(119 days)
This in vitro method is intended to quantitatively measure the antiepileptic drug valproic acid in human serum and plasma on the Bayer ADVIA® IMS systems. Measurements of valproic acid are used to aid in monitoring therapeutic levels of valproic acid to ensure appropriate therapy and in the treatment of valproic acid overdose.
The Bayer ADVIA IMS Valproic Acid method is for in vitro diagnostic use to measure the antiepileptic drug valproic acid in human serum and plasma. Measurements of valproic acid (2-propylpentanoic acid) are used as an aid in the diagnosis and treatment of valproic acid overdose, and in monitoring therapeutic levels of valproic acid to ensure appropriate therapy.
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1. Acceptance Criteria and Reported Device Performance
| Performance Metric | Acceptance Criteria (Implied) | Reported Device Performance (ADVIA IMS) | Predicate Device Performance (Centaur) |
|---|---|---|---|
| Minimum Detectable Concentration (MDC) | Lower than or comparable to predicate device. | 0.57 µg/mL | 1.0 µg/mL |
| Imprecision (Total CV%) | Comparable to or better than predicate device (lower CV%). | Level 34.03: 4.4%Level 70.16: 2.9%Level 98.86: 2.0% | Level 22.8: 6.9%Level 64.6: 6.1%Level 102.7: 6.4% |
| Correlation (R value) | High correlation (close to 1) with the predicate device. | 0.997 | N/A (Comparison System) |
| Regression Equation (Slope) | Close to 1 (indicating proportional agreement). | 0.98 | N/A (Comparison System) |
| Regression Equation (Y-intercept) | Close to 0 (indicating minimal constant bias). | 4.9 | N/A (Comparison System) |
| Syx µg/mL (Standard error of estimate) | Low, indicating good agreement between methods. | 3.1 | N/A (Comparison System) |
| Interfering Substances | Effects of interfering substances should be minimal (e.g., % change < 10%). | Minimal effects on Valproic acid concentration (e.g., Bilirubin -3.3% to 2.3%, Hemoglobin 3.1%, Lipids 9.8%) | Not explicitly stated but generally expected for diagnostic devices. |
| Analytical Range | Sufficiently broad for intended use (monitoring therapeutic levels and overdose). | 0.57 µg/mL up to ~150 µg/mL | Not explicitly stated but expected to cover therapeutic range. |
Study Proving Acceptance Criteria:
The provided document describes a validation study comparing the performance of the ADVIA® IMS Valproic Acid Method to a predicate device, the Bayer Centaur Valproic Acid method. The study design is a comparative effectiveness study demonstrating substantial equivalence rather than explicitly listing acceptance criteria targets. The "acceptance criteria" are implied by showing performance that is either equivalent or superior to the legally marketed predicate device across various metrics.
2. Sample Size Used for the Test Set and Data Provenance:
- Sample Size for Test Set:
- Correlation Study: N = 50 (specimens)
- Minimum Detectable Concentration: Multiple measurements to determine the detection limit.
- Imprecision: Not explicitly stated as a number of patient samples, but "Level" indicates control or spiked samples were likely run repeatedly.
- Interfering Substances: Not explicitly stated as a number of patient samples, but specific concentrations of interferents were used with a valproic acid concentration.
- Data Provenance: Not explicitly stated in the provided text. It is a submission by Bayer Corporation, so the data is likely generated in a regulated environment for a diagnostic product. The document does not specify the country of origin of the data or whether it was retrospective or prospective.
3. Number of Experts Used to Establish Ground Truth for the Test Set and Qualifications of those Experts:
This is a study for an in vitro diagnostic (IVD) device that measures a chemical analyte (valproic acid) quantitatively. The "ground truth" for such devices is established by reference methods or established analytical techniques, often using certified reference materials or highly accurate comparative methods.
- Experts: Not applicable in the sense of clinical experts interpreting images or patient conditions. The "ground truth" is analytical.
- Qualifications: The "expert" in this context is the predicate device and its established analytical performance. The comparison system (Centaur) acts as the reference for determining correlation.
4. Adjudication Method for the Test Set:
Not applicable. Adjudication methods (e.g., 2+1, 3+1) are typically used in clinical studies where human interpretation of ambiguous data (like medical images) requires consensus among experts. For a quantitative IVD device like this, the "data" are numerical results, and the comparison is statistical.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study:
No, an MRMC study was not done. MRMC studies are used to evaluate human reader performance, often with and without AI assistance, in interpreting clinical cases (e.g., radiology images). This document describes the performance of an automated analytical method on an in vitro test, not a human interpretation task.
Effect Size: Not applicable, as no MRMC study was performed.
6. Standalone Performance Study:
Yes, a standalone performance study was done. The entire document describes the standalone performance of the ADVIA IMS Valproic Acid method in terms of its analytical characteristics (MDC, imprecision, correlation, interference, analytical range) when compared against or measured relative to a predicate device and known standards. The "algorithm" is the reagent and instrument system, and its performance is evaluated without human intervention in the measurement process itself. The readings produced by the device are the output being evaluated.
7. Type of Ground Truth Used:
The ground truth used for this quantitative measurement device is primarily:
- Comparison to a Legally Marketed Predicate Device (Centaur): For correlation studies, the results from the Centaur system serve as the comparative reference.
- Known Concentrations/Standards: For MDC, imprecision, and interference studies, presumably, samples with known, controlled valproic acid concentrations (e.g., spiked samples, control materials) were used.
- This falls under the category of analytical validation against established methods and reference materials, rather than pathology or complex outcomes data.
8. Sample Size for the Training Set:
The document does not provide information on a "training set" or its sample size. This is common for IVD devices that rely on established chemical reactions and optical/electrical detection rather than machine learning algorithms that require explicit training data. The "training" for such a system would involve optimizing reagent formulations and instrument calibration procedures, but not in the sense of a machine learning model.
9. How the Ground Truth for the Training Set Was Established:
As there is no mention of a "training set" in the context of machine learning, this question is not applicable. For a traditional IVD device, the "ground truth" for establishing methods and calibrating instruments would be based on:
- Reference Methods: Using highly accurate and validated analytical techniques to assign values to calibrators and controls.
- Certified Reference Materials: Using materials whose valproic acid concentrations are traceable to international standards.
- Method Development and Optimization: The design and chemical properties of the reagents, along with instrument parameters, are developed based on known chemical principles and extensive testing during the R&D phase to ensure accurate measurement across the analytical range.
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510(k) SUMMARY OF SAFETY AND EFFECTIVENESS Valproic Acid Method for ADVIA® Modular System (IMS)™
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of the Safe Medical Device Act of 1990 and 21 CFR 807.92.
The assigned 510(k) number is: // 0 4 2 8 0 7 = (leave blank)
1. Intended Use
This in vitro method is intended to quantitatively measure the antiepileptic drug valproic acid in human serum and plasma on the Bayer ADVIA® IMS systems. Measurements of valproic acid are used to aid in monitoring therapeutic levels of valproic acid to ensure appropriate therapy and in the treatment of valproic acid overdose.
Predicate Device 2.
| Product Name | Reagent Ref # | Calibrator Ref # |
|---|---|---|
| Bayer Centaur ValproicAcid | 03783810(129219) | 02700784(129221) |
Device / Method 3.
| Product Name | Reagent Ref # | Calibrator Ref # |
|---|---|---|
| ADVIA IMS ValproicAcid | 00329833 | 00419360 |
4. Performance
A. Minimum Detectable Concentration
| Method | ADVIA IMS | Centaur |
|---|---|---|
| MDC | 0.57 $\mu$ g/mL | 1.0 $\mu$ g/mL |
B. Imprecision
| ADVIA IMS | Bayer Centaur | ||
|---|---|---|---|
| Levelµg/mL | TotalCV (%) | Levelµg/mL | TotalCV(%) |
| 34.03 | 4.4 | 22.8 | 6.9 |
| 70.16 | 2.9 | 64.6 | 6.1 |
| 98.86 | 2.0 | 102.7 | 6.4 |
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C. Correlation (Y=ADVIA IMS, X=Comparison system)
| Specimen type | Comparison System (X) | N | Regression Equation | Syx µg/mL | R | IMS Sample Range µg/mL |
|---|---|---|---|---|---|---|
| Serum | Centaur | 50 | $Y=0.98X + 4.9$ | 3.1 | 0.997 | 13.4 - 144 |
D. Interfering Substances
| InterferingSubstance | Interfering Sub.Conc. (mg/dL) | Valproic acidConcentrationμg/mL | Effect(% change) |
|---|---|---|---|
| Bilirubin(unconjugated) | 25 | 112.01 | -3.3 |
| Bilirubin(conjugated) | 25 | 108.71 | 2.3 |
| Hemoglobin | 600 | 107.13 | 3.1 |
| Lipids(Triglycerides) | 750 | 102.67 | 9.8 |
E. Analytical Range
- 57ug/mL up to valproic acid concentration in highest calibrator (Level 6) (approximately 150 µg/mL).
Rin Ha
10/4/04
Date
Andres Holle Regulatory Affairs Bayer Corporation 511 Benedict Avenue Tarrytown, New York, 10591 - 5097
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DEPARTMENT OF HEALTH & HUMAN SERVICES
Image /page/2/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a circular seal with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" arranged around the perimeter. Inside the circle is a stylized graphic of an abstract symbol, which is often interpreted as representing the human form.
FEB - 8 2005
Food and Drug Administration 2098 Gaither Road Rockville MD 20850
Mr. Andres Holle Manager, Regulatory Affairs Bayer Healthcare, LLC. Diagnostics Division 511 Benedict Avenue Tarrytown, NY 10591
K042807 Re:
Trade/Device Name: ADVIA® IMS Valproic Acid Method ADVIA® IMS Valproic Acid Calibrator Regulation Number: 21 CFR 862.3645 Regulation Name: Neuroleptic drugs radioreceptor assay test system Regulatory Class: Class II Product Code: LEG, DKB Dated: October 4, 2004 Received: October 13, 2004
Dear Mr. Holle:
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.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to such additional controls. Existing major regulations affecting your device can be found in Title 21, Code of Federal Regulations (CFR), Parts 800 to 895. 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
.
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Page 2 -
This letter will allow you to begin marketing your device as described in your Section 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.
If you desire specific information about the application of labeling requirements to your device, or questions on the promotion and advertising of your device, please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at (240)276-0484. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807.97). You may obtain other general information on your responsibilities under the Act from the Division of Small Manufacturers, International and Consumer Assistance at its toll-free number (800) 638-2041 or (301) 443-6597 or at its Internet address http://www.fda.gov/cdrh/industry/support/index.html
Sincerely yours,
Jean M. Cooper, MS, DUM
Jean M. Cooper, MS, D.V.M. Director Division of Chemistry and Toxicology Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known): _K042807
Device Name: ADVIA® IMS Valproic Acid Calibrator
Indications For Use:
The Bayer ADVIA IMS Valproic Acid calibrator is for in vitro diagnostic use in the calibration of valproic acid using the ADVIA® IMS system.
Prescription Use _ (Part 21 CFR 801 Subpart D) AND/OR
Over-The-Counter Use (21 CFR 807 Subpart C)
(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF NEEDED)
Concurrence of CDRH, Office of In Vitro Diagnostic Devices (OIVD)
Division Sign-Off
Division Slop-02
Page 1 of ____________________________________________________________________________________________________________________________________________________________________
Office of In Vitro Diagnostic Device Evaluation and Se
51062
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Indications for Use
510(k) Number (if known):_____________________________________________________________________________________________________________________________________________________
Device Name: ADVIA® IMS Valproic Acid Method
Indications For Use:
The Bayer ADVIA IMS Valproic Acid method is for in vitro diagnostic use to measure the antiepileptic drug valproic acid in human serum and plasma. Measurements of valproic acid (2-propylpentanoic acid) are used as an aid in the diagnosis and treatment of valproic acid overdose, and in monitoring therapeutic levels of valproic acid to ensure appropriate therapy.
Prescription Use X (Part 21 CFR 801 Subpart D) AND/OR
Over-The-Counter Use (21 CFR 807 Subpart C)
(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF NEEDED)
Concurrence of CDRH, Office of In Vitro Diagnostic Devices (OIVD)
Albert CR
Division Slari-Of
Page 1 of
Office of In Vitro Diagnostic Device Evaluation and Satety
Lo420807
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§ 862.3645 Neuroleptic drugs radioreceptor assay test system.
(a)
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.(b)
Classification. Class II.