Reagents: For the quantitative measurement of C-Reactive Protein (CRP) concentration in serum or plasma. For In Vitro Diagnostic Use. Calibrator: For the calibration of the N-geneousTM Wide Range CRP assay. For In Vitro Diagnostic Use.

Device Description

The Genzyme N-geneous™ Wide Range CRP Reagent is a two-reagent method for the quantitative measurement of CRP concentration from 0.04 to 320 mg/L in serum or plasma. The test is an enhanced latex-agglutination turbidimetric immunoassay. Sample is added to a buffer solution and mixed with a suspension of mouse anti-human CRP monoclonal antibody, which is bound to latex. CRP binds to the latex-bound antibody, which agglutinates. The light scattering caused by the increase in particle size is used as a measure of CRP concentration. The amount of light scattering is proportional to the concentration of CRP in the sample. N-geneous™ Wide Range CRP Calibrator Set is a stabilized human serum designed to be used to calibrate the N-geneous™ Wide Range CRP Reagent and is sold separately.

AI/ML Overview

Here's an analysis of the provided text regarding the N-geneous™ Wide Range CRP Reagent Kit, structured to answer your questions:

Acceptance Criteria and Device Performance Study for N-geneous™ Wide Range CRP Reagent Kit

The 510(k) submission for the N-geneous™ Wide Range CRP Reagent Kit demonstrates substantial equivalence to a predicate device, the Dade Behring N High Sensitive CRP method, primarily through comparative performance and precision studies.

1. Table of Acceptance Criteria and Reported Device Performance

The provided document does not explicitly state "acceptance criteria" for the comparative performance and precision studies in terms of pre-defined thresholds. Instead, it presents the results of these studies and concludes that the device's performance is "substantially equivalent" or "acceptable."

However, we can infer the implicit performance targets based on the evaluation presented. For devices seeking substantial equivalence, a high correlation with a legally marketed predicate device and acceptable precision (low variability) are key.

Performance Metric	Implicit Acceptance Criteria (Inferred from Substantial Equivalence and Acceptability)	Reported Device Performance (N-geneous™ Wide Range CRP Reagent)
Comparative Performance (vs. Predicate)
Correlation Coefficient (r)	Very high correlation (e.g., >0.95) with predicate method	0.995 (with Dade Behring N High Sensitive CRP)
Linear Relationship Equation	Close to identity line (slope near 1, intercept near 0) with predicate method	1.05 X (N High Sensitive CRP) – 0.31
Precision (Within-Run)
%CV (across various CRP concentrations)	Low percentage of coefficient of variation, indicating good reproducibility	5.5% (0.30 mg/L), 1.8% (1.00 mg/L), 1.3% (2.97 mg/L), 1.2% (51.3 mg/L), 1.5% (202 mg/L)
Precision (Total)
%CV (across various CRP concentrations)	Low percentage of coefficient of variation, indicating good reproducibility	6.7% (0.30 mg/L), 2.3% (1.00 mg/L), 1.7% (2.97 mg/L), 1.9% (51.3 mg/L), 1.5% (202 mg/L)
Overall Precision Conclusion	Acceptable total precision	"yielded acceptable total precision"
Traceability of Calibrator	Traceable to internationally recognized reference material	Traceable to CRM470 (IRMM, certified by BCR)

2. Sample Size and Data Provenance

Sample Size for Test Set (Comparative Performance): 229 serum samples.
Data Provenance: The document does not explicitly state the country of origin. It describes "comparative performance studies" and "precision studies" conducted on the Hitachi 912 clinical analyzer. Given Genzyme Diagnostics is located in Cambridge, MA, it's reasonable to infer the studies were likely conducted in the US, but this is not explicitly stated. The studies used "serum samples" and "sera that were stored frozen (-20°C) and thawed prior to use." This indicates the data is retrospective in the sense that the samples were collected prior to the full study, but they are prospectively analyzed in the context of this study.

3. Number of Experts and Qualifications for Ground Truth

This document describes a diagnostic device (reagent and calibrator) for quantitative measurement of CRP. The "ground truth" for the comparative performance study is the measurement obtained from the predicate device, the Dade Behring N High Sensitive CRP method.
No human experts were used to establish ground truth in the sense of a subjective interpretation or diagnosis. The ground truth is established by the measurement value from the predicate device.

4. Adjudication Method for the Test Set

Since the "ground truth" is derived from the quantitative measurement of a predicate device, there was no adjudication method involving human experts for the test set.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No, an MRMC comparative effectiveness study was not done. This type of study is typically performed for image-based diagnostic devices or tests where human interpretation is involved (e.g., radiology, pathology). This submission is for an in vitro diagnostic reagent and calibrator kit, where the output is a quantitative measure of CRP.

6. Standalone Performance Study

Yes, a standalone performance study was done. The precision studies (within-run and total precision) directly assess the performance of the N-geneous™ Wide Range CRP Reagent Kit in isolation, without direct comparison to human interpretation or a human-in-the-loop scenario. The comparative performance study also evaluates the algorithm's (reagent's) output against the predicate device's output, essentially a standalone comparison to another device.

7. Type of Ground Truth Used

The ground truth used for the comparative performance study was the quantitative measurement value obtained from the legally marketed predicate device (Dade Behring N High Sensitive CRP method).
For the precision studies, the "ground truth" is inherent to the intrinsic variability of the device itself when measuring known concentrations, and the results are reported as mean, standard deviation, and %CV.

8. Sample Size for the Training Set

The document does not specify a separate training set or its sample size. This is common for in vitro diagnostic device submissions where the 'algorithm' is essentially the chemical reaction and light scattering measurement, and the parameters (e.g., reagent concentrations) are established during product development, not typically through a distinct machine learning "training phase" on a separate dataset in the same way an AI/ML diagnostic would. The comparative and precision studies are validation studies, not training studies.

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

As no explicit training set is described for an AI/ML algorithm, the concept of establishing ground truth for a training set in this context is not applicable. The underlying chemical and physical principles of the immunoassay, along with established laboratory practices and quality control, govern the development and calibration of such a device. The calibrator itself is traceable to CRM470, which serves as a widely accepted "ground truth" or reference material for CRP measurements.

Summary

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K040241

JUN 2 5 2004

510(k) PREMARKET NOTIFICATION

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

Trade or Proprietary Name:	N-geneous™ Wide Range CRP ReagentN-geneous™ Wide Range CRP Calibrator Set
Common or Usual Name:	C-Reactive Protein immunological test systemCalibrator for C-Reactive Protein
Classification Name:	C-Reactive Protein immunological test systemCalibrator, Primary
Manufacturer:	Genzyme DiagnosticsOne Kendall SquareCambridge, MA 02139-1562
Contact Person:	Fred D. Lasky, Ph.D., Director, Regulatory Affairs (617) 591-5512Robert Yocher, Vice President, Regulatory Affairs (617) 768-6275

The use of the Genzyme N-geneous™ Wide Range CRP Reagent in the clinical laboratory setting is substantially equivalent to the Dade Behring N High Sensitive CRP method.

The Genzyme N-geneous™ Wide Range CRP Reagent is a two-reagent method for the quantitative measurement of CRP concentration from 0.04 to 320 mg/L in serum or plasma.

The test is an enhanced latex-agglutination turbidimetric immunoassay. Sample is added to a buffer solution and mixed with a suspension of mouse anti-human CRP monoclonal antibody, which is bound to latex. CRP binds to the latex-bound antibody, which agglutinates. The light scattering caused by the increase in particle size is used as a measure of CRP concentration. The amount of light scattering is proportional to the concentration of CRP in the sample.

N-geneous™ Wide Range CRP Calibrator Set is a stabilized human serum designed to be used to calibrate the N-geneous™ Wide Range CRP Reagent and is sold separately. The Ngeneous™ Wide Range CRP Calibrator Set is traceable to CRM470, available from theInstitute for Reference Materials and Measurements (IRMM), and certified by the European Commission, Community Bureau of Reference (BCR).

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Comparative performance studies were conducted using the N-geneous™ Wide Range CRP Reagent on the Hitachi 912 clinical analyzer and the Dade Behring N High Sensitive CRP method in which CRP was measured in 229 serum samples. The relationship between methods is:

N-geneous™ Wide Range CRP = 1.05 X (N High Sensitive CRP) – 0.31

Correlation coefficient (r) = 0.995

Precision studies were conducted using the N-geneous™ Wide Range CRP Reagent on the Hitachi 912 clinical analyzer. The studies were performed using sera that were stored frozen (-20°C) and thawed prior to use.

The mean, standard deviation (SD) and coefficient of variation (%CV) for within-run precision:

Control	1	2	3	4	5
Mean (mg/L)	0.30	1.00	2.97	51.3	202
SD (mg/L)	0.02	0.02	0.04	0.61	3.0
%CV	5.5	1.8	1.3	1.2	1.5

The mean, standard deviation (SD) and coefficient of variation (%CV) for total precision:

Control	1	2	3	4	5
Mean (mg/L)	0.30	1.00	2.97	51.3	202
SD (mg/L)	0.02	0.02	0.05	0.96	3.1
%CV	6.7	2.3	1.7	1.9	1.5

The N-geneous™ Wide Range CRP reagents yielded acceptable total precision.

These data demonstrate that the performance of the N-geneous™ Wide Range CRP Reagent in the clinical laboratory is substantially equivalent to the performance of a commercially available method.

In addition, N-geneous™ Wide Range CRP Reagent is substantially equivalent to a currently marketed method, in that they measure the same analyte and have the same intended use. Additionally, they both use the same sample matrices and utilize mouse monoclonal antibody to CRP. Furthermore, they measure concentration by the magnitude of particle agglutination and light scatter, are in ready-to-use liquid format and both are traceable to CRM470 reference material. The N-geneous™ Wide Range CRP Reagent differs from the Dade Behring N High Sensitive CRP method in that the N-geneous™ Wide Range CRP Reagent utilizes a turbidimetric technique, whereas the Dade Behring N High Sensitive CRP

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is a nephelometric method. Also, the reportable range of the N-geneous™ Wide Range CRP Reagent is up to 320 mg/L before dilution is required, whereas the Dade Behring N High Sensitive CRP method requires additional on board sample dilution for concentrations above 11 mg/L. The N-geneous™ Wide Range CRP Reagent uses a set of five standards for calibration; the Dade Behring N High Sensitive CRP method has one calibrator.

N-geneous ™ Wide Range CRP Calibrator Set is substantially equivalent to a currently marketed calibrator, the Dade Behring N Rheumatology Standard SL in that they are both used to establish calibration of CRP methods to be used for measurement of CRP in serum or plasma. Both are human serum-base materials that are traceable to CRM470 available from the Institute for Reference Materials and Measurements (IRMM), and certified by the European Commission, Community Bureau of Reference (BCR).

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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DEPARTMENT OF HEALTH & HUMAN SERVICES

Image /page/3/Picture/1 description: The image shows the logo for the Department of Health & Human Services (HHS). The logo consists of a stylized eagle with three lines representing its body and wings. The eagle is facing to the right. The text "DEPARTMENT OF HEALTH & HUMAN SERVICES USA" is arranged in a circular pattern around the eagle.

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

Fred D. Lasky, Ph.D. Director, Regulatory Affairs Genzyme Corparation 500 Kendall Street Cambridge, MA 02142

JUN 2 5 2004

K040241 Re: R040241
Trade/Device Name: N-geneous™ Wide Range CRP Reagent Kit Regulation Number: 21 CFR 866.5270 Regulation Name: C-reactive protein immunological test system Regulatory Class: Class II Product Code: DCK, JIS Dated: April 19, 2004 Received: April 21, 2004

Dear Dr. Lasky:

We have reviewed your Section 510(k) premarket notification of intent to market the device we nave reviewed your becaon 3 ro(x) premium is substantially equivalent (for the indications felerenced above and nave uctoringed law marketed predicate devices marketed in interstate for use stated in the encrosule) to regary manent date of the Medical Device Amendments, or to commerce prior to May 20, 1778, the exactions of the Federal Food, Drug, devices that have been recatismed in assessoval of a premarket approval application (PMA).
and Cosmetic Act (Act) that do not require approval of a premarket approval applica and Cosment Act (Act) that do not require approval es eneral controls provisions of the Act. The You may, merciole, market me devices, course requirements for annual registration, listing of general controls provisions of the fiel here here and prohibitions against misbranding and adulteration.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), If your device is classified (360 above) into e. Existing major regulations affecting your device it may be subject to sach additional controllar - Entistigation - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - can be found in Thic 21, Code of I concerning your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean Please be advised that IDA s issualled of a baskuin complies with other requirements of the Act that FDA has made a decemmandir and Jointer Federal agencies. You must of any Federal statures and regulations administer or of limited to: registration and listing (21 comply with an the Act 3 requirements, morants 801 and good manufacturing practice CFK I art 807), labening (21 CF F 1 litt systems (QS) regulation (21 CFR Part 820).

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Page 2

If you desire specific information about the application of labeling requirements to your device, or yeastions on the promotion and advertising of your device, please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at (301) 594-3084. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807.97). You may obtain other general information on your responsibilities under the Act from the I ou may of Small Manufacturers, International and Consumer 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,

Robert L. Beckerh

Robert L. Becker, Jr., M.D., Ph. Director Division of Immunology and Hematology Devices Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known): K040241

Device Name: N-geneous™ Wide Range CRP Reagent Kit

Indications For Use:

Reagents:

For the quantitative measurement of C-Reactive Protein (CRP) concentration in serum or plasma.

For In Vitro Diagnostic Use

Calibrator:

For the calibration of the N-geneousTM Wide Range CRP assay.

For In Vitro Diagnostic Use

Prescription Use' X (Part 21 CFR 801 Subpart D) AND/OR

Over-The-Counter Use (21 CFR 807 Subpart C)

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

Concurrence of CDRH, Office of In Vitro Diagnostic Devices (OIVD)

Alberts

Division Sign-Off

Office of In Vitro Diagno Device Evaluatio

510(k) K040241

Page 1 of ____________________________________________________________________________________________________________________________________________________________________

Regulation Number and Section

§ 866.5270 C-reactive protein immunological test system.

(a)
Identification. A C-reactive protein immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the C-reactive protein in serum and other body fluids. Measurement of C-reactive protein aids in evaluation of the amount of injury to body tissues.(b)
Classification. Class II (performance standards).