CR3 Keyless Split Sample Cup Nortriptyline-Buprenorphine is a rapid test for the qualitative detection of Nortriptyline (a major metabolite of Tricyclic Antidepressants) and Buprenorphine in human urine at a cutoff concentration of 1000ng/mL and 10ng/mL, respectively. The test is the first step in a two-step process. The second step is to send the sample for laboratory testing if preliminary positive results are obtained. The test is intended for over-the-counter and for prescription use.

The test may yield preliminary positive results even when prescription drugs including Tricyclic Antidepressants and Buprenorphine are ingested, at prescribed doses; it is not intended to distinguish between prescription use or abuse of these drugs. There are no uniformly recognized cutoff concentration levels for Nortriptyline in urine. The test provides only preliminary test results. A more specific alternative chemical method must be used in order to obtain a confirmed analytical result. GC/MS is the preferred confirmatory method. Clinical consideration and professional iudgment should be exercised with any drug of abuse test result, particularly when the preliminary result is positive.

For in vitro diagnostic use only.

Device Description

The CR3 Keyless Split Sample Cup Nortriptyline-Buprenorphine test uses immunochromatographic assays for nortriptyline and buprenorphine. The test is a lateral flow, one step system for the qualitative detection of nortriptyline and buprenorphine in human urine.

AI/ML Overview

Here's an analysis of the provided text to extract the acceptance criteria and study details for the CR3 Keyless Split Sample Cup Nortriptyline - Buprenorphine device:

Acceptance Criteria and Device Performance for CR3 Keyless Split Sample Cup Nortriptyline - Buprenorphine

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state "acceptance criteria" for precision or accuracy using specific numerical thresholds. Instead, it presents the raw performance data from various studies. For the purpose of this analysis, I will infer the implicit acceptance criteria from the observed performance and the nature of drug screening tests (i.e., high agreement around cutoff, 100% detection for significantly positive, 100% negative for significantly negative).

Analytical Performance (Precision/Cut-off Verification)

Criterion Type	Acceptance Criteria (Implied)	Reported Device Performance (Nortriptyline - TCA)	Reported Device Performance (Buprenorphine - BUP)
Precision	Should show 100% negative results at concentrations significantly below the cutoff (-50%, -75%, -100%) and 100% positive results at concentrations significantly above the cutoff (+50%, +75%, +100%). At the cutoff and near-cutoff concentrations (-25%, +25%), some variability is expected and acceptable, but a clear trend towards positive above cutoff and negative below cutoff should be observed.	-100%, -75%, -50% cut-off: 50-/0+ (100% Negative)-25% cut-off: 50-/0+ (100% Negative)Cut-off: 43-44+/6-7 (86-88% Positive)+25%, +50%, +75%, +100% cut-off: 50+/0- (100% Positive)	-100%, -75%, -50% cut-off: 50-/0+ (100% Negative)-25% cut-off: 50-/0+ (100% Negative)Cut-off: 42-43+/7-8 (84-86% Positive)+25%, +50%, +75%, +100% cut-off: 50+/0- (100% Positive)
Cut-off	Device should consistently classify samples at or above +25% of the cutoff as positive and samples at or below -25% of the cutoff as negative.	All positive at +25% and +50% cut-off. All negative at -25% and -50% cut-off.	All positive at +25% and +50% cut-off. All negative at -25% and -50% cut-off.
Interference	No interference from tested endogenous or exogenous substances at specified concentrations (100 µg/mL).	All listed compounds showed no interference at 100 µg/mL.	All listed compounds showed no interference at 100 µg/mL.
Specificity	Should demonstrate expected cross-reactivity with drug metabolites and related compounds, reflecting the immunological basis of the test, and minimal cross-reactivity with unrelated substances.	Nortriptyline: High cross-reactivity with Nordoxepine (100%), Desipramine (500%), Imipramine (250%). Lower cross-reactivity with Amitriptyline, Promazine, Doxepine, Maprotiline, Trimipramine, Clomipramine, Promethazine.	Buprenorphine: High cross-reactivity with Buprenorphine-3-D-Glucuronide (67%), Norbuprenorphine (50%). Very low cross-reactivity with Norbuprenorphine-3-D-Glucuronide (5%), Morphine, Oxymorphone, Hydromorphone (<0.1%).
Specific Gravity and pH Effect	Device performance should not be significantly affected by varying specific gravity (1.000 to 1.035) and pH (4.00 to 9.00) of urine samples.	Device performance was found not affected by varying specific gravity and pH.	Device performance was found not affected by varying specific gravity and pH.

Clinical/Method Comparison Performance (vs. GC/MS)

Criterion Type	Acceptance Criteria (Implied)	Reported Device Performance (Nortriptyline - TCA)	Reported Device Performance (Buprenorphine - BUP)
Accuracy (In-field/Lay-User vs. GC/MS)	High agreement (e.g., >90-95%) with GC/MS for clearly negative (e.g., -100%, -75%, -50% below cutoff) and clearly positive samples (e.g., +50%, +75% above cutoff). Reasonable agreement (e.g., >80%) in near-cutoff regions, acknowledging the inherent variability and intended screening nature of the device. For OTC use, acceptable agreement demonstrates that lay users can correctly interpret results following instructions.	Method Comparison: Consistently identified 100% of "Negative" and "Low Negative" samples as negative. Consistently identified 100% of "High Positive" samples as positive. Variability in "Near Cutoff Negative" (7-8/11 negative, 3-4/11 positive) and "Near Cutoff Positive" (3-4/12 negative, 8-9/12 positive) expected for a qualitative screening test. Lay User Study: 100% agreement for Drug-free, -75%, -50% cut-off. 85% agreement for -25% cut-off (17/20 negative) & +25% cut-off (17/20 positive). 100% agreement for +50%, +75% cut-off.	Method Comparison: Consistently identified 100% of "Negative" and "Low Negative" samples as negative. Consistently identified 100% of "High Positive" samples as positive. Variability in "Near Cutoff Negative" (14-16/19 negative, 3-5/19 positive) and "Near Cutoff Positive" (3-4/17 negative, 13-14/17 positive) expected for a qualitative screening test. Lay User Study: 100% agreement for -75%, -50% cut-off. 90% agreement for -25% cut-off (18/20 negative). 85% agreement for +25% cut-off (17/20 positive). 100% agreement for +50%, +75% cut-off.
Ease of Use (Lay User Study)	Lay users should indicate that instructions are easy to follow, and the reading grade level of instructions should be appropriate for OTC use.	All lay users indicated instructions were easy to follow. Flesch-Kincaid score indicated a reading grade level less than 7.	All lay users indicated instructions were easy to follow. Flesch-Kincaid score indicated a reading grade level less than 7.

The study demonstrates that the device performs as expected for a qualitative drug screening test, with high accuracy for samples well outside the cutoff and reasonable performance near the cutoff, which is acceptable given its intended "first step in a two-step process" role where preliminary positives require laboratory retesting.

2. Sample Sizes Used for the Test Set and Data Provenance

Analytical Performance (Precision, Cut-off, Interference, Specificity, Specific Gravity/pH):

Precision:
- For each of 9 concentration levels, for both Nortriptyline and Buprenorphine: 50 tests were performed (2 runs per day for 25 days).
- Total tests for precision: 9 concentrations * 2 drugs * 50 tests/concentration = 900 tests.
Cut-off Verification:
- 125 Nortriptyline samples and 125 Buprenorphine samples, equally distributed at -50%, -25%, cut-off, +25%, +50% of their respective cut-offs. (Total 250 samples).
Interference & Specificity & Effect of Specific Gravity and pH:
- Number of samples not explicitly stated beyond "tested for each condition (drug-free, 25% below cut-off, 25% above cut-off)" against a long list of potential interferents/cross-reactants.
Data Provenance: The document does not explicitly state the country of origin for these analytical samples. They appear to be spiked samples developed in a laboratory setting for controlled testing rather than clinical samples. The studies are prospective in nature in that samples were prepared and then tested.

Clinical/Method Comparison Study (vs. GC/MS):

Sample Size: 80 "unaltered clinical samples" for Nortriptyline and 80 "unaltered clinical samples" for Buprenorphine. (Total 160 clinical samples).
Data Provenance: Not explicitly stated, but described as "clinical samples," implying human origin. The study was performed "in-house," and the samples were "unaltered," and "masked and randomized," indicating a prospective evaluation of existing or collected clinical samples.

Lay-User Study:

Sample Size: 260 lay persons, using urine samples (20 drug-free, 120 nortriptyline, 120 buprenorphine).
- For Nortriptyline and Buprenorphine, each: 20 samples were tested at -100% (drug-free), -75%, -50%, -25%, +25%, +50%, +75% of the cutoff. (7 concentrations * 20 samples/concentration = 140 samples * 2 drugs = 280 samples for the lay user study, but the text says 20 drug-free, 120 nortriptyline, 120 buprenorphine, summing to 260 samples).
Data Provenance: Urine samples were "spiked drug(s) into drug free-pooled urine specimens." The concentrations were confirmed by GC/MS. This indicates laboratory-prepared, prospectively tested samples, not necessarily from patients with the conditions. Lay users had diverse educational and professional backgrounds from 21 to >50 years of age.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications

Analytical Ground Truth: For precision, cut-off, interference, specificity, specific gravity/pH studies, the ground truth was established by preparing samples with known concentrations of analytes (e.g., standard solutions, spiked urine). The "experts" are the laboratory personnel who accurately prepare these samples and use calibrated instrumentation.
Clinical/Method Comparison Ground Truth: The ground truth for the 160 "unaltered clinical samples" was established by GC/MS (Gas Chromatography/Mass Spectrometry), which is stated as "the preferred confirmatory method." The number of experts interpreting the GC/MS results is not specified, but GC/MS involves trained laboratory professionals.
Lay-User Study Ground Truth: The ground truth for the spiked samples was established by preparing samples with known concentrations and confirmed by GC/MS.

4. Adjudication Method for the Test Set

Analytical Studies (Precision, Cut-off, Interference, Specificity, Specific Gravity/pH):
- In some cases, samples were tested using "three different lots by three different operators." The results were then summarized. No formal expert adjudication method (e.g., 2+1) is explicitly described for discrepancies in these analytical studies. It implies direct data recording and analysis.
Clinical/Method Comparison Study:
- "Three laboratory assistants" ran the samples. The obtained results were compared to GC/MS results. The results are presented for "Viewer A, Viewer B, Viewer C," suggesting individual interpretations. The discordant tables list individual viewer's results against the GC/MS result. There is no mention of an adjudication process among the three viewers for their interpretations. The ground truth (GC/MS) is presented as definitive.
Lay-User Study:
- Each participant was given one blind-labeled sample and a device. The participants' results were then compared to the GC/MS confirmed concentration of the sample. No adjudication was explicitly performed for the lay users' interpretations; their results were simply recorded and compared to the established ground truth.

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

No, a traditional MRMC comparative effectiveness study comparing human readers with AI assistance versus without AI assistance was not done. This device is a rapid drug screening test and not an imaging AI device. The method comparison study involved "three laboratory assistants" (human readers) interpreting the device results and comparing them to a gold standard (GC/MS), but it did not involve an AI component or evaluate the "effect size of how much human readers improve with AI vs without AI assistance."

6. Standalone Performance Study

Yes, the analytical performance studies (Precision, Cut-off, Interference, Specificity, Specific Gravity/pH) and the "Comparison Studies" (method comparison with GC/MS) represent standalone (algorithm only, without human-in-the-loop performance), as the performance of the device (its ability to detect the substances) is characterized independently. While human operators perform the test and read the result line, the inherent accuracy of the device's chemical assay is what is being evaluated in these sections. The lay-user study then assesses whether an untrained human can properly interpret the standalone device's output.

7. Type of Ground Truth Used

Analytical Studies: Known concentrations of target analytes (spiked samples) and confirmed by GC/MS for lay-user study samples. This is a form of reference standard ground truth.
Clinical/Method Comparison Study: GC/MS (Gas Chromatography/Mass Spectrometry) results. This is considered a definitive laboratory reference method or gold standard for drug detection and quantification.

8. Sample Size for the Training Set

The document does not mention a training set for an algorithm or AI. This device is an immunochromatographic assay (lateral flow immunoassay), which is a chemical/biological test, not a software algorithm that requires training data.

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

As there is no training set for an algorithm, this question is not applicable. The device operates based on antigen-antibody reactions, not a learned model.

Summary

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Image /page/0/Picture/1 description: The image shows the logo for the Department of Health & Human Services - USA. The logo consists of a circular seal with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" arranged around the perimeter. Inside the circle is an emblem featuring a stylized depiction of three human profiles facing to the right, with flowing lines suggesting movement or connection.

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

December 18, 2014

GUANGZHOU WONDFO BIOTECH CO., LTD. C/O JOE SHIA LSI INTERNATIONAL INC. 504 EAST DIAMOND AVE. SUITE F GAITHERSBURG MD 20878

Re: K142609

Trade/Device Name: CR3 Keyless Split Sample Cup Nortriptyline-Buprenorphine Regulation Number: 21 CFR 862.3910 Regulation Name: Tricyclic antidepressant drugs test system Regulatory Class: II Product Code: LFG. DJG Dated: October 13, 2014 Received: October 16, 2014

Dear Mr. Joe Shia:

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.

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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 -S

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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DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration

Indications for Use

Form Approved: OMB No. 0910-0120 Expiration Date: January 31, 2017 See PRA Statement below.

510(k) Number (if known) K142609

Device Name

CR3 Keyless Split Sample Cup Nortriptyline - Buprenorphine

Indications for Use (Describe)

For in vitro diagnostic use only.

Type of Use (Select one or both, as applicable)

Prescription Use (Part 21 CFR 801 Subpart D)

X 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."

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510(k) SUMMARY

	1. Date:	December 10, 2014
2.	Submitter:		Guangzhou Wondfo Biotech Co., Ltd.No.8 Lizhishan Road, Science City, Luogang District,Guangzhou, P.R. China 510663
	3. Contact person:	Joe ShiaFax: 301-916-6213	LSI International Inc.504 East Diamond Ave., Suite FGaithersburg, MD 20878Telephone: 240-505-7880Email:shiajl(@yahoo.com
4.	Device Name:		CR3 Keyless Split Sample Cup Nortriptyline - Buprenorphine
	Classification:	Class IIProductCodeLFGDIG	CFR #21CFR 862.391021CFR 862.3650
	5. Predicate Devices:	K132812	UCP Multi-Drug Test Key Cups

1. Intended Use
  CR3 Keyless Split Sample Cup Nortriptyline-Buprenorphine is a rapid test for the qualitative detection of Nortriptyline (a major metabolite of Tricyclic Antidepressants) and Buprenorphine in human urine at a cutoff concentration of 1000ng/mL, respectively. The test is the first step in a two-step process. The second step is to send the sample for laboratory testing if preliminary positive results are obtained. The test is intended for over-the-counter and for prescription use.

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method must be used in order to obtain a confirmed analytical result. GC/MS is the preferred confirmatory method. Clinical consideration and professional judgment should be exercised with any drug of abuse test result, particularly when the preliminary result is positive.

For in vitro diagnostic use only.

1. Device Description
  The CR3 Keyless Split Sample Cup Nortriptyline-Buprenorphine test uses immunochromatographic assays for nortriptyline and buprenorphine. The test is a lateral flow, one step system for the qualitative detection of nortriptyline and buprenorphine in human urine.

Item	Device	Predicate
Indication(s)for use	For the qualitative determination ofdrugs of abuse in human urine	Same
Methodology	Competitive binding, lateral flowimmunochromatographic assaysbased on the principle of antigenantibody immunochemistry.	Same
Results	Qualitative	Same
SpecimenType	Human urine	Same
Cut Off Values	Nortriptyline: 1000ng/mlBuprenorphine: 10ng/ml	Same forNortriptyline andBuprenorphine
Configurations	Cup	Cup
Conditions forUse	Over-the-Counter & PrescriptionUse	Same

1. Substantial Equivalence Information

9. Test Principle

The CR3 Keyless Split Sample Cup Nortriptyline - Buprenorphine test is a rapid test for the qualitative detection of Nortriptyline and Buprenorphine in urine samples and contains lateral flow chromatographic immunoassays for nortriptyline and buprenorphine. Each assay uses a mouse monoclonal anti-drug antibody-dye conjugate, fixed drug-protein conjugates, and anti-mouse IgG polyclonal antibodies coated on the test membranes. When the absorbent end of the test is immersed into a urine sample, the urine is absorbed into the

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device by capillary action and mixes with the antibody-dye conjugate, flowing across the pre-coated membrane. At analyte concentrations below the target cut-off, antibody-dye conjugates bind to the drug-protein conjugate immobilized in the Test Region (T) of the device. This produces a colored test line that indicates a negative result. When analyte concentration is above the cut-off, analyte molecules bind to the antibody-dye conjugate, preventing the antibody-dye conjugate from binding to the drug-protein conjugate immobilized in the Test Region (T) of the device. No colored band shows in the test region, indicating a potentially positive result. A band should form in the control region (C) of the device regardless of the presence of drug or metabolite in the sample.

1. Performance Characteristics
- 1. Analytical Performance
  - a. Precision

Precision studies were carried out for samples with concentrations of -100% cut-off, -75% cut-off, -50% cut-off, -25% cut-off, at the cut-off, +25% cut-off, +50% cut-off , +75% cut-off and +100% cut-off. For each concentration, tests were performed two runs per day for 25 days. All sample aliquots were masked and randomized. The results obtained are summarized in the following tables:

ResultTCA	-100%cut-off	-75%cut-off	-50%cut-off	-25%cut-off	cut-off	+25%cut-off	+50%cut-off	+75%cut-off	+100%cut-off
W11910601CU5	50-/0+	50-/0+	50-/0+	50-/0+	44+/6-	50+/0-	50+/0-	50+/0-	50+/0-
W11910602CU5	50-/0+	50-/0+	50-/0+	50-/0+	43+/7-	50+/0-	50+/0-	50+/0-	50+/0-
W11910603CU5	50-/0+	50-/0+	50-/0+	50-/0+	43+/7-	50+/0-	50+/0-	50+/0-	50+/0-

A. For Nortriptyline (TCA) testing

B. For Buprenorphine (BUP) testing

ResultBUP	-100%cut-off	-75%cut-off	-50%cut-off	-25%cut-off	cut-off	+25%cut-off	+50%cut-off	+75%cut-off	+100%cut-off
W11910601CU5	50-/0+	50-/0+	50-/0+	50-/0+	42+/8-	50+/0-	50+/0-	50+/0-	50+/0-
W11910602CU5	50-/0+	50-/0+	50-/0+	50-/0+	43+/7-	50+/0-	50+/0-	50+/0-	50+/0-
W11910603CU5	50-/0+	50-/0+	50-/0+	50-/0+	43+/7-	50+/0-	50+/0-	50+/0-	50+/0-

b. Linearity

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Not applicable.

c. Stability
The CR3 Keyless Split Sample Cup Nortriptyline - Buprenorphine is stable at 4-30°C for 18 months as determined by conducting accelerated and real-time stability testing.

Control materials are not provided with the device. The labeling provides information on how to obtain control materials.

d. Cut-off
A total of 125 nortriptyline samples and 125 buprenorphine samples equally distributed at concentrations of -50%, -25%, at the cut-off, +25%, +50% of their respective cut-offs were labeled by a person who prepared them and would not participate in the sample testing. These samples were tested using three different lots by three different operators. Results were all positive at +25% and +50% cut-off and all negative at -25% and -50% cut-off for both nortriptyline and buprenorphine. The following cut-off values for the test devices have been verified.

Test	Calibrator	Cut-off(ng/ml)
Nortriptyline (TCA)	nortriptyline	1000
Buprenorphine (BUP)	buprenorphine	10

e. Interference
Potential interfering substances found in human urine of physiological or pathological conditions were added to drug-free urine and to urine containing target drugs (nortriptyline or buprenorphine) at 25% below and 25% above the cut-off. These urine samples were tested using three batches of the CR3Keyless Split Sample Cup Nortriptyline - Buprenorphine by three different operators. Compounds that showed no interference at a concentration of 100µg/mL are summarized below:

Nortriptyline

4-Acetamidophenol	Erythromycin	Oxycodone
Acetophenetidin	β-Estradiol	Oxymetazoline
N-Acetylprocainamide	Estrone-3-sulfate	Papaverine
Acetylsalicylic acid	Ethyl-p-aminobenzoate	Penicillin-G

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Aminopyrine	Fenoprofen	Pentazocine hydrochloride
Amobarbital	Furosemide	Pentobarbital
Amoxicillin	Gentisic acid	Perphenazine
Ampicillin	Hemoglobin	Phencyclidine
L-ascorbic acid	Hydralazine	Phenelzine
DL-Amphetamine sulfate	Hydrochlorothiazide	Phenobarbital
Apomorphine	Hydrocodone	Phentermine
Aspartame	Hydrocortisone	β-Phenylethylamine
Atropine	O-Hydroxyhippuric acid	Trans-2-phenylcyclopropylamine hydrochloride
Benzilic acid	p-Hydroxyamphetamine	L-Phenylephrine
Benzoic acid	p-Hydroxy- methamphetamine	Phenylpropanolamine
Benzoylecgonine	3-Hydroxytyramine	Prednisolone
Benzphetamine	Ibuprofen	Prednisone
Bilirubin	Iproniazid	Procaine
(±) - Brompheniramine	(±) - Isoproterenol	DL-Propanolol
Caffeine	Isoxsuprine	D-Propoxyphene
Cannabidiol	Ketamine	D-Pseudoephedrine
Cannabinol	Ketoprofen	Quinacrine
Chloralhydrate	Labetalol	Quinidine
Chloramphenicol	Loperamide	Quinine
Chlorothiazide	MDE	Ranitidine
(±) Chlorpheniramine	Meperidine	Salicylic acid
Chlorpromazine	Meprobamate	Secobarbital
Chlorquine	Methadone	Serotonin
Cholesterol	(L)Methamphetamine	Sulfamethazine
Clonidine	Methoxyphenamine	Sulindac
Cocaethylene	(±)-3,4-Methylenedioxyamphetamine hydrochloride	Tetracycline
Cocaine hydrochloride	(+)3,4-Methylenedioxymethamphetamine hydrochloride	Tetrahydrocortisone,3-acetate
Codeine	Morphine-3-β-D-Glucuronide	Tetrahydrocortisone,3-(β-D-glucuronide)
Cortisone	Morphine sulfate	Tetrahydrozoline
(-) Cotinine	Nalidixic acid	Thiamine
Creatinine	Naloxone	Thioridazine
Deoxycorticosterone	Naltrexone	DL-Tyrosine
Dextromethorphan	Naproxen	Tolbutamide
Diclofenac	Niacinamide	Triamterene
Diflunisal	Nifedipine	Trifluoperazine
Digoxin	Norcodeine	Trimethoprim

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Diphenhydramine
Doxylamine
Ecgonine hydrochloride
Ecgonine methylester
Ephedrine
(L) - Epinephrine

Buprenorphine

4-Acetamidophenol Acetophenetidin N-Acetylprocainamide Acetylsalicylic acid Aminopyrine Amobarbital Amoxicillin Ampicillin L-ascorbic acid DL-Amphetamine sulfate Apomorphine Aspartame Atropine Benzilic acid Benzoic acid Benzoylecgonine Benzphetamine Bilirubin (±) - Brompheniramine Caffeine Cannabidiol Cannabinol Chloralhydrate Chloramphenicol Chlorothiazide (±) Chlorpheniramine Chlorpromazine Chlorquine Cholesterol

Clonidine

Norethindrone D-Norpropoxyphene Noscapine Oxalic acid Oxazepam Oxolinic acid

Erythromycin ß-Estradiol Estrone-3-sulfate Ethyl-p-aminobenzoate Fenoprofen Furosemide Gentisic acid Hemoglobin Hydralazine Hydrochlorothiazide Hydrocodone Hydrocortisone O-Hydroxyhippuric acid p-Hydroxyamphetamine p-Hydroxy- methamphetamine 3-Hydroxytyramine Ibuprofen Iproniazid (±) - Isoproterenol Isoxsuprine Ketamine Ketoprofen Labetalol Loperamide MDE Meperidine Meprobamate Methadone (L)Methamphetamine Methoxyphenamine

Tryptamine DL-Tryptophan Tyramine Uric acid Verapamil Zomepirac

Oxycodone Oxymetazoline Papaverine Penicillin-G Pentazocine hydrochloride Pentobarbital Perphenazine Phencyclidine Phenelzine Phenobarbital Phentermine β-Phenylethylamine Trans-2-phenylcyclopropyl amine hydrochloride L-Phenylephrine Phenylpropanolamine Prednisolone Prednisone Procaine DL-Propanolol D-Propoxyphene D-Pseudoephedrine Quinacrine Quinidine Quinine Ranitidine Salicylic acid Secobarbital Serotonin Sulfamethazine Sulindac

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Cocaethylene	(±)-3,4-Methylenedioxyamphetamine hydrochloride	Tetracycline
Cocaine hydrochloride	(+)3,4-Methylenedioxymethamphetamine hydrochloride	Tetrahydrocortisone,3-acetate
Codeine	Morphine-3-β-Dglucuronide	Tetrahydrocortisone3-(β-D-glucuronide)
Cortisone	Morphine sulfate	Tetrahydrozoline
(-) Cotinine	Nalidixic acid	Thiamine
Creatinine	Naloxone	Thioridazine
Deoxycorticosterone	Naltrexone	DL-Tyrosine
Dextromethorphan	Naproxen	Tolbutamide
Diclofenac	Niacinamide	Triamterene
Diflunisal	Nifedipine	Trifluoperazine
Digoxin	Norcodeine	Trimethoprim
Diphenhydramine	Norethindrone	Tryptamine
Doxylamine	D-Norpropoxyphene	DL-Tryptophan
Ecgonine hydrochloride	Noscapine	Tyramine
Ecgonine methylester	Oxalic acid	Uric acid
Ephedrine	Oxazepam	Verapamil
(L) - Epinephrine	Oxolinic acid	Zomepirac

ﻧﮯ Specificity
To test the specificity, drug metabolites and other components that are likely to be present in urine samples were tested. The target drug (Nortriptyline or Buprenorphine), its drug metabolites and the related compounds were studied. These samples were tested using three batches of the CR3Keyless Split Sample Cup Nortriptyline-Buprenorphine by three different operators. The drug metabolites and other components were tested at different concentrations. The obtained lowest detectable concentration was used to calculate the cross-reactivity. Results are shown in the following tables.

TCA(Nortriptyline,Cut-off=1000 ng/mL)	Result	%Cross-Reactivity
Nortriptyline	Positive at 1000 ng/mL	100%
Nordoxepine	Positive at 1,000 ng/mL	100%
Trimipramiine	Positive at 3,000 ng/mL	33%
Amitriptyline	Positive at 1,500 ng/mL	67%
Promazine	Positive at 1,500 ng/mL	67%
Desipramine	Positive at 200 ng/mL	500%
Imipramine	Positive at 400 ng/mL	250%
Clomipramine	Positive at 12,500 ng/mL	8%

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Doxepine	Positive at 2,000 ng/mL	50%
Maprotiline	Positive at 2,000 ng/mL	50%
Promethazine	Positive at 25,000 ng/mL	4%

BUP(Buprenorphine,Cut-off=10 ng/mL)	Result	%Cross-Reactivity
Buprenorphine	Positive at 10 ng/mL	100%
Buprenorphine -3-D-Glucuronide	Positive at 15 ng/mL	67%
Norbuprenorphine	Positive at 20 ng/mL	50%
Norbuprenorphine -3-D-Glucuronide	Positive at 200 ng/mL	5%
Morphine	>100,000	<0.1%
Oxymorphone	>100,000	<0.1%
Hydromorphone	>100,000	<0.1%

Effect of Specific Gravity and pH g.

Twelve urine samples of normal, high, and low specific gravity ranges (1.000 to 1.035) were collected and spiked with either Nortriptyline or Buprenorphine at 25% below and 25% above the corresponding cut-off level. These samples were tested using three batches of the CR3Keyless Split Sample Cup Nortriptyline-Buprenorphine by three different operators.

The pH of an aliquot negative urine pool was adjusted to pH ranges of 4.00 to 9.00 in 1 pH unit increments and spiked with Nortriptyline or Buprenorphine at 25% below and 25% above the corresponding cut-off levels. These samples were tested using three batches of the CR3Keyless Split Sample Cup Nortriptyline-Buprenorphine by three different operators.

The device performance was found not affected by varying specific gravity and pH.

2. Comparison Studies

The method comparison for the CR2 Keyless Split Sample Cup Nortriptyline-Buprenorphine was performed in-house with three laboratory assistants. Operators ran 80 (40 negative and 40 positive) unaltered clinical samples. The samples were masked

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and randomized. The obtained test results are compared to GC/MS results. The results are presented in the table below:

Nortriptyline

GroupOperators		Negative	LowNegative byGC/MS(less than-50%)	Near CutoffNegative byGC/MS(Between-50% andcutoff)	Near CutoffPositive byGC/MS(Betweenthe cutoffand +50%)	HighPositive byGC/MS(greaterthan +50%)
Viewer A	Positive	0	0	3	9	28
	Negative	10	19	8	3	0
Viewer B	Positive	0	0	4	9	28
	Negative	10	19	7	3	0
Viewer C	Positive	0	0	3	8	28
	Negative	10	19	8	4	0

Discordant table:

Viewer	Sample number	GC/MS result	Viewer result
Viewer A	TCAC1061	919	positive
Viewer A	TCAC1062	964	positive
Viewer A	TCAC1063	944	positive
Viewer A	TCAC1064	1082	negative
Viewer A	TCAC1065	1012	negative
Viewer A	TCA 1218	1245	negative
Viewer B	TCAC1034	754	positive
Viewer B	TCAC1061	919	positive
Viewer B	TCAC1062	964	positive
Viewer B	TCAC1063	944	positive
Viewer B	TCAC1064	1082	negative
Viewer B	TCAC1065	1012	negative
Viewer B	TCAC1093	1237	negative
Viewer C	TCAC1061	919	positive
Viewer C	TCAC1062	964	positive
Viewer C	TCAC1063	944	positive
Viewer C	TCAC1064	1082	negative
Viewer C	TCAC1065	1012	negative
Viewer C	TCAC1093	1237	negative
Viewer C	TCA 1218	1245	negative

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GroupOperators		Negative	Low Negative by GC/MS(less than -50%)	Near Cutoff Negative by GC/MS(Between -50% and cutoff)	Near Cutoff Positive by GC/MS(Between the cutoff and +50%)	High Positive by GC/MS(greater than +50%)
Viewer A	Positive	0	0	3	13	23
	Negative	10	11	16	4	0
Viewer B	Positive	0	0	4	13	23
	Negative	10	11	15	4	0
Viewer C	Positive	0	0	5	14	23
	Negative	10	11	14	3	0

Discordant table:

Viewer	Sample number	GC/MS result	viewer results
Viewer A	BUPC1063	9	positive
Viewer A	BUPC1064	9	positive
Viewer A	BUP1217	9	positive
Viewer A	BUPC1061	11	negative
Viewer A	BUPC1062	10	negative
Viewer A	BUPC1093	12	negative
Viewer A	BUP1224	11	negative
Viewer B	BUPC1063	9	positive
Viewer B	BUPC1064	9	positive
Viewer B	BUP1216	8	positive
Viewer B	BUP1217	9	positive
Viewer B	BUPC1061	11	negative
Viewer B	BUPC1062	10	negative
Viewer B	BUPC1091	12	negative
Viewer B	BUP1224	11	negative
Viewer C	BUPC1033	8	positive
Viewer C	BUPC1065	9	positive
Viewer C	BUP1213	9	positive
Viewer C	BUP1216	8	positive
Viewer C	BUP1217	9	positive
Viewer C	BUPC1061	11	negative
Viewer C	BUPC1091	12	negative
Viewer C	BUP1224	11	negative

Lay-user study

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A lay user study was performed at three intended user sites with 260 lay persons, of which, 20 tested for drug-free samples, 120 for nortriptyline samples, 120 for buprenorphine 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; -100%, +/-75%, +/-50%, +/-25% of the cut-off by spiking drug(s) into drug free-pooled urine specimens. The concentrations of the samples were confirmed by GC/MS. Each sample was aliquoted into individual containers, blind-labeled and randomized. Each participant was provided with the package insert, 1 blind labeled sample and a device. The results are summarized below:

Cup format		Numberofsamples	OTC user		%AgreementWithGC/MS
Drug	Concentration		Negative	Positive
Drug -free	-100%	20	20	0	100%
	-75%	20	20	0	100%
Nortriptyline	-50%	20	20	0	100%
	-25%	20	17	3	85%
	+25%	20	3	17	85%
	+50%	20	0	20	100%
	+75%	20	0	20	100%
Buprenorphine	-75%	20	20	0	100%
	-50%	20	20	0	100%
	-25%	20	18	2	90%
	+25%	20	3	17	85%
	+50%	20	0	20	100%
	+75%	20	0	20	100%

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 the package insert and the score revealed a reading grade level of less than 7.

1. Clinical Studies
  Not applicable

11. Conclusion

Based on the test principle and performance characteristics of the device, it's concluded that CR Keyless Split Sample Cup Nortriptyline -Buprenorphine is substantially equivalent to the predicate.

Regulation Number and Section

§ 862.3910 Tricyclic antidepressant drugs test system.

(a)
Identification. A tricyclic antidepressant drugs test system is a device intended to measure any of the tricyclic antidepressant drugs in serum. The tricyclic antidepressant drugs include imipramine, desipramine, amitriptyline, nortriptyline, protriptyline, and doxepin. Measurements obtained by this device are used in the diagnosis and treatment of chronic depression to ensure appropriate therapy.(b)
Classification. Class II (special controls). A tricyclic antidepressant drugs 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).