K Number
K150162
Manufacturer
Date Cleared
2015-02-26

(31 days)

Product Code
Regulation Number
862.3610
Reference & Predicate Devices
Predicate For
N/A
AI/MLSaMDIVD (In Vitro Diagnostic)TherapeuticDiagnosticis PCCP AuthorizedThirdpartyExpeditedreview
Intended Use

First Sign™ Drug of Abuse Tests are immunochromatographic assays for the qualitative determination of Oxazepam , Methamphetamine, and Morphine in human urine at cut-off concentrations of 300 ng/mL, and 2000 ng/mL, respectively. The tests are available in a Cup format and a Dip Card format.

The tests may yield preliminary positive results even when prescription drug Oxazepam is ingested, at prescribed doses; it is not intended to distinguish between prescription use or abuse of this drug. There is no uniformly recognized cutoff concentration level for oxazepam in urine. The tests provide only preliminary test results. A more specific alternative chemical method must be used in order to obtain a confirmed analytical result. Gas Chromatography/Mass Spectrometry is the preferred confirmatory method. Clinical consideration and professional judgment should be exercised with any drug of abuse test result, particularly when the preliminary result is positive.

For in vitro diagnostic use only. The tests are intended for over-the-counter and for prescription use.

Device Description

First Sign™ Drug of Abuse Tests are immunochromatographic assays. Each assay test is a lateral flow system for the qualitative detection of Oxazepam , Methamphetamine , and Morphine in human urine. The products are single-use in vitro diagnostic devices, which come in the formats of DipCards or Cups. Each test kit contains a Test Device (in one of the two formats), a package insert and a urine cup for sample collection. Each test device is sealed with a desiccant in an aluminum pouch.

AI/ML Overview

Here's an analysis of the acceptance criteria and study detailed in the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state formal "acceptance criteria" in terms of specific quantitative benchmarks (e.g., "sensitivity must be >90%"). Instead, it describes performance characteristics and then presents the results of studies to demonstrate that the device performs acceptably. The implied acceptance criterion for these qualitative drug tests is that they generally agree with GC/MS results, especially at and significantly above/below cut-off values.

Based on the provided performance characteristics, here's a summary:

FeatureAcceptance Criteria (Implied)Reported Device Performance
PrecisionConsistent results at various concentrations relative to the cut-off.Oxazepam, Methamphetamine, Morphine (Dip/Cup): Samples at -100%, -75%, -50%, -25% cut-off showed 100% negative results. Samples at +25%, +50%, +75%, +100% cut-off showed 100% positive results (with very few exceptions noted at the exact cut-off concentration, e.g., 3-4/46-47 +/-).
Cut-offCorrect qualitative determination (positive/negative) around the defined cut-off.Oxazepam (300 ng/mL), Methamphetamine (1000 ng/mL), Morphine (2000 ng/mL): All devices (all lots, all formats) were positive at and above +25% cut-off and negative at and below -25% cut-off.
InterferenceNo interference from common physiological substances at specified concentrations.Numerous compounds (e.g., Acetamidophenol, Ibuprofen, Caffeine for all drugs; specific examples listed for each drug) showed no interference at 100 µg/mL.
SpecificityCross-reactivity minimized for non-target drugs; appropriate reactivity for metabolites.Oxazepam: Showed expected cross-reactivity with some benzodiazepine metabolites/analogs (e.g., Alprazolam 240%, Clonazepam 3%, Triazolam 12%). No detection of Methamphetamine or Morphine. Methamphetamine: Showed cross-reactivity with some related compounds (e.g., (+/-)3,4-Methylenedioxy-n-ethylamphetamine (MDEA) 2%, (+/-)3,4-Methylenedioxymethamphetamine (MDMA) 13%, L-Methamphetamine 10%). No detection of Morphine or Oxazepam. Morphine: Showed cross-reactivity with Codeine (200%), Ethylmorphine (357%), Hydrocodone (40%), Hydromorphone (27%), σ-Monoacetylmorphine (200%), Morphine 3-b-D-glucuronide (154%). No detection of Oxazepam or Methamphetamine. (Note: % cross-reactivity values are relative to the drug's own cut-off concentration).
Urine Specific Gravity & pHPerformance unaffected by normal variations in urine specific gravity and pH.Results were all positive for samples at and above +25% cut-off and all negative for samples at and below -25% Cut-Off across a specific gravity range of 1.000-1.035 and a pH range of 4-9.
Method Comparison (Professional User)High concordance with GC/MS results, especially for clearly positive/negative samples.Oxazepam Dip/Cup: For 40 negative (incl. low and near cut-off) and 40 positive (incl. near cut-off and high) samples, there were very few discordant results (e.g., 2-4 negative calls for samples slightly above cut-off, or 1 negative call for a sample slightly above cut-off per viewer/format). Overall high agreement. Methamphetamine Dip/Cup: Similar high concordance, with few discordant results (e.g., 1-2 negative calls for samples slightly above cut-off per viewer/format). Morphine Dip/Cup: Similar high concordance, with few discordant results (e.g., 1 negative call for a sample slightly above cut-off per viewer/format).
Lay-user StudyHigh percentage of correct results by lay users, clear instructions.Oxazepam (Dip/Cup): 100% correct for negative samples, 90-100% correct for positive samples, with minor discrepancies (-25% cutoff for cup, +25% cutoff for dip card). Methamphetamine (Dip/Cup): 100% correct for negative samples, 95-100% correct for positive samples, with minor discrepancies (+25% cutoff). Morphine (Dip/Cup): 95-100% correct for negative samples (one false positive at -25% Cutoff for dip card), 95-100% correct for positive samples (one false negative at +25% Cutoff for cup/dip card). All lay users could easily follow instructions.

2. Sample Size and Data Provenance (Test Set)

  • Sample Size (Trained Professionals, Method Comparison):
    • For each of the three drugs (Oxazepam, Methamphetamine, Morphine) and each format (Dip Card, Cup), 80 clinical samples were used.
    • Total samples for method comparison: 3 drugs * 2 formats * 80 samples/drug/format = 480 samples.
    • Breakdown of 80 samples: 10 Negative, 10 Low Negative, 20 Near Cutoff Negative, 15 Near Cutoff Positive, 25 High Positive.
  • Sample Size (Lay User Study):
    • 280 lay persons for Oxazepam devices.
    • 280 lay persons for Methamphetamine devices.
    • 280 lay persons for Morphine devices.
    • Each lay person tested 1 blind labeled sample and a device.
    • Total samples tested by lay users: Roughly 280 samples/drug * 3 drugs = 840 samples.
  • Data Provenance (Method Comparison): "unaltered clinical samples" - implies retrospective collection, origin unknown based on the text.
  • Data Provenance (Lay User Study): "Urine samples were prepared... by spiking drugs into drug free-pooled urine specimens." This indicates the samples were synthesized or spiked rather than naturally occurring clinical samples, and then blind-labeled.

3. Number of Experts and Qualifications for Ground Truth (Test Set)

  • Number of Experts:
    • Method Comparison (Professional User): "three different laboratory assistants for each format of the device." Total of 6 unique readers (3 for dip card, 3 for cup) if they were distinct, or 3 if the same 3 read both formats (the wording "Different set of operators tested each format" in the precision study suggests distinct operators, but here it states "for each format", which could mean the same set of 3 rotated). The data is presented as Viewer A, B, C for each.
    • Lay User Study: 280 lay persons per drug. Not "experts" in the traditional sense, but the intended users.
  • Qualifications of Experts: The "three different laboratory assistants" are not further qualified (e.g., radiologist with 10 years of experience).

4. Adjudication Method (Test Set)

  • None specified for the professional user readings. The raw results from each "Viewer" (laboratory assistant) are presented individually, and then compared against the GC/MS result. They are not pooled or adjudicated to form a single "device" result.
  • For the Lay User Study: There is no "adjudication" between lay users. Each lay user's individual result is recorded and compared to the GC/MS confirmed concentration.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

  • No MRMC comparative effectiveness study was done to measure human reader improvement with AI vs. without AI assistance. This device is a standalone qualitative diagnostic test (immunochromatographic assay), not an AI-assisted interpretation tool for human readers.

6. Standalone Performance (Algorithm Only)

  • Yes, a standalone performance was done, but it's not an "algorithm" in the typical AI sense. The device itself (the immunochromatographic assay) is designed to provide a result (positive/negative) based on a chemical reaction, which can then be visually interpreted. The precision studies, cut-off studies, interference, specificity, and specific gravity/pH studies all demonstrate the standalone performance of the device without explicit human interpretation variability considered (though a human reads the test line).
  • The "Method Comparison" and "Lay-user study" then introduce the human element (laboratory assistants and lay users, respectively) reading these standalone device results.

7. Type of Ground Truth Used (Test Set)

  • Gas Chromatography/Mass Spectrometry (GC/MS) was explicitly used as the preferred confirmatory method for establishing ground truth for both the professional method comparison study and for confirming the concentrations of the spiked samples in the lay user study and precision/cut-off studies.

8. Sample Size for the Training Set

  • The document describes performance characteristics and equivalence to a predicate device, but does not specify a separate "training set" for the development of the device itself or for any AI/algorithmic component (as there isn't one). The studies described are performance validation studies.

9. How the Ground Truth for the Training Set was Established

  • Not applicable as no "training set" is mentioned in the context of device development. The ground truth for all performance evaluation studies (precision, cut-off, method comparison, lay user) was established using GC/MS.

{0}------------------------------------------------

Image /page/0/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a circular seal with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" around the perimeter. Inside the circle is a stylized symbol that resembles a human figure in profile, with three overlapping heads.

February 26, 2015

Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002

W.H.P.M., INC. JOHN WAN 5358 IRWINDALE AVENUE IRWINDALE CA 91706

Re: K150162 Trade/Device Name: First Sign® Drug Of Abuse Cup Test First Sign® Drug Of Abuse Dip Card Test Regulation Number: 21 CFR 862.3610 Regulation Name: Methamphetamine test system Regulatory Class: II Product Code: LAF, JXM, DJG Dated: January 19, 2015 Received: January 26, 2015

Dear Mr. John Wan:

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 Parts 801 and 809); medical device reporting (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 Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

{1}------------------------------------------------

If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638 2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/Resourcesfor You/Industry/default.htm. 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.

You may obtain other general information on your responsibilities under the Act from the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.

Sincerely yours,

Katherine Serrano -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

{2}------------------------------------------------

Indications for Use

510(k) Number (if known) K150162

Device Name First Sign® Drug of Abuse Cup Test First Sign® Drug of Abuse Dip Card Test

Indications for Use (Describe)

First Sign™ Drug of Abuse Tests are immunochromatographic assays for the qualitative determination of Oxazepam , Methamphetamine, and Morphine in human urine at cut-off concentrations of 300 ng/mL, and 2000 ng/mL, respectively. The tests are available in a Cup format and a Dip Card format.

The tests may yield preliminary positive results even when prescription drug Oxazepam is ingested, at prescribed doses; it is not intended to distinguish between prescription use or abuse of this drug. There is no uniformly recognized cutoff concentration level for oxazepam in urine. The tests provide only preliminary test results. A more specific alternative chemical method must be used in order to obtain a confirmed analytical result. Gas Chromatography/Mass Spectrometry is the preferred confirmatory method. Clinical consideration and professional judgment should be exercised with any drug of abuse test result, particularly when the preliminary result is positive.

For in vitro diagnostic use only. The tests are intended for over-the-counter and for prescription use.

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 NEEDED.

This 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}------------------------------------------------

510(k) SUMMARY K150162

  • February 24, 2015 1. Date: 2. Submitter W.H.P.M., Inc. 5358 Irwindale Ave. Irwindale, CA 91706 3. Contact person:
    John Wan W.H.P.M., Inc. 5358 Irwindale Ave. Irwindale, CA 91706 Telephone: 626-443-8480 Fax: 626-443-8065 Email: johnwan@whpm.com

  • First Sign® Drug of Abuse Cup Test 4. Device Name: First Sign® Drug of Abuse Dip Card Test

Classification: Class II

ProductCodeCFR #Panel
LAF21 CFR, 862.3610 Methamphetamine Test SystemToxicology
JXM21 CFR, 862.3170 Benzodiazepine Test SystemToxicology
DJG21 CFR, 862.3650 Opiate Test SystemToxicology
    1. Predicate Devices:
      K052115 First Check Multi Drug Cup 12

{4}------------------------------------------------

6. Intended Use

First Sign™ Drug of Abuse Tests are immunochromatographic assays for the qualitative determination of Oxazepam , Methamphetamine , and Morphine in human urine at cut-off concentrations of 300 ng/mL, 1000 ng/mL, and 2000 ng/mL, respectively. The tests are available in a Cup format and a Dip Card format.

The tests may yield preliminary positive results even when prescription drug Oxazepam is ingested, at prescribed doses; it is not intended to distinguish between prescription use or abuse of this drug. There is no uniformly recognized cutoff concentration level for oxazepam in urine. The tests provide only preliminary test results. A more specific alternative chemical must be used in order to obtain a confirmed analytical result. Gas Chromatography/Mass Spectrometry is the preferred confirmatory method. Clinical consideration and professional judgment should be exercised with any drug of abuse test result, particularly when the preliminary result is positive.

For in vitro diagnostic use only. The tests are intended for over-the-counter and for prescription use.

    1. Device Description
      First Sign™ Drug of Abuse Tests are immunochromatographic assays. Each assay test is a lateral flow system for the qualitative detection of Oxazepam , Methamphetamine , and Morphine in human urine. The products are single-use in vitro diagnostic devices, which come in the formats of DipCards or Cups. Each test kit contains a Test Device (in one of the two formats), a package insert and a urine cup for sample collection. Each test device is sealed with a desiccant in an aluminum pouch.
    1. Substantial Equivalence Information
      A summary comparison of features of the First Sign™ Drug of Abuse Test and the predicate device is provided in Table 1, Table 2 & Table 3.
ItemDevicePredicate -K052115
Indication(s)for UseFor the qualitative determination ofOxazepam in human urine.Same
CalibratorOxazepamSame
MethodologyCompetitive binding, lateral flowimmunochromatographic assays based onthe principle of antigen antibodyimmunochemistry.Same
Specimen TypeHuman UrineSame
Cut-Off Values300 ng/mLSame

Table 1: Features Comparison of First Sign™ Oxazepam Test and the Predicate Device

{5}------------------------------------------------

ItemDevicePredicate -K052115
IntendedPopulationFor over-the-counter and prescriptionuses.Forover-the-counteruse.
ConfigurationsCup, Dip CardCup

Table 2: Features Comparison of First Sign™ Methamphetamine Test and the Predicate Device

ItemDevicePredicate - K052115
Indication(s) for UseFor the qualitative determination of methamphetamine in human urine.Same
CalibratorD-methamphetamineSame
MethodologyCompetitive binding, lateral flow immunochromatographic assays based on the principle of antigen antibody immunochemistry.Same
Specimen TypeHuman UrineSame
Cut-Off Values1000 ng/mLSame
Intended PopulationFor over-the-counter and prescription uses.For over-the-counter use.
ConfigurationsCup, Dip CardCup

Table 3: Features Comparison of First Sign™ Morphine Test and the Predicate Device

ItemDevicePredicate - K052115
Indication(s)for UseFor the qualitative determination ofmorphine in human urine.For the qualitativedetermination ofopiates in humanurine, includingmorphine.
CalibratorMorphineSame
MethodologyCompetitive binding, lateral flowimmunochromatographic assays basedon the principle of antigen antibodySame

{6}------------------------------------------------

ItemDevicePredicate - K052115
immunochemistry.
Specimen TypeHuman UrineSame
Cut-Off Values2000 ng/mLSame
IntendedFor over-the-counter and prescriptionFor over-the-counter
Populationuses.use.
ConfigurationsCup, Dip CardCup

9. Test Principle

First Sign™ Drug of Abuse Tests are rapid tests for the qualitative detection of Oxazepam . Methamphetamine , and Morphine in urine samples. Each assay test is a lateral flow chromatographic immunoassay. During testing, a urine specimen migrates upward by capillary action. If target drugs are present in the urine specimen below its cut-off concentration, it will not saturate the binding sites of its specific antibody (monoclonal mouse antibody) coated on the particles. The antibody-coated particles will then be captured by immobilized drug-conjugate and a visible colored line will show up in the test line region. The colored line will not form in the test line region if the target drug level exceeds its cut-off concentration because it will saturate all the binding sites of the antibody coated on the particles. A band should form in the control region of the devices regardless of the presence of drug or metabolite in the sample.

10. Performance Characteristics

1. Analytical Performance

  • a. Precision
    Precision studies were carried out for samples with concentrations of -100% cut-off, -50% cut-off, -25% cut-off, at the cut-off, +25% cut-off, +75% cut-off, +75% cut-off and +100% cut-off. These samples were prepared by spiking drug in negative samples. Each drug concentration was confirmed by GC/MS. All sample aliquots were blind-labeled and randomized by the person who prepared samples and did not take part in the sample testing. For each concentration, tests were performed two runs per day for 25 days by three different operators for each format of devices. Different set of operators tested each format. The results obtained are summarized in the following tables:

{7}------------------------------------------------

Oxazepam Dip Card Format

Result-100%Cut-off-75%Cut-off-50%Cut-off-25%Cut-offCut-off+25%Cut-off+50%Cut-off+75%Cut-off+100%Cut-off
DrugLot: D401055850-/0+50-/0+50-/0+50-/0+3-/47+50+/0-50+/0-50+/0-50+/0-
DrugLot: D401056050-/0+50-/0+50-/0+50-/0+4-/46+50+/0-50+/0-50+/0-50+/0-
DrugLot: D401056250-/0+50-/0+50-/0+50-/0+3-/47+50+/0-50+/0-50+/0-50+/0-

Oxazepam Cup Format

Result-100%Cut-off-75%Cut-off-50%Cut-off-25%Cut-offCut-off+25%Cut-off+50%Cut-off+75%Cut-off+100%Cut-off
Drug
Lot: D401055950-/0+50-/0+50-/0+50-/0+3-/47+50+/0-50+/0-50+/0-50+/0-
Lot: D401056150-/0+50-/0+50-/0+50-/0+3-/47+50+/0-50+/0-50+/0-50+/0-
Lot: D401056350-/0+50-/0+50-/0+50-/0+4-/46+50+/0-50+/0-50+/0-50+/0-

Methamphetamine (mAMP) Dip Card Format

Result-100%Cut-off-75%Cut-off-50%Cut-off-25%Cut-offCut-off+25%Cut-off+50%Cut-off+75%Cut-off+100%Cut-off
DrugLot: D401055850-/0+50-/0+50-/0+50-/0+4-/46+50+/0-50+/0-50+/0-50+/0-
Lot: D401056050-/0+50-/0+50-/0+50-/0+3-/47+50+/0-50+/0-50+/0-50+/0-
Lot: D401056250-/0+50-/0+50-/0+50-/0+3-/47+50+/0-50+/0-50+/0-50+/0-

(mAMP) Cup Format

Result-100%Cut-off-75%Cut-off-50%Cut-off-25%Cut-offCut-off+25%Cut-off+50%Cut-off+75%Cut-off+100%Cut-off
Drug
Lot: D401055950-/0+50-/0+50-/0+50-/0+3-/47+50+/0-50+/0-50+/0-50+/0-
Lot: D401056150-/0+50-/0+50-/0+50-/0+2-/48+50+/0-50+/0-50+/0-50+/0-
Lot: D401056350-/0+50-/0+50-/0+50-/0+3-/47+50+/0-50+/0-50+/0-50+/0-

Morphine Dip Card Format

Result-100%Cut-off-75%Cut-off-50%Cut-off-25%Cut-offCut-off+25%Cut-off+50%Cut-off+75%Cut-off+100%Cut-off
Drug
Lot: D401055850-/0+50-/0+50-/0+50-/0+3-/47+50+/0-50+/0-50+/0-50+/0-
Lot: D401056050-/0+50-/0+50-/0+50-/0+3-/47+50+/0-50+/0-50+/0-50+/0-
Lot: D401056250-/0+50-/0+50-/0+50-/0+4-/46+50+/0-50+/0-50+/0-50+/0-

{8}------------------------------------------------

Result-100% Cut-off-75% Cut-off-50% Cut-off-25% Cut-offCut-off+25% Cut-off+50% Cut-off+75% Cut-off+100% Cut-off
Drug
Lot: D401055950-/0+50-/0+50-/0+50-/0+2-/48+50+/0-50+/0-50+/0-50+/0-
Lot: D401056150-/0+50-/0+50-/0+50-/0+3-/47+50+/0-50+/0-50+/0-50+/0-
Lot: D401056350-/0+50-/0+50-/0+50-/0+3-/47+50+/0-50+/0-50+/0-50+/0-

Morphine Cup Format

b. Linearity

Not applicable.

c. Stability

The devices are stable at 4-30°C (39-86°F) for 24 months based on the accelerated stability study at 50°C. Control materials are not provided with the device. The labeling provides information on how to obtain control materials.

d. Cut-off

A total of 150 samples equally distributed at concentrations of -50% cut-off; -25% cut-off; cut-off; +25% cut-off; +50% cut-off were tested using three different lots of each device by three different operators. Results were all positive at and above +25% cut-off and all negative at and below -25% cut-off for Oxazepam, Methamphetamine and Morphine. The following cut-off values for the test devices have been verified.

TestCalibratorCut-off (ng/mL)
One Step Oxazepam TestOxazepam300
One Step Methamphetamine TestD-methamphetamine1000
One Step Morphine TestMorphine2000

e. Interference

Potential interfering substances found in human urine of physiological conditions were added to drug-free urine and to urine containing target drugs at 25% below and 25% above cut-off levels. These urine samples were tested using three batches of each device for all formats.

Compounds that showed no interference at a concentration of 100µg/mL are summarized in the following tables. There were no differences observed for different formats.

{9}------------------------------------------------

Oxazepam 4-Acetamidophenol Diphenhydramine D.L-Octopamine Acetophenetidin Doxylamine Oxalic acid N-Acetvprocainamide Ecaonine dydrochloride Oxolinic acid Acetvsalicvlic acid Ecqonine methylester Pentobarbital Aminopvrine (-)-Y-Ephedrine Perphenazine Amityptvline Fenoprofen Phencyclidine Amorbarbital Phenelzine Furosemide Amoxicillin Gentisic acid Phenobarbital Ampicillin Hemoglobin Phentermine l-Ascorbic Acid Hydrocortisone L-Phenylephrine O-Hydroxyhippuric acid B-Phenylethylamine D.L-Amphetamine p-Hydroxy-Apormorphine methamphetamine Phenylpropanotamine Aspartame 3-Hydroxytyramine Prednisone Atropine Ibuprofen D.L-Propanolol Benzillic acid Imipramine D-Pseudoephedrine Benzoic acid Iproniazid Quinine Benzoylecaonine (±)Isoproterenol Ranitidine Benzphetamine Isoxsuprine Salicylic acid Bilirubin Ketamine Secobarbital Serotonin (±) Chlorpheniramine Ketoprofen (5-Hydroxytyramine) Caffeine Labetalol Sertraline Cannabidiol Loperamide Sulfamethazine Chloralhvdrate Maprotiline Sulindac Tetrahydrocortisone,(b-D Chloramphenicol Meperidine glucuronide) Chlorothiazide Meprobamate Tetrahydrozoline (±)Chlorpheniramine Thiamine Methadone Methoxyphenamine Thioridazine Chlorpromazine (+) 3,4-Methylenedioxy-Chlorquine amphetamine D.L-Tyrosine (+)3,4-Methylenedioxy-Cholesterol Tolbutamide methamphetamine Clomipramine Nalidixic acid Triamterene Clonidine Nalorphine Trifluoperazine Cocaine hydrochloride Naloxone Trimethoprim Cortisone Naltrexone Triyptamine D.L-Tryptophan (-)cotinine Naproxen

{10}------------------------------------------------

CreatinineNiacinamideTyramine
DextromethlorphanNifedipineUric acid
DiclolrfenacNorethindroneVerapamil
DiflunisalD-NorpropoxypheneZomepirac
DiaoxinNoscapine

Methamphetamine

AcetamidophenGentisic acidOxycodone
AcetophenetidinGlucuronideOxymetazoline
N-AcetylprocainamideGlutethimidePapaverine
AcetylsalicylateGuaifenesinPenicillin-G
AminopyrineHippuric acidPentazocine
AmitryptylineHydralazinePentobarbital
AmobarbitalHydrochlorothiazidePerphenazine
AmoxicillinHydrocodonePhencyclidine
AmpicillinHydrocortisonePhenelzine
ApomorphineO-Hydroxyhippuric acidPhenobarbital
Aspartame3-HydroxytyraminePrednisolone
AtropineIbuprofenPhenylpropanolamine
Benzilic acidImipraminePrednisone
Benzoic acid(-) IsoproterenolProcaine
BenzoylecgonineIsoxsuprinePromazine
ButabartitalKetaminePromethazine
CannabidiolKetoprofenD,L-Propanolol
ChloralhydrateLabetalolD-Propoxyphene
ChloramphenicolLevorphanolD-Pseudoephedrine
ChlordiazepoxideLoperamideQuinidine
ChlorothiazideLoxapine succinateQuinine
ChlorpromazineMaprotilineRanitidine
CholesterolMeperidineSalicylic acid
ClomipramineMeprobamateSecobarbital
ClonidineMethadoneSerotonin (5-Hydroxytyramine)
Cocaine hydrochlorideMethaqualoneSulfamethazine
CodeineMethylphenidalSulindac
CortisoneMethyprylonTemazepam
(-) CotinineMorphine-3- $\beta$ -DglucuronideTetracycline
CreatinineNalidixic acidTetrahydrocortisone
DeoxycorticosteroneNalorphine3 ( $\beta$ -D glucuronide)
Tetrahydrozoline

{11}------------------------------------------------

DextromethorphanNaloxoneThebaine
DiazepamNaltrexoneThiamine
DiclofenacNaproxenThioridazine
DiflunisalNiacinamideTolbutamine
DigoxinNifedipineTriamterene
DiphenhydramineNorcodeinTrifluoperazine
DoxylamineNorethindroneTrimethoprim
Ecgonine hydrochlorideNoroxymorphoneTrimipramine
Ecgonine methyl esterD-NorpropoxypheneD, L-Tryptophan
ErythromycinNoscapineTyramine
β-EstradiolNylidrinD, L-Tyrosine
Estrone-3-sulfateD,L-OctopamineUric acid
Ethyl-p-aminobenzoateOxalic acidVerapamil
FenoprofenOxazepamZomepirac
FurosemideOxolinic acid

Morphine

4-AcetamidophenolEcgonine methylesterOxolinic acid
Acetophenetidin(-) -Y -EphedrineOxymetazoline
N-AcetylprocainamideErythromycinPapaverine
Acetylsalicylic acidẞ-EstradiolPenicillin-G
AminopyrineEstrone-3-sulfatePentazocine
AmitryptylineEthyl-p-aminobenzoatePentobarbital
AmobarbitalFenoprofenPerphenazine
AmoxicillinFurosemidePhencyclidine
AmpicillinGentisic acidPhenelzine
Ascorbic acidHemoglobinPhenobarbital
D,L-AmphetamineHydralazinePhentermine
ApomorphineHydrochlorothiazideL-Phenylephrine
AspartameHydrocortisoneẞ-Phenylethylamine
AtropineO-Hydroxyhippuric acidPhenylpropanolamine
Benzilic acidp-Hydroxy methamphetaminePrednisone
Benzoic acid3-HydroxytyramineD,L-Propanolol
BenzoylecgonineIbuprofenD-Propoxyphene
BenzphetamineImipramineD-Pseudoephedrine
Bilirubin (±)IproniazidQuinidine
BrompheniramineIsoproterenolQuinine
CaffeineIsoxsuprineRanitidine
CannabidiolKetamineSalicylic acid
ChloralhydrateKetoprofenSecobarbital

{12}------------------------------------------------

ChloramphenicolLabetalolSerotonin (5-Hydroxytyramine)
ChlordiazepoxideLoperamideSulfamethazine
ChlorothiazideMaprotilineSulindac
(±) ChlorpheniramineMeperidineTemazepam
ChlorpromazineMeprobamateTetracycline
ChlorquineMethadoneTetrahydrocortisone3 (β-Dglucuronide)
CholesterolMethoxyphenamineTetrahydrozoline
Clomipramine(+) 3,4-Methylenedioxy-amphetamineThiamine
Clonidine(+)3,4-Methylenedioxy-methamphetamineThioridazine
Cocaine hydrochlorideNalidixic acidD, L-Tyrosine
CortisoneNalorphineTolbutamide
(-) CotinineNaloxoneTriamterene
CreatinineNaltrexoneTrifluoperazine
DeoxycorticosteroneNaproxenTrimethoprim
DextromethorphanNiacinamideTrimipramine
DiazepamNifedipineTryptamine
DiclofenacNorethindroneD, L-Tryptophan
DiflunisalD-NorpropoxypheneTyramine
DigoxinNoscapineUric acid
DiphenhydramineD,L-OctopamineVerapamil
DoxylamineOxalic acidZomepirac
Ecgonine hydrochlorideOxazepam
  • f. Specificity
    To test the specificity, drug metabolites and other components that are likely to interfere in urine samples were tested using three batches of each device for all formats. The obtained lowest detectable concentration was used to calculate the cross-reactivity. There were no differences observed for different formats.

{13}------------------------------------------------

OxazepamResult%Cross-Reactivity
Cut-off=300 ng/mL
OxazepamPositive at 300 ng/mL100%
AlprazolamPositive at 125 ng/mL240%
a-HydroxyalprazolamPositive at 2500 ng/mL12%
BromazepamPositive at 1565 ng/mL19%
ChlordiazepoxidePositive at 1560 ng/mL19%
ClobazamPositive at 65 ng/mL462%
ClonazepamPositive at 10000 ng/mL3%
Clorazepate dipotassiumPositive at 195ng/mL154%
DelorazepamPositive at 1560 ng/mL19%
DesalkylflurazepamPositive at 1560 ng/mL19%
DiazepamPositive at 115 ng/mL261%
EstazolamPositive at 165 ng/mL182%
FlunitrazepamPositive at 166 ng/mL181%
MidazolamPositive at 6500 ng/mL5%
NitrazepamPositive at 300 ng/mL100%
NorchlordiazepoxidePositive at 250 ng/mL120%
NordiazepamPositive at 400 ng/mL75%
TemazepamPositive at 100 ng/mL300%
TriazolamPositive at 2500 ng/mL12%
D,L-LorazepamNegative at ≤ 105 ng/mLNot Detected
MethamphetamineNegative at ≤ 105 ng/mLNot Detected
MorphineNegative at ≤ 105 ng/mLNot Detected

{14}------------------------------------------------

mAMP(Methamphetamine,Cut-off=1000 ng/mL)Result%Cross-Reactivity
D-MethamphetaminePositive at 1000 ng/mL100%
(+/-)3,4-Methylenedioxy-n-ethylamphetamine(MDEA)Positive at 41600 ng/mL2%
D/L-MethamphetaminePositive at 1000 ng/mL100%
p-HydroxymethamphetaminePositive at 27000 ng/mL4%
(+/-)3,4-Methylenedioxymethamphetamine (MDMA)Positive at 8000 ng/mL13%
L-MethamphetaminePositive at 10000 ng/mL10%
TrimethobenzamideNegative at ≤ 105 ng/mLNot Detected
ChloroquineNegative at ≤ 105 ng/mLNot Detected
EphedrineNegative at ≤ 105 ng/mLNot Detected
FenfluramineNegative at ≤ 105 ng/mLNot Detected
Procaine (Novocaine)Negative at ≤ 105 ng/mLNot Detected
Ranitidine (Zantac)Negative at ≤ 105 ng/mLNot Detected
D-amphetamineNegative at ≤ 105 ng/mLNot Detected
L-amphetamineNegative at ≤ 105 ng/mLNot Detected
MorphineNegative at ≤ 105 ng/mLNot Detected
OxazepamNegative at ≤ 105 ng/mLNot Detected

{15}------------------------------------------------

MorphineCut-off=2000 ng/mLResult%Cross-Reactivity
MorphinePositive at 2000 ng/mL100%
CodeinePositive at 1000 ng/mL200%
EthylmorphinePositive at 560 ng/mL357%
HydrocodonePositive at 5000 ng/mL40%
HydromorphonePositive at 7315 ng/mL27%
LevorphanolPositive at 16000 ng/mL13%
σ-MonoacetylmorphinePositive at 1000 ng/mL200%
Morphine 3-b-D-glucuronidePositive at 1300 ng/mL154%
ThebaineNegative at ≤ 105 ng/mLNot Detected
NorcodeineNegative at ≤ 105 ng/mLNot Detected
NormorphoneNegative at ≤ 105 ng/mLNot Detected
OxycodoneNegative at ≤ 105 ng/mLNot Detected
OxymorphineNegative at ≤ 105 ng/mLNot Detected
ProcaineNegative at ≤ 105 ng/mLNot Detected
OxazepamNegative at ≤ 105 ng/mLNot Detected
MethamphetamineNegative at ≤ 105 ng/mLNot Detected

g. Effect of Urine Specific Gravity and Urine pH

To investigate the effect of urine specific gravity and urine pH, urine samples with a range of 1.000 to 1.035 specific gravity or urine samples with a range of pH 4 to 9 were spiked with target drugs at 25% below and 25% above cut-off levels. These samples were tested using three batches of each device for all formats. Results were all positive for samples at and above +25% cut-off and all negative for samples at and below -25% Cut-Off. There were no differences observed for different formats.

{16}------------------------------------------------

2. Comparison Studies

The method comparison studies for the First Sign™ Drug Tests (Cup and Dip Card) for Oxazepam , Methamphetamine , and Morphine were performed in-house with three different laboratory assistants for each format of the device. Operators ran 80 (40 negative and 40 positive) unaltered clinical samples for each drug. The samples were blind labeled and compared to GC/MS results. The results are presented in the tables below:

Dip Card formatNegativeLow Negative by GC/MS (less than -50%)Near Cutoff Negative by GC/MS (Between -50% and cut-off)Near Cutoff Positive by GC/MS (Between the cut-off and +50%)High Positive by GC/MS (greater than +50%)
Viewer APositive0001325
Negative10102020
Viewer BPositive0001425
Negative10102010
Viewer CPositive0001325
Negative10102020

Discordant Results of Oxazepam Dip Card

ViewerSample NumberGC/MS ResultDipcard FormatViewer Results
Viewer A94638975324Negative
Viewer A83001567325Negative
Viewer B94638975324Negative
Viewer C83002215326Negative
Viewer C94639027328Negative

{17}------------------------------------------------

CupformatNegativeLowNegativeby GC/MS(less than-50%)Near CutoffNegative byGC/MS(Between-50% andcut-off)NearCutoffPositive byGC/MS(Betweenthe cut-offand +50%)HighPositive byGC/MS(greaterthan +50%)
Viewer APositive0001425
Negative10102010
Viewer BPositive0001425
Negative10102010
Viewer CPositive0001325
Negative10102020

Discordant Results of Oxazepam Cup

ViewerSample NumberGC/MS ResultCup FormatViewer Results
Viewer A83002215326Negative
Viewer B83001567325Negative
Viewer C83001567325Negative
Viewer C94639027328Negative

Methamphetamine

Dip CardLowNear
formatNegativeNegativeby GC/MS(less than-50%)Near CutoffNegative byGC/MS(Between-50% andcut-off)CutoffPositive byGC/MS(Betweenthe cut-offand +50%)HighPositive byGC/MS(greaterthan +50%)
Viewer APositive0001821
Negative10102010
Viewer BPositive0001821
Negative10102010
Viewer CPositive0001721
Negative10102020

{18}------------------------------------------------

ViewerSample NumberGC/MS ResultDipCard Format Viewer Results
Viewer A830005301156Negative
Viewer B830018071094Negative
Viewer C830018111065Negative
Viewer C830018071094Negative

Discordant Results of Methamphetamine DipCard

CupformatNegativeLowNegativeby GC/MS(less than-50%)Near CutoffNegative byGC/MS(Between-50% andcut-off)NearCutoffPositive byGC/MS(Betweenthe cut-offand +50%)HighPositive byGC/MS(greaterthan +50%)
Viewer APositive0001821
Negative10102010
Viewer BPositive0001821
Negative10102010
Viewer CPositive0001721
Negative10102020

Discordant Results of Methamphetamine Cup

ViewerSample NumberGC/MS ResultCup FormatViewer Results
Viewer A830018211079Negative
Viewer B830018071094Negative
Viewer C830018211079Negative
Viewer C830018071094Negative

{19}------------------------------------------------

Morphine

DipCardformatMorphine
NegativeLow Negativeby GC/MS(less than -50%)Near CutoffNegative byGC/MS(Between -50% andcut-off)Near CutoffPositive byGC/MS(Betweenthe cut-offand +50%)High Positive byGC/MS(greaterthan +50%)
Viewer APositive0001524
Negative10102010
Viewer BPositive0001524
Negative10102010
Viewer CPositive0001524
Negative10102010

Discordant Results of Morphine DipCard

ViewerSample NumberGC/MS ResultDipCard FormatViewer Results
Viewer A946390122119Negative
Viewer B946390122119Negative
Viewer C830002192325Negative
CupformatNegativeLowNegativeby GC/MS(less than-50%)Near CutoffNegative byGC/MS(Between-50% andcut-off)Near CutoffPositive byGC/MS(Betweenthe cut-offand +50%)HighPositive byGC/MS(greaterthan+50%)
Viewer APositive0001524
Negative10102010
Viewer BPositive0001524
Negative10102010
Viewer CPositive0001524
Negative10102010

Discordant Results of Morphine Cup

ViewerSample NumberGC/MS ResultCup FormatViewer Results
Viewer A830002192325Negative
Viewer B830005722227Negative
Viewer C946390122119Negative

{20}------------------------------------------------

Lay-user study

A lay user study was performed at three intended user sites with 280 lay persons testing the Oxazepam devices, 280 lay persons testing the Methamphetamine devices and 280 lay persons testing the Morphine devices. A total of 139 females and 141 males tested the Oxazepam samples, 138 females and 142 males tested Methamphetamine samples, and 137 females and 143 males tested the Morphine samples. They had diverse educational and professional backgrounds and ranged in age from 21 to > 50 years. Urine samples were prepared at the following concentrations; negative, +/-75%, +/-50%, +/-25% of the cutoff by spiking drugs into drug free-pooled urine specimens. The concentrations of the samples were confirmed by GC/MS. Each sample was aliquoted into individual containers and blind-labeled. Each participant was provided with the package insert, 1 blind labeled sample and a device. The results are summarized below.

NumberofsamplesOxazepam Concentrationby GC/MS(ng/mL)Lay person resultsThepercentage ofcorrect results(%)
% of CutoffNo. ofPositiveNo. ofNegative
-100% Cutoff200020100%
-75% Cutoff2076020100%
-50% Cutoff20145020100%
-25% Cutoff20222020100%
+25% Cutoff2038418290%
+50% Cutoff20468200100%
+75% Cutoff20542200100%

Comparison between GC/MS and Lay Person Results (Oxazepam DipCard)

Comparison between GC/MS and Lay Person Results (Oxazepam Cup)

% of CutoffNumberofsamplesOxazepam Concentrationby GC/MS(ng/mL)Lay person resultsThepercentage ofcorrect results(%)
No. ofPositiveNo. ofNegative
-100% Cutoff200020100%
-75% Cutoff2076020100%
-50% Cutoff20145020100%
-25% Cutoff2022221890%
+25% Cutoff20384200100%
+50% Cutoff20468200100%
+75% Cutoff20542200100%

{21}------------------------------------------------

NumberofsamplesMethamphetamineConcentration by GC/MS(ng/mL)Lay person resultsThepercentage ofcorrect results(%)
% of CutoffNo. ofPositiveNo. ofNegative
-100% Cutoff200020100%
-75% Cutoff20245020100%
-50% Cutoff20488020100%
-25% Cutoff20729020100%
+25% Cutoff20121219195%
+50% Cutoff201441200100%
+75% Cutoff201666200100%

Comparison between GC/MS and Lay Person Results (Methamphetamine DipCard)

Comparison between GC/MS and Lay Person Results (Methamphetamine Cup)

% of CutoffNumberofsamplesMethamphetamineConcentration by GC/MS(ng/mL)Lay person resultsThepercentage ofcorrect results(%)
No. ofPositiveNo. ofNegative
-100% Cutoff200020100%
-75% Cutoff20245020100%
-50% Cutoff20488020100%
-25% Cutoff20729020100%
+25% Cutoff20121219195%
+50% Cutoff201441200100%
+75% Cutoff201666200100%

Comparison between GC/MS and Lay Person Results (Morphine DipCard)

% of CutoffNumberofsamplesMorphine Concentrationby GC/MS(ng/mL)Lay person resultsThepercentage ofcorrect results(%)
-100% Cutoff200020100%
-75% Cutoff20527020100%
-50% Cutoff201053020100%
-25% Cutoff20157311995%
+25% Cutoff202652200100%
+50% Cutoff203254200100%
+75% Cutoff203711200100%

{22}------------------------------------------------

% of CutoffNumberofsamplesMorphine Concentrationby GC/MS(ng/mL)Lay person resultsThe
No. ofPositiveNo. ofNegativepercentage ofcorrect results(%)
-100% Cutoff200020100%
-75% Cutoff20527020100%
-50% Cutoff201053020100%
-25% Cutoff201573020100%
+25% Cutoff20265219195%
+50% Cutoff203254200100%
+75% Cutoff203711200100%

Comparison between GC/MS and Lay Person Results (Morphine Cup)

Lay-users were also given surveys on the ease of understanding the package insert instructions. All lay users indicated that the device instructions can be easily followed. A Flesch-Kincaid reading analysis was performed on each package insert and the scores revealed a reading Grade Level of 7.

    1. Clinical Studies
      Not applicable.

11. Conclusion

Based on the test principle and acceptable performance characteristics including precision, cut-off, interference, specificity and method comparison of the devices, it's concluded that the First Sign™ Drug of Abuse Dip Card Test and First Sign™ Drug of Abuse Cup Test are substantially equivalent to the predicate.

§ 862.3610 Methamphetamine test system.

(a)
Identification. A methamphetamine test system is a device intended to measure methamphetamine, a central nervous system stimulating drug, in serum, plasma, and urine. Measurements obtained by this device are used in the diagnosis and treatment of methamphetamine use or overdose.(b)
Classification. Class II (special controls). A methamphetamine 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).