SIGMA DIAGNOSTICS VALPROIC ACID FPIA REAGENT SET, SIGMA DIAGNOSTICS VALPROIC ACID FPIA CALIBRATORS by SIGMA DIAGNOSTICS, INC.

Sigma Diagnostics Valproic Acid FPIA Reagent Set is intended to measure valproic acid, an anticonvulsant drug, in serum. Measurements obtained by this device are used in the diagnosis and treatment of valproic acid overdose and in monitoring levels of valproic acid to ensure appropriate therapy.

Device Description

The method of testing used by Sigma Diagnostics follows closely the antibody-antigen reaction scheme first introduced by Berson and Yallow (1) with a monitoring method employed by Dandlicker, et al.(2)

AI/ML Overview

The provided document is a 510(k) premarket notification letter from the FDA to Sigma Diagnostics for their Valproic Acid FPIA Reagent Set and Calibrators. It focuses on demonstrating substantial equivalence to a legally marketed predicate device rather than presenting a detailed study proving the device meets specific acceptance criteria in the manner of a clinical trial for an AI/ML medical device.

Therefore, many of the requested elements for describing "acceptance criteria and the study that proves the device meets the acceptance criteria" are not directly applicable or available in this type of regulatory document for an in-vitro diagnostic reagent set from 1997.

However, I can extract the relevant information and infer the "acceptance criteria" based on the provided "Summary of Safety and Effectiveness":

Inferred Acceptance Criteria and Reported Device Performance for Sigma Diagnostics Valproic Acid FPIA Reagent Set:

Acceptance Criteria Category	Specific Criteria (Inferred from Predicate Equivalence)	Reported Device Performance
Correlation with Predicate Device	The device's measurements for valproic acid in serum should correlate strongly with those obtained by a legally marketed predicate device (Abbott TDx Valproic Acid Reagent Pack).	"Results of the regression analysis gave a correlation coefficient of 0.996" when patient samples were assayed using both the Sigma Diagnostics Valproic Acid Reagents and the Abbott TDx Valproic Acid Reagent Pack.
Precision	The device should demonstrate sufficient precision to accurately differentiate between subtherapeutic, therapeutic, and toxic levels of valproic acid.	"Precision studies indicate acceptable values can be obtained to differentiate between subtherapeutic, therapeutic, and toxic levels."
Specificity	The monoclonal antibody used in the reagent set should exhibit acceptable specificity for valproic acid.	"Specificity of the monoclonal antibody used was assessed and found to be acceptable."
Safety and Effectiveness	The device must be demonstrated as safe and effective for its intended use, typically by showing substantial equivalence to a predicate device already deemed safe and effective.	"The safety and effectiveness of the Sigma Diagnostics Valproic Acid FPIA Reagent Set is demonstrated by its substantial equivalency to the Abbott Laboratories Valproic Acid TDx Reagent Set."

Given the nature of the document (a 510(k) summary for an in-vitro diagnostic reagent set from 1997), most of the detailed questions regarding AI/ML device studies, ground truth establishment, training sets, and expert adjudication are not applicable (N/A). However, I will address what can be gleaned:

1. A table of acceptance criteria and the reported device performance:
Provided in the table above.

2. Sample size used for the test set and the data provenance (e.g., country of origin of the data, retrospective or prospective):

Sample Size for Test Set: The document states, "Patient samples, ranging from 13.63 to 131.08 ug/mL, were assayed..." It does not specify the number of patient samples.
Data Provenance: Not explicitly stated in terms of country of origin. Given Sigma Diagnostics is a US company, it is highly probable the samples were from the US. The context suggests a prospective comparison with a predicate device, but this is not explicitly stated.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:

N/A. This is an in-vitro diagnostic assay for measuring a chemical compound (valproic acid). The "ground truth" for each sample would be the actual concentration of valproic acid in the sample, typically validated by a reference method or assumed from the predicate device's measurement. Experts in the sense of clinicians or radiologists establishing a diagnosis from an image are not involved.

4. Adjudication method (e.g., 2+1, 3+1, none) for the test set:

N/A. Adjudication methods are typically relevant for subjective interpretations (e.g., image reading). For a reagent set measuring a chemical concentration, the comparison is quantitative.

5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:

N/A. This applies to AI/ML devices often used in diagnostic imaging or clinical decision support. This document is for a chemical assay reagent set.

6. If a standalone (i.e., algorithm only without human-in-the-loop performance) was done:

N/A. This concept is for AI/ML algorithms. The device is a FPIA (Fluorescence Polarization Immunoassay) reagent set, which is a laboratory assay. While an instrument is used, the "performance" is of the reagent's ability to measure the target analyte, not an AI algorithm's interpretive output.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.):

The "ground truth" for this type of device is the actual concentration of valproic acid in the patient samples. In the context of a substantial equivalence submission, the predicate device's measurements serve as the de facto reference for comparison.

8. The sample size for the training set:

N/A. This concept is for AI/ML models. A chemical reagent set does not have a "training set" in this sense. Quality control and calibration are part of standard manufacturing and laboratory practice.

9. How the ground truth for the training set was established:

N/A. As above, no "training set" for a chemical reagent.

Summary

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Food and Drug Administration 2098 Gaither Road Rockville MD 20850

William R. Gilbert, Ph.D. · Manager, Scientific Affairs Sigma Diagnostics 545 South Ewinq Avenue St. Louis, Missouri 63103

JUL 30 1997

Re: K972132 Siqma Diagnostics Valproic Acid FPIA Reagent Set Calibrators Requlatory Class: II Product Code: LEG Dated: June 5, 1997 Received: June 6, 1997

Dear Dr. Gilbert:

We have reviewed your Section 510(k) notification of intent to market the device referenced above and we have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to 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 You may, therefore, market the device, subject to the (Act) . . 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 (Premarket Approval), it may be subject to such additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 895. A substantially equivalent determination assumes compliance with the current Good Manufacturing Practice requirement, as set forth in the Quality System Regulation (QS) for Medical Devices: General regulation (21 CFR Part 820) and that, through periodic (QS) inspections, the Food and Drug Administration (FDA) will verify such assumptions. Failure to comply with the GMP requlation may result in regulatory action. In addition, FDA may publish further announcements concerning your device in the Federal Register. Please note: this response to your premarket notification submission does not affect any obligation you might have under sections 531 through 542 of the Act for devices under the Electronic Product Radiation Control provisions, or other Federal Laws or Regulations.

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Under the Clinical Laboratory Improvement Amendments of 1988 (CLIA-88), this device may require a CLIA complexity categorization. To determine if it does, you should contact the Centers for Disease Control and Prevention (CDC) at (770) 488-7655.

This letter will allow you to begin marketing your device as ----described in your 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 advice for your device on our labeling requlation (21 CFR Part 801 and additionally 809.10 for in vitro diagnostic devices), please contact the Office of Compliance at (301) 594-4588. Additionally, for questions on the promotion and advertising of your device, please contact the Office of Compliance at (301) 594-4639. Also, please note the regulation entitled, "Misbranding by reference to
premarket notification" (21 CFR 807.97). Other general information on your responsibilities under the Act may be obtained from the Division of Small Manufacturers Assistance at its toll-free number (800) 638-2041 or (301) 443-6597 or at its internet address "http://www.fda.gov/cdrh/dsmamain.html".

sincerely yours,
Steven Gutman

Steven I. Gutman, M.D., M.B.A. Director Division of Clinical Laboratory Devices Office of Device Evaluation Center for Devices and Radiological Health

Enclosure

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K 972132

SUMMARY OF SAFETY AND EFFECTIVENESS

VALPROIC ACID FPIA REAGENT SET AND CALIBRATORS

JUL 30 1997

Valproic acid (Depakene®) is an anticonvulsant drug used both alone and in combination with other drugs in the treatment of simple (petit mal) and complex absence seizures. The drug is also helpful in the treatment of myoclonic and tonic seizures; however, it is less effective in controlling partial seizures.

The drug is rapidly and completely absorbed, peaking in approximately four hours. The halflife of valproic acid is approximately 15 hours; however, this is reduced in patients taking other anticonvulsants. The relationship between dosage, serum levels and clinical effectiveness for valproic acid has not been clearly defined. Therefore, serum concentrations should be monitored in order to achieve adequate seizure control while maintaining minimal serum levels. A review of the different methods used for this purpose was conducted.

Material Safety Data Sheets (MSDS) for the chemicals used in preparing the reagents are readily available from the manufacturers and are routinely furnished to customers.
Patient samples, ranging from 13.63 to 131.08 ug/mL, were assayed using the Sigma Diagnostics Valproic Acid Reagents and the Abbott TDx Valproic Acid Reagent Pack. Results of the regression analysis gave a correlation coefficient of 0.996.

Precision studies indicate acceptable values can be obtained to differentiate between subtherapeutic, therapeutic, and toxic levels.

Specificity of the monoclonal antibody used was assessed and found to be acceptable.

The safety and effectiveness of the Sigma Diagnostics Valproic Acid FPIA Reagent Set is demonstrated by its substantial equivalency to the Abbott Laboratories Valproic Acid TDx Reagent Set.

1. Yallow RS, and Berson SA, J. Clin. Invest., 39, 1157, (1960).
1. Dandlicker WB, et al, "Application of Fluorescence Polarization to the Antigen-Antibocy Reaction", Immunochemistry, Pergamon Press, Vol 1, pp 165-191, (1964).

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510(k) Number (if known):

Device Name: Sigma Diagnostics Valproic Acid FPIA Reagent Set

Indications For Use:

(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF NEEDED)

Concurrence of CDRH, Office of Device Evaluation (ODE)

Division of Clinical Laboratory Devices
510(k) Number K972132

Prescription Use_ (Per 21 CFR 801.109) Over-The-Counter Use _

Regulation Number and Section

§ 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.