(283 days)
The SEKURE HbA1c assay is used to measure the percent concentration of hemoglobin A1c (NGSP) or the HbA1c fraction mmol/mol (IFCC) in human venous whole blood and hemolysate on the SK500 Clinical Chemistry System. Measurement of HbA 1c is used as an aid in the diagnosis of diabetes mellitus, as an aid in the identification of patients at risk for development of diabetes mellitus, and for the monitoring of long-term blood glucose with diabetes mellitus. For In Vitro Diagnostic Use Only.
The SEKURE HbA1c assay is an enzymatic assay for the measurement of the percent hemoglobin A1c concentration. The assay consists of a pre-treatment hemolyzing buffer solution and two working reagents. Testing is performed on the SK500 K103531in conjunction with calibrators and controls which will be provided separately.
The SEKURE HbA1c Assay is an in vitro diagnostic device used to measure the percentage concentration of hemoglobin A1c (HbA1c) in human venous whole blood and hemolysate. It's intended to aid in the diagnosis and monitoring of diabetes mellitus. The device's performance was evaluated through various non-clinical studies to demonstrate its substantial equivalence to a predicate device.
1. Acceptance Criteria and Reported Device Performance
Precision (NGSP Units, Whole Blood)
| Test | Acceptance Criteria (NGSP Within-Laboratory %CV) | Reported Performance (Total Precision %CV) (Range across samples) |
|---|---|---|
| Precision (NGSP Units) | ≤ 2.5% | 0.8% - 1.6% |
| Precision (IFCC Units) | ≤ 4.5% | 0.9% - 2.7% |
| Linearity (NGSP) | ± 7% across 4.0 to 14.0 %HbA1c | Pass (linear across 4.0 to 14.0 %HbA1c) |
| Linearity (IFCC) | ± 7% across 20.02 to 129.34 mmol/mol HbA1c | Pass (linear across 20.02 to 129.34 mmol/mol HbA1c) |
| HbF Interference | Relative % Difference < 5% | -15.42% to -15.33% at ~6.0% and ~9.0% HbA1c |
| Other Hb Variants Interference | Relative % Difference < 5% | Pass (No significant interference observed) |
| Method Comparison (r) | ≥ 0.95 | 0.9977 (Whole Blood), 0.9981 (Hemolysate) |
| Method Comparison (Slope, NGSP) | 1.1 ± 0.10 | 0.974/0.987 (Passing-Bablok/Deming) for Whole Blood, 0.969/0.984 (Passing-Bablok/Deming) for Hemolysate |
| Bias (NGSP) | ≤ 3% at 5.0, 6.5, 8.0, and 12.0 %HbA1c | -2.40% to -2.50% (Whole blood, Passing-Bablok) |
| Anticoagulant %Bias | 5% | 0.72-0.80% (Tripotassium EDTA), -0.51 - -0.42% (Sodium Fluoride/Disodium EDTA) |
| Anticoagulant Slope | 1.0 ± 0.1 | 1.015/0.998 (Tripotassium EDTA), 1.006/0.995 (Sodium Fluoride/Disodium EDTA) |
| Anticoagulant Correlation | ≥ 0.95 | 0.9992 (Tripotassium EDTA), 0.9994 (Sodium Fluoride/Disodium EDTA) |
2. Sample Size and Data Provenance
- Precision:
- 2 levels of controls and 4 levels of human whole blood pools.
- Each assayed in 2 replicates at 2 separate times per day for 20 different days.
- Analytical Sensitivity (LoB and LoD):
- 5 blank samples and 5 low concentration samples.
- Analyzed in quadruplicate for 3 days (total of 60 measurements per level).
- Low concentration samples were dilutions of dipotassium EDTA venous whole blood.
- Linearity/Reportable Range:
- 11 levels configured as a dilution series by mixing high and low HbA1c dipotassium EDTA venous whole blood samples.
- Samples run in quadruplicate.
- Analytical Specificity (Interference):
- All interferents and potential drug interferents tested at ~6.5% and 8.0% HbA1c concentrations in replicates of ten.
- Hemoglobin Variants:
- HbA2: 36 samples (4.1% - 6.2% abnormal variant, 4.06% - 10.0% HbA1c)
- HbC: 14 samples (27.4% - 38.4% abnormal variant, 4.81% - 10.46% HbA1c)
- HbD: 25 samples (19.6% - 40.0% abnormal variant, 4.79% - 12.62% HbA1c)
- HbE: 22 samples (24.0% - 28.0% abnormal variant, 5.2% - 10.0% HbA1c)
- HbF: 25 samples (4.4% - 29.3% abnormal variant, 5.1% - 12.8% HbA1c)
- HbS: 15 samples (28.2% - 37.5% abnormal variant, 4.45% - 12.31% HbA1c)
- Method Comparison with Predicate Device:
- 130 dipotassium EDTA whole blood specimens.
- Assayed over 5 operating days in duplicate.
- Matrix Comparison:
- 41 matched patient specimens.
- Analyzed in duplicate.
- Reference Range Verification:
- 20 fresh blood samples from clinically healthy patients.
- Tested in singlicate.
Data Provenance: The document does not explicitly state the country of origin for the patient data used in these studies. The studies are non-clinical performance evaluations, conducted to support the device's substantial equivalence. The nature of the studies indicates a prospective collection for the purpose of device validation.
3. Number of Experts and Qualifications for Ground Truth
- Precision, Analytical Sensitivity, Linearity, Interferents, Matrix Comparison, Reference Range Verification: The ground truth for these studies is established by the methods, instrumentation, and protocols themselves (e.g., control values, dilution series, analytical measurements). No human experts are explicitly mentioned for establishing ground truth in these specific sections.
- Hemoglobin Variants (Comparative Method): The HbA1c values for samples containing hemoglobin variants were compared to a "comparative method" which serves as the ground truth. The specific nature and qualifications of experts associated with this comparative method are not detailed.
- Method Comparison (NGSP Secondary Reference Laboratory Method): The device's performance was compared to an "NGSP secondary reference laboratory method." The NGSP (National Glycohemoglobin Standardization Program) provides standardization and certification for HbA1c methods, implying that the reference lab adheres to established standards. However, the number of experts or their specific qualifications at this reference laboratory are not provided.
4. Adjudication Method
The document does not describe an adjudication method for a test set in the context of expert review. The studies are primarily analytical performance evaluations where results are compared against established analytical standards, reference methods, or statistical criteria.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No MRMC comparative effectiveness study is mentioned. This device is an in vitro diagnostic assay, meaning its performance is evaluated based on its analytical accuracy and precision in measuring a biomarker, not on human reader interpretation of images or other subjective data. Therefore, the concept of "human readers improve with AI vs without AI assistance" is not applicable.
6. Standalone (Algorithm Only) Performance
Yes, the studies described are essentially a standalone evaluation of the SEKURE HbA1c Assay. The performance metrics (precision, linearity, bias, interference, method comparison) quantify the analytical capability of the assay system (reagents plus SK500 analyzer) independent of human interpretation of the results beyond the technical execution of the test.
7. Type of Ground Truth Used
- Precision: Internal control values and human whole blood pools with calculated means.
- Analytical Sensitivity (LoB and LoD): Based on statistical analysis of blank and low-concentration measurements to determine the lowest detectable limit.
- Linearity/Reportable Range: Based on theoretical expected values of a dilution series.
- Traceability: Traceable to the International Federation of Clinical Chemistry (IFCC) reference calibrators and NGSP certification.
- Analytical Specificity (Interference): Established by comparing results in the presence of interferents to control samples (without interferents).
- Hemoglobin Variants: A "comparative method" for HbA1c measurement.
- Method Comparison: An "NGSP secondary reference laboratory method" for HbA1c.
- Matrix Comparison: Dipotassium EDTA whole blood (control tube) serves as the reference for comparison against other anticoagulants.
- Reference Range Verification: A published "Reference Range for Adults" (Source: ROCHE - Reference Ranges for Adults, Pre-Analytical Considerations - 2008).
8. Sample Size for the Training Set
The document describes performance studies for the SEKURE HbA1c Assay, not the development or training of an AI algorithm. Therefore, there is no "training set" in the context of machine learning. The data presented are for validation of the assay's analytical performance.
9. How the Ground Truth for the Training Set Was Established
As there is no AI algorithm being trained, the concept of establishing ground truth for a training set is not applicable to this document. The ground truth for the validation studies is established as described in section 7.
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July 12, 2018
Sekisui Diagnostics PEI Inc. Penny White Regulatory Affairs Manager 70 Watts Ave. Charlottetown, Prince Edward Island C1E 2B9 Canada
Re: K173206
Trade/Device Name: SEKURE HbA1c Assay Regulation Number: 21 CFR 862.1373 Regulation Name: Hemoglobin A1c Test System Regulatory Class: Class II Product Code: PDJ, LCP Dated: May 31, 2018 Received: June 4, 2018
Dear Penny White:
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 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) K173206
Device Name SEKURE HbA1c Assay
Indications for Use (Describe)
The SEKURE HbA1c assay is used to measure the percent concentration of hemoglobin A1c (NGSP) or the HbA1c fraction mmol/mol (IFCC) in human venous whole blood and hemolysate on the SK500 Clinical Chemistry System. Measurement of HbA 1c is used as an aid in the diagnosis of diabetes mellitus, as an aid in the identification of patients at risk for development of diabetes mellitus, and for the monitoring of long-term blood glucose with diabetes mellitus.
For In Vitro Diagnostic Use Only.
| 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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Section 5 510k Summary
This 510(k) Summary of Safety and Effectiveness is being submitted in accordance with the requirements of 21 CFR §807.92. This is a Traditional 510(k).
The assigned 510(k) number: K173206
5.1. Applicant Information and Date [807.92(a) (1)]
| Applicant Name and Address: | SEKISUI DIAGNOSTICS P.E.I. INC. |
|---|---|
| 70 Watts Avenue, Charlottetown, PE | |
| Canada, C1E 2B9 | |
| Establishment Registration Number: 8020316 | |
| Application correspondent: | Penny White |
| Regulatory Affairs Manager | |
| 902-628-0934 | |
| Penny.white@sekisuidiagnostics.com | |
| Date Summary prepared: | 06 July 2018 |
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| Trade Name | Common Name | Classification Name | Regulation | Classification | Product Code | Panel |
|---|---|---|---|---|---|---|
| SEKUREHbA1c Assay | HemoglobinA1c TestSystem | HemoglobinA1c TestSystem | 21 CFR862.1373 | Class II | PDJ | ClinicalChemistry |
| 21 CFR864.7470 | Class II | LCP | Hematology |
5.2. Device Name and Classification [807.92 (a)(2)]
5.3. Identification of Legally Marketed Predicate Devices [807.92(a)(3)]
| Trade Name | Predicate Device | Predicate 510(k) Number |
|---|---|---|
| SEKURE HbA1c Assay | Architect Hemoglobin A1c | K130255 |
5.4. Device Description [807.92 (a)(4)]
| Trade Name | Device Description |
|---|---|
| SEKURE HbA1cAssay | The SEKURE HbA1c assay is an enzymatic assay for the measurement of thepercent hemoglobin A1c concentration. The assay consists of a pre-treatmenthemolyzing buffer solution and two working reagents. Testing is performed on theSK500 K103531in conjunction with calibrators and controls which will beprovided separately. |
| NGSPManufacturerCertification | Sekisui has obtained NGSP manufacturer certification for the SEKURE HbA1cassay on the SK500. The certification process included a method comparison of 40patient samples with a Secondary Reference Laboratory and an assessment of theagreement analysis. |
| SK500 ClinicalChemistryAnalyzer | The SK500 Analyzer is manufactured as Clinical Chemistry Analyzer TokyoBoeki Medisys Inc. Biolis 50i Superior, cleared under K103531. “SK500" is theSekisui Diagnostics labeled name for the Tokyo Boeki Medisys Inc. Biolis 50iSuperior instrument. |
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5.5. Intended Use [807.92 (a)(5)]
| Trade Name | Intended Use |
|---|---|
| SEKURE HbA1c Assay | The SEKURE HbA1c assay is used to measure the percent concentration ofhemoglobin A1c (NGSP) or the HbA1c fraction mmol/mol (IFCC) inhuman venous whole blood and hemolysate on the SK500 ClinicalChemistry System. |
| Measurement of HbA1c is used as an aid in the diagnosis of diabetesmellitus, as an aid in the identification of patients at risk for developmentof diabetes mellitus, and for the monitoring of long-term blood glucosecontrol in individuals with diabetes mellitus.For In Vitro Diagnostic Use Only |
5.6. Technological Similarities and Differences to the Predicate [807.92 (a)(6)]
The SEKURE HbA1c Assay included in the submission each have a predicate device, as described in the tables below.
| Predicate Device | New Device | |
|---|---|---|
| Characteristic | Hemoglobin A1cAbbottLaboratories | SEKURE HbA1c Assay |
| Intended Use | The HbA1c assay is used in clinicallaboratories for the quantitative invitro measurement of hemoglobinA1c or HbA1c fraction mmol/mol(IFCC) in human whole blood andhemolysate on the ARCHITECT c8000 System.HbA1c measurement is used as anaid in the diagnosis of diabetesmellitus and as and aid to identifypatients who may be at risk fordeveloping diabetes mellitus, and forthe monitoring of long-term bloodglucose control in individuals withdiabetes mellitus. | The SEKURE HbA1c assay is used tomeasure the percent concentration ofHbA1c (NGSP) or the HbA1c fractionmmol/mol (IFCC) in human venouswhole blood and hemolysate on theSK500 Clinical Chemistry System.Measurement of hemoglobin A1c is usedas an aid in the diagnosis of diabetesmellitus, as an aid in the identification ofpatients who may be at risk fordevelopment of diabetes mellitus, and forthe monitoring of long-term bloodglucose control in individuals withdiabetes mellitus.For In Vitro Diagnostic Use Only. |
5.6.1 SEKURE HbA1c Assay
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| Predicate Device | New Device | |
|---|---|---|
| Characteristic | Hemoglobin A1cAbbottLaboratories | SEKURE HbA1c Assay |
| Platform | ARCHITECT c 8000 (ClinicalChemistry Analyzer) | SK500 (K103531) (Clinical ChemistryAnalyzer) |
| Methodology | Enzymatic | SAME |
| Specimen type | Whole blood and hemolysateDipotassium EDTALithium HeparinSodium HeparinSodium fluoride/disodium EDTATripotassium EDTA | Whole blood and HemolysateDipotassium EDTASodium fluoride/disodium EDTATripotassium EDTA |
| Measuring interval | 4.0 to 14.0% HbA1c (DCCT/NGSP)20.22-129.51 mmol/mol HbA1c(IFCC) | 4.0 to 14.0% HbA1c (DCCT/NGSP)20.02 to 129.34 mmol/mol HbA1c |
5.7. Summary of Non-Clinical Performance Data [807.92 (b)(1)]
5.7.1 SEKURE HbA1c Assay
Precision
Testing was conducted using 3 lots of HbA1c Reagents and Calibrators and 3 instruments. Two levels of controls and 4 levels of human whole blood pools were assayed in 2 replicates at 2 separate times per day for 20 different days. Each reagent lot was calibrated fresh daily.
IFCC
The HbA1c assay is designed to have an imprecision of ≤4.5% within laboratory %CV.
NGSP
The HbA1c assay is designed to have an imprecision of ≤2.5% within laboratory %CV.
| Repeatability | Between Run | Between Day | Between Instruments | Between Lot | Total Precision | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Sample | Mean | SD | CV | SD | CV | SD | CV | SD | CV | SD | CV | SD | CV |
| QC 1 | 5.23 | 0.055 | 1.1 | 0.028 | 0.5 | 0.056 | 1.1 | 0.053 | 1.0 | 0.009 | 0.2 | 0.083 | 1.6 |
| QC 2 | 9.77 | 0.064 | 0.7 | 0.037 | 0.4 | 0.061 | 0.6 | 0.041 | 0.4 | 0.004 | 0.0 | 0.096 | 1.0 |
| Patient 1 | 5.01 | 0.044 | 0.9 | 0.034 | 0.7 | 0.041 | 0.8 | 0.056 | 1.1 | 0.007 | 0.1 | 0.069 | 1.4 |
| Patient 2 | 6.33 | 0.045 | 0.7 | 0.037 | 0.6 | 0.047 | 0.7 | 0.059 | 0.9 | 0.011 | 0.2 | 0.074 | 1.2 |
| Patient 3 | 7.79 | 0.037 | 0.5 | 0.044 | 0.6 | 0.045 | 0.6 | 0.059 | 0.8 | 0.015 | 0.2 | 0.074 | 0.9 |
| Patient 4 | 12.07 | 0.036 | 0.3 | 0.049 | 0.4 | 0.067 | 0.6 | 0.061 | 0.5 | 0.021 | 0.2 | 0.091 | 0.8 |
Precision, All Instruments, Whole Blood, NGSP Units (%HbA1c)
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| Repeatability | Between Run | Between Day | Between Instruments | Between Lot | Total Precision | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Sample | Mean | SD | CV | SD | CV | SD | CV | SD | CV | SD | CV | SD | CV |
| QC 1 | 4.99 | 0.048 | 1.0 | 0.032 | 0.6 | 0.035 | 0.7 | 0.015 | 0.3 | 0.009 | 0.2 | 0.067 | 1.4 |
| QC 2 | 9.61 | 0.037 | 0.4 | 0.046 | 0.5 | 0.036 | 0.4 | 0.021 | 0.2 | 0.009 | 0.1 | 0.069 | 0.7 |
| Patient 1 | 5.00 | 0.033 | 0.7 | 0.032 | 0.6 | 0.037 | 0.7 | 0.059 | 1.2 | 0.008 | 0.2 | 0.060 | 1.2 |
| Patient 2 | 6.34 | 0.036 | 0.6 | 0.036 | 0.6 | 0.041 | 0.6 | 0.057 | 0.9 | 0.011 | 0.2 | 0.066 | 1.0 |
| Patient 3 | 7.81 | 0.029 | 0.4 | 0.055 | 0.7 | 0.037 | 0.5 | 0.057 | 0.7 | 0.017 | 0.2 | 0.073 | 0.9 |
| Patient 4 | 12.05 | 0.048 | 0.4 | 0.47 | 0.4 | 0.054 | 0.5 | 0.058 | 0.5 | 0.021 | 0.2 | 0.086 | 0.7 |
Precision, All Instruments, Hemolysate, NGSP Units (%HbA1c)
Precision, All Instruments, Whole Blood, IFCC Units (mmol/mol)
| Repeatability | Between Run | Between Day | Between Instruments | Between Lot | Total Precision | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Sample | Mean | SD | CV | SD | CV | SD | CV | SD | CV | SD | CV | SD | CV |
| QC 1 | 33.60 | 0.600 | 1.8 | 0.302 | 0.9 | 0.617 | 1.8 | 0.576 | 1.7 | 0.101 | 0.3 | 0.912 | 2.7 |
| QC 2 | 83.33 | 0.698 | 0.8 | 0.407 | 0.5 | 0.667 | 0.8 | 0.451 | 0.5 | 0.048 | 0.1 | 1.047 | 1.3 |
| Patient 1 | 31.19 | 0.482 | 1.5 | 0.74 | 1.2 | 0.452 | 1.4 | 0.612 | 2.0 | 0.081 | 0.3 | 0.759 | 2.4 |
| Patient 2 | 45.64 | 0.488 | 1.1 | 0.406 | 0.9 | 0.509 | 1.1 | 0.643 | 1.4 | 0.118 | 0.3 | 0.814 | 1.8 |
| Patient 3 | 61.66 | 0.406 | 0.7 | 0.486 | 0.8 | 0.495 | 0.8 | 0.650 | 1.1 | 0.166 | 0.3 | 0.804 | 1.3 |
| Patient 4 | 108.43 | 0.394 | 0.4 | 0.539 | 0.5 | 0.731 | 0.7 | 0.669 | 0.6 | 0.227 | 0.2 | 0.990 | 0.9 |
Precision, All Instruments, Hemolysate, IFCC Units (mmol/mol)
| Repeatability | Between Run | Between Day | Between Instruments | Between Lot | Total Precision | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Sample | Mean | SD | CV | SD | CV | SD | CV | SD | CV | SD | CV | SD | CV |
| QC 1 | 31.02 | 0.524 | 1.7 | 0.351 | 1.1 | 0.380 | 1.2 | 0.166 | 0.5 | 0.104 | 0.3 | 0.736 | 2.4 |
| QC 2 | 81.57 | 0.402 | 0.5 | 0.500 | 0.6 | 0.395 | 0.5 | 0.226 | 0.3 | 0.100 | 0.1 | 0.754 | 0.9 |
| Patient 1 | 31.13 | 0.366 | 1.2 | 0.354 | 1.1 | 0.409 | 1.3 | 0.650 | 2.1 | 0.092 | 0.3 | 0.653 | 2.1 |
| Patient 2 | 45.74 | 0.398 | 0.9 | 0.397 | 0.9 | 0.449 | 1.0 | 0.629 | 1.4 | 0.117 | 0.3 | 0.719 | 1.6 |
| Patient 3 | 61.80 | 0.314 | 0.5 | 0.604 | 1.0 | 0.408 | 0.7 | 0.624 | 1.0 | 0.182 | 0.3 | 0.794 | 1.3 |
| Patient 4 | 108.20 | 0.528 | 0.5 | 0.510 | 0.5 | 0.593 | 0.5 | 0.632 | 0.6 | 0.234 | 0.2 | 0.944 | 0.9 |
Analytical Sensitivity
Limit of Blank (LoB) and Limit of Detection (LoD):
Limit of Blank and Limit of Detection testing was based on guidance from the CLSI guidance document EP17-A2. Testing was completed by analyzing 5 blank samples and 5 low concentration samples in quadruplicate for 3 days producing a total of 60 measurements of each level using 2 lots of SEKURE HbA1c reagent on two SK500 analyzers. Low concentration samples were dilutions of dipotassium EDTA venous whole blood.
| Limit | %HbA1c | umol/L A1c | umol/L THb |
|---|---|---|---|
| Limit of Blank (LoB) | 3.27 | 0.66 | 0.2 |
| Limit of Detection (LoD) | 3.32 | 0.75 | 0.5 |
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Linearity/Assay Reportable Range:
A linearity study was performed based on guidance from the CLSI guidance document EP06-A. The linearity study was performed using two lots of SEKURE HbA1c reagent on one SK500. A dilution series consisting of 11 levels across the assay range were prepared by mixing high and low HbA lc dipotassium EDTA venous whole blood samples. Samples were run in quadruplicate, mean values are presented.
IFCC
The HbA1c assay is linear across the range of 20.02 to 129.34 mmol/mol HbA1c based on an allowable tolerance of within or equal to ±7%.
NGSP
The HbA1c assay is linear across the range of 4.0 to 14.0 %HbA1c based on an allowable tolerance of within or equal to ±7%.
The linearity study supports an assay measuring range of 4.0 to 14.0% HbA1c (20.02 to 129.34 mmol/mol IFCC).
Traceability, Stability, Expected Values (controls calibrators or methods):
Traceability:
The SEKURE HbA1c Assay standardization is traceable to the International Federation of Clinical Chemistry (IFCC) reference calibrators. The SEKURE HbA1c Assay is NGSP certified. The NGSP certification expires in one year. The derived result of (%) from the NGSP correlation is calculated from the individual quantitative results for the total hemoglobin A1c (HbA1c). The IFCC units of mmol/mol are calculated using the equation IFCC = (NGSP-2.152) / 0.09148. Two different units are provided to users: NGSP equivalent units (%) and IFCC equivalent units (mmol/mol).
Value Assignment:
The SEKURE HbA 1c calibrators are aligned to IFCC reference calibrators through internal value assignment in which the calibrator values must meet the pre-determined acceptance criteria within a set specification. Each lot of calibrators is value-assigned. The concentration of glycated hemoglobin (HbA1c) and total hemoglobin (THb) is provided for each lot. Calibrators are prepared gravimetrically, lyophilized and then value assigned using secondary calibrators that are traceable to the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) reference method.
The value assigned HbA1c concentration falls within the following HbA1c ranges:
Calibrator 1: 4.59% to 6.02% HbA1c
Calibrator 2: 10.52% to 13.37% HbA1c
The SEKURE HbA1c Controls are value assigned using the secondary calibrators. The values obtained must meet the pre-determined acceptance criteria.
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The value-assigned HbA1c Control values are within the following HbA1c ranges: Control L: 4.59% to 6.02% HbA1c Control H: 9.42% to 11.07 % HbA1c
Stability:
Shelf-life claims: Current testing supports a shelf life of 11 months for un-opened calibrators and controls stored at 2-8 °C. Testing is ongoing to extend the shelf life further.
Onboard Stability for the SK500 was established by real time studies on the SK500 analyzer and demonstrated on-board reagent stability of 28 days. Current testing supports a stability of 11 months for un-opened SEKURE HbA1c Assay. Testing is ongoing to extend the shelf life further.
Analytical Specificity (Endogenous and Exogenous Interference)
An interference study was performed based on the CLSI EP7-A2 guideline to assess common or known substances that could interfere with the HbA1c Assay. Interference testing was conducted using 2 lots of SEKURE HbA1c reagent. All interferents were tested at % HbA1c concentrations of ~ 6.5 and 8.0% in replicates of ten. Significant interference was identified as a percent difference greater than 5% from control.
| Highest Tested Concentration at which no significant | |||
|---|---|---|---|
| Potential Interferent | interference (>5%) was observed | ||
| Conventional Units | SI Units | ||
| Conjugated Bilirubin | 18 mg/dL | 216 umol/L | |
| Unconjugated Bilirubin | 18 mg/dL | 307.8 umol/L | |
| Total Protein | 22 g/dL | 220 g/L | |
| Triglycerides | 3000 mg/dL | 33.9 mmol/L | |
| Rheumatoid Factor | 200 IU/mL | 200 IU/mL | |
| Ascorbic Acid | 3.0 mg/dL | 0.15 mmol/L | |
| Glucose | 1000 mg/dL | 55.5 mmol/L | |
| Urea | 667 mg/dL | 111.06 mmol/L | |
| Vitamin E | 8.6 mg/dL | 200 umol/L |
The interference study results are summarized in the following table:
The HbA1c assay is susceptible to interference effects from conjugated bilirubin at > 18 mg/dL (216 umol/L) and unconjugated bilirubin at > 18 mg/dL (307.8 umol/L). The bias at 18 mg/dL conjugated bilirubin is -4.2% and the bias at 18 mg/dL unconjugated bilirubin is -4.5%.
Potential drug interference testing was performed based on the CLSI EP7-A2 guideline to assess common or known drugs that could interfere with the HbA1c Assay. All potential drug interferents were tested at % HbA1c concentrations of ~ 6.5 and 8.0% in replicates of ten. Significant interference was identified as a percent difference greater than 5% from control.
The drug interference study results are summarized in the following table:
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| Potential Drug Interferent | Highest Tested Concentration at which no significantinterference (>5%) was observed | ||
|---|---|---|---|
| Conventional Units | SI Units | ||
| Acarbose | 50 mg/dL | 0.77 mmol/L | |
| Acetaminophen | 20 mg/dL | 1324 umol/L | |
| Acetylsalicylate | 50.8 mg/dL | 2.82 mmol/L | |
| Atorvastatin | 0.06mg/dL | 600 µg Eq/L | |
| Captopril | 0.5 mg/dL | 23 umol/L | |
| Chlorpropamide | 74.7 mg/dL | 2.7 mmol/L | |
| Cyanate | 65 mg/dL | 10 mmol/L | |
| Furosemide | 6.0 mg/dL | 181 umol/L | |
| Gemfibrozil | 7.5 mg/dL | 300 umol/L | |
| Ibuprofen | 50 mg/dL | 2425 umol/L | |
| Insulin | 450 uUlmL | 450 µUlmL | |
| Losartan | 5 mg/dL | 0.11 mmol/L | |
| Metformin | 5.1 mg/dL | 310 µmol/L | |
| Nicotinic Acid | 61 mg/dL | 4.95 mmol/L | |
| Propranolol | 0.2 mg/dL | 7.71 umol/L | |
| Repaglinide | 0.006 mg/dL | 132.57 nmol/L |
Hemoglobin Variants
The hemoglobin variant study was performed according to guidance from the CLSI EP7-A2. The interference effects of the hemoglobin variants were assessed by comparing the HbA1c values to a comparative method for samples containing potentially interfering hemoglobin variants. The number and concentrations hemoglobin variants tested, and the range of % HbA1c concentrations in which they were tested are shown below:
| Hemoglobin Variant | n | Range in % Abnormal Variant | Range in % HbA1cConcentration |
|---|---|---|---|
| HbA2 | 36 | 4.1 - 6.2 | 4.06 - 10.0 |
| HbC | 14 | 27.4 - 38.4 | 4.81 - 10.46 |
| HbD | 25 | 19.6 - 40.0 | 4.79 - 12.62 |
| HbE | 22 | 24.0 - 28.0 | 5.2 - 10.0 |
| HbF | 25 | 4.4 - 29.3 | 5.1 - 12.8 |
| HbS | 15 | 28.2 - 37.5 | 4.45 - 12.31 |
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| HemoglobinVariant | Relative % Difference from Reference Concentration at Low and HighConcentrations | |||
|---|---|---|---|---|
| ~ 6.0 % HbA1c(5.5 to 6.5 %HbA1c) | ~9.0 %HbA1c(7.5 to 10.5 %HbA1c)* | |||
| Relative %Difference | Range | Relative %Difference | Range | |
| HbA2 | -2.28 | -5.56 to 5.08 | -1.28 | -2.30 to -0.14 |
| HbC | -1.64 | -3.30 to 1.90 | -0.97 | -1.72 to -0.38 |
| HbD | 0.10 | -5.69 to 2.91 | -1.14 | -2.83 to 0.67 |
| HbE | 3.41 | 1.85 to 5.42 | 3.50 | -0.50 to 6.34 |
| HbF | -15.42 | -23.06 to -6.25 | -15.33 | -21.73 to -4.81 |
| HbF interferes with this assay | ||||
| HbS | 1.83 | 0.51 to 2.40 | 0.41 | -0.94 to 1.73 |
The results for the hemoglobin variant study are summarized below:
*The HbA2 results at ~9.0 %HbA1c consisted of samples between 7.2 – 10.0% HbA1c
There was no significant (Relative % Difference >5%) interference observed for HbA2, HbC, HbD, HbE or HbS at the concentrations tested above. There was significant negative interference with fetal hemoglobin (HbF). HbA1c results are not valid for patients with elevated levels of HbF, including those with known Hereditary Persistence of Fetal Hemoglobin. A warning to this effect will be included in product labeling.
Summary of Method Comparison 5.8
Method comparison with Predicate Device:
Method comparison testing was conducted based on CLSI EP09-A3 on 2 SK500 analyzers using 2 lots of SEKURE HbA1c reagent. Testing was completed on 130 dipotassium EDTA whole blood specimens over 5 operating days in duplicate. Samples were assayed using both online (whole blood) and offline hemolysis (hemolysate) using the SEKURE HbA1c assay on the SK500.
The sample range tested was 4.3 to 13.8% NGSP. The distribution of samples spanned the measuring interval with a concentration of samples around the clinical decision points as demonstrated in the table below.
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Method Comparison Sample Range Summary
| Hemoglobin A1c level | n | % Samples tested |
|---|---|---|
| < ૨% | 6 | 4.6 |
| 5 - 6% | 11 | 8.5 |
| 6 – 6.5% | 34 | 26.2 |
| 6.5 – 7% | 33 | 25.4 |
| > 7% | 46 | 35.3 |
| Total samples | 130 | 100 |
First replicate analysis is summarized below. The Hemoglobin A1c assay is designed to have a slope of 1.1 ± 0.10 and a correlation coefficient (r) of ≥ 0.95 for specimens across the measuring interval when compared to an NGSP secondary reference laboratory method.
A correlation study was performed using CLSI protocol EP09-A3 with Passing-Bablok regression and Deming analysis. Human venous whole blood specimen results from the SEKURE Hemoglobin A 1 c assay were compared with those from an NGSP secondary reference laboratory method.
The data are summarized in the following tables:
Whole blood: Passing-Bablok Regression
| Units | Comparison Assay (x) | N | r | Regression Equation | Sample Range |
|---|---|---|---|---|---|
| NGSP | NGSP Reference Method | 130 | 0.9977 | $y = 0.974x + 0.007$ | 4.30 to 13.80 |
| IFCC | NGSP Reference Method | 130 | 0.9977 | $y = 0.974x - 0.671$ | 23.48 to 127.33 |
Hemolysate: Passing-Bablok Regression
| Units | Comparison Assay (x) | N | r | Regression Equation | Sample Range |
|---|---|---|---|---|---|
| NGSP | NGSP Reference Method | 130 | 0.9981 | $y = 0.969x + 0.101$ | 4.30 to 13.80 |
| IFCC | NGSP Reference Method | 130 | 0.9981 | $y = 0.969x + 0.185$ | 23.48 to 127.33 |
Whole blood: Deming Regression
| Units | Comparison Assay (x) | N | r | Regression Equation | Sample Range |
|---|---|---|---|---|---|
| NGSP | NGSP Reference Method | 130 | 0.9977 | $y = 0.987x - 0.087$ | 4.30 to 13.80 |
| IFCC | NGSP Reference Method | 130 | 0.9977 | $y = 0.987x - 1.442$ | 23.48 to 127.33 |
Hemolysate: Deming Regression
| Units Comparison Assay (x) | N | r | Regression Equation | Sample Range | |
|---|---|---|---|---|---|
| NGSP NGSP Reference Method | 130 | 0.9981 | y=0.984x-0.012 | 4.30 to 13.80 | |
| IFCC | NGSP Reference Method | 130 0.9981 | ッ=0.984x - 0.706 | 23.48 to 127.33 |
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Bias (NGSP)
The HbA1c assay is designed to have a bias of ≤ 3% at 5.0, 6.5, 8.0 and 12.0 %HbA1c using Passing- Bablok regression.
The bias in %HbA1c (NGSP) ranged from -2.40 to -2.50%.
Total Error Near the Cutoff
12.0
Using the results of bias estimation (%Bias) in the method comparison study and precision estimates in the reproducibility study, the Total Error (TE) at the following concentrations (5%, 6.5%, 8% and 12%) was calculated as follows: %TE =%Bias| + 1.96 * %CV * (1+%Bias/100). The results are presented in the tables below.
0.8
4.03
| 70 Total Effor Summary – Whole Blood (NGSP) Passing Dablok | |||
|---|---|---|---|
| % Alc - Decision Level | % Bias | % CV | % TE |
| 5.0 | -2.40 | 1.4 | 5.08 |
| 6.5 | -2.46 | 1.2 | 4.75 |
| 8.0 | -2.50 | 0.9 | 4.22 |
-2.50
al Error Summery - Whole Rlood (NGSP) Peccing Reblok
% Total Error Summary – Hemolysate (NGSP) Passing Bablok
| % A1c - Decision Level | % Bias | % CV | % TE |
|---|---|---|---|
| 5.0 | -1.20 | 1.2 | 3.52 |
| 6.5 | -1.54 | 1.0 | 3.47 |
| 8.0 | -1.88 | 0.9 | 3.61 |
| 12.0 | -2.33 | 0.7 | 3.67 |
% Total Error Summary - Whole Blood (NGSP) Deming
| % Alc - Decision Level | % Bias | % CV | % TE |
|---|---|---|---|
| 5.0 | -3.04 | 1.4 | 5.70 |
| 6.5 | -2.64 | 1.2 | 4.93 |
| 8.0 | -2.39 | 0.9 | 4.11 |
| 12.0 | -2.03 | 0.8 | 3.56 |
% Total Error Summary - Hemolysate (NGSP) Deming
| % A1c - Decision Level | % Bias | % CV | % TE |
|---|---|---|---|
| 5.0 | -1.84 | 1.2 | 4.15 |
| 6.5 | -1.78 | 1.0 | 3.71 |
| 8.0 | -1.75 | 0.9 | 3.48 |
| 12.0 | -1.70 | 0.7 | 3.05 |
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Matrix Comparison:
A matrix study was performed to determine the suitability of various anticoagulants for use with the SEKURE HbA1c Assay. The evaluation of different anticoagulants was completed using two lots of reagents, and 41 matched patient specimens analyzed in duplicate. Sample %HbA1c concentrations s panned the range of the assay.
The first replicate Passing-Bablok regression analysis data is summarized in the following table:
| Specification | AcceptanceCriteria | Tripotassium EDTA | Sodium Fluoride/Disodium EDTA | ||
|---|---|---|---|---|---|
| Lot 1 | Lot 2 | Lot 1 | Lot 2 | ||
| %Bias | 5% | 0.72 | 0.80 | -0.51 | -0.42 |
| Slope | $1.0 \pm 0.1$ | 1.015 | 0.998 | 1.006 | 0.995 |
| Intercept | N/A | -0.043 | 0.062 | -0.084 | -0.021 |
| CorrelationCoefficient | $\geq 0.95$ | 0.9992 | 0.9992 | 0.9994 | 0.9994 |
| Pass/Fail | Pass | Pass | Pass | Pass |
Control Tube - Dipotassium EDTA
The data supports the use of the following blood collection tubes with the SEKURE HbA lc assay:
- . Dipotassium EDTA (control tube)
- Sodium Fluoride/Disodium EDTA
- Tripotassium EDTA ●
Clinical studies:
(clinical sensitivity, clinical specificity, other clinical supportive data) Not Applicable
Expected values/Reference Range:
HbA1c values above 6.5 %HbA1c (48 mmol/mol) meet the criteria for diagnosis of diabetes mellitus. Patients with HbA1c values in the range of 5.7 - 6.4 %HbA1c (39 - 47 mmol/mol) are at an increased risk for diabetes (pre-diabetes). HbA1c levels below 5.7 %HbA1c (39 mmol/mol) are considered normal.
-
- American Diabetes Association Position Statement: Standards of medical care in diabetes 2018. In: Diabetes Care 2018; 41 (Suppl 1): S13-S64.
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Verification of the Reference Range was conducted using two lots of SEKURE HbA1c reagent and fresh blood from 20 clinically healthy patient samples tested in singlicate.
The data in %HbA1c are summarized in the following table:
| SEKURE HbA1c Lot 1 | SEKURE HbA1c Lot 2 | |
|---|---|---|
| Reference Range* | 4.8 – 5.9% | 4.8 to 5.9% |
| Observed Range | 4.60 to 5.66 | 4.74 to 5.83 |
| Verification Rangex – 1/3(y-x) to y +1/3(y-x)where x = smallest valuey = largest value | 4.43 to 6.27 | 4.43 to 6.27 |
| Samples within verificationrange | 20/20 | 20/20 |
| Pass/Fail | Pass | Pass |
*Source: ROCHE - Reference Ranges for Adults, Pre-Analytical Considerations - 2008
5.8 Proposed Labeling
The labeling is sufficient and it satisfies the requirements of 21 CFR Part 809.10
5.9. Conclusion
The submitted information in this premarket notification is complete and supports a substantial equivalence decision.
§ 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.