(218 days)
Not Found
No
The summary describes a fully automated, self-contained benchtop analyzer that performs quantitative measurements based on chemical reactions and optical detection. There is no mention of AI, ML, image processing, or any algorithms that would typically be associated with AI/ML technology. The calculations are based on ratios of measured concentrations, not complex learning models.
No
Explanation: This device is an in vitro diagnostic (IVD) device used to quantitatively determine glycated hemoglobin (HbA1c) to assess diabetes control. It does not directly treat or prevent a disease; rather, it provides diagnostic information.
Yes
The "Intended Use / Indications for Use" section explicitly states that the system is intended for "in vitro diagnostic use" and the "cobas HbA1c Test is an in vitro diagnostic test designed to quantitatively determine glycated hemoglobin (HbA1c)". Additionally, the description of its use for assessing and monitoring diabetes demonstrates its diagnostic purpose.
No
The device description clearly states it is a "bench top analyzer" which is a hardware instrument that measures HbA1c using reagent discs and optical measurements. While it has software components for control and data management, it is fundamentally a hardware device.
Based on the provided information, the cobas b 101 system is an IVD (In Vitro Diagnostic) device.
Here's why:
- Intended Use/Indications for Use: The document explicitly states the system is "intended for professional, in vitro diagnostic use in a clinical laboratory setting or point-of-care (PoC) locations." It also describes the HbA1c test as an "in vitro diagnostic test designed to quantitatively determine glycated hemoglobin (HbA1c) in human capillary and venous whole blood."
- Device Description: The description details how the system analyzes biological samples (whole blood) to provide quantitative results for a specific analyte (HbA1c). This aligns with the definition of an in vitro diagnostic device, which is used to examine specimens derived from the human body to provide information for diagnostic purposes.
- Performance Studies: The document includes detailed descriptions of performance studies, including precision, linearity, interference, and method comparison to a reference method. These types of studies are standard for demonstrating the analytical performance of IVD devices.
Therefore, the cobas b 101 system, as described, clearly fits the definition of an In Vitro Diagnostic device.
N/A
Intended Use / Indications for Use
cobas b 101 system: The cobas b 101 instrument is a multi-assay system designed to quantitatively analyze cobas reagent discs. The system is intended for professional, in vitro diagnostic use in a clinical laboratory setting or point-of-care (PoC) locations.
HbA1c test: The cobas HbA1c Test is an in vitro diagnostic test designed to quantitatively determine glycated hemoglobin (HbA1c) in human capillary and venous whole blood on the cobas b 101 instrument. The system is intended for professional use in a clinical laboratory setting or point-of-care (PoC) locations. Measurement of hemoglobin A1c is used to assess the level of control of a patient's diabetes and to monitor long term blood glucose control. Elevated levels of hemoglobin A1c indicate uncontrolled diabetes in a patient.
Product codes
LCP, JJE
Device Description
The cobas b 101 system is a bench top analyzer which measures HbA1c. The system is fully automated, self-contained and utilizes a single use reagent disc. The system has the ability to measure capillary or venous whole blood samples. Sample is applied directly from the fingerstick or via a pipette when testing venous whole blood. The operator simply applies sample to the disc and places the disc in the instrument. There are no pre-analytics needed as the disc is self-filling by capillary forces. There is no intervention by the operator during measurement. At completion of the test, the instrument displays a quantitative result. No calculations or interpretation are required by the operator.
Calibration of the instrument is completed as part of the manufacturing process. Calibration information is contained on each disc and is read when the disc is loaded on the instrument. No calibration intervention is required by the operator.
An optional barcode scanner can be provided to read barcode information for patient identification. The barcode scanner uses LED as the light source. Results can be printed out by using an optional external printer.
A connection to a Data Management System is possible either via a USB interface to a local PC or via an Ethernet converted to a Laboratory Information Management System (LIMS). The communication protocol is defined according to the CLSI approved POCT1-A2 standard.
HbA1c (glycated hemoglobin) can be determined by using samples from capillary blood directly from the fingertip or from venous whole blood with heparin or EDTA (K2 or K3) anticoagulant. The blood sample is diluted and mixed with TRIS buffer to release hemoglobin from the erythrocytes. A fraction of the sample is conveyed into a reaction chamber where it is mixed with sodium lauryl sulfate (SLS). SLS is used to form the SLS-hemoglobin complex. The concentration of total hemoglobin is calculated by measuring SLS-hemoglobin complex with a wavelength of 525 nm. Hemoglobin A1c (HbA1c) in another fraction of the sample is first denaturated by potassium ferricyanide and sucrose laurate. The denatured HbA1c bonds with HbA1c antibody on the latex particle. Latex agglutination inhibition reaction then occurs by reacting the agglutinator that has synthetic antigen which can bond with HbA1c antibody. The concentration of HbA1c is calculated by measuring the latex agglutination inhibition reaction with a wavelength of 625 nm. The % hemoglobin A1c value is measured using a ratio of concentrations of HbA1c to total hemoglobin.
Mentions image processing
Not Found
Mentions AI, DNN, or ML
Not Found
Input Imaging Modality
Not Found
Anatomical Site
Not Found
Indicated Patient Age Range
Not Found
Intended User / Care Setting
professional use in a clinical laboratory setting or point-of-care (PoC) locations.
Description of the training set, sample size, data source, and annotation protocol
Not Found
Description of the test set, sample size, data source, and annotation protocol
Not Found
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
Precision (Non-Clinical):
Internal precision was evaluated according to CLSI EP05-A3 on one cobas b 101 instrument with 2 cobas HbA1c Test disc lots and 1 cobas HbA1c Control lot. Two control samples and 8 K2EDTA or K3EDTA venous whole blood samples were measured over 21 days (n=84 results per sample). Results showed good precision with total %CV ranging from 1.3% to 2.9% for samples and 1.8% to 1.9% for controls.
External precision was performed according to CLSI EP05-A3 at 3 Point-of-Care sites using 6 cobas b 101 instruments and 3 reagent disc lots. Each site assessed 2 reagent disc lots on 2 instruments. Three lots of controls and 4 human sample pools were tested. Samples were measured in duplicate 2x/day for 21 days (n=84 measurements per site, total n=504 combined per sample/control). Combined total %CV ranged from 1.3% to 1.9% for samples and 3.1% to 3.7% for controls.
Linearity/Assay Reportable Range:
The linearity study was conducted to demonstrate linearity across the claimed measuring range (4-12% HbA1c) according to CLSI guideline EP06-A. It was performed on the cobas b 101 system by measuring 11 dilutions of a low (3.6% HbA1c) and high (12.9% HbA1c) K2EDTA whole blood sample. A Pearson r of 0.9961 was obtained, supporting linearity.
Hemoglobin Linearity:
This study assessed the linearity of HbA1c measurements throughout the specified total hemoglobin concentration range (6-20 g/dL). Four K2EDTA and Li-Heparin venous whole blood samples with HbA1c concentrations of approx. 4.5 - 14% and high total hemoglobin (approx. 22g/dL) were used. A 10-level dilution series was prepared for each sample. Each sample and dilution level was tested in triplicate. All results were within acceptance criteria.
Endogenous Interferences (Albumin/Bilirubin/Lipemia/Glucose/Rheumatoid Factor/Total Protein):
Evaluated according to CLSI guideline EP07-A2. Two HbA1c levels (normal and pathological) were evaluated for each interferent in K2EDTA venous whole blood. No significant interference was found up to the tested concentrations (e.g., Albumin 77.5 g/L, Bilirubin 85 mg/dL, Lipemia 750 mg/dL, Glucose 2800 mg/dL, Rheumatoid Factor 1200 IU/mL, Total Protein 126 g/L).
Exogenous Interferences – Drugs:
Evaluated according to CLSI guideline EP07-A2 using K2EDTA venous whole blood. No interference was found at therapeutic concentrations for drugs tested (e.g., Acetyl Cysteine 1660 mg/L, Ascorbic acid 300 mg/L, Heparin 5000 U/L).
Cross-Reactivity (Carbamylated Hemoglobin, Acetylated Hemoglobin and Labile HbA1c):
Evaluated according to CLSI guideline EP07-A2 using K2EDTA venous whole blood. No relevant cross-reactivity was found up to the listed concentrations (Carbamylated Hb 3000 mg/dL, Acetylated Hb 3000 mg/dL, Labile HbA1c 3000 mg/dL).
Cross-Reactivity (HbA0):
A correlation analysis was performed between HbA1c results from cobas b 101 and the reference system cobas c 501 using approx. 60 K2EDTA whole blood samples. The data supports claims of no cross-reactions with HbA0 at physiologically occurring concentrations.
Cross-Reactivity (HbA1a and HbA1b):
Ten dilutions of HbA1a+b stock solution were prepared and mixed with normal and pathological K2EDTA whole blood samples. All samples were measured in triplicate (n=33 per sample type) on the cobas b 101. Results met predefined acceptance criteria, supporting claims of no cross-reactions with HbA1a and HbA1b at physiologically occurring concentrations.
Hemoglobin Variants:
Tested to determine interference with major hemoglobin variants (HbS, HbC, HbD, HbE, HbF, HbA2). A total of 130 samples (HbAS, HbAC, HbAD, HbAE, Elevated F, Elevated A2) with HbA1c values ranging from 4.35-11.58% were measured once on the cobas b 101. Reference methods (with no interference for the particular variant) were used for comparison. Non-significant interference was defined as ≤ 10% difference. The results met acceptance criteria for HbAS, HbAC, HbAE and HbA2. HbF interference was excluded up to 10% HbF.
Stability:
Studies performed according to CLSI guideline EP025-A support a shelf life of 16 months for cobas reagent disks stored at 2-30 °C.
Method Comparison versus Reference (External Clinical Testing):
Performed according to CLSI EP09-A3 at 3 Point of Care sites. Capillary whole blood and venous whole blood (EDTA (K2) and Li-Heparin) were measured on the cobas b 101 in singlicate. The Tosoh G8 HPLC Analyzer was the reference method for venous EDTA (K2) whole blood.
- Capillary blood (N=121-133 per site): Pearson's r of 0.99 for all sites. Regression lines were approximately y = 1.00x - 0.10 or y = 1.00x - 0.20.
- EDTA K2 blood (N=121-133 per site): Pearson's r of 0.99 for all sites. Regression lines were approximately y = 1.00x - 0.20 or y = 0.97x + 0.04.
- Lithium Heparin blood (N=117-130 per site): Pearson's r of 0.99 for all sites. Regression lines were approximately y = 1.00x - 0.20.
Matrix Comparison:
A study was performed comparing EDTA (K2) whole blood (reference) and EDTA (K3) whole blood. Ninety-one samples were tested in singlicate on the cobas b 101. Pearson's r was 0.99, with a regression line of y = 1.03x - 0.00.
Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)
Not Found. Precision data provided in %CV. Linearity supported by Pearson's r.
Predicate Device(s)
Reference Device(s)
Not Found
Predetermined Change Control Plan (PCCP) - All Relevant Information
Not Found
§ 864.7470 Glycosylated hemoglobin assay.
(a)
Identification. A glycosylated hemoglobin assay is a device used to measure the glycosylated hemoglobins (A1a , A1b , and A1c ) in a patient's blood by a column chromatographic procedure. Measurement of glycosylated hemoglobin is used to assess the level of control of a patient's diabetes and to determine the proper insulin dosage for a patient. Elevated levels of glycosylated hemoglobin indicate uncontrolled diabetes in a patient.(b)
Classification. Class II (performance standards).
0
Image /page/0/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a stylized caduceus symbol, which is a staff with two snakes coiled around it. The caduceus is positioned to the right of the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA", which is arranged in a circular fashion around the symbol.
Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002
July 28, 2017
ROCHE DIAGNOSTICS OPERATIONS PATTY BATES REGULATORY AFFAIRS PRINCIPAL 9115 HAGUE ROAD INDIANAPOLIS, IN 46250
Re: K163633
Trade/Device Name: cobas HbA1c Test, cobas b 101 System Regulation Number: 21 CFR 864.7470 Regulation Name: Glycosylated hemoglobin assay Regulatory Class: II Product Code: LCP. JJE Dated: June 15, 2017 Received: June 16, 2017
Dear Patty Bates:
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.
1
Page 2-Ms. Bates
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,
Kellie B. Kelm -S
for Courtney H. Lias, Ph.D. Director Division of Chemistry and Toxicology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health
Enclosure
2
Indications for Use
510(k) Number (if known)
K163633
Device Name cobas b 101 system cobas HbA1c Test
Indications for Use (Describe)
cobas b 101 system: The cobas b 101 instrument is a multi-assay system designed to quantitatively analyze cobas reagent discs. The system is intended for professional, in vitro diagnostic use in a clinical laboratory setting or point-of-care (PoC) locations.
HbA1c test: The cobas HbA1c Test is an in vitro diagnostic test designed to quantitatively determine glycated hemoglobin (HbA ic) in human capillary and venous whole blood on the cobas b 101 instrument. The system is intended for professional use in a clinical laboratory setting or point-of-care (PoC) locations. Measurement of hemoglobin A 1c is used to assess the level of control of a patient's diabetes and to monitor long term blood glucose control. Elevated levels of hemoglobin Alc indicate uncontrolled diabetes in a patient.
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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cobas b 101 system 510(k) Summary K163633
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of 21 CFR 807.92.
In accordance with 21 CFR 807.87, Roche Diagnostics hereby submits official notification as required by Section 510(k) of the Federal Food, Drug and Cosmetics Act of our intention to market the device described in this Premarket Notification 510(k).
The purpose of this Traditional 510(k) Premarket Notification is to obtain FDA review and clearance for the cobas b 101 system and cobas HbA1c Test.
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| Submitter Name | Roche Diagnostics |
|---|---|
| Address | 9115 Hague Road |
| P.O. Box 50416 | |
| Indianapolis, IN 46250-0457 | |
| Contact | Patty Bates |
| Phone: (317) 521-4572 | |
| FAX: (317) 521-2324 | |
| Email: patty.bates@roche.com |
Tracy Bush
Phone: (317) 521-3723
FAX: (317) 521-2324
Email: tracy.bush@roche.com |
| Date Prepared | November 30, 2016 |
| Proprietary Name | cobas HbA1c Test
cobas b 101 system |
| Common Name | Test system for HbA1c
Discrete photometric chemistry analyzer for clinical use |
| Classification Name | Glycosylated hemoglobin assay – Class II
Analyzer, chemistry (Photometric, discrete), for clinical use – Class I |
| Product Codes,
Regulation Numbers | LCP, 21 CFR 864.7470
JJE, 21 CFR 862.2160 |
| Predicate Devices | DCA Vantage |
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1. DEVICE DESCRIPTION
1.1. System: cobas b 101 system
The cobas b 101 system is a bench top analyzer which measures HbA1c. The system is fully automated, self-contained and utilizes a single use reagent disc. The system has the ability to measure capillary or venous whole blood samples. Sample is applied directly from the fingerstick or via a pipette when testing venous whole blood. The operator simply applies sample to the disc and places the disc in the instrument. There are no pre-analytics needed as the disc is self-filling by capillary forces. There is no intervention by the operator during measurement. At completion of the test, the instrument displays a quantitative result. No calculations or interpretation are required by the operator.
Calibration of the instrument is completed as part of the manufacturing process. Calibration information is contained on each disc and is read when the disc is loaded on the instrument. No calibration intervention is required by the operator.
An optional barcode scanner can be provided to read barcode information for patient identification. The barcode scanner uses LED as the light source. Results can be printed out by using an optional external printer.
A connection to a Data Management System is possible either via a USB interface to a local PC or via an Ethernet converted to a Laboratory Information Management System (LIMS). The communication protocol is defined according to the CLSI approved POCT1-A2 standard.
Reagent: cobas HbA1c Test 1.2.
HbA1c (glycated hemoglobin) can be determined by using samples from capillary blood directly from the fingertip or from venous whole blood with heparin or EDTA (K2 or K3) anticoagulant. The blood sample is diluted and mixed with TRIS buffer to release hemoglobin from the erythrocytes. A fraction of the sample is conveyed into a reaction chamber where it is mixed with sodium lauryl sulfate (SLS). SLS is used to form the SLS-hemoglobin complex. The concentration of total hemoglobin is calculated by measuring SLS-hemoglobin complex with a wavelength of 525 nm. Hemoglobin A1c (HbA1c) in another fraction of the sample is first
6
denaturated by potassium ferricyanide and sucrose laurate. The denatured HbA1c bonds with HbA1c antibody on the latex particle. Latex agglutination inhibition reaction then occurs by reacting the agglutinator that has synthetic antigen which can bond with HbA1c antibody. The concentration of HbA1c is calculated by measuring the latex agglutination inhibition reaction with a wavelength of 625 nm. The % hemoglobin A1c value is measured using a ratio of concentrations of HbA1c to total hemoglobin.
2. INDICATIONS FOR USE
2.1. System: cobas b 101 system
The cobas b 101 instrument is a multi-assay system designed to quantitatively analyze cobas reagent discs. The system is intended for professional, in vitro diagnostic use in a clinical laboratory setting or point-of-care (PoC') locations.
Reagent: cobas HbA1c Test 2.2.
The cobas HbA1c Test is an in vitro diagnostic test designed to quantitatively determine glycated hemoglobin (HbA1c) in capillary finger-stick or venous whole blood, collected in EDTA (K2 or K3) or lithium heparin tubes, on the cobas b 101 instrument. This test is intended for professional use in a clinical laboratory setting or point-of-care (PoC) locations. This test is not for screening or diagnosis of diabetes or neonatal use. Measurement of hemoglobin A1c is used to monitor long term blood glucose control in patients previously diagnosed with diabetes.
TECHNOLOGICAL CHARACTERISTICS 3.
The following tables compare the cobas b 101 system with its predicate devices.
| Candidate Device Name | Predicate Device Name | K-Number |
|---|---|---|
| cobas b 101 system and cobas | ||
| HbA1c Test | DCA Vantage | K071466 |
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| Feature | Predicate Device: DCA Vantage (K071466) | Candidate Device: cobas b 101
system/cobas HbA1c Test |
|-------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Instrument Intended Use | The DCA VantageTM is a semi-automated,
benchtop system. It is designed to
quantitatively measure the percent
Hemoglobin A1c in blood and low
concentrations of albumin in urine
(microalbuinuria), creatinine in urine, and
albumin/creatinine ratio in urine. | The cobas b 101 instrument is a
multi-assay system designed to
quantitatively analyze cobas
reagent discs. The system is
intended for professional, in vitro
diagnostic use in a clinical
laboratory setting or point-of-care
(PoC) locations. |
| Assay Intended Use | This assay provides a convenient,
quantitative method for measuring the
percent concentration of hemoglobin A1c in
blood. | The cobas HbA1c Test is an in
vitro diagnostic test designed to
quantitatively determine glycated
hemoglobin (HbA1c) in capillary
finger-stick or venous whole
blood, collected in EDTA (K2 or
K3) or lithium heparin tubes, on
the cobas b 101 instrument. This
test is intended for professional
use in a clinical laboratory setting
or point-of-care (PoC) locations.
This test is not for screening or
diagnosis of diabetes or neonatal
use. |
| Assay Indications for Use | The measurement of hemoglobin A1c
concentration is recommended for
monitoring the long-term care of persons
with diabetes. | Measurement of hemoglobin A1c
is used to monitor long term
blood glucose control in patients
previously diagnosed with
diabetes. |
| Assay Method | Latex agglutination - inhibition immunoassay | Same |
| Detection Method | photometry | Same |
| Applications/Test Time | 6.5 minutes | 9.0 % HbA1c.
For each interferent, a separate stock solution containing the potentially interfering material was prepared. All pools were prepared using KsEDTA venous whole blood. Two HbA1c levels, one in the normal and another in the pathological range, were evaluated for each of the endogenous substances.
To achieve the target high concentration interferent pool (high sample pool), pooled whole blood was spiked with the interferent. Another pool (low sample pool), without interferent, was created by dilution of the pooled whole blood with the same volume of diluent as the high sample pool. This pool contains no interferent and serves as the reference pool for the testing. The high and low sample pools were mixed in different ratios to vield a dilution series with varying concentrations of the interferent.
There was no significant interference found up to the tested concentrations. The table below summarizes the results and claims for the endogenous substances.
| Endogenous
Substance | Highest Level Tested with No
Significant Interference | Labeling Claim:
No significant interference up to |
|--------------------------------|----------------------------------------------------------|------------------------------------------------------|
| Albumin | 77.5 g/L | 60 g/L |
| Conjugated Bilirubin | 85 mg/dL | 60 mg/dL |
| Unconjugated Bilirubin | 85 mg/dL | 60 mg/dL |
| Lipemia / Intralipid | 750 mg/dL | 500 mg/dL |
| Lipemia / Native Triglycerides | 694 mg/dL | 500 mg/dL |
| Glucose | 2800 mg/dL | 2000 mg/dL |
| Rheumatoid Factor (RF) | 1200 IU/mL | 750 IU/mL |
| Total Protein | 126 g/L | 120 g/L |
Table 5: Potentially Interfering Endogenous Substances Results Summary
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Exogenous Interferences – Drugs 4.6.
The effect on quantitation of HbA1c in the presence of exogenous interfering substances was determined on the cobas b 101 system with the cobas HbA1c Test.
The table below lists the potential exogenous interferents and the concentrations tested:
| Drug | Highest Level Tested with No
Significant Interference (mg/L) |
|----------------------|-----------------------------------------------------------------|
| Acetyl Cysteine | 1660 |
| Ampicillin-Na | 1000 |
| Ascorbic acid | 300 |
| Cyclosporine | 5 |
| Cefoxitin | 2500 |
| Heparin | 5000 U/L |
| Levodopa | 20 |
| Methyldopa +1,5 | 20 |
| Metronidazole | 200 |
| Phenylbutazone | 400 |
| Doxycycline | 50 |
| Acetylsalycilic acid | 1000 |
| Rifampicin | 60 |
| Acetaminophen | 200 |
| Ibuprofen | 500 |
| Theophylline | 100 |
Table 6: Potentially Interfering Drugs and Test Concentrations
The interference study was performed according to CLSI guideline EP07-A2. For each substance, a separate stock solution containing the potentially interfering drug was prepared. All pools were prepared using K2EDTA venous whole blood. To achieve the target concentration drug pool, pooled whole blood was spiked with the drug. Another pool, without drug, was created by dilution of the pooled whole blood with the same volume of diluent as the high concentration drug pool. This pool contains no drug and serves as the reference pool for the testing. Each sample was tested in 5 replicates and the mean value used for the assessment. No interference was found at therapeutic concentrations using common drug panels.
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Cross-Reactivity 4.7.
Carbamylated Hemoglobin, Acetylated Hemoglobin and Labile HbA1c 4.7.1.
The effect on quantitation of HbA1c in the presence of potential cross-reactants was determined on the cobas b 101 system with the cobas HbA1c Test. The study was performed according to CLSI guideline EP07-A2. Sample pool material was K₂EDTA venous whole blood with a concentration of approximately 5.5 and > 9.0 % HbA1c.
To prepare the carbamylated Hb high sample pool, sodium cyanate (final concentration is 3000 mg/dL) in isotonic saline is added to the whole blood sample. For the low sample pool, the same volume of isotonic saline (no sodium cyanate) is added to the whole blood sample.
To prepare the acetylated Hb high sample pool, acetylsalicylic acid in 75% Ethyl Alcohol (final concentration is 3000 mg/dL) is added to the whole blood sample. For the low sample pool, the same volume of 75% Ethyl Alcohol (no acetylsalicylic acid) is added to whole blood sample.
To prepare the labile HbA1c high sample pool, glucose in isotonic saline (final concentration is 3000 mg/dL) is added to the whole blood sample and incubated for one hour at 37°C. For the low sample pool, the same volume of isotonic saline (no glucose) is added to the whole blood sample.
For each interferent, a separate stock solution containing the potentially interfering cross-reactant was prepared. All pools were prepared using K2EDTA venous whole blood. Two HbA1c levels, one in the normal and another in the pathological range, were evaluated for each of the crossreactants.
To achieve the target high concentration cross-reactant pool (high sample pool), pooled whole blood was spiked with the cross-reactant. Another pool (low sample pool), without crossreactant, was created by dilution of the pooled whole blood with the same volume of diluent as the high sample pool. This pool contains no cross-reactant and serves as the reference pool for the testing. The high and low sample pools were mixed in different ratios to yield a dilution series with varying concentrations of the cross-reactant. Each dilution level was tested in singlicate on 3 instruments and the median was used for calculations.
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No relevant cross-reactivity was found up to the listed concentrations. The table below summarizes the results and claims for the hemoglobin derivative cross-reactants.
| Cross-reactant | Highest Level Tested with No
Significant Interference | Physiologically occurring
concentration |
|-----------------|----------------------------------------------------------|--------------------------------------------|
| Carbamylated Hb | 3000 mg/dL | 750 -1100 mg/dL |
| Acetylated Hb | 3000 mg/dL | 320 - 500 mg/dL |
| Labile HbA1c | 3000 mg/dL | 430 - 650 mg/dL |
Table 7: Hemoglobin Derivative Cross-reactant Results and Claims
4.7.2. HbA0
A correlation analysis was performed. Correlation was determined between increasing amounts of hemoglobin (and hence HbA0) and the % relative bias of measured HbA1c using the cobas b 101 and the reference system cobas c 501. The HbA1c values were measured from approximately 60 K2EDTA whole blood samples with cobas b 101 and cobas c 501 as the reference system. Total hemoglobin was measured with the reference system cobas c 501.
The relative bias between HbA1c results from cobas b 101 and cobas c 501 was calculated and plotted against the measured amounts of hemoglobin. A linear regression and the corresponding Pearson's correlation coefficient was calculated.
The data supports the claims that at physiologically occurring concentrations, no cross reactions with HbA0 were found.
HbA1a and HbA1b 4.7.3.
A separate stock solution containing the potential cross-reactant HbA1a+b was prepared. This stock solution consisted of ~10.35 mg/ml HbA1a+b diluted in buffer. Ten dilutions of the stock were prepared at varying HbA1a+b concentrations. These samples were mixed with a normal and pathological K2EDTA whole blood sample to create 11 K2EDTA samples of varying HbA1a+b concentrations.
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All K2EDTA samples were measured in triplicate on the cobas b 101 instrument resulting in n=33 results per sample type (normal and pathological). The median value for each sample was used for calculation.
Because the instrument only reports the HbA 1c concentrations and not the individual concentrations of A1c and total Hemoglobin, the expected HbA1c concentrations were calculated based on the c501 results for A1c and Hb total.
The results obtained met the predefined acceptance criteria. These results support the crossreactivity claims in the labeling that at physiologically occurring concentrations, no cross reactions with HbA1a and HbA1b were found.
4.8. Hemoglobin Variants
Hemoglobin variant testing was conducted to determine if there is any significant interference with the major hemoglobin variants and the cobas HbA1c Test. Hemoglobin variants are structurally altered hemoglobin molecules with at least one amino acid exchange compared to the normal beta chain of hemoglobin. These changes are caused by mutations in the coding region of the globin genes which encode the protein part of hemoglobin. The most common hemoglobin variants are HbS, HbC, HbD and HbE. Moreover, in some conditions, the fetal hemoglobin HbF is elevated. Also, the erythrocytes of some patients (e.g. beta thalassemia minor) contain elevated levels of HbA2. It is crucial to ensure accurate HbA1c results from patients who are carriers of these variants.
| Variant Type | Number of Samples | % Variant |
|---|---|---|
| AS | 20 | 29 - 41% |
| AC | 20 | 28 - 36% |
| AD | 20 | 36 - 42% |
| AE | 20 | 20 - 27% |
| Elevated F | 20 | 3 - 29% |
| Elevated A2 | 10 | 4.3 - 6.2% |
| Total | 130 |
Table 8: Hemoglobin Variant Samples
Each sample was tested once in at least one run on 1 cobas b 101 instrument. A total of 130 samples were measured with a sample range of 4.35-11.58% HbA1c. Reference methods were
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selected based on no interference for a particular variant. Results obtained were compared to those obtained with the reference methods. Mean values of triplicate measurements on the reference systems were used for comparison. Non-significant interference was defined as ≤≤≤≤≤≤≤≤≤≤≤≤≤≤≤≤≤≤≤ 10% difference between the candidate and reference methods.
The results obtained met the defined acceptance criteria for HbAS, HbAC, HbAE and HbA2. HbF interference can be excluded up to an HbF concentration of 10%.
The sponsor has the following limitations in the labeling:
Heterozygous presence of the most common hemoglobin variants (HbAS, HbAD, HbAE, HbA2) does not interfere.
Specimens containing high amounts of HbF (> 10 %) may result in lower than expected % HbA1c values (DCCT/NGSP).
Traceability 4.9.
The cobas HbA1c Test has been standardized against the approved IFCC reference method for the measurement of hemoglobin A1c in human blood. The cobas b 101 instrument reports values in % hemoglobin A1c traceable to DCCT/NGSP by calculation. The cobas b 101 is certified with the National Glycohemoglobin Standardization Program (NGSP). The certification expires in one year. See NGSP website for current certification at http://www.ngsp.org.
4.10. Stability
The studies were performed according to CLSI guideline EP025-A. The cobas reagent disks can be stored at 2-30 °C for 16 months. The stability studies were found to be acceptable and support the claimed stability.
4.11. Expected Values
In 2016, the American Diabetes Association (ADA) recommended a reasonable A1c goal for many nonpregnant adults is