(434 days)
The Hemoglobin Alc assay is used in clinical laboratories for the quantitative in vitro measurement of percent hemoglobin A 1c (NGSP) or HbA1c fraction mmol/mol (IFCC) in human whole blood and hemolysate on the ARCHITECT c 4000 System.
Hemoglobin A1c measurements are used as an aid in the diagnosis of diabetes mellitus, as an aid to identify patients who may be at risk for developing diabetes mellitus, and for the monitoring of long-term blood glucose control in individuals with diabetes mellitus.
The Hemoglobin Alc Calibrators are for use in the callbration of the Hemoglobin A1c assay on the ARCHITECT e 4000 System.
The Hemoglobin A 1c Controls are used for the estimation of test precision of systematic analytical deviations of the Hemoglobin A1c assay on the ARCHITECT c 4000 System.
The Hemoglobin A1c assay consists of two separate concentration measurements: glycated hemoglobin (HbA1c) and total hemoglobin (THb). The two concentrations are used to determine the percent HbA1c (NGSP units) or the hemoglobin fraction in mmol/mol (IFCC units). The assay utilizes an enzymatic method that specifically measures N-terminal fructosyl dipeptides of the ß-chain of HbA1c. The total hemoglobin is determined by measuring absorbance. The final result is expressed as %HbA1c (NGSP) or mmol/mol HbA1c (IFCC) and is automatically calculated by the system from the HbA1c/THb ratio. The device also includes Hemoglobin A1c Calibrators and Hemoglobin A1c Controls.
This document describes the Hemoglobin A1c Assay, Calibrators, and Controls, a device used for the quantitative in vitro measurement of percent hemoglobin A1c (NGSP) or HbA1c fraction mmol/mol (IFCC) in human whole blood and hemolysate on the ARCHITECT c 4000 System. The information provided primarily focuses on the device's technical specifications, performance evaluation, and substantial equivalence to a predicate device (ARCHITECT Hemoglobin A1c assay, K130255).
I will extract the requested information based on the provided document:
1. Table of Acceptance Criteria and Reported Device Performance
The document does not explicitly state "acceptance criteria" in a definitive table format with pass/fail thresholds. However, performance studies are conducted with implied expectations for meeting certain analytical standards. I will synthesize the performance data provided across various sections to address the "reported device performance."
| Performance Metric | Acceptance Criteria (Implied/Standard) | Reported Device Performance (NGSP) | Reported Device Performance (IFCC) |
|---|---|---|---|
| Precision (20-Day) | Low %CV for varying HbA1c levels | Whole Blood: 0.02-0.04 SD; 0.3-0.4 %CV; 0.3 %CV | Not explicitly detailed in the document |
| Hemolysate: 0.01-0.02 SD; 0.2-0.5 %CV; 0.3-0.4 %CV | Not explicitly detailed in the document | ||
| Limit of Blank (LoB) | Low value | 2.51 %HbA1c | 3.89 mmol/mol |
| Limit of Detection (LoD) | Low value | 2.52 %HbA1c | 4.05 mmol/mol |
| Interferences (Endogenous Substances) | Difference within ± 5% for samples ≥ 5.7 %HbA1c | No significant interference observed for listed substances | No significant interference observed for listed substances |
| Interferences (Hemoglobin Variants) | No significant interference; Difference within ± 5% for samples ~6.0 and ~9.0 %HbA1c | HbC, HbD, HbE, HbS, HbA2: Generally within acceptable ranges. HbF: Significant interference if >5% | HbC, HbD, HbE, HbS, HbA2: Generally within acceptable ranges. HbF: Significant interference if >5% |
| Interferences (Drugs) | Difference within ± 5% for samples ≥ 5.7 %HbA1c | No significant interference observed for listed drugs | No significant interference observed for listed drugs |
| Interferences (Rheumatoid Factor) | Difference within ± 5% for samples ≥ 5.7 %HbA1c | No significant interference for RF ≤ 200 IU/mL | No significant interference for RF ≤ 200 IU/mL |
| Interferences (Hemoglobin Derivatives) | Difference within ± 5% for samples ≥ 5.7 %HbA1c | No significant interference from acetylated, carbamylated, or labile Hb | No significant interference from acetylated, carbamylated, or labile Hb |
| Linearity (Correlation Coefficient) | Close to 1 | 0.9996 (intercept -0.40, slope 0.9709) | 0.9997 (intercept -6.17, slope 0.9831) |
| Method Comparison (to Reference) | Slope ~1, r-value ~1 | Hemolysate: Slope 1.00, r 0.996. Whole Blood: Slope 1.01, r 0.995 | Hemolysate: Slope 0.98, r 0.996. Whole Blood: Slope 1.00, r 0.996 |
| Method Comparison (ATD Zone) | High percentage in ATD Zone | Hemolysate: 100.0% (95% CI 97.1%). Whole Blood: 100.0% (95% CI 97.1%) | Hemolysate: 96.9% (95% CI 92.2%). Whole Blood: 96.9% (95% CI 92.2%) |
| Total Error (TE) | Acceptable values (device-specific) | Hemolysate: 2.5 - 3.4%. Whole Blood: 1.9 - 3.6% | Not explicitly detailed in the document |
| Measuring Interval | Demonstrated range | 4.0 to 14.0 %HbA1c | 20.22 to 129.51 mmol/mol HbA1c |
| Method Comparison (to Predicate) | Slope ~1, r-value ~1 | Hemolysate: Slope 0.99, r 0.999. Whole Blood: Slope 1.00, r 0.999 | Hemolysate: Slope 0.99, r 1.000. Whole Blood: Slope 1.00, r 1.000 |
2. Sample size used for the test set and the data provenance
- Precision Study (Within-Laboratory Precision):
- Sample Size: Three levels of human whole blood controls and human whole blood panels were tested. Each level was tested a minimum of 2 replicates, twice per day, for 20 testing days.
- Data Provenance: Not specified (e.g., country of origin, retrospective/prospective).
- Limit of Blank (LoB) and Detection (LoD) Study:
- Sample Size: Zero-level samples (minimum 3 replicates), low-level samples (minimum 2 replicates).
- Data Provenance: Not specified.
- Interferences (Endogenous Substances, Hemoglobin Variants, Drugs, Rheumatoid Factor, Hemoglobin Derivatives):
- Sample Size: Test and reference samples were tested in a minimum of 12 replicates for endogenous substances, drugs, RF, and hemoglobin derivatives. For hemoglobin variants, the number of samples (n) varied per variant (e.g., HbC: 43, HbD: 40, HbE: 50, HbS: 31, HbA2: 24, HbF: 28).
- Data Provenance: Not specified.
- Matrix Comparison:
- Sample Size: Specimens from a minimum of 43 different donors. Each sample tested in a minimum of 2 replicates.
- Data Provenance: Not specified.
- Linearity:
- Sample Size: 9 samples (4 commercial linearity levels + 5 prepared samples). Each sample tested in a minimum of 2 replicates.
- Data Provenance: Not specified.
- Method Comparison and Predicted Bias (against NGSP secondary reference laboratory method):
- Sample Size: A minimum of 120 human whole blood specimens. Tested in replicates of 2.
- Data Provenance: Not specified (likely laboratory-based, not patient-derived with demographic context).
- Method Comparison to Predicate Device:
- Sample Size: A minimum of 120 human whole blood specimens. Tested in replicates of 2.
- Data Provenance: Not specified.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)
The document does not mention the use of "experts" in the traditional sense (e.g., radiologists, pathologists) for establishing ground truth. Instead, the ground truth for the method comparison studies was established using NGSP secondary reference laboratory methods for HbA1c measurement. These are highly standardized analytical methods, not dependent on expert interpretation. For calibrators and controls, traceability is to the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) reference method. The qualifications of personnel performing these reference methods are typically certified laboratory technicians or scientists, but this is not detailed.
4. Adjudication method (e.g. 2+1, 3+1, none) for the test set
There is no mention of an adjudication method in the context of expert review for establishing ground truth, as the ground truth is based on reference analytical measurements.
5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance
This is a clinical chemistry assay, not an imaging or diagnostic device that involves "human readers" or "AI assistance" in interpretation in the way a MRMC study would apply. Therefore, no MRMC comparative effectiveness study was conducted or is applicable here. The device automatically provides a quantitative measurement.
6. If a standalone (i.e. algorithm only without human-in-the loop performance) was done
Yes, the studies presented are standalone performance evaluations of the assay system (reagents + instrument). The device provides a quantitative measurement of Hemoglobin A1c, and its performance (precision, linearity, interference, method comparison) is assessed based on the accuracy and reliability of these measurements against reference methods or established analytical standards. There is no "human-in-the-loop" component for result generation, only for sample handling and result interpretation for clinical decision-making.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc)
The ground truth used for performance evaluation, particularly for method comparison, is based on:
- Reference Laboratory Methods: Specifically, an NGSP secondary reference laboratory method (e.g., Tosoh HPLC analyzer) for comparison of patient samples.
- Traceability to International Standards: Calibrators and controls are "value assigned using secondary calibrators that are traceable to the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) reference method."
8. The sample size for the training set
The document describes performance evaluation (test set data) for the device. It does not provide information about a "training set" in the context of machine learning/AI development. This device is a quantitative in vitro diagnostic assay, not an AI/ML-based diagnostic software.
9. How the ground truth for the training set was established
Not applicable, as no training set (in the AI/ML context) is described for this in vitro diagnostic device.
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Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002
May 22, 2015
ABBOTT LABORATORIES JUDITH WALLACH DIAGNOSTICS DIVISION, DEPT. 09V6 AP8 100 ABBOTT PARK ROAD. ABBOTT PARK IL 60064
Re: K140654
Trade/Device Name: Hemoglobin A1c Assay. Hemoglobin A1c Calibrators, Hemoglobin A1c Controls Regulation Number: 21 CFR 862.1373 Regulation Name: Glycosylated hemoglogbin assay Regulatory Class: II Product Code: PDJ, LCP, JIT, JJX Dated: May 4, 2015 Received: May 5, 2015
Dear Ms. Judith Wallach:
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 Parts 801 and 809); medical device reporting (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 Part 820); and if applicable, the
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electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638 2041 or (301) 796-7100 or at its Internet address
http://www.fda.gov/MedicalDevices/Resourcesfor You/Industry/default.htm. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to
http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.
You may obtain other general information on your responsibilities under the Act from the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address
http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.
Sincerely yours,
Courtney H. Lias -S
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) K140654
Device Name Hemoglobin A1c Assay Hemoglobin A1c Calibrators Hemoglobin A1c Controls
Indications for Use (Describe)
The Hemoglobin Alc assay is used in clinical laboratories for the quantitative in vitro measurement of percent hemoglobin A 1c (NGSP) or HbA1c fraction mmol/mol (IFCC) in human whole blood and hemolysate on the ARCHITECT c 4000 System.
Hemoglobin A1c measurements are used as an aid in the diagnosis of diabetes mellitus, as an aid to identify patients who may be at risk for developing diabetes mellitus, and for the monitoring of long-term blood glucose control in individuals with diabetes mellitus.
The Hemoglobin Alc Calibrators are for use in the callbration of the Hemoglobin A1c assay on the ARCHITECT e 4000 System.
The Hemoglobin A 1c Controls are used for the estimation of test precision of systematic analytical deviations of the Hemoglobin A1c assay on the ARCHITECT c 4000 System.
| 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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Section 5: 510(k) Summary
This summary of the 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.
1. Applicant Name
Judith Wallach, ADD, Regulatory Affairs Project Manager Abbott Laboratories Diagnostics Division Dept. 9V6, AP8 100 Abbott Park Road Abbott Park, IL 60064 Telephone Number: (224) 667-1132 Fax Number: (224) 667-4836 E-Mail: judith.r.wallach@abbott.com Date Summary prepared: March 13, 2014 Revised May 4, 2015
Grace LeMieux, ADD, Regulatory Affairs Director Phone (224) 668-0409 Fax (224) 668-4836 E-mail grace.lemieux@abbott.com
2. Device Name
Hemoglobin A1c Assay Hemoglobin A1c Calibrators Hemoglobin A1c Controls
Reagents
Classification Name: Assay, Glycosylated Hemoglobin Regulation Description: Glycosylated hemoglobin assay Trade Name: Hemoglobin A1c Common Name: HbA1c Governing Regulation: 862.1373 Device Classification: Class II Product Code: PDJ, LCP Panel Classification: Chemistry
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Calibrators
Classification Name: Calibrator, Secondary Regulation Description: Calibrator Trade Name: Hemoglobin A1c Calibrators (1 and 2) Common Name: Calibrator Governing Regulation: 862.1150 Device Classification: Class II Product Code: JIT Panel Classification: Clinical Chemistry
Controls
Classification Name: Single (Specified) Analyte Controls (assayed and unassayed) Regulation Description: Quality control material (assayed and unassayed) Trade Name: Hemoglobin A1c Controls (Low and High) Common Name: Control Governing Regulation: 862.1660 Device Classification: Class II Product Code: JJX Panel Classification: Clinical Chemistry
3. Predicate Device
ARCHITECT Hemoglobin A1c Reagents, Calibrators, and Controls (K130255)
Note: The candidate device consists of the same reagents as the predicate device, and utilizes the same calibrators and controls. The candidate device is intended for use on the ARCHITECT c 4000 System. The predicate device (K130255) was cleared for use on the ARCHITECT c 8000 System.
4. Description of Device
Reagents Description
The Hemoglobin A1c Reagent Kit contains:
| Component | Number of Bottles x Volume |
|---|---|
| Reagent 1 (R1) | 1 x 52 mL |
| Reagent 2 (R2) | 1 x 20 mL |
| Diluent (A1cDIL) | 2 x 35 mL |
Estimated tests per kit: 300
Calculation is based on the minimum fill volume per kit.
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| Reagent | Reactive Ingredients | Concentration |
|---|---|---|
| Reagent 1 | 10-(carboxymethylaminocarbonyl)-3,7-bis(dimethylamino)phenothiazine sodium salt | 0.000817% |
| Protease (Bacterial) | < 1 mU/dL | |
| Reagent 2 | Peroxidase (Horseradish) | 5 to 15 kU/dL |
| Fructosyl-peptide-oxidase ( E. coli , recombinant) | 300 to 900 U/dL | |
| Diluent | Sodium nitrite | > 0.05 to < 0.3% |
Inactive Ingredients: Reagent 1 contains sodium azide as a stabilizer and preservative. Reagent 1 and Diluent contain ProClin 300 as a preservative. Reagent 2 contains ofloxacin as a preservative.
Calibrators
The Hemoglobin A1c Calibrator Kit contains:
| Component | Number of Bottles x Volume |
|---|---|
| Calibrator 1 (Cal 1) | 1 x 1.6 mL* |
| Calibrator 2 (Cal 2) | 1 x 1.6 mL* |
- Volume after reconstitution
- A 1c Calibrators (lyophilized) contain hemoglobin and glycated hemoglobin from human whole blood. Prior to lyophilization, the calibrator matrix is an MES-buffered solution. Preservative: Ofloxacin.
- The value-assigned A1c Calibrator values are within the following hemoglobin A1c . ranges:
| Calibrator 1 | Calibrator 2 | |
|---|---|---|
| Hemoglobin A1c Ranges | 4.59% to 6.02% HbA1c | 10.52% to 13.37% HbA1c |
- Actual analyte concentrations for each lot of calibrators are listed in the Hemoglobin A1c Calibrator Value Sheet, packaged with the calibrator.
- 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.
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Controls
The Hemoglobin A1c Control Kit contains:
| Component | Number of Bottles x Volume |
|---|---|
| Low Control (Control L) | 1 x 1 mL* |
| High Control (Control H) | 1 x 1 mL* |
- Volume after reconstitution
- A 1c Controls (lyophilized) contain hemoglobin and glycated hemoglobin from human whole blood. Prior to lyophilization, the control matrix is an MES-buffered solution. Preservative: Ofloxacin.
- . The value-assigned A1c Control values are within the following hemoglobin A1c ranges:
| Low Control | High Control | |
|---|---|---|
| Hemoglobin A1cRanges | 4.59% to 6.02% HbA1c | 9.42% to 11.07% HbA1c |
- . Actual analyte concentration ranges for each lot of controls is listed in the Hemoglobin A1c Control Value Sheet, packaged with the controls.
- Each lot of controls is value-assigned. The glycated hemoglobin value in National Glycohemoglobin Standardization Program (NGSP) units (%HbA1c) and in International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) units (mmol/mol HbA1c) are provided for each lot. Controls are prepared gravimetrically, lyophilized, and then value assigned using secondary calibrators that are traceable to the IFCC reference method.
Principles of the Procedure
The Hemoglobin A1c assay consists of two separate concentration measurements: glycated hemoglobin (HbA1c) and total hemoglobin (THb). The two concentrations are used to determine the percent HbA1c (NGSP units) or the hemoglobin fraction in mmol/mol (IFCC units).
The individual concentration values of HbA1c and THb generated by the Hemoglobin A1c assay are used only for calculating the percent hemoglobin A1c or HbA1c fraction, and must not be used individually for diagnostic purposes.
The anticoagulated whole blood specimen is lysed automatically on the system for the Whole Blood application or may be lysed manually using the Hemoglobin A1c Diluent (A1cDIL) for the Hemolysate application.
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Glycated Hemoglobin (HbA1c)
The Hemoglobin A1c assay utilizes an enzymatic method that specifically measures N-terminal fructosyl dipeptides of the ß-chain of HbA1c.
- In the pretreatment process, the erythrocytes are lysed and the hemoglobin is transformed to methemoglobin by reaction with sodium nitrite.
- . With the addition of Reagent 1 (R1) to the sample, the glycosylated N-terminal dipeptide (fructosyl-VH) of the ß-chain of hemoglobin is cleaved by the action of protease. The hemoglobin is transformed to stable methemoglobin azide by the action of sodium azide and the concentration of the hemoglobin is determined by measuring absorbance.
- Addition of Reagent 2 (R2) starts a reaction and fructosyl peptide oxidase (FPOX) is allowed to react with fructosyl-VH. The HbA1c concentration is measured by determining the resultant hydrogen peroxide.
Total Hemoglobin (THb)
The hemoglobin is oxidized to stable methemoglobin azide by the action of sodium nitrite and sodium azide and the concentration of the hemoglobin is determined by measuring absorbance (sample + R1).
Hemoglobin A1c Calculations
The final result is expressed as %HbA1c (NGSP) or mmol/mol HbA1c (IFCC) and is automatically calculated by the system from the HbA1c/THb ratio as follows:
mmol/mol HbA1c IFCC: HbA1c (mmol/mol) = (HbA1c/THb) $\times$ 1000
%HbA1c DCCT/NGSP: HbA1c (%) = IFCC x 0.09148 + 2.152
Methodology: Enzymatic
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5. Intended Use of Device
The Hemoglobin A1c assay is used in clinical laboratories for the quantitative in vitro measurement of percent hemoglobin A1c (NGSP) or HbA1c fraction mmol/mol (IFCC) in human whole blood and hemolysate on the ARCHITECT c 4000 System.
Hemoglobin A1c measurements are used as an aid in the diagnosis of diabetes mellitus. as an aid to identify patients who may be at risk for developing diabetes mellitus, and for the monitoring of long-term blood glucose control in individuals with diabetes mellitus.
The Hemoglobin A1c Calibrators are for use in the calibration of the Hemoglobin A1c assay on the ARCHITECT c 4000 System.
The Hemoglobin A1c Controls are used for the estimation of test precision and the detection of systematic analytical deviations of the Hemoglobin A1c assay on the ARCHITECT c 4000 System.
6. Comparison of Technological Characteristics
The candidate device, Hemoglobin A1c, and the predicate device, Hemoglobin A1c (K130255) utilize an enzymatic methodology for the quantitative in vitro measurement of percent hemoglobin A1c or HbA1c fraction. The candidate device consists of the same reagents as the predicate device, and utilizes the same calibrators and controls. The candidate device is intended for use on the ARCHITECT c 4000 System. The predicate device (K130255) was cleared for use on the ARCHITECT c 8000 System.
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The following tables provide the similarities and differences between the candidate device and the predicate device.
| ReagentsSimilarities and Differences | ||
|---|---|---|
| Characteristics | Candidate DeviceHemoglobin A1c | Predicate DeviceHemoglobin A1c (K130255) |
| Intended Useand Indicationsfor Use | For the quantitative in vitro measurementof percent hemoglobin A1c (NGSP) orHbA1c fraction mmol/mol (IFCC) inhuman whole blood and hemolysate on theARCHITECT c 4000 System.Hemoglobin A1c measurements are usedas an aid in the diagnosis of diabetesmellitus, as an aid to identify patients whomay be at risk for developing diabetesmellitus, and for the monitoring of long-term blood glucose control in individualswith diabetes mellitus. | For the quantitative in vitro measurementof percent hemoglobin A1c (NGSP) orHbA1c fraction mmol/mol (IFCC) inhuman whole blood and hemolysate onthe ARCHITECT c 8000 Systems.Hemoglobin A1c measurements are usedas an aid in the 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. |
| Platform | ARCHITECT c 4000 System(clinical chemistry analyzer) | ARCHITECT c 8000 System(clinical chemistry analyzer) |
| Methodology | Same as predicate device. | Enzymatic |
| Specimen Type | Same as predicate device. | Whole blood and Hemolysate:Dipotassium EDTALithium HeparinSodium HeparinSodium Fluoride/Disodium EDTATripotassium EDTA |
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| ReagentsSimilarities and Differences | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Characteristics | Candidate DeviceHemoglobin A1c | Predicate DeviceHemoglobin A1c (K130255) | ||||||||
| ExpectedValues | Same as predicate device. | For monitoring diabetic patients, it isrecommended that glycemic goals areindividualized following currentprofessional society recommendations.The American Diabetes Association(ADA) recommendations are summarizedin the following table.HbA1c Value Glycemic Goal < 8 %HbA1c(64 mmol/mol) Less Stringent < 7 %HbA1c(53 mmol/mol) General(Non-PregnantAdults) < 6.5 %HbA1c(48 mmol/mol) More stringent HbA1c values above 6.5 %HbA1c(48 mmol/mol) are an indication ofhyperglycemia during the preceding 2 to3 months or longer. According to therecommendations of the ADA, HbA1cvalues above 6.5 %HbA1c (48mmol/mol) are suitable for the diagnosisof diabetes mellitus. Patients with HbA1cvalues in the range of 5.7 - 6.4 %HbA1c(39 - 46 mmol/mol) may be at a risk ofdeveloping diabetes. | ||||||||
| MeasuringInterval | Same as predicate device. | 4.0 to 14.0 %HbA1c (DCCT/NGSP)20.22 to 129.51 mmol/mol HbA1c(IFCC) |
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| CalibratorsSimilarities and Differences | |||
|---|---|---|---|
| Characteristics | Candidate DeviceHemoglobin A1c | Predicate DeviceHemoglobin A1c (K130255) | |
| Intended use | For use in the calibration of theHemoglobin A1c assay on theARCHITECT c 4000 System. | For use in the calibration of theHemoglobin A1c assay on theARCHITECT c 8000 System. | |
| Platform | ARCHITECT c 4000 System(clinical chemistry analyzer) | ARCHITECT c 8000 System(clinical chemistry analyzer) | |
| Levels | Same as predicate device. | 2 levels (Calibrator 1 and 2)Each lot of calibrators is value-assignedand values are reported in both NGSP andIFCC units. Actual analyte concentrationsfor each lot of calibrators are listed in theHemoglobin A1c Calibrator Value Sheet,packaged with the calibrator. Theconcentration of glycated hemoglobin(HbA1c) and total hemoglobin (THb) isprovided for each lot. | |
| Standardization/Traceability | Same as predicate device. | Calibrators are prepared gravimetrically,lyophilized, and then value assigned usingsecondary calibrators that are traceable tothe International Federation of ClinicalChemistry and Laboratory Medicine(IFCC) reference method. |
| ControlsSimilarities and Differences | ||
|---|---|---|
| Characteristics | Candidate DeviceHemoglobin A1c | Predicate DeviceHemoglobin A1c (K130255) |
| Intended use | For the estimation of test precision and thedetection of systematic analyticaldeviations of the Hemoglobin A1c assayon the ARCHITECT c 4000 System. | For the estimation of test precision andthe detection of systematic analyticaldeviations of the Hemoglobin A1c assayon the ARCHITECT c 8000 System. |
| Platform | ARCHITECT c 4000 System(clinical chemistry analyzer) | ARCHITECT c 8000 System(clinical chemistry analyzer) |
| Levels | Same as predicate device. | 2 levels (Low and High Control)LyophilizedAssignment of values is specific for eachlot. |
| Material | Same as predicate device. | Controls are prepared using hemoglobinand glycated hemoglobin from humanwhole blood. Prior to lyophilization, thematrix used is MES buffered solution. |
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7. Summary of Nonclinical Performance
Within-Laboratory Precision (20-Day)
A 20-day precision study was conducted to evaluate the precision performance of the Hemoglobin A1c assay based on guidance from the Clinical and Laboratory Standards Institute (CLSI) document EP5-A2.
Testing was performed using 3 lots of Hemoglobin A1c Reagents, 3 lots of Hemoglobin A1c Calibrators, 1 lot of Hemoglobin A1c Controls (Low and High), and 1 lot of commercially available controls (Control Levels 1, 2, and 3) on 3 ARCHITECT c 4000 instruments. The calibration curve generated for each reagent lot was stored on each instrument for the duration of the study. Three levels each of human whole blood controls and human whole blood panels were tested a minimum of 2 replicates, twice per day (separated by a minimum of 2 hours), for a total of 20 testing days. The results for all replicates were reported in both NGSP and IFCC units.
NGSP:
The total imprecision (within-run, between-run, and between-day) by instrument system and reagent lot was as follows for each application:
Whole Blood
- 0.02 to 0.04 SD for Control Level 1 .
- 0.3 to 0.4 %CV for Control Level 2
- 0.4 to 0.5 %CV for Control Level 3* •
- . 0.02 to 0.03 SD for the panel targeted near 4.0 %HbA1c
- 0.3 to 0.4 %CV for the panel with a target range of 6.0 7.0 %HbA1c •
- . 0.3 %CV for the panel with a target range of 8.0 – 10.0 % HbA1c
- Note: The Control Level 3 data were not included in the draft reagent package insert because the concentration value for Control Level 3 was above the upper limit of the measuring interval.
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Hemolysate
- 0.01 to 0.02 SD for the Hemoglobin A1c Low Control .
- 0.2 to 0.3 %CV for the Hemoglobin A1c High Control ●
- 0.3 to 0.5 %CV for Control Level 3 •
- 0.01 to 0.03 SD for the panel targeted near 4.0 %HbA1c •
- 0.3 to 0.5 %CV for the panel with a target range of 6.0 7.0 %HbA1c ●
- 0.3 to 0.4 %CV for the panel with a target range of 8.0 10.0 %HbA1c .
Limit of Blank (LoB) and Detection (LoD)
A Limit of Blank (LoB)/Limit of Detection (LoD) study was performed based on guidance from the CLSI document EP17-A.
The zero-level samples were tested in a minimum of 3 replicates and the low-level samples were tested in a minimum of 2 replicates. Five separate runs were performed over a minimum of three days using 2 lots of Hemoglobin A 1c Reagents, 2 lots of Hemoglobin A1c Calibrators, and 1 lot of commercially available controls on 2 ARCHITECT c 4000 instruments. Each reagent and calibrator lot was tested on each instrument.
The Hemoglobin A1c LoB result is 2.51 %HbA1c (3.89 mmol/mol) and LoD result is 2.52 %HbA1c (4.05 mmol/mol).
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Interferences: Endogenous Substances
A study was performed based on guidance from the CLSI document EP7-A2. Interference effects were assessed by comparing test samples containing potentially interfering endogenous substances to reference samples.
The test and reference samples were tested in a minimum of 12 replicates using 1 lot of Hemoglobin A1c Reagents and Calibrators and 1 lot of commercially available controls on 1 ARCHITECT c 4000 instrument. The results were reported in both NGSP and IFCC units.
The Hemoglobin A1c assay had a difference within ± 5% for samples ≥ 5.7 %HbA1c. The Hemoglobin A1c assay is not susceptible to interference effects from the following endogenous substances and high test levels:
| Endogenous Substance Name | Highest Test Level At Which No SignificantInterference Was Observed |
|---|---|
| Ascorbic Acid | 3.0 mg/dL |
| Conjugated Bilirubin | 20.0 mg/dL |
| Glucose | 1000 mg/dL |
| Triglycerides | 3000 mg/dL |
| Total Protein* | 22 g/dL |
| Unconjugated Bilirubin | 15.0 mg/dL |
| Urea | 667 mg/dL |
| Vitamin E | 8.6 mg/dL |
The total protein concentration of 22 g/dL includes serum protein as well as hemoglobin.
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Interferences: Hemoglobin Variants
A study was performed based on guidance from the CLSI document EP7-A2. The samples were tested using 1 lot of Hemoglobin A1c Reagents and Calibrators, 1 lot of Hemoglobin A1c Controls (for the hemolysate application), and 1 lot of commercially available controls (for the whole blood application) on 1 ARCHITECT c 4000 instrument. Interference effects were assessed by comparing the Hemoglobin A1c values to reference/expected values for samples containing potentially interfering hemoglobin variants. The results were reported in both NGSP and IFCC units. No significant interference was observed for the HbC, HbD, HbE, HbS, and HbA2 variants at the levels summarized in the tables below (NGSP units).
| HemoglobinVariant | n | Range in % AbnormalVariant | Range in %HbA1cConcentration |
|---|---|---|---|
| HbC | 43 | 27 - 43 | 4.7 - 13.6 |
| HbD | 40 | 34 - 43 | 4.7 - 8.8 |
| HbE | 50 | 14 - 32 | 4.7 - 11.8 |
| HbS | 31 | 18 - 42 | 4.6 - 13.5 |
| HbA2 | 24 | 4.1 - 6.1 | 4.6 - 11.7 |
| HbF | 28 | 3 - 33 | 4.2 - 7.9 |
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| Relative % Difference from Reference Concentration | ||||
|---|---|---|---|---|
| ~6.0 %HbA1c(5.5 to 6.5 %HbA1c) | ~9.0 %HbA1c(7.5 to 10.5 %HbA1c) a | |||
| HemoglobinVariant | Relative %Difference | Range b | Relative %Difference | Range b |
| HbC | -3.1 | -6.9, 3,3 | -0.5 | -4.2, 2.7 |
| HbD | 0.6 | -3.4, 3.2 | 0.2 | -1.3, 2.6 |
| HbE | 1.0 | -3.3, 7.8 | 2.5 | -2.1, 6.3 |
| HbS | -0.8 | -3.6, 3.3 | -0.5 | -3.8, 2.2 |
| HbA2 | 0.7 | 0.0, 1.7 | 2.9 | 1.4, 4.5 |
| HbF | Difference exceeds -5% when the amount of HbF in the sampleexceeds 5% ° |
a The HbA2 results at ~9.0 %HbA1c consisted of samples between 7.2 to 11.2 %HbA1c.
b The range is defined as the minimum and maximum relative % difference at each concentration level (~6.0 and ~9.0 %HbA1c).
c A negative % difference with HbF is proportional in magnitude to the % HbF present in the sample. For example, when the amount of HbF in the sample was 20.4%, the % difference was -20.0% on the ARCHITECT c 4000 System. Refer to the LIMITATIONS OF THE PROCEDURE section of this package insert for further information.
NOTE: The presence of multiple variants in a sample may impact the % difference.
For HbF interference, the device has the following prominent boxed warning:
The Hemoglobin A1c assay has significant interference with the fetal hemoglobin (HbF). Hemoglobin A1c results are invalid for patients with abnormal amounts of HbF, including those with known Hereditary Persistence of Fetal Hemoglobin.
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Interferences: Drugs
A study was performed based on guidance from the CLSI document EP7-A2. Interference effects were assessed by comparing test samples containing potentially interfering drugs to reference samples.
The test and reference samples were tested in a minimum of 12 replicates using 1 lot of Hemoglobin A1c Reagents and Calibrators and 1 lot of commercially available controls on 1 ARCHITECT c 4000 instrument. The results were reported in both NGSP and IFCC units.
The Hemoglobin A1c assay had a difference within ± 5% for samples ≥ 5.7 %HbA1c. The Hemoglobin A1c assay is not susceptible to interference effects from the following potentially interfering drugs and high test levels:
| Drug Name | Highest Test Level AtWhich No SignificantInterference Was Observed |
|---|---|
| Acarbose | < 50 mg/dL |
| Acetaminophen | < 200 µg/mL |
| Acetylsalicylate | < 50.8 mg/dL |
| Atorvastatin | < 0.06 mg/dL |
| Captopril | < 0.5 mg/dL |
| Chloropropamide | < 74.7 mg/dL |
| Cyanate | < 50 mg/dL |
| Furosemide | < 6.0 mg/dL |
| Gemfibrozil | < 7.5 mg/dL |
| Ibuprofen | < 50 mg/dL |
| Insulin | < 450 micro units per mL |
| Losartan | < 5 mg/dL |
| Metformin | < 5.1 mg/dL |
| Nicotinic Acid | < 61 mg/dL |
| Propranolol | < 0.2 mg/dL |
| Repaglinide | < 0.006 mg/dL |
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Interferences: Rheumatoid Factor
A study was performed based on guidance from the CLSI document EP7-A2. Interference effects were assessed by comparing test samples containing rheumatoid factor to reference samples.
Each sample was tested in a minimum of 12 replicates using 1 lot of Hemoglobin A1c Reagents and Calibrators and 1 lot of commercially available controls on ARCHITECT c 4000 instrument. The results were reported in both NGSP and IFCC units.
The Hemoglobin A1c assay had a difference within ± 5% for samples ≥ 5.7 %HbA1c. The Hemoglobin A1c assay is not susceptible to interference effects from RF less than or equal to 200 IU/mL.
Interferences: Hemoglobin Derivatives
A study was performed based on guidance from the CLSI document EP7-A2. Interference effects were assessed by comparing test samples containing the following concentrations of potentially interfering hemoglobin derivatives to reference samples:
- Acetylated Hemoglobin with ≥ 50 mg/dL of ASA (aspirin)
- Carbamylated Hemoglobin with > 10 mmol/L of Cyanate
- Labile Hemoglobin with $\geq$ 1000 mg/dL of Glucose
The test and reference samples were tested in a minimum of 12 replicates using 1 lot of Hemoglobin A1c Reagents and Calibrators and 1 lot of commercially available controls on 1 ARCHITECT c 4000 instrument. The results were reported in both NGSP and IFCC units.
The Hemoglobin A1c assay had a difference within $\pm$ 5% for samples $\geq$ 5.7 %HbA1c. The Hemoglobin A1c assay is not susceptible to interference effects from acetylated hemoglobin, carbamylated hemoglobin, or labile hemoglobin.
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Matrix Comparison
A matrix comparison study was performed to evaluate the blood collection tube types that are suitable for use with the Hemoglobin A1c assay. Specimens with concentration values spanning the measuring interval of the assay were collected from a minimum of 43 different donors in the control tube type (dipotassium EDTA, plastic) and the blood collection tubes under evaluation. The blood collection tubes collected from one individual constituted one sample set.
Each sample was tested in a minimum of 2 replicates using 1 lot of Hemoglobin A1c Reagents and Calibrators and 1 lot of commercially available controls on 1 ARCHITECT c 4000 instrument.
The results support the use of the following blood collection tube types with the Hemoglobin A1c assay:
- Dipotassium EDTA, plastic
- Lithium heparin, plastic
- Sodium heparin, plastic
- Sodium Fluoride/Disodium EDTA, plastic
- Tripotassium EDTA, plastic
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Linearity
A linearity study was performed based on guidance from the CLSI document EP6-A.
Commercially available linearity sets, comprised of Levels 1, 2, 3, and 4, were obtained. Five additional samples were prepared by combining the 4 levels of the commercially available linearity sets in specific ratios. The 9 samples were tested using the Hemoglobin A1c assay. The 9 samples were tested in a minimum of 2 replicates using 1 lot of Hemoglobin A1c Reagents and Calibrators and 1 lot of commercially available controls on 1 ARCHITECT c 4000 instrument. All samples were tested as a set within a single run. The results were reported in both NGSP and IFCC units.
NGSP:
There was no deviation from linearity for samples ranging from 2.8 to 18.1 %HbA1c. The linearity regression analysis results in NGSP units are provided in the table below:
| CorrelationCoefficient | Intercept | Slope | r2 |
|---|---|---|---|
| 0.9996 | -0.40 | 0.9709 | 0.999 |
IFCC:
There was no deviation from linearity for samples ranging from 15.31 to 174.68 mmol/mol. The linearity regression analysis results in IFCC units are provided in the table below:
| CorrelationCoefficient | Intercept | Slope | r2 |
|---|---|---|---|
| 0.9997 | -6.17 | 0.9831 | 0.999 |
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Method Comparison and Predicted Bias
To demonstrate the assay effectiveness as an aid in the diagnosis of diabetes mellitus, 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, a method comparison study was performed using an NGSP secondary reference laboratory method (Tosoh HPLC analyzer) as the comparator (reference) method.
The study was performed based on guidance from the CLSI document EP9-A2-IR. A minimum of 120 human whole blood specimens were evaluated with the Hemoglobin A1c assay and the reference method.
For the Hemoglobin A1c assay, the specimens were tested internally in replicates of 2 using 2 lots each of Hemoglobin A1c Reagents and Calibrators, 1 lot of Hemoglobin A 1c Controls (for the hemolysate application), and 1 lot of commercially available controls (for the whole blood application) on 2 ARCHITECT c 4000 instruments.
The specimens were also tested with an NGSP secondary reference laboratory method in replicates of 2. The specimens were tested over a minimum of 5 days. The results were reported in both NGSP and IFCC units.
NGSP:
Method Comparison
- · For the Hemolysate application, the Deming regression slope was 1.00 and the correlation coefficient (r-value) was 0.996 for samples across the measuring interval when comparing the Hemoglobin A1c to the reference method.
- · For the Whole Blood application, the Deming regression slope was 1.01 and the correlation coefficient (r-value) was 0.995 for samples across the measuring interval when comparing the Hemoglobin A1c to the reference method.
Predicted Bias
The predicted bias from the regression ranged from -2.4% to -0.7% for the Hemolysate application and -3.0% to -0.6% for the Whole Blood application at 5%, 6.5%, and 12 %HbA1c.
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ATD Zone
- · For the Hemolysate application, the percentage of observations in the ATD zone was 100.0 (128/128) and the lower limit of the two-sided 95% CI was 97.1%.
- · For the Whole Blood application, the percentage of observations in the ATD zone 100.0 (128/128) and the lower limit of the two-sided 95% CI was 97.1%.
IFCC:
Method Comparison
- · For the Hemolysate application, the Deming regression slope was 0.98 and the correlation coefficient (r-value) was 0.996 for samples across the measuring interval when comparing the Hemoglobin A1c to the reference method.
- · For the Whole Blood application, the Deming regression slope was 1.00 and the correlation coefficient (r-value) was 0.996 for samples across the measuring interval when comparing the Hemoglobin A1c to the reference method.
Predicted Bias
The predicted bias from the regression ranged from -4.3% to -0.5% for the Hemolysate application and -5.1% to -0.1% for the Whole Blood application at 31.13, 47.53, 63.93, and 107.65 mmol/mol.
ATD Zone
- · For the Hemolysate application, the percentage of observations in the ATD zone was 96.9 (124/128) and the lower limit of the two-sided 95% CI was 92.2%.
- · For the Whole Blood application, the percentage of observations in the ATD zone was 96.9 (124/128) and the lower limit of the two-sided 95% CI was 92.2%.
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Total Error Near the Cutoff
Using the results of bias estimation (% Bias) in the method comparison study and precision estimates in the reproducibility study, the Total Error (TE) at four %HbA1c levels (approximately 5.0%, 6.5%, 8.0%, and 12.0%) was calculated as follows:
$$\text{\textbullet TE} = |\text{\textbullet Bias}| + 1.96 \ge \text{\textbullet CV} \ge (1 + \text{\textbullet Bias})^2$$
The results are presented in the tables below.
| % Total Error Summary - Hemolysate (NGSP) | |||||
|---|---|---|---|---|---|
| -- | -- | -- | -- | ------------------------------------------- | -- |
| % HbA1c Level | Average % Bias | % CV | % TE |
|---|---|---|---|
| 5.0 | -2.2 | 0.6 | 3.4 |
| 6.5 | -1.6 | 0.9 | 3.3 |
| 8.0 | -1.3 | 0.8 | 2.8 |
| 12.0 | -0.8 | 0.9 | 2.5 |
% Total Error Summary – Whole Blood (NGSP)
| % HbA1c Level | Average % Bias | % CV | % TE |
|---|---|---|---|
| 5.0 | -2.5 | 0.6 | 3.6 |
| 6.5 | -1.8 | 0.7 | 3.1 |
| 8.0 | -1.3 | 0.6 | 2.5 |
| 12.0 | -0.7 | 0.6 | 1.9 |
Measuring Interval
The measuring interval of the Hemoglobin A1c assay is 4.0 to 14.0 %HbA1c (20.22 to 129.51 mmol/mol HbA1c). The limits of the measuring interval were demonstrated through the results of the Within-Laboratory Precision, Tube Type, Linearity, and Method Comparison studies.
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Method Comparison to Predicate Device
The study was performed based on guidance from the CLSI document EP9-A2-IR.
A minimum of 120 human whole blood specimens were evaluated with the Hemoglobin A1c assay. The specimens were tested in replicates of 2 using 1 lot each of Hemoglobin A1c Reagents, Calibrators, and Controls (for the hemolysate application), and 1 lot of commercially available controls (for the whole blood application) on 2 ARCHITECT c 4000 and 2 ARCHITECT c 8000 instruments. The results were reported in both NGSP and IFCC units.
NGSP:
First Replicate versus First Replicate Regression Analysis
- · For the Hemolysate application, the Deming regression slope was 0.99 and the correlation coefficient (r-value) was 0.999.
- · For the Whole Blood application, the Deming regression slope was 1.00 and the correlation coefficient (r-value) was 0.999.
Mean versus Mean Regression Analysis
- · For the Hemolysate application, the Deming regression slope was 0.99 and the correlation coefficient (r-value) was 0.999.
- · For the Whole Blood application, the Deming regression slope was 0.99 and the correlation coefficient (r-value) was 0.999.
IFCC:
First Replicate versus First Replicate Regression Analysis
- · For the Hemolysate application, the Deming regression slope was 0.99 and the correlation coefficient (r-value) was 1.000.
- · For the Whole Blood application, the Deming regression slope was 1.00 and the correlation coefficient (r-value) was 1.000.
Mean versus Mean Regression Analysis
- · For the Hemolysate application, the Deming regression slope was 0.99 and the correlation coefficient (r-value) was 1.000.
- · For the Whole Blood application, the Deming regression slope was 0.99 and the correlation coefficient (r-value) was 0.999.
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Automated Lyse (Whole Blood Application) versus Manual Lyse Methods (Hemolysate Application)
Whole blood specimens are lysed automatically on the ARCHITECT c 4000 instrument with the Whole Blood application or may be lysed manually using the Hemoglobin A1c Diluent with the Hemolysate application. The performance of the Hemoglobin A1c automated lyse method versus the manual lyse method was evaluated by testing whole blood specimens using both applications (i.e., Whole Blood and Hemolysate) in the Within-Laboratory Precision and the Method Comparison studies. The results from these studies met the study evaluation criteria and therefore demonstrated acceptable automated and manual lyse methods.
8. Conclusion
The data presented in this premarket notification demonstrates that the Hemoglobin A 1c assay performs substantially equivalent to the predicate device, the ARCHITECT Hemoglobin A1c assay (K130255). Correlation was demonstrated by comparison to a National Glycohemoglobin Standard Program (NGSP) secondary reference laboratory method and by comparison to the predicate device (Hemoglobin A1c on the ARCHITECT c 8000 System).
§ 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.