GlyPro Reagent: For the quantitative determination of glycated proteins. Measurement of glycated serum protein is representative of the mean blood glucose levels over the preceding 2-3 weeks. For In Vitro Diagnostic Use.
GlyPro Calibrator: For calibration of the GlyPro™ assay. For In Vitro Diagnostic Use.
GlyPro Low and High Controls: To monitor the performance of the GlyPro assay. For In Vitro Diagnostic Use.

Device Description

The Genzyme GlyPro Assay System (consisting of Reagent, Calibrator, Low Control and High Control) is a quantitative method for the detection of glycated proteins in serum and plasma.

AI/ML Overview

Here's a breakdown of the acceptance criteria and study information for the Genzyme GlyPro™ Reagent, Calibrator, and Controls, based on the provided 510(k) summary:

Description of Acceptance Criteria and Study Findings

The Genzyme GlyPro™ Assay System is intended for the quantitative determination of glycated proteins in serum and plasma, serving as a measure of mean blood glucose levels over the preceding 2-3 weeks for diabetes management. The primary study presented is a comparative performance study against a predicate device (Roche Unimate Fructosamine) and Furosine, along with linearity, precision, and interference studies. The overarching acceptance criterion for the premarket notification is demonstrating substantial equivalence to a legally marketed predicate device.

1. Table of Acceptance Criteria and Reported Device Performance

Acceptance Criteria Category	Specific Criteria/Tests	Reported Device Performance
Comparative Performance	Correlation with Predicate (Roche Unimate Fructosamine)	Slope: 1.33Intercept (µmol/L): -127.45Correlation Coefficient (r): 0.9915Sample Range (µmol/L): 169.0 - 675.5Conclusion: Acceptable correlation.
	Correlation with Furosine Method	Slope: 15.25Intercept (µmol/L): 0.41Correlation Coefficient (r): 0.9881Sample Range (peak area x 10^4): 7.40 - 48.58Conclusion: Acceptable correlation.
Linearity	Demonstrate linearity across the usable range	Linear up to 1734 µmol/L.
Precision (Within-Run)	Coefficient of Variation (CV) ≤ 1.0% and SD ≤ 5 µmol/L	Low Level: Mean 180.7 µmol/L, SD 1.34, %CV 0.74Medium Level: Mean 405.3 µmol/L, SD 1.25, %CV 0.31High Level: Mean 663.6 µmol/L, SD 4.55, %CV 0.69Conclusion: Excellent within-run precision (CVs ≤ 1.0%, SDs ≤ 5 µmol/L).
Precision (Between-Run)	Coefficient of Variation (CV) ≤ 2.0% and SD ≤ 6 µmol/L	Low Level: Mean 179.6 µmol/L, SD 2.99, %CV 1.66Medium Level: Mean 402.3 µmol/L, SD 3.17, %CV 0.79High Level: Mean 654.6 µmol/L, SD 5.73, %CV 0.88Conclusion: Excellent between-run precision (CVs ≤ 2.0%, SDs ≤ 6 µmol/L).
Interference	No significant interference from common substances at specified levels; identify interfering drugs.	No Interference (up to indicated levels): Triglyceride (Avian) 750 mg/dL, Ascorbic Acid 8 mg/dL, Bilirubin 29 mg/dL, Hemoglobin 200 mg/dL, Uric Acid 33 mg/dL, Glucose 1800 mg/dL.Interfering Drugs: Dobesilate (10 mg/L), Gentisic Acid (25 mg/L), Methampyrone (100 mg/L) at concentrations less than therapeutic dose.
Sample Type Equivalence	Understand differences between serum and plasma	EDTA plasma results are 6% lower than serum results. Recommendation: use the same sample type for comparative analyses of the same patient.
Reference Range	Establish a normal reference range	95% Reference Range: 122 - 238 µmol/L.

2. Sample Size Used for the Test Set and Data Provenance

Comparative Performance Studies: n = 61 samples were used for comparison against both the predicate Roche Unimate Fructosamine and the Furosine method.
Linearity, Within-Run, Between-Run, and Interference Studies: Specific sample sizes are given for each:
- Within-Run and Between-Run Precision: 20 replicates for each of 3 serum pools (total 60 measurements per study).
- Interference Studies: "a specimen pool" and "varying levels" of interferents were used; specific 'n' for each interferent not provided but implied to be sufficient for evaluation.
- Serum vs. Plasma: "Matched sets of serum and EDTA plasma specimens" were tested; specific 'n' not provided.
- Reference Range: Calculated using non-parametric analysis (NCCLS C28-A), but the number of individuals/samples used to establish the range is not specified.
Data Provenance: The document does not explicitly state the country of origin or whether the data was retrospective or prospective. Given it is a 510(k) submission from a US-based manufacturer for a clinical laboratory device, it is highly probable the data was generated in a clinical laboratory setting, likely in the US, and was prospective for the purpose of the submission.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications

This device is an in-vitro diagnostic (IVD) assay measuring a quantitative analyte. The "ground truth" for the test set is established by the performance of reference methods (Roche Unimate Fructosamine and Furosine) and the analytical characteristics of the device itself (linearity, precision). It does not involve human expert interpretation of images or other qualitative assessments requiring expert consensus. Therefore, the concept of "number of experts" and their "qualifications" for establishing ground truth in the traditional sense for diagnostic imaging AI is not directly applicable here. The "experts" are the validated methodologies and laboratory instrumentation.

4. Adjudication Method for the Test Set

Not applicable. This is an IVD device for quantitative measurement. Adjudication methods (like 2+1, 3+1) are typically used in studies involving subjective human interpretation of results, such as reading medical images, where there might be disagreement among readers. For an analytical assay, the "adjudication" is inherent in the analytical method's performance and comparison to a quantitative standard or predicate.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done

No, an MRMC comparative effectiveness study was not done. This type of study is relevant for diagnostic devices that involve human interpretation (like radiologists reading images) and aims to measure the improvement in human reader performance with the assistance of the device. The GlyPro™ Assay is an automated quantitative assay, not an assistive AI tool for human readers.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done

The studies presented are standalone performance evaluations of the GlyPro™ assay system. The device's performance characteristics (correlation, linearity, precision, interference) were assessed directly, without the involvement of a human-in-the-loop for interpretation beyond standard laboratory procedures for running the assay and reporting results. The device itself is an "algorithm only" in the sense that it performs its quantitative measurement automatically.

7. The Type of Ground Truth Used

The ground truth for the comparative performance studies was the results obtained from the predicate device (Roche Unimate Fructosamine) and another established method, Furosine. For other studies like linearity and precision, the ground truth is based on reference materials/serum pools with known or precisely characterized analyte concentrations. The interference studies used controlled additions of potential interferents. For the reference range, it was established using non-parametric analysis of a reference population, which implies direct measurement of a healthy population.

8. The Sample Size for the Training Set

This document describes a premarket notification for an in-vitro diagnostic assay, not a machine learning or AI algorithm in the contemporary sense that requires distinct "training" and "test" sets. The "training" for such an assay typically involves the manufacturer's internal development, optimization, and validation of the reagent formulation, instrument parameters, and assay protocol. This information is not typically detailed in this section of a 510(k) summary. The studies described are validation and verification studies, analogous to what might be considered "test sets" for evaluation of the final product.

9. How the Ground Truth for the Training Set Was Established

As mentioned above, the concept of a separate "training set" with established ground truth as understood for modern AI/ML models is not directly applicable here. The assay's development and optimization ("training") would have involved:

Analytical chemistry principles: ensuring the reagents react specifically and quantitatively with glycated proteins.
Calibration: using a calibrator (GlyPro™ Calibrator) with known or assigned values to establish the relationship between instrument signal and analyte concentration.
Control materials: using GlyPro™ Low and High Controls with known ranges to monitor assay performance and ensure accuracy and precision over time.

The "ground truth" during this development phase would be established through careful analytical measurements, use of certified reference materials (if available for glycated proteins), and comparison to established laboratory methods during the internal R&D process. This information is typically proprietary and not disclosed in the 510(k) summary.

Summary

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K983726

510(k) PREMARKET NOTIFICATION

GlvPro™ Reagent. Low Control and High Control October 5, 1998

NOV 25 1998

ATTACHMENT 1

510(k) Summary Of Safety and Effectiveness Information Upon Which An Equivalence Determination Could be Made

Trade or Proprietary Name:	GlyPro™ ReagentGlyPro™ CalibratorGlyPro™ Low ControlGlyPro™ High Control
Common or Usual Name:	Assay, Glycosylated Hemoglobin
Classification Name:	Glycosylated Hemoglobin Assay
Manufacturer:	Genzyme DiagnosticsOne Kendall SquareCambridge, MA 02139-1562
Contact Person:	Barbara Pizza, Manager, Regulatory Affairs, (617) 252-7953

The use of the Genzyme GlyPro™ Reagent assay in the clinical laboratory setting is substantially equivalent to a currently marketed method for Fructosamine for the management of Diabetes.

The Genzyme GlyPro Assay System (consisting of Reagent, Calibrator, Low Control and High Control) is a quantitative method for the detection of glycated proteins in serum and plasma.

PERFORMANCE STUDIES

Comparative Performance Studies

A Comparative performance study was conducted using the Genzyme GlyPro Reagent, and predicate method (Roche Unimate Fructosamine).

The slope, intercept, correlation coefficient, and sample range for these comparisons are provided below.

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	GlyPro vs. Furosinen= 61	GlyPro vs. Rochen= 61
Slope	15.25	1.33
Intercept (µmol/L)	0.41	-127.45
Correlation Coefficient (r)	0.9881	0.9915
Sample Range	7.40 - 48.58(peak area x 104)	169.0 - 675.5 (µmol/L)

The Genzyme method yielded acceptable correlation with the predicate and Furosine methods in samples across the usable range of the product.

Linearity

Linearity studies demonstrated that the GlyPro assay is linear up to 1734 umol/L.

Precision

Both within-run and between-run studies were performed. Testing was done using frozen serum pools at three target levels of glycated serum protein for within-run precision and between-run.

Within-Run

Each serum pool was tested 20 times in one batch using the GlyPro Reagent assay . The mean, standard deviation (SD) and coefficient of variation (%CV) was calculated for each serum pool.

	Low	Medium	High
n	20	20	20
Sample Range (µmol/L)	179-182	403-408	656-670
Mean (µmol/L)	180.7	405.3	663.6
SD (µmol/L)	1.34	1.25	4.55
%CV	0.74	0.31	0.69

The GlyPro assay yielded excellent within-run precision with CVs of ≤ 1.0% and SD values of ≤ 5 µmo/L.

Between-Run

Each serum pool was tested twice per day, for ten days using the GlyPro assay for a total of 20 determinations. The mean, SD and %CV were calculated for each pool as follows:

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	Low	Medium	High
n	20	20	20
Sample Range (umol/L)	175 - 185	396 - 408	644 - 665
Mean (umol/L)	179.6	402.3	654.6
SD (umol/L)	2.99	3.17	5.73
%CV	1.66	0.79	0.88

The GlyPro assay yielded excellent between-run precision with CVs ≤ 2.0% and SDs ≤ 6 µmol/L.

Interference Studies

The effects of interfering substances was evaluated by adding varying levels of potential interferents to a specimen pool. These determined that triglyceride (Avian), ascorbic acid, bilirubin, hemoglobin, uric acid and glucose did not interfere with the performance of the Genzyme GlyPro assay at the levels up to and including those indicated below.

Interfering Substance	Concentration*
Triglyceride (Avian)	750 mg/dL
Ascorbic Acid	8 mg/dL
Bilirubin	29 mg/dL
Hemoglobin	200 mg/dL
Uric Acid	33 mg/dL
Glucose	1800 mg/dL

*Different analyzer applications will have different interferences.

Additionally, a drug interference study was performed. Only the drugs listed below were found to interfere significantly at concentrations less than the therapeutic dose:

Drug	Interfering concentration
Dobesilate	10 mg/L
Gentisic Acid	25 mg/L
Methampyrone	100 mg/L

Serum vs. Plasma

Matched sets of serum and EDTA plasma specimens were tested with the GlyPro Reagent. Data demonstrate that EDTA plasma results are 6% lower than serum results. It is preferable that the same sample type be used for all comparative analyses of the same patient.

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Reference Range

The reference range was calculated according to NCCLS C28-A using non-parametric analysis. The 95% 122 - 238 umol/L reference range of the assay is:

Conclusion

Based on the results of the studies described above, the Genzyme GlyPro Reagent assay is substantially equivalent in performance to the predicate, Roche Unimate Fructosamine, a commercially marketed method for quantifying glycated proteins in serum and plasma.

In lieu of a 510(k) statement under 513(i) of the Act, this information is provided as a 510(k) summary for disclosure to any other persons/companies without the specific written authorization from Genzyme Corporation.

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Image /page/4/Picture/2 description: The image shows the seal of the U.S. Department of Health & Human Services. The seal is circular and contains the words "DEPARTMENT OF HEALTH & HUMAN SERVICES USA" around the perimeter. In the center of the seal is an abstract image of a caduceus, a symbol often associated with medicine and healthcare. The caduceus is depicted with three intertwined strands and a stylized head at the top.

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

NOV 2 5 1998

Ms. Barbara Pizza Manager, Regulatory Affairs GENZYME CORPORATION One Kendall Square Cambridge, MA 02139

Re: K983726

Trade Name: GlyPro™ Reagent, GlyPro™ Calibrator, GlyPro™ Low Control, GlyPro™ High Control Requlatory Class: II Product Code: 81 LCP Dated: October 20, 1998 Received: October 22, 1998

Dear Ms. Pizza:

We have reviewed your Section 510(k) notification of intent to market the device referenced above and we 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). 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.

If your device is classified (see above) into either class II (Special Controls) or class III (Premarket Approval), it may be subject to such additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 895. A substantially equivalent determination assumes compliance with the Current Good Manufacturing Practice requirements, as set forth in the Quality System Requlation (QS) for Medical Devices: General regulation (21 CFR Part 820) and that, through periodic QS inspections, the Food and Druq Administration (FDA) will verify such assumptions. Failure to comply with the GMP regulation may result in In addition, FDA may publish further regulatory action. announcements concerning your device in the Federal Register. Please note: this response to your premarket notification submission does not affect any obligation you might have under sections 531 through 542 of the Act for devices under the Electronic Product Radiation Control provisions, or other Federal laws or regulations.

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Page 2

This letter will allow you to begin marketing your device as described in your 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.

If you desire specific advice for your device on our labeling requlation (21 CFR Part 801 and additionally 809.10 for in vitro diagnostic devices), please contact the Office of Compliance at (301) 594-4588. Additionally, for questions on the promotion and advertising of your device, please contact the Office of Compliance at (301) 594-4639. Also, please note the regulation entitled, "Misbranding by reference to premarket notification"(21 CFR 807.97). Other general information on your responsibilities under the Act may be obtained from the Division of Small Manufacturers Assistance at its toll-free number (800) 638-2041 or (301) 443-6597, or at its internet address "http://www.fda.gov/cdrh/dsma/dsmamain.html".

Sincerely yours,

Steven Autman

Steven I. Gutman, M.D., M.B.A. Director Division of Clinical Laboratory Devices Office of Device Evaluation Center for Devices and Radiological Health

Enclosure

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510(k) PREMARKET NOTIFICATION

Genzyme Corporation One Kendall Square Cambridge, MA 02139

GlyPro™ Reagent, Calibrator, Controls Reference No. K983726 Confidential

November 20, 1998

Page_1 of____________________________________________________________________________________________________________________________________________________________________________

K983726 SIO(K) NUMBER (IF KNOWN):

GlyPro™ Reagent, Callbrator, Controls DEVICE NAME:

INDICATIONS FOR USE:

GlyPro Reagent

For the quantitative determination of glycated proteins.

Measurement of glycated serum protein is representative of the mean blood glucose levels over the preceding 2-3 weeks

For In Vitro Diagnostic Use.

GlyPro Callbrator

For calibration of the GlyPro™ assay.

For In Vitro Diagnostic Use.

GlyPro Low and High Controls

To monitor the performance of the GlyPro assay. For In Vitro Diagnostic Use.

Avonsty

(Division Sign-Off)
Division of Clinical Laboratory Devices

510(k) Number

(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF NEEDED.)

Concurrence of CDRH, Office of Device Evaluation (ODE)

Prescription Use
(Per 21 CFR 801.109)

Over-The-Counter-Use
(Optional Format 1-2-96

Regulation Number and Section

§ 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).