(892 days)
The Hipro® Glycosylated Hemoglobin (HbA1c) Test System comprised of the Hipro Glycosylated hemoglobin (HbA1c) test kit and the HP-AFS/1 automatic immunoassay analyzer is used as an aid in diagnosis of diabetes mellitus, as an aid to identify patients who may be at risk for developing diabetes mellitus, and for the monitoring of long-term blood glucose control in individuals with diabetes mellitus. It is an in vitro diagnostics reagent system intended for quantitative determination of % hemoglobin A1c (DCCT/NGSP) in venous whole blood.
The Hipro® Glycosylated hemoglobin (HbA1c) test system is intended for quantitative determination of % hemoglobin A 1c (DCCT/NGSP) in venous whole blood. It is composed of Glycosylated hemoglobin (HbA1c) test kit and automatic immunoassay analyzer. Glycosylated hemoglobin (HbA1c) test kit consists of two reagents R1 and R2, which are liquid and ready to use. Reagent R1 contains glycine buffer and latex, and reagent R2 contains glycine buffer and two types of antibodies, Goat anti-mouse IgG, mouse anti-human HbAlc monoclonal antibody.
HP-AFS/1 Automatic Immunoassay Analyzer is made up of light absorption test module, scattered light test module, fluorescence test module, press components, data transmission interface and printer. And the absorption test module is made up of absorption light path unit, and lightabsorption sensor part. The scattered light test module is made up of scattered light path unit and scattered light sensor part.
Here's a breakdown of the acceptance criteria and the study details for the Hipro® Glycosylated Hemoglobin (HbA1c) Test System:
1. Table of Acceptance Criteria and Reported Device Performance
The document does not explicitly state pre-defined acceptance criteria values for most tests. Instead, it describes performing studies and concluding whether "All acceptance criteria were met" or providing summary statistics. For the purpose of this table, I will infer relevant criteria based on common industry standards for diagnostic devices and the structure of the reported results. For Method Comparison, Total Error, and Linearity, the reported results are directly in line with typical performance metrics. For Interference and Hemoglobin Variants, "met acceptance criteria" and specific thresholds are mentioned.
| Performance Characteristic | Acceptance Criterion (Inferred/Stated) | Reported Device Performance |
|---|---|---|
| Precision (Total %CV) | Not explicitly stated. Implied to be within acceptable clinical limits. | For HbA1c concentrations ranging from 5.2% to 12.3%, Total %CV ranged from 1.5% to 2.7% across multiple analyzers and lots. For controls (6%, 11%), Total %CV was 3.0% and 1.6% respectively. |
| Method Comparison (Mean Bias) | Not explicitly stated. Implied to show good agreement. | Mean bias vs. NGSP Bio-Rad: -0.0148. 95% CI for mean bias: -0.0470 to 0.0174. |
| Bias at Specific Concentrations | Not explicitly stated. | -0.5% at 5.23% HbA1c, -0.26% at 6.34%, -0.02% at 8.03%, 0.31% at 12.53%. |
| Total Error (%TE) | Not explicitly stated. Implied to be within acceptable clinical limits. | %TE ranged from 3.3% to 5.5% for HbA1c concentrations 5.23% to 12.53%. |
| Linearity (R value) | Not explicitly stated. Implied to be high (close to 1). | R = 0.999 |
| Linearity (Range) | Not explicitly stated. | 4.3% - 14% HbA1c |
| Endogenous Interference (Deviation) | >7% deviation in % HbA1c considered significant interference. | All tested substances (Lipemia, Unconjugated Bilirubin, Conjugated Bilirubin, Glucose, Rheumatoid Factor, Total Protein) showed no significant interference at the highest tested concentrations. |
| Drug Interference (Deviation) | >7% deviation from reference value considered significant interference. | All 16 commonly used drugs tested showed no significant interference. |
| Cross-reactivity | Not explicitly stated. Implied no significant cross-reactivity. | Studies performed for Hb A0, Labile Hb A1c, Carbamylated Hb, Acetylated Hb, Glycated Albumin, Hb A1a+b. Results not detailed, but implied acceptance. |
| Hemoglobin Variants (Interference) | Not explicitly stated. Implied to be minimal or within acceptable clinical limits. Interference with HbF > 8% was observed. | Average bias for HbC: -0.17 at ~6.5% HbA1c, 2.27 at ~9.0% HbA1c. Average bias for HbD: 1.67 at ~6.5% HbA1c, 2.10 at ~9.0% HbA1c. Average bias for HbE: 1.58 at ~6.5% HbA1c, 1.38 at ~9.0% HbA1c. Interference was observed when the concentration of HbF is > 8%. Average bias for HbS: 1.69 at ~6.5% HbA1c, 1.20 at ~9.0% HbA1c. Average bias for HbA2: 1.57 at ~6.5% HbA1c, -0.51 at ~9.0% HbA1c. |
2. Sample Size Used for the Test Set and Data Provenance
- Precision: Four EDTA K2 whole blood samples with targeted HbA1c concentrations (5.2%, 6.4%, 8.0% and 12.3%) and two controls (6% and 11%). Each sample was analyzed in duplicate per run, two runs per day for 20 days on three analyzers (total of 240 measurements per sample/control).
- Method Comparison: One hundred and twenty (120) samples.
- Linearity: One dilution series consisting of 9 levels. Each level measured in triplicate.
- Endogenous Interference: Pooled whole blood samples with two HbA1c levels, spiked with 5 interferents (10 spiked samples), and one unspiked pool. A 10-level dilution series was created for each. Tested ten-fold.
- Drug Interference: Native patient samples at 2 different HbA1c levels, spiked with 16 drugs at two defined concentrations. Measured ten-fold.
- Hemoglobin Variants: 20 samples for each variant (HbC, HbD, HbE, HbF, HbS, HbA2) for a total of 120 samples. Each sample was tested twice.
Data Provenance:
- Method Comparison: The 120 samples were obtained from the NGSP reference laboratory.
- General: The document does not explicitly state the country of origin or whether samples were retrospective or prospective, but the reliance on the NGSP reference laboratory suggests a standardized, potentially retrospective, approach for the method comparison component. The use of "native patient samples" for drug interference suggests clinical sources.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications
The establishment of ground truth is primarily through a traceable reference method and a standardization program.
- Method Comparison: The test system was compared against the Bio-Rad Hemoglobin Testing System which was certified by the National Glycohemoglobin Standardization Program (NGSP). The NGSP is a program that standardizes HbA1c results to align with the results of the Diabetes Control and Complications Trial (DCCT). This implies that the 'ground truth' is established by the NGSP's reference methods and processes, rather than individual experts adjudicating each case. The document specifies that the NGSP reference laboratory measured the "X axis" samples.
The document does not specify a number of "experts" in the traditional sense of clinicians or radiologists adjudicating individual cases.
4. Adjudication Method for the Test Set
Not applicable. This is not a study requiring human adjudication of imaging or clinical cases. The "ground truth" is established by a reference laboratory measurement (NGSP Bio-Rad Hemoglobin Testing System) for chemical analysis.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done
No, an MRMC comparative effectiveness study was not done. This device is an in vitro diagnostic (IVD) test system for quantitative determination of HbA1c, not a diagnostic imaging or AI-assisted interpretation device that involves human readers.
6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) Was Done
Yes, the studies described are standalone performance evaluations of the Hipro® Glycosylated Hemoglobin (HbA1c) Test System (the automatic immunoassay analyzer and test kit) without human intervention in the measurement process. The system quantifies HbA1c levels directly.
7. The Type of Ground Truth Used
- Reference Method: For method comparison, the ground truth was established by the NGSP (National Glycohemoglobin Standardization Program) Bio-Rad Hemoglobin Testing System. The device is certified with NGSP.
- Reference Materials: For precision, linearity, interference, and hemoglobin variant studies, the ground truth for HbA1c concentrations was established using characterized samples (e.g., targeted HbA1c concentrations, spiked samples, varying hemoglobin variant concentrations) which would derive their values from established reference methods or known preparations.
8. The Sample Size for the Training Set
The document does not mention a separate "training set" in the context of an AI/ML algorithm that is trained. This device is a chemical assay system, not an AI/ML-based diagnostic. The described studies are all for performance evaluation (test set) of the final device.
9. How the Ground Truth for the Training Set Was Established
Not applicable, as there is no specific "training set" for an AI/ML algorithm mentioned for this device.
{0}------------------------------------------------
Image /page/0/Picture/0 description: The image contains the logo of the U.S. Food and Drug Administration (FDA). On the left is the Department of Health & Human Services logo. To the right of that is the FDA logo, which is a blue square with the letters "FDA" in white. To the right of the blue square is the text "U.S. FOOD & DRUG ADMINISTRATION" in blue.
September 12, 2024
Shijiazhuang Hipro Biotechnology Co., Ltd. % Hanson Chen, Official Correspondent Shenzhen Joyantech Consulting Co., Ltd. 1713A, 17th Floor, Block A Zhongguan Times Square, Liuxian Avenue, Xili Town, Nanshan District Shenzhen. Gaungdong 518000 China
Re: K220999
Trade/Device Name: Hipro Glycosylated Hemoglobin (HbA1c) Test System Regulation Number: 21 CFR 862.1373 Regulation Name: Hemoglobin A1c Test System Regulatory Class: Class II Product Code: PDJ, LCP Dated: October 13, 2023 Received: October 13, 2023
Dear Hanson Chen:
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 (the 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 available 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.
Additional information about changes that may require a new premarket notification are provided in the FDA guidance documents entitled "Deciding When to Submit a 510(k) for a Change to an Existing Device" (https://www.fda.gov/media/99812/download) and "Deciding When to Submit a 510(k) for a Software Change to an Existing Device" (https://www.fda.gov/media/99785/download).
{1}------------------------------------------------
Your device is also subject to, among other requirements, the Quality System (QS) regulation (21 CFR Part 820), which includes, but is not limited to, 21 CFR 820.30, Design controls; 21 CFR 820.90, Nonconforming product; and 21 CFR 820.100, Corrective and preventive action. Please note that regardless of whether a change requires premarket review. the OS regulation requires device manufacturers to review and approve changes to device design and production (21 CFR 820.30 and 21 CFR 820.70) and document changes and approvals in the device master record (21 CFR 820.181).
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 Part 803) for devices or postmarketing safety reporting (21 CFR Part 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safetyreporting-combination-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 Part 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR Parts 1000-1050.
All medical devices, including Class I and unclassified devices and combination product device constituent parts are required to be in compliance with the final Unique Device Identification System rule ("UDI Rule"). The UDI Rule requires, among other things, that a device bear a unique device identifier (UDI) on its label and package (21 CFR 801.20(a)) unless an exception or alternative applies (21 CFR 801.20(b)) and that the dates on the device label be formatted in accordance with 21 CFR 801.18. The UDI Rule (21 CFR 830.300(a) and 830.320(b)) also requires that certain information be submitted to the Global Unique Device Identification Database (GUDID) (21 CFR Part 830 Subpart E). For additional information on these requirements, please see the UDI System webpage at https://www.fda.gov/medical-device-advicecomprehensive-regulatory-assistance/unique-device-identification-system-udi-system.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 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.
{2}------------------------------------------------
For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/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,
Joshua Balsam -S
Joshua M. Balsam, Ph.D. Branch Chief Division of Chemistry and Toxicology Devices OHT7: Office of In Vitro Diagnostics Office of Product Evaluation and Quality Center for Devices and Radiological Health
Enclosure
{3}------------------------------------------------
Indications for Use
510(k) Number (if known) K220999
Device Name
Hipro® Glycosylated Hemoglobin (HbA1c) Test System
Indications for Use (Describe)
The Hipro® Glycosylated Hemoglobin (HbA1c) Test System comprised of the Hipro Glycosylated hemoglobin (HbA1c) test kit and the HP-AFS/1 automatic immunoassay analyzer is used as an aid in diagnosis of diabetes mellitus, as an aid to identify patients who may be at risk for developing diabetes mellitus, and for the monitoring of long-term blood glucose control in individuals with diabetes mellitus. It is an in vitro diagnostics reagent system intended for quantitative determination of % hemoglobin A1c (DCCT/NGSP) in venous whole blood.
| 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) |
CONTINUE ON A SEPARATE PAGE IF NEEDED.
This section applies only to requirements of the Paperwork Reduction Act of 1995.
DO NOT SEND YOUR COMPLETED FORM TO THE PRA STAFF EMAIL ADDRESS BELOW.
The burden time for this collection of information is estimated to average 79 hours per response, including the time to review instructions, search existing data sources, gather and maintain the data needed and complete and review the collection of information. Send comments regarding this burden estimate or any other aspect of this information collection, including suggestions for reducing this burden, to:
Department of Health and Human Services Food and Drug Administration Office of Chief Information Officer Paperwork Reduction Act (PRA) Staff PRAStaff(@fda.hhs.gov
"An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB number."
{4}------------------------------------------------
| 510(k) Summary | K220999 |
|---|---|
| 1. Contact Details1.1 Applicant information | |
| Applicant Name | Shijiazhuang Hipro Biotechnology Co., Ltd. |
| Address | No. 3 Building, Block C Fang Yi Science Park, No. 365 Huai'an EastRoad, Hi-tech Zone, Shijiazhuang, 050000 Hebei, P.R. China |
| Phone No. | +86-311-83855889 |
| Contact person | Bruce |
| Date Prepared | Sep 12, 2024 |
| Website | http://www.hiprochina.com/ |
1.2 Submission Correspondent
| Image: Logo | Shenzhen Joyantech Consulting Co., Ltd | |
|---|---|---|
| 卓远天成 | 1713A, 17th Floor, Block A, Zhongguan Times Square, LiuxianAvenue, Xili Town, Nanshan District, Shenzhen, Guangdong,518000, China | |
| Phone No. | +86-755-86069197 | |
| Contact person | Hanson Chen | |
| Contact person's e-mail | hanson@cefda.com | |
| Website | http://www.cefda.com |
2. Device information
| Trade name | Hipro® Glycosylated Hemoglobin (HbA1c) Test System |
|---|---|
| Model | / |
| Classification | II |
| Classification name | Hemoglobin A1c Test System |
| Product code | PDJ, LCP |
| Regulation No. | 862.1373 |
{5}------------------------------------------------
3. Legally Marketed Predicate Device
| Trade Name | D-100™ HbA1c |
|---|---|
| 510(k) Number | K151321 |
| Product Code | PDJ, LCP |
| Manufacturer | Bio-Rad Laboratories, Inc. |
4. Device Description
The Hipro® Glycosylated hemoglobin (HbA1c) test system is intended for quantitative determination of % hemoglobin A 1c (DCCT/NGSP) in venous whole blood. It is composed of Glycosylated hemoglobin (HbA1c) test kit and automatic immunoassay analyzer. Glycosylated hemoglobin (HbA1c) test kit consists of two reagents R1 and R2, which are liquid and ready to use. Reagent R1 contains glycine buffer and latex, and reagent R2 contains glycine buffer and two types of antibodies, Goat anti-mouse IgG, mouse anti-human HbAlc monoclonal antibody.
HP-AFS/1 Automatic Immunoassay Analyzer is made up of light absorption test module, scattered light test module, fluorescence test module, press components, data transmission interface and printer. And the absorption test module is made up of absorption light path unit, and lightabsorption sensor part. The scattered light test module is made up of scattered light path unit and scattered light sensor part.
న్. Intended Use/Indication for Use
The Hipro® Glycosylated Hemoglobin (HbA1c) Test System comprised of the Hipro Glycosylated hemoglobin (HbA1c) test kit and the HP-AFS/1 automatic immunoassay analyzer is used as an aid in diagnosis of diabetes mellitus, as an aid to identify patients who may be at risk for developing diabetes mellitus, and for the monitoring of long-term blood glucose control in individuals with diabetes mellitus. It is an in vitro diagnostics reagent system intended for quantitative determination of % hemoglobin A 1c (DCCT/NGSP) in venous whole blood.
| Item | Candidate Device:Hipro® Glycosylated Hemoglobin(HbA1c) Test System | Predicate Device:D-100™ HbA1c(K151321) |
|---|---|---|
| Regulationnumber | 862.1373 | 862.1373 |
| Classification | II | II |
| Product Code | PDJ, LCP | PDJ, LCP |
| Item | Candidate Device:Hipro® Glycosylated Hemoglobin(HbA1c) Test System | Predicate Device:D-100™ HbA1c(K151321) |
| Intendeduse/Indications for use | The Hipro® GlycosylatedHemoglobin (HbA1c) Test Systemcomprised of the HiproGlycosylated hemoglobin(HbA1c) test kit and the HP-AFS/1automatic immunoassay analyzer isused as an aid in diagnosis ofdiabetes mellitus, as an aid toidentify patients who may be at riskfor developing diabetes mellitus,and for the monitoring of long-termblood glucose control in individualswith diabetes mellitus. It is an invitro diagnostics reagent systemintended for quantitativedetermination of % hemoglobinAlc (DCCT/NGSP) in venouswhole blood. | The D-100™ HbA1c test is intended forthe quantitative determination ofhemoglobin A1c (IFCC mmol/mol andNGSP %) in human whole blood usingion-exchange high-performance liquidchromatography (HPLC) on the D-100Hemoglobin Testing System.Hemoglobin A1c measurements are usedas an aid in diagnosis of diabetesmellitus, as an aid to identify patientswho may be at risk for developingdiabetes mellitus, and for the monitoringof long-term blood glucose control inindividuals with diabetes mellitus.The D-100™ HbA1c test is intended forProfessional Use Only. |
| Methodology | Nephelometry ImmunoassayMethod | Ion-exchange HPLC |
| TestingEnvironment | Prescription use | Prescription use |
| Specimentype | Human Whole blood | Human Whole blood |
| Matrices | K2-EDTA | K2-EDTAK3-EDTAPotassium Oxalate/SodiumFluoride, Sodium Citrate,Sodium Heparin, LithiumHeparin |
| ReportingUnits | % HbA1c NGSP/DCCT | % HbA1c NGSP/DCCT and mmol/molIFCC |
| Measurementrange | 4.3-14% HbA1c | 3.5-20 % HbA1c15-195 mmol/mol HbA1c |
| Item | Candidate Device:Hipro® Glycosylated Hemoglobin(HbA1c) Test System | Predicate Device:D-100™ HbA1c(K151321) |
| ReagentStability | 2-8°C for 12 months | On-board stability for the D-100 HbA1ccalibrator pack and reagentsdemonstrated 90 days stability on the D-100 Hemoglobin Testing System. |
| Traceability | The assigned HbA1c value of theGlycosylated hemoglobin (HbA1c)test kit is certified with the NationalGlycohemoglobinStandardization Program (NGSP). | The D-100 HbA1c test standardization istraceable to the International Federationof Clinical Chemistry (IFCC) referencecalibrators. The D-100 HbA1c assay isNGSP certified. |
Substantial Equivalence Comparison 6.
{6}------------------------------------------------
{7}------------------------------------------------
7. Non-clinical Performance Evaluation
The assigned HbA 1c values of the Automatic Immunoassay Analyzer (Model: HP-AFS/1) is certified with the National Glycohemoglobin Standardization Program (NGSP). See NGSP website for current certification at http://www.ngsp.org.
The following performance data were provided in support of the substantial equivalence determination.
7.1 Precision
Precision experiments were performed for the Glycosylated hemoglobin Test Kit based on CLSI Guideline EP5-A3 using four EDTA K2 whole blood samples with targeted HbA1c concentrations (5.2%, 6.4%, 8.0% and 12.3%), two controls (6% and 11%).Samples were analyzed on three Automatic Immunoassay Analyzer instruments using three lots of reagents. Each sample was analyzed in duplicate per run, two runs per day for 20 days. The samples were randomized in experiment. The results are shown below:
| Repeatability | Between run | Between day | Between lot | Total | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Sample | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| 5.2% | 0.107 | 2.0% | 0.032 | 0.6% | 0.000 | 0.0% | 0.000 | 0.0% | 0.111 | 2.1% |
| 6.4% | 0.179 | 2.8% | 0.000 | 0.0% | 0.000 | 0.0% | 0.029 | 0.5% | 0.182 | 2.8% |
| 8.0% | 0.162 | 2.0% | 0.000 | 0.0% | 0.000 | 0.0% | 0.020 | 0.2% | 0.163 | 2.0% |
| 12.3% | 0.145 | 1.2% | 0.051 | 0.4% | 0.000 | 0.0% | 0.017 | 0.1% | 0.155 | 1.2% |
Analyzer 1 precision:
{8}------------------------------------------------
| 6% | 0.176 | 2.9% | 0.000 | 0.0% | 0.000 | 0.0% | 0.020 | 0.3% | 0.177 | 2.9% |
|---|---|---|---|---|---|---|---|---|---|---|
| 11% | 0.189 | 1.7% | 0.000 | 0.0% | 0.000 | 0.0% | 0.038 | 0.3% | 0.193 | 1.8% |
Analyzer 2 precision:
| Sample | Repeatability | Between run | Between day | Between lot | Total | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | |
| 5.2% | 0.109 | 2.1% | 0.000 | 0.0% | 0.014 | 0.3% | 0.000 | 0.0% | 0.110 | 2.1% |
| 6.4% | 0.171 | 2.7% | 0.000 | 0.0% | 0.013 | 0.2% | 0.000 | 0.0% | 0.170 | 2.7% |
| 8.0% | 0.145 | 1.8% | 0.000 | 0.0% | 0.036 | 0.4% | 0.000 | 0.0% | 0.150 | 1.9% |
| 12.3% | 0.181 | 1.4% | 0.026 | 0.2% | 0.000 | 0.0% | 0.000 | 0.0% | 0.183 | 1.5% |
| 6% | 0.177 | 2.9% | 0.000 | 0.0% | 0.020 | 0.3% | 0.027 | 0.5% | 0.180 | 3.0% |
| 11% | 0.176 | 1.6% | 0.000 | 0.0% | 0.056 | 0.5% | 0.000 | 0.0% | 0.185 | 1.7% |
| Analyzer 3 precision: |
|---|
| Sample | Repeatability | Between run | Between day | Between lot | Total | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | |
| 5.2% | 0.093 | 1.8% | 0.000 | 0.0% | 0.011 | 0.2% | 0.000 | 0.0% | 0.094 | 1.8% |
| 6.4% | 0.163 | 2.6% | 0.000 | 0.0% | 0.033 | 0.5% | 0.000 | 0.0% | 0.166 | 2.6% |
| 8.0% | 0.243 | 3.0% | 0.000 | 0.0% | 0.000 | 0.0% | 0.022 | 0.3% | 0.244 | 3.0% |
| 12.3% | 0.145 | 1.2% | 0.000 | 0.0% | 0.063 | 0.5% | 0.050 | 0.4% | 0.166 | 1.3% |
| 6% | 0.192 | 3.2% | 0.000 | 0.0% | 0.000 | 0.0% | 0.000 | 0.0% | 0.192 | 3.2% |
| 11% | 0.147 | 1.3% | 0.000 | 0.0% | 0.039 | 0.4% | 0.036 | 0.3% | 0.156 | 1.4% |
All analyzers precision:
| Sample | Mean% | RepeatabilitySD | Repeatability%CV | Between runSD | Between run%CV | Between daySD | Between day%CV | Between lotSD | Between lot%CV | Between analyzerSD | Between analyzer%CV | TotalSD | Total%CV |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 5.2% | 5.23 | 0.103 | 2.0% | 0.014 | 0.3% | 0.000 | 0.0% | 0.000 | 0.0% | 0.010 | 0.2% | 0.103 | 2.0% |
| 6.4% | 6.34 | 0.171 | 2.7% | 0.000 | 0.0% | 0.000 | 0.0% | 0.011 | 0.2% | 0.061 | 1.0% | 0.171 | 2.7% |
{9}------------------------------------------------
| 8.0% | 8.03 | 0.188 | 2.3% | 0.000 | 0.0% | 0.000 | 0.0% | 0.016 | 0.2% | 0.031 | 0.4% | 0.191 | 2.4% |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 12.3% | 12.53 | 0.158 | 1.3% | 0.011 | 0.1% | 0.030 | 0.2% | 0.028 | 0.2% | 0.093 | 0.7% | 0.188 | 1.5% |
| 6% | 6.04 | 0.182 | 3.0% | 0.000 | 0.0% | 0.000 | 0.0% | 0.018 | 0.3% | 0.006 | 0.1% | 0.183 | 3.0% |
| 11% | 11.03 | 0.172 | 1.6% | 0.000 | 0.0% | 0.031 | 0.3% | 0.030 | 0.3% | 0.000 | 0.0% | 0.177 | 1.6% |
7.2 Method Comparison
A method comparison study was performed to compare the sample results from the candidate method, Hipro® Glycosylated hemoglobin (HbA1c) test kit on the Hipro HP-AFS/1 Automatic Immunoassay analyzer, to results from the Bio-Rad Hemoglobin Testing System. This study was conducted with the EDTA K2 whole blood samples.
One hundred and twenty (120) samples from the NGSP reference laboratory were used in the evaluation. These samples were measured by the NGSP reference laboratory using a Bio-Rad Hemoglobin Testing System (X axis) and by the Hipro® Glycosylated Hemoglobin (HbA1c) Test System (Y axis).
All acceptance criteria for method comparison were met. The difference plots show there is good agreement between the Hipro® Glycosylated Hemoglobin (HbA 1c) Test System and the NGSP Bio-Rad Hemoglobin Testing System.
The table below summarizes the bias between the Hipro Glycosylated Hemoglobin (HbA1c) Test System and the NGSP's Bio-Rad Hemoglobin Testing System.
| Hipro Glycosylated Hemoglobin (HbA1c) TestSystem | |
|---|---|
| Mean bias vs. NGSP Bio-Rad | -0.0148 |
| Mean bias at lower 95% CI | -0.0470 |
| Mean bias at upper 95% CI | 0.0174 |
Bias at Concentration Data Summary
| Concentration | Bias | % Bias |
|---|---|---|
| 5.23% | -0.0262 | -0.5% |
| 6.34% | -0.0163 | -0.26% |
| 8.03% | -0.0012 | -0.02% |
| 12.53% | 0.0388 | 0.31% |
{10}------------------------------------------------
7.3 Total Error
Using the results of bias estimation (%Bias) in the method comparison study and precision estimates in the precision study, the Total Error (TE) at the following concentrations (5.2%, 6.4%, 8.0% and 12.3%) near the cut-off was calculated as follows:
%TE =|%Bias| + 1.96 * %CV * (1+%Bias/100)
The results are presented in the tables below.
| Concentration | %Bias | CV% | %TE |
|---|---|---|---|
| 5.23% | 0.5% | 2.0 | 4.4 |
| 6.34% | 0.26% | 2.7 | 5.5 |
| 8.03% | 0.02% | 2.4 | 4.7 |
| 12.53% | 0.31% | 1.5 | 3.3 |
7.4 Linearity
One dilution series consisting of 9 levels were prepared using the EDTA K2 WB sample pools with HbA1c through mixing high and low concentrations at the upper and lower end of the measuring range. Samples were measured in triplicate and data analysis was done separately for each sample. Linear regression analysis was done according to EP6-2nd edition. Study result is provided in the table below.
| Analyte | Low End ofLinear Range (%) | High End ofLinear Range (%) | Slope | Intercept | R |
|---|---|---|---|---|---|
| HbA1c | 4.3 | 14 | 1.0225 | -0.1524 | 0.999 |
7.5 Endogenous Interference
A study evaluated several endogenous substances for potential interference with the measure of % HbA1c. The following five endogenous substances were evaluated:
Pooled whole blood samples with two HbA1c levels, one near the medical decision level and one above it, were spiked with the maximum level of the above five interferents in separate preparations resulting in 10 spiked samples. Another pool, without interferent, was equally prepared. A 10-level dilution series was then created for each of the 10 spiked samples by using the interferent free pool as the diluting reagent.
The experiment was performed with one reagent lot, one Hipro HP-AFS/1 Automatic Immunoassay analyzer, and in a single run from the same calibration. The ten dilution series were
{11}------------------------------------------------
tested ten-fold for % HbA1c using the EDTA K2 WB sample only.
The mean of the ten replicates was determined and compared to the result from the reference sample (no interfering substance). The comparison was evaluated as a percent deviation. An interferent will be significant if it causes >7% deviation of a measurement in terms of % HbA1c.
| Interferent | Highest Tested Concentration without Significant Interference |
|---|---|
| Lipemia | 600mg/dL |
| Unconjugated Bilirubin | 60mg/dL |
| Conjugated Bilirubin | 60mg/dL |
| Glucose | 9000mg/dL |
| Rheumatoid Factor | 100IU/mL |
| Total Protein | 15g/dL |
7.8 Drug Interference
A study evaluated several drugs for potential interference with the measurement of %HbA1c using the EDTA K2 WB sample. The following drugs were studied:
| Potential Interferent | Highest Tested Concentration withoutSignificant Interference |
|---|---|
| N-Acetylcysteine | 166mg/dL |
| Ampicillin-Na | 100mg/dL |
| Ascorbic acid | 30mg/dL |
| Cefoxitin | 250mg/dL |
| Heparin | 5000 U/L |
| Levodopa | 2mg/dL |
| Methyldopa | 2mg/dL |
| Metronidazole | 20mg/dL |
| Doxycycline | 5mg/dL |
| Acetylsalicylic acid | 100mg/dL |
| Rifampicin | 6mg/dL |
| Cyclosporin | 1.66mg/dL |
| Phenylbutazone | 40mg/dL |
| Acetaminophen | 20mg/dL |
| Ibuprofen | 50mg/dL |
| Theophylline | 10mg/dL |
{12}------------------------------------------------
The 16 commonly used drugs listed above were added to native patient samples and examined for potential effect on % HbA1c determination. Drug interference testing was performed with EDTA K2 WB samples at 2 different HbA1c levels. The two different HbA1c concentrations will be approximately 6.5% and 8.5% HbA1c. Each drug was added in two defined concentrations with concentration 1 being several times (typically 5 times) the maximum daily dosage and concentration 2 being the maximum daily dosage level. Samples were measured in ten-fold using the Hipro® Glycosvlated Hemoglobin (HbA1c) Test System. The median value was compared to the reference value (HbA1c sample with no drug added) and the deviation from the reference was calculated.
Significant interference is defined as > ±7% deviation from the reference value observed. All acceptance criteria for drug interferences were met.
7.9 Cross-reactivity
Studies were performed to determine if the Hipro® Glycosylated hemoglobin (HbA 1c) test kit demonstrates cross-reactivity with any of the following hemoglobin fractions and glycated albumin.
| Hb A0 | Carbamylated Hb | Glycated Albumin |
|---|---|---|
| Labile Hb A1c | Acetylated Hb | Hb A1a+b |
7.10 Hemoglobin variants
Hemoglobin variant testing was conducted to determine if there was any significant interference with any of the major hemoglobin variants and the Hipro® Glycosylated hemoglobin (HbA I c) test kit. Hemoglobin variants are structurally altered hemoglobin molecules with at least one amino acid exchange compared to the normal beta chain of hemoglobin. These changes are caused by mutations in the coding region of the globin genes which encode the protein part of hemoglobin. The most common hemoglobin variants are HbS, HbC, HbD and HbE. Moreover, in some conditions, the fetal hemoglobin HbF is elevated. Also, the erythrocytes of some patients (e.g. beta thalassemia minor) contain elevated levels of HbA2. Therefore, it is crucial to ensure accurate HbA1c results from patients who are carriers of these variants.
| HemoglobinVariant | Number ofSamples | Variant ConcentrationRange (%) | Range of%HbA1cConcentration |
|---|---|---|---|
| HbC | 20 | 25 - 66.6% | 4.7-9.7 |
| HbD | 20 | 12.9 - 41.1% | 5.2-10.2 |
| HbE | 20 | 13.8 - 30.5% | 5.1-12.2 |
| HbF | 20 | 1.3 - 40.5% | 4.4-8.4 |
{13}------------------------------------------------
| HbS | 20 | 16.8 - 76.9% | 5.1-9.4 |
|---|---|---|---|
| HbA2 | 20 | 3.1 - 6.4% | 4.7-9.7 |
Each sample was tested twice on one Hipro HP-AFS/1 Automatic Immunoassay analyzer. Results obtained with the Hipro® Glycosylated hemoglobin (HbA1c) test kit on the Hipro HP-AFS/1 Automatic Immunoassay analyzer will be compared to those obtained with the reference methods. Results are summarized in the table below.
| Hb Variant | ~6.5 % HbA1c | ~9.0% HbA1c | ||
|---|---|---|---|---|
| Average | Range (%) | Average | Range (%) | |
| HbC | -0.17 | -3.77~3.77 | 2.27 | -1.15~4.11 |
| HbD | 1.67 | -1.79~5.08 | 2.10 | 1.16~3.03 |
| HbE | 1.58 | -1.67~5.36 | 1.38 | 0.00~4.17 |
| HbF | Interference was observed when the concentration of HbF is > 8%. | |||
| HbS | 1.69 | -3.08~6.15 | 1.20 | 1.08~1.35 |
| HbA2 | 1.57 | -1.79~5.00 | -0.51 | -1.02~0.00 |
8. Clinical testing
Not applicable.
-
- Other information (such as required by FDA guidance/Test)
Not applicable.
- Other information (such as required by FDA guidance/Test)
- Conclusions Drawn from Non-Clinical and Clinical Tests
The Hipro® Glycosylated Hemoglobin (HbA1c) Test System is substantially equivalent to the legally marketed predicate device Bio-Rad D-100™ HbA1c (K151321).
§ 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.