked samples recover within 80-120% of the nominal values.
- c) Analytical Recovery and Dilution Linearity -To demonstrate the dilution linearity for purpose of sample dilution and quality control of the entire assay range, drug free urine is spiked to the high calibrator level (20ng/mL) by using 6-Acetylmorphine methanol solution and diluted with drug free urine to generate 10 intermediate levels.
{7}------------------------------------------------
Each sample is run in replicates of five in semi-quantitative mode and the average is used to determine percent recovery compared to the expected target value.
| Level | TargetConcentration(ng/mL) | ObservedConcentration(ng/mL) | AverageRecovery (%) | Range ofRecovery (%) |
|---|---|---|---|---|
| 1 | 0 | 0.39 | N/A | N/A |
| 2 | 2 | 2.31 | 115.6 | 92.0 - 134.0 |
| 3 | 4 | 4.62 | 115.6 | 100.8 - 130.5 |
| 4 | 6 | 6.25 | 104.2 | 97.7 - 113.5 |
| 5 | 8 | 8.04 | 100.5 | 94.6 – 106.5 |
| 6 | 10 | 10.19 | 101.9 | 97.0 – 108.4 |
| 7 | 12 | 12.33 | 102.7 | 99.6 – 105.1 |
| 8 | 14 | 14.36 | 102.6 | 98.3 – 106.1 |
| 9 | 16 | 15.81 | 98.8 | 95.4 - 100.1 |
| 10 | 18 | 18.27 | 101.5 | 98.1 - 103.3 |
| 11 | 20 | 19.46 | 97.3 | 95.5 - 99.0 |
- d) Method Comparison and Accuracy One hundred and three patient samples were analyzed by the CEDIA Heroin Metabolite (6-AM) Assay in both qualitative and semiquantitative modes and the results were compared to LC-MS/MS. The overall concordance between LC-MS/MS and CEDIA Heroin Metabolite (6-Acetylmorphine) Assay was 100% for the samples evaluated in this study.
Qualitative Results
| CandidateDeviceResults | Negative | < 50% ofCutoffconcentrationn by 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 thecutoffconcentrationas determinedby LC-MS/MS)(10 – 15.0ng/mL) | High Positives(Greater than50% abovecutoffconcentration(> 15.0ng/mL) |
|---|---|---|---|---|---|
| Positive | 0 | 0 | 0 | 6 | 45 |
| Negative | 44 | 2 | 6 | 0 | 0 |
{8}------------------------------------------------
Semi-Quantitative Results
| CandidateDeviceResults | Negative | < 50% ofCutoffconcentrationn by 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 (Betweenthe cutoff and50% above thecutoffconcentration asdetermined byLC-MS/MS)(10 – 15.0 ng/mL) | High Positives(Greater than50% abovecutoffconcentration(> 15.0ng/mL) |
|---|---|---|---|---|---|
| Positive | 0 | 0 | 0 | 6 | 45 |
| Negative | 44 | 2 | 6 | 0 | 0 |
- e) Specificity The cross-reactivity of Heroin Metabolite (6-AM) and its metabolites was 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% crossreactivity. Heroin showed 8.3% cross-reactivity.
| Heroin Metabolite (6-AM) and itsmetabolites | Tested Concentration(ng/mL) | Positive/Negative | Cross-reactivity(%) |
|---|---|---|---|
| 6-Acetylmorphine | 10 | Positive | 100 |
| Heroin | 120 | Positive | 8.3 |
Cross Reactivity of Structurally Related or Unrelated Opiate Compounds
| Structurally related compounds andother opiates | TestedConcentration(ng/mL) | Positive/Negative | Cross-reactivity (%) |
|---|---|---|---|
| 6-Acetylcodeine | 100,000 | Negative | <0.01 |
| Buprenorphine | 100,000 | Negative | <0.01 |
| Buprenorphine-3ß-D-glucuronide | 100,000 | Negative | <0.01 |
| Codeine | 100,000 | Negative | <0.01 |
| Dextromethorphan | 90,000 | Positive | 0.01 |
| Dihydrocodeine | 100,000 | Negative | <0.01 |
| EDDP | 100,000 | Negative | <0.01 |
| EMDP | 100,000 | Negative | <0.01 |
| Ethylmorphine | 100,000 | Negative | <0.01 |
| Fentanyl | 100,000 | Negative | <0.01 |
| Hydrocodone | 100,000 | Negative | <0.01 |
| Hydromorphone | 20,000 | Positive | 0.05 |
| Hydromorphone-3B-D-glucuronide | 100,000 | Negative | <0.01 |
| LAAM | 100,000 | Negative | <0.01 |
| Levorphanol | 15,000 | Positive | 0.07 |
| Methadone | 100,000 | Negative | <0.01 |
| Meperidine | 100,000 | Negative | <0.01 |
| Mitragynine | 100,000 | Negative | <0.01 |
| 7-Hydroxymitragynine | 100,000 | Negative | <0.01 |
| Morphine | 13,500 | Positive | 0.07 |
{9}------------------------------------------------
| Structurally related compounds andother opiates | TestedConcentration(ng/mL) | Positive/Negative | Cross-reactivity (%) |
|---|---|---|---|
| Morphine-3β-D-Glucuronide | 100,000 | Negative | <0.01 |
| Morphine-6β-D-Glucuronide | 100,000 | Negative | <0.01 |
| Nalorphine | 10,500 | Positive | 0.1 |
| Naloxone | 100,000 | Negative | <0.01 |
| Naltrexone | 100,000 | Negative | <0.01 |
| Norbuprenorphine | 100,000 | Negative | <0.01 |
| Norbuprenorphine glucuronide | 100,000 | Negative | <0.01 |
| Norcodeine | 100,000 | Negative | <0.01 |
| Norhydrocodone | 100,000 | Negative | <0.01 |
| Normorphine | 50,000 | Positive | 0.02 |
| Norpropoxyphene | 100,000 | Negative | <0.01 |
| Noroxycodone | 100,000 | Negative | <0.01 |
| Noroxymorphone | 100,000 | Negative | <0.01 |
| Oxycodone | 100,000 | Negative | <0.01 |
| Oxymorphone | 100,000 | Negative | <0.01 |
| Oxymorphone-3β-D-glucuronide | 100,000 | Negative | <0.01 |
| Tapentadol HCl | 100,000 | Negative | <0.01 |
| Tramadol | 100,000 | Negative | <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) and High Control (12.5 ng/mL) levels at the concentrations indicated. As shown in the table below, the Controls were detected accurately, the Low Control as negative and the High Control as positive, indicating that all the compounds evaluated exhibited minimal cross reactivity at the concentrations tested.
Structurally Unrelated Compounds Spiked at the Concentration Listed Below into Low Control and High Control
| Cross reactants | SpikedConcentration(ng/mL) | Spiked 6-Acetylmorphine Level | |
|---|---|---|---|
| Low Control | High Control | ||
| 10,11 Dihydrocarbamazepine | 85,000 | Negative | Positive |
| 11-nor-Δ9-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 |
| Spiked | Spiked 6-Acetylmorphine Level | ||
| Cross reactants | Concentration(ng/mL) | Low Control | High Control |
| Captopril | 500,000 | Negative | Positive |
| Chlordiazepoxide | 100,000 | Negative | Positive |
| 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 |
| Nortriptyline | 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 |
| SpikedConcentration(ng/mL) | Spiked 6-Acetylmorphine Level | ||
| Cross reactants | Low Control | High Control | |
| Triprolidine | 125,000 | Negative | Positive |
| Verapamil | 500,000 | Negative | Positive |
{10}------------------------------------------------
{11}------------------------------------------------
- Interference The potential interference of pH and endogenous physiologic substances f) on recovery of 6-Acetylmorphine using CEDIA Heroin Metabolite (6-AM) Assay was assessed by spiking known compounds of potentially interfering substances into the Low Control (7.5 ng/mL) and High Control (12.5 ng/mL). In the presence of the compounds listed below, the controls are detected accurately, indicating that these compounds did not show interference in the assay.
| TestedConcentration(mg/dL) | Spiked 6-Acetylmorphine Level | ||
|---|---|---|---|
| Compound | Low Control | High Control | |
| 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 | 3.0 | Negative | Positive |
| pH | 4.0 | Negative | Positive |
| pH | 5.0 | Negative | Positive |
| pH | 6.0 | Negative | Positive |
| pH | 7.0 | Negative | Positive |
| pH | 8.0 | Negative | Positive |
| pH | 9.0 | Negative | Positive |
| pH | 10.0 | Negative | Positive |
| pH | 11.0 | Negative | Positive |
Specific Gravity - Drug free urine samples with specific gravity ranging in value within 1.002 to 1.029 were split and spiked to a final concentration of either 7.5 ng/mL or 12.5 ng/mL (the Low Control and High Control concentrations, respectively). No interference is observed.
{12}------------------------------------------------
| Spiked 6-Acetylmorphine Concentration | ||
|---|---|---|
| Specific Gravity | Low Control | High Control |
| 1.002 | Negative | Positive |
| 1.004 | Negative | Positive |
| 1.005 | Negative | Positive |
| 1.007 | Negative | Positive |
| 1.010 | Negative | Positive |
| 1.012 | Negative | Positive |
| 1.014 | Negative | Positive |
| 1.019 | Negative | Positive |
| 1.023 | Negative | Positive |
| 1.025 | Negative | Positive |
| 1.029 | Negative | Positive |
g) Stability
Open Vial Stability:
Open Vial stability studies for one lot stored at 2-8°C supports the claim of 60 days for qualitative and semi-quantitative modes. This data was presented in the original 510(k) submission K173183.
Reagent On-Board Stability:
Reagent On-Board stability studies for one lot stored on-board clinical analyzer supports the claim of 60 days for qualitative and semi-quantitative modes.
Reconstituted Reagent Stability:
Reconstituted Reagent stability studies for one lot stored at 2-8°C supports the claim of 60 days for qualitative and semi-quantitative modes.
Real Time Stability for Reagent
Real time stability studies for three lots of reagents stored at 2-8°C have been carried out for up to 26 months. Proposed shelf-life claim is 24 months. This data was presented in the original 510(k) submission K173183.
- h) Detection Limit Limit of detection is not provided in a 510(k) of this type of assay.
- Clinical Sensitivity Clinical sensitivity is not provided in a 510(k) of this type of assay. i)
- Clinical Specificity Clinical specificity is not provided in a 510(k) of this type of assay. i)
- k) 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 Heroin Metabolite (6-AM) Assay (K173183)
§ 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).