Predicate Devices

Reference Devices

AI/ML (Artificial Intelligence / Machine Learning)

No
The device description and performance studies focus on a boronate affinity assay and reflectance measurements, which are standard biochemical and optical methods. There is no mention of AI, ML, or related concepts in the provided text.

Therapeutic

No
This device is an in vitro diagnostic test used to measure glycated hemoglobin (HbA1c) in blood. It aids in the diagnosis of diabetes and identification of at-risk patients, but it does not directly treat or prevent a disease or condition; therefore, it is not a therapeutic device.

Diagnostic

Yes

Explanation: The "Intended Use / Indications for Use" section explicitly states that the device is "an in vitro diagnostic test" and is to be used "as an aid in the diagnosis of diabetes."

SaMD (Software as a Medical Device)

No

The device description clearly outlines a physical analyzer (Alere Afinion™ AS100 Analyzer) and test cartridges that process blood samples. This involves hardware components and chemical reactions, not solely software.

IVD (In Vitro Diagnostic)

Yes, this device is an IVD (In Vitro Diagnostic).

Here's why:

Intended Use: The intended use explicitly states it is an "in vitro diagnostic test" for the quantitative determination of HbA1c in human venous and capillary whole blood. It also specifies its use as an aid in the diagnosis of diabetes and identifying patients at risk.
Device Description: The description details a laboratory-based assay that analyzes a biological sample (whole blood) outside of the body to provide diagnostic information.
Performance Studies: The performance studies described are typical for IVD devices, evaluating analytical performance characteristics like precision, method comparison against a reference method, interference, and linearity.
Predicate Device: The submission lists a predicate device with "Dx" in its name (Cobas C501 Tina-Quant HbA1cDx Gen.3 assay), further indicating its classification as a diagnostic device.

The information provided clearly aligns with the definition and characteristics of an In Vitro Diagnostic device.

PCCP (Predetermined Change Control Plan) Authorized

N/A

Overview

Intended Use / Indications for Use

quantitativedetermination of glycated hemoglobin (% hemoglobin A1c, HbA1c) in human venous and capillary whole blood. This test is to be used as an aid in the diagnosis of diabetes and as an aid in identifying patients who may be at risk for developing diabetes. The measurement of % HbA1c is recommended as a marker of long-term metabolic control in persons with diabetes mellitus.

Product codes

PDJ

Device Description

The Afinion™ HbA1c Dx is a fully automated boronate affinity assay for the determination of the percentage of hemoglobin A1c in human whole blood. The Afinion™ HbA1c Dx is a modification of the existing device, Alere Afinion™ HbA1c for use with the Alere Afinion™ AS100 Analyzer, with the addition of a diagnostic intended use. The test begins with a blood sample collected with the integrated sampling device before the test cartridge is placed in the cartridge chamber of the Alere Afinion™ AS100 Analyzer. The sample is then automatically diluted and mixed with a solution that releases hemoglobin from the erythrocytes. After the hemoglobin is precipitated, the sample mixture is soaked through a filter membrane and all precipitated hemoglobin, conjugate-bound and unbound (i.e. glycated and non-glycated hemoglobin) remains on the membrane. Excess conjugate is removed with a washing reagent. The analyzer measures the reflectance of the precipitate on the membrane as blue (glycated hemoglobin) and red (total hemoglobin) color intensities. The analyzer calculates a ratio proportional to the percentage of HbA1c in the sample and displays as the % HbA1c (NGSP).

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

For use by health care professionals in clinical laboratories

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

Precision/Reproducibility:
A. Precision Internal (Within-laboratory precision):
- Study Type: CLSI guideline EP05-A3.
- Sample Size: 240 replicates per analyzer (total 720 for 3 analyzers) of anticoagulated venous whole blood patient samples for each of four HbA1c levels (5, 6.5, 8, 12 %HbA1c).
- Key Results:
- Analyzer 1: Total %CV ranged from 1.17% to 1.74%.
- Analyzer 2: Total %CV ranged from 1.04% to 1.63%.
- Analyzer 3: Total %CV ranged from 1.27% to 1.43%.
- All Analyzers Combined: Total %CV ranged from 1.31% to 1.64%.
B. Precision - External (Venous Whole Blood):
- Study Type: External precision evaluation.
- Sample Size: Four levels of HbA1c (5, 6.5, 8, 12 %HbA1c) were evaluated at each of three study sites. Four replicates of venous whole blood were analyzed twice a day for ten days with each of three lots at each of the three sites, utilizing three Alere Afinion™ AS100 Analyzers.
- Key Results: Total %CV ranged from 1.22% to 1.78% (for 3 sites combined).
C. Precision - Fingerstick Samples:
- Study Type: Combined data from three studies (Accuracy Study A, Venous Whole Blood Precision Study B, Fingerstick Precision Study C).
- Sample Size:
- Study A: Duplicate measurements from 172 subjects.
- Study B: Components derived from internal precision study on venous whole blood (section 1A).
- Study C: Fingerstick precision testing at three sites, 15-16 subjects per level, 90-96 fingerstick measurements per level.
- Key Results: Combined Total %CV ranged from 1.30% to 2.03% across different HbA1c ranges.
D. Precision - Between-Instrument:
- Study Type: Evaluation using 14 Alere Afinion™ AS100 Analyzers.
- Sample Size: Four venous whole blood samples measured in six replicates on each analyzer.
- Key Results: Between analyzer CV (%) ranged from 0.7% to 1.0%.
E. Lot-to-lot Variation:
- Study Type: Evaluation using three test cartridge lots.
- Sample Size: 18 EDTA venous whole blood samples.
- Key Results: Relative Bias (%) ranged from -0.17 to 0.25.
Method Comparison:
- Study Type: Comparison with NGSP secondary reference laboratory method (Tosoh Glycohemoglobin test on the G8 HPLC analyzer).
- Sample Size: 120 subjects.
- Key Results:
  - Fingerstick samples (Weighted Deming Regression): Slope 0.997, Intercept 0.000, Correlation coefficient (r) 0.991.
  - Venous whole blood (Weighted Deming Regression): Slope 0.991, Intercept 0.053, Correlation coefficient (r) 0.990.
  - Passing-Bablok Regression showed slopes of 1.000 for both fingerstick and venous whole blood.
Total Error:
- Study Type: Calculation using bias estimation and precision estimates.
- Key Results:
  - Fingerstick whole blood samples: %TE ranged from 2.87% to 4.75% (acceptable ≤6.0%).
  - Venous whole blood samples (internal precision study): %TE ranged from 2.77% to 3.80% (acceptable ≤6.0%).
  - Venous whole blood samples at the Point of Care (external precision study): %TE ranged from 2.64% to 4.07% (acceptable ≤6.0%).
Endogenous Interference:
- Study Type: Evaluation of six endogenous substances (Bilirubin conjugated, Bilirubin unconjugated, Glucose, Intralipid, Rheumatoid factor, Total protein) at two HbA1c levels.
- Sample Size: Each sample tested with ten replicates.
- Key Results: No significant interference at stated concentrations (e.g., Bilirubin 600 mg/L, Glucose 10 000 mg/L).
Hemolysis Interference:
- Study Type: Assessment of potential assay interference from hemolysis.
- Key Results: No interference up to 24% hemolysis. Information codes related to hemolysis may occur above 14% hemolysis.
Drug Interference:
- Study Type: Evaluation of twenty drug substances.
- Sample Size: Each spiked sample tested in ten replicates.
- Key Results: No significant interference at stated test concentrations.
Cross reactivity with Hemoglobin Derivatives:
- Study Type: Assessment of Acetylated hemoglobin, Carbamylated hemoglobin, Labile HbA1c, and Glycated albumin.
- Key Results: No significant interference at stated test concentrations.
Hemoglobin Variants Interference:
- Study Type: Evaluation of six common hemoglobin variants (HbA0, HbA1a, HbA1b, HbA2, HbS, HbC, HbE, HbD, HbF).
- Sample Size: 234 fresh EDTA whole blood samples.
- Key Results: No significant interference observed for HbA2, HbS, HbC, HbE and HbD. Significant negative interference described for HbF at concentrations above 10.4% HbF.
Linearity:
- Linearity was previously established (K050574).
- Reportable range: 4.00-15.00 % HbA1c (DCCT/NGSP).

Key Metrics

Precision (Total %CV): Ranged from 1.04% to 2.03% depending on the study and HbA1c level.
Correlation coefficient (r): 0.991 for fingerstick, 0.990 for venous whole blood.
Total Error (%TE): Ranged from 2.64% to 4.75%. Acceptable %TE is +7%.

Predicate Device(s)

Cobas C501 Tina-Quant HbA1cDx Gen.3 assay (K121610)

Reference Device(s)

Not Found

Predetermined Change Control Plan (PCCP) - All Relevant Information

Not Found

Regulation Number and Section

§ 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.

Summary

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Image /page/0/Picture/0 description: The image contains the logos of the Department of Health and Human Services and the Food and Drug Administration (FDA). The Department of Health and Human Services logo is on the left, and the FDA logo is on the right. The FDA logo includes the letters "FDA" in a blue square, followed by the words "U.S. FOOD & DRUG ADMINISTRATION" in blue text.

May 7, 2018

Alere Technologies AS Annie Wright Senior Manager, Regulatory Affairs Kjelsaasveien 161 PO Box 6863 Rodeloekka NO-0504 Oslo Norway

Re: K180296

Trade/Device Name: Afinion HbA1c Dx Regulation Number: 21 CFR 862.1373 Regulation Name: Hemoglobin A1c test system Regulatory Class: Class II Product Code: PDJ Dated: February 5, 2018 Received: February 6, 2018

Dear Annie Wright:

We have reviewed vour 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 Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR

1

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.

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.

For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/) and CDRH Learn (http://www.fda.gov/Training/CDRHLearn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (http://www.fda.gov/DICE) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely, 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

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	2301V932 ИАМИН ОНА НТТАЭН 70 ТИЭМТУААРЭQ

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3

Image /page/3/Picture/0 description: The image contains the logo for Abbott, a healthcare company. The logo features a stylized, sans-serif letter 'a' in a bright blue color. Below the symbol, the company name "Abbott" is written in a bold, black, sans-serif font.

510(k) SUMMARY-K180296

GENERAL INFORMATION

| Applicant Name: | Alere Technologies AS
Kjelsaasveien 161
PO Box 6863 Rodeloekka
NO-0504 Oslo
Norway
Establishment #9613069 |
|------------------|--------------------------------------------------------------------------------------------------------------------------|
| Company Contact: | Annie Wright
Senior Manager, Regulatory Affairs
Phone: (858) 805-2316
Email: annie.wright@alere.com |

Date Prepared: April 26, 2018

DEVICE IDENTIFICATION

Trade or Proprietary Names:	Afinion™ HbA1c Dx
Common Name:	HbA1c test
Device Classification Name:	Hemoglobin A1c Test System
Product Codes:	PDJ
Regulatory Class:	Class II (Special Controls)
Classification Regulation:	21 CFR 862.1373
Predicate Device:	Cobas C501 Tina-Quant HbA1cDx Gen.3 assay (K121610)

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Image /page/4/Picture/0 description: The image shows the logo for Abbott, a healthcare company. The logo consists of a stylized letter "A" in blue, with the word "Abbott" written in black below it. The "A" is designed with rounded corners and a gap in the middle, giving it a modern and abstract look. The font used for the company name is bold and sans-serif, providing a clean and professional appearance.

DEVICE DESCRIPTION

The Afinion™ HbA1c Dx is a fully automated boronate affinity assay for the determination of the percentage of hemoglobin A1c in human whole blood. The Afinion™ HbA1c Dx is a modification of the existing device, Alere Afinion™ HbA1c for use with the Alere Afinion™ AS100 Analyzer, with the addition of a diagnostic intended use.

The test begins with a blood sample collected with the integrated sampling device before the test cartridge is placed in the cartridge chamber of the Alere Afinion™ AS100 Analyzer. The sample is then automatically diluted and mixed with a solution that releases hemoglobin from the erythrocytes. After the hemoglobin is precipitated, the sample mixture is transferred to a blue boronic acid conjugate which binds to the cis-diols of glycated hemoglobin. This reaction mixture is soaked through a filter membrane and all precipitated hemoglobin, conjugate-bound and unbound (i.e. glycated and non-glycated hemoglobin) remains on the membrane. Excess conjugate is removed with a washing reagent. The analyzer measures the reflectance of the precipitate on the membrane as blue (glycated hemoglobin) and red (total hemoglobin) color intensities. The analyzer calculates a ratio proportional to the percentage of HbA1c in the sample and displays as the % HbA1c (NGSP).

INTENDED USE

Afinion™ HbA1c Dx is an in vitro diagnostic test for quantitative determination of glycated hemoglobin (% hemoglobin A1c, HbA1c) in human venous and capillary whole blood.

This test is to be used as an aid in the diagnosis of diabetes and as an aid in identifying patients who may be at risk for developing diabetes.

The measurement of % HbA1c is recommended as a marker of long-term metabolic control in persons with diabetes mellitus.

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Image /page/5/Picture/0 description: The image shows the Abbott logo. The logo consists of a stylized letter 'A' in blue, with the word 'Abbott' written in black below it. The 'A' is made up of three connected lines, forming a rounded, geometric shape.

COMPARISON WITH PREDICATE

Attribute	Predicate Device	Candidate Device
	Cobas C501 Tina-Quant HbA1cDx Gen.3
assay (K121610)	Afinion™ HbA1c Dx
	Similarities
Intended Use	Quantitative determination
of hemoglobin A1c for the diagnosis of diabetes
and as an aid in identifying patients who may
be at risk for developing diabetes	Same
User
environment	For use by health care professionals in clinical
laboratories	Same
Sample types	Anticoagulated venous blood	Anticoagulated venous or
capillary blood
Anticoagulants	Li-Heparin, K2-EDTA, K3-EDTA, KF/Na2-
EDTA, Na-Heparin, NaF/K-Oxalate and
NaF/Na2-EDTA	K2-EDTA
Units of
measurement	% HbA1c (DCCT/NGSP)	Same
Storage
requirements	2-8°C until expiration date	Same
Standardization	Traceable to the International Federation of
Clinical Chemistry and Laboratory Medicine
(IFCC) and Diabetes Control and
Complications Trial (DCTT) reference method.
Certified via the National Glycohemoglobin
Standardization Program (NGSP).	Same
Expected values	Protocol 1 (IFCC)
20-42 mmol/mol HbA1c
Protocol 2 (DCCT/NGSP)
4.0 - 6.0 %HbA1c	DCCT/NGSP
4.0 - 6.0 %HbA1c
	Differences
Assay principle	HbA1c determination by turbidimetric
inhibition immunoassay method.
Hemoglobin determination by converting to a
derivative with a characteristic absorption
spectrum which is measured bi-chromatically.	Boronate affinity assay.
Hemoglobin determination by
reflectance measurements of
blue conjugate of glycated
hemoglobin and red total
hemoglobin.
Hardware	Cobas c501	Alere Afinion™ AS100
Analyzer
Calibrators	Provided by manufacturer	Calibration by user not
required; factory calibrated
Reporting range	4.2-20.1 % HbA1c	4.00–15.00 % HbA1c

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Image /page/6/Picture/0 description: The image shows the logo for Abbott, a healthcare company. The logo consists of a stylized letter "a" in blue, with the word "Abbott" written in bold, black letters underneath. The "a" symbol is a rounded, geometric shape. The overall design is simple and modern.

PERFORMANCE CHARACTERISTICS

1. Precision/Reproducibility

A. Precision Internal
The precision of the Afinion™ HbA1c Dx was evaluated based on CLSI guideline EP05-A3. Four levels of HbA1c in anticoagulated venous whole blood patient samples at the following targeted HbA1c values - 5, 6.5, 8 and 12 %HbA1c - were utilized in the study. Three test cartridge lots were included in the study. Two replicates of venous whole blood were tested twice a day for twenty days with each of the three lots on three Alere Afinion™ AS100 Analyzers.

	Mean		Repeatability	Between run	Between day	Between lot	Total
Level	%HbA1c	SD	%CV	SD	%CV	SD	%CV	SD	%CV	SD	%CV
Low	5.13	0.067	1.31	0.017	0.33	0.029	0.56	0.037	0.72	0.084	1.63
Threshold	6.53	0.086	1.31	0.000	0.00	0.039	0.60	0.064	0.98	0.114	1.74
Medium	8.09	0.082	1.01	0.000	0.00	0.045	0.56	0.019	0.23	0.095	1.17
High	11.33	0.100	0.88	0.000	0.00	0.035	0.31	0.105	0.93	0.149	1.32

Table 1a: Within-laboratory precision - results from analyzer 1 (n=240)

Table 1b: Within-laboratory precision - results from analyzer 2 (n=240)

	Mean	Repeatability		Between run		Between day		Between lot		Total
Level	%HbA1c	SD	%CV	SD	%CV	SD	%CV	SD	%CV	SD	%CV
Low	5.11	0.061	1.19	0.000	0.00	0.034	0.67	0.046	0.89	0.084	1.63
Threshold	6.53	0.070	1.07	0.019	0.30	0.044	0.67	0.064	0.98	0.106	1.62
Medium	8.01	0.060	0.75	0.010	0.13	0.038	0.48	0.042	0.52	0.083	1.04
High	11.17	0.086	0.77	0.015	0.13	0.060	0.54	0.094	0.84	0.142	1.27

Table 1c: Within-laboratory precision - results from analyzer 3 (n=240)

	Mean	Repeatability		Between run		Between day		Between lot		Total
Level	%HbA1c	SD	%CV	SD	%CV	SD	%CV	SD	%CV	SD	%CV
Low	5.18	0.053	1.02	0.007	0.14	0.030	0.58	0.041	0.79	0.074	1.43
Threshold	6.58	0.066	1.00	0.000	0.00	0.038	0.58	0.035	0.53	0.084	1.27
Medium	8.08	0.086	1.06	0.035	0.43	0.052	0.64	0.047	0.58	0.116	1.43
High	11.30	0.114	1.00	0.023	0.21	0.031	0.28	0.098	0.87	0.155	1.37

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Image /page/7/Picture/0 description: The image shows the logo for Abbott Laboratories. The logo consists of a stylized, rounded letter "a" in blue, positioned above the word "Abbott" in a bold, black font. The "a" symbol is simple and modern, while the company name is clear and legible.

| | | | | | | | | | | Between
analyzer | | | |
|-----------|--------|---------------|------|-------------|------|-------------|------|-------------|------|---------------------|------|-------|------|
| | Mean | Repeatability | | Between run | | Between day | | Between lot | | | | Total | |
| Level | %HbA1c | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| Low | 5.14 | 0.061 | 1.18 | 0.000 | 0.00 | 0.031 | 0.60 | 0.041 | 0.81 | 0.030 | 0.58 | 0.084 | 1.64 |
| Threshold | 6.55 | 0.074 | 1.13 | 0.000 | 0.00 | 0.040 | 0.62 | 0.056 | 0.85 | 0.000 | 0.00 | 0.099 | 1.51 |
| Medium | 8.06 | 0.077 | 0.95 | 0.016 | 0.20 | 0.045 | 0.56 | 0.038 | 0.47 | 0.039 | 0.49 | 0.106 | 1.31 |
| High | 11.26 | 0.101 | 0.89 | 0.014 | 0.12 | 0.044 | 0.39 | 0.099 | 0.88 | 0.059 | 0.52 | 0.160 | 1.42 |

Table 1d: Within-laboratory precision – all analyzers combined (n=720)

B. Precision - External (Venous Whole Blood)

The precision of the Afinion™ HbA1c Dx was evaluated externally. Four levels of HbA1c in anticoagulated venous whole blood patient samples at the following targeted HbA1c values: 5, 6.5, 8 and 12 %HbA1c -were evaluated at each of three study sites. Three test cartridge lots were included in the study. Four replicates of venous whole blood were analyzed twice a day for ten days with each of the three lots at each of the three sites, utilizing three Alere Afinion™ AS100 Analyzers.

Table 2: External precision results from 3 sites combined. Root Mean Squared SD and %CV. Between analyzer precision component from internal study added.

| Level | Mean
%HbA1c | Repeatability | | Between run | | Between day | | Between lot | | Between analyzer | | Total | |
|-----------|----------------|---------------|------|-------------|------|-------------|------|-------------|------|------------------|------|-------|------|
| | | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| Low | 5.02 | 0.061 | 1.21 | 0.029 | 0.57 | 0.022 | 0.44 | 0.046 | 0.92 | 0.030 | 0.58 | 0.090 | 1.78 |
| Threshold | 6.41 | 0.071 | 1.11 | 0.030 | 0.48 | 0.026 | 0.40 | 0.047 | 0.74 | 0.000 | 0.00 | 0.094 | 1.48 |
| Medium | 8.18 | 0.090 | 1.10 | 0.019 | 0.23 | 0.022 | 0.28 | 0.042 | 0.51 | 0.039 | 0.49 | 0.111 | 1.36 |
| High | 12.09 | 0.118 | 0.97 | 0.046 | 0.38 | 0.030 | 0.25 | 0.033 | 0.27 | 0.059 | 0.52 | 0.147 | 1.22 |

Table 3: External precision results from 3 sites combined (abbreviated version of Table 5). Root Mean Squared %CV. Between analyzer precision component from internal study added.

	External Precision Study					Total %CV
	Repeatability %CV	Between-run %CV	Between-day %CV	Between-lot %CV	Between-analyzer %CV
Low	1.21	0.57	0.44	0.92	0.58	1.78
Threshold	1.11	0.48	0.40	0.74	0.00	1.48
Medium	1.10	0.23	0.28	0.51	0.49	1.36
High	0.97	0.38	0.25	0.27	0.52	1.22

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C. Precision - Fingerstick Samples

In order to estimate precision components for fingerstick samples, data from three studies are combined.

1) Within run precision estimates from accuracy study (Study A)

Duplicate measurements of fingerstick samples from 172 subjects were conducted as part of the external accuracy study. The study was conducted at three sites, using three lots of test cartridges. Two lots were assigned to each of three study sites and the fingerstick measurements were performed with one replicate from each of the two available lots for each subject. The duplicate analyses were grouped into four bins of %HbA1c levels, and the CV for each bin was initially estimated by taking the Root Mean Square (RMS) of the pairwise SD within each bin and dividing by the mean of each bin. This initial CV estimate includes both the within-run and the between-lot components of variance.

A more detailed analysis was also conducted to separate the Repeatability from the Between-Lot component. Two of the 172 subjects used the same cartridge lot for both fingersticks and were considered unevaluable for estimating the between-lot component of variance; these two subjects were therefore excluded from the ANOVA model (as reported in Table 12.1.25-5 and 12.1.25-6 of the Performance Testing - Clinical).

			SD from ANOVA			%CV
%HbA1c
Range	Number
Subjects	Mean	Repeatability	Between-
Lot	Total	Repeatability	Between-
Lot	Total
4.00-5.99	45	5.42	0.0823	0.0650	0.1049	1.52	1.20	1.93
6.00-6.99	68	6.46	0.0876	0.0270	0.0916	1.36	0.42	1.42
7.00-9.99	51	7.93	0.1067	0.0000	0.1067	1.35	0.00	1.35
≥10	6	10.72	0.0665	0.0080	0.0670	0.62	0.07	0.62

Table 4: Fingerstick components of variance from Accuracy study (study A)

The results shown above for the Total %CV calculated via ANOVA differ slightly (but not significantly) from the initial CV estimate based on the RMS of the pairwise SD within each bin, also noting that the initial CV estimate included the two subjects (who used the same cartridge lot for both fingersticks).

Between run and between day precision from venous whole blood precision study (Study B) Estimates for between run and between day precision on fingerstick samples were derived from the internal precision study on venous whole blood samples described above in section 1A of this summary and were based on the assumption that these components of variation for fingerstick and venous whole blood are essentially the same. Results for between-run and between-day precision for fingerstick samples are therefore taken from the data summarized in Table 4 above for the four levels of HbA1c.

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3) Between-instrument and between operator precision estimates (Study C)

Fingerstick precision testing was conducted at three sites, utilizing three Alere Afinion™ AS100 Analyzers. Four levels of HbA1c were assessed, with each site targeting five subjects per level. From each subject three operators collected two fingerstick samples each and

tested them with one replicate on each of two instruments. One of the sites, at the Medium levels enrolled 6 subjects prior to the close of the study. This resulted in six fingerstick sample results from each subject, a total of 15 subjects per level (or 16 subjects per level) and total of 90 fingerstick measurements per level (or 96 fingerstick measurements per level). The analysis of the Medium level was conducted two ways, with first 15 subjects to fill the level (this was the primary analysis) and with all 16 subjects enrolled (this was the secondary analysis). There was no significant difference between the primary and the secondary results; the results of the secondary analysis (2º) of the Medium level are reported in the summary table below.

| HbA1c
Level | Grand
Mean
%HbA1c | N (M) | Between
Instrument | | Between
Operator | | Within-run
(Repeatability) | | Total* | |
|----------------|-------------------------|---------|-----------------------|-------|---------------------|-------|-------------------------------|-------|--------|-------|
| | | | SD | CV(%) | SD | CV(%) | SD | CV(%) | SD | CV(%) |
| Low | 5.33 | 15 (90) | 0.0076 | 0.14 | 0.0000 | 0.00 | 0.0742 | 1.39 | 0.0745 | 1.40 |
| Threshold | 6.51 | 15 (90) | 0.0192 | 0.30 | 0.0000 | 0.00 | 0.0811 | 1.25 | 0.0834 | 1.28 |
| Medium (2°) | 8.32 | 16 (96) | 0.0000 | 0.00 | 0.0171 | 0.21 | 0.0918 | 1.10 | 0.0934 | 1.12 |
| High | 12.20 | 15 (90) | 0.0570 | 0.47 | 0.0000 | 0.00 | 0.1389 | 1.14 | 0.1501 | 1.23 |

Table 5: Precision of fingerstick samples - Fingerstick precision study (Study C)

Notes: N (M) is the number of subjects (number of test results). CV is SD from ANOVA divided by Grand Mean. * Total CV is the sum of squares of between instrument, between operator, and within-run (repeatability).

The combined precision estimates from the three studies are shown in Table 6. For the high HbA1c level, the Repeatability CV is taken from the fingerstick precision study (study C) instead of the accuracy study (study A) due to higher number of subjects and replicates in study C. The total CV (%) was calculated from each of the individual components of variation as also summarized in Table 6.

Table 6: Precision of fingerstick samples - results from three studies combined

| | | Fingerstick precision from Accuracy Study
A | | | Venous Whole Blood
Precision Study B | Fingerstick Precision Study C | | | |
|-----------------|---------------|------------------------------------------------|--------------------|------------------------|-----------------------------------------|-------------------------------|------------------------------|----------------------------|---------------|
| %HbA1c
Range | N
Subjects | Repeatability
%CV | Between
Lot %CV | Between
Run %C
V | Between
Day %C
V | Repeatabilit
y %CV | Between
Instrument
%CV | Between
Operator
%CV | *Total
%CV |
| 4.00-5.99 | 45 | 1.52 | 1.20 | 0.00 | 0.60 | 1.39 | 0.14 | 0.00 | 2.03 |
| 6.00-6.99 | 68 | 1.36 | 0.42 | 0.00 | 0.62 | 1.25 | 0.30 | 0.00 | 1.58 |
| 7.00-9.99 | 51 | 1.35 | 0.00 | 0.20 | 0.56 | 1.10 | 0.00 | 0.21 | 1.49 |
| ≥10 | 6 | 0.62 | 0.07 | 0.12 | 0.39 | 1.14 | 0.47 | 0.00 | 1.30 |

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*The Total CV is based on the sum of squares of the 6 components (Repeatability %CV, Between Lot %CV, Between Run %CV, Between Day %CV, Between Instrument %CV, and Between Operator %CV). For the %HbA1c Range ≥10, the

Repeatability estimate from study C was used to estimate the Total CV; for all other %HbA1c Ranges the Repeatability estimate from study A was used to estimate the Total CV. The number of test results is 2N per level for study A, 720 per level for study B, and 90 (or 96) per level for Study C.

D. Precision - Between -Instrument

Between analyzer precision of the Afinion™ HbA1c Dx was evaluated using 14 Alere Afinion™ AS100 Analyzers. Four venous whole blood samples were measured in six replicates on each analyzer with one test cartridge lot for a total of 84 replicates per sample.

Level	Mean %HbA1c	Between analyzer SD	Between analyzer CV (%)
Low	5.46	0.04	0.7
Low	5.47	0.05	0.9
Threshold	6.54	0.05	0.8
Medium	8.85	0.09	1.0

Table 7: Between-analyzer results

E. Lot-to-lot Variation

The lot-to-lot variation for the Afinion™ HbA1c Dx assay was evaluated using three test cartridge lots and 18 EDTA venous whole blood samples spanning the assay measuring (reportable) range. Each sample was analysed in one replicate with each test cartridge lot on the same Alere Afinion™ AS100 Analyzer. The results from all lots were compared pairwise using Bland-Altman analysis.

Table 8: Lot-to-lot variation results
---------------------------------------	--	--	--	--

| Comparison | Relative Bias
(%) | 95% Confidence interval of
Relative Bias (%) | 95% Limit of Agreement |
|---------------|----------------------|-------------------------------------------------|------------------------|
| Lot 3 - Lot 1 | 0.08 | -0.8 to 1.0 | -3.5 to 3.7 |
| Lot 2 - Lot 1 | -0.17 | -1.1 to 0.8 | -4.0 to 3.6 |
| Lot 3 - Lot 2 | 0.25 | -0.9 to 1.4 | -4.4 to 4.9 |

2. Method Comparison

The method comparison study was performed using an NGSP secondary reference laboratory method (Tosoh Glycohemoglobin test on the G8 HPLC analyzer) as the

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comparator (reference) method. Three production lots of Afinion™ HbA1c Dx test cartridges were evaluated with two lots assigned to each of three study sites. Samples from each study subject were tested with both fingerstick samples and fresh venous EDTA samples in single replicates per lot. A total of 120 subjects were included in the study.

| %HbA1c Interval

Alere Afinion™ HbA1c Dx	Number of subjects				Total %
	Site 1	Site 2	Site 3	Total
4.0 - 5.0	2	2	1	5	4.2
5.1 - 6.0	5	5	5	15	12.5
6.1 - 6.5	10	10	10	30	25.0
6.6 - 7.0	12	8	10	30	25.0
7.1 - 8.0	7	6	7	20	16.7
8.1 - 9.0	3	4	3	10	8.3
9.1 - 15.0	3	3	4	10	8.3
Total	42	38	40	120	100.0

Table 9: Sample distribution

Table 10: Weighted Deming regression – combined results from 3 sites and 3 lots

| | Weighted Deming
Regression | | Passing-Bablok Regression | |
|-----------------------------------|-------------------------------|-----------------------|---------------------------|-----------------------|
| | Fingerstick
samples | Venous whole
blood | Fingerstick
samples | Venous whole
blood |
| Slope | 0.997 | 0.991 | 1.000 | 1.000 |
| Intercept | 0.000 | 0.053 | -0.040 | -0.030 |
| Correlation coefficient
(r) | 0.991 | 0.990 | 0.991 | 0.990 |
| Number of samples | 120 | 120 | 120 | 120 |
| Results range Afinion
(%HbA1c) | 4.66 to 11.58 | 4.72 to 11.49 | 4.66 to 11.58 | 4.72 to 11.49 |

3. Total Error

For fingerstick samples the results of bias estimation (%Bias) from the accuracy study and the combined precision estimates for fingerstick samples from three studies were used for calculation of the Total Error (TE) at four concentrations (5.0, 6.5, 8.0 and 12.0 %HbA1c). These results are shown in Table 11.

For venous whole blood, the results of bias estimation (%Bias) from the accuracy study and precision estimates in the internal precision study using three lots and three Alere

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Afinion™ Analyzers over 20 days, were used for calculation of the Total Error (TE) at four concentrations of HbA1c (5.0, 6.5, 8.0 and 12.0 %). These results are shown in Table 12.

For venous whole blood, the Total Error (TE) was also estimated by a second method, similar those described above, but where the precision estimates are from the external precision study, as described in Table 3, which also includes the Between Analyzer component of variance from the internal study. These results are shown in Table 13, labeled as "Total error - venous whole blood samples at the Point of Care" to distinguish these estimates from those in Table 12.

The acceptable %TE is ≤6.0%. (Refer to Section 12.4 of the Performance Testing – Clinical for the Total Error formula.)

	Weighted Deming Regression			Passing-Bablok regression
%HbA1c Level	%Bias	%CV	%TE	%Bias	%CV	%TE
5.0	-0.335	2.03	4.30	-0.800	2.03	4.75
6.5	-0.334	1.58	3.42	-0.615	1.58	3.69
8.0	-0.334	1.49	3.24	-0.500	1.49	3.40
12.0	-0.333	1.30	2.87	-0.333	1.30	2.87

Table 11: Total error - fingerstick whole blood samples

Table 12: Total error - venous whole blood samples

	Weighted Deming Regression				Passing-Bablok regression
%HbA1c Level	%Bias	%CV	%TE	%Bias	%CV	%TE
5.0	0.195	1.64	3.42	-0.600	1.64	3.80
6.5	-0.052	1.51	3.01	-0.462	1.51	3.41
8.0	-0.206	1.31	2.77	-0.375	1.31	2.93
12.0	-0.429	1.42	3.20	-0.250	1.42	3.03

Table 13: Total error - venous whole blood samples at the Point of Care

	Weighted Deming Regression			Passing-Bablok regression
%HbA1c Level	%Bias	%CV	%TE	%Bias	%CV	%TE
5.0	0.195	1.78	3.69	-0.600	1.78	4.07
6.5	-0.052	1.48	2.95	-0.462	1.48	3.35
8.0	-0.206	1.36	2.87	-0.375	1.36	3.03
12.0	-0.429	1.22	2.81	-0.250	1.22	2.64

4. Endogenous Interference

Six endogenous substances spiked into whole blood sample pools were evaluated for potential assay interference in accordance with CLSI guideline EP07-A2. Two HbA1c levels, one near the medical decision level and one above it, were tested for each endogenous substance. Each sample was tested for %HbA1c with ten replicates on a single

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Alere Afinion™ AS100 Analyzer, using a single test cartridge lot. The corresponding nonspiked sample which contained no added substance was also tested with ten replicates. A mean was calculated for each set of ten. Significant interference was defined as exceeding a 7% change in %HbA1c value from the control (non-spiked sample). The results for the spiked samples were compared to the control with no interference at the stated concentrations.

Endogenous substance	Test concentration with no significant interference
Bilirubin, conjugated	600 mg/L
Bilirubin, unconjugated	600 mg/L
Glucose	10 000 mg/L
Intralipid	10 000 mg/L
Rheumatoid factor	780 000 IU/L
Total protein	15 g/dL

Table 14: Endogenous interference results

5. Hemolysis Interference

Potential assay interference from hemolysis was assessed in accordance with CLSI guideline EP07-A2. Whole blood samples with two HbA1c levels, one near the medical decision level and one above it, were used for the testing. Hemolysis in the blood samples was simulated by spiking with fresh hemolysate prepared from the native samples. Hemolysate was added to the corresponding native sample to volume percentages of 5, 10, 15 and 20%. The exact degree of hemolysis was measured in each spiked fraction. Each spiked sample and corresponding non-spiked sample was tested in ten replicates on a single Alere Afinion™ AS100 analyzer using one test cartridge lot. The mean result from the manipulated sample was compared to the mean result from the corresponding native control sample. Significant interference was defined as exceeding a 7% change in %HbA1c value from the control (native sample). The results demonstrated no interference up to 24% hemolysis, however at hemolysis above 14% (2000 mg/dL) information codes related to hemolysis may occur with a frequency which increases with increasing degrees of hemolysis.

6. Drug Interference

Twenty drugs spiked into whole blood sample pools were tested for potential assay interference in accordance with CLSI guideline EP7-A2. The drug substances included commonly used antibiotics, analgesic agents, immunosupressants, anti-inflammatory drugs, anticoagulants and prescription drugs for diabetes treatment. Two HbA1c levels, one near the medical decision level and one above it, were tested for each endogenous substance. Each spiked sample was tested for %HbA1c in ten replicates on a single Alere Afinion™ AS100 Analyzer, using a single test cartridge lot. The corresponding non-spiked

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sample which contained no added substance was also tested with ten replicates. A mean was calculated for each set of ten. Significant interference was defined as exceeding a 7% change in %HbA1c value from the control (non-spiked sample). The results for the spiked samples were compared to the control with no interference at the stated concentrations.

| Drug substance interference (mg/L) |
|----------------------|---- | Acetaminophen | 200 | Acetylcysteine | 1663 | Ascorbic acid | 300 | Cefoxitin | 2500 | Metformin | 40 | Methyldopa | 20 | Cyclosporine C | 5 | Glyburide | 1.9 | Metronidazole | 200 | Ampicillin | 1000 | Acetylsalicylic acid | 1000 | Doxycycline | 50 | Ibuprofen | 500 | Cyclosporine A | 5 | Levodopa | 20 | Heparin | 5000 U/L | Salicylic acid | 599 | Theophylline | 100 | Phenylbutazone | 400 | Rifampicin | 64 | Test concentration with no significant
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Table 15: Drug interference results

7. Cross reactivity with Hemoglobin Derivatives

Potential assay interference from hemoglobin derivatives was assessed in accordance with CLSI guideline EP07-A2. Whole blood samples with two HbA1c levels, one near the medical decision level and one above it, were used for the testing. For each HbA1c level, two whole blood pools were prepared for each derivative, one without derivative (control) and one with high concentration of derivative. Each sample was tested in ten replicates on a single Alere Afinion™ AS100 Analyzer using one test cartridge lot. A mean was calculated for each set of ten. Significant interference was defined as exceeding a 7% change in %HbA1c value from the control (non-spiked sample). The results for the spiked samples were compared to the control with no interference at the stated concentrations.

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| Hemoglobin derivative | Test concentration with no significant
interference |
|-------------------------|--------------------------------------------------------|
| Acetylated hemoglobin | 4.6 mg/mL |
| Carbamylated hemoglobin | 13.8 mg/mL |
| Labile HbA1c | 11.4 mg/mL |
| Glycated albumin | 7.7 mg/mL |

Table 16: Cross reactivity with hemoglobin derivatives results

Hemoglobin Variants Interference 8.

Potential assay interference from hemoglobin variants was evaluated in accordance with CLSI guideline EP07-A2. A total of 234 fresh EDTA whole blood samples that contained one of six common hemoglobin variants were included in the study. All samples were tested by the Afinion™ HbA1c Dx and with an NGSP reference method that is known to be free from the hemoglobin interference being tested. The level of Hb variant was determined by the Capillarys 2 Flex Piercing method. Interference effect was assessed by comparing the HbA1c results from Afinion HbA1c Dx to the reference method result for samples with potentially interfering hemoglobin variants. Significant interference was defined as exceeding a 7% change in %HbA1c value from the reference method.

Cross-reactivity from HbA0, HbA1a and HbA1b components was also evaluated in a study including 100 samples with characterization of these fractions and comparison to a reference method (Tosoh G8 HPLC).

Table 16 indicates the number, range and concentration of samples and Table 17 summarizes the results from the study.

| Hemoglobin
Variant | Number of
samples | Range of % content of
variant | Range of concentration
in %HbA1c |
|-----------------------|----------------------|----------------------------------|-------------------------------------|
| HbA0 | 100 | 82-95 | |
| HbA1a | 100 | 0.4-1.4 | 4.27-13.93 |
| HbA1b | 100 | 0.4-2.3 | |
| HbA2 | 26 | 3.9-5.7 | 5.8-10.6 |
| HbS | 21 | 35-42 | 5.6-8.8 |
| HbC | 25 | 30-36 | 5.5-9.7 |
| HbE | 20 | 17-26 | 6.1-8.9 |
| HbD | 21 | 27-42 | 6.1-9.4 |
| HbF | 121 | 3.4-28.1 | 5.0-11.3 |

Table 17: Sample profile for hemoglobin variant study

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| | Percent relative bias from reference method at two levels of the HbA1c
samples | | | | |
|-----------------------|------------------------------------------------------------------------------------------------------------------------------------------------|-----------------|---------------------------|------------------|--|
| Hemoglobin
Variant | Level 1: ~6.5 %HbA1c | | Level 2: ~8.5 %HbA1c | | |
| | Mean Relative
bias (%) | Range
%Bias^ | Mean Relative
bias (%) | Range %Bias^ | |
| HbA0 | | | | | |
| HbA1a | 0.1 | -6.1, 8.5 | -0.4 | -6.0, 6.7 | |
| HbA1b | | | | | |
| HbA2 | -3.4 | -6.2, -1.3 | -2.5 | -6.6, 2.8 | |
| HbS | -4.1 | -6.6, 3.2 | -1.0 | -9.9, 3.5 | |
| HbC | -5.5 | -8.5, -1.8 | -1.8 | -5.2, 1.1 | |
| HbE | 3.5 | 1.4, 7.9 | 3.7 | 0.0, 4.7 (14.0*) | |
| HbD | -2.2 | -4.1, 0.0 | -2.9 | -5.9, 0.0 | |
| HbF | 10.4% HbF is the highest HbF concentration where no significant interference is
observed with significant interference defined as > +7%. ^^ | | | | |

Table 18: Hemoglobin variant results

^The range is defined as the minimum relative % difference at each concentration level. ^^ A negative relative bias with HbF has increasing magnitude with HbF and also with increasing %HbA1c.

*One single outlier for a sample with HbE level of 22.8%.

No significant interference was observed for the HbA2, HbS, HbC, HbE and HbD. For HbF interference, the device includes the following prominent boxed warning:

This device has significant negative interference with fetal hemoglobin (HbF). HbA1c results are invalid for patients with abnormal amounts of HbF including those with known Heredity Persistence of Fetal Hemoglobin. Refer to the Analytical specificity and Limitations sections in this package insert for details.

9. Linearity

The linearity of the Alere Afinion™ HbA1c assay was previously established in K050574, and was not re-established for the additional indications for use for the Afinion™ HbA1c Dx assay. The reportable range for this device is 4.00-15.00 % HbA1c (DCCT/NGSP).

CONCLUSION

The information and data in this 510(k) application demonstrate that the Afinion™ HbA1c Dx assay is an accurate and precise test that correlates well with current cleared methods and is NGSP standardized for the quantitation of HbA1c. Performance criteria as outlined in the special control requirements of 21 CFR 862.1373 for the diagnosis of diabetes have been met. Based on the criteria stated above, this device is found to be substantially equivalent to the predicate device.