The Dimension® Hemoglobin A1c assay is an in vitro diagnostic assay for the quantitative determination of %HbA 1c (DCCT/NGSP) and mmol/mol HbA1c (IFCC) in human anticoagulated venous whole blood for use on the Dimension® clinical chemistry system. Measurement of Hemoglobin A1c is used as an aid in diagnosis and monitoring of long-term blood glucose control in patients with diabetes mellitus and as an aid in the identification of patients at risk for developing diabetes mellitus.

Device Description

The Dimension® Hemoglobin A1C assay is an in vitro diagnostic device intended to measure the concentration of hemoglobin A1c in venous human anticoagulated whole blood. The assay consists of three reagents packaged in Dimension® Flex® cartridges. The reagents are liquid and ready to use.

AI/ML Overview

The provided text describes the Siemens Healthcare Diagnostics Inc.'s Dimension® Hemoglobin A1c Assay, a Class II medical device for quantitative determination of %HbA1c and mmol/mol HbA1c in human anticoagulated venous whole blood. The document details studies undertaken to demonstrate the device's performance, primarily for a 510(k) premarket notification to show substantial equivalence to a predicate device.

Here's a breakdown of the requested information based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state "acceptance criteria" with numerical targets for each performance characteristic. Instead, it presents study results and, for some criteria, qualitative conclusions (e.g., "No significant interference," "No deviations from linearity"). The assessment of "substantial equivalence" to the predicate device implies that the reported performance meets acceptable clinical standards for HbA1c measurement.

Performance Metric	Acceptance Criteria (Implied / Qualitative)	Reported Device Performance
Method Comparison (against NGSP Reference Method)	Agreement with NGSP reference method; low bias.	Passing-Bablok: Slope [0.966 to 1.001], Y-int [-0.095 to 0.144] (%HbA1c); Bias at decision levels: -1.10% to -1.45% (%HbA1c)
		Deming: Slope [0.957 to 1.000], Y-int [-0.094 to 0.198] (%HbA1c); Bias at decision levels: -1.16% to -1.77% (%HbA1c)
Precision	Low variability (Repeatability, Between-Run, Between-Day, Between-Instrument, Between-Lot, Total CV).	Total CV: 1.7% to 2.6% for %HbA1c (QC samples), 1.6% to 2.4% for %HbA1c (patient pools)
Total Error	Acceptable total error at decision levels.	Ranged from 4.4% to 5.8% (%TE) for %HbA1c at various decision levels.
Endogenous & Exogenous Interference	No significant interference (e.g., < ± 5.0% bias) from common interferents.	No significant interference observed for interferents listed in Table J.
Hemoglobin Variant Interference	No significant interference from common Hb variants (e.g., < ± 5.0% bias).	No significant interference observed for HbC, HbD, HbE, HbA2. Significant interference observed for HbF (-23.2% to -24.7% bias).
Hemoglobin Derivatives	Inaccuracies/biases ≤ 5% due to acetylated, carbamylated, or labile Hb.	Inaccuracies (biases) due to these substances are less than or equal to 5%.
Linearity	Linearity across the assay range.	No deviations from linearity observed for results from 3.6 to 15.9% HbA1c.
Limit of Blank (LoB)	Defined LoB value.	LoB: 3.6% for %HbA1c, 0.0 g/dL for tHb, 0.21 g/dL for HbA1c.
Limit of Detection (LoD)	Defined LoD value.	LoD: 3.7% for %HbA1c, 0.5 g/dL for tHb, 0.23 g/dL for HbA1c.
Anticoagulant Comparison	Equivalence between different anticoagulants.	Slopes [0.982 to 1.023] and y-intercepts close to zero in comparison to K2-EDTA.

2. Sample size used for the test set and the data provenance

Method Comparison: 147 human whole blood samples. The document does not specify the country of origin or if the data was retrospective or prospective.
Precision: Two (2) commercial quality controls and four (4) whole blood patient pools (with specific target values). The number of individual patient samples in these pools is not specified, but the testing was performed over 20 days by 2 operators on 3 instruments.
Endogenous & Exogenous Interference: Not explicitly stated as a "test set" of patient samples, but each interferent was evaluated using samples at two HbA1c levels (6.5% ± 1.0% and 8.0% ± 1.0%).
Hemoglobin Variant Interference:
- HbC: 37 samples
- HbD: 20 samples
- HbE: 22 samples
- HbS: 22 samples
- HbA2: 23 samples
- HbF: 20 samples
- These were "anticoagulated human blood samples with known concentrations of hemoglobin variant and HbA1c." The document does not specify the country of origin or if the data was retrospective or prospective.
Linearity: Nine (9) samples with HbA1c levels across the assay range.
Limit of Blank (LoB) and Limit of Detection (LoD):
- LoB: 60 determinations with 5 blank samples each for tHb, and 75 determinations with 5 blank samples each for % HbA1c/HbA1c.
- LoD: 60 determinations with 5 low-level samples each for tHb, and 75 determinations with 5 low samples each for % HbA1c/HbA1c.
Anticoagulant Comparison: 79 samples. The document does not specify the country of origin or if the data was retrospective or prospective.

Data Provenance: For all studies, the document does not explicitly state the country of origin of the data or whether the studies were retrospective or prospective. However, based on the nature of lab-based validation studies for a diagnostic assay, they are typically prospective, controlled experimental setups.

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

For the method comparison study, the ground truth was established by "NGSP reference method results from testing performed at an NGSP reference laboratory." The document does not specify the number or qualifications of experts at this reference laboratory, but an NGSP (National Glycohemoglobin Standardization Program) reference laboratory adheres to strict standardization protocols.

For other studies (e.g., interference, linearity), the ground truth was based on preparing samples with known concentrations or characteristics, rather than expert consensus on diagnostic images or conditions.

4. Adjudication method for the test set

Not applicable in the context of this device. The studies directly measure quantitative values and compare them against reference methods or known concentrations, rather than relying on multiple expert interpretations that would require an adjudication process.

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

Not applicable. This is an in vitro diagnostic assay for quantitative laboratory measurement, not an AI-assisted diagnostic imaging or interpretation device. There are no "human readers" in the traditional sense involved in interpreting results that would be improved with AI assistance.

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

Yes, the studies described are for the standalone performance of the Dimension® Hemoglobin A1c Assay. The device is a clinical chemistry system designed for automated quantitative determination, implying an "algorithm only" or automated performance. The studies evaluate the accuracy, precision, and interference characteristics of this automated system.

7. The type of ground truth used

Method Comparison: NGSP reference method results. This is a standardized, high-accuracy laboratory method.
Interference (Endogenous, Exogenous, Hemoglobin Variant, Derivatives): Samples with known concentrations of interferents or variants, and known HbA1c values.
Precision: Commercial quality controls and meticulously prepared patient pools with target values.
Linearity: Prepared samples with a range of known HbA1c levels.
LoB/LoD: Blank samples and low-level samples with known very low concentrations.
Anticoagulant Comparison: K2-EDTA samples served as the comparator (reference) for other anticoagulants.

In essence, the ground truth is established through highly controlled laboratory preparations and comparisons to recognized reference methods or established comparator methods, rather than expert consensus or pathology in the context of imaging.

8. The sample size for the training set

Not applicable. This is an in vitro diagnostic assay, not a machine learning or AI-based device that typically requires a separate training set. The performance evaluation is based on standard analytical validation studies.

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

Not applicable, as there is no training set in the context of this traditional in vitro diagnostic assay.

Summary

{0}------------------------------------------------

Image /page/0/Picture/0 description: The image contains the logo of the U.S. Food and Drug Administration (FDA). The logo consists of two parts: on the left, there is a seal with an abstract design, and on the right, there is the text "FDA U.S. FOOD & DRUG ADMINISTRATION" in blue. The seal is a stylized representation of an eagle, and the text is arranged in three lines, with "FDA" being the largest and most prominent.

July 13, 2018

Siemens Healthcare Diagnostics Inc. Alan Haley Regulatory and Clinical Affairs Specialist 500 GBC Drive Newark, DE 19702

Re: K173909

Trade/Device Name: Dimension Hemoglobin A1c Assay Regulation Number: 21 CFR 862.1373 Regulation Name: Hemoglobin A1c test system Regulatory Class: Class II Product Code: PDJ Dated: June 11, 2018 Received: June 12, 2018

Dear Alan Haley:

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. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. 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 Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR

{1}------------------------------------------------

803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

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 comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/) and CDRH Learn (http://www.fda.gov/Training/CDRHLearn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (http://www.fda.gov/DICE) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely,

Kellie B. Kelm -S

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

Enclosure

{2}------------------------------------------------

Indications for Use

510(k) Number (if known) K173909

Device Name Dimension® Hemoglobin A1c Assay

Indications for Use (Describe)

Type of Use (Select one or both, as applicable)

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

CONTINUE ON A SEPARATE PAGE IF NEEDED.

This section applies only to requirements of the Paperwork Reduction Act of 1995.

DO NOT SEND YOUR COMPLETED FORM TO THE PRA STAFF EMAIL ADDRESS BELOW.

The burden time for this collection of information is estimated to average 79 hours per response, including the time to review instructions, search existing data sources, gather and maintain the data needed and complete and review the collection of information. Send comments regarding this burden estimate or any other aspect of this information collection, including suggestions for reducing this burden, to:

Department of Health and Human Services Food and Drug Administration Office of Chief Information Officer Paperwork Reduction Act (PRA) Staff PRAStaff(@fda.hhs.gov

"An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB number."

{3}------------------------------------------------

SIEMEN

510(k) Summary - K173909

This 510(k) Summary of Safety and Effectiveness is being submitted in accordance with the requirements of Safe Medical Device Act of 1990 and 21 CFR 807.92.

1. Submitter

Company	Siemens Healthcare Diagnostics Inc.
Address	500 GBC DriveNewark, DE 19702
Contact	Alan Haley
Telephone	302.631.9883
Fax	302.631.6299
Date of Preparation	July 12, 2018

2. Device Information

Trade Name	Dimension® Hemoglobin A1C Assay
Common Name	Hemoglobin A1c Test System
Classification Name	Hemoglobin A1c Test System
Regulation	21 CFR 862.1373
Device Class	Class II
Product Code	PDJ
Panel	Clinical Chemistry

3. Identification of Predicate

Trade Name	Roche Diagnostics Operations (RDO)
510(k) Submitter	Cobas C13 Tina-Quant HbA1cDx Gen.3 Assay
510(k) Number	K160571
Clearance Date	December 19, 2016

4. Device Description

5. Intended Use Statement

The Dimension® Hemoglobin A1C assay is an in vitro diagnostic assay for the quantitative determination of %HbA1c (DCCT/NGSP) and mmol/mol HbA1c (IFCC) in human anticoagulated venous whole blood for use on the Dimension® clinical chemistry system. Measurement of Hemoglobin A1c is used as an aid in diagnosis and monitoring of long-term blood glucose control in patients with diabetes mellitus and as an aid in the identification of patients at risk for developing diabetes mellitus.

{4}------------------------------------------------

SIEMENS

6. Technological Characteristics

(a) Similarities and Differences

DeviceCharacteristic	Predicate DeviceCobas C13 Tina-QuantHbA1cDx Gen.3 Assay(K160571)	Proposed DeviceDimension®Hemoglobin A1C Assay
Intended Use	This test is intended for use as anaid in diagnosis of diabetes andas an aid in identifying patientswho may be at risk for developingdiabetes. It is an in vitrodiagnostics reagent systemintended for quantitativedetermination of mmol/molhemoglobin A1c (IFCC) and %hemoglobin A1c (DCCT/NGSP) inhemolysate or whole blood on theRoche/Hitachi cobas c 513clinical chemistry analyzer.HbA1c determinations are usefulfor monitoring of long-term bloodglucose control in individuals withdiabetes mellitus.	The Dimension® HemoglobinA1C assay is an in vitrodiagnostic assay for thequantitative determination of%HbA1c (DCCT/NGSP) andmmol/mol HbA1c (IFCC) inhuman anticoagulated venouswhole blood for use on theDimension® clinical chemistrysystem. Measurement ofHemoglobin A1c is used as anaid in diagnosis and monitoringof long-term blood glucosecontrol in patients with diabetesmellitus and as an aid in theidentification of patients at riskfor developing diabetes mellitus.
Type of Test	Quantitative turbidimetricinhibition immunoassay	Same
Measurand	Whole blood GlycosylatedHemoglobin (HbA1c)	Same
Reporting Units	% HbA1c NGSP/DCCT andmmol/mol IFCC	Same
MeasuringRanges	Hemoglobin4 to 35 g/dL(2.48 to 21.7 mmol/L)	Hemoglobin5.0 to 25.0 g/dL(3.1 to 15.5 mmol/L)
	HbA1c0.3 to 3.4 g/dL(0.186 to 2.11 mmol/L)	HbA1c0.25 to 2.90 g/dL(0.16 to 1.80 mmol/L)
	%HbA1c4.2 to 15.5%(23 to 146 mmol/mol)	%HbA1c3.8 to 14.0%(18 to 130 mmol/mol)
InstrumentPlatform	Cobas c 513(absorbance spectroscopy)	Dimension® RxL clinicalchemistry system(absorbance spectroscopy)
Anticoagulants	Li-HeparinK2-EDTAK3-EDTAEDTA/Fluoride	K2-EDTAK3-EDTANa Fluoride/Na2-EDTALithium HeparinNa Fluoride/ K-Oxalate
DeviceCharacteristic	Predicate DeviceCobas C13 Tina-QuantHbA1cDx Gen.3 Assay(K160571)	Proposed DeviceDimension®Hemoglobin A1C Assay
CalibrationFrequency	Each lot, every 29 days, and asrequired following quality controlprocedures	Each lot, every 30 days, and asrequired following quality controlprocedures
ReagentStability	Unopened2 – 8°C until expiration date	Unopened2 – 8°C until expiration date
	On-board in use2 – 8°C for 28 days	On-board sealed2 – 8°C for 30 days
Antibody	Polyclonal anti-HbA1c, ovine	Same

{5}------------------------------------------------

(b) Non-Clinical Performance Evaluation

(i) Method Comparison

Method comparison testing was performed in accordance with CLSI EP09-A3, Measurement Procedure Comparison and Bias Estimation Using Patient Samples; Approved Guideline – Third Edition. 147 human whole blood samples with values spanning the assay range were tested using the Dimension® Hemoglobin A1C Assay on the Dimension® RxL clinical chemistry system. Assay results were compared to NGSP reference method results from testing performed at an NGSP reference laboratory. Sample distribution is shown in Table A. Slope and Y-intercept results were generated with both Passing-Bablok and Deming regressions. Results are presented in Tables B, C, D, and E.

Table A. Method Comparison Sample Distribution

Range of Results(%HbA1c)	Percentage ofSamples	Number ofSamples
< 5	4.8%	7
5 to 6	12.2%	18
6 to 6.5	20.4%	30
6.5 to 7	21.8%	32
7 to 8	14.3%	21
8 to 9	8.2%	12
> 9	18.4%	27
Total	100%	147

Table B. Method Comparison, Passing-Bablok

Units	N	Slope[95% CI]	y-int.[95% CI]
NGSP(%HbA1c)	147	0.983[0.966 to 1.001]	0.030[-0.095 to 0.144]
IFCC(mmol/mol HbA1c)	147	0.973[0.955 to 0.992]	0.437[-0.474 to 1.450]

{6}------------------------------------------------

%HbA1c	Bias	% Bias
5.0	-0.05	-1.10
6.5	-0.08	-1.24
8.0	-0.11	-1.33
12.0	-0.17	-1.45

Table C. Bias Estimations, Passing-Bablok

Table D. Method Comparison, Deming

Units	N	Slope[95% CI]	y-int.[95% CI]
NGSP(%HbA1c)	147	0.978[0.957 to 1.000]	0.052[-0.094 to 0.198]
IFCC(mmol/mol HbA1c)	147	0.970[0.948 to 0.992]	0.532[-0.603 to 1.666]

Table E. Bias Estimations, Deming

%HbA1c	Bias	% Bias
5.0	-0.06	-1.16
6.5	-0.09	-1.40
8.0	-0.12	-1.55
12.0	-0.21	-1.77

(ii) Precision

Precision testing was performed in accordance with CLSI EP05-A3, Evaluation of Precision Performance of Quantitative Measurement Methods: Approved Guideline – Third Edition. Samples consisted of two (2) commercial quality controls and four (4) whole blood patient pools with target values of 5.0%, 6.5%, 8.0%, and 12.0% HbA1c. Testing was performed over twenty (20) testing days by two (2) operators using three (3) instruments and three (3) reagent lots on each instrument. One (1) calibration was performed over the duration of the study. Each testing day, two (2) runs were performed (with a minimum of 2 hours in between) for a total of 80 results for each sample. Data were analyzed using Analysis of Variance (ANOVA), consistent with the recommendations of CLSI EP05-A3. Results are presented in Tables F and G.

SAMPLEMean		Repeat-ability		BetweenRun		BetweenDay		BetweenInstrument		BetweenLot		Total
		SD	CV	SD	CV	SD	CV	SD	CV	SD	CV	SD	CV
MDP1	5.3	0.05	0.9	0.04	0.7	0.01	0.1	0.07	1.4	0.09	1.6	0.13	2.4
MDP2	6.4	0.05	0.7	0.03	0.5	0.03	0.4	0.09	1.4	0.00	0.0	0.11	1.7
MDP3	7.8	0.06	0.8	0.04	0.5	0.03	0.3	0.10	1.3	0.00	0.0	0.13	1.6
MDP4	11.9	0.09	0.8	0.05	0.4	0.05	0.4	0.06	0.5	0.18	1.5	0.22	1.8
QC 1	5.2	0.05	1.0	0.04	0.8	0.02	0.4	0.03	0.5	0.11	2.1	0.13	2.6
QC 2	9.5	0.08	0.8	0.06	0.7	0.03	0.3	0.12	1.2	0.03	0.3	0.16	1.7

Table F. Precision, All Instruments, NGSP Units (%HbA1c)

Units: SD = % HbA1c, CV = %

{7}------------------------------------------------

SAMPLE	Mean	Repeatability		Between Run		Between Day		Between Instrument		Between Lot		Total
		SD	CV	SD	CV	SD	CV	SD	CV	SD	CV	SD	CV
MDP1	35	0.54	1.5	0.40	1.2	0.08	0.2	0.81	2.3	0.95	2.7	1.42	4.1
MDP2	47	0.52	1.1	0.33	0.7	0.28	0.6	0.95	2.0	0.00	0.0	1.17	2.5
MDP3	62	0.68	1.1	0.44	0.7	0.28	0.5	1.13	1.8	0.00	0.0	1.41	2.3
MDP4	107	0.99	0.9	0.57	0.5	0.56	0.5	0.60	0.6	1.96	1.8	2.41	2.3
QC 1	34	0.56	1.7	0.48	1.4	0.24	0.7	0.31	0.9	1.19	3.5	1.47	4.4
QC 2	81	0.87	1.1	0.68	0.8	0.36	0.4	1.26	1.6	0.27	0.3	1.73	2.2

Table G. Precision, All Instruments, IFCC Units (mmol/mol HbA1c)

Units: SD = mmol/mol HbA1c, CV = %

(iii) Total Error at Decision Levels

The bias estimation values determined in the method comparison study and precision estimates determined in the precision study were used to determine the total error at each of the levels listed in Tables H and I. Total error was calculated as follows:

$$1%TE = |%Bias| + 1.96 \times %CV \times \left(1 + \frac{%Bias}{100}\right)|$$

Table H. Total Error Summary, Passing-Bablok

%HbA1cDecision Level	% Bias	% CV	%TE
5.0	-1.10	2.4	5.8
6.5	-1.24	1.7	4.5
8.0	-1.33	1.6	4.4
12.0	-1.45	1.8	4.9

Table I. Total Error Summary, Deming

%HbA1cDecision Level	% Bias	% CV	%TE
5.0	-1.16	2.4	5.8
6.5	-1.40	1.7	4.7
8.0	-1.55	1.6	4.6
12.0	-1.77	1.8	5.2

(iv) Endogenous and Exogenous Interference

Testing to determine the interference bias of various endogenous interferents on the Dimension® Hemoglobin A1C Assay was performed according to CLSI EP07-A2, Interference Testing in Clinical Chemistry; Approved Guideline - Second Edition. The effect of each interferent was evaluated using a paired difference analysis. Four replicates were tested at each of two HbA1c levels: 6.5% ± 1.0% and 8.0% ± 1.0%. No significant interference (i.e., greater than ± 5.0%) was observed for the potential interferents at the concentrations listed in Table J.

{8}------------------------------------------------

SIEMEN

Interferent	Concentration
Acetaminophen	20 mg/dL
Ampicillin	100 mg/dL
Acetylsalicylic acid	100 mg/dL
Ascorbic acid	30 mg/dL
Calcium dobesilate	20 mg/dL
Bilirubin (Conjugated)	66 mg/dL
Bilirubin (Unconjugated)	66 mg/dL
Cefoxin sodium	250 mg/dL
Cholesterol	503 mg/dL
Cyclosporin	1.66 mg/dL
Doxycycline hyclate	5 mg/dL
Glucose	2000 mg/dL
Heparin	5 U/mL
Ibuprofen	50 mg/dL
Insulin	593 U/mL
Intralipid	1000 mg/dL
Levodopa	2 mg/dL
Metformin	4 mg/dL
Methyldopa	2 mg/dL
Metronidazole	20 mg/dL
N-acetylcysteine	166.3 mg/dL
Phenylbutazone	40 mg/dL
Protein: Total	22 g/dL
Rheumatoid Factor	750 IU/mL
Rifampicin	6 mg/dL
Rosiglitazone	0.8mg/dL
Salicylic acid	60 mg/dL
Theophylline	10 mg/dL
Triglycerides	600 mg/dL

Table J. Endogenous and Exogenous Interference

(v) Hemoglobin Variant Interference

Interference testing to determine the effect of hemoglobin variants on the Dimension® Hemoglobin A1C Assay was performed according to CLSI EP07-A2, Interference Testing in Clinical Chemistry; Approved Guideline – Second Edition. Anticoagulated human blood samples with known concentrations of hemoglobin variant and HbA1c were analyzed. The effect of each hemoglobin variant on assay performance was evaluated comparing the mean observed %HbA1c values to the mean expected %HbA1c values. Four (4) replicates were tested for each sample. No significant interference bias (i.e., greater than ± 5.0%) was observed for HbC, HbD, HbE, and HbA2. Significant interference bias was observed for HbF. Results are presented in Tables K and L.

Hb Variant	n	Range (% Variant)	Range (%HbA1c)
HbC	37	26.1 to 40.0	4.4 to 15.7
HbD	20	24.8 to 38.4	5.0 to 13.0
HbE	22	19.7 to 30.4	4.7 to 11.0
HbS	22	27.2 to 36.3	5.3 to 14.0
HbA2	23	4.3 to 6.2	5.1 to 8.4
HbF	20	4.3 to 29.3	4.3 to 10.1

Table K. Hemoglobin Variant Samples

{9}------------------------------------------------

Hb Variant	Relative %Bias [Range of %Bias]Observed to Reference Method
	HbA1c ~6%	HbA1c ~8%
HbC	-1.0%[-5.0% to 4.9%]	-0.9%[-4.6% to 4.4%]
HbD	-2.2%[-4.9% to 4.4%]	-2.5%[-4.4% to -1.3%]
HbE	-2.1%[-4.9% to 3.1%]	-2.5%[-4.3% to -1.0%]
HbS	-1.3%[-4.7% to 4.9%]	-2.0%[-4.9% to 3.5%]
HbA2	0.1%[-4.8% to 3.6%]	-2.0%[-3.0% to -1.1%]
HbF	-23.2%[-30.3% to 1.2%]	-24.7%[-25.8% to -23.3%]

Table L. Hemoglobin Variant Interference

(vi) Hemoqlobin Derivatives

Interference testing to determine the effect of hemoglobin derivatives, including acetylated hemoglobin, carbamvlated hemoglobin, labile hemoglobin fractions on the Dimension® A1C assay was performed in accordance with CLSI document EP07-A2. Inaccuracies (biases) due to these substances are less than or equal to 5 % at Hemoglobin A1c concentrations of 5.0% ± 1.0%, 6.5% ± 1.0%, and 8.0% ± 1.0%.

Acetylated Hemoglobin with ≥ 50 mg/dL of acetylsalicylic acid
Carbamylated Hemoglobin with ≥ 10 mmol/L of Cyanate ●
. Labile Hemoglobin with ≥ 1500 mg/dL of Glucose

(vii) Linearitv

Linearity testing was conducted CLSI EP06-A, Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical Approach; Approved Guideline. Nine (9) samples with HbA1c levels across the assay range were prepared and tested. Four (4) replicates were tested at each level. No deviations from linearity were observed for results from 3.6 to 15.9% HbA1c.

(viii) Limit of Blank (LoB) and Limit of Detection (LoD)

Limit of Blank (LoB) and Limit of Detection (LoD) testing was conducted in accordance with CLSI EP17-A2, Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures. The LoB was determined using 60 determinations with 5 blank samples each for tHb and 75 determinations with 5 blank samples each for % HbA1c/HbA1c. The LoD was determined using 60 determinations, with 5 low level samples each for tHb and 75 determinations with 5 low samples each for % HbA1c/HbA1c. Results are presented in Table M.

Table M. Limit of Blank / Limit of Detection

	HbA1c (%)	tHb (g/dL)	HbA1c (g/dL)
LoB	3.6	0.0	0.21
LoD	3.7	0.5	0.23

{10}------------------------------------------------

SIEMENS

(ix) Anticoagulant Comparison

Testing was performed to demonstrate equivalence between five different anticoaqulants in accordance with CLSI EP09-A2, Method Comparison and Bias Estimation Using Patient Samples. Testing was performed to demonstrate equivalence between Ko EDTA, Ky EDTA, Na Fluoride/Naz EDTA, Lithium Heparin and Na Fluoride/K-Oxalate collection tubes. HbA1c values were measured for each sample using the Dimension® Hemoglobin A1C Assay on the Dimension® RxL clinical chemistry system. Regression analysis was used to analyze the measured values using the K₂ EDTA samples as the comparator. The slope and y-intercept values were determined by Passing-Bablok and Deming regression. HbA1c values for the samples ranged from 4.7 to 12.8%. Results are presented in Tables N and O.

Anticoagulant(y axis)	Comparator(x axis)	N	Slope[95% CI]	y-intercept[95% CI]
K3-EDTA	K2-EDTA	79	0.994[0.982 to 1.007]	0.030[-0.055 to 0.102]
Na Fluoride/Na2-EDTA	K2-EDTA	79	0.997[0.986 to 1.011]	0.006[-0.080 to 0.074]
Lithium Heparin	K2-EDTA	79	1.006[0.995 to 1.019]	-0.038[-0.120 to 0.041]
Na Fluoride/K-Oxalate	K2-EDTA	79	1.010[0.994 to 1.023]	-0.037[-0.113 to 0.059]

Table N. Anticoagulant Equivalence Summary, Passing-Bablok

Table O. Anticoaqulant Equivalence Summary, Deming

Anticoagulant(y axis)	Comparator(x axis)	N	Slope[95% CI]	y-intercept[95% CI]
K3-EDTA	K2-EDTA	79	0.997[0.978 to 1.015]	0.011[-0.102 to 0.124]
Na Fluoride/Na2-EDTA	K2-EDTA	79	1.003[0.985 to 1.020]	-0.033[-0.135 to 0.069]
Lithium Heparin	K2-EDTA	79	1.008[0.990 to 1.027]	-0.042[-0.152 to 0.068]
Na Fluoride/K-Oxalate	K2-EDTA	79	1.007[0.989 to 1.025]	-0.018[-0.127 to 0.091]

(x) Conclusion

The proposed Dimension® Hemoglobin A1C assay is substantially equivalent to the legally marketed predicate based on the similarities in intended use, technological characteristics, and performance testing presented above.

Regulation Number and Section

§ 862.1373 Hemoglobin A1c test system.

(a)
Identification. A hemoglobin A1c test system is a device used to measure the percentage concentration of hemoglobin A1c in blood. Measurement of hemoglobin A1c is used as an aid in the diagnosis of diabetes mellitus and as an aid in the identification of patients at risk for developing diabetes mellitus.(b)
Classification. Class II (special controls). The special controls for this device are:(1) The device must have initial and annual standardization verification by a certifying glycohemoglobin standardization organization deemed acceptable by FDA.
(2) The premarket notification submission must include performance testing to evaluate precision, accuracy, linearity, and interference, including the following:
(i) Performance testing of device precision must, at a minimum, use blood samples with concentrations near 5.0 percent, 6.5 percent, 8.0 percent, and 12 percent hemoglobin A1c. This testing must evaluate precision over a minimum of 20 days using at least three lots of the device and three instruments, as applicable.
(ii) Performance testing of device accuracy must include a minimum of 120 blood samples that span the measuring interval of the device and compare results of the new device to results of a standardized test method. Results must demonstrate little or no bias versus the standardized method.
(iii) Total error of the new device must be evaluated using single measurements by the new device compared to results of the standardized test method, and this evaluation must demonstrate a total error less than or equal to 6 percent.
(iv) Performance testing must demonstrate that there is little to no interference from common hemoglobin variants, including Hemoglobin C, Hemoglobin D, Hemoglobin E, Hemoglobin A2, and Hemoglobin S.
(3) When assay interference from Hemoglobin F or interference with other hemoglobin variants with low frequency in the population is observed, a warning statement must be placed in a black box and must appear in all labeling material for these devices describing the interference and any affected populations.