DRI METHADONE METABOLITE ENZYME IMMUNOASSAY

K023617 · Microgenics Corp. · DJR · Aug 27, 2003 · Clinical Toxicology

Device Facts

• Record ID: K023617
• Device Name: DRI METHADONE METABOLITE ENZYME IMMUNOASSAY
• Applicant: Microgenics Corp.
• Product Code: DJR · Clinical Toxicology
• Decision Date: Aug 27, 2003
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 862.3620
• Device Class: Class 2

Indications for Use

The Methadone Metabolite Immunoassay is intended to be used for the qualitative and semi-quantitative determination of the presence of Methadone Metabolite (2ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine or EDDP) in human urine at cutoffs of 300 and 1000 ng/mL. The semi-quantitative range of the assay is 31-2000 ng/mL. The assay provides a simple and rapid analytical screening procedure to detect methadone metabolite in human urine.

Device Story

Liquid homogeneous enzyme immunoassay; detects EDDP in human urine; utilizes competition between G6PDH-labeled drug and free drug in sample for antibody binding sites; enzyme activity measured spectrophotometrically at 340 nm; inverse relationship between drug concentration and enzyme activity; used in clinical chemistry analyzers; provides preliminary screening results; requires GC/MS confirmation; aids clinical decision-making in drug abuse testing.

Clinical Evidence

Clinical performance established via method comparison against GC/MS reference method. Study showed 95% concordance (69 true positives, 73 true negatives). Sensitivity is approximately 31 ng/mL; linearity up to 2000 ng/mL. Intra- and inter-assay reproducibility (CV) ≤ 5.7%. Specificity testing confirmed no cross-reactivity with methadone or common endogenous/pharmaceutical substances.

Technological Characteristics

Ready-to-use liquid homogeneous enzyme immunoassay. Sensing principle: competitive binding between G6PDH-labeled drug and sample drug for antibody sites. Detection: spectrophotometric measurement of NADH production at 340 nm. Requires clinical chemistry analyzer with temperature control and pipetting capabilities. Calibrators/controls gravimetrically prepared and GC/MS verified.

Indications for Use

Indicated for qualitative and semi-quantitative detection of methadone metabolite (EDDP) in human urine for screening purposes. Applicable to patients requiring methadone metabolite monitoring. Positive results require confirmation by GC/MS.

Regulatory Classification

Identification

A methadone test system is a device intended to measure methadone, an addictive narcotic pain-relieving drug, in serum and urine. Measurements obtained by this device are used in the diagnosis and treatment of methadone use or overdose and to determine compliance with regulations in methadone maintenance treatment.

Special Controls

*Classification.* Class II (special controls). A methadone 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).

Predicate Devices

• DRI® Methadone Metabolite Enzyme Assay (K931780)

Submission Summary (Full Text)

{0}

510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION
DECISION SUMMARY
DEVICE ONLY TEMPLATE

A. 510(k) Number:
K023617

B. Analyte:
2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine or EDDP a methadone metabolite

C. Type of Test:
Qualitative and Semi-quantitative immunoassay

D. Applicant:
Microgenics Corporation

E. Proprietary and Established Names:
DRI® Methadone Metabolite Enzyme Assay and DRI® Methadone Metabolite Urine Calibrators and Controls

F. Regulatory Information:
1. Regulation section:
21 CFR §862.3620, 21 CFR §862.3200 and 21 CFR §862.3280
2. Classification:
Class II
3. Product Code:
DJR, DLJ, and LAS
4. Panel:
Toxicology (91)

G. Intended Use:
1. Intended use(s):
Refer to Indications for use.
2. Indication(s) for use:
The Methadone Metabolite Immunoassay is intended to be used for the qualitative and semi-quantitative determination of the presence of Methadone Metabolite (2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine or EDDP) in human urine at cutoffs of 300 and 1000 ng/mL. The semi-quantitative range of the assay is 31-2000 ng/mL. The assay provides a simple and rapid analytical screening procedure to detect methadone metabolite in human urine.

{1}

Page 2 of 6

3. Special condition for use statement(s):
The DRI® Methadone Metabolite Enzyme Assay provides only a preliminary analytical test result. A more specific alternative chemical method must be used in order to obtain a confirmed analytical result. Gas chromatography/mass spectrometry (GC/MS) is the preferred confirmatory method. Clinical consideration and professional judgment should be applied to any drug of abuse test result, particularly when preliminary positive results are used.

4. Special instrument Requirements:
Clinical chemistry analyzers capable of maintaining a constant temperature, pipetting samples, mixing reagents, measuring enzymatic rates at 340 nm and timing the reaction accurately can be used to perform this immunoassay. Equivalence was demonstrated using a Hitachi 717 analyzer.

H. Device Description:

I. Substantial Equivalence Information:
1. Predicate device name(s):
DRI® Methadone Metabolite Enzyme Assay
2. Predicate K number(s):
K931780
3. Comparison with predicate:

| Similarities | | |
| --- | --- | --- |
| Item | Device | Predicate |
| Analyte | EDDP | EDDP |
| Matrix | Urine | Urine |
| Differences | | |
| Item | Device | Predicate |
| Cutoff | 300 and 1000 ng/mL | 1000 ng/mL |
| Antibody | Mouse monoclonal anti-EDDP with better stability and performance characteristics | Monoclonal anti-EDDP |

J. Standard/Guidance Document Referenced (if applicable):
Guidance for Prescription Use Drugs of Abuse Assays Premarket Notifications, published November 2000.

K. Test Principle:
The subject device, the DRI® Methadone Metabolite Enzyme Assay, is a ready-to-use, liquid homogeneous enzyme immunoassay. The assay uses specific antibodies that detect EDDP in human urine without cross-reactivity to the parent drug,

{2}

Page 3 of 6

methadone. The assay is based on the competition between a drug labeled with glucose-6-phosphate dehydrogenase (G6PDH), and free drug from the urine sample for a fixed amount of specific antibody binding sites. In the absence of free drug from the sample, the specific antibody binds the drug labeled with G6PDH and causes a decrease in enzyme activity. This phenomenon creates a direct relationship between drug concentration in urine and the enzyme activity. The enzyme activity is determined spectrophotometrically at 340 nm by measuring its ability to convert nicotinamide adenine dinucleotide (NAD) to NADH.

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

### 1. Analytical performance:

#### a. Precision/Reproducibility:

Specimen description: Drug free urine spiked with EDDP.

Number of days: Ten

Replicates per day: 3 cups, 2 replicates, 2 runs per day for a total of 120 determinations

Lots of product used: not specified

## Qualitative

| 300 ng/mL Cutoff (n=120) | Within Run | | | Total Run | | |
| --- | --- | --- | --- | --- | --- | --- |
| | Avg (mA/min) | SD | %CV | Avg (mA/min) | SD | %CV |
| Calibrator (150ng/mL) | 287 | 2.6 | 0.9 | 287 | 2.7 | 0.9 |
| Cutoff Calibrator (300ng/mL) | 335 | 2.2 | 0.7 | 335 | 2.6 | 0.8 |
| Calibrator (500 ng/mL) | 383 | 2.7 | 0.7 | 383 | 3.1 | 0.8 |
| 1000 ng/mL Cutoff (n=120) | Within Run | | | Total Run | | |
| --- | --- | --- | --- | --- | --- | --- |
| | Avg (mA/min) | SD | %CV | Avg (mA/min) | SD | %CV |
| Negative Control (750 ng/mL) | 426 | 2.7 | 0.6 | 426 | 3.1 | 0.7 |
| Cutoff Calibrator (1000 ng/mL) | 456 | 3.1 | 0.7 | 456 | 3.2 | 0.7 |
| Positive Control (1250 ng/mL) | 480 | 2.7 | 0.6 | 480 | 3.1 | 0.6 |

## Semi-quantitative

| 300 ng/mL Cutoff (n=120) | Within Run | | | Total Run | | |
| --- | --- | --- | --- | --- | --- | --- |
| | Avg (ng/mL) | SD | %CV | Avg (mA/min) | SD | %CV |
| Calibrator (150ng/mL) | 150 | 5.6 | 3.7 | 150 | 8.6 | 5.7 |
| Cutoff Calibrator (300ng/mL) | 300 | 7.1 | 2.4 | 300 | 9.4 | 3.1 |
| Calibrator (500 ng/mL) | 498 | 11.6 | 2.3 | 498 | 16.3 | 3.3 |

{3}

Page 4 of 6

| 1000 ng/mL Cutoff (n=120) | Within Run | | | Total Run | | |
| --- | --- | --- | --- | --- | --- | --- |
| | Avg (ng/mL) | SD | %CV | Avg (mA/min) | SD | %CV |
| Negative Control (750 ng/mL) | 763 | 19.7 | 2.6 | 763 | 22.1 | 2.9 |
| Cutoff Calibrator (1000 ng/mL) | 1016 | 23.6 | 2.3 | 1016 | 25.7 | 2.5 |
| Positive Control (1250 ng/mL) | 1270 | 34.7 | 2.7 | 1270 | 36.8 | 2.9 |

b. Linearity/assay reportable range: 31-2000 ng/mL

c. Traceability (controls, calibrators, or method): Calibrators and controls are gravimetrically prepared and verified by GC/MS analysis. Stability studies were summarized for calibrators and controls.

d. Detection limit: 31-2000 ng/mL

e. Analytical specificity: Various common over-the-counter medications and structurally related compounds were tested for cross-reactivity in the assay using both 300 ng/mL and 1000 ng/mL EDDP as cutoff calibrators.

| Compound | 300 ng/mL Cutoff Concentration | 1000 ng/mL Cutoff Concentration |
| --- | --- | --- |
| Methadone | 9,000,000 | 35,000,000 |
| EMDP | 200,000 | 200,000 |
| LAAM-HCl | 100,000 | 100,000 |
| Nor-LAAM-HCl | 100,000 | 100,000 |
| Compound | Concentration (ng/mL) | Compound | Concentration (ng/mL) |
| --- | --- | --- | --- |
| Acetaminophen | 1,000,000 | Ibuprofen | 500,000 |
| Acetylsalicylic Acid | 1,000,000 | Ketamine | 1,000,000 |
| Amphetamine | 1,000,000 | Levothyroxine | 500,000 |
| Benzoylecgonine | 1,000,000 | Meperidine | 1,000,000 |
| Caffeine | 100,000 | d-Methamphetamine | 100,000 |
| Captopril | 500,000 | l-Methamphetamine | 100,000 |
| Chlorazepoxide | 100,000 | Morphine | 1,000,000 |
| Cimetidine | 500,000 | Oxazepam | 500,000 |
| Cocaine | 200,000 | Phencyclidine | 500,000 |
| Codeine | 1,000,000 | Phenobarbital | 1,000,000 |
| Dextromethorphan | 300,000 | Phentermine | 1,000,000 |
| Diazepam | 100,000 | Promethazine | 100,000 |
| Diphenhydramine | 500,000 | Propoxyphene | 1,000,000 |

{4}

Page 5 of 6

| Compound | Concentration (ng/mL) | Compound | Concentration (ng/mL) |
| --- | --- | --- | --- |
| Disopyramide | 1,000,000 | Rantidine | 500,000 |
| Doxylamine | 500,000 | Salicycluric Acid | 500,000 |
| Ephedrine | 1,000,000 | Secobarbital | 1,000,000 |
| Fluoxetine | 500,000 | 11-Nor-Δ⁹-THC-9-COOH | 10,000 |

f. Assay cut-off:
300 and 1000 ng/mL.

2. Comparison studies:

a. Method comparison with predicate device:
For the qualitative and semi-quantitative assays at 300 and 1000 ng/mL cutoff, a total of 150 clinical specimens obtained from patients receiving methadone treatment were tested using the DRI Methadone Metabolite Assay and GC/MS.

Qualitative:

| | Subject Device 300 ng/mL Cutoff | | |
| --- | --- | --- | --- |
| | | Pos | Neg |
| GC/MS
300 ng/mL Cutoff | Pos | 71 | 2 |
| | Neg | 0 | 77 |
| | Subject Device 1000 ng/mL Cutoff | | |
| --- | --- | --- | --- |
| | | Pos | Neg |
| GC/MS
1000 ng/mL Cutoff | Pos | 69 | 5 |
| | Neg | 0 | 76 |

Semi-quantitative:

| | Subject Device 300 ng/mL Cutoff | | |
| --- | --- | --- | --- |
| | | Pos | Neg |
| GC/MS
300 ng/mL Cutoff | Pos | 71 | 2 |
| | Neg | 0 | 77 |
| | Subject Device 1000 ng/mL Cutoff | | |
| --- | --- | --- | --- |
| | | Pos | Neg |
| GC/MS
1000 ng/mL Cutoff | Pos | 69 | 7 |
| | Neg | 1 | 73 |

{5}

Page 6 of 6

b. Matrix comparison:
Not Applicable. The assay is intended for only one sample matrix.

3. Clinical studies:
a. Clinical sensitivity:
Not applicable. Clinical studies are not typically submitted for this device type.
b. Clinical specificity:
Not applicable. Clinical studies are not typically submitted for this device type.
c. Other clinical supportive data (when a and b are not applicable):

4. Clinical cut-off:
Not applicable

5. Expected values/Reference range:
Not applicable

M. Conclusion:
Based upon the information provided, I recommend that the DRI® Methadone Metabolite Enzyme Assay and the DRI® Methadone Metabolite Urine Calibrators and Controls be found substantially equivalent to predicate devices according to 21 CFR §862.3620, 21 CFR §862.3200 and 21 CFR §862.3280.