(392 days)
The Hemoglobin A Ic assay is used in clinical laboratories for the quantitative in vitro measurement of percent hemoglobin A le (NGSP) or HbA Ic fraction mmobile blood and hemolysate on the ARCHITECT c 8000 System. Hemoglobin Alc measurements are used as an aid in the diagnosis of diabetes mellinus, as an aid to identify patients who may be at risk for developing diabetes mellitus, and for the monitoring of long-eem blood glucose control in individuals with diabetes mellitus.
The Hemoglobin Alc Calibrators are for use in the Hemoglobin Alc assay on the ARCHITECT c 8000 System.
The Hemoglobin Alc Controls are used for the estimation and the detection of systematic analytical deviations of the ARCHITECT c 8000 System.
The Hemoglobin A1c Reagent Kit contains Reagent 1 (R1), Reagent 2 (R2), and Diluent (A1cDIL). The Hemoglobin A1c Calibrator Kit contains Calibrator 1 (Cal 1) and Calibrator 2 (Cal 2), which are lyophilized human whole blood containing hemoglobin and glycated hemoglobin. The Hemoglobin A1c Control Kit contains Low Control (Control L) and High Control (Control H), which are lyophilized human whole blood containing hemoglobin and glycated hemoglobin. The assay utilizes an enzymatic method to measure glycated hemoglobin (HbA1c) and total hemoglobin (THb) concentrations, which are then used to calculate percent HbA1c (NGSP units) or HbA fraction (IFCC units). The assay is performed on the ARCHITECT c 8000 System.
Here's a summary of the acceptance criteria and the study details for the Hemoglobin A1c assay:
Acceptance Criteria and Device Performance
| Study | Acceptance Criteria (Implicit from observed performance) | Reported Device Performance |
|---|---|---|
| Within-Laboratory Precision (NGSP - Whole Blood) | SD for Control Level 1: Low (e.g., ~0.02-0.03 SD) | 0.02 to 0.03 SD |
| %CV for Control Level 2: Low (e.g., ~0.3-0.5% CV) | 0.3 to 0.5% CV | |
| %CV for Control Level 3: Low (e.g., ~0.4-0.6% CV) | 0.4 to 0.6% CV | |
| SD for 4.0% HbA1c panel: Low (e.g., ~0.02 SD) | 0.02 SD | |
| %CV for 6.0-7.0% HbA1c panel: Low (e.g., ~0.3-0.5% CV) | 0.3 to 0.5% CV | |
| %CV for 8.0-10.0% HbA1c panel: Low (e.g., ~0.3-0.5% CV) | 0.3 to 0.5% CV | |
| Within-Laboratory Precision (NGSP - Hemolysate) | SD for Low Control: Low (e.g., ~0.01-0.02 SD) | 0.01 to 0.02 SD |
| %CV for High Control: Low (e.g., ~0.3-0.5% CV) | 0.3 to 0.5% CV | |
| %CV for Control Level 3: Low (e.g., ~0.3-0.8% CV) | 0.3 to 0.8% CV | |
| SD for 4.0% HbA1c panel: Low (e.g., ~0.02-0.03 SD) | 0.02 to 0.03 SD | |
| %CV for 6.0-7.0% HbA1c panel: Low (e.g., ~0.3-0.5% CV) | 0.3 to 0.5% CV | |
| %CV for 8.0-10.0% HbA1c panel: Low (e.g., ~0.3-0.5% CV) | 0.3 to 0.5% CV | |
| Limit of Blank (LoB) & Detection (LoD) | LoB/LoD should be low (e.g., <3% HbA1c based on range) | LoB: 2.51% HbA1c (3.89 mmol/mol) LoD: 2.52% HbA1c (4.05 mmol/mol) |
| Interferences (Endogenous Substances, Drugs, RF, Hb Derivatives) | Difference within ±5% for samples ≥ 5.7% HbA1c | Achieved for all tested substances/drugs (except HbF > 5%) |
| Interferences (Hgb Variants) | Relative % Bias within acceptable limits (e.g., < +/- 5% for samples around 6% and 9% HbA1c) | HbC: -1.6 to -1.9% HbD: -0.8 to 1.8% HbE: 0.0 to 4.3% HbS: -1.4 to 4.7% HbA2: -0.6 to -0.5% HbF: Bias exceeds -5% when > 5% HbF (significant interference) |
| Matrix Comparison | Demonstrate compatibility with specified tube types | Results support use of 5 listed tube types |
| Linearity (NGSP) | High correlation (e.g., r2 > 0.999), minimal deviation from linearity | Correlation Coefficient: 0.9996 r2: 0.999 No deviation from linearity for 3.5 to 18.1% HbA1c |
| Linearity (IFCC) | High correlation (e.g., r2 > 0.999), minimal deviation from linearity | Correlation Coefficient: 0.9997 r2: 0.999 No deviation from linearity for 14.48 to 173.79 mmol/mol |
| Method Comparison (NGSP - Hemolysate) | Deming regression slope close to 1 (e.g., 0.99-1.01) Correlation coefficient (r-value) high (e.g., > 0.99) | Slope: 0.99 r-value: 0.995 |
| Method Comparison (NGSP - Whole Blood) | Deming regression slope close to 1 (e.g., 0.99-1.01) Correlation coefficient (r-value) high (e.g., > 0.99) | Slope: 1.01 r-value: 0.995 |
| Method Comparison (IFCC - Hemolysate) | Slope close to 1, r-value high | Slope: 0.98 r-value: 0.996 |
| Method Comparison (IFCC - Whole Blood) | Slope close to 1, r-value high | Slope: 0.99 r-value: 0.995 |
| ATD Zone (NGSP - Hemolysate) | Percentage of observations in ATD zone high (e.g., >95%), lower limit of 95% CI high (e.g., >90%) | 100.0% (128/128) 95% CI: 97.1% |
| ATD Zone (NGSP - Whole Blood) | Percentage of observations in ATD zone high (e.g., >95%), lower limit of 95% CI high (e.g., >90%) | 99.2% (127/128) 95% CI: 95.7% |
| ATD Zone (IFCC - Hemolysate) | Percentage of observations in ATD zone high (e.g., >90%), lower limit of 95% CI high (e.g., >85%) | 96.1% (123/128) 95% CI: 91.2% |
| ATD Zone (IFCC - Whole Blood) | Percentage of observations in ATD zone high (e.g., >90%), lower limit of 95% CI high (e.g., >85%) | 95.3% (122/128) 95% CI: 90.2% |
| Total Error Near Cutoff (NGSP) | Total Error (%TE) within acceptable clinical limits (not explicitly stated, but typical for HbA1c is a target) | 5.0% HbA1c: 5.2% TE 6.5% HbA1c: 4.6% TE 8.0% HbA1c: 4.4% TE 12.0% HbA1c: 4.2% TE |
Study Details
-
Sample sizes used for the test set and data provenance:
- Within-Laboratory Precision: Not specified for sample patients, but involved 3 reagent lots, 3 calibrator lots, 1 control lot (L/H), 1 lot of commercial controls (3 levels), human whole blood controls, and human whole blood panels. Tested in 2 replicates, twice per day for 20 days.
- Limit of Blank (LoB) & Detection (LoD): Zero-level samples (minimum 3 replicates), low-level samples (minimum 2 replicates). Five runs over minimum 3 days.
- Interferences (Endogenous, Drugs, Hb Variants, RF, Hb Derivatives): Minimum of 12 replicates for test and reference samples.
- Hb Variants specific:
- HbC: n=21
- HbD: n=20
- HbE: n=20
- HbS: n=20
- HbA2: n=26
- HbF: n=19
- Hb Variants specific:
- Matrix Comparison: Specimens from a minimum of 43 different donors. Each sample tested in a minimum of 2 replicates.
- Linearity: 9 samples (commercially available linearity sets + 5 prepared by combining them). Tested in a minimum of 2 replicates.
- Method Comparison and Predicted Bias: Minimum of 120 human whole blood specimens. Tested internally in replicates of 2. Tested over a minimum of 5 days.
- Data Provenance: Not explicitly stated for all studies (e.g., country of origin). However, the "human whole blood specimens" and "human whole blood controls" suggest these are human samples. Studies were performed in-house at Abbott Laboratories. All studies are retrospective in the sense that they are laboratory performance evaluations on collected samples, not prospective patient trials.
-
Number of experts used to establish the ground truth for the test set and qualifications of those experts (e.g. radiologist with 10 years of experience):
- Not applicable as this is an in vitro diagnostic (IVD) device for quantitative measurement. The ground truth for the method comparison study was established using an NGSP secondary reference laboratory method (Tosoh HPLC analyzer), which is a recognized standardized method for HbA1c.
-
Adjudication method (e.g. 2+1, 3+1, none) for the test set:
- Not applicable. The ground truth was established by comparison to a recognized reference method or by preparing samples with known concentrations/characteristics.
-
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:
- Not applicable. This is an IVD device, not an imaging AI device that involves human readers.
-
If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:
- Yes, the performance studies described (Precision, LoB/LoD, Interferences, Linearity, Method Comparison) are all standalone performance evaluations of the device and its reagents. The device operates as an automated system measuring HbA1c concentrations.
-
The type of ground truth used (expert consensus, pathology, outcomes data, etc):
- For Method Comparison: A National Glycohemoglobin Standardization Program (NGSP) secondary reference laboratory method (Tosoh HPLC analyzer) was used as the comparator (reference) method. This is a highly standardized and traceable ground truth for HbA1c measurements.
- For Precision, LoB/LoD, Linearity, Interferences: Ground truth was established by:
- Using calibrators traceable to the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) reference method.
- Using controls with value-assigned concentrations (traceable to IFCC reference method and NGSP units).
- Creating samples with known concentrations (e.g., "zero-level," "low-level," linearity sets, spiked interference samples, samples with known Hb variants).
-
The sample size for the training set:
- Not applicable. This is an IVD device based on an enzymatic methodology, not a machine learning or AI algorithm that requires a "training set" in the traditional sense. The device's performance is based on its chemical and enzymatic reactions, and the calibration process uses a dedicated calibrator kit, not a "training set" of patient data for model learning.
-
How the ground truth for the training set was established:
- Not applicable, as there is no "training set" for a machine learning model. The device's calibration involves calibrators that are value-assigned using secondary calibrators traceable to the IFCC reference method.
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FEB 2 8 2014
510(k) Summary (Summary of Safety and Effectiveness)
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: (847) 937-1132 Fax Number: (847) 937-4836 E-Mail: judith.r.wallach@abbott.com Date Summary prepared: January 31, 2013 Revised February 25, 2014
Grace LeMieux, ADD, Regulatory Affairs Director Phone (847) 935-0409 Fax (847) 937-4836 E-mail grace.lemieux(a)abbott.com
2. Device Name
Hemoglobin Alc Hemoglobin Alc Calibrators Hemoglobin Alc Controls
Reagents
Classification Name: Assay, Glycosylated Hemoglobin Regulation Description: Glycosylated hemoglobin assay Trade Name: Hemoglobin Alc Common Name: HbAıc 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 unassaved) Regulation Description: Quality control material (assayed and unassaved) 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
Reagents
COBAS INTEGRA 800 Tina-quant HbA1cDx Gen.2 assay (K121291)
Calibrators
Roche C.f.a.s. (Calibrator for Automated Systems) HbA1c (K052101)
Controls
Roche PreciControl HbA1c norm and PreciControl HbA1c path (K103099)
4. Description of Device
Reagents
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 Are 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 Ic Calibrators (lyophilized) contain hemoglobin and glycated hemoglobin from . human whole blood. Prior to lyophilization, the calibrator matrix is an MESbuffered solution. Preservative: Ofloxacin.
- The value-assigned A Ic Calibrator values are within the following hemoglobin . Alc 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 I c 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 A1c Ranges | 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 (%HbA1}} and in International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) units (mmol/mol HbA12) 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 HbA 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 A ي Diluent (AlcDIL) 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 $\beta$-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 (RI) 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 + RI).
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 HbAic/THb ratio as follows:
mmol/mol HbAic IFCC: HbA1c (mmol/mol) = (HbA1c/THb) $\times$ 1000
%HbA1c DCCT/NGSP: HbA1c (%) = IFCC x 0.09148 + 2.152
Methodology: Enzymatic
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 8000 System.
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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 8000 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 8000 System. ,
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.
6. Comparison of Technological Characteristics
:
The Hemoglobin Are assay (candidate assay) utilizes an enzymatic methodology for the quantitative in vitro measurement of percent hemoglobin A1c or HbA1c fraction and is intended for use on the ARCHITECT c 8000 System. The COBAS INTEGRA 800 Tina-quant HbA 1cDx Gen.2 assay is an in vitro diagnostics reagent system intended for quantitative determination of mmol/mol hemoglobin A1c (IFCC) and % hemoglobin A1c (DCCT/NGSP) in hemolysate or whole blood on the Roche COBAS INTEGRA 800 clinical chemistry analyzer.
The following table provides the similarities and differences between the candidate assay and the predicate assay.
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| ReagentSimilarities and Differences | ||
|---|---|---|
| Characteristics | Submission DeviceHemoglobin A₁c | Predicate DeviceCOBAS INTEGRA 800 Tina-quant HbA1cDxGen.2 (K121291) |
| Intended Useand Indicationsfor Use | For the quantitative in vitro measurement ofpercent hemoglobin A₁c (NGSP) or HbA₁cfraction mmol/mol (IFCC) in human wholeblood and hemolysate on the ARCHITECT c8000 System.Hemoglobin A₁e measurements are used asan aid in the diagnosis of diabetes mellitus,as an aid to identify patients who may be atrisk for developing diabetes mellitus, and forthe monitoring of long-term blood glucosecontrol in individuals with diabetes mellitus. | This test is to be used as an aid in diagnosis ofdiabetes and as an aid in identifying patients whomay be at risk for developing diabetes. TheCOBAS INTEGRA 800 Tina-quant HbA1cDxGen.2 assay is an in vitro diagnostics reagentsystem intended for quantitative determinationof mmol/mol hemoglobin A1c (IFCC) and %hemoglobin A1c (DCCT/NGSP) in hemolysateor whole blood on the Roche COBASINTEGRA 800 clinical chemistry analyzer. |
| Platform | ARCHITECT c 8000 System(clinical chemistry analyzer) | Roche COBAS INTEGRA 800(clinical chemistry analyzer) |
| Methodology | Enzymatic | Immunoassay |
| Specimen Type | Whole blood and Hemolysate:Dipotassium EDTALithium HeparinSodium HeparinSodium Fluoride/Disodium EDTATripotassium EDTA | Whole blood and Hemolysate:Li-HeparinK2-EDTAK3-EDTAKF/Na₂-EDTANa-HeparinNaF/K-oxalateNaF/Na₂-EDTA |
:
.
・
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| ReagentSimilarities and Differences | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Characteristics | Submission DeviceHemoglobin A1c | Predicate DeviceCOBAS INTEGRA 800 Tina-quant HbA1cDxGen.2 (K121291) | ||||||||
| ExpectedValues | For monitoring diabetic patients, it isrecommended that glycemic goals areindividualized following current professionalsociety recommendations. The AmericanDiabetes Association (ADA)recommendations are summarized in thefollowing table.HbA1c Value Glycemic Goal < 8 %HbA1c(64 mmol/mol) Less Stringent < 7 %HbA1c(53 mmol/mol) General (Non-Pregnant Adults) < 6.5 %HbA1c(48 mmol/mol) More stringentHbA1c values above 6.5 %HbA1c (48mmol/mol) are an indication ofhyperglycemia during the preceding 2 to 3months or longer. According to therecommendations of the ADA, HbA1cvalues above 6.5 %HbA1c (48 mmol/mol)are suitable for the diagnosis of diabetesmellitus. Patients with HbA1c values in therange of 5.7 - 6.4 %HbA1c (39 - 46mmol/mol) may be at a risk of developingdiabetes. | Protocol 1 (acc. to IFCC): 20-42 mmol/molHbA1cProtocol 2 (acc. to DCCT/NGSP): 4.0-6.0 %HbA1cHbA1c levels higher than the upper end of thisreference range are an indication ofhyperglycemia during the preceding 2 to 3months or longer. According to therecommendations of the American DiabetesAssociation values above 48 mmol/mol HbA1c(IFCC) or 6.5 % HbA1c (DCCT/NGSP) aresuitable for the diagnosis of diabetes mellitus.Patients with HbA1c values in the range of 39-46 mmol/mol HbA1c (IFCC) or 5.7-6.4 %HbA1c (DCCT/NGSP) may be at a risk ofdeveloping diabetes.HbA1c levels may reach 195 mmol/mol (IFCC)or 20 % (DCCT/NGSP) or higher in poorlycontrolled diabetes. Therapeutic action issuggested at levels above 64 mmol/mol HbA1c(IFCC) or 8 % HbA1c (DCCT/NGSP). Diabetespatients with HbA1c levels below 53 mmol/molHbA1c (IFCC) or 7 % HbA1c (DCCT/NGSP)meet the goal of the American DiabetesAssociation.HbA1c levels below the established referencerange may indicate recent episodes ofhypoglycemia, the presence of Hb variants, orshortened lifetime of erythrocytes. | ||||||||
| MeasuringInterval | 4.0 to 14.0 %HbA1c (DCCT/NGSP)20.22 to 129.51 mmol/mol HbA1c (IFCC) | 4.2 to 20.1% HbA1c (DCCT/NGSP)23 to 196 mmol/mol HbA1c (IFCC) |
.
:
:
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| CalibratorSimilarities and Differences | ||
|---|---|---|
| Characteristics | Submission DeviceHemoglobin A1c | Predicate DeviceRoche C.f.a.s. HbA1c (K052101) |
| Intended use | For use in the calibration of the HemoglobinA1c assay on the ARCHITECT c 8000System. | C.f.a.s. (Calibrator for automated systems)HbA1c is for use in the calibration ofquantitative Roche methods on Roche clinicalchemistry analyzers as specified in the enclosedvalue sheets. |
| Levels | 2 levels (Calibrator 1 and 2)Each lot of calibrators is value-assigned andvalues are reported in both NGSP and IFCCunits. Actual analyte concentrations for eachlot of calibrators are listed in the HemoglobinA1c Calibrator Value Sheet, packaged withthe calibrator. The concentration of glycatedhemoglobin (HbA1c) and total hemoglobin(THb) is provided for each lot. | 1 levelThe C.f.a.s. HbA1c calibrator is automaticallydiluted by the system. |
| Standardization/Traceability | Calibrators are prepared gravimetrically.lyophilized, and then value assigned usingsecondary calibrators that are traceable to theInternational Federation of Clinical Chemistryand Laboratory Medicine (IFCC) referencemethod. | This method has been standardized against theapproved IFCC reference method for themeasurement of HbA1c in human blood and canbe transferred to results traceable to DCCT/NGSPby calculation. |
.
| ControlSimilarities and Differences | ||
|---|---|---|
| Characteristics | Submission DeviceHemoglobin A1c | Predicate DeviceRoche PreciControl HbA1c norm andPreciControl HbA1c path (K103099) |
| Intended use | For the estimation of test precision andthe detection of systematic analyticaldeviations of the Hemoglobin A1c assayon the ARCHITECT c 8000 System. | For use in quality control by monitoring accuracy andprecision for the qualitative methods as specified inthe value sheets. |
| Levels | 2 levels (Low and High Control)LyophilizedAssignment of values is specific foreach lot. | PreciControl HbA1c norm: 1 levelPreciControl HbA1c path:1 levelAssignment of values is specific for each lot. |
| Material | Controls are prepared usinghemoglobin and glycated hemoglobinfrom human whole blood. Prior tolyophilization, the matrix used is MESbuffered solution. | PreciControl HbA1c norm is a liquid control based onhemolyzed human blood. The adjusted concentrationsof the control components are usually in the normalrange or at the normal/pathological threshold.PreciControl HbA1c path is a lyophilized controlbased on hemolyzed sheep blood. The adjustedconcentrations of the control components are usuallyin the pathological range. |
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7. Summary of Nonclinical Performance
Within-Laboratory Precision (20-Dav)
A 20-day precision study was conducted to evaluate the precision performance of the Hemoglobin A ic 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 8000 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 0.03 SD for Control Level 1
- 0.3 to 0.5 %CV for Control Level 2 . •
- 0.4 to 0.6 %CV for Control Level 3 .
- 0.02 SD for the panel targeted near 4.0 %HbAir .
- 0.3 to 0.5 %CV for the panel with a target range of 6.0 7.0 %HbA1c .
- . 0.3 to 0.5 %CV for the panel with a target range of 8.0 - 10.0 %HbA1c
Hemolysate
- 0.01 to 0.02 SD for the Hemoglobin A1c Low Control .
- 0.3 to 0.5 %CV for the Hemoglobin A1c High Control .
- . 0.3 to 0.8 %CV for Control Level 3
- 0.02 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 0.5 %CV for the panel with a target range of 8.0 10.0 %HbA1c �
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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 16 Reagents, 2 lots of Hemoglobin A1c Calibrators, and 1 lot of commercially available controls on 2 ARCHITECT c 8000 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).
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 A & Reagents and Calibrators and 1 lot of commercially available controls on 1 ARCHITECT c 8000 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:
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| Endogenous Substance Name | Highest Test Level At Which No SignificantInterference Was Observed |
|---|---|
| Ascorbic Acid | 3.0 mg/dL |
| Conjugated Bilirubin | 15.0 mg/dL |
| Glucose | 1000 mg/dL |
| Triglycerides | 3000 mg/dL |
| Total Protein* | 22 g/dL |
| Unconjugated Bilirubin | 10.0 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.
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 8000 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).
| Hemoglobin Variant | n | Range in % AbnormalVariant | Range in %HbA1cConcentration |
|---|---|---|---|
| HbC | 21 | 33% - 42% | 5.2 - 9.3 |
| HbD | 20 | 35% - 41% | 5.2 - 10.7 |
| HbE | 20 | 27% - 32% | 5.0 - 10.1 |
| HbS | 20 | 33% - 44% | 5.1 - 9.9 |
| HbA2 | 26 | 4.7% - 8.5% | 4.7 - 13.3 |
| HbF | 19 | 3% - 27.8% | 5.2 - 9.0 |
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| Hemoglobin Variant | Relative % Bias from Reference/Expected Concentration | |
|---|---|---|
| ~ 6.0 %HbA1c | ~ 9.0 %HbA1c | |
| HbC | -1.6 | -1.9 |
| HbD | -0.8 | 1.8 |
| HbE | 0.0 | 4.3 |
| HbS | -1.4 | 4.7 |
| HbA2 | -0.6 | -0.5 |
| HbF | Bias exceeds -5% when the amount of HbF in the sample exceeds 5%a |
4 A negative bias with HbF is directly proportional in magnitude to the % HbF present in the sample. NOTE: The presence of multiple variants in a sample may impact the % bias.
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.
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 8000 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:
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| Drug Name | Highest Drug Level Tested |
|---|---|
| Acarbose | ≤ 50 mg/dL |
| Acetaminophen | ≤ 200 µg/mL |
| Acetylsalicylate | ≤ 50.8 mg/dL |
| Atorvastatin | ≤ 600 µg Eq/L |
| 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 | ≤ 0.5 mg/mL |
| 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 | < 60 ng/mL |
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 1 ARCHITECT c 8000 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 A t assay is not susceptible to interference effects from RF less than or equal to 200 IU/mL.
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Interferences: Hemoglobin Derivates
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)
- . Carbamlyated 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 8000 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.
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 8000 instrument.
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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
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 8000 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 3.5 to 18.1 %HbA1c. The linearity regression analysis results in NGSP units are provided in the table below:
| CorrelationCoefficient | Intercept | Slope | r2 |
|---|---|---|---|
| 0.9996 | -0.59 | 0.9782 | 0.999 |
IFCC:
There was no deviation from linearity for samples ranging from 14.48 to 1 73.79 mmol/mol. The linearity regression analysis results in IFCC units are provided in the table below:
| CorrelationCoefficient | Intercept | Slope | r2 |
|---|---|---|---|
| 0.9997 | -7.23 | 0.9847 | 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 A1c Controls (for the hemolysate application), and 1 lot of commercially available controls (for the whole blood application) on 2 ARCHITECT c 8000 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 0.99 and the correlation coefficient (r-value) was 0.995 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 -2.5% to -2.7% for the Hemolysate application and -2.4% to -3.0% for the Whole Blood application.
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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 was 99.2 (127/128) and the lower limit of the two-sided 95% Cl was 95.7%.
IFCC:
Method Comparison
- · For the Hemolysate application, the 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 regression slope was 0.99 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 -3.7% to -4.0% for the Hemolysate application and -3.7% to -4.5% for the Whole Blood application.
ATD Zone
- · For the Hemolysate application, the percentage of observations in the ATD zone was 96.1% (123/128) and the lower limit of the two-sided 95% CI was 91.2%.
- · For the Whole Blood application, the percentage of observations in the ATD zone was 95.3 (122/128) and the lower limit of the two-sided 95% Cl was 90.2%.
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 %HbAic levels (approximately 5.0%, 6.5%, 8.0%, and 12.0%) was calculated as follows:
$$% \text{TE} = |% \text{Bias}| + |\text{.96} \ge % \text{CV}|$$
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The results are presented in the tables below.
| %HbA1c Level | Average % Bias | % CV | % TE |
|---|---|---|---|
| 5.0 | -3.6 | 0.8 | 5.2 |
| 6.5 | -2.8 | 0.9 | 4.6 |
| 8.0 | -2.4 | 1.0 | 4.4 |
| 12.0 | -1.7 | 1.3 | 4.2 |
% Total Error Summary - Hemolysate (NGSP)
% Total Error Summary - Whole Blood (NGSP)
| %HbA1c Level | Average % Bias | % CV | % TE |
|---|---|---|---|
| 5.0 | -3.9 | 0.6 | 5.1 |
| 6.5 | -2.9 | 0.7 | 4.3 |
| 8.0 | -2.3 | 0.7 | 3.7 |
| 12.0 | -1.4 | 1.6 | 4.5 |
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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Automated Lyse (Whole Blood Application) versus Manual Lyse Methods (Hemolysate Application)
Whole blood specimens are lysed automatically on the ARCHITECT c 8000 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 A1c assay performs substantially equivalent to the predicate device, the COBAS INTEGRA 800 Tina-quant HbA1cDx Gen.2 assay (K121291). Correlation was demonstrated by comparison to a National Glycohemoglobin Standard Program (NGSP) secondary reference laboratory method.
The data presented in the premarket notification provide reasonable assurance that the Hemoglobin A1c assay is safe and effective for the stated intended use.
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Image /page/20/Picture/1 description: The image shows the logo for the U.S. Department of Health and Human Services. The logo consists of a circular seal with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" around the perimeter. Inside the circle is a stylized symbol that resembles a human figure embracing a globe, representing the department's mission to protect the health of all Americans.
Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002
February 28, 2014
ABBOTT LABORATORIES JUDITH WALLACH 100 ABBOTT PARK RD. ABBOTT PARK IL 60064-3502
Re: K130255 Trade/Device Name: Hemoglobin A1c Hemoglobin Alc Calibrators Hemogiobin Alc Controls Regulation Number: 21 CFR 862.1373 Regulation Name: Hemoglobin Alc Test System Regulatory Class: II Product Code: PDJ, LCP, JIT, JJX Dated: February 20, 2014 Received: February 21, 2014
Dear Ms. 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 electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
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If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Division of Small Manufacturers, International and Consumer Assistance 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. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR 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 Small Manufacturers, International and Consumer Assistance 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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DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration
Indications for Use
510(k) Number (if known) K130255
Device Name
Hemoglobin Alc / Hemoglobin Alc Calibrators / Hemoglobin Alc Controls
Indications for Use (Describe)
The Hemoglobin A Ic assay is used in clinical laboratories for the quantitative in vitro measurement of percent hemoglobin A le (NGSP) or HbA Ic fraction mmobile blood and hemolysate on the ARCHITECT c 8000 System. Hemoglobin Alc measurements are used as an aid in the diagnosis of diabetes mellinus, as an aid to identify patients who may be at risk for developing diabetes mellitus, and for the monitoring of long-eem blood glucose control in individuals with diabetes mellitus.
The Hemoglobin Alc Calibrators are for use in the Hemoglobin Alc assay on the ARCHITECT c 8000 System.
The Hemoglobin Alc Controls are used for the estimation and the detection of systematic analytical deviations of the ARCHITECT c 8000 System.
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)
PLEASE DO NOT WRITE BELOW THIS LINE - CONTINUE ON A SEPARATE PAGE IF NEEDED.
FOR FDA USE ONLY
Concurrence of Center for Devices and Radiological Health (CDRH) (Signature)
erine Serr
Form Approved: OMB No. 0910-0120 Expiration Date: December 31, 2013 See PRA Statement on last page.
§ 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.