(486 days)
The Tosoh Automated Glycohemoglobin Analyzer HLC-723G8 is intended for in vitro diagnostic use for the measurement of % hemoglobin A1c (HbA1c) (DCCT/NGSP) and mmol/mol hemoglobin A1c (IFCC) in venous whole blood specimens using ion-exchange high-performance liquid chromatography (HPLC). This test is an aid in diagnosis of diabetes and identifying patients who may be at risk for developing diabetes, and for monitoring of long-term blood glucose control in individuals with diabetes mellitus.
The Tosoh Automated Glycohemoglobin Analyzer HLC-723G8 is an automated High-Performance Liguid Chromatography (HPLC) system that separates and reports stable hemoglobin A1c (sA1c) percentage in venous whole blood. The operational portion of the G8 is composed of a sampling unit, liquid pump, degasser, column, detector, microprocessors, sample loader, smart media card, operation panel, and a printer. The Tosoh Automated Glycohemoglobin Analyzer HLC-723G8 uses ion-exchange HPLC for rapid, accurate, and precise separation of the stable form of HbA1c (sA1c) from other hemoglobin fractions. The G8 uses a non-porous cation exchange column and separates the hemoglobin components in the blood. Separation is achieved by utilizing differences in ionic interactions between the cation and exchange group on the column resin surface and the hemoglobin components in a step gradient elution. The hemoglobin fractions (designated as A1a. A1b. F. LA1c+, SA1c, A0, and, if present, H-V0, H-V2, H-V2 and H-V3) are subsequently removed from the column by performing a step-wise elution gradient using the varied salt concentrations in the Variant Elution Buffers HSi 1, 2 and 3. The peaks, H-V0, H-V1, H-V2 and H-V3 are typically presumptive HbAD, HbAS, HbAC and HbAE respectively. The software compares the retention times of hemoglobin fractions in a sample to the expected "windows of retention" and labels each fraction that correctly elutes within a defined expected window of retention. The software designates a hemoglobin fraction as POX (where X is the order of the peak as it elutes from the column) if it does not match a defined window of retention. All automated processes in the G8 are controlled by internal microprocessors, using software downloaded via a smart media card. The result report is printed and can be stored on the instrument. The data can be transmitted to a host computer through a bi-directional interface. The result report includes the sample ID, date, percentage and retention time of each fraction of hemoglobin, sA1c percentage and total A1 percentage, along with a chromatogram of the elution pattern of the hemoglobin fractions. If a sample contains a hemoglobin variant, the column elutes the fraction depending upon its charge.
The provided text describes the non-clinical performance testing of the Tosoh Automated Glycohemoglobin Analyzer HLC-723G8 (subject device) to support its substantial equivalence to a predicate device. This document focuses on the analytical performance of a diagnostic device rather than an AI/ML powered device, so some of the specific questions regarding AI/ML study design (e.g., number of experts, adjudication methods, MRMC studies) are not applicable.
Here's the information extracted from the document:
1. Acceptance Criteria and Reported Device Performance
The acceptance criteria are generally implied by the statement "All performance testing results met their pre-determined acceptance criteria." While explicit numerical acceptance criteria for each test are not listed in a consolidated table, the discussion throughout the "Summary of Non-Clinical Performance Testing" implicitly defines them through the methodology and results. For example, for precision/repeatability, the claim of "imprecision at ≤ 2%" was a pre-established criterion. Similarly, for hemoglobin variant interference, "Non-clinically significant interference was defined as <= 6% relative difference in the results from a comparative method."
It's important to note that the provided text is a 510(k) summary, which often summarizes detailed study reports. The full reports would contain explicit acceptance criteria thresholds.
Table of Acceptance Criteria (Implied) and Reported Device Performance:
| Acceptance Criteria (Implied/Defined) | Reported Device Performance |
|---|---|
| Precision/Repeatability: Pre-established claim of imprecision at ≤ 2% CV (for Total CV across all factors, or similar) | Total CV for combined analyzers: - 5.46% HbA1c: 0.97% - 6.38% HbA1c: 1.04% - 7.60% HbA1c: 1.28% - 11.91% HbA1c: 0.87% (All reported Total CVs are well below the implied 2% or potentially a specific lower threshold per concentration) |
| Method Comparison (Bias): No explicit acceptance criterion given for bias in the tables, but implied by outcome. | Passing-Bablok Bias: - 5.0% HbA1c: 0.1753 (3.5% bias) - 6.5% HbA1c: 0.2068 (3.2% bias) - 8.0% HbA1c: 0.2383 (3.0% bias) - 12.0% HbA1c: 0.3224 (2.7% bias) Deming Bias: - 5.0% HbA1c: 0.1979 (4.0% bias) - 6.5% HbA1c: 0.2172 (3.3% bias) - 8.0% HbA1c: 0.2366 (3.0% bias) - 12.0% HbA1c: 0.2884 (2.4% bias) (The device is found to be "substantially equivalent" based on these results, implying acceptance) |
| Hemoglobin Variant Interference: Non-clinically significant interference defined as <= 6% relative difference in the results from a comparative method at 6.5% or 8.0% HbA1c. | Reported Relative Bias from Reference Method: HbAD: -0.5% (~6.5% HbA1c), -1.7% (~8.0% HbA1c) HbAS: -2.7% (~6.5% HbA1c), -3.2% (~8.0% HbA1c) HbAC: -1.9% (~6.5% HbA1c), -1.1% (~8.0% HbA1c) HbAE: -1.3% (~6.5% HbA1c), -1.2% (~8.0% HbA1c) HbA2: -4.2% (~6.5% HbA1c), -5.1% (~8.0% HbA1c) HbF: -0.7% (~6.5% HbA1c), -1.6% (~8.0% HbA1c) (All reported relative biases are within the <= 6% redefined significant interference threshold) |
| Endogenous Interfering Substances: Significant interference defined as percent recovery ± 5% of the expected 100% recovery. | No Interference concluded up to specific concentrations: - Albumin: 5000 mg/dL - Ascorbic Acid: 25 mg/dL - Bilirubin C: 21 mg/dL - Bilirubin F: 18 mg/dL - Lipemia: 1000 mg/dL - Rheumatoid Factor: 550 IU/mL (Implies results were within ± 5% recovery for these substances up to the tested concentrations) |
| Cross Reactivity with Hemoglobin Derivatives: Concluded as "not interfering with the assay". | Not interfering concluded for: - Acetylated Hb up to 50 mg/dL - Carbamylated Hb up to 25 mg/dL - Aldehyde Hb up to 25 mg/dL - Labile HbA1c up to 1000 mg/dL |
| Matrix Comparison: No clinical or statistical difference between K2-EDTA and K3-EDTA. | Data supports interchangeable use of K2-EDTA and K3-EDTA blood collection tubes. |
| Linearity and Detection Limit: Reportable range 4.0 to 16.9% HbA1c. | Previously established under 510(k) K071132, and the range is maintained. |
2. Sample Size Used for the Test Set and Data Provenance:
- Precision/Repeatability Study:
- Sample Size: Four concentrations of HbA1c% in K2EDTA venous whole blood. A total of 720 measurements per concentration were performed (three analyzers, over 20 non-consecutive days, with three reagent lots, samples run in duplicate, two times per day).
- Data Provenance: The study was implicitly conducted retrospectively on collected samples. The country of origin is not explicitly stated, but the testing was performed at "Tosoh Bioscience, Inc." laboratories, likely in the US (given the South San Francisco address).
- Method Comparison Study:
- Sample Size: 220 K₂EDTA venous whole blood specimens with HbA1c concentrations spanning the measuring range (4.0-16.9%). Each specimen was tested in duplicate.
- Data Provenance: The study was conducted at "two separate sites," one a "moderate complexity clinical laboratory" (for the candidate device) and the other an "NGSP SRL" (for the comparator device). The precise country of origin is not explicitly stated. The specimens were collected and likely used retrospectively for the comparison.
- Endogenous Interfering Substances / Hemoglobin Variant Interference Studies:
- Sample Size:
- Endogenous interference: Not explicitly stated per substance, but specimens were "spiked with increasing amounts of the interfering substance."
- Hemoglobin Variant Interference:
- HbC: 26 samples
- HbD: 24 samples
- HbE: 26 samples
- HbS: 29 samples
- HbA2: 20 samples
- HbF: 21 samples
- Data Provenance: Not explicitly stated, but implies lab-tested, potentially spiked, and clinical samples from unknown origin (likely retrospective).
- Sample Size:
3. Number of Experts and Qualifications for Ground Truth:
This device is an automated in vitro diagnostic analyzer for quantitative measurement of HbA1c. The "ground truth" for such devices is typically established by:
- Reference methods (e.g., NGSP SRL certified methods).
- Traceability to international standards (DCCT, IFCC).
- Direct analytical measurements and statistical comparisons, rather than expert consensus on image interpretation.
Therefore, the concept of "number of experts used to establish the ground truth" similar to that in an AI imaging study is not applicable here. The ground truth is the chemical measurement itself, validated against recognized reference standards.
4. Adjudication Method for the Test Set:
Not applicable, as this is an analytical device for quantitative measurement, not an interpretative AI/ML system requiring human adjudication of results. The "adjudication" is through statistical agreement with reference methods and assessment against predetermined analytical performance criteria.
5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done:
No. An MRMC study is relevant for AI/ML systems that assist human readers in tasks like image interpretation. This device performs automated quantitative measurements, and its performance is evaluated against reference methods and analytical standards, not human readers.
6. If a standalone (i.e., algorithm only without human-in-the-loop performance) was done:
Yes, the studies described are standalone performance studies of the device (Tosoh Automated Glycohemoglobin Analyzer HLC-723G8) without human intervention in the measurement process itself. The device is an automated HPLC system.
7. The Type of Ground Truth Used:
The ground truth for evaluating the subject device's performance is based on:
- Reference Methods: Specifically, the NGSP SRL (National Glycohemoglobin Standardization Program Secondary Reference Laboratory) using the Trinity Biotech Premier Hb9210™ HbA1c Analyzer (for method comparison) and Primus Model CLC 330 (for some hemoglobin variant interference testing), and the Bio-Rad VARIANT II TURBO HbA1c Kit - 2.0 (for some hemoglobinopathy interference testing).
- Traceability and Standardization: The device's results are traceable to the Diabetes Control and Complications Trial (DCCT) reference method and IFCC, and it is certified by the NGSP.
- Analytical Standards: For precision, linearity, and interference, the "ground truth" reflects the known concentrations of spiked samples or validated concentrations in patient samples, against which the device's measurements are compared.
8. The Sample Size for the Training Set:
The provided document describes non-clinical performance testing to support substantial equivalence after a software modification (v5.24). It does not provide information on the training set used for the development of the device's algorithms or software. This 510(k) summary is focused on verification and validation of the modified device.
9. How the Ground Truth for the Training Set Was Established:
This information is not provided in the 510(k) summary. Given that the device is an automated HPLC system, its "training" per se would involve optimization of its operational parameters, calibration curves, and potentially peak detection/integration algorithms, likely using well-characterized samples with known HbA1c concentrations established by reference methods. However, the details of such a "training set" and its ground truth establishment are not discussed here.
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September 14, 2021
Tosoh Bioscience, Inc. Louise Musante Regulatory Compliance Consultant, Senior Regulatory Specialist 6000 Shoreline Court. Suite 101 South San Francisco, California 94080
Re: K200904
Trade/Device Name: Tosoh Automated Glycohemoglobin Analyzer HLC-723G8 Regulation Number: 21 CFR 862.1373 Regulation Name: Hemoglobin A1c test system Regulatory Class: Class II Product Code: PDJ, LCP
Dear Louise Musante:
The Food and Drug Administration (FDA) is sending this letter to notify you of an administrative change related to your previous substantial equivalence (SE) determination letter dated August 5, 2021. Specifically, FDA is updating this SE Letter as an administrative correct a typo in the sponsor's 510(k) summary.
Please note that the 510(k) submission was not re-reviewed. For questions regarding this letter please contact Leslie Landreee, OHT7: Office of In Vitro Diagnostics and Radiological Health, (301) 796-6147, leslie.landree@fda.hhs.gov.
Sincerely.
Leslie
Landree -S
Digitally signed by Leslie
Landree -S
Date: 2021.09.14 17:43:06
-04'00'
Leslie Landree Acting Diabetes Diagnostic Devices Branch Chief OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Quality Center for Devices and Radiological Health
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August 5, 2021
Tosoh Bioscience, Inc. Louise Musante Regulatory Compliance Consultant, Senior Regulatory Specialist 6000 Shoreline Court, Suite 101 South San Francisco, California 94080
Re: K200904
Trade/Device Name: Tosoh Automated Glycohemoglobin Analyzer HLC-723G8 Regulation Number: 21 CFR 862.1373 Regulation Name: Hemoglobin A1c test system, Glycosylated hemoglobin assay Regulatory Class: Class II Product Code: PDJ, LCP Dated: September 25, 2020 Received: September 29, 2020
Dear Louise Musante:
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. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. 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
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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) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (OS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; 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 https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). 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 (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE(@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely,
Marianela Perez-torres -S
Marianela Perez-Torres, Ph.D. Deputy Director OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Quality Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known) K200904
Device Name
Tosoh Automated Glycohemoglobin Analyzer HLC-723G8
Indications for Use (Describe)
The Tosoh Automated Glycohemoglobin Analyzer HLC-723G8 is intended for in vitro diagnostic use for the measurement of % hemoglobin A1c (HbA1c) (DCCT/NGSP) and mmol/mol hemoglobin A1c (IFCC) in venous whole blood specimens using ion-exchange high-performance liquid chromatography (HPLC). This test is an aid in diagnosis of diabetes and identifying patients who may be at risk for developing diabetes, and for monitoring of long-term blood glucose control in individuals with diabetes mellitus.
| Type of Use (Select one or both, as applicable) | |
|---|---|
| X Prescription Use (Part 21 CFR 801 Subpart D) | Over-The-Counter Use (21 CFR 801 Subpart C) |
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K200904 510(k) Summary Tosoh Bioscience, Inc.'s Tosoh Automated Glycohemoglobin Analyzer HLC-723G8
May 26, 2020 DATE PREPARED:
-
- COMPANY NAME/CONTACT Tosoh Bioscience, Inc. 6000 Shoreline Court, Suite 101 South San Francisco, CA 94080
-
- CONTACT: Louise Musante Regulatory Compliance Consultant Email: louise.musante@tosoh.com Cell Phone: (650) 242-5563
3. DEVICE INFORMATION
Device Trade Name: Tosoh Automated Glycohemoglobin Analyzer HLC-723G8 Regulation Numbers: 21 CFR Part 862.1373 and 21 CFR Part 864.7470 Regulation Names: Hemoglobin A1c test system, Glycosylated hemoglobin assay Product Code: PDJ, LCP Device Class: Class II 510(k) Review Panel: Clinical Chemistry
4. PREDICATE DEVICE
Trade name: VARIANT II TURBO HbA1c Kit – 2.0 on the VARIANT II TURBO Hemoglobin Testing System
| 510(k) submitter/holder: | Bio-Rad Laboratories, Inc., |
|---|---|
| Clinical Diagnostics Group | |
| 4000 Alfred Nobel Drive Hercules, CA 94547 |
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510(k) Numbers:
K122472 (monitoring claim) K142448 (diagnostic claim)
5. REFERENCE DEVICES USED IN NON-CLINICAL PERFORMANCE TESTING
Method Comparison testing:
Trinity Biotech Premier Hb9210™ HbA1c Analyzer, by Primus Corporation DBA Trinity Biotech, K112015, Product Code LCP
Hemoglobin Variant Interference (HbC, HbE and HbS) testing:
Primus Model CLC 330, aka Ultra2 Affinity HbA1c Analyzer, by Primus Corporation DBA Trinity Biotech, K891235, Product Code LCP
Hemoglobinopathy Interference (HbF and HbA2) testing:
VARIANT II TURBO HbA1c Kit - 2.0 on the VARIANT II TURBO Hemoglobin Testing System by Bio-Rad Laboratories, Inc., K142448, Product Code LCP
6. DEVICE DESCRIPTION
The Tosoh Automated Glycohemoglobin Analyzer HLC-723G8 is an automated High-Performance Liguid Chromatography (HPLC) system that separates and reports stable hemoglobin A1c (sA1c) percentage in venous whole blood. The operational portion of the G8 is composed of a sampling unit, liquid pump, degasser, column, detector, microprocessors, sample loader, smart media card, operation panel, and a printer.
The Tosoh Automated Glycohemoglobin Analyzer HLC-723G8 system consists of the following components, which are 510(k) exempt and clearance is not required;
- G8 Variant Elution Buffer HSi No. 1 (S), No. 2 (S), No. 3 (S) ●
- TSKgel® G8 Variant HSi (column)
- Hemoglobin A1c Controls Levels 1 and 2 ●
- 21 CFR 862.1660, Product Code JJX o
- Hemoglobin A1c Calibrator Set
- 21 CFR 862.1150, Product Code JIT o
- Hemolysis and Wash Solution
- 21 CFR 864.8540, Product Code GGK o
The Tosoh Automated Glycohemoglobin Analyzer HLC-723G8 uses ion-exchange HPLC for rapid, accurate, and precise separation of the stable form of HbA1c (sA1c) from other hemoglobin fractions. The G8 uses a non-porous cation exchange column and separates the hemoglobin
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components in the blood. Separation is achieved by utilizing differences in ionic interactions between the cation and exchange group on the column resin surface and the hemoglobin components in a step gradient elution. The hemoglobin fractions (designated as A1a. A1b. F. LA1c+, SA1c, A0, and, if present, H-V0, H-V2, H-V2 and H-V3) are subsequently removed from the column by performing a step-wise elution gradient using the varied salt concentrations in the Variant Elution Buffers HSi 1, 2 and 3. The peaks, H-V0, H-V1, H-V2 and H-V3 are typically presumptive HbAD, HbAS, HbAC and HbAE respectively.
The software compares the retention times of hemoglobin fractions in a sample to the expected "windows of retention" and labels each fraction that correctly elutes within a defined expected window of retention. The software designates a hemoglobin fraction as POX (where X is the order of the peak as it elutes from the column) if it does not match a defined window of retention. All automated processes in the G8 are controlled by internal microprocessors, using software downloaded via a smart media card.
The result report is printed and can be stored on the instrument. The data can be transmitted to a host computer through a bi-directional interface. The result report includes the sample ID, date, percentage and retention time of each fraction of hemoglobin, sA1c percentage and total A1 percentage, along with a chromatogram of the elution pattern of the hemoglobin fractions. If a sample contains a hemoglobin variant, the column elutes the fraction depending upon its charge.
7. INDICATION FOR USE STATEMENT
The Tosoh Automated Glycohemoglobin Analyzer HLC-723G8 is intended for in vitro diagnostic use for the measurement of % hemoglobin A1c (HbA1c) (DCCT/NGSP) and mmol/mol hemoglobin A1c (IFCC) in venous whole blood specimens using ion-exchange high-performance liquid chromatography (HPLC). This test is to be used as an aid in diagnosis of diabetes and identifying patients who may be at risk for developing diabetes, and for monitoring of long-term blood glucose control in individuals with diabetes mellitus.
8. INTENDED USE STATEMENTS:
The Tosoh Automated Glycohemoglobin Analyzer HLC-723G8 is intended for in vitro diagnostic use for the measurement of % hemoglobin A1c (HbA1c) (DCCT/NGSP) and mmol/mol hemoglobin A1c (IFCC) in venous whole blood specimens using ion-exchange high-performance liguid chromatography (HPLC). This test is to be used as an aid in diagnosis of diabetes and identifying patients who may be at risk for developing diabetes, and for monitoring of long-term blood glucose control in individuals with diabetes mellitus.
9. SUBSTANTIAL EQUIVALENCE COMPARISON
The Tosoh Automated Glycohemoglobin Analyzer HLC-723G8, v5.24, is substantially equivalent to the claimed predicate device; the Bio-Rad VARIANT II TURBO HbA1c Kit – 2.0 on the VARIANT II TURBO Hemoglobin Testing System (K122472 and K142448), based on comparisons of the intended use and technological characteristics.
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Table 1 – Comparison Table of Subject Device to Predicate Device
| Attributes | Tosoh AutomatedGlycohemoglobinAnalyzer HLC-723G8,v5.24(Subject Device) | VARIANT II TURBO HbA1cKit - 2.0 on the VARIANTII TURBO HemoglobinTesting System(K142448) | VARIANT II TURBO HbA1cKit - 2.0 on VARIANT IITURBO HemoglobinTesting System(K122472) | Differences | Differencesraise anyadditionalsafetyissues? |
|---|---|---|---|---|---|
| General Information | |||||
| Regulation # | 21 CFR 862.137321 CFR 864.747021 CFR 862.1150 | 21 CFR 862.1373 | 21 CFR 864.7470 | Same | N/A |
| RegulationName | Hemoglobin A1c TestSystemGlycosylatedHemoglobin AssayCalibrator | Hemoglobin A1c testsystem | Glycosylated HemoglobinAssay | Same | N/A |
| Regulatory Class | Class II | Class II | Class II | Same | N/A |
| Product Code | PDJ, LCP, JIS | PDJ | LCP | Same | N/A |
| Indications forUse | The Tosoh AutomatedGlycohemoglobin AnalyzerHLC-723G8 is intended forin vitro diagnostic use forthe measurement of %hemoglobin A1c (HbA1c)(DCCT/NGSP) andmmol/mol hemoglobinA1c (IFCC) in venous wholeblood specimens usingion-exchange high-performance liquidchromatography (HPLC).This test is to be used asan aid in diagnosis ofdiabetes and identifyingpatients who may be atrisk for developingdiabetes, and formonitoring of long-termblood glucose control inindividuals with diabetesmellitus. | The VARIANT II TURBOHbA1c Kit - 2.0 is intendedfor the quantitativedetermination ofhemoglobin A1c (IFCCmmol/mol and NGSP %) inhuman whole blood usingion-exchange high-performance liquidchromatography (HPLC) onthe VARIANT™ II TURBOHemoglobin TestingSystem and VARIANT IITURBO Link HemoglobinTesting System.This test is to be used asan aid in diagnosis ofdiabetes and as an aid inidentifying patients whomay be at risk fordeveloping diabetes.The VARIANT™ II TURBOHbA1c Kit – 2.0 is intendedfor Professional Use Only.The Hemoglobin CapillaryCollection System (HCCS)is intended for thecollection of human wholeblood for the percentage | The Bio-Rad VARIANT IITURBO HbA1c Kit - 2.0 isintended for thequantitativedetermination ofhemoglobin A1c in humanwhole blood using ion-exchange highperformance liquidchromatography (HPLC) onthe VARIANT II TURBOHemoglobin TestingSystem. Measurement ofhemoglobin A1c iseffective in monitoringlong-term glycemic controlin individuals withdiabetes mellitus. The Bio-Rad VARIANT II TURBOHbA1c Kit - 2.0 is intendedfor Professional Use Only. | Different | No |
| Attributes | Tosoh AutomatedGlycohemoglobinAnalyzer HLC-723G8,v5.24(Subject Device) | VARIANT II TURBO HbA1cKit - 2.0 on the VARIANTII TURBO HemoglobinTesting System(K142448) | VARIANT II TURBO HbA1cKit - 2.0 on VARIANT IITURBO HemoglobinTesting System(K122472) | Differences | Differencesraise anyadditionalsafetyissues? |
| determination ofhemoglobin A1c using Bio-Rad HPLC methods. |
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Table 2 – Comparison Table of Technological Characteristics: Subject Device to Predicate Device
| Attributes | Tosoh AutomatedGlycohemoglobinAnalyzer HLC-723G8,v5.24(Subject Device) | Bio-Rad VARIANT IITURBO HbA1c Kit - 2.0 onthe VARIANT II TURBOHemoglobin TestingSystem(K142448) | VARIANT II TURBOHbA1c Kit - 2.0 onVARIANT II TURBOHemoglobin TestingSystem(K122472) | Differences | Differencesraise anyadditionalsafetyissues? |
|---|---|---|---|---|---|
| Product Specifications | |||||
| InstrumentPlatform | AutomatedGlycohemoglobin AnalyzerHLC-723G8 | VARIANT™ II TURBOHemoglobin TestingSystem and VARIANT™ IITURBO Link HemoglobinTesting System | VARIANT™ II TURBOHemoglobin TestingSystem and VARIANT™ IITURBO Link HemoglobinTesting System | Different | No |
| DetectionMethod | Analyte passes through aflow cell where changes inabsorbance are measureat 415nm and recorded asa digital chromatogram.An additional filter at500nm corrects forbackground absorbance. | Analyte passes through aflow cell where changes inabsorbance are measureat 415nm and recorded asa digital chromatogram.An additional filter at690nm corrects forbackground absorbance. | Analyte passes through aflow cell where changes inabsorbance are measureat 415nm and recorded asa digital chromatogram.An additional filter at690nm corrects forbackground absorbance. | Different | No |
| Assay Principle | Ion-exchange HPLC | Ion-exchange HPLC | Ion-exchange HPLC | Same | N/A |
| Specimen Types | Human Venous WholeBlood | Human Venous WholeBlood | Human Venous WholeBlood | Same | N/A |
| Methodology | Dilutes whole bloodspecimen with Hemolysis& Wash Solution, and theninjects a small volume ofthis specimen onto theTSKgel G8 Variant HSicolumn. | Dilutes whole bloodspecimen and then injectsa small volume of thisspecimen onto theanalytical cartridge. | Dilutes whole bloodspecimen and then injectsa small volume of thisspecimen onto theanalytical cartridge. | Same | N/A |
| Attributes | Tosoh AutomatedGlycohemoglobinAnalyzer HLC-723G8,v5.24(Subject Device) | Bio-Rad VARIANT IITURBO HbA1c Kit - 2.0 onthe VARIANT II TURBOHemoglobin TestingSystem(K142448) | VARIANT II TURBOHbA1c Kit - 2.0 onVARIANT II TURBOHemoglobin TestingSystem(K122472) | Differences | Differencesraise anyadditionalsafetyissues? |
| Performance Specifications | |||||
| MeasuringRange | 4.0 to 16.9% HbA1c(NGSP) | 3.4 to 20.6% HbA1c(NGSP) | 3.4 to 20.6% HbA1c(NGSP) | Different | No |
| Traceability andStandardization | Traceable to the DiabetesControl and ComplicationsTrial (DCCT) referencemethod and IFCC.Certified via the NationalGlycohemoglobinStandardization Program(NGSP) | Traceable to the DiabetesControl and ComplicationsTrial (DCCT) referencemethod and IFCC.Certified via the NationalGlycohemoglobinStandardization Program(NGSP) | Traceable to the DiabetesControl and ComplicationsTrial (DCCT) referencemethod and IFCC.Certified via the NationalGlycohemoglobinStandardization Program(NGSP) | Same | N/A |
| Matrix | K2-EDTA and K3-EDTAVenous Whole Blood | K2-EDTA, K3-EDTA,Capillary blood inHemoglobin CapillaryCollection System (HCCS) | K2-EDTA, K3-EDTA,Capillary blood inHemoglobin CapillaryCollection System (HCCS) | Same | N/A |
| HemoglobinVariantInterference | Accurate and reportableHbA1c% results in thepresence of HbC (39%),HbD (39.5%), HbS (39%).Non-clinically significantinterference is defined as<= 6% relative differencein the results from acomparative method at6% or 9% HbA1c.Accurate HbA1c% in thepresence of HbF up to25%. Non-clinicallysignificant interference isdefined as = 6% relative<br difference in the resultsfrom a comparativemethod at 6% or 9%HbA1c.Accurate HbA1c% in thepresence of HbA2 up to12%. Non-clinicallysignificant interference isdefined as = 6% relative<br difference in the resultsfrom a comparative | Accurate and reportableHbA1c% results in thepresence of HbC, HbD,HbS. Non-clinicallysignificant interferencedefined as ±7% from thecontrol.Accurate HbA1c% in thepresence of HbF up to25%.Accurate HbA1c% in thepresence of HbA2 up to10%. | Accurate and reportableHbA1c% results in thepresence of HbC, HbD,HbS. Non-clinicallysignificant interferencedefined as ±7% from thecontrol.Accurate HbA1c% in thepresence of HbF up to25%.Accurate HbA1c% in thepresence of HbA2 up to10%. | Different | No |
| Attributes | Tosoh AutomatedGlycohemoglobinAnalyzer HLC-723G8,v5.24(Subject Device) | Bio-Rad VARIANT IITURBO HbA1c Kit - 2.0 onthe VARIANT II TURBOHemoglobin TestingSystem(K142448) | VARIANT II TURBOHbA1c Kit - 2.0 onVARIANT II TURBOHemoglobin TestingSystem(K122472) | Differences | Differencesraise anyadditionalsafetyissues? |
| method at 6% or 9%HbA1c. | |||||
| Accurate and reportableHbA1c% results in thepresence of 26% HbE.Non-clinically significantinterference is defined as<= 6% relative differencein the results from acomparative method at6% or 9% HbA1c. | Accurate and reportableHbA1c% results in thepresence of HbE. Non-clinically significantinterference defined as±7% from the control. | Accurate and reportableHbA1c% results in thepresence of HbE. Non-clinically significantinterference defined as±7% from the control. | Different | No |
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10. SUMMARY OF TECHNOLOGICAL DIFFERENCES
Indications for Use:
The predicate device is cleared separately for the monitoring claim (K122472) and diagnostic claim (K142448). Tosoh seeks clearance for both the monitoring and diagnostic claim combined in this pre-market submission by combining the claims sought and obtained separately for previously cleared Tosoh Automated Glycohemoglobin Analyzer HLC-723G8 submissions; K071132 for the long-term monitoring of people diagnosed with diabetes under 21 CFR 864.7470 as well as the same analyzer cleared in K131580 as a diagnostic HbA1c device under 21 CFR 862.1373. As both clearances are for the same device, with incremental changes, the combination of "Indications for Use" does not raise any additional safety or efficacy questions for the subject device.
Instrument Platform:
The subject device and predicate device are both automated High-Performance Liquid Chromatography (HPLC) systems that separate and report hemoglobin A1c percentage in venous whole blood. Aside for the sample volume requirement (3μL of whole blood and 80μL of diluted samples for the subject device and 50μL of venous whole blood and diluted samples for the predicate device), both systems use software algorithms to measure HbA1c concentrations, in the presence of variants. The difference in instrument platform does not raise any additional safety or efficacy questions for the subject device.
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Detection Method:
The subject device allows the analyte to pass through a flow cell where changes in absorbance are measure at 415nm and recorded as a digital chromatogram. An additional filter at 500nm corrects for background absorbance. The predicated device uses the same absorbance wavelength to detect and record the sample as a digital chromatogram. The additional filter, however, uses a wavelength of 690nm, correcting for background absorbance. The difference in background wavelength subtraction does not raise any additional safety or efficacy questions for the subject device.
Measuring Range:
The subject device has a measuring range of 4.0 to 16.9% HbA1c (NGSP), whereas the predicate device has a measuring range of 3.4 to 20.6% HbA1c (NGSP). The difference in measuring range does not raise any additional safety or efficacy questions for the subject device.
11. SUMMARY OF NON-CLINICAL PERFORMANCE TESTING
Non-clinical performance tests were conducted to support the substantial equivalence determination of this 510(k) submission. No clinical performance tests were conducted to support the substantial equivalence determination of this 510(k) submission. The non-clinical performance tests and summary of results are as follows;
a) Precision/Repeatability
The precision repeatability study was performed in compliance with CLSI EP05-A3, Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline – Third Edition, to verify whether or not the previously established claim of imprecision at ≤ 2% was affected by the software modification to version 5.24 of the Tosoh Automated Glycohemoglobin Analyzer HLC723-G8. Four concentrations of HbA1c% in K2EDTA venous whole blood were tested. The concentrations were approximately 5.0%, 6.5%, 8.0% and 12.0%. A total of seven-hundred and twenty measurements per concentration were measured using the study design: three analyzers over twenty non-consecutive days with three reagent lots. Specimens were run in duplicate, two times per day for a total of seven-hundred and twenty unique results per concentration.
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| HbA1c%(Target)Mean | Repeatability | Between Run | Between Day | Between Lot | BetweenInstruments | Total | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| SD | CV (%) | SD | CV (%) | SD | CV (%) | SD | CV (%) | SD | CV (%) | SD | CV (%) | |
| Sample1[5%]5.46% | 0.0188 | 0.35 | 0.0132 | 0.24 | 0.0266 | 0.49 | 0.0291 | 0.53 | 0.0272 | 0.50 | 0.0532 | 0.97 |
| Sample2[6.5%]6.38% | 0.0212 | 0.33 | 0.0084 | 0.13 | 0.0288 | 0.45 | 0.0280 | 0.44 | 0.0478 | 0.75 | 0.0665 | 1.04 |
| Sample3[8%]7.60% | 0.0199 | 0.26 | 0.0146 | 0.19 | 0.0386 | 0.51 | 0.0441 | 0.58 | 0.0737 | 0.97 | 0.0973 | 1.28 |
| Sample4[12%]11.91% | 0.0277 | 0.23 | 0.0167 | 0.14 | 0.0666 | 0.56 | 0.0684 | 0.57 | 0.0239 | 0.20 | 0.1036 | 0.87 |
| *: Negative variance component's values have been set to '0'. |
Table 3 - Summary of Precision Analysis of All Analyzers Combined
*: Negative variance component's values have been set to '0'.
Abbreviations: CV = coefficient of variation, SD = standard deviation
| HbA1c%(Target)Mean | Repeatability | Between Run | Between Day | Between Lot | Total | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| SD | CV (%) | SD | CV (%) | SD | CV (%) | SD | CV (%) | SD | CV (%) | |
| Sample1[5%] 5.43% | 0.0178 | 0.33 | 0.0146 | 0.27 | 0.0230 | 0.42 | 0.0145 | 0.27 | 0.0356 | 0.66 |
| Sample2[6.5%] 6.32% | 0.0204 | 0.32 | 0.0109 | 0.17 | 0.0252 | 0.40 | 0.0061 | 0.10 | 0.0348 | 0.55 |
| Sample3[8%] 7.51% | 0.0218 | 0.29 | 0.0204 | 0.27 | 0.0276 | 0.37 | 0.0203 | 0.27 | 0.0454 | 0.60 |
| Sample4[12%]11.89% | 0.0288 | 0.24 | 0.0254 | 0.21 | 0.0509 | 0.43 | 0.0154 | 0.13 | 0.0656 | 0.55 |
Table 4 - Summary of Precision Analysis for Analyzer 1 (SN 14736306)
*: Negative variance component's values have been set to '0'.
Abbreviations: CV = coefficient of variation, SD = standard deviation
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| Table 5 - Summary of Precision Analysis for Analyzer 2 (SN 14927602) | |||||
|---|---|---|---|---|---|
| HbA1c% (Target) | Repeatability | Between Run | Between Day | Between Lot | Total |
Section 5 - 510(k) Summary or 510(k) Statement
| (Target)Mean | SD | CV (%) | SD | CV (%) | SD | CV (%) | SD | CV (%) | SD | CV (%) |
|---|---|---|---|---|---|---|---|---|---|---|
| Sample1[5%] 5.48% | 0.0202 | 0.37 | 0.0151 | 0.28 | 0.0204 | 0.37 | 0.0402 | 0.73 | 0.0517 | 0.94 |
| Sample2[6.5%] 6.41% | 0.0231 | 0.36 | 0.0* | 0.0* | 0.0199 | 0.31 | 0.0480 | 0.75 | 0.0569 | 0.89 |
| Sample3[8%] 7.64% | 0.0217 | 0.28 | 0.0141 | 0.18 | 0.0278 | 0.36 | 0.0720 | 0.94 | 0.0814 | 1.07 |
| Sample4[12%] 11.93% | 0.0266 | 0.22 | 0.0146 | 0.12 | 0.0558 | 0.47 | 0.1228 | 1.03 | 0.1383 | 1.16 |
| *: Negative variance component's values have been set to '0'. |
Abbreviations: CV = coefficient of variation, SD = standard deviation
MeanHbA1c | Repeatability | Between Run | Between Day | Between Lot | Total | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| SD | CV (%) | SD | CV (%) | SD | CV (%) | SD | CV (%) | SD | CV (%) | |
| Sample1[5%] 5.47% | 0.0184 | 0.34 | 0.0092 | 0.17 | 0.0317 | 0.58 | 0.0312 | 0.57 | 0.0489 | 0.89 |
| Sample2[6.5%]6.40% | 0.0201 | 0.31 | 0.0099 | 0.15 | 0.0292 | 0.46 | 0.0300 | 0.47 | 0.0475 | 0.74 |
| Sample3[8%]7.64% | 0.0156 | 0.20 | 0.0050 | 0.06 | 0.0395 | 0.52 | 0.0475 | 0.62 | 0.0640 | 0.84 |
| Sample4[12%]11.90% | 0.0277 | 0.23 | 0.0* | 0.0* | 0.0602 | 0.51 | 0.0678 | 0.57 | 0.0948 | 0.80 |
| *: Negative variance component's values have been set to '0' |
Table 6 - Summary of Precision Analysis for Analyzer 3 (SN 12521504)
b) Method Comparison
The method comparison study was performed in compliance to CLSI EP09c: Measurement Procedure Comparison and Bias Estimation Using Patient Samples; Approved Guideline – Third Edition. The study was conducted at two separate sites with the candidate device; Tosoh G8 v5.24 Analyzer, located at a moderate complexity clinical laboratory and the comparator device; Trinity Biotech Premier Hb9210™ HbA1c Analyzer, located at an NGSP SRL. Two Hundred and Twenty (220) K₂EDTA venous whole blood specimens with HbA1c concentrations that span the G8 v5.24 measuring range (4.0-16.9%) were tested in duplicate on both analyzers.
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| Target A1cConcentration (%) | No. ofSpecimens | Percent of TotalSamples |
|---|---|---|
| <5% | 4 | 1.8% |
| 5.0 - 6.0% | 30 | 13.6% |
| 6.0 - 6.5% | 25 | 11.4% |
| 6.5 - 7.0% | 33 | 15.0% |
| 7.0 - 8.0% | 38 | 17.3% |
| 8.0 - 9.0% | 18 | 8.2% |
| >9.0% | 72 | 32.7% |
| Total | 220 | 100% |
Table 7 - Sample Distribution Across HbA1c Concentration Range
Table 8 - Summary of Method Comparison Results
| y-Intercept | 95% CI | Slope | 95% CI | |
|---|---|---|---|---|
| Deming | 0.1336 | -0.0331 to 0.3005 | 1.013 | 0.9894 to 1.036 |
| Passing-Bablok | 0.0720 | -0.0472 to -0.1819 | 1.021 | 1.007 to 1.037 |
Figure 1 - Method Comparison Deming Regression Analysis of G8 v5.24 vs NGSP SRL (Trinity Premier)
Image /page/14/Figure/7 description: This scatter plot compares two different measurement methods, G8 v5.24 and Premier. The x-axis represents the Premier measurements, while the y-axis represents the G8 v5.24 measurements. The plot includes a Deming fit line, represented by the equation y = -0.1336 + 1.013x, along with a 95% confidence interval (CI) indicated by dashed lines. The data points are clustered tightly around the Deming fit line, suggesting a strong correlation between the two measurement methods.
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Table 9 - Method Comparison Bias Results – Passing Bablok
| Decision Level | Bias | % Bias |
|---|---|---|
| 5.0% | 0.1753 | 3.5% |
| 6.5% | 0.2068 | 3.2% |
| 8.0% | 0.2383 | 3.0% |
| 12.0% | 0.3224 | 2.7% |
Table 10 - Method Comparison Bias Results - Deming
| Decision Level | Bias | % Bias |
|---|---|---|
| 5.0% | 0.1979 | 4.0% |
| 6.5% | 0.2172 | 3.3% |
| 8.0% | 0.2366 | 3.0% |
| 12.0% | 0.2884 | 2.4% |
Table 11 - Total Error Estimation
| Total Error [%] | |||||
|---|---|---|---|---|---|
| Passing Bablok | Deming | ||||
| HbA1c Level | `%TE´* | %Bias | `%TE´* | %Bias | %CVTotal |
| Sample1 [5%] | 5.48 | 3.5 | 5.99 | 4.0 | 0.974054 |
| Sample2 [6.5%] | 5.31 | 3.2 | 5.41 | 3.3 | 1.042108 |
| Sample3 [8%] | 5.59 | 3.0 | 5.59 | 3.0 | 1.281173 |
| Sample4 [12%] | 4.45 | 2.7 | 4.15 | 2.4 | 0.870450 |
| *: Calculated as: $` %Bias + 1.96 x %CVTotal x (1+ %Bias/100)´$ |
c) Matrix Comparison
The data supports the use of K2-EDTA and K3-EDTA blood collection tubes, as they show no clinical or statistical difference and thus may be used interchangeably for testing HbA1c on the G8 HPLC Analyzer.
d) Traceability and Expected Values (calibrators)
The assigned HbA1c values of the Tosoh Automated Glycohemoglobin Analyzer are certified with The National Glycohemoglobin Standardization Program (NGSP). The NGSP certification expires in one year. See NGSP website for current certification at http://www.ngsp.org.
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The final reportable result is traceable to both the International Federation of Clinical Chemistry (IFCC) and the Diabetes Control and Complications Trial (DCCT). The International Federation of Clinical Chemistry (IFCC) units of mmol/mol are calculated using the Master Equation NGSP (%) = [0.09148 x IFCC (mmol/mol)] + 2.152. HbA1c results are provided to the customers using two different units: NGSP equivalent units (%) and IFCC equivalent units (mmol/mol).
Calibrators (Tosoh A1c Calibrator Set) and Controls (Canterbury Scientific Hemoglobin A1c Control) are recommended for use with this device. The calibrators and controls were previously cleared under 510(k) K071132 and K021484, respectively.
-
e) Linearity and Detection Limit
Linearity and Detection Limit was previously established for this assay under 510(k) K071132. The reportable range for this device is 4.0 to 16.9% HbA1c. -
f) Analytical Specificity
- i. Endogenous Interfering Substances
The endogenous interference study was performed in compliance to CLSI EP07-A2. Interference Testing in Clinical Chemistry; Approved Guideline-Second Edition. Significant interference was defined as percent recovery ± 5% of the expected 100% recovery. Interference studies were conducted on known concentrations of HbA1c%. Specimens were spiked with increasing amounts of the interfering substance.
| Potential InterferingSubstance | Range Tested | HbA1c% Concentrations | Concentration with NoInterference |
|---|---|---|---|
| Albumin | 500 to 5000 mg/dL | 6.6 and 14.7 | 5000 mg/dL |
| Ascorbic Acid | 3.0 to 25 mg/dL | 6.4 and 10.8 | 25 mg/dL |
| Bilirubin C | 2.0 to 21 mg/dL | 6.5 and 14.3 | 21 mg/dL |
| Bilirubin F | 2.0 to 18 mg/dL | 6.5 and 14.3 | 18 mg/dL |
| Lipemia | 1 to 1000 mg/dL | 6.4 and 14.1 | 1000 mg/dL |
| Rheumatoid Factor | 110 to 550 IU/mL | 6.3 and 12.6 | 550IU/mL |
Table 12 - Endogenous Interfering Substances Tested
- ii. Drug Interference
The exogenous drug interference study was performed under clearance of K071132. Acetylsalicylic Acid was tested because it does form acetylated hemoglobin, which may interfere with the %HbA1c when measured by HPLC. Acetaldehyde was tested because it can form aldehyde hemoglobin, which can cause an increase in the LA1c fraction.
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With HPLC, the red cells are lysed and eluted across the column for separation of the hemoglobin fractions. Research of the FDA website and others show no contraindication of Levodopa. Methyldopa. Acetaminophen and Ibuprofen when used by pre-diabetic or diabetic patients, and the drugs do not interfere with the HPLC technology as they might during an antigen/antibody reaction. FDA stated that based on the technology of the device, it has been shown that the additional substances do not appear to interfere with this type of device; therefore, the additional interference data on these drugs was not needed.
-
iii. Cross Reactivity with Hemoglobin Derivatives
A cross-reactivity study was performed with potential interferences from Acetylated hemoglobin (Hb), Carbamylated Hb, Aldehyde Hb, and Labile HbA1c with HbA1c values of ~6.5% and ~8% HbA1c. The following results were concluded as not interfering with the assay. -
Acetylated Hb up to 50 mg/dL
-
Carbamylated Hb up to 25 mg/dL ●
-
. Aldehyde Hb up to 25 mg/dL
-
Labile HbA1c up to 1000 mg/dL
iv. Hemoglobin Variant Interference
The hemoglobin variant interference study was performed in compliance to CLSI EPO7-A2, Interference Testing in Clinical Chemistry; Approved Guideline-Second Edition. Interference when measuring %HbA1c in clinical specimens due to certain levels of Hb variants (HbC, HbD, HbE, and HbS) and hemoglobinopathies (HbA2 and HbF) is wellknown. To reduce possible interference and to enhance the performance of the G8 in the presence of these variants and hemoglobinopathies, Tosoh modified the software algorithms. The modified software, version 5.24, reduces interference when measuring %HbA1c.
An interference study was performed to identify the level of Hb variants and hemoglobinopathies likely to cause interference, thus verifying that the G8 software modification (version 5.24) did reduce measurement interference of %HbA1c under these conditions. Non-clinically significant interference was defined as <= 6% relative difference in the results from a comparative method at 6.5% or 8.0% HbA1c.
| HemoglobinVariant/Hemoglobinopathy | n | Range in % Abnormal Variant/Hemoglobinopathy | Range in % HbA1cConcentration |
|---|---|---|---|
| HbC | 26 | 30.8 to 37.8 | 4.8 to 9.8 |
| HbD | 24 | 22.6 to 40.7 | 5.3 to 9.347 |
| HbE | 26 | 20.0 to 30.9 | 4.763 to 9.7 |
| HbS | 29 | 28.2 to 38.9 | 4.9 to 10.05 |
| HbA2* | 20 | 2.7 to 5.5 | 5.85 to 10.1 |
Table 13 - Variant Samples Used in Hemoglobin Variant Study
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| HbF* | 21 | 0.4 to 43.35 | 4.36 to 8.9 |
|---|---|---|---|
| ------ | ---- | -------------- | ------------- |
| Hemoglobin Variant/Hemoglobinopathy | Percent Relative Bias from Reference Methodat Low and High Concentrations of HbA1c Samples | |||
|---|---|---|---|---|
| ~6.5 % HbA1c | ~8.0 % HbA1c | |||
| Calibrated Relative% Difference | Range | Calibrated Relative% Difference | Range | |
| HbAD | -0.5 | 0.08 to 0.30 | -1.7 | -0.04 to 0.36 |
| HbAS | -2.7 | -0.04 to 0.13 | -3.2 | -0.14 to 0.21 |
| HbAC | -1.9 | 0.03 to 0.17 | -1.1 | 0.06 to 0.34 |
| HbAE | -1.3 | 0.001 to 0.27 | -1.2 | -0.10 to 0.49 |
| HbA2 | -4.2 | -0.17 to 0.06 | -5.1 | -0.37 to 0.12 |
| HbF | -0.7 | 0.10 to 0.25 | -1.6 | -0.01 to 0.34 |
Table 14 - Hemoglobin Variant Study - Reporting Percent Relative Bias
All performance testing results met their pre-determined acceptance criteria. In all instances, the Tosoh Automated Glycohemoglobin Analyzer HLC-723G8, v5.24 performed as intended. Additionally, a risk hazard analysis and design FMEA were performed for the Tosoh Automated Glycohemoglobin Analyzer HLC-723G8, v5.24. The risk management report concluded that all identified risks were mitigated to an acceptable risk level through design and/or labeling, and that the benefits of using the Tosoh Automated Glycohemoglobin Analyzer HLC-723G8, v5.24 for its intended use outweigh any residual risk from use of the device.
12. CONCLUSION
Tosoh Bioscience, Inc. believes that the Tosoh Automated Glycohemoglobin Analyzer HLC-723G8, v5.24, is substantially equivalent in intended use and technological characteristics to the Bio-Rad VARIANT II TURBO HbA1c Kit – 2.0 on the VARIANT II TURBO Hemoglobin Testing System (K122472 and K142448). The Tosoh Automated Glycohemoglobin Analyzer HLC-723G8, v5.24 therefore meets the Federal Food, Drug and Cosmetic Act criteria for 510(k) clearance of this device.
§ 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.