The VARIANT™ II Hemoglobin A1c Program is intended for the determination of hemoglobin A1c in human whole blood using ion-exchange high performance liquid chromatography (HPLC).

The VARIANT™ II Hemoglobin A1c Program is intended for use only with the Bio-Rad VARIANT™ II Hemoglobin Testing System.

For in vitro diagnostic use only.

Device Description

The VARIANT™ II Hemoglobin A1c Program is based on chromatographic separation of HbA1c on a cation exchange cartridge. The analytical system of instrument and reagent kit provides a means of measuring Hemoglobin A1c, formed by the non-enzymatic attachment of circulating blood glucose to the N terminal valine of the B-chain of the hemoglobin molecule (HbAo). Attachment of glucose to hemoglobin is achieved in a two step process. The first step is the formation of an unstable aldimine (Schiff base, labile, or pre-A1c), a reversible reaction between the carbonyl group of glucose and the N terminal valine of the ß-chain of hemoglobin. The amount of Schiff base formed is directly proportional to the blood glucose concentration. The second step is the much slower and irreversible conversion of the Schiff base intermediate to the stable "ketoamine" product (Hemoglobin A1c). The percentage of Hemoglobin A1c in whole blood is dependent on the level of sustained blood glucose and indicative of mean blood glucose over the lifetime of red blood cells (~ 120 days).

The VARIANT™ II HbA1c Program has added front end automation and Clinical Data Management Software capabilities. The front end automation allows sampling from primary sample tubes. The predicate used a hemolysis reagent during sample preparation to remove Schiff base. The VARIANT™ II HbA1c Program separates Schiff base from HbA1c in the analysis step.

AI/ML Overview

Here's a breakdown of the acceptance criteria and study information for the Bio-Rad VARIANT™ II HbA1c Program, based on the provided text:

Acceptance Criteria and Device Performance

Acceptance Criteria	Reported Device Performance
Precision
Within-run %CV (low patient sample)	1.51%
Within-run %CV (medium patient sample)	1.93%
Within-run %CV (high patient sample)	1.04%
Between-run %CV (low patient sample)	2.40%
Between-run %CV (medium patient sample)	2.01%
Between-run %CV (high patient sample)	0.92%
Total Precision (low patient sample)	4.10%
Total Precision (medium patient sample)	3.36%
Total Precision (high patient sample)	2.00%
Correlation with Predicate Device	r² = 0.9885
National Glycohemoglobin Standardization Program (NGSP) Precision Requirements	Met

Study Information:

Sample Size Used for the Test Set and Data Provenance:
- Precision Study: Low, medium, and high patient whole blood samples were used. The exact number of samples or runs is not specified, but the study implies multiple measurements for within-run and between-run variability.
- Correlation Study: The document does not specify the exact sample size for the correlation study against the VARIANT™ HbA1c Program.
- Data Provenance: Not specified, but generally, clinical validations for these types of devices in the US would use samples from the US or a similar regulatory environment. The document is for a US FDA submission.
Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts:
- This device is an in vitro diagnostic (IVD) for quantitative measurement of HbA1c. The "ground truth" for such devices is typically established through reference methods or comparison to a predicate device, rather than expert consensus on image interpretation or similar qualitative assessments. For the precision studies, the device measures the HbA1c values directly. For accuracy, it's compared to another device. Therefore, no "experts" in the sense of clinical reviewers are explicitly mentioned for establishing ground truth.
Adjudication Method:
- Not applicable as the "ground truth" for this quantitative IVD is based on direct measurement or comparison to a predicate device, not qualitative assessments requiring adjudication.
Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study:
- No. This is an In Vitro Diagnostic (IVD) device that performs a biochemical assay. MRMC studies are typically for imaging devices where human readers interpret results, often with and without AI assistance. This device provides a quantitative numerical output, not an image for human interpretation.
Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study:
- Yes, implicitly. The performance data presented (precision, correlation) are measurements of the device's analytical performance on its own, without direct human intervention in the result generation beyond operating the instrument and loading samples.
Type of Ground Truth Used:
- For precision, the ground truth is the inherent variability of the assay itself when measuring known samples (low, medium, high patient whole blood).
- For accuracy/correlation, the ground truth is considered to be the results obtained from the predicate device, VARIANT™ HbA1c Program (K926469).
Sample Size for the Training Set:
- This is an IVD device, not a machine learning algorithm in the typical sense that would have a "training set" for model development. The "training" for this device involves analytical method development and optimization, and subsequent validation using characterized samples. No specific "training set" relevant to AI/ML is mentioned or applicable here.
How the Ground Truth for the Training Set was Established:
- As explained above, the concept of a "training set" and its ground truth in the context of AI/ML does not directly apply to this traditional IVD device. The development process would involve extensive analytical testing and optimization using characterized biological samples and controls, but this is distinct from the training of a machine learning model.

Summary

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K984268

DEC 1 7 1998

510(k) Summary of Safety and Effectiveness

Submitter:

Hercules, California 94547 Phone: 1-510-741-6188 1-510-741-6471 FAX:

Juliet Carrara Regulatory Affairs/Quality Assurance Manager

Date of Summary Preparation:

Device Name:

Contact Person:

Classification Name:

Predicate Device:

Statement of Intended Use:

November 23, 1998

Bio-Rad Laboratories, Inc.

4000 Alfred Nobel Drive

VARIANT™ II HbA1c Program

Assay, Glycosylated Hemoglobin, 81 LCP

VARIANT™ HbA1c Program K926469 Bio-Rad Laboratories Hercules, CA 94547

The VARIANT™ II Hemoglobin AJc Program is intended for the determination of hemoglobin A1c in human whole blood using ion-exchange high performance liquid chromatography (HPLC).

The VARIANT™ II Hemoglobin A1c Program is intended for use only with the Bio-Rad VARIANT™ II Hemoglobin Testing System.

For in vitro diagnostic use only.

Description of Device

The VARIANT™ II Hemoglobin A1c Program is based on chromatographic separation of HbAr on a cation exchange cartridge. The analytical system of instrument and reagent kit provides a means of measuring Hemoglobin A1c, formed by the non-enzymatic attachment of circulating blood glucose to the N terminal valine of the B-chain of the hemoglobin molecule (HbAo). Attachment of glucose to hemoglobin is achieved in a two

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step process. The first step is the formation of an unstable aldimine (Schiff base, labile, or pre-A1c), a reversible reaction between the carbonyl group of glucose and the N terminal valine of the ß-chain of hemoglobin. The amount of Schiff base formed is directly proportional to the blood glucose concentration. The second step is the much slower and irreversible conversion of the Schiff base intermediate to the stable "ketoamine" product (Hemoglobin Alc). The percentage of Hemoglobin A1c in whole blood is dependent on the level of sustained blood glucose and indicative of mean blood glucose over the lifetime of red blood cells (~ 120 days).

Testing To Establish Substantial Equivalence

To establish substantial equivalence to an existing device, and thus establish the safety and effectiveness, the VARIANT™ II HbAlc Program has been compared to the VARIANT™ HbA1c Program (K926469). A review of the intended use of each system shows them to be the same, in that, they both measure Hemoglobin A1c in a sample of whole blood using cation exchange high performance liquid chromatography.

Technical Characteristics Compared to Predicate

	VARIANT™ II HbA1c	VARIANT™ HbA1c
Separation Mechanism	Cation exchangechromatography	Cation exchangechromatography
Sample Preparation	Direct dilution of wholeblood in aqueous medium	Direct dilution of wholeblood in aqueous medium
Measurement Type	Quantitative area percent	Quantitative area percent
Use of Controls	Two levels of control perrun	Two levels of control perrun
Visible DetectionWavelength	415nm / 690nm	415nm / 690nm

Both systems have the same technical characteristic as presented in the table below:

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The performance of the VARIANT™ II HbA Ic Program was evaluated for precision, measuring range, and accuracy. The precision studies were done using a modified protocol based on the NCCLS Evaluation protocol, Vol. 12, No 4, EP5-T2. Using this protocol, precision of the system was determined using a low, medium, and high patient whole blood sample. The Within-run %CV for the low was 1.51%, for the medium 1.93%, and for the high patient 1.04%. The Between run %CV for the low was 2.40%, for the medium 2.01%, and for the high patient 0.92%. Total precision was 4.10% for the low, 3.36% for the medium, and 2.00% for the high patient. The VARIANT™ II HbA1c Program meets the precision requirements of the National Glycohemoglobin Standardization Program (NGSP).

A correlation study, to determine accuracy of the VARIANT™ II HbA1c Program, was done against the VARIANT™ HbA1c Program. The study followed NCCLS Document EP9-T. The "r2" for the correlation was 0.9885.

When considering the similarities of the intended use, general characteristics of the two assays, the use of the same technology and the excellent correlation between the two methods, it can be concluded that the VARIANT™ II HbA1c Program and the VARIANT™ HbA 1c Program are substantially equivalent. Based on the establishment of substantial equivalence, the safety and effectiveness of the VARIANT™ II HbA1c Program is confirmed.

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DEPARTMENT OF HEALTH & HUMAN SERVICES

Image /page/3/Picture/2 description: The image shows the logo for the U.S. Department of Health and Human Services. The logo consists of a stylized eagle with three tail feathers, representing the department's commitment to health, human services, and well-being. The words "DEPARTMENT OF HEALTH & HUMAN SERVICES • USA" are arranged in a circular pattern around the eagle.

DEC 17 1998

Ms. Juliet Carrara Manager, Regulatory Affairs and Quality Assurance Bio-Rad Laboratories, Diagnostic Group 4000 Alfred Nobel Drive Hercules, California 94547-1803

Re : K984268 Trade Name: VARIANT II HbAlc Program Regulatory Class: II Product Code: LCP Dated: November 23, 1998 November 30, 1998 Received:

Dear Ms. Carrara:

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 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). 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 (Premarket Approval), it may be subject to such additional controls. Existing major regulations affecting your device can be found in the Code of Federal Requlations, Title 21, Parts 800 to 895. A substantially equivalent determination assumes compliance with the Current Good Manufacturing Practice requirements, 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 Druq Administration (FDA) will verify such assumptions. Failure to comply with the GMP regulation may result in regulatory action. In addition, FDA may publish further announcements concerning your device in the Federal Reqister. 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.

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

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Page 2

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 regulation (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/dsma/dsmamain.html".

Sincerely yours,

Steven Putman

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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Statement of Indications for Use

510(k) Number:

Device Name:

Indications for Use:

K984268

Bio-Rad VARIANT™II Hemoglobin A16 Program

The VARIANT™ II Hemoglobin A1c Program is intended for the determination of hemoglobin Ate in human whole blood using ion-exchange high performance liquid chromatography (HPLC).

The VARIANT™ II Hemoglobin A16 Program is intended for use only with the Bio-Rad VARIANT™ II Hemoglobin Testing System.

For in vitro diagnostic use only.

(Division Sign-Off)
Division of Clinical Laboratory Devides
510(k) Number. K984268

(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF NEEDED) Concurrence of CDHR, Office of Device Evaluation (ODE)

Prescriptive Use
(Per 21 CFR 801.109)

OR Over-The-Counter Use

Regulation Number and Section

§ 864.7470 Glycosylated hemoglobin assay.

(a)
Identification. A glycosylated hemoglobin assay is a device used to measure the glycosylated hemoglobins (A1a , A1b , and A1c ) in a patient's blood by a column chromatographic procedure. Measurement of glycosylated hemoglobin is used to assess the level of control of a patient's diabetes and to determine the proper insulin dosage for a patient. Elevated levels of glycosylated hemoglobin indicate uncontrolled diabetes in a patient.(b)
Classification. Class II (performance standards).