For in vitro diagnostic use in the quantitative determination of Hemoglobin A1c, a diabetes marker, in whole blood on the ADVIA Chemistry systems. Such measurements are used for monitoring the long-term care of persons with diabetes. The A1c_3 and total hemoglobin (tHb_3) values generated as part of the ADVIA Chemistry HbA1c% and HbA1cR assays are intended for use in the calculation of the A1c/total hemoglobin ratio, and must not be used individually for diagnostic purposes.

Device Description

The concentration of A1c and the concentration of total hemoglobin are measured and their ratio is reported. The automated pretreatment assays (ADVIA Chemistry A1c 3 and ADV)A Chemistry tHb_3) use 3 ADVIA Chemistry reagents:

· A1c 3 Agglutinator/Total Hemoglobin Reagent (A1c 3 R1)
· A1c_3 Antibody Reagent (A1c_3 R2)
· A1c_3 Denaturant Reagent (A1c_3 DENAT)

AI/ML Overview

The Siemens Healthcare Diagnostics ADVIA® 1800 Chemistry Hemoglobin A1c_3 (A1c_3) Automated Pretreatment Assay is intended for in vitro diagnostic use in the quantitative determination of Hemoglobin A1c in whole blood on ADVIA Chemistry systems for monitoring the long-term care of persons with diabetes.

Here's an analysis of its acceptance criteria and supporting study:

1. Table of Acceptance Criteria and Reported Device Performance

The provided document describes the performance characteristics without explicitly stating pre-defined "acceptance criteria" through numerical thresholds. However, substantial equivalence is claimed based on acceptable results compared to a predicate device. Based on the data presented, the implied acceptance is that the new device's performance characteristics demonstrate similar or equivalent performance to the predicate device and meet general analytical chemistry standards for precision, linearity, and lack of significant interference.

Performance Characteristic	Acceptance Criteria (Implied)	Reported Device Performance
Imprecision	Low coefficient of variation (CV) for within-run and total precision. Consistent with clinical needs and predicate device.	Within Run Imprecision (NGSP Units %):- Normal Control: Level 5.45%, SD 0.07%, CV 1.3%- Abnormal Control: Level 8.70%, SD 0.06%, CV 0.7%Total Imprecision (NGSP Units %):- Normal Control: Level 5.45%, SD 0.13%, CV 2.4%- Abnormal Control: Level 8.70%, SD 0.14%, CV 1.6%Within Run Imprecision (IFCC Units mmol/mol):- Normal Control: Level 36, SD 0.78, CV 2.2%- Abnormal Control: Level 71, SD 0.67, CV 0.9%Total Imprecision (IFCC Units mmol/mol):- Normal Control: Level 36, SD 1.41, CV 3.9%- Abnormal Control: Level 71, SD 1.47, CV 2.1%
Linearity/Assay Range	Linear performance across the intended measuring range.	Linear/Measuring Range:- A1c_3 specific A1c concentrations: 1.0 to 8.83 µmol/L- tHb_3 total hemoglobin concentrations: 7 to 24 g/dL- HbA1c% assay: 2.9 to 15.4% HbA1c- HbA1cR assay: 8 to 144 mmol/molThe range of samples tested in the linearity study was 1.13-19.44% A1c.
Limit of Detection (LoD)	LoD sufficiently low for clinical utility.	LoD for HbA1c_3 assays: 0.48 µmol/L (0.91 %HbA1c).
Method Comparison	High correlation and minimal bias compared to the predicate.	Correlation Coefficient: 0.9942 (between new method and predicate device) Linear Regression Equation: This method = 1.00 (predicate device) - 2.90 mmol/mol
Analytical Specificity	No significant interference from common interfering substances.	No significant lipemia interference (Intralipid 0-1000 mg/dL).No significant unconjugated bilirubin interference (0-60 mg/dL).No significant conjugated bilirubin interference (0-60 mg/dL). (Significance criterion >10% variance from control).

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

Imprecision Study: 80 replicates for each of two control levels (Normal and Abnormal) for both within-run and total imprecision analyses.
Linearity Study: Nine intermediate levels were prepared from low and high commercial linearity set solutions. The total number of samples or discrete measurements is not explicitly stated but implies multiple measurements for each of the 9 levels.
Limit of Detection (LoD) Study: 60 replicates of 0.9% Saline (Blank) and five HbA1c low samples. Data was obtained from a 3-day precision study.
Method Comparison Study: 98 whole blood samples.
Analytical Specificity Study: Specific sample numbers for bilirubin and lipid interference are not given, but levels of interferrents were tested in HbA1c samples (e.g., 5.16%, 9.84% HbA1c for lipemia; 5.16%, 9.90% HbA1c for unconjugated bilirubin; 5.03%, 9.78% HbA1c for conjugated bilirubin).

Data Provenance: The document does not specify the country of origin of the data or explicitly state if it was retrospective or prospective. Given the nature of in-vitro diagnostic device testing, it is generally prospective testing conducted in a laboratory setting.

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

N/A. This device is an automated in vitro diagnostic assay. The "ground truth" for the test set values (e.g., A1c percentages, total hemoglobin concentrations, and control values) would be established by reference methods or validated laboratory methods, not by human expert consensus or interpretation of images.

4. Adjudication Method for the Test Set

N/A. Adjudication methods (like 2+1, 3+1) are typically used in studies involving human interpretation (e.g., radiology reads) where discrepancies between readers need to be resolved. This is not applicable to a quantitative in vitro diagnostic assay.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

N/A. An MRMC study assesses the performance of human readers, typically for image-based diagnostics, with and without AI assistance. This is not relevant to a fully automated Hemoglobin A1c assay.

6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study

Yes, the studies described (imprecision, linearity, LoD, method comparison, analytical specificity) represent standalone performance of the algorithm/device. The device is designed to be fully automated for the determination of Hemoglobin A1c, without ongoing human intervention in the measurement process itself.

7. Type of Ground Truth Used

The ground truth for the in vitro diagnostic assay is established through:

Reference materials/methods: For calibration, linearity, and control samples, values are based on established, highly accurate reference methods or certified reference materials traceable to international standards (IFCC and NGSP).
Predicate device comparison: For the method comparison study, the results from the legally marketed predicate device (ADVIA® Chemistry Hemoglobin A1c Assay, K081895) served as the reference for comparison, indicating that the new device's measurements align with an already accepted method.
Known concentrations: For studies like linearity and analytical specificity, samples with known concentrations of analyte or interferents are used.

8. The Sample Size for the Training Set

The document does not specify a distinct "training set" or its size. For an in vitro diagnostic device like this, the development process would involve internal validation and optimization, but the provided K110934 summary focuses on the performance characteristics for market submission using test sets, not on algorithmic training data.

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

N/A. As mentioned above, a "training set" in the context of an AI/ML algorithm is not explicitly described for this in vitro diagnostic device. The ground truth for developing and validating the assay's performance would have been established through a combination of:

Standard laboratory protocols.
Use of calibrated reference materials and control samples.
Comparison with established, validated methods.
Traceability to international standards (IFCC and NGSP).

Summary

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AUG 25 2011

510(k) Summary of Safety and Effectiveness for the ADVIA® 1800 Chemistry Hemoglobin A1c_3 (A1c 3) Automated Pretreatment Assay

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.

A. 510(k) Number: K110934

B. Date of Preparation: July 8, 2011

C. Proprietary and Established Names:

ADVIA® 1800 Chemistry Hemoglobin A1c_3 (A1c_3) Automated Pretreatment Assay

D. Applicant

Contact:	Sandra D. White, MS, RACSr. Regulatory Technical Specialist
Address:	Siemens Healthcare Diagnostics, Inc333 Coney Street

East Walpole, MA 02032

(508) 660-4553 Phone: (508) 660-4591 (fax)

E. Regulatory Information:

1. Regulation section: 21 CFR §864.7470, Glycosylated hemoglobin assay
1. Classification: Class II
1. Product Code: LCP
1. Panel: Hematology (81)
F. Predicate Device:
1. Device Name:
- ADVIA® Chemistry Hemoglobin A1c (A1c)
1. Common Name:
ADVIA® Chemistry Hemoglobin A1c (A1c)
1. 510(k) Number: K081895
1. Manufacturer: Siemens Healthcare Diagnostics Inc.

G. Intended Use:

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(tHb 3) values generated as part of the ADVIA Chemistry HbA1c% and HbA1cR assays are intended for use in the calculation of the A1c/total hemoglobin ratio, and must not be used individually for diagnostic purposes.

H. Device Description:

· A1c 3 Agglutinator/Total Hemoglobin Reagent (A1c 3 R1)
· A1c_3 Antibody Reagent (A1c_3 R2)
· A1c_3 Denaturant Reagent (A1c_3 DENAT)

I. Test Principle:

: : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : :

HbA1c is formed by the non-enzymatic glycation of the ß-chain of hemoglobin A. The level of HbA1c is proportional to the level of glucose in the blood and is widely accepted as an indicator of the mean daily blood glucose concentration over the preceding 2 months. Recent studies have shown that the regular measurement of HbA 1c leads to changes in diabetes treatment and improvement of metabolic control as indicated by a lowering of HbA1c values.

In an automated pretreatment step, the whole blood sample is mixed with the A1c 3 Denaturant Reagent. The red blood cells are lysed and the hemoglobin chain is hydrolyzed by the protease present in the reagent. For the measurement of total hemoglobin, the A1c 3 Aqquitinator Reagent (A1c_3 R1) is used. The assay is based on the determination of released heme in the Soret region at 410 nm.

A latex agglutination inhibition assay is used for the measurement of specific A 1c. A second protease in the R1 reagent further hydrolyzes the HbA1c sample to a divcated pentapentide. which competes with the agglutinator (synthetic polymer containing multiple copies of the immunoreactive portion of A1c) for the anti-HbA1c antibody, thereby reducing the rate of agglutination. A concentration curve is obtained by monitoring the change in scattered light at 694 nm as a change of absorbance. The actual change in absorbance is inversely proportional to the concentration of A1c in the sample.

The A1c 3 and tHb 3 results use the HbA1c% Ratio to determine HbA1c results in NGSP equivalent units (%). The HbA1cR Ratio is used to determine HbA1c results in IFCC equivalent units (mmol/mol). The required assays and parameter sheets are summarized in the following table:

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J. Substantial Equivalence Information:

Predicate device name: ADVIA® Chemistry Hemoglobin A1c Assay
Predicate K number: K081895
Comparison with predicate:

	SIMILARITIES
Item	ADVIA® 1800 Chemistry HemoglobinA1c_3(A1c_3) Automated Pretreatment Assay(New Device)	ADVIA® Chemistry HemoglobinA1c Assay(Predicate Device)
Intended Use	For in vitro diagnostic use in the quantitativedetermination of Hemoglobin A1c, a diabetesmarker, in whole blood on the ADVIAChemistry systems. Such measurements areused for monitoring the long-term care ofpersons with diabetes.	Same
Expected values	4-6% (20-42 mmol/mol)	Same
Format	Liquid, ready for use	Same
Sample Type	Human whole blood (lithium heparin orpotassium EDTA)	Same
Calibrators	Siemens ADVIA® Chemistry A1c Calibrators	Same
Standardization	Traceable to International Federation ofClinical Chemistry (IFCC) andNational Glycohemoglobin StandardizationProgram (NGSP)	Same
Analytical range	2.9-15.4%(8-144 mmol/mol)	Same
Reagent StorageTemperature	2-8°C	Same
DIFFERENCES
Item	ADVIA® 1800 Chemistry HemoglobinA1c_3(A1c_3) Automated PretreatmentAssay(New Device)	ADVIA® Chemistry HemoglobinA1c Assay(Predicate Device)
Test Principle	For Hemoglobin:Measurement of released heme in the Soretregion at 410 nmFor HbA1c:Latex agglutination inhibition	For Hemoglobin:Conversion of all hemoglobinderivatives into alkaline hematinFor HbA1c:Latex agglutination inhibition
MeasurementWavelength	A1c_3: 694 nmtHb_3: 410/694 nm	A1c: 694 nmtHb_2: 596 nm

K. Performance Characteristics

・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・

Grand Banks - 1. 2. 2. 2. 2.

Substantial equivalence was demonstrated by testing several performance characteristics including imprecision, method comparison, interfering substances and analytical range. All of the evaluation studies gave acceptable results compared to the predicate device. These

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studies support that the ADVIA® 1800 Chemistry Hemoglobin A1c 3 (A1c 3) Automated Pretreatment Assay is substantially equivalent to the ADVIA® Chemistry Hemoglobin A1c (A1c) Assay that is currently marketed.

1. Imprecision

Within run and Total Precision were established by assaying a normal whole blood sample and an abnormal whole blood sample. Each sample was assayed 2 replicates per run, 2 runs per day, for at least 20 days. Precision estimates were computed according to CLSI document EP05-A2, Evaluation of Precision Performance of Quantitative Measurement Methods; Approved Guideline.

Sample	LevelNGSP Units(%)	Standard DeviationNGSP Units(%)	Coefficient ofVariation(%)	N
WITHIN RUN IMPRECISION
Normal Control	5.45	0.07	1.3	80
Abnormal Control	8.70	0.06	0.7	80
TOTAL IMPRECISION
Normal Control	5.45	0.13	2.4	80
Abnormal Control	8.70	0.14	1.6	80

Sample	LevelIFCC Units(mmol/mol)	Standard DeviationIFCC Units(mmol/mol)	Coefficient ofVariation %	N
WITHIN RUN IMPRECISION
Normal Control	36	0.78	2.2	80
Abnormal Control	71	0.67	0.9	80
TOTAL IMPRECISION
Normal Control	36	1.41	3.9	80
Abnormal Control	71	1.47	2.1	80

II. Linearity/assav reportable range:

A linearity study across the entire measuring range was assessed using commercially available linearity set solutions. The low and high levels of the linearity set were mixed to make nine (9) intermediate levels and all samples were tested on the ADVIA Chemistry 1800 analyzer. The range of samples tested was from 1.13-19.44% A1c. The observed values were compared to the expected values.

Linear/measuring range of the assay is

. . . . . . .

. :

..............................................................................................................................................................................

The A1c_3 assay can be used for specific A1c concentrations from 1.0 to 8.83 µmol/L. .
The tHb_3 assay can be used for total hemoglobin concentrations from 7 to 24 g/dL. .
The HbA1c% assay is linear from 2.9 to 15.4% HbA1c. .
The HbA1cR assay is linear from 8 to 144 mmol/mol. .

The low end of the assay range is calculated based on the Limit of Detection. The high end of the assay range is based on the linearity calculation.

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Limit of detection III.

The estimations of the Limit of Blank (LoB) and Limit of Detection (LoD) were performed by running 60 replicates of 0.9% Saline (Blank) and five (5) HbA1c low samples. Data were obtained from a 3-day precision study. The LoD for the HbA1c_3 assays is 0.48 umo//L (0.91 %HbA1c).

Method comparison with predicate device: IV.

The performance of this method (y) on an ADVIA 1800 was compared with performance of ADVIA® Chemistry System A1c method (x). Ninety-eight (98) whole blood samples in EDTA were tested and the sample results ranged from 3.14 - 14.92 %HbA1c (11 - 139) mmolimol) and gave a correlation coefficient of 0.9942.

Linear regression analysis gave the following equation: This method = 1.00 (predicate device) - 2.90 mmol/mol

Analytical specificity IV.

Interferences from icterus, lipemia, and hemolysis were evaluated for this Hemoglobin A1c method on an ADVIA 1800 analyzer using a significance criterion of >10% variance from the control. No significant lipenia interference was found at Intralipid levels from 0-1000 mg/dL in a 5.16%, 9.84% HbA1c sample. No significant interference was found at unconjugated bilirubin levels from 0-60 mg/dL in a 5.16%. 9.90% HbA1c sample. No significant interference was found at conjugated bilirubin levels from 0-60 mg/dL in a 5.03%, 9.78% HbA1c sample.

L. Conclusion:

The ADVIA® 1800 Chemistry Hemoglobin A1c 3 (A1c 3) Automated Pretreatment assay is substantially equivalent to other products in commercial distribution intended for similar use. Most notably, it is substantially equivalent to the currently marketed Siemens Healthcare Diagnostics ADVIA® Chemistry Hemoglobin A1c Assay (K081895).

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Food and Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20993

Siemens Healthcare Diagnostics c/o Sandra White 333 Coney Street Walpole, MA, 02032-1516

AUG 2 5 2011

K110934 Re: Trade Name: Advia 1800 Chemistry Hemoglobin A1C 3 Automated Pretreatment Assay Regulation Number: 21 CFR $864.7470 Regulation Name: Glycosylated Hemoglobin Assay Regulatory Class: Class II Product Codes: LCP Dated: July 29, 2011 Received: August 1, 2011

Dear Ms. White:

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); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); and good manufacturing practice requirements as set forth in the quality systems (OS) regulation (21 CFR Part 820).

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If you desire specific advice for your device on our labeling regulation (21 CFR Parts 801 and 809), please contact the Office of In Vitro Diagnostic Device Evaluation (27 CPN Paul Sufficial (301) 796-5450. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to

http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.

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) 796-7100 or at its Internet address http://www.fda.gov/cdrh/industry/support/index.html.

Sincerely vours.

C.C.

Courthey Harper, Ph.D. 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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Indication for Use

510(k) Number (if known): K ||0934

Device Name:

ADVIA® 1800 Chemistry Hemoglobin A1c 3 (A1c 3) Automated Pretreatment Assay

Indication for Use:

For in vitro diagnostic use in the quantitative determination of Hemoglobin A1c, a diabetes marker, in whole blood on the ADVIA Chemistry systems. Such measurements are used for monitoring the long-term care of persons with diabetes. The A1c 3 and total hemoglobin (tHb_3) values generated as part of the ADVIA Chemistry HbA1c% and HbA1cR assays are intended for use in the calculation of the A1c/total hemoglobin ratio, and must not be used individually for diagnostic purposes.

Prescription Use × (21 CFR Part 801 Subpart D) And/Or

Over the Counter Use (21 CFR Part 801 Subpart C)

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

Concurrence of CDRH, Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD)

Signature

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

510(k) K110934

Page 1 of 1

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).