ROCHE ONLINE TDM VALPROIC ACID

K032049 · Roche Diagnostics Corp. · LEG · Aug 22, 2003 · Clinical Toxicology

Device Facts

• Record ID: K032049
• Device Name: ROCHE ONLINE TDM VALPROIC ACID
• Applicant: Roche Diagnostics Corp.
• Product Code: LEG · Clinical Toxicology
• Decision Date: Aug 22, 2003
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 862.3645
• Device Class: Class 2

Indications for Use

For the quantitative determination of valproic acid in human serum or plasma on automated clinical chemistry analyzers. The Roche ONLINE TDM Valproic Acid assay contains an in vitro diagnostic reagent system indicated for the quantitative determination of valproic acid in human serum or plasma on automated clinical chemistry analyzers. Valproic acid is primarily used in the treatment of petit mal seizures and other generalized and partial complex seizures.

Device Story

The Roche ONLINE TDM Valproic Acid assay is a homogeneous immunoassay used on automated clinical chemistry analyzers. It utilizes microparticles coated with valproic acid and a valproic acid antibody solution. In the absence of sample drug, microparticles aggregate, changing light scatter or absorbance. When patient serum or plasma containing valproic acid is introduced, the drug competes for the antibody, inhibiting microparticle aggregation. The rate of aggregation is inversely proportional to the valproic acid concentration. The analyzer monitors these optical changes to generate a concentration-dependent inhibition curve. Results are used by clinicians to monitor therapeutic drug levels in patients treated for seizures, aiding in dosage adjustment and toxicity prevention.

Clinical Evidence

Bench testing only. Precision evaluated per modified NCCLS EP5-T2 (n=63). Linearity established 4.3–152.4 ug/ml. Method comparison against predicate (n=75) yielded Y = 0.969X + 3.003, R = 0.992. Analytical specificity tested against 16 common drugs with no significant interference found.

Technological Characteristics

Homogeneous immunoassay; principle of particle-enhanced turbidimetric inhibition. Reagents include valproic acid-coated microparticles and valproic acid antibody solution. Designed for use on automated clinical chemistry analyzers. No specific materials or software algorithm class (e.g., ML) described; relies on standard optical absorbance/scatter measurement.

Indications for Use

Indicated for quantitative determination of valproic acid in human serum or plasma on automated clinical chemistry analyzers for patients undergoing treatment for petit mal seizures and other generalized and partial complex seizures.

Regulatory Classification

Identification

A neuroleptic drugs radioceptor assay test system is a device intended to measure in serum or plasma the dopamine receptor blocking activity of neuroleptic drugs and their active metabolites. A neuroleptic drug has anti-psychotic action affecting principally psychomotor activity, is generally without hypnotic effects, and is a tranquilizer. Measurements obtained by this device are used to aid in determining whether a patient is taking the prescribed dosage level of such drugs.

Predicate Devices

• Roche Valproic II Assay (K930734)

Submission Summary (Full Text)

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

A. 510(k) Number: K032049
B. Analyte: Valproic Acid
C. Type of Test: quantitative chemistry
D. Applicant: Roche Diagnostics
E. Proprietary and Established Names: Roche Online TDM Valproic Acid Assay

F. Regulatory Information:
1. Regulation section: 21 CFR 862.3645
2. Classification: Class II
3. Product Code: LEG
4. Panel: 91

G. Intended Use:
1. Intended use(s): For the quantitative determination of valproic acid in human serum or plasma on automated clinical chemistry analyzers.
2. Indication(s) for use: The Roche Online TDM Valproic Acid assay contains an in vitro diagnostic reagent system indicated for the quantitative determination of valproic acid in human serum or plasma on automated clinical chemistry analyzers. Valproic acid is primarily used in the treatment of petit mal seizures and other generalized and partial complex seizures.
3. Special condition for use statement(s): none stated
4. Special instrument Requirements: Roche/Hitachi 911, 912, 917 and Modular P clinical analyzers

H. Device Description: The Roche Online TDM Valproic Acid assay contains an in vitro diagnostic reagent system indicated for the quantitative determination of valproic acid in human serum or plasma on automated clinical chemistry analyzers.

I. Substantial Equivalence Information:
1. Predicate device name(s): Roche Valproic Acid II Assay

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2. Predicate K number(s): K930734
3. Comparison with predicate:

| Item | Device | Predicate |
| --- | --- | --- |
| Fundamental method principle differs between the two assays | The assay is a homogenous immunoassay based on the principle of measuring changes in scattered light or absorbance which result when activated microparticles aggregate. The microparticles are coated with valproic acid antibody solution. When a sample containing valproic acid is introduced, the aggregation reaction is partially inhibited, slowing the rate of the aggregation process. Antibody bound to the sample drug is no longer available to promote microparticle aggregation, and subsequent particle lattice formulation is inhibited. Thus, a classic inhibition curve with respect to valproic acid concentration is obtained, with the maximum rate of aggregation at the lowest valproic acid concentration. By monitoring the change in scattered light or absorbance, a concentration-dependent curve is obtained. | The Valproic Acid II assay uses recombinant DNA technology to produce a unique homogenous enzyme immunoassay system.
The assay is based on the bacterial enzyme beta-galctosidase, which has been genetically engineered into two inactive fragments. These fragments spontaneously reassociates to form a fully active enzyme that, in the assay format, cleaves a substrate, generating a color change that can be measured spectrophotometrically. |

J. Standard/Guidance Document Referenced (if applicable): NCCLS/EP5-T2,

K. Test Principle: The Roche ONLINE TDM Valproic Acid assay contains an in vitro diagnostic reagent system indicated for the quantitative determination of valproic acid in human plasma or serum. The calibrators and controls for this assay are sold separately.

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

## 1. Analytical performance:

a. Precision/Reproducibility: Reproducibility was determined using controls and human serum pools (HSP) in an internal protocol (modified version of NCCLS EP5-T2). Within run n=63, between day n=21, total n=63

| Sample | Within run | | | Between day | | | Total | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | mean ug/ml | SD ug/ml | %cv | mean ug/ml | SD ug/ml | %cv | mean ug/ml | SD ug/ml | %cv |
| Control 1 | 34.8 | 0.29 | 0.8 | 34.7 | 0.80 | 2.3 | 34.8 | 0.73 | 2.1 |
| Control 2 | 74.1 | 0.47 | 0.6 | 74.3 | 1.78 | 2.4 | 74.1 | 1.80 | 2.4 |
| Control 3 | 118.9 | 0.73 | 0.6 | 119.0 | 2.22 | 1.9 | 118.9 | 2.21 | 1.9 |
| HSP 1 | 55.6 | 0.34 | 0.6 | 55.7 | 1.94 | 3.5 | 55.6 | 1.95 | 3.5 |
| HSP 2 | 119.8 | 0.74 | 0.6 | 120.1 | 2.61 | 2.2 | 119.8 | 2.60 | 2.2 |

b. Linearity/assay reportable range: To assess the linearity of the assay, an 11-level dilution series was prepared using a valproic acid spiked human serum pool diluted with a non-spiked human pool. Results were evaluated by linear regression. Established linear range is 4.3 – 152.4 ug/ml.

c. Traceability (controls, calibrators, or method): The COBAS-FP Valproic Acid calibrators are prepared to contain known quantities of Valproic Acid in normal human serum and are traceable to USP reference standards. These calibrators are used to create a standard curve from which the quantity of drug in unknown specimens can be determined.

d. Detection limit: The detection limit of the Valproic Acid assay is 4.3 ug/ml. The lower detection limit represents the lowest valproic acid concentration that can be distinguished from zero. It is calculated as the concentration lying two standard deviations above that of the 0 ug/ml calibrator (within run precision n=21).

e. Analytical specificity: Samples were spiked with 16 common drugs and tested for specificity. No significant interference with the assay was found. Acetyl cysteine, Acetylsalicylic Acid, Ampicillin-Na, Acetaminophen, Ascorbic Acid, K-Doesilate, Cefoxin, Cyclosporin, Doxycycline, Ibuprofen, Levodopa, Methyldopa+1,5, Metronidiazole, Phenylbutazone, Rifampicin, and Theophylline. The manufacturer states "As with any assay employing mouse antibodies, the possibility exists for interference by human anti-mouse antibodies (HAMA) in the sample, which cause falsely low results."

f. Assay cut-off: The assay measuring range is 4.3 – 140 ug/ml. Serum therapeutic levels are 50 – 100 ug/ml while toxic levels are >150 ug/ml (based upon the Applied Therapeutic Drug Monitoring, Washington

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D.C., The American Association of Clinical Chemistry and Essentials of Therapeutic Drug Monitoring, Gerson,B., editor).

# 2. Comparison studies:

a. Method comparison with predicate device: The Roche ONLINE TDM Valproic Acid was evaluated for several performance characteristics, including precision, lower detection limit, method comparison, specificity, and interfering substances. All of the evaluation studies gave acceptable results compared to the predicate device. The following represents the precision and method comparison results.

Roche ONLINE TDM Valproic Acid vs. Roche Valproic Acid II Assay (predicate device) $n = 75$ , $Y = 0.969X + 3.003$ $R = 0.992$ Range of samples $11.3 - 144.2$ ug/ml.

NCCLS

| Precision: | Level 1 | Level 2 | Level 3 |
| --- | --- | --- | --- |
| Mean (ug/ml) | 34.8 | 74.1 | 118.9 |
| CV% (within run) | 0.8 | 0.6 | 0.6 |
| CV(%) (total) | 2.1 | 2.4 | 1.9 |

b. Matrix comparison: Reproducibility was determined using controls and human serum pools (HSP) in an internal protocol (modified version of NCCLS EP5-T2). Within run $n = 63$ , between day $n = 21$ , total $n = 63$

| Sample | Within run | | | Between day | | | Total | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | mean ug/ml | SD ug/ml | %cv | mean ug/ml | SD ug/ml | %cv | mean ug/ml | SD ug/ml | %cv |
| Control 1 | 34.8 | 0.29 | 0.8 | 34.7 | 0.80 | 2.3 | 34.8 | 0.73 | 2.1 |
| Control 2 | 74.1 | 0.47 | 0.6 | 74.3 | 1.78 | 2.4 | 74.1 | 1.80 | 2.4 |
| Control 3 | 118.9 | 0.73 | 0.6 | 119.0 | 2.22 | 1.9 | 118.9 | 2.21 | 1.9 |
| HSP 1 | 55.6 | 0.34 | 0.6 | 55.7 | 1.94 | 3.5 | 55.6 | 1.95 | 3.5 |
| HSP 2 | 119.8 | 0.74 | 0.6 | 120.1 | 2.61 | 2.2 | 119.8 | 2.60 | 2.2 |

# 3. Clinical studies:

a. Clinical sensitivity: none stated
b. Clinical specificity: none stated
c. Other clinical supportive data (when $a$ and $b$ are not applicable):

# 4. Clinical cut-off: none stated

5. Expected values/Reference range: The assay measuring range is $4.3 - 140$ ug/ml. Serum therapeutic levels are $50 - 100\mathrm{ug / ml}$ while toxic levels are $>150$ ug/ml (based upon the Applied Therapeutic Drug Monitoring, Washington D.C., The American Association of Clinical Chemistry and Essentials of Therapeutic Drug Monitoring, Gerson,B., editor).

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M. Conclusion: Based upon the performance characteristics and correlation data supplied, I recommend that the Roche Online TDM Valproic Acid Assay be found substantially equivalent to the respective predicate device.