(173 days)
Not Found
No
The summary describes a standard in vitro diagnostic assay using enzymatic methods and does not mention any AI or ML components.
No.
This device is an in vitro diagnostic assay used for the quantitative determination of HbA1c to aid in the diagnosis and monitoring of diabetes, not for direct treatment or therapy.
Yes
The "Intended Use / Indications for Use" states that the assay is "an aid in the 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." This clearly indicates its role in diagnosis.
No
The device is an in vitro diagnostic assay consisting of liquid reagents and is used on a chemistry analyzer system. It is not solely software.
Yes, this device is an IVD (In Vitro Diagnostic).
The "Intended Use / Indications for Use" section explicitly states: "The ADVIA® Chemistry Enzymatic Hemoglobin A1c (A1c E) assay is an in vitro diagnostic assay for the quantitative determination of mmol/mol HbA1c (IFCC) and % HbA1c (DCCT/NGSP) in human anticoagulated venous whole blood and hemolysate for use on the ADVIA® Chemistry systems."
This statement clearly identifies the device as an in vitro diagnostic assay.
N/A
Intended Use / Indications for Use
The ADVIA® Chemistry Enzymatic Hemoglobin A1c (A1c E) assay is an in vitro diagnostic assay for the quantitative determination of mmol/mol HbA1c (IFCC) and % HbA1c (DCCT/NGSP) in human anticoagulated venous whole blood and hemolysate for use on the ADVIA® Chemistry systems. Measurement of Hemoglobin A1c is used as an aid in the 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 (comma separated list FDA assigned to the subject device)
PDJ, LCP
Device Description
The ADVIA® Chemistry Enzymatic Hemoglobin A1c (A1c_E) assay measures hemoglobin A1c in human anticoagulated whole blood and hemolysate. The assay consists of three reagents (R1, R2, and Pretreatment). These reagents are liquid and are ready to use. The assay offers both an automated and a manual application. The automated application (A1c_E) lyses the anticoagulated whole blood specimen on the system for the automated application (A1c_E). Samples may also be lysed manually using the ADVIA® Chemistry A1c_E pretreatment solution to obtain hemolysate for the manual application (A1c EM). The two applications yield the same results.
Mentions image processing
Not Found
Mentions AI, DNN, or ML
Not Found
Input Imaging Modality
Not Found
Anatomical Site
Not Found
Indicated Patient Age Range
Not Found
Intended User / Care Setting
Not Found
Description of the training set, sample size, data source, and annotation protocol
Not Found
Description of the test set, sample size, data source, and annotation protocol
Not Found
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
Non-Clinical Performance Evaluation:
(i) Method Comparison: 163 human whole blood samples were tested on the ADVIA® 1800 Clinical Chemistry System in both automated (A1c E) and manual (A1c EM) modes. Results were compared to NGSP reference method testing. Correlation (r) values were 0.99 for automated NGSP and IFCC units, and 1.00 for manual NGSP and IFCC units. Slope and y-intercept values were also provided.
(ii) Precision: Testing was performed over 20 days, 2 runs per day, using 2 commercial quality controls and 4 whole blood patient pools (target values 5.0%, 8.0%, 8.0%, and 12.0% HbA1c). Testing used 3 reagent lots and 3 ADVIA® 1800 instruments. Data were analyzed using ANOVA. Total CV ranged from 1.0% to 1.6% for automated NGSP units and 1.2% to 3.1% for automated IFCC units. For manual NGSP units, total CV ranged from 0.9% to 1.6%, and for manual IFCC units, 1.2% to 3.0%.
(iii) Total Error at Decision Levels: Calculated using bias estimation from method comparison and precision estimates from precision study. Percent total error (%TE) ranged from 2.24% to 2.88% (automated, Passing-Bablok), 1.97% to 3.06% (manual, Passing-Bablok), 2.24% to 2.88% (automated, Deming), and 1.81% to 3.22% (manual, Deming).
(iv) Endogenous Interference: Evaluated with various endogenous interferents (Ascorbic Acid, Bilirubin, Total Protein, Triglycerides, Urea, Vitamin E) at two HbA1c levels (~6.5% and ~8.0%). No significant interference (greater than ± 5.0%) was observed.
(v) Exogenous Interference: Evaluated with various exogenous interferents (Acarbose, Acetaminophen, Acetylsalicylate, Atorvastatin, Captopril, Chlorpropamide, Cyanate, Furosemide, Gemfibrozil, Glucose, Ibuprofen, Insulin, Intralipid, Losartan, Metamizole, Metformin, N-acetylcysteine, Nicotinic Acid, Propranolol, Repaglinide, Rheumatoid Factor) at two HbA1c levels (~6.5% and ~8.0%). No significant interference (greater than ± 5.0%) was observed.
(vi) Hemoglobin Derivative Interference: No significant interference was observed for HbA0, HbA1b, Acetylated Hemoglobin, Carbamylated Hemoglobin, and Labile Hemoglobin.
(vii) Hemoglobin Variant Interference: Tested with HbC (n=45), HbD (n=24), HbE (n=20), HbS (n=25), HbA2 (n=20), and HbF (n=20). No significant interference bias (greater than ± 5.0%) was observed for HbC, HbD, HbE, HbS, and HbA2. Significant interference bias was observed for HbF.
(viii) Linearity: A dilution series of 11 levels across the assay range (2.77 to 14.60% HbA1c) was tested. No deviations from linearity were observed. The regression analysis equation was Observed %HbA1c = 1.0088 x Expected %HbA1c = 0.1110 with an R2 of 0.9998.
(ix) Limit of Blank (LoB) and Limit of Detection (LoD): LoB for HbA1c was 3.18%, and LoD was 3.60%.
(x) Anticoagulant Comparison: Tested equivalence between K2 EDTA, K3 EDTA, Na Fluoride/Na2 EDTA, and Lithium Heparin collection tubes using 96 or 97 samples for each comparison. Demonstrated equivalence based on regression analysis.
Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)
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Predicate Device(s): If the device was cleared using the 510(k) pathway, identify the Predicate Device(s) K/DEN number used to claim substantial equivalence and list them here in a comma separated list exactly as they appear in the text. List the primary predicate first in the list.
Reference Device(s): Identify the Reference Device(s) K/DEN number and list them here in a comma separated list exactly as they appear in the text.
Not Found
Predetermined Change Control Plan (PCCP) - All Relevant Information for the subject device only (e.g. presence / absence, what scope was granted / cleared under the PCCP, any restrictions, etc).
Not Found
§ 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 shows the logos of the Department of Health & Human Services and the Food and Drug Administration (FDA). The Department of Health & Human Services logo is on the left, and the FDA logo is on the right. The FDA logo includes the letters "FDA" in a blue square, followed by the words "U.S. FOOD & DRUG ADMINISTRATION" in blue text.
December 4, 2017
Siemens Healthcare Diagnostics Inc. Alan Haley Regulatory Clinical Affairs Specialist 500 GBC Drive Newark, Delaware 19714-6101
Re: K171771
Trade/Device Name: ADVIA Chemistry Enzymatic Hemoglobin A1c (A1c E) Assay Regulation Number: 21 CFR 862.1373 Regulation Name: Hemoglobin A1c Test System Regulatory Class: Class II Product Code: PDJ, LCP Dated: October 16, 2017 Received: October 17, 2017
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 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR
1
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 the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.
For comprehensive regulatory information about mediation-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) K171771
Device Name
ADVIA® Chemistry Enzymatic Hemoglobin A1c (A1c E) Assay
Indications for Use (Describe)
The ADVIA® Chemistry Enzymatic Hemoglobin A1c (A1c E) assay is an in vitro diagnostic assay for the quantitative determination of mmol/mol HbA1c (IFCC) and % HbA1c (DCCT/NGSP) in human anticoagulated venous whole blood and hemolysate for use on the ADVIA® Chemistry systems. Measurement of Hemoglobin A1c is used as an aid in the 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 – K171771
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 | November 29, 2017 |
2. Device Information
| Trade Name | ADVIA® Chemistry Enzymatic Hemoglobin A1c (A1c_E) Assay | |
|---|---|---|
| Common Name | Hemoglobin A1c Test System Assay, Glycosylated Hemoglobin | |
| Classification Name | Hemoglobin A1c Test System Glycosylated hemoglobin assay | |
| Regulation | 21 CFR 862.1373 21 CFR 864.7470 | |
| Device Class | Class II Class II | |
| Product Code | PDJ LCP | |
| Panel | Clinical Chemistry Hematology |
3. Identification of Predicate
| Trade Name | ARCHITECT Hemoglobin A1C |
|---|---|
| 510(k) Submitter | Abbott Laboratories Diagnostics Division |
| 510(k) Number | K130255 |
| Clearance Date | February 28, 2014 |
4. Device Description
The ADVIA® Chemistry Enzymatic Hemoglobin A1c (A1c_E) assay measures hemoglobin A1c in human anticoagulated whole blood and hemolysate. The assay consists of three reagents (R1, R2, and Pretreatment). These reagents are liquid and are ready to use. The assay offers both an automated and a manual application. The automated application (A1c_E) lyses the anticoagulated whole blood specimen on the system for the automated application (A1c_E). Samples may also be lysed manually using the ADVIA® Chemistry A1c_E pretreatment solution to obtain hemolysate for the manual application (A1c EM). The two applications yield the same results.
4
SIEMENS
5. Intended Use Statement
The ADVIA® Chemistry Enzymatic Hemoglobin A1c (A1c E) assay is an in vitro diagnostic assay for the quantitative determination of mmol/mol HbA1c (IFCC) and % HbA1c (DCCT/NGSP) in human anticoagulated venous whole blood and hemolysate for use on the ADVIA® Chemistry systems. Measurement of Hemoglobin A1c is used as an aid in the 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.
Technological Characteristics 6.
(a) Similarities and Differences
| Device
Characteristic | Proposed Device
ADVIA® Chemistry
Enzymatic Hemoglobin A1c
(A1c_E) Assay | Predicate Device
Abbott Architect
Hemoglobin A1c
(K130255) |
|--------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Intended Use | The ADVIA® Chemistry
Enzymatic Hemoglobin A1c
(A1c_E) assay is an in vitro
diagnostic assay for the
quantitative determination of
mmol/mol HbA1c (IFCC) and %
HbA1c (DCCT/NGSP) in human
anticoagulated venous whole
blood and hemolysate for use
on the ADVIA® Chemistry
systems. Measurement of
Hemoglobin A1c is used as an
aid in the 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 Hemoglobin A1c assay is
used in clinical laboratories for
the quantitative in vitro
measurement of percent
hemoglobin A1c (NGSP) or
HbA1c fraction mmol/mol
(IFCC) in human whole blood
and hemolysate on the
ARCHITECT c 8000 System.
Hemoglobin A1c measurements
are used as an aid in the
diagnosis of diabetes mellitus,
as an aid to identify patients
who may be at risk for
developing diabetes mellitus,
and for the monitoring of long-
term blood glucose control in
individuals with diabetes
mellitus. |
| Type of Test | Quantitative, enzymatic | Same |
| Measuring Range | 3.8 to 14.0% HbA1c
(DCCT/NGSP)
18.03 -129.50 mmol/mol HbA1c
(IFCC) | 4.0 to 14.0% HbA1c
(DCCT/NGSP)
20.22-129.50 mmol/mol HbA1c
(IFCC) |
| Specimen Types | Whole blood and Hemolysate | Same |
| Anticoagulant
Types | • Dipotassium EDTA
• Lithium Heparin
• Sodium Fluoride/Disodium
EDTA
• Tripotassium EDTA | • Dipotassium EDTA
• Lithium Heparin
• Sodium Fluoride/Disodium
EDTA
• Tripotassium EDTA
• Sodium Heparin |
5
| Device
Characteristic | Proposed Device
ADVIA® Chemistry
Enzymatic Hemoglobin A1c
(A1c_E) Assay | Predicate Device
Abbott Architect
Hemoglobin A1c
(K130255) |
|--------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Standardization
and Certification | Assay standardization is
traceable to International
Federation of Clinical Chemistry
(IFCC) reference calibrators.
Assay is certified with the
National Glycohemoglobin
Standardization Program
(NGSP). The NGSP certification
expires in one year. | The Architect HbA1c assay
standardization is traceable to
the International Federation of
Clinical Chemistry (IFCC)
reference calibrators. The
Architect HbA1c assay is NGSP
certified. The NGSP certification
expires in one year. |
| Instrument
Platform | ADVIA® 1800 Clinical
Chemistry System | ARCHITECT c 8000 System
(clinical chemistry analyzer) |
| Reporting Units | % HbA1c NGSP/DCCT and
mmol/mol IFCC | % HbA1c NGSP/DCCT and
mmol/mol IFCC |
(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.
One hundred sixty-three (163) human whole blood samples with values spanning the assay range were tested on the ADVIA® 1800 Clinical Chemistry System. Testing was performed in both automated (A1c E) and manual (A1c EM) modes.
Results on the ADVIA® 1800 were compared to results from NGSP reference method testing performed at an NGSP primary reference laboratory. Sample distribution is shown in Tables A and B. Slope and Y-intercept results were generated with both Passing-Bablok regression and Deming analysis. Correlation (r) values are Pearson correlation coefficients. Results are presented in Tables C, D, E, and F.
| Range of Results
(%HbA1c) | Percentage of
Samples | Number of
Samples |
|------------------------------|--------------------------|----------------------|
| 9 | 10% | 17 |
| Total | 100% | 163 |
Table A. Method Comparison Sample Distribution, Automated (Whole Blood)
6
SIEMEN
| Range of Results
(%HbA1c) | Percentage of
Samples | Number of
Samples |
|------------------------------|--------------------------|----------------------|
| 9 | 11% | 18 |
| Total | 100% | 163 |
Table B. Method Comparison Sample Distribution, Manual (Hemolysate)
Table C. Method Comparison, Passing-Bablok
| Units | Option | N | r | Slope
[95% CI] | y-int.
[95% CI] | Sample
Range |
|-----------------------------|----------------------------|-----|------|---------------------------|------------------------------|--------------------|
| NGSP
(%HbA1c) | Automated
(Whole Blood) | 163 | 0.99 | 1.019
[1.000 to 1.037] | -0.110
[-0.248 to 0.010] | 3.80 to
13.60 |
| NGSP
(%HbA1c) | Manual
(Hemolysate) | 163 | 1.00 | 1.022
[1.004 to 1.041] | -0.132
[-0.280 to -0.019] | 3.80 to
13.60 |
| IFCC
(mmol/mol
HbA1c) | Automated
(Whole Blood) | 163 | 0.99 | 1.019
[1.000 to 1.037] | -0.761
[-1.848 to 0.109] | 18.01 to
125.14 |
| IFCC
(mmol/mol
HbA1c) | Manual
(Hemolysate) | 163 | 1.00 | 1.022
[1.004 to 1.041] | -0.923
[-2.092 to -0.109] | 18.01 to
125.14 |
Table D. Bias Estimations, Passing-Bablok
| %HbA1c | Automated
(Whole Blood) | | Manual
(Hemolysate) | |
|--------|----------------------------|--------|------------------------|--------|
| | Bias | % Bias | Bias | % Bias |
| 5.00 | -0.01 | -0.20 | -0.02 | -0.40 |
| 6.50 | 0.01 | 0.15 | 0.01 | 0.15 |
| 8.00 | 0.04 | 0.50 | 0.04 | 0.50 |
| 12.00 | 0.12 | 1.00 | 0.13 | 1.08 |
Table E. Method Comparison, Deming
| Units | Option | N | r | Slope
[95% CI] | y-int.
[95% CI] | Sample
Range |
|-----------------------------|----------------------------|-----|------|---------------------------|------------------------------|--------------------|
| NGSP
(%HbA1c) | Automated
(Whole Blood) | 163 | 0.99 | 1.020
[1.004 to 1.036] | -0.120
[-0.265 to -0.006] | 3.80 to
13.60 |
| NGSP
(%HbA1c) | Manual
(Hemolysate) | 163 | 1.00 | 1.027
[1.012 to 1.042] | -0.176
[-0.280 to -0.072] | 3.80 to
13.60 |
| IFCC
(mmol/mol
HbA1c) | Automated
(Whole Blood) | 163 | 0.99 | 1.020
[1.004 to 1.036] | -0.840
[-1.738 to 0.058] | 18.01 to
125.14 |
| | Manual
(Hemolysate) | 163 | 1.00 | 1.027
[1.012 to 1.042] | -1.290
[-2.098 to -0.438] | 18.01 to
125.14 |
7
Table F. Bias Estimations, Deming
| %HbA1c | Automated
(Whole Blood) | | Manual
(Hemolysate) | |
|--------|----------------------------|--------|------------------------|--------|
| | Bias | % Bias | Bias | % Bias |
| 5.00 | -0.02 | -0.40 | -0.04 | -0.80 |
| 6.50 | 0.01 | 0.15 | 0.00 | 0.00 |
| 8.00 | 0.04 | 0.50 | 0.04 | 0.50 |
| 12.00 | 0.12 | 1.00 | 0.15 | 1.25 |
(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 whole blood patient pools with target values of 5.0% HbA1c, 8.0% HbA1c, 8.0% HbA1c, and 12.0% HbA1c. Whole blood pools were aliquoted and frozen prior to the start of the study. Each testing day, whole blood pool aliquots were thawed. QC materials were handled according to manufacturer's instructions.
Testing was performed over twenty (20) days, two (2) runs per day (with a minimum of 2 hours in between), a single test from two (2) independent cups were analyzed for each test material. Testing was performed using three (3) reagent lots and three (3) ADVIA® 1800 instruments for a total of nine (9) sets of data. Testing was performed in both automatic and manual modes. Two calibrations were performed over the duration of the study. Data were analyzed using Analysis of Variance (ANOVA), consistent with the recommendations of CLSI EP05-A3. Results are presented in Tables I, J, K, and L.
| Repeat- | Between | Between | Between | Between | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ability | Run | Day | Instrument | Lot | Total | ||||||||
| SAMPLE | Mean | SD | CV | SD | CV | SD | CV | SD | CV | SD | CV | SD | CV |
| QC 1 | 4.49 | 0.02 | 0:5 | 0.03 | 0.7 | 0.04 | 0.8 | 0.05 | 1.1 | 0.00 | 0.0 | 0.07 | 1.6 |
| QC 2 | 9.05 | 0.03 | 0.3 | 0.06 | 0.6 | 0.06 | 0.7 | 0.09 | 1.0 | 0.00 | 0.0 | 0.13 | 1.4 |
| MDP1 | 5.36 | 0.02 | 0.4 | 0.02 | 0.4 | 0.04 | 0.7 | 0.04 | 0.8 | 0.00 | 0.0 | 0.06 | 1.2 |
| MDP2 | 6.56 | 0.02 | 0.3 | 0.02 | 0.4 | 0.05 | 0.7 | 0.04 | 0.6 | 0.01 | 0.2 | 0.07 | 1.1 |
| MDP3 | 8.01 | 0.02 | 0.3 | 0.03 | 0.4 | 0.06 | 0.7 | 0.03 | 0.4 | 0.02 | 0.3 | 0.08 | 1.0 |
| MDP4 | 12.11 | 0.04 | 0.4 | 0.05 | 0.4 | 0.09 | 0.7 | 0.03 | י 0.2 י | 0.02 | ' 0.2 ' | 0.12 | 1.0 |
Table I. Precision, All Instruments, Automated (Whole Blood), NGSP Units (%HbA1c)
Table J. Precision, All Instruments, Automated (Whole Blood), IFCC Units (mmol/mol)
| 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 |
| QC 1 | 25.56 | 0.25 | 1.0 | 0.35 | 1.4 | 0.41 | 1.6 | 0.53 | 2.1 | 0.00 | 0.0 | 0.80 | 3.1 |
| QC 2 | 75.18 | 0.30 | 0.4 | 0.64 | 0.8 | 0.70 | 0.9 | 0.98 | 1.3 | 0.00 | 0.0 | 1.39 | 1.8 |
| MDP1 | 35.17 | 0.21 | 0.6 | 0.24 | 0.7 | 0.43 | 1.2 | 0.44 | 1.3 | 0.00 | 0.0 | 0.69 | 2.0 |
| MDP2 | 48.40 | 0.22 | 0.5 | 0.27 | 0.6 | 0.54 | 1.1 | 0.40 | 0.8 | 0.12 | 0.3 | 0.76 | 1.6 |
| MDP3 | 64.14 | 0.24 | 0.4 | 0.33 | 0.5 | 0.64 | 1.0 | 0.34 | 0.5 | 0.24 | 0.4 | 0.86 | 1.4 |
| MDP4 | 108.90 | 0.49 | 0.4 | 0.53 | 0.5 | 0.98 | 0.9 | 0.29 | 0.3 | 0.23 | 0.2 | 1.27 | 1.2 |
8
| | | Repeat-
ability | | Between
Run | | Between
Day | | Between
Instrument | | Between
Lot | | Total | |
|--------|-------|--------------------|-----|----------------|-----|----------------|-----|-----------------------|-----|----------------|-----|-------|-----|
| | | | | | | | | | | | | | |
| SAMPLE | Mean | SD | CV | SD | CV | SD | CV | SD | CV | SD | CV | SD | CV |
| QC 1 | 4.72 | 0.02 | 0.4 | 0.03 | 0.7 | 0.04 | 0.9 | 0.05 | 1.1 | 0.00 | 0.0 | 0.08 | 1.6 |
| QC 2 | 9.27 | 0.03 | 0.4 | 0.03 | 0.4 | 0.08 | 0.9 | 0.08 | 0.9 | 0.00 | 0.0 | 0.13 | 1.4 |
| MDP1 | 5.29 | 0.02 | 0.4 | 0.03 | 0.5 | 0.04 | 0.7 | 0.01 | 0.2 | 0.02 | 0.3 | 0.05 | 1.0 |
| MDP2 | 6.48 | 0.02 | 0.3 | 0.03 | 0.4 | 0.05 | 0.7 | 0.00 | 0.0 | 0.02 | 0.3 | 0.06 | 0.9 |
| MDP3 | 7.91 | 0.03 | 0.3 | 0.03 | 0.4 | 0.06 | 0.7 | 0.01 | 0.1 | 0.02 | 0.3 | 0.07 | 0.9 |
| MDP4 | 12.03 | 0.05 | 0.4 | 0.04 | 0.3 | 0.09 | 0.7 | 0.05 | 0.4 | 0.01 | 0.1 | 0.12 | 1.0 |
Table K. Precision, All Instruments, Manual (Hemolysate), NGSP Units (%HbA1c)
Table L. Precision, All Instruments, Manual (Hemolysate), IFCC Units (%HbA1c)
| Repeat- | Between | Between | Between | Between | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ability | Run | Day | Instrument | Lot | Total | ||||||||
| SAMPLE | Mean | SD | CV | SD | CV | SD | CV | SD | CV | SD | CV | SD | CV |
| QC 1 | 28.06 | 0.23 | 0.8 | 0.36 | 1.3 | 0.45 | 1.6 | 0.58 | 2.1 | 0.00 | 0.0 | 0.85 | 3.0 |
| QC 2 | 77.78 | 0.37 | 0.5 | 0.36 | 0.5 | 0.92 | 1.2 | 0.91 | 1.2 | 0.00 | 0.0 | 1.39 | 1.8 |
| MDP1 | 34.31 | 0.22 | 0.6 | 0.27 | 0.8 | 0.41 | 1.2 | 0.14 | 0.4 | 0.18 | 0.5 | 0.59 | 1.7 |
| MDP2 | 47.34 | 0.25 | 0.5 | 0.27 | 0.6 | 0.50 | 1.1 | 0.00 | 0.0 | 0.20 | 0.4 | 0.66 | 1.4 |
| MDP3 | 62.96 | 0.30 | 0.5 | 0.31 | 0.5 | 0.61 | 1.0 | 0.12 | 0.2 | 0.27 | 0.4 | 0.81 | 1.3 |
| MDP4 | 107.94 | 0.54 | 0.5 | 0.43 | 0.4 | 0.96 | 0.9 | 0.57 | 0.5 | 0.14 | 0.1 | 1.32 | 1.2 |
(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 M and N. Total error was calculated as follows:
$$1%TAE = |%Bias| + 1.96 \times %CV \times \left(1 + \frac{%Bias}{100}\right)|$$
Table M. Total Error Summary, Passing-Bablok
| Option | %HbA1c
Decision Level | % Bias | % CV | %TE |
|----------------------------|--------------------------|--------|------|------|
| Automated
(Whole Blood) | 5.0 | -0.20 | 1.19 | 2.52 |
| | 6.5 | 0.15 | 1.07 | 2.24 |
| | 8.0 | 0.50 | 0.99 | 2.44 |
| | 12.0 | 1.00 | 0.96 | 2.88 |
| Manual
(Hemolysate) | 5.0 | -0.40 | 1.01 | 2.38 |
| | 6.5 | 0.15 | 0.93 | 1.97 |
| | 8.0 | 0.50 | 0.93 | 2.33 |
| | 12.0 | 1.08 | 1.01 | 3.06 |
9
SILEN
| Table N. Total Error Summary, Deming | ||||
|---|---|---|---|---|
| -- | -- | -- | -------------------------------------- | -- |
| Option | %HbA1c
Decision Level | % Bias | % CV | %TE |
|----------------------------|--------------------------|--------|------|------|
| Automated
(Whole Blood) | 5.0 | -0.40 | 1.19 | 2.72 |
| | 6.5 | 0.15 | 1.07 | 2.24 |
| | 8.0 | 0.50 | 0.99 | 2.44 |
| | 12.0 | 1.00 | 0.96 | 2.88 |
| Manual
(Hemolysate) | 5.0 | -0.80 | 1.01 | 2.78 |
| | 6.5 | 0.00 | 0.93 | 1.81 |
| | 8.0 | 0.50 | 0.93 | 2.33 |
| | 12.0 | 1.25 | 1.01 | 3.22 |
(iv) Endogenous Interference
Testing to determine the interference bias of various endogenous interferents on the ADVIA A1c E 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. Three replicates were tested at each of two HbA1c levels: 6.5% ± 1.0% and 8.0% ± 1.0%. No significant interference (greater than ± 5.0%) was observed for the potential interferents at the concentrations listed in Table O.
| Interferent | Interferent Level | Approximate
HbA1c Level |
|------------------------|-------------------|----------------------------|
| Ascorbic Acid | 3.0 mg/dL | ~6.5 % |
| Ascorbic Acid | 3.0 mg/dL | ~8.0 % |
| Conjugated Bilirubin | 10 mg/dL | ~6.5 % |
| Conjugated Bilirubin | 10 mg/dL | ~8.0 % |
| Unconjugated Bilirubin | 10 mg/dL | ~6.5 % |
| Unconjugated Bilirubin | 10 mg/dL | ~8.0 % |
| Total Protein | 22 g/dL | ~6.5 % |
| Total Protein | 22 g/dL | ~8.0 % |
| Triglycerides | 2000 mg/dL | ~6.5 % |
| Triglycerides | 2000 mg/dL | ~8.0 % |
| Urea | 667 mg/dL | ~6.5 % |
| Urea | 667 mg/dL | ~8.0 % |
| Vitamin E | 8.6 mg/dL | ~6.5 % |
| Vitamin E | 8.6 mg/dL | ~8.0 % |
| Interferent | Interferent Level | Approximate
HbA1c Level |
| Acarbose | 50 mg/dL | ~6.5 % |
| Acarbose | 50 mg/dL | ~8.0 % |
| Acetaminophen | 200 µg/mL | ~6.5 % |
| Acetaminophen | 200 µg/mL | ~8.0 % |
| Acetylsalicylate | 50.0 mg/dL | ~6.5 % |
| Acetylsalicylate | 50.0 mg/dL | ~8.0 % |
| Atorvastatin | 600 µg Eq/L | ~6.5 % |
| Atorvastatin | 600 µg Eq/L | ~8.0 % |
| Captopril | 0.5 mg/dL | ~6.5 % |
| Captopril | 0.5 mg/dL | ~8.0 % |
| Chlorpropamide | 74.7 mg/dL | ~6.5 % |
| Chlorpropamide | 74.7 mg/dL | ~8.0 % |
| Cyanate | 64.8 mg/dL | ~6.5 % |
| Cyanate | 64.8 mg/dL | ~8.0 % |
| Furosemide | 6.0 mg/dL | ~6.5 % |
| Furosemide | 6.0 mg/dL | ~8.0 % |
| Gemfibrozil | 7.5 mg/dL | ~6.5 % |
| Gemfibrozil | 7.5 mg/dL | ~8.0 % |
| Glucose | 1000 mg/dL | ~6.5 % |
| Glucose | 1000 mg/dL | ~8.0 % |
| Ibuprofen | 0.5 mg/mL | ~6.5 % |
| Ibuprofen | 0.5 mg/mL | ~8.0 % |
| Insulin | 450 μU/mL | ~6.5 % |
| Insulin | 450 μU/mL | ~8.0 % |
| Intralipid | 1000 mg/dL | ~6.5 % |
| Intralipid | 1000 mg/dL | ~8.0 % |
| Losartan | 5 mg/dL | ~6.5 % |
| Losartan | 5 mg/dL | ~8.0 % |
| Metamizole | 90 mg/dL | ~6.5 % |
| Metamizole | 90 mg/dL | ~8.0 % |
| Metformin | 5.1 mg/dL | ~6.5 % |
| Metformin | 5.1 mg/dL | ~8.0 % |
| N-acetylcysteine | 5 mmol/L | ~6.5 % |
| N-acetylcysteine | 5 mmol/L | ~8.0 % |
| Nicotinic Acid | 61 mg/dL | ~6.5 % |
| Nicotinic Acid | 61 mg/dL | ~8.0 % |
| Propranolol | 0.2 mg/dL | ~6.5 % |
| Propranolol | 0.2 mg/dL | ~8.0 % |
| Repaglinide | 60 ng/mL | ~6.5 % |
| Repaglinide | 60 ng/mL | ~8.0 % |
| Rheumatoid Factor | 200 IU/mL | ~6.5 % |
| Rheumatoid Factor | 200 IU/mL | ~8.0 % |
Table O. Endogenous Interference
(v) Exogenous Interference
Testing to determine the interference bias of various exogenous interferents on the ADVIA A1c E 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. Three replicates were tested at each of two HbA1c levels: 6.5% ± 1.0% and 8.0% ± 1.0%. No significant (bias greater than ± 5.0%) interference was observed for the potential interferents at the concentrations listed in Table P.
10
SIEMENS
Table P. Exogenous Interference
11
SIEMEN
(vi) Hemoglobin Derivative Interference
Hemoglobin derivative interference was determined per CLSI EP7-A2. No significant interference was observed for HbA0. HbA1b and for the hemoglobin derivatives listed below.
- Acetylated Hemoglobin with ≥ 50 mg/dL of acetylsalicylic acid .
- . Carbamylated Hemoglobin with ≥ 10 mmol/L of Cyanate
- Labile Hemoglobin with ≥ 1000 mg/dL of Glucose .
(vii) Hemoglobin Variant Interference
Interference testing to determine the effect of hemoglobin variants on the ADVIA A1c E Assav 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. Three 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 Q and R.
| Hb Variant | n | Range (% Variant) | Range (%HbA1c) |
|---|---|---|---|
| HbC | 45 | 26.1 - 40.0% | 4.4 – 15.7% |
| HbD | 24 | 22.7 – 37.5% | 4.8 – 13.0% |
| HbE | 20 | 19.7 – 30.4% | 4.7 - 11.0% |
| HbS | 25 | 23.0 – 37.4% | 5.3 - 13.5% |
| HbA2 | 20 | 4.3 - 6.2% | 5.0 – 10.0% |
| HbF | 20 | 5.7 - 30.9% | 5.3 - 9.3% |
Table Q. Hemoglobin Variant Samples
Table R. Hemoglobin Variant Interference
| Hb Variant | Relative %Bias [Range of %Bias]
Observed to Reference Method | |
|------------|-----------------------------------------------------------------|----------------------------|
| | HbA1c ~6% | HbA1c ~9% |
| HbC | 0.65%
[-6.17% to 7.46%] | 1.36%
[-7.00% to 8.41%] |
| HbD | 0.28%
[-8.16% to 6.47%] | 2.27%
[-1.52% to 5.94%] |
| HbE | 2.02%
[-5.65% to 7.89%] | 4.35%
[-1.63% to 7.41%] |
| HbS | 2.96%
[-0.22% to 6.55%] | 2.51%
[-2.04% to 7.94%] |
| HbA2 | -1.49%
[-3.87% to 5.00%] | 1.47%
[-1.26% to 6.63%] |
| HbF | Bias exceeds 5% | |
12
(viii) Linearity
Linearity testing was conducted CLSI EP06-A, Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical Approach; Approved Guideline.
A dilution series consisting of eleven (11) levels across the assay range were prepared by mixing high HbA1c and low HbA1c whole blood pools. The high pools were prepared by spiking whole blood with HbA1c. The low pools were prepared by mixing whole blood with cord blood. The expected value for each level was calculated from the measurand concentrations and volumes of the low and high samples. Three replicates were tested at each level. Samples ranged from 2.77 to 14.60% HbA1c.
No deviations from linearity were observed for results from 2.77 to 14.60% HbA1c. The regression analysis equation is Observed %HbA1c = 1.0088 x Expected %HbA1c = 0.1110 with an R2 of 0.9998.
(ix) 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.
To determine LoB, four (4) blank samples were processed using three (3) reagent lots and one (1) instrument. Testing was performed for three (3) days at five (5) replicates per day for a total of 60 measurements per reagent lot (180 measurements total).
To determine LoD, four (4) low samples were processed using three (3) reagent lots and one (1) instrument. Testing was performed for three (3) days at five (5) replicates per day for a total of 60 measurements per reagent lot (180 measurements total). Results are presented in Table S.
| HbA1c (%) | tHb (µmol/L) | A1c (µmol/L) | |
|---|---|---|---|
| Limit of | |||
| Blank (LoB) | 3.18 | 60.15 | 1.77 |
| Limit of | |||
| Detection (LoD) | 3.60 | 69.42 | 2.50 |
Table S. Limit of Blank / Limit of Detection
(x) Anticoaqulant Comparison
Testing was performed to demonstrate equivalence between five different anticoagulants in accordance with CLSI EP09-A2, Method Comparison and Bias Estimation Using Patient Samples.
Testing was performed to demonstrate equivalence between Ko EDTA, K3 EDTA, Na Fluoride/Na2 EDTA, and Lithium Heparin collection tubes. HbA1c values were measured for each sample using the ADVIA A1c E assay on the ADVIA 1800. Regression analysis was used to analyze the measured values using the K, EDTA samples as the comparator. Results are presented in Tables T and U.
13
| Anticoagulant | Comparator | N | r | Slope
[95% CI] | y-intercept
[95% CI] |
|--------------------------|------------|----|--------|---------------------------|------------------------------|
| K3-EDTA | K2-EDTA | 96 | 0.9996 | 1.010
[1.000 to 1.018] | -0.021
[-0.077 to 0.035] |
| Na Fluoride/
Na2-EDTA | K2-EDTA | 97 | 0.9989 | 0.998
[0.986 to 1.005] | -0.002
[-0.049 to 0.072] |
| Lithium Heparin | K2-EDTA | 96 | 0.9992 | 1.025
[1.016 to 1.034] | -0.096
[-0.146 to -0.039] |
Table T. Passing-Bablok Regression Analysis Summary for Anticoagulant Equivalency
Table U. Deming Regression Analysis Summary for Anticoagulant Equivalency
| Anticoagulant | Comparator | N | r | Slope
[95% CI] | y-intercept
[95% CI] |
|--------------------------|------------|----|--------|---------------------------|------------------------------|
| K3-EDTA | K2-EDTA | 96 | 0.9996 | 1.011
[1.000 to 1.023] | -0.034
[-0.102 to 0.033] |
| Na Fluoride/
Na2-EDTA | K2-EDTA | 97 | 0.9989 | 0.996
[0.986 to 1.006] | 0.008
[-0.045 to 0.062] |
| Lithium Heparin | K2-EDTA | 96 | 0.9992 | 1.033
[1.023 to 1.042] | -0.131
[-0.183 to -0.079] |
(xi) Conclusion
The proposed ADVIA® Chemistry Enzymatic Hemoglobin A1c (A1c_E) assay is substantially equivalent to the legally marketed predicate based on intended use, principle and the performance characteristics presented above.