Dimension Hemoglobin A1c Assay
Device Facts
| Record ID | K173909 |
|---|---|
| Device Name | Dimension Hemoglobin A1c Assay |
| Applicant | Siemens Healthcare Diagnostics, Inc. |
| Product Code | PDJ · Clinical Chemistry |
| Decision Date | Jul 13, 2018 |
| Decision | SESE |
| Submission Type | Traditional |
| Regulation | 21 CFR 862.1373 |
| Device Class | Class 2 |
Intended Use
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 Story
Dimension® Hemoglobin A1c Assay is an in vitro diagnostic reagent system for use on Dimension® clinical chemistry analyzers. It measures HbA1c concentration in human anticoagulated venous whole blood samples. The device utilizes a quantitative turbidimetric inhibition immunoassay principle; reagents are provided in ready-to-use Flex® cartridges. The assay is operated by laboratory personnel in a clinical setting. The system performs absorbance spectroscopy to quantify HbA1c levels. Results are reported as %HbA1c (DCCT/NGSP) and mmol/mol HbA1c (IFCC). Healthcare providers use these quantitative results to assess long-term glycemic control, aiding in the diagnosis of diabetes and the identification of patients at risk for developing the condition.
Clinical Evidence
Bench testing only. Precision studies (n=720 results per sample) showed total CVs ranging from 1.6% to 2.8%. Linearity was confirmed across the 3.8-14.0% HbA1c range (r=0.9986). Method comparison against the Tosoh G8 reference method (n=147) showed high correlation (r=0.996). Interference testing confirmed no significant interference from common endogenous/exogenous substances or hemoglobin variants (HbS, HbC, HbD, HbE, HbA2), except for fetal hemoglobin (HbF).
Technological Characteristics
Quantitative turbidimetric inhibition immunoassay; uses polyclonal ovine anti-HbA1c antibodies. Reagents are liquid, ready-to-use in Dimension® Flex® cartridges. Instrument platform: Dimension® RxL clinical chemistry system (absorbance spectroscopy). Compatible with K2-EDTA, K3-EDTA, Na Fluoride/Na2-EDTA, Lithium Heparin, and Na Fluoride/K-Oxalate anticoagulants. Calibration frequency: every 30 days.
Indications for Use
Indicated for patients with diabetes mellitus or those at risk for developing diabetes mellitus. Used for quantitative determination of HbA1c in human anticoagulated venous whole blood to aid in diagnosis and monitoring of long-term blood glucose control.
Regulatory Classification
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.
Special Controls
(b) Classification. Class II (special controls). Hemoglobin A1c test systems must comply with the following special controls: 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%, 6.5%, 8.0% and 12% hemoglobin A1c. This testing must evaluate precision over a minimum of 20 days using at least 3 lots of the device and 3 instruments, as applicable. ii) Performance testing of device accuracy must include a minimum of 120 blood samples that span the measuring interval of the new device and compare results of the new device to results of the 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%. 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.
*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.
Predicate Devices
- Roche Diagnostics Cobas c513 Tina-Quant HbA1cDx Gen.3 Assay (k160571)
Related Devices
- K011852 — DIMENSION HAIC ASSAY, MODEL DF105 · Dade Behring, Inc. · Nov 15, 2001
- K182651 — HbA1c Advanced · Beckman Coulter Ireland, Inc. · Jan 16, 2019
- K102510 — DIMENSIONS HB1C KIT, MODEL DF105A · Siemens Healthcare Diagnostics · May 13, 2011
- K102045 — DIMENSION VISA HBA1C, MODEL K3105A · Siemens Heatlhcare Diagnostics, Inc. · Feb 14, 2011
Submission Summary (Full Text)
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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
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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
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## Indications for Use
510(k) Number (if known) k173909
Device Name Dimension® Hemoglobin A1c Assay
#### Indications for Use (Describe)
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.
Type of Use (Select one or both, as applicable)
| <span style="font-size: 16px;"> <input checked="true" type="checkbox"/> </span> Prescription Use (Part 21 CFR 801 Subpart D) |
|------------------------------------------------------------------------------------------------------------------------------|
| <span style="font-size: 16px;"> <input type="checkbox"/> </span> Over-The-Counter Use (21 CFR 801 Subpart C) |
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## 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 Drive<br>Newark, 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
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.
#### 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.
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# SIEMENS
### 6. Technological Characteristics
### (a) Similarities and Differences
| Device<br>Characteristic | Predicate Device<br>Cobas C13 Tina-Quant<br>HbA1cDx Gen.3 Assay<br>(K160571) | Proposed Device<br>Dimension®<br>Hemoglobin A1C Assay |
|--------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Intended Use | This test is intended for use as an<br>aid in diagnosis of diabetes and<br>as an aid in identifying patients<br>who may be at risk for developing<br>diabetes. It is an in vitro<br>diagnostics reagent system<br>intended for quantitative<br>determination of mmol/mol<br>hemoglobin A1c (IFCC) and %<br>hemoglobin A1c (DCCT/NGSP) in<br>hemolysate or whole blood on the<br>Roche/Hitachi cobas c 513<br>clinical chemistry analyzer.<br>HbA1c determinations are useful<br>for monitoring of long-term blood<br>glucose control in individuals with<br>diabetes mellitus. | The Dimension® Hemoglobin<br>A1C assay is an in vitro<br>diagnostic assay for the<br>quantitative determination of<br>%HbA1c (DCCT/NGSP) and<br>mmol/mol HbA1c (IFCC) in<br>human anticoagulated venous<br>whole blood for use on the<br>Dimension® clinical chemistry<br>system. Measurement of<br>Hemoglobin A1c is used as an<br>aid in diagnosis and monitoring<br>of long-term blood glucose<br>control in patients with diabetes<br>mellitus and as an aid in the<br>identification of patients at risk<br>for developing diabetes mellitus. |
| Type of Test | Quantitative turbidimetric<br>inhibition immunoassay | Same |
| Measurand | Whole blood Glycosylated<br>Hemoglobin (HbA1c) | Same |
| Reporting Units | % HbA1c NGSP/DCCT and<br>mmol/mol IFCC | Same |
| Measuring<br>Ranges | Hemoglobin<br>4 to 35 g/dL<br>(2.48 to 21.7 mmol/L) | Hemoglobin<br>5.0 to 25.0 g/dL<br>(3.1 to 15.5 mmol/L) |
| | HbA1c<br>0.3 to 3.4 g/dL<br>(0.186 to 2.11 mmol/L) | HbA1c<br>0.25 to 2.90 g/dL<br>(0.16 to 1.80 mmol/L) |
| | %HbA1c<br>4.2 to 15.5%<br>(23 to 146 mmol/mol) | %HbA1c<br>3.8 to 14.0%<br>(18 to 130 mmol/mol) |
| Instrument<br>Platform | Cobas c 513<br>(absorbance spectroscopy) | Dimension® RxL clinical<br>chemistry system<br>(absorbance spectroscopy) |
| Anticoagulants | Li-Heparin<br>K2-EDTA<br>K3-EDTA<br>EDTA/Fluoride | K2-EDTA<br>K3-EDTA<br>Na Fluoride/Na2-EDTA<br>Lithium Heparin<br>Na Fluoride/ K-Oxalate |
| Device<br>Characteristic | Predicate Device<br>Cobas C13 Tina-Quant<br>HbA1cDx Gen.3 Assay<br>(K160571) | Proposed Device<br>Dimension®<br>Hemoglobin A1C Assay |
| Calibration<br>Frequency | Each lot, every 29 days, and as<br>required following quality control<br>procedures | Each lot, every 30 days, and as<br>required following quality control<br>procedures |
| Reagent<br>Stability | Unopened<br>2 – 8°C until expiration date | Unopened<br>2 – 8°C until expiration date |
| | On-board in use<br>2 – 8°C for 28 days | On-board sealed<br>2 – 8°C for 30 days |
| Antibody | Polyclonal anti-HbA1c, ovine | Same |
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#### (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<br>(%HbA1c) | Percentage of<br>Samples | Number of<br>Samples |
|------------------------------|--------------------------|----------------------|
| < 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<br>[95% CI] | y-int.<br>[95% CI] |
|--------------------------|-----|---------------------------|----------------------------|
| NGSP<br>(%HbA1c) | 147 | 0.983<br>[0.966 to 1.001] | 0.030<br>[-0.095 to 0.144] |
| IFCC<br>(mmol/mol HbA1c) | 147 | 0.973<br>[0.955 to 0.992] | 0.437<br>[-0.474 to 1.450] |
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| %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<br>[95% CI] | y-int.<br>[95% CI] |
|--------------------------|-----|---------------------------|----------------------------|
| NGSP<br>(%HbA1c) | 147 | 0.978<br>[0.957 to 1.000] | 0.052<br>[-0.094 to 0.198] |
| IFCC<br>(mmol/mol HbA1c) | 147 | 0.970<br>[0.948 to 0.992] | 0.532<br>[-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.
| SAMPLE<br>Mean | | Repeat-<br>ability | | Between<br>Run | | Between<br>Day | | Between<br>Instrument | | Between<br>Lot | | 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 = %
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| 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
| %HbA1c<br>Decision 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
| %HbA1c<br>Decision 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.
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# 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
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| Hb Variant | Relative %Bias [Range of %Bias]<br>Observed to Reference Method | |
|------------|-----------------------------------------------------------------|------------------------------|
| | HbA1c ~6% | HbA1c ~8% |
| HbC | -1.0%<br>[-5.0% to 4.9%] | -0.9%<br>[-4.6% to 4.4%] |
| HbD | -2.2%<br>[-4.9% to 4.4%] | -2.5%<br>[-4.4% to -1.3%] |
| HbE | -2.1%<br>[-4.9% to 3.1%] | -2.5%<br>[-4.3% to -1.0%] |
| HbS | -1.3%<br>[-4.7% to 4.9%] | -2.0%<br>[-4.9% to 3.5%] |
| HbA2 | 0.1%<br>[-4.8% to 3.6%] | -2.0%<br>[-3.0% to -1.1%] |
| HbF | -23.2%<br>[-30.3% to 1.2%] | -24.7%<br>[-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<br>(y axis) | Comparator<br>(x axis) | N | Slope<br>[95% CI] | y-intercept<br>[95% CI] |
|---------------------------|------------------------|----|---------------------------|-----------------------------|
| K3-EDTA | K2-EDTA | 79 | 0.994<br>[0.982 to 1.007] | 0.030<br>[-0.055 to 0.102] |
| Na Fluoride/<br>Na2-EDTA | K2-EDTA | 79 | 0.997<br>[0.986 to 1.011] | 0.006<br>[-0.080 to 0.074] |
| Lithium Heparin | K2-EDTA | 79 | 1.006<br>[0.995 to 1.019] | -0.038<br>[-0.120 to 0.041] |
| Na Fluoride/<br>K-Oxalate | K2-EDTA | 79 | 1.010<br>[0.994 to 1.023] | -0.037<br>[-0.113 to 0.059] |
Table N. Anticoagulant Equivalence Summary, Passing-Bablok
Table O. Anticoaqulant Equivalence Summary, Deming
| Anticoagulant<br>(y axis) | Comparator<br>(x axis) | N | Slope<br>[95% CI] | y-intercept<br>[95% CI] |
|---------------------------|------------------------|----|---------------------------|-----------------------------|
| K3-EDTA | K2-EDTA | 79 | 0.997<br>[0.978 to 1.015] | 0.011<br>[-0.102 to 0.124] |
| Na Fluoride/<br>Na2-EDTA | K2-EDTA | 79 | 1.003<br>[0.985 to 1.020] | -0.033<br>[-0.135 to 0.069] |
| Lithium Heparin | K2-EDTA | 79 | 1.008<br>[0.990 to 1.027] | -0.042<br>[-0.152 to 0.068] |
| Na Fluoride/<br>K-Oxalate | K2-EDTA | 79 | 1.007<br>[0.989 to 1.025] | -0.018<br>[-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.
