The Bio-Rad VARIANT II Hemoglobin A1c Program is intended for the percent determination of hemoglobin A1c in human whole blood using ion-exchange highperformance liquid chromatography (HPLC).
The Bio-Rad VARIANT II Hemoglobin A1c Program is intended for Professional Use Only.
Measurement of percent hemoglobin A1c is effective in monitoring long-term glucose control in individuals with diabetes mellitus.

Device Description

The VARIANT II Hemoglobin Testing System uses the principles of high performance liquid chromatography (HPLC). The VARIANT II Hemoglobin A1c Program is based on chromatographic separation of Hemoglobin A1c on a cation exchange cartridge.

AI/ML Overview

Here's a breakdown of the acceptance criteria and the study details for the Bio-Rad VARIANT™ II Hemoglobin A1c Program, based on the provided text:

Acceptance Criteria and Reported Device Performance

The provided document describes a substantial equivalence study comparing a new device (VARIANT™ II Hemoglobin A1c Program (270-2101NU)) to a predicate device (VARIANT™ II Hemoglobin A1c Program (270-2101)). Therefore, the acceptance criteria are implicitly defined by the demonstration that the new device performs equivalently to the predicate device across various metrics. The study aims to show that the new device is "substantially equivalent" rather than meeting specific numerical performance targets against a predefined standard.

Table of Acceptance Criteria (Implied by Predicate Equivalence) and Reported Device Performance:

Performance Metric	Acceptance Criteria (Implied - Equivalence to Predicate)	Reported Device Performance (New Device: 270-2101NU vs. Predicate: 270-2101)
Accuracy (Method Correlation)	The new device should show comparable correlation to the predicate device across the clinical range of HbA1c values.	Evaluated using 42 EDTA whole blood patient samples (4.2% to 10.9% HbA1c). The document states, "The results are presented in the following regression table." However, the regression table itself is missing, making it impossible to report specific intercept and slope values that would demonstrate correlation.
Precision	The new device should exhibit comparable precision (within-run, within-device, total) to the predicate device.	New Device (270-2101NU):- Low Patient (n=240, Mean 5.5%): Within run %CV = 0.9, Within Device %CV = 1.60- High Patient (n=160, Mean 8.8%): Within run %CV = 0.6, Within Device %CV = 1.38Predicate Device (270-2101):- Low Patient (n=80, Mean 5.4%): Within run %CV = 1.46, Total Precision %CV = 2.14- High Patient (n=80, Mean 13.7%): Within run %CV = 0.65, Total Precision %CV = 1.68Conclusion: "the precision results...are equivalent."
Linearity (Linear Range)	The linear measuring range of the new device should be comparable to the predicate device.	New Device (270-2101NU): 3.1 - 18.5 % HbA1cPredicate Device (270-2101): 1.3 - 18.9 % HbA1c(Interpretation: Ranges are similar, supporting substantial equivalence.)
Interfering Substances	The new device should demonstrate similar resistance to common interfering substances at comparable concentrations.	New Device (270-2101NU) & Predicate (270-2101):- Bilirubin: No interference up to 20 mg/dL- Lipids (Triglycerides): No interference up to 6000 mg/dL- EDTA: No interference up to 11X EDTA- Hemoglobin F: 10% (New), 15% (Predicate)(Interpretation: Generally similar, with a slight difference in HbF tolerance for the new device which isn't explicitly flagged as non-equivalent.)

Study Details:

Sample size used for the test set and the data provenance:
- Accuracy (Method Correlation):
  - Sample Size: 42 EDTA whole blood patient samples.
  - Data Provenance: Not explicitly stated, but the samples are described as "patient samples," implying human origin. Country of origin and whether retrospective or prospective are not mentioned.
- Precision:
  - New Device (270-2101NU): 240 samples for "Low Patient" and 160 samples for "High Patient."
  - Predicate Device (270-2101): 80 samples for "Low Patient" and 80 samples for "High Patient."
  - Data Provenance: "EDTA whole blood patient samples." Country of origin and whether retrospective or prospective are not mentioned, but the samples were analyzed at "three Bio-Rad sites" for the new device and on "one VARIANT II Hemoglobin Testing System" for the predicate.
Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- The study is a method correlation and precision study for an in vitro diagnostic device, not an AI or imaging device requiring expert interpretation of results.
- No human experts are mentioned as establishing ground truth in the context of diagnostic performance for this type of device. The ground truth for HbA1c values would be considered the measured value obtained from the method itself (or a reference method if specified).
- The study compares the new device's measurements to the predicate device's measurements, implying the predicate device's results serve as a form of reference for comparison, and the predicate itself is standardized "Traceable to the Diabetes Control and Complications Trial (DCCT) reference method and IFCC. Certified via the National Glycohemoglobin Standardization Program (NGSP)."
Adjudication method (e.g. 2+1, 3+1, none) for the test set:
- This concept of "adjudication" is typically relevant for studies where human interpretation or labeling is involved, such as in image analysis or clinical trials with subjective endpoints.
- For this in vitro diagnostic device study, the outputs are quantitative measurements of HbA1c. Therefore, no adjudication method in the traditional sense was used or needed for the test set.
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:
- No, an MRMC comparative effectiveness study was not done.
- This study is for an in vitro diagnostic (IVD) device, specifically an automated assay, which does not involve human readers interpreting AI outputs. The device directly measures a biomarker (HbA1c).
If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:
- Yes, a standalone performance evaluation was done. The entire study assessed the performance of the Bio-Rad VARIANT™ II Hemoglobin A1c Program (an automated analytical instrument) in generating HbA1c measurements, without human intervention in the result generation itself. The "algorithm" here refers to the instrument's internal processes for chromatographic separation and calculation, not an AI algorithm in the contemporary sense.
The type of ground truth used (expert consensus, pathology, outcomes data, etc):
- The "ground truth" for the performance evaluation is established through comparison to a legally marketed predicate device (Bio-Rad VARIANT™ II Hemoglobin A1c Program (270-2101)).
- Both the new and predicate devices are stated to be "Traceable to the Diabetes Control and Complications Trial (DCCT) reference method and IFCC. Certified via the National Glycohemoglobin Standardization Program (NGSP)." This indicates that the measurements themselves are standardized against established reference methods, which serve as the ultimate "ground truth" for HbA1c values.
The sample size for the training set:
- This is a study for an IVD device, not an AI/machine learning model. Therefore, the concept of a "training set" for an algorithm is not applicable. The device's operational parameters are based on its physical and chemical design, calibrated using established standards, not trained on a dataset.
How the ground truth for the training set was established:
- As explained above, there is no training set in the AI sense for this device. The device operates based on principles of high-performance liquid chromatography calibrated against reference methods (DCCT, IFCC, NGSP).

Summary

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Summary of Safety and Effectiveness

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.

The assigned 510(k) number is:_ 070452__

Submitter:	Bio-Rad Laboratories, Inc.Clinical Diagnostics Group4000 Alfred Nobel Drive,Hercules, California 94547Phone: (510) 741-5309FAX: (510) 741-6471
Contact Person:	Jackie BuckleyRegulatory Affairs Representative
Date of Summary Preparation:	February 14, 2007
Device Name:	VARIANT™ II Hemoglobin A1c Program(Catalog number 270-2101NU)
Classification Name:	Assay, Glycosylated Hemoglobin, 81LCP
Predicate Device:	VARIANT™ II Hemoglobin A1c ProgramK984268Bio-Rad Laboratories, Inc.(Catalog number 270-2101)
Intended Use:	The Bio-Rad VARIANT II Hemoglobin A1cProgram is intended for the percent determinationof hemoglobin A1c in human whole blood usingion-exchange high performance liquidchromatography (HPLC).The Bio-Rad VARIANT II Hemoglobin A1cProgram is intended for Professional Use Only.
Indications for Use:	Measurement of percent hemoglobin A1c iseffective in monitoring long-term glucose control inindividuals with diabetes mellitus.

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Description of the Device:

Technical Characteristics Compared to the Predicate:

The new VARIANT II Hemoglobin A1c Program (270-2101NU) and the predicate VARIANT II Hemoglobin A1c Program (270-2101) have the same technical characteristics that are summarized in the table below:

Characteristics	VARIANT II Hemoglobin A1c(270-2101NU)	VARIANT II Hemoglobin A1c(270-2101) (k)984268
Analyte Measured: Reported	%Hemoglobin A1c	%Hemoglobin A1c
Intended Use	The Bio-Rad VARIANT II Hemoglobin A1cProgram is intended for the percentdetermination of hemoglobin A1c in humanwhole blood using ion-exchange highperformance liquid chromatography (HPLC).The Bio-Rad VARIANT II Hemoglobin A1cProgram is intended for Professional UseOnly.	The Bio-Rad VARIANT II Hemoglobin A1cProgram is intended for the percent determinationof hemoglobin A1c in human whole blood usingion-exchange high performance liquidchromatography (HPLC).For In Vitro Diagnostic Use.
Assay Principle	Cation exchange high performance liquidchromatography	Cation exchange high performance liquidchromatography
Sample Type	Human anticoagulated whole blood (EDTA)	Human anticoagulated whole blood (EDTA)
Visible Detection	415 nm	415 nm
Total Area Range	1.5 – 4.5 million μvolt·second	1.0 – 4.0 million μvolt·second
Calibration Frequency	After installation of the analyticalcartridge and once every 30 days	After installation of the analytical cartridge
Reconstituted Calibrator Stability	30 days	7 days
Calibrator Reconstitution Volume	7 mL	5 mL
Cartridges Included in Kit	1 Cartridge (1000 tests)	2 Cartridges (500 tests each)
Standardization	Traceable to the Diabetes Control andComplications Trial (DCCT) referencemethod and IFCC. Certified via the NationalGlycohemoglobin Standardization Program(NGSP).	Traceable to the Diabetes Control andComplications Trial (DCCT) reference methodand IFCC. Certified via the NationalGlycohemoglobin Standardization Program(NGSP).

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Testing To Establish Substantial Equivalence:

Accuracy:

Method correlation between the new VARIANT II Hemoglobin A1c Program (270-2101NU) and current VARIANT II Hemoglobin A1c Program (270-2101) was evaluated using 42 EDTA whole blood patient samples ranging from 4.2% to 10.9% HbA12. The results are presented in the following regression table.

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Precision:

The following table provides comparison data on the precision between the new VARIANT II Hemoglobin A1c (270-2101NU) and VARIANT II Hemoglobin A1c (270-2101) Programs, each utilizing low and high EDTA whole blood patient samples, and both tested against samples with moderate (5.4/5.5) and high (8.8- 13.7) % A1c content.

Method precision was performed using a protocol based on the NCCLS Evaluation protocol, Vol.24, No. 25, EP5-A2 (2004) for the new VARIANT II Hemoglobin A1c (270-2101NU) and NCCLS Evaluation protocol, Vol.12, No. 4, EP5-T2 (Mar. 1992) for the current VARIANT II Hemoglobin Air Program (270-2101). The protocols for both the new VARIANT II Hemoglobin A1c and current VARIANT II Hemoglobin A1c Programs are similar.

For the new VARIANT II Hemoglobin A1c Program protocol, six VARIANT II Hemoglobin Testing Systems at three Bio-Rad sites were utilized. Each site was provided with the same sample set and performed two replicates of each sample on each of 2 runs/day for 10 days.

For the current VARIANT II Hemoglobin A1c Program protocol, 40 runs (2 per day) were performed on one VARIANT II Hemoglobin Testing System over 20 working days. In each duplicate daily run, one aliquot of low HbAIc and one aliquot of high HbA1c patient samples were each analyzed per run.

Although the precision samples are different, since they were run at different time periods, the precision results between the new VARIANT II Hemoglobin A1c (270-2101NU) and the current VARIANT II Hemoglobin A1c Program (270-2101) are equivalent. A summary of combined comparative precision results is presented in the following precision table.

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VARIANT II Hemoglobin A1c (270-2101NU) and VARIANT II Hemoglobin A1c (270-2101) Precision

New VARIANT II Hemoglobin A1c(270-2101NU)		VARIANT II Hemoglobin A1c(270-2101)
Low Patient (HbA1c)	High Patient (HbA1c)	Low Patient (HbA1c)	High Patient (HbA1c)
n= (number of samples)	240	160	80	80
Mean	5.5	8.8	5.4	13.7
Within run (%CV)	0.9	0.6	1.46	0.65
Within DevicePrecision (%CV)	1.60	1.38	NA	NA
Total Precision (%CV)	NA	NA	2.14	1.68

Linearity:

	VARIANT II Hemoglobin A1cProgram (210-2101NU)	VARIANT II Hemoglobin A1cProgram (270-2101)
Linear Range	3.1 - 18.5 % HbA1c	1.3 - 18.9 % HbA1c

Interfering Substances:

Interfering Substance	VARIANT II Hemoglobin A1c(270-2101NU)	VARIANT II Hemoglobin A1c(270-2101)
Bilirubin	No interference up to 20 mg/dL	No interference up to 20 mg/dL
Lipids(Triglycerides)	No interference up to 6000mg/dL	No interference up to 6000mg/dL
EDTA	No interference up to 11X EDTA	No interference up to 11X EDTA
Hemoglobin F	10%	15%

Conclusion:

When considering the similarities of the intended use, the general characteristics of the two assays, the use of the same technology and the similar correlation, accuracy and linearity between the two methods, it can be concluded that the new VARIANT II Hemoglobin Alc Program (270-2101NU) is substantially equivalent to the cleared and currently marketed predicate, VARIANT II Hemoglobin A1c Program (270-2101).

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DEPARTMENT OF HEALTH & HUMAN SERVICES

Image /page/4/Picture/1 description: The image shows the logo for the Department of Health & Human Services - USA. The logo features a stylized eagle with three bars representing its wings, and the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" is arranged in a circular fashion around the eagle. The logo is black and white.

Public Health Service

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

Bio-Rad Laboratories, Inc. c/o Ms. Jackie H. Buckley 4000 Alfred Nobel Drive Hercules, CA 94547

MAY -7 2007

Re: K070452

Trade Name: Variant II Hemoglobin A1c Program Regulation Number: 21 CFR 864.7470 Regulation Name: Glycosylated hemoglobin assay Regulatory Class: Class II Product Code: LCP, KRZ Dated: February 14, 2007 Received: February 16, 2007

Dear Ms. Buckley:

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 CFR Part 807); labeling (21 CFR Parts 801 and 809); and good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820).

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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) 276-0490. 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 (240) 276-3150 or at its Internet address at http://www.fda.gov/cdrh/industry/support/index.html.

Sincerely vours.

Jean M. Cooper, M.S., D.v.M.

Jean M. Cooper, M.S., 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): K070452

Device Name: VARIANT II Hemoglobin A1c Program

Indications For Use:

The Bio-Rad VARIANT II Hemoglobin A1c Program is intended for the percent determination of hemoglobin A1c in human whole blood using ion-exchange highperformance liquid chromatography (HPLC).

The Bio-Rad VARIANT II Hemoglobin A1c Program is intended for Professional Use Only.

Measurement of percent hemoglobin A1c is effective in monitoring long-term glucose control in individuals with diabetes mellitus.

Prescription Use × (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 IF NEEDED)

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

Sign-Off

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ිffice of In Vitro Diagnostic Device i

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).