The Bio-Rad VARIANT™ II TURBO HbA1c Kit - 2.0 is intended for the quantitative determination of hemoglobin A1c in human whole blood using ion-exchange high performance liquid chromatography (HPLC) on the VARIANT™ II TURBO Hemoglobin Testing System. Measurement of hemoglobin A1c is effective in monitoring long term glycemic control in individuals with diabetes mellitus. The Bio-Rad VARIANT™ II TURBO HbA1c Kit-2.0 is intended for Professional Use Only.

Device Description

The VARIANT II TURBO Hemoglobin Testing System uses the principles of high performance liquid chromatography (HPLC). The VARIANT II TURBO HbA12 Kit - 2.0 is based on chromatographic separation of Hemoglobin A10 on a cation exchange cartridge. The VARIANT II TURBO HbA1c Kit - 2.0 contains an analytical cartridge, 5 prefilters, Elution Buffer A and B, Calibrator Level 1, Calibrator Level 2, Whole Blood Primer, sample vials and a CD-ROM with test parameters.

The VARIANT II TURBO Hemoglobin Testing System provides an integrated method for sample preparation, separation and the quantitative determination of HbAle in EDTA human whole blood. The VARIANT II TURBO Hemoglobin Testing System is a fully automated, high-throughput hemoglobin analyzer. It consists of two modules - the VARIANT II Chromatographic Station (VCS) and the VARIANT II Sampling Station (VSS). There have been hardware updates due to obsolescence of parts and firmware updates to support the replacement hardware components.

A personal computer is used to control the VARIANT II TURBO Hemoglobin Testing System using updated Clinical Data Management (CDM) software version 5.1.1.

AI/ML Overview

Here's an analysis of the provided 510(k) summary, structured to answer your questions about acceptance criteria and the supporting study:

Some of the requested information, such as the specific country of origin for the data, the exact qualifications of experts, and the adjudication method for the test set, are not explicitly detailed in the provided 510(k) summary. This is typical for such regulatory documents, which focus on summarizing key performance data rather than granular study design details.

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria for the "Method Comparison" study were based on a relative bias not exceeding +/- 10% at the decision points of 6% and 9% HbA1c.

Criteria	Acceptance Criteria (Bias)	Reported Device Performance (Predicted Bias by regression)	Upper 95% confidence limit	Lower 95% confidence limit
Decision point: 6.0 %HbA1c	Between -10% and +10% relative bias	0.2%	0.5%	-0.1%
Decision point: 9.0 %HbA1c	Between -10% and +10% relative bias	-0.1%	0.1%	-0.3%

The "Analytical Specificity" study aimed to show no significant interference from common hemoglobin variants at specified concentrations.

Interference Type	Acceptance Criteria	Reported Device Performance
Hemoglobin variants (HbS, HbC, HbD, HbE)	No significant interference (implicitly, results within pre-defined clinical limits or not exceeding a certain difference from non-variant samples). The predicate had issues with specific variants showing > ±10% difference.	No significant interference was observed at the following concentrations: HbS ≤67%, HbC ≤72%, HbD ≤55%, and HbE ≤41%.
Interference from HbA2	No interference from β-thalassemia trait HbA2 concentrations up to 10% of total hemoglobin.	β-thalassemia trait, as indicated by increased HbA2 concentrations up to 10%, does not interfere with the assay.

2. Sample Size Used for the Test Set and Data Provenance

Sample Size (Method Comparison): 100 EDTA whole blood human samples and 16 samples prepared by mixing EDTA whole blood samples with either purified HbAo or purified HbA1c. Total: 116 samples.
Sample Size (Analytical Specificity): Not explicitly stated as a number of individual samples, but described as "Two fresh, EDTA non-variant human blood sample pools at 6.5% and 8.0-9.0% HbA1c" and "Fresh, EDTA human homozygous blood samples for each of the 4 hemoglobin variants (e.g. E, D, S, and C)." Series of test sample pools prepared by dilution.
Data Provenance: The data used for method comparison and analytical specificity were "EDTA whole blood human samples" and "fresh, EDTA human homozygous blood samples." The country of origin is not specified but is implicitly from a clinical laboratory setting. The studies appear to be prospective or concurrent as they involved preparing and running samples specifically for the study.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts

This information is not provided in the summary. The ground truth for the method comparison study was established by the predicate device's software version 4.03. For the analytical specificity, the "true" HbA1c values for the variant samples were likely determined by a reference method or assumed based on the preparation of the samples (e.g., dilution of homozygous variant samples).

4. Adjudication Method for the Test Set

This information is not provided in the summary. For a quantitative assay like HbA1c, adjudication typically involves comparing the device's results against a gold standard or a highly accurate reference method. In the method comparison, the predicate device's results served as the reference for the modified software.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done, and the effect size of how much human readers improve with AI vs without AI assistance

A Multi-Reader Multi-Case (MRMC) comparative effectiveness study is not applicable here. This document describes a medical device, the Bio-Rad VARIANT™ II TURBO HbA1c Kit - 2.0, which is an automated in vitro diagnostic (IVD) assay to measure HbA1c. It is not an AI-based diagnostic tool that assists human readers/interpreters.

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

The device itself is a standalone automated system for quantitative determination of HbA1c. The evaluation performed (method comparison and analytical specificity) effectively represents its standalone performance because it directly measures HbA1c levels without human interpretation of complex images or signals requiring AI assistance. The study compares the performance of the updated software/system to a previous version, which is a standalone comparison.

7. The Type of Ground Truth Used

Method Comparison: The ground truth for the method comparison study was established by the predicate device's software version 4.03 (meaning the measurements obtained from the same system running the older software). This is a "comparative ground truth" when assessing software changes.
Analytical Specificity: For variant interference, the ground truth was effectively implicit in the preparation of the samples (known variant concentrations, and expected HbA1c values in the pools). The goal was to show that the presence of these variants does not interfere with the HbA1c measurement, meaning the device's reading should remain accurate despite the variant's presence.

8. The Sample Size for the Training Set

This information is not provided in the summary. This device is an in vitro diagnostic (IVD) kit using high-performance liquid chromatography (HPLC) and associated software. While software might undergo internal development and validation (which could involve "training" in a broad sense, especially for algorithms identifying peaks), the concept of a "training set" as it applies to machine learning or AI models is not directly relevant or typically disclosed for this type of IVD device in a 510(k) summary. The summary focuses on comparing the new software's performance against the old, representing an update to an established analytical method.

9. How the Ground Truth for the Training Set Was Established

As noted above, a "training set" in the context of AI/ML is not directly applicable. If one considers the development of the analytical method and software, the ground truth for establishing parameters would have been derived from extensive analytical chemistry principles and experiments, likely involving reference methods and characterized samples to ensure accurate chromatographic separation and calculation of HbA1c. This foundational work would be part of the product's overall development, not explicitly detailed as a "training set" in this 510(k) summary.

Summary

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KI22472

510(k) Summary for VARIANT™ II TURBO HbA1c Kit - 2.0

This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.

OCT 26 2012

The assigned 510(k) number is:

Preparation Date: August 8, 2012

A. Applicant

Bio-Rad Laboratories, Inc. Clinical Systems Group 4000 Alfred Nobel Drive Hercules, CA 94547

Contact Person: Jackie Buckley, Regulatory Affair Representative IV Email: Jackie buckley@bio-rad.com Phone: (510) 741-5309 FAX: (510) 741-3954

B. Device Name and Regulatory Information

Proprietary Name: VARIANT™ II TURBO HbA1c Kit - 2.0 Regulation section: 21 CFR 864.7470, Glycosylated Hemoglobin Assay Device Classification: Class II Product Code: LCP, Assay, Glycosylated Hemoglobin Panel: Hematology

C. Predicate Device

VARIANT™ II TURBO HbAre Kit - 2.0 (k)090699

D. Intended Use

Intended Use:

The Bio-Rad VARIANT™ II TURBO HbA1c Kit-2.0 is intended for the quantitative determination of hemoglobin Ate in human whole blood using ionexchange high performance liquid chromatography (HPLC) on the VARIANT™ II TURBO Hemoglobin Testing System. Measurement of hemoglobin A1c is effective in monitoring long term glycemic control in individuals with diabetes mellitus. The Bio-Rad VARIANT™ II TURBO HbA1c Kit-2.0 is intended for Professional Use Only.

1. Indications for Use: Same as above
1. Special conditions for use statement(s):

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For Prescription Use Only

Special instrument requirements:

For use with the Bio-Rad VARIANT™II TURBO Hemoglobin Testing System

E. Description of Device:

A personal computer is used to control the VARIANT II TURBO Hemoglobin Testing System using updated Clinical Data Management (CDM) software version 5.1.1.

F. Summary of the device technological characterizes:

The VARIANT II TURBO HbA1c- 2.0 Kit and modified System have the same characteristics as the predicate, VARIANT II TURBO HbAtc- 2.0 Kit (k)090699. Comparisons of features are provided in the table below:

Feature	Predicate:	Modified device:
	Bio-Rad VARIANT TM II TURBOHbA1c Kit -2.0(k)090699	Bio-Rad VARIANT TM II TURBOHbA1c Kit -2.0
Similarities
Technology	Ion-exchange high performance liquid chromatography
Sample type	Anticoagulated whole blood (EDTA)
Calibrator	Human anticoagulated whole blood treated with EDTA
Calibration frequency	Once every 500 injections/ 2500 injections total column life
Certification	Certified by the NGSP as traceable to the Diabetes Control andComplications Trial (DCCT) Reference method.
Certification	Certified by the IFCC as traceable to the IFCC ReferenceMeasurement Procedure.
Instrument Control	Windows Operating System with Proprietary Assay Software
Kit configuration	One analytical cartridge, 5 prefilters, Elution Buffer A and B,Calibrator Level 1, Calibrator Level 2, Whole Blood Primer,sample vials and a CD-ROM with test parameters.
Feature	Predicate:Bio-Rad VARIANT™ II TURBOHbA1c Kit -2.0(k)090699	Modified device:Bio-Rad VARIANT™ II TURBOHbA1c Kit -2.0
Chemistry	Cation Exchange Matrix
Safety Standards forElectrical Equipmentfor IVD Use	BS EN 61010 Certified
ElectromagneticCompatibility	BS EN 61326 Certified
	Differences
Reporting units	% HbA1c (NGSP)	% HbA1c (NGSP), mmol/molHbA1c (IFCC), or %HbA1c (JDS)
Intended Use	Intended for the percentdetermination of HbA1c in humanwhole blood using ion-exchangeHPLC.Measurement of percent HbA1c iseffective in monitoring long-termglucose control in individualswith diabetes mellitus.	Intended for the quantitativedetermination of HbA1c inhuman whole blood using ion-exchange HPLC on theVARIANT II TURBOHemoglobin Testing System.Measurement of percent HbA1cis effective in monitoring long-term glucose control inindividuals with diabetesmellitus.
Interference fromvariants (HbD,HbE, HbS, HbC)	Hemoglobin variants: Two out of7 hemoglobin AD-trait, 2 out of11 hemoglobin AS-trait, 1 out of12 hemoglobin AE-trait, and 3out of 9 hemoglobin AC-traitpatient samples at the clinicallysignificant levels of 6% and 9%HbA1c exhibited differences ofmore than ±10% from valuesobtained using boronate affinityreference method.	No significant interference wasobserved at the followingconcentrations:• HbS ≤67%• HbC ≤72%• HbD ≤55%• HbE ≤41%
Interference fromHbA2	No claim previously	β-thalassemia trait, as indicatedby increased HbA2concentrations up to 10%, doesnot interfere with the assay.
Expected RangeFrom AmericanDiabetes AssociationStandard of Care	Hemoglobin A1c RangesHemoglobinA1c (%)>8<7<6	Hemoglobin A1c RangesHemoglobinA1c (%)<8<7<6.5
	Degree ofGlucoseControlActionSuggestedGoalNon-DiabeticGoal	GlycemicGoalLessStringentGoalGeneral GoalMoreStringent

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Bio-Rad Laboratories, Inc. VARIANT™ II TURBO HbA1c Kit -2.0

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Feature	Predicate:Bio-Rad VARIANT™ II TURBOHbA1c Kit -2.0(k)090699	Modified device:Bio-Rad VARIANT™ II TURBOHbA1c Kit -2.0
		<5.7 Goal Non-DiabeticGoal
	From American DiabetesAssociation Standard of Care(2001)	From American DiabetesAssociation Standard of Care(2012)

Method Comparison:

This study was performed following CLSI guideline EP9-A2 Method Comparison and Bias Estimation Using Patient Samples. To demonstrate the correlation between CDM Software Versions 5.1 and 4.03, the VARIANT II TURBO HbA1c Kit - 2.0 was run on the VARIANT II TURBO Hemoglobin Testing System using both software versions. The protocol consisted of 100 EDTA whole blood human samples and 16 samples prepared by mixing EDTA whole blood samples with either purified HbAo or purified HbA1c. The samples were run as a single injection and the ranges of values are presented in Table 2 below.

The purpose of this study was to demonstrate that the modified version of software (v5.1) did not produce a clinically significant effect on HbA1c results with the use of +/- 10% relative bias at 6% and 9% HbAic as evaluation limits. The Bias Estimation data is presented in Table 1 and acceptable error at the decision points were met. The linear regression correlation data is presented in Table 2.

Criteria	First Decision Point	Second Decision Point
Decision point	6.0 %HbA1c	9.0 %HbA1c
Predicted value by regression	6.01	8.99
Predicted bias by regression	0.2%	-0.1%
Upper 95% confidence limit	0.5%	0.1%
Lower 95% confidence limit	-0.1%	-0.3%

Table 1: Bias Estimation at two Decision Points of %HbArc (NGSP)

Table 2: Linear Regression Data

	Regression Equation	R2	Sample Range
%HbA1c (NGSP)	Y=0.99x + 0.06	0.999	3.5 - 19.5%
mmol/mol (IFCC)	Y=0.99x + 0.48		15-190 mmol/mol
%HbA1c (JDS)	Y=0.99x + 0.06		3.1 - 19.3%

Analytical specificity:

Hemoglobin variant Interference study:

This study was performed following CLSI EP7-A2: Guidelines Interference Testing in Clinical Chemistry; Approved Guidelines, Second Edition.

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Two fresh, EDTA non-variant human blood sample pools at 6.5% and 8.0-9.0% HbA1c were collected. Fresh, EDTA human homozygous blood samples for each of the 4 hemoglobin variants (e.g. E, D, S, and C) was obtained for dilution. For the interference testing of each variant, a series of test sample pools were prepared by the dilution of a homozygous variant patient sample (as interferent) in the non-variant patient sample pool. The samples were run in duplicate on two VARIANT II TURBO Hemoglobin Testing Systems. The conclusion of this study demonstrated that no interference was observed at the following concentrations: HbS ≤ 67%, HbC ≤ 72%, HbD ≤ 55%, and HbE < 41%.

8. Conclusion:

When considering the similarities of the intended use, the general features and characteristics of the assay, the use of the same technology, it can be concluded that the VARIANT II TURBO HbA1e Kit - 2.0 is substantially equivalent to the cleared and currently marketed predicate, VARIANT II TURBO HbA1c Kit - 2.0 (K090699).

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DEPARTMENT OF HEALTH & HUMAN SERVICES

Image /page/5/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" around the perimeter. Inside the circle is an abstract symbol that resembles an eagle or a stylized human figure.

10903 New Hampshire Avenue Silver Spring, MD 20993

Bio-Rad Laboratories, Inc. Clinical System Division c/o Jackie Buckley Regulatory Affairs Representative IV 4000 Alfred Nobel Drive Hercules, CA 94547

OCT 2 6 2012

K122472 Re:

Trade Name: VARIANT II TURBO HbA1c Kit – 2.0 Regulation Number: 21 CFR §864.7470 Regulation Name: Glycosylated Hemoglobin Assay Regulatory Class: Class II Product Code: LCP Dated: August 10, 2012 Received: August 14, 2012

Dear Ms. Buckley:

We have reviewed your Section 510(k) premarket notification of intent to market the We have fevenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices the indications for ace commerce prior to May 28, 1976, the enactment date of the marketed in interstate commits, 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 with the provisions of the Poural Poola, 2007, 1997, 1997, 1997, 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, pro ristories facturing 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 (1 Mrs), it may be sacreer to our a in Title 21, Code of Federal Regulations (CFR), Parts arroomig your 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 I loase of as 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 requirements of the reveals with all the Act's requirements, including, but not I coderal agencies: " o a nd listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 11mical to: registration and issues of medical device-related adverse events) (21 007), medical de rece reportains (iig practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820).

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Page 2

If you desire specific advice for your device on our labeling regulation (21 CFR Part 801), please If you desire specific advice for your devices and Radiological Health at (301) 796-5450.
Contact the Office of In Vitro Diagnostic Devices and Radiological Health at (301) 7 Also, please note the regulation entitled, "Misbranding by reference to premarket notification" Also, please note the regulation entired, and securities please contact CDRH'S (21 CFR Fall 807.97). For questions regarding prises
Office of Surveillance and Biometric's (OSB's) Division of Postmarks Surveillance at (301) Office of Surveiner and Dromers of (322-57 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 CFR Part 803), please go to http://www.fda.gov/Medical

CFK I all 805), prease go to http://www.brunes.org/w/index.php?title=Office of Surveillance and Biometrics/Division of Postmarket Surveillance...

You may obtain other general information on your responsibilities under the Act from the You may outlail other general mionnation on Jour Copyright (800 638-2041 or (301) 796-5680 or at its Internet address http://www.fda/gov/MedicalDevices/ResourcesforYou/Industry/default.html

Sincerely yours,

Courtney H. Lias, Ph.D Director Division of Chemistry and Toxicology Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known): K122472

Device Name: VARIANTTM II TURBO HbA16 Kit -- 2.0

Indications for Use:

The Bio-Rad VARIANT™ II TURBO HbA1c Kit - 2.0 is intended for the quantitative determination of hemoglobin A1c in human whole blood using ion-exchange highperformance liquid chromatography (HPLC) on the VARIANT™ II TURBO Hemoglobin Testing System. Measurement of hemoglobin A16 is effective in monitoring long-term glycemic control in individuals with diabetes mellitus. The Bio-Rad VARIANT II TURBO HbA1e Kit – 2.0 is intended for Professional Use Only.

Prescription Use X (Part 21 CFR 801 Subpart D)

AND/OR

Over-The-Counter Use (21 CFR 801 Subpart C)

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

Concurrence of CDRH, Office of In Vitro Diagnostic Devices (OIVD)

Raul Lemo

Division Sign-ON Office of In Vitro Diagnostic Device Evaluation and Safety

510(k) K122472

Page 1 of 1

Vol001 004

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).