LZI Carisoprodol Metabolite (Meprobamate) Enzyme Immunoassay

DEN170010 · Lin-Zhi International, Inc. · QBK · Apr 20, 2018 · Clinical Toxicology

Device Facts

• Record ID: DEN170010
• Device Name: LZI Carisoprodol Metabolite (Meprobamate) Enzyme Immunoassay
• Applicant: Lin-Zhi International, Inc.
• Product Code: QBK · Clinical Toxicology
• Decision Date: Apr 20, 2018
• Decision: DENG
• Submission Type: Direct
• Regulation: 21 CFR 862.3590
• Device Class: Class 2

Indications for Use

The LZI Carisoprodol Metabolite (Meprobamate) Enzyme Immunoassay is intended for the qualitative and semi-quantitative determination of carisoprodol metabolite (meprobamate) in human urine at a cutoff value of 100 ng/mL when calibrated against meprobamate. The assay is designed for prescription use with a number of automated clinical chemistry analyzers. The semi-quantitative mode is for purposes of enabling laboratories to determine an appropriate dilution of the specimen for verification by a confirmatory method such as GC/MS, LC/MS or permitting laboratories to establish quality control procedures. The assay provides only a preliminary analytical result. A more specific alternative chemical confirmatory method (e.g., gas or liquid chromatography and mass spectrometry) must be used to obtain a confirmed analytical result. Clinical consideration and professional judgment must be exercised with any drug of abuse test, particularly when the preliminary test result is positive.

Device Story

Homogeneous enzyme immunoassay for detection of meprobamate in human urine; utilizes competitive binding between sample meprobamate and drug-labeled G6PDH enzyme for anti-meprobamate antibody. Binding of antibody to enzyme-drug conjugate inhibits enzyme activity; presence of sample meprobamate displaces conjugate, restoring enzyme activity. Active enzyme converts NAD to NADH, measured spectrophotometrically at 340 nm. Used in clinical laboratories on automated chemistry analyzers; operated by laboratory technicians. Provides preliminary analytical results; requires confirmation by GC/MS or LC/MS. Assists in substance abuse monitoring and identifying potential medication interactions; not for acute clinical management or therapeutic drug monitoring.

Clinical Evidence

No clinical data provided. Bench testing only required, including accuracy comparisons against FDA-accepted methods (GC/MS or LC/MS), specificity, cross-reactivity, and reproducibility around the cutoff.

Technological Characteristics

Homogeneous enzyme immunoassay; liquid reagents (mouse monoclonal anti-meprobamate antibody, G6P, NAD, meprobamate-labeled G6PDH). Energy source: spectrophotometric measurement at 340 nm. Connectivity: compatible with automated clinical chemistry analyzers. Sterilization: not applicable (reagents).

Indications for Use

Indicated for qualitative and semi-quantitative determination of meprobamate in human urine for prescription use in clinical settings to screen for drug use or abuse.

Regulatory Classification

Identification

A meprobamate test system is a device intended to measure meprobamate in human specimens. Measurements obtained by this device are used to detect the presence of meprobamate to diagnose the use or overdose of meprobamate or structurally-related drug compounds (e.g., prodrugs).

Special Controls

(b) Classification. Class II (special controls). The special controls for this device are: - 1) Design verification and validation must include: - Robust data demonstrating the accuracy of the device when used in the intended (i) specimen matrix. The accuracy data must include a comparison between the meprobamate test system results and meprobamate results that are measured on an FDA-accepted measurement method that is specific and accurate (e.g., gas or liquid chromatography combined with tandem mass spectrometry). - (ii) Robust analytical data demonstrating the performance characteristics of the device, including, but not limited to, specificity, cross-reactivity to relevant endogenous and exogenous substances, and the reproducibility of analyte detection around the cutoff(s). - 2) The intended use of the device must not include an indication for use in monitoring therapeutic drug concentrations or informing dosing adjustment decisions. - 3) Your 21 CFR 809.10 labeling must include the following: - (i) If indicated for use as a screening test to identify preliminary results for further confirmation, the intended use must state "This assay provides only a preliminary analytical result. A more specific alternative chemical confirmatory method (e.g., gas or liquid chromatography and mass spectrometry) must be used to obtain a confirmed analytical result. Clinical consideration and professional judgment must be exercised with any drug of abuse test, particularly when the preliminary test result is positive." - (ii) A limiting statement that reads as follows: "This test should not be used to monitor therapeutic drug concentrations or to inform dosing adjustment decisions."

*Classification.* Class II (special controls). The special controls for this device are:(1) Design verification and validation must include: (i) Robust data demonstrating the accuracy of the device when used in the intended specimen matrix. The accuracy data must include a comparison between the meprobamate test system results and meprobamate results that are measured on an FDA-accepted measurement method that is specific and accurate (e.g., gas or liquid chromatography combined with tandem mass spectrometry). (ii) Robust analytical data demonstrating the performance characteristics of the device, including, but not limited to, specificity, cross-reactivity to relevant endogenous and exogenous substances, and the reproducibility of analyte detection around the cutoff(s). (2) The intended use of the device must not include an indication for use in monitoring therapeutic drug concentrations or informing dosing adjustment decisions. (3) Your 21 CFR 809.10 labeling must include the following: (i) If indicated for use as a screening test to identify preliminary results for further confirmation, the intended use must state “This assay provides only a preliminary analytical result. A more specific alternative chemical confirmatory method (e.g., gas or liquid chromatography and mass spectrometry) must be used to obtain a confirmed analytical result. Clinical consideration and professional judgment must be exercised with any drug of abuse test, particularly when the preliminary test result is positive.” (ii) A limiting statement that reads as follows: “This test should not be used to monitor therapeutic drug concentrations or to inform dosing adjustment decisions.”

Submission Summary (Full Text)

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## EVALUATION OF AUTOMATIC CLASS III DESIGNATION FOR LZI Carisoprodol Metabolite (Meprobamate) Enzyme Immunoassay

## DECISION SUMMARY

## A. DEN Number:

DEN170010

### B. Purpose for Submission:

De Novo request for evaluation of automatic class III designation for the LZI Carisoprodol Metabolite (Meprobamate) Enzyme Immunoassay

### C. Measurand:

Meprobamate

## D. Type of Test:

Homogenous Enzyme Immunoassay, Qualitative and Semi-quantitative

### E. Applicant:

Lin-Zhi International, Inc.

## F. Proprietary and Established Names:

LZI Carisoprodol Metabolite (Meprobamate) Enzyme Immunoassay

## G. Regulatory Information:

- 1. Regulation: 21 CFR 862.3590
- 2. Classification: Class II
- 3. Product code: QBK
- 4. Panel: Toxicology (91)

## H. Intended Use:

- 1. Indications for use:
The LZI Carisoprodol Metabolite (Meprobamate) Enzyme Immunoassay is intended for

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the qualitative and semi-quantitative determination of carisoprodol metabolite (meprobamate) in human urine at a cutoff value of 100 ng/mL when calibrated against meprobamate. The assay is designed for prescription use with a number of automated clinical chemistry analyzers.

The semi-quantitative mode is for purposes of enabling laboratories to determine an appropriate dilution of the specimen for verification by a confirmatory method such as GC/MS, LC/MS or permitting laboratories to establish quality control procedures.

The assay provides only a preliminary analytical result. A more specific alternative chemical confirmatory method (e.g., gas or liquid chromatography and mass spectrometry) must be used to obtain a confirmed analytical result. Clinical consideration and professional judgment must be exercised with any drug of abuse test, particularly when the preliminary test result is positive.

- 2. Special conditions for use statement(s):
- For in vitro diagnostic use only.
- For prescription use only. ●
- 3. Special instrument requirements:

The assay was validated on the Beckman AU400e automated clinical chemistry analyzer. Clinical chemistry analyzers capable of maintaining a constant temperature, pipetting samples, mixing reagents, measuring enzyme rates at 340 nm and timing the reaction accurately can be used to perform this assay.

## I. Device Description:

The LZI Carisoprodol Metabolite (Meprobamate) Enzyme Immunoassay is a homogeneous enzyme immunoassay with ready-to-use liquid reagents. The assay is a kit comprised of two reagents (antibody/substrate reagent R1 and enzyme-drug conjugate reagent R2), which are bottled separately but sold together within the kit. The Ri solution contains mouse monoclonal anti-meprobamate antibody, glucose-6- phosphate (G6P), nicotinamide adenine dinucleotide (NAD), stabilizers, and sodium azide (0.09 %) as a preservative. The R2 solution contains meprobamate-labeled glucose-6-phosphate dehydrogenase (G6PDH) in buffer with sodium azide (0.09 %) as a preservative.

## J. Standard/Guidance Documents Referenced:

CLSI EP07-A2: Interference Testing in Clinical Chemistry; Approved Guideline - Second Edition.

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## K. Test Principle:

The LZI Carisoprodol Metabolite (Meprobamate) Enzyme Immunoassay is based on competition between meprobamate in the sample and the enzyme glucose-6-phosphate dehydrogenase (G6PDH) labeled with meprobamate for a fixed amount of antibody in the reagent. G6PDH enzyme activity decreases upon binding to the antibody, and thus meprobamate concentration in the sample is proportional to enzyme activity. In the absence of meprobamate in the sample, meprobamate-labeled G6PDH conjugate is bound to antibody, and the enzyme activity is inhibited. When meprobamate is present in the sample competes with drug-labeled G6PDH for binding to antibody; the unbound meprobamatelabeled G6PDH then exhibits its maximal enzyme activity. Active enzyme converts nicotinamide adenine dinucleotide (NAD) to NADH, resulting in an absorbance change that can be measured spectrophotometrically at 340 nm.

## L. Performance Characteristics (if/when applicable):

The following performance characteristics were obtained on the Beckman AU400e automated clinical chemistry analyzer.

### 1. Analytical performance:

### a. Reproducibility/Precision

A precision study was performed over 22 days, with 2 runs per day in duplicate (n = 88) using pooled negative urine samples spiked with meprobamate to concentrations of 25, 50, 75, 100, 125, 150, 175, and 200 ng/mL. All concentrations for precision studies were confirmed by Gas Chromatography/Mass Spectrometry (GC/MS) testing. The results from samples assaved using the qualitative and semi-quantitative modes are summarized below.

| Target<br>meprobamate<br>concentration<br>(ng/mL) | GC/MS<br>meprobamate<br>concentration<br>(ng/mL) | % of<br>Cutoff | # of<br>Determinations | Result |
|---------------------------------------------------|--------------------------------------------------|----------------|------------------------|--------------------|
| 0 | not<br>determined | -100% | 88 | 88 Neg / 0<br>Pos |
| 25 | 24.7 | -75% | 88 | 88 Neg / 0<br>Pos |
| 50 | 51.7 | -50% | 88 | 88 Neg / 0<br>Pos |
| 75 | 76.8 | -25% | 88 | 88 Neg / 0<br>Pos |
| 100 | 94.9 | Cutoff | 88 | 40 Neg / 48<br>Pos |

#### Qualitative Analysis

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| Target<br>meprobamate<br>concentration<br>(ng/mL) | GC/MS<br>meprobamate<br>concentration<br>(ng/mL) | % of<br>Cutoff | # of<br>Determinations | Result |
|---------------------------------------------------|--------------------------------------------------|----------------|------------------------|-------------------|
| 125 | 122.3 | +25% | 88 | 0 Neg / 88<br>Pos |
| 150 | 149.4 | +50% | 88 | 0 Neg / 88<br>Pos |
| ા તર | 176.8 | +75% | 88 | 0 Neg / 88<br>Pos |
| 200 | 211.0 | +100% | 88 | 0 Neg / 88<br>Pos |

| Semi-Quantitative Analysis | |
|----------------------------|--|

| Sample<br>concentration<br>(ng/mL) | GC/MS<br>meprobamate<br>concentration<br>(ng/mL) | % of Cutoff | # of<br>Determinations | Result |
|------------------------------------|--------------------------------------------------|-------------|------------------------|--------------------|
| 0 | not<br>determined | -100% | 88 | 88 Neg / 0<br>Pos |
| 25 | 24.7 | -75% | 88 | 88 Neg / 0<br>Pos |
| 50 | 51.7 | -50% | 88 | 88 Neg / 0<br>Pos |
| 75 | 76.8 | -25% | 88 | 88 Neg / 0<br>Pos |
| 100 | 94.9 | Cutoff | 88 | 60 Neg / 28<br>Pos |
| 125 | 122.3 | +25% | 88 | 0 Neg / 88<br>Pos |
| 150 | 149.4 | +50% | 88 | 0 Neg / 88<br>Pos |
| 175 | 176.8 | +75% | 88 | 0 Neg / 88<br>Pos |
| 200 | 211.0 | +100% | 88 | 0 Neg / 88<br>Pos |

## b. Linearity/assay reportable range:

A recovery study was performed by spiking a pool of negative urine with a high dose of meprobamate and generating serial dilutions to achieve the following concentrations: 10, 40, 80, 120, 160, 200, 240, 280, 320, 360, and 400 ng/mL meprobamate. Each sample was run in replicates of 10 in semi-quantitative mode with a calibration curve established with five meprobamate calibrators (0, 50, 100, 200, and 400 ng/mL). Percent recovery was calculated using the mean concentration of the 10 replicates relative to the expected concentration as shown below.

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| Expected<br>Concentration<br>(ng/mL) | Mean Observed<br>Concentration<br>(ng/mL) | Mean Recovery<br>(%) | Range of<br>Recovery (%) |
|--------------------------------------|-------------------------------------------|----------------------|--------------------------|
| 0 | 2.2 | N/A | N/A |
| 10 | 6.7 | 66.6 | 38.0 - 87.0 |
| 40 | 39.9 | 99.7 | 93.8 - 104.8 |
| 80 | 81.8 | 102.2 | 98.0 - 108.4 |
| 120 | 123.3 | 102.8 | 99.9 - 107.3 |
| 160 | 163.7 | 102.3 | 98.3 - 107.5 |
| 200 | 195.3 | 97.7 | 95.4 - 99.7 |
| 240 | 251.6 | 104.8 | 95.3 - 110.5 |
| 280 | 305.7 | 109.2 | 102.0 - 114.3 |
| 320 | 348.9 | 109.0 | 105.5 - 111.9 |
| 360 | 386.6 | 107.4 | 102.3 - 111.8 |
| 400 | 412.5 | 103.1 | 100.3 - 105.4 |

c. Traceability, Stability, Expected values (controls, calibrators, or methods):

The LZI Carisoprodol Metabolite (Meprobamate) Enzyme Immunoassay is traceable to a commercially available meprobamate source material having 99% analytical purity as determined by LC/MS.

Specimen stability information was provided to support the following specimen storage conditions: storage at 2-8℃ for up to 1 week and at -20℃ for up to 17 months.

- d. Detection limit
Not applicable.

- e. Analytical specificity:
Endogenous Compounds: Potential interference from endogenous compounds was evaluated in the qualitative and semi-quantitative modes by spiking these compounds (at the test concentrations shown in the table below) into urine containing either 75 ng/mL or 125 ng/mL meprobamate (±25% of the assay cutoff). Samples were tested in duplicate. The results, which were the same for the qualitative and semiquantitative modes, are shown below.

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| Endogenous | Concentration | -25% Cutoff | +25% Cutoff |
|---------------------------------------------|-----------------------------|-------------|-------------|
| Compound | Tested (mg/dL) | (75 ng/mL) | (125 ng/mL) |
| Acetone | 1000 | Negative | Positive |
| Ascorbic acid | 1500 | Negative | Positive |
| Beta-<br>hydroxybutyric<br>acid sodium salt | 100 | Negative | Positive |
| Bilirubin | 2 | Negative | Positive |
| Calcium chloride<br>dihydrate | 300 (saturated<br>solution) | Negative | Positive |
| Citric acid | 800 | Negative | Positive |
| Creatinine | 500 | Negative | Positive |
| Ethanol | 1000 | Negative | Positive |
| Galactose | 10 | Negative | Positive |
| γ-Globulin | 500 | Negative | Positive |
| Glucose | 3000 | Negative | Positive |
| Hemoglobin | 300 | Negative | Positive |
| Human Serum<br>Albumin | 500 | Negative | Positive |
| Oxalic Acid | 100 | Negative | Positive |
| Potassium<br>chloride | 6000 | Negative | Positive |
| Riboflavin | 0.3 | Negative | Positive |
| Urea | 6000 | Negative | Positive |
| Uric acid<br>monosodium salt | 10 | Negative | Positive |
| Sodium Chloride | 6000 | Negative | Positive |
| Sodium phosphate<br>dibasic salt | 300 | Negative | Positive |

Urine sample preservatives: To evaluate potential interference from common urine sample preservatives, device performance in qualitative and semi-quantitative modes was tested by spiking sodium azide (1% w/v), sodium fluoride (1% w/v), or boric acid (1% w/v) into negative urine to ± 25% of the 100 ng/mL meprobamate cutoff (75 ng/mL and 125 ng/mL). Samples were tested in duplicate. Boric acid was found to cause false negative results at +25% of the 100 ng/mL cutoff (125 ng/mL) and up to +125% of the 100 ng/mL cutoff (225 ng/mL) in both the qualitative and semiquantitative modes. The following statement is provided in the limitations section of the labeling: Boric Acid at 1% w/v may cause false negative results. Boric Acid is not recommended as a preservative for urine.

pH: To evaluate potential interference from the pH of urine, device performance in the qualitative and semi-quantitative modes was tested using a range of urine pH values (3, 4, 5, 6, 7, 8, 9, 10, and 11). Test samples were prepared in negative urine, which was spiked to ±25% of the 100 ng/mL meprobamate cutoff (75 ng/mL and 125 ng/mL), and tested in duplicate. No positive or negative interference was observed at

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urine pH values ranging from 3 to 11 for the qualitative and semi-quantitative modes.

Specific Gravity: To evaluate potential interference from the specific gravity of urine. device performance in the qualitative and semi-quantitative modes was tested using a range of urine specific gravities (1.002, 1.003, 1.006, 1.007, 1.008, 1.012, 1.014, 1.015, 1.019, 1.025, and 1.029). These 12 negative urine samples were spiked with meprobamate to ±25% of the 100 ng/mL meprobamate cutoff (75 ng/mL and 125 ng/mL), and tested in duplicate. No positive or negative interference was observed at urine specific gravities ranging from 1.002 to 1.029 for the qualitative and semi-quantitative modes.

Cross-reactivity of structurally related compounds: The cross-reactivity of various structurally related drugs was evaluated in qualitative and semi-quantitative modes by spiking each substance into negative urine. The following table shows the quantity of each potential cross-reacting compound that produced assay reactivity equivalent to the 100 ng/mL meprobamate cutoff, or the maximum concentration tested (concentration tested), and calculated cross-reactivity for each compound (% crossreactivity). The results were the same for the qualitative and semi-quantitative modes.

| Compound | Concentration Tested (ng/mL) | % Cross-Reactivity |
|---------------------------|------------------------------|--------------------|
| Carisoprodol | 110 | 90.9 |
| Darunavir | 200,000 | <0.1 |
| Efavirenz | 200,000 | <0.1 |
| Felbamate | 400 | 25.0 |
| Hydroxymeprobamate | 65,000 | 0.2 |
| Meprobamate | 100 | 100.0 |
| Meprobamate-N-Glucuronide | 20,000 | 0.5 |
| Methocarbamol | 200,000 | <0.1 |
| Mitocycin C | 200,000 | <0.1 |
| Neostigmine bromide | 200,000 | <0.1 |
| Retigabine | 200,000 | <0.1 |
| Ritonavir | 100,000 | <0.1 |
| Rivastigmine tartrate | 200,000 | <0.1 |
| Zafirlukast | 200,000 | <0.1 |

Interference by structurally unrelated compounds: The potential for positive or negative interference by various structurally unrelated compounds was evaluated by spiking these compounds (at the test concentrations shown in the table below) into urine containing either 75 ng/mL or 125 ng/mL meprobamate (±25% of the assay cutoff). Samples were tested in duplicate. The results, which are the same for the qualitative and semi-quantitative modes, are shown below.

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| | | -25% | +25% |
|-----------------------------------------------------|---------------------------------|---------------------------------|----------------------------------|
| | | Cutoff | Cutoff |
| | Concentration | (75 | (125 |
| Compound | Tested (ng/mL) | ng/mL) | ng/mL) |
| Acetaminophen | 100,000 | Negative | Positive |
| 6-Acetylmorphine | 10,000 | Negative | Positive |
| Acetylsalicylic Acid | 100,000 | Negative | Positive |
| Albuterol(Salbutamol) | 100,000 | Negative | Positive |
| Amitriptyline | 100,000 | Negative | Positive |
| d-Amphetamine | 100,000 | Negative | Positive |
| Benzoylecgonine | 100,000 | Negative | Positive |
| Buprenorphine | 15,000 | Negative | Positive |
| Bupropion | 100,000 | Negative | Positive |
| Caffeine | 100,000 | Negative | Positive |
| Carbamazepine | 100,000 | Negative | Positive |
| Cetirizine | 20,000 | Negative | Positive |
| Chlorpheniramine | 100,000 | Negative | Positive |
| Chlorpromazine | 100,000 | Negative | Positive |
| Clomipramine | 100,000 | Negative | Positive |
| Codeine | 100,000 | Negative | Positive |
| Cyclobenzaprine | 100,000 | Negative | Positive |
| Desipramine | 100,000 | Negative | Positive |
| Diphenhydramine | 100,000 | Negative | Positive |
| Ephedrine | 100,000 | Negative | Positive |
| Fentanyl | 10,000 | Negative | Positive |
| Fluoxetine | 100,000 | Negative | Positive |
| Fluphenazine | 100,000 | Negative | Positive |
| Hydrocodone | 100,000 | Negative | Positive |
| Hydromorphone | 100,000 | Negative | Positive |
| Ibuprofen | 100,000 | Negative | Positive |
| Imipramine | 100,000 | Negative | Positive |
| Lidocaine | 100,000 | Negative | Positive |
| Loratadine | 100,000 | Negative | Positive |
| Maprotiline | 30,000 | Negative | Positive |
| MDA (3,4-<br>methylenedioxyamphetamine) | 100,000 | Negative | Positive |
| MDEA | 100,000 | Negative | Positive |
| MDMA (3,4-<br>methylenedioxymethamphetamine) | 100,000 | Negative | Positive |
| Meperidine | 100,000 | Negative | Positive |
| Methadone | 100,000 | Negative | Positive |
| d-Methamphetamine | 100,000 | Negative | Positive |
| Methapyrilene | 100,000 | Negative | Positive |
| Methaqualone | 100,000 | Negative | Positive |
| | | -25%<br>Cutoff<br>(75<br>ng/mL) | +25%<br>Cutoff<br>(125<br>ng/mL) |
| Compound | Concentration<br>Tested (ng/mL) | | |
| Metronidazole | 100,000 | Negative | Positive |
| Morphine | 100,000 | Negative | Positive |
| Nicotine | 100,000 | Negative | Positive |
| Nortriptyline | 100,000 | Negative | Positive |
| Oxazepam | 100,000 | Negative | Positive |
| Oxycodone | 100,000 | Negative | Positive |
| Oxymorphone | 100,000 | Negative | Positive |
| PCP (phencyclidine) | 10,000 | Negative | Positive |
| Pentazocine | 20,000 | Negative | Positive |
| Phenobarbital | 100,000 | Negative | Positive |
| d-Propoxyphene | 100,000 | Negative | Positive |
| Propranaolol | 100,000 | Negative | Positive |
| Ranitidine | 100,000 | Negative | Positive |
| Sertraline | 100,000 | Negative | Positive |
| THC-COOH (11-Nor-Delta-9-<br>THC-9-carboxylic acid) | 1,000 | Negative | Positive |
| Thioridazine | 100,000 | Negative | Positive |
| Tramadol | 100,000 | Negative | Positive |
| Valproic Acid | 100,000 | Negative | Positive |

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## f. Assay cut-off:

Characterization of how the device performs analytically around the claimed cutoff concentrations of 100 ng/mL is described in the precision section, M.1.a. above.

#### 2. Comparison studies:

#### a. Method comparison:

A method comparison study was performed using 127 unaltered clinical urine samples from subjects that were (b) (4) taking prescribed or nonprescribed Carisoprodol. Each sample was run in singlicate using the LZI Carisoprodol Metabolite (Meprobamate) Enzyme Immunoassay on the AU400e automated clinical analyzer and the result was compared to that obtained by LC/MS or GC/MS. Samples with meprobamate concentrations < 100 ng/mL by LC/MS or GC/MS were defined as "negative." Samples with meprobamate concentrations > 100 ng/mL by LC/MS or GC/MS were defined as "positive." The results are summarized below.

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#### Qualitative analysis

| Candidate<br>device<br>results | Negative<br>(Drug-free or<br>less than 50%<br>of the cutoff<br>concentration) | Near Cutoff<br>Negative<br>(Between<br>50% below<br>the cutoff and<br>the cutoff<br>concentration) | Near Cutoff<br>Positive<br>(Between the<br>cutoff and<br>50% above<br>the cutoff<br>concentration) | High Positive<br>(Greater than<br>50% above<br>the cutoff<br>concentration) | %<br>Agreement |
|--------------------------------|-------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------|----------------|
| Positive | 0 | 2* | 11 | 56 | 98.5 |
| Negative | 43 | 14 | 1** | 0 | 96.6 |

| Sample<br># | LC/MS or GC/MS<br>Meprobamate (ng/mL) | LC/MS or<br>GC/MS result | Candidate device<br>result |
|-------------|---------------------------------------|--------------------------|----------------------------|
| 58* | 92 | Negative | Positive |
| 59* | 98 | Negative | Positive |
| 60** | 103 | Positive | Negative |

## Semi-Quantitative analysis

| Candidate<br>device<br>results | Negative<br>(Drug-free or<br>less than 50%<br>of the cutoff<br>concentration) | Near Cutoff<br>Negative<br>(Between<br>50% below<br>the cutoff and<br>the cutoff<br>concentration) | Near Cutoff<br>Positive<br>(Between the<br>cutoff and<br>50% above<br>the cutoff<br>concentration) | High Positive<br>(Greater than<br>50% above<br>the cutoff<br>concentration) | %<br>Agreement |
|--------------------------------|-------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------|----------------|
| Positive | 0 | 1* | 11 | 56 | 98.5 |
| Negative | 43 | 15 | 1** | 0 | 98.3 |

| Sample<br># | LC/MS Meprobamate<br>(ng/mL) | LC/MS<br>result | Candidate device<br>result |
|-------------|------------------------------|-----------------|----------------------------|
| 59* | 98 | Negative | Positive |
| 60** | 103 | Positive | Negative |

- b. Matrix comparison:
Not applicable. Urine is the only claimed matrix for the candidate device.

- 3. Clinical studies:
- a. Clinical Sensitivity: Not applicable.
- b. Clinical Specificity: Not applicable.

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- c. Other clinical supportive data (when a. and b. are not applicable): Not applicable.
- 4. Clinical cut-off:

The assay has a clinical cut-off of 100 ng/mL meprobamate in human urine. To support the clinical validity of this cut-off, the sponsor submitted information from pharmacokinetic studies of carisoprodol and meprobamate in plasma following single dose administration and detailed information about meprobamate elimination in urine as a first-order elimination. This information indicates that meprobamate levels above the cutoff of this assay (100 ng/mL) are present in the urine for up to a few days following a single dose of drug. The information provided supported the clinical validity of the claimed cutoff of this device.

- 5. Expected values/Reference range:
Not applicable.

## M. Other Supportive Instrument Performance Characteristics Data Not Covered In The "Performance Characteristics" Section above:

Not applicable.

## N. Proposed Labeling:

The labeling is sufficient and it satisfies the requirements of 21 CFR Parts 801 and the special controls for this device type.

## O. Patient Perspectives:

This submission did not include specific information on patient perspectives for this device. In general, patients benefit from reliable tests to screen for the presence of drugs of abuse.

## P. Identified Risks to Health and Required Mitigations

| Identified Risks to Health | Required Mitigations |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------|
| Clinical action based on incorrect test results<br>(false positive results, false negative results)<br>may lead to inappropriate clinical decision<br>making. | Special controls (1), (2), and (3) |
| Incorrect understanding of the device,<br>including the results, may lead to<br>inappropriate clinical decision making. | Special controls (2) and (3) |

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# Q. Benefit/Risk Analysis

| Summary | |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Summary of<br>the Benefit(s) | There are benefits related to the detection of the presence of the carisoprodol metabolite or<br>meprobamate drug in human urine. While the test is not indicated for acute clinical<br>management of patients it may have value in settings of drug treatment programs,<br>including decreasing the risk of potentially dangerous medication interactions. For<br>example, identifying the presence of meprobamate may help prevent drug interactions with<br>other sedating drugs that could potentiate the sedating effect. The test also has benefit for<br>use in substance abuse programs to monitor the illicit use of carisoprodol or meprobamate<br>which have abuse potential and are categorized as Schedule IV controlled substances by<br>the Drug Enforcement Administration (DEA). |
| Summary of<br>the Risk(s) | The risk of the test is limited to false negative or false positive test results and the incorrect<br>understanding of how to interpret the results. |
| | A false positive result could result in the misidentification of a patient as having taken<br>carisoprodol or meprobamate; however, device labelling states that positive results must be<br>confirmed with a more specific analytical testing method; and when performed this<br>confirmatory testing mitigates the risk of false positive results. |
| | A false negative result could increase the risk of drug interactions if other drugs which<br>contribute to or potentiate the side effects are prescribed. However, the analytical<br>performance of the test appears mitigates the risk of false negative results. Negative<br>agreement among the 127 samples tested was 96.6% and the one false negative result in<br>the study showed a level of meprobamate (established by a confirmatory analytical<br>method) that was very near the cut-off. |
| | Misinterpretation of a positive test as indicative of toxicity, when the test is used in an<br>acute care setting, could delay appropriate treatment if the result leads to confusion in the<br>diagnosis of another acute condition that is present. This risk is mitigated by labelling of<br>the device which specifically limits against the use of the test in being used for diagnosing<br>drug intoxication or for the purposes of determining appropriate therapy. |
| Summary of<br>Other<br>Factors | The studies conducted included assessment of the accuracy, specificity, and precision<br>around the cutoff of the device. |
| Conclusions<br>Do the probable benefits outweigh the probable risks? | |
| Given the device's indications for use, required general controls and special controls established for this device,<br>the probable benefits outweigh the probable risks. | |

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

### R. Conclusion:

The information provided in this de novo submission is sufficient to classify this device into class II under regulation 21 CFR 862.3590. FDA believes that the stated special controls, and applicable general controls, including design controls, provide reasonable assurance of the safety and effectiveness of the device type. The device is classified under the following:

| Product Code: | QBK |
|---------------|-------------------------|
| Device Type: | Meprobamate test system |
| Class: | II (special controls) |
| Regulation: | 21 CFR 862.3590 |

(a) Identification. A meprobamate test system is a device intended to measure meprobamate in human specimens. Measurements obtained by this device are used to detect the presence of meprobamate to diagnose the use or overdose of meprobamate or structurally-related drug compounds (e.g., prodrugs).

(b) Classification. Class II (special controls). The special controls for this device are:

- 1) Design verification and validation must include:
- Robust data demonstrating the accuracy of the device when used in the intended (i) specimen matrix. The accuracy data must include a comparison between the meprobamate test system results and meprobamate results that are measured on an FDA-accepted measurement method that is specific and accurate (e.g., gas or liquid chromatography combined with tandem mass spectrometry).
- (ii) Robust analytical data demonstrating the performance characteristics of the device, including, but not limited to, specificity, cross-reactivity to relevant endogenous and exogenous substances, and the reproducibility of analyte detection around the cutoff(s).
- 2) The intended use of the device must not include an indication for use in monitoring therapeutic drug concentrations or informing dosing adjustment decisions.
- 3) Your 21 CFR 809.10 labeling must include the following:
- (i) If indicated for use as a screening test to identify preliminary results for further confirmation, the intended use must state "This assay provides only a preliminary analytical result. A more specific alternative chemical confirmatory method (e.g., gas or liquid chromatography and mass spectrometry) must be used to obtain a confirmed analytical result. Clinical consideration and professional judgment must be exercised with any drug of abuse test, particularly when the preliminary test result is positive."
- (ii) A limiting statement that reads as follows: "This test should not be used to monitor therapeutic drug concentrations or to inform dosing adjustment decisions."