(203 days)
Not Found
No
The summary describes a standard in vitro diagnostic assay for measuring HbA1c using chemical reagents and a clinical chemistry system. There is no mention of AI, ML, image processing, or any other technology typically associated with AI/ML in the context of medical devices. The performance studies described are standard analytical validation methods for IVD assays.
No
The device is described as an "in vitro diagnostic assay" used for "quantitative determination" of HbA1c to "aid in diagnosis and monitoring," not to treat conditions.
Yes
The "Intended Use / Indications for Use" section explicitly states that the assay is "an in vitro diagnostic assay" and 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." The "Device Description" also refers to it as "an in vitro diagnostic device."
No
The device is an in vitro diagnostic assay consisting of liquid reagents packaged in cartridges, which are physical components. It is used on a clinical chemistry system, which is also a hardware device.
Yes, this device is an IVD (In Vitro Diagnostic).
Here's why:
- Intended Use/Indications for Use: The description explicitly states it is an "in vitro diagnostic assay" for the quantitative determination of %HbA1c and mmol/mol HbA1c in human anticoagulated venous whole blood. It also clearly outlines its use as an aid in the diagnosis and monitoring of diabetes mellitus and identifying patients at risk.
- Device Description: The description reiterates that it is an "in vitro diagnostic device" intended to measure the concentration of hemoglobin A1c in venous human anticoagulated whole blood.
- Performance Studies: The document details various performance studies (Method Comparison, Precision, Interference, Linearity, LoB/LoD, Anticoagulant Comparison) conducted using human biological samples (whole blood) to evaluate the device's analytical performance. This is characteristic of IVD testing.
- Predicate Device: The mention of a predicate device (K160571; Cobas C13 Tina-Quant HbA1cDx Gen.3 Assay) which is also an HbA1c assay, further supports its classification as an IVD.
All these points align with the definition and characteristics of an In Vitro Diagnostic device, which is used to examine specimens derived from the human body to provide information for diagnostic purposes.
N/A
Intended Use / Indications for 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.
Product codes
PDJ
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.
Mentions image processing
Not Found
Mentions AI, DNN, or ML
Not Found
Input Imaging Modality
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Anatomical Site
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Indicated Patient Age Range
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Intended User / Care Setting
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Description of the training set, sample size, data source, and annotation protocol
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Description of the test set, sample size, data source, and annotation protocol
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.
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
- Method Comparison: Performed with 147 human whole blood samples across the assay range. Compared results to NGSP reference method. Passing-Bablok and Deming regressions were used. Key results included slopes and y-intercepts for NGSP (%HbA1c) and IFCC (mmol/mol HbA1c) units, and bias estimations.
- Precision: Sample size not explicitly stated for individual categories, but total of 80 results for each of the six samples (two commercial quality controls, four whole blood patient pools). Testing performed over 20 days by 2 operators using 3 instruments and 3 reagent lots. Data analyzed using ANOVA. Results reported as SD and CV for repeatability, between run, between day, between instrument, between lot, and total precision.
- Total Error at Decision Levels: Calculated using bias estimations from method comparison and precision estimates from precision study. Total error (TE) was calculated for %HbA1c decision levels of 5.0, 6.5, 8.0, and 12.0 for both Passing-Bablok and Deming methods.
- Endogenous and Exogenous Interference: Evaluated the effect of various interferents (e.g., Acetaminophen, Bilirubin, Glucose, Heparin) on the assay. Four replicates were tested at two HbA1c levels (6.5% ± 1.0% and 8.0% ± 1.0%). No significant interference (greater than ± 5.0%) was observed for listed interferents.
- Hemoglobin Variant Interference: Tested the effect of hemoglobin variants (HbC, HbD, HbE, HbS, HbA2, HbF) using anticoagulated human blood samples with known concentrations. Effects were evaluated by comparing observed mean %HbA1c to expected %HbA1c. No significant interference was observed for HbC, HbD, HbE, and HbA2. Significant interference was observed for HbF.
- Hemoglobin Derivatives: Tested the effect of acetylated hemoglobin, carbamylated hemoglobin, and labile hemoglobin fractions. Inaccuracies were less than or equal to 5% at HbA1c concentrations of 5.0% ± 1.0%, 6.5% ± 1.0%, and 8.0% ± 1.0%.
- Linearity: Nine samples with HbA1c levels across the assay range were prepared and tested. Four replicates were tested at each level. No deviations from linearity were observed for results from 3.6 to 15.9% HbA1c.
- Limit of Blank (LoB) and Limit of Detection (LoD): LoB for HbA1c (%) was 3.6, for tHb (g/dL) was 0.0, and for HbA1c (g/dL) was 0.21. LoD for HbA1c (%) was 3.7, for tHb (g/dL) was 0.5, and for HbA1c (g/dL) was 0.23.
- Anticoagulant Comparison: Evaluated equivalence between five different anticoagulants (K2-EDTA, K3-EDTA, Na Fluoride/Na2-EDTA, Lithium Heparin, Na Fluoride/K-Oxalate) using K2-EDTA as the comparator. HbA1c values ranged from 4.7 to 12.8%. Regression analysis (Passing-Bablok and Deming) was used to compare values.
Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)
- Precision:
- Example for MDP1 NGSP: Repeatability SD 0.05, CV 0.9%; Total SD 0.13, CV 2.4%
- Example for MDP1 IFCC: Repeatability SD 0.54, CV 1.5%; Total SD 1.42, CV 4.1%
- Total Error (%TE):
- Passing-Bablok: 5.0% HbA1c had 5.8% TE; 6.5% HbA1c had 4.5% TE; 8.0% HbA1c had 4.4% TE; 12.0% HbA1c had 4.9% TE.
- Deming: 5.0% HbA1c had 5.8% TE; 6.5% HbA1c had 4.7% TE; 8.0% HbA1c had 4.6% TE; 12.0% HbA1c had 5.2% TE.
- Interference Bias (Hb Variants):
- HbC: -1.0% bias at ~6% HbA1c; -0.9% bias at ~8% HbA1c.
- HbD: -2.2% bias at ~6% HbA1c; -2.5% bias at ~8% HbA1c.
- HbE: -2.1% bias at ~6% HbA1c; -2.5% bias at ~8% HbA1c.
- HbS: -1.3% bias at ~6% HbA1c; -2.0% bias at ~8% HbA1c.
- HbA2: 0.1% bias at ~6% HbA1c; -2.0% bias at ~8% HbA1c.
- HbF: -23.2% bias at ~6% HbA1c; -24.7% bias at ~8% HbA1c.
Predicate Device(s)
Reference Device(s)
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Predetermined Change Control Plan (PCCP) - All Relevant Information
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§ 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.
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)
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)
| Prescription Use (Part 21 CFR 801 Subpart D) |
|---|
| Over-The-Counter Use (21 CFR 801 Subpart C) |
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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 Drive |
| 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.
4
SIEMENS
6. Technological Characteristics
(a) Similarities and Differences
| Device
Characteristic | Predicate Device
Cobas C13 Tina-Quant
HbA1cDx Gen.3 Assay
(K160571) | Proposed Device
Dimension®
Hemoglobin A1C Assay |
|--------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Intended Use | This test is intended for use as an
aid in diagnosis of diabetes and
as an aid in identifying patients
who may be at risk for developing
diabetes. It is an in vitro
diagnostics reagent system
intended for quantitative
determination of mmol/mol
hemoglobin A1c (IFCC) and %
hemoglobin A1c (DCCT/NGSP) in
hemolysate or whole blood on the
Roche/Hitachi cobas c 513
clinical chemistry analyzer.
HbA1c determinations are useful
for monitoring of long-term blood
glucose control in individuals with
diabetes mellitus. | 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. |
| Type of Test | Quantitative turbidimetric
inhibition immunoassay | Same |
| Measurand | Whole blood Glycosylated
Hemoglobin (HbA1c) | Same |
| Reporting Units | % HbA1c NGSP/DCCT and
mmol/mol IFCC | Same |
| Measuring
Ranges | Hemoglobin
4 to 35 g/dL
(2.48 to 21.7 mmol/L) | Hemoglobin
5.0 to 25.0 g/dL
(3.1 to 15.5 mmol/L) |
| | HbA1c
0.3 to 3.4 g/dL
(0.186 to 2.11 mmol/L) | HbA1c
0.25 to 2.90 g/dL
(0.16 to 1.80 mmol/L) |
| | %HbA1c
4.2 to 15.5%
(23 to 146 mmol/mol) | %HbA1c
3.8 to 14.0%
(18 to 130 mmol/mol) |
| Instrument
Platform | Cobas c 513
(absorbance spectroscopy) | Dimension® RxL clinical
chemistry system
(absorbance spectroscopy) |
| Anticoagulants | Li-Heparin
K2-EDTA
K3-EDTA
EDTA/Fluoride | K2-EDTA
K3-EDTA
Na Fluoride/Na2-EDTA
Lithium Heparin
Na Fluoride/ K-Oxalate |
| Device
Characteristic | Predicate Device
Cobas C13 Tina-Quant
HbA1cDx Gen.3 Assay
(K160571) | Proposed Device
Dimension®
Hemoglobin A1C Assay |
| Calibration
Frequency | Each lot, every 29 days, and as
required following quality control
procedures | Each lot, every 30 days, and as
required following quality control
procedures |
| Reagent
Stability | Unopened
2 – 8°C until expiration date | Unopened
2 – 8°C until expiration date |
| | On-board in use
2 – 8°C for 28 days | On-board sealed
2 – 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 of
Samples | Number of
Samples |
|------------------------------|--------------------------|----------------------|
| 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.
| SAMPLE
Mean | | Repeat-
ability | | Between
Run | | Between
Day | | Between
Instrument | | Between
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 = %
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
| %HbA1c
| 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
| 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.
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.