(173 days)
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 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.
Here's a breakdown of the acceptance criteria and study details for the ADVIA Chemistry Enzymatic Hemoglobin A1c (A1c E) Assay, based on the provided text:
1. Table of Acceptance Criteria and Reported Device Performance
The document defines satisfactory performance based on multiple aspects rather than a single set of explicit "acceptance criteria" presented in a table format with specific numerical targets. Instead, the performance evaluations demonstrate that the device meets clinically acceptable metrics as per established guidelines (e.g., CLSI documents) and is comparable to a predicate device. For the purpose of this request, I will extract relevant performance metrics and indicate what constitutes acceptable performance from the context.
| Performance Characteristic | Acceptance Criteria (Implicit from Context / Guidelines) | Reported Device Performance |
|---|---|---|
| Method Comparison | High correlation (r), slopes and y-intercepts close to 1 and 0 respectively, and clinically acceptable bias when compared to reference method. | Automated (Whole Blood) vs. NGSP Reference:- Passing-Bablok: r = 0.99, Slope = 1.019 (95% CI: 1.000 to 1.037), y-int = -0.110 (95% CI: -0.248 to 0.010)- Deming: r = 0.99, Slope = 1.020 (95% CI: 1.004 to 1.036), y-int = -0.120 (95% CI: -0.265 to -0.006)Manual (Hemolysate) vs. NGSP Reference:- Passing-Bablok: r = 1.00, Slope = 1.022 (95% CI: 1.004 to 1.041), y-int = -0.132 (95% CI: -0.280 to -0.019)- Deming: r = 1.00, Slope = 1.027 (95% CI: 1.012 to 1.042), y-int = -0.176 (95% CI: -0.280 to -0.072) |
| Precision | Low coefficients of variation (CV) across different levels, runs, days, and instruments, demonstrating reproducibility. | Automated (Whole Blood) NGSP Units: Total CVs ranged from 1.0% to 1.6%.Automated (Whole Blood) IFCC Units: Total CVs ranged from 1.2% to 3.1%.Manual (Hemolysate) NGSP Units: Total CVs ranged from 0.9% to 1.6%.Manual (Hemolysate) IFCC Units: Total CVs ranged from 1.2% to 3.0%. |
| Total Error (TE) | Clinically acceptable total error at decision levels. | Passing-Bablok: TE ranged from 1.97% to 3.06% across decision levels (5-12% HbA1c).Deming: TE ranged from 1.81% to 3.22% across decision levels (5-12% HbA1c). |
| Endogenous Interference | No significant interference (bias greater than ± 5.0%). | No significant interference was observed for the tested endogenous interferents (Ascorbic Acid, Bilirubin, Total Protein, Triglycerides, Urea, Vitamin E) at specified concentrations and HbA1c levels. |
| Exogenous Interference | No significant interference (bias greater than ± 5.0%). | No significant interference was observed for the tested exogenous interferents (e.g., Acarbose, Acetaminophen, Insulin, Metformin, etc.) at specified concentrations and HbA1c levels. |
| Hemoglobin Derivative Interference | No significant interference. | No significant interference observed for HbA0, HbA1b, Acetylated Hemoglobin, Carbamylated Hemoglobin, and Labile Hemoglobin at tested levels. |
| Hemoglobin Variant Interference | No significant interference (bias greater than ± 5.0%). | No significant interference observed for HbC, HbD, HbE, and HbA2. Significant interference bias was observed for HbF. |
| Linearity | Deviations from linearity not observed within the assay range. | No deviations from linearity observed for results from 2.77 to 14.60% HbA1c. Regression equation: Observed %HbA1c = 1.0088 x Expected %HbA1c = 0.1110, R² = 0.9998. |
| Limit of Blank (LoB) | LoB value established. | 3.18% HbA1c |
| Limit of Detection (LoD) | LoD value established. | 3.60% HbA1c |
| Anticoagulant Comparison | Equivalence demonstrated for tested anticoagulants compared to K2-EDTA. | High correlation (r ≥ 0.9989) and slopes near 1 (0.998 to 1.033) for K3-EDTA, Na Fluoride/Na2-EDTA, and Lithium Heparin compared to K2-EDTA. |
2. Sample Size Used for the Test Set and Data Provenance
- Method Comparison: 163 human whole blood samples.
- Provenance: Not explicitly stated, but "human whole blood samples" usually implies clinically obtained samples. Given the context of a 510(k) submission, these would typically be retrospective or prospectively collected samples from a clinical population relevant to diabetes diagnosis and monitoring. No country of origin is specified.
- Precision: Two commercial quality controls and four whole blood patient pools. The number of individual patient samples in the pools is not specified, but the testing was extensive (20 days, 2 runs/day, 2 independent cups, 3 reagent lots, 3 instruments).
- Provenance: Whole blood pools were aliquoted and frozen, indicating patient samples. No country of origin is specified.
- Interference (Endogenous, Exogenous, Hemoglobin Derivative): Not specified as individual patient samples, but tested at two HbA1c levels using fortified samples or samples with known derivatives.
- Provenance: Not specified.
- Hemoglobin Variant Interference:
- HbC: 45 samples
- HbD: 24 samples
- HbE: 20 samples
- HbS: 25 samples
- HbA2: 20 samples
- HbF: 20 samples
- Provenance: "Anticoagulated human blood samples with known concentrations of hemoglobin variant and HbA1c." Implies clinical samples with confirmed variant types. No country of origin specified.
- Linearity: Dilution series created from high and low HbA1c whole blood pools. The number of original patient samples making up these pools is not specified.
- Provenance: "High HbA1c and low HbA1c whole blood pools," suggesting patient samples. No country of origin specified.
- Limit of Blank (LoB) and Limit of Detection (LoD): 4 blank samples and 4 low samples.
- Provenance: Not specified, likely commercial or laboratory-prepared samples.
- Anticoagulant Comparison: 96-97 samples depending on comparator.
- Provenance: Not specified, but "HbA1c values were measured for each sample," implying patient samples. No country of origin specified.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications
- Ground Truth Establishment: For the Method Comparison study, the device's results were compared to "NGSP reference method testing performed at an NGSP primary reference laboratory."
- Number of Experts: Not specified.
- Qualifications of Experts: The ground truth is based on an NGSP primary reference laboratory method, which implies that the method itself is the "expert" or gold standard, rather than individual human experts interpreting data. NGSP (National Glycohemoglobin Standardization Program) certification ensures traceability to the IFCC reference method, which is the highest standard for HbA1c measurement.
4. Adjudication Method for the Test Set
- Adjudication Method: Not applicable. The ground truth for the method comparison study was established by an NGSP primary reference laboratory method, which is an objective measurement, not a subjective interpretation requiring human adjudication. For other studies (precision, interference, linearity), performance was evaluated against statistical or predefined criteria, not against a human-adjudicated ground truth.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was Done
- MRMC Study: No, an MRMC comparative effectiveness study was not done. This device is an in vitro diagnostic assay (a laboratory test) that provides a quantitative numerical result. It does not involve human readers interpreting images, and therefore, an MRMC study comparing human readers with and without AI assistance is not relevant or applicable.
6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) was Done
- Standalone Performance: Yes, the entire performance evaluation presented in the document represents the standalone performance of the ADVIA Chemistry Enzymatic Hemoglobin A1c (A1c E) Assay. As an automated in vitro diagnostic assay, it operates without human "interpretation" in the loop once the sample is loaded and the assay runs. The results are generated by the assay system itself.
7. The Type of Ground Truth Used
- Ground Truth Type:
- For Method Comparison, the ground truth was established by NGSP primary reference laboratory method (which is directly traceable to the IFCC reference method). This is the gold standard for HbA1c measurement.
- For other studies (Precision, Interference, Linearity, LoB/LoD, Anticoagulant Comparison), the evaluations were performed against established analytical performance goals, spiked samples with known concentrations, or comparisons between different collection methods, rather than an external "ground truth" expert consensus or pathological diagnosis.
8. The Sample Size for the Training Set
- Training Set Sample Size: This information is not provided in the document. The document describes analytical performance studies of a finished in vitro diagnostic device, not the development or training of its underlying "algorithm" (which for a chemical assay is the assay's chemistry and detection principles, rather than a machine learning algorithm in the typical sense). Therefore, a "training set" in the context of AI/machine learning isn't directly applicable here. The assay's parameters would have been optimized during its development and verified through the studies presented.
9. How the Ground Truth for the Training Set Was Established
- Training Set Ground Truth Establishment: As mentioned above, the concept of a "training set" and its associated ground truth in the machine learning sense is not applicable to this type of in vitro diagnostic chemical assay. The "ground truth" for developing such assays typically relates to thoroughly characterized reference materials, known concentrations of analytes, and established analytical methods used during the research and development phase to optimize the assay's chemical reactions, instrumentation parameters, and calibration. The performance studies presented here are for the verification and validation of the final device.
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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
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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
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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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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 DriveNewark, 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.
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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
| DeviceCharacteristic | Proposed DeviceADVIA® ChemistryEnzymatic Hemoglobin A1c(A1c_E) Assay | Predicate DeviceAbbott ArchitectHemoglobin A1c(K130255) |
|---|---|---|
| Intended Use | The ADVIA® ChemistryEnzymatic Hemoglobin A1c(A1c_E) assay is an in vitrodiagnostic assay for thequantitative determination ofmmol/mol HbA1c (IFCC) and %HbA1c (DCCT/NGSP) in humananticoagulated venous wholeblood and hemolysate for useon the ADVIA® Chemistrysystems. Measurement ofHemoglobin A1c is used as anaid in the diagnosis andmonitoring of long-term bloodglucose control in patients withdiabetes mellitus, and as an aidin the identification of patients atrisk for developing diabetesmellitus. | The Hemoglobin A1c assay isused in clinical laboratories forthe quantitative in vitromeasurement of percenthemoglobin A1c (NGSP) orHbA1c fraction mmol/mol(IFCC) in human whole bloodand hemolysate on theARCHITECT c 8000 System.Hemoglobin A1c measurementsare used as an aid in thediagnosis of diabetes mellitus,as an aid to identify patientswho may be at risk fordeveloping diabetes mellitus,and for the monitoring of long-term blood glucose control inindividuals with diabetesmellitus. |
| 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 |
| AnticoagulantTypes | • Dipotassium EDTA• Lithium Heparin• Sodium Fluoride/DisodiumEDTA• Tripotassium EDTA | • Dipotassium EDTA• Lithium Heparin• Sodium Fluoride/DisodiumEDTA• Tripotassium EDTA• Sodium Heparin |
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| DeviceCharacteristic | Proposed DeviceADVIA® ChemistryEnzymatic Hemoglobin A1c(A1c_E) Assay | Predicate DeviceAbbott ArchitectHemoglobin A1c(K130255) |
|---|---|---|
| Standardizationand Certification | Assay standardization istraceable to InternationalFederation of Clinical Chemistry(IFCC) reference calibrators.Assay is certified with theNational GlycohemoglobinStandardization Program(NGSP). The NGSP certificationexpires in one year. | The Architect HbA1c assaystandardization is traceable tothe International Federation ofClinical Chemistry (IFCC)reference calibrators. TheArchitect HbA1c assay is NGSPcertified. The NGSP certificationexpires in one year. |
| InstrumentPlatform | ADVIA® 1800 ClinicalChemistry System | ARCHITECT c 8000 System(clinical chemistry analyzer) |
| Reporting Units | % HbA1c NGSP/DCCT andmmol/mol IFCC | % HbA1c NGSP/DCCT andmmol/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 ofSamples | Number ofSamples |
|---|---|---|
| <5 | 7% | 12 |
| 5 - 6 | 14% | 23 |
| 6 - 6.5 | 25% | 40 |
| 6.5 - 7 | 18% | 30 |
| 7 - 8 | 12% | 20 |
| 8 - 9 | 13% | 21 |
| >9 | 10% | 17 |
| Total | 100% | 163 |
Table A. Method Comparison Sample Distribution, Automated (Whole Blood)
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SIEMEN
| Range of Results(%HbA1c) | Percentage ofSamples | Number ofSamples |
|---|---|---|
| <5 | 9% | 14 |
| 5 - 6 | 15% | 24 |
| 6 - 6.5 | 21% | 35 |
| 6.5 - 7 | 20% | 33 |
| 7 - 8 | 13% | 21 |
| 8 – 9 | 11% | 18 |
| >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] | SampleRange |
|---|---|---|---|---|---|---|
| NGSP(%HbA1c) | Automated(Whole Blood) | 163 | 0.99 | 1.019[1.000 to 1.037] | -0.110[-0.248 to 0.010] | 3.80 to13.60 |
| NGSP(%HbA1c) | Manual(Hemolysate) | 163 | 1.00 | 1.022[1.004 to 1.041] | -0.132[-0.280 to -0.019] | 3.80 to13.60 |
| IFCC(mmol/molHbA1c) | Automated(Whole Blood) | 163 | 0.99 | 1.019[1.000 to 1.037] | -0.761[-1.848 to 0.109] | 18.01 to125.14 |
| IFCC(mmol/molHbA1c) | Manual(Hemolysate) | 163 | 1.00 | 1.022[1.004 to 1.041] | -0.923[-2.092 to -0.109] | 18.01 to125.14 |
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] | SampleRange |
|---|---|---|---|---|---|---|
| NGSP(%HbA1c) | Automated(Whole Blood) | 163 | 0.99 | 1.020[1.004 to 1.036] | -0.120[-0.265 to -0.006] | 3.80 to13.60 |
| NGSP(%HbA1c) | Manual(Hemolysate) | 163 | 1.00 | 1.027[1.012 to 1.042] | -0.176[-0.280 to -0.072] | 3.80 to13.60 |
| IFCC(mmol/molHbA1c) | Automated(Whole Blood) | 163 | 0.99 | 1.020[1.004 to 1.036] | -0.840[-1.738 to 0.058] | 18.01 to125.14 |
| Manual(Hemolysate) | 163 | 1.00 | 1.027[1.012 to 1.042] | -1.290[-2.098 to -0.438] | 18.01 to125.14 |
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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 | BetweenRun | BetweenDay | BetweenInstrument | BetweenLot | 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 |
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| Repeat-ability | BetweenRun | BetweenDay | BetweenInstrument | BetweenLot | 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 | %HbA1cDecision 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 | %HbA1cDecision 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 | ApproximateHbA1c 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 | ApproximateHbA1c 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.
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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 ofBlank (LoB) | 3.18 | 60.15 | 1.77 |
| Limit ofDetection (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.
§ 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.