The cassette COBAS INTEGRA HDL - Cholesterol Direct (HDL-D) contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative determination of HDL - cholesterol direct concentration in serum and plasma.

Device Description

The COBAS INTEGRA HDL-D reagent cassette is intended for use with the COBAS INTEGRA Analyzer. The COBAS INTEGRA Analyzer and COBAS INTEGRA Reagent cassettes together provide an integrated system for in vitro diagnostic testing. The COBAS INTEGRA Analyzer utilizes three measuring principles, i.e., absorbance, fluorescence polarization and ion-selective electrodes. The analyzer has a throughput of up to 600 tests per hour with STAT samples prioritized and tested immediately. Random sample access, robotics and a user interface optimize time management and streamline workflow. The COBAS INTEGRA can store up to 68 COBAS INTEGRA Reagent Cassettes on board, 24 hours a day at 2-8°C. The COBAS INTEGRA Reagent Cassettes are compact and preparation-free with the added convenience of long term on-board stability. Barcode readers are used to identify newly loaded reagent cassettes, samples for patient identification, and rack inserts and to read calibration and control data from the cassette label. COBAS INTEGRA tests include chemistry, drugs of abuse, immunology, ion selective electrodes, therapeutic drug monitoring, and hematology reagents.

The COBAS INTEGRA HDL-D reagent cassette is an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative determination of High Density Lipoprotein cholesterol direct (HDL-D) in serum and plasma.

The principle of the COBAS INTEGRA HDL-D reagent cassette is based on the absorption of synthetic polyanions to the surface of lipoproteins. LDL, VLDL, and chylomicrons are transformed into a detergent-resistant form. whereas HDL is not. Combined action of polyanions and detergent solubilizes cholesterol from HDL, but not from LDL, VLDL, and chylomicrons. Solubilized cholesterol is oxidized by the sequential enzymatic action of cholesterol esterase and cholesterol oxidase. The hydrogen peroxide produced in this reaction is reacted with chromogens to form a colored dye. The increase in absorbance at 552 nm is directly proportional to the HDL cholesterol concentration of the sample.

AI/ML Overview

Here's an analysis of the acceptance criteria and study as presented in the provided text for the Roche COBAS INTEGRA® HDL-D Reagent Cassette:

1. Table of Acceptance Criteria and Reported Device Performance

The document compares the new device (COBAS INTEGRA HDL-D reagent cassette) to a predicate device (COBAS INTEGRA HDL reagent system) rather than explicitly stating acceptance criteria a priori. However, the performance characteristics of the new device serve as its reported performance, and by demonstrating substantial equivalence to the predicate, it implicitly meets the established performance expectations for such devices.

Performance Characteristic	Acceptance Criteria (Predicate Device Performance)	Reported Device Performance (COBAS INTEGRA HDL-D)
Assay Range	0 - 5.0 mmol/L (0 - 193 mg/dL)	0.01 - 4.0 mmol/L (0.386 - 155 mg/dL)
Precision (Level 1)
Mean (mmol/L)	0.82 mmol/L (31.7 mg/dL)	0.60 mmol/L (23.2 mg/dL)
% CV (within run)	1.2%	1.4%
% CV (total)	2.7%	2.2%
Precision (Level 2)
Mean (mmol/L)	1.42 mmol/L (54.9 mg/dL)	1.41 mmol/L (54.6 mg/dL)
% CV (within run)	0.85%	1.1%
% CV (total)	5.5%	2.3%
Sensitivity	6.4 X 10⁻² ΔA per mmol/L (1.7 X 10⁻³ ΔA per mg/dL)	8.2 X 10⁻² ΔA per mmol/L (2.1 X 10⁻³ ΔA per mg/dL)
Accuracy (Sample Size n)	232	258
Corr. Coefficient	0.998	0.901
Linear Regression	0.99x - 0.05 mmol/L (0.99x - 1.93 mg/dL)	0.77x + 0.33 mmol/L (0.77x + 12.8 mg/dL)
On-board Stability	8 weeks	12 weeks

Note: The document presents the performance of both the "new device" (COBAS INTEGRA HDL-D reagent cassette) and the "predicate device" (COBAS INTEGRA HDL reagent system) side-by-side. The acceptance criteria for the new device are implied to be achieving comparable performance to the predicate, demonstrating substantial equivalence. The table above uses the predicate's performance as the benchmark for "acceptance criteria."

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

Sample Size for Accuracy: 258 clinical samples were used for the accuracy study of the COBAS INTEGRA HDL-D reagent cassette.
Data Provenance: The document does not explicitly state the country of origin or whether the data was retrospective or prospective. Given the nature of medical device submissions, it would typically be prospective clinical data collected under controlled conditions.

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

The document describes an assay for quantitative determination of HDL-Cholesterol Direct. The "ground truth" in this context refers to the true concentration of HDL cholesterol in the samples.

Experts: Not applicable in the traditional sense for establishing ground truth for a quantitative assay. The ground truth for such assays is established through a reference method or a predicate device that has already been validated and accepted. The predicate device (COBAS INTEGRA HDL reagent system) served as the comparator for accuracy.
Qualifications of Experts: Not relevant here as ground truth is determined by chemical analysis or comparative measurement, not expert opinion.

4. Adjudication Method for the Test Set

Not applicable. Adjudication is typically used when human interpretation or subjective assessment is part of the ground truth determination (e.g., in imaging studies). For a quantitative chemical assay, the comparison is directly between the result of the new device and the result of the reference/predicate method.

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

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not conducted. MRMC studies are typically used for imaging or diagnostic tools where human readers interpret results, and the study aims to assess the impact of AI assistance on human performance. This submission is for a quantitative in vitro diagnostic reagent, which does not involve human interpretation in the same manner.

6. Standalone (Algorithm Only) Performance Study

Yes, a standalone performance study was conducted. The accuracy, precision, and sensitivity results presented in Table 2 for the COBAS INTEGRA HDL-D reagent cassette represent its standalone performance without human-in-the-loop assistance. The device directly measures HDL-D concentration.

7. Type of Ground Truth Used

The ground truth used for performance evaluation, particularly for accuracy, was based on comparison to a legally marketed predicate device (COBAS INTEGRA HDL reagent system). This predicate device itself quantifies HDL cholesterol using an enzymatic, colorimetric method. In essence, the new device's measurements were compared against the established measurements from the predicate device to show agreement.

8. Sample Size for the Training Set

The document does not provide information regarding a separate training set. For in vitro diagnostic reagents like this, the development process typically involves internal method development and optimization, but the specific term "training set" (common in AI/ML contexts) is not used, nor is a sample size provided for such a set. The presented data appears to be for verification and validation of the final product.

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

As no training set information is provided, there is no information on how ground truth for a training set (if one existed during development) was established. For chemical assays, the development process would involve optimizing reagents and reaction conditions against known standards or reference methods to ensure accurate measurement across a range of concentrations.

Summary

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K973284
Dec 18, 1997

510(k) Summary

Roche COBAS INTEGRA® HDL-D Reagent Cassette

In accordance with the Safe Medical Devices Act of 1990, a 510(k) summary is provided as outlined in 21 CFR 807.92.

I. Identification of 510(k) Sponsor:

Roche Diagnostic Systems, Inc. a subsidiary of Hoffmann-La Roche, Inc. Branchburg Township 1080 U.S. Highway 202 Somerville, New Jersey 08876-3771

510(k) Submission dated August 28, 1997

Contact: Maria Feijoo Manager, Regulatory Affairs Phone: (908) 253-7310 Fax: (908) 253-7547

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II. Device Name:

The device name, including both the trade/proprietary name and the classification name are provided in Table 1.

Table 1

Proprietary Name	Classification Name	Product Code	Regulation Number
COBAS INTEGRA HDL -Cholesterol Direct	Cholesterol test system	CHH	862.1175

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Identification of the legally marketed device to which the 510(k) sponsor claims III. equivalence:

The COBAS INTEGRA HDL-D Reagent Cassette is substantially equivalent to the currently marketed COBAS INTEGRA HDL reagent system (K951595).

Description of the Device/Statement of Intended Use: IV.

The COBAS INTEGRA Analyzer utilizes three measuring principles, i.e., absorbance, fluorescence polarization and ion-selective electrodes. The analyzer has a throughput of up to 600 tests per hour with STAT samples prioritized and tested immediately. Random sample access, robotics and a user interface optimize time management and streamline workflow. The COBAS INTEGRA can store up to 68 COBAS INTEGRA Reagent Cassettes on board, 24 hours a day at 2-8°C. The COBAS INTEGRA Reagent Cassettes are compact and preparation-free with the added convenience of long term on-board stability. Barcode readers are used to identify newly loaded reagent cassettes, samples for patient identification, and rack inserts and to read calibration and control data from the cassette label. COBAS INTEGRA tests include chemistry, drugs of abuse, immunology, ion selective electrodes, therapeutic drug monitoring, and hematology reagents. For additional information on the COBAS INTEGRA Analyzer and its constituent modules, please refer to the Operator's Manual in Volumes 1 through 2, pages 92-703, of the original 510(k) submission (K951595).

Through this submission, it is the intention of Roche Diagnostic Systems to gain clearance for the COBAS INTEGRA HDL-D Cassette.

Low HDL levels are recognized as a strong and common risk factor for atherosclerotic Coronary Artery Disease (CAD). Therefore, determination of HDL cholesterol is routinely offered as part of a lipid profile. Usually VLDL and LDL are selectively precipitated from serum or plasma samples followed by determination of cholesterol in the HDL - containing supernatant. These techniques require a centrifugation step to remove the precipitated lipoproteins and thus cannot be fully automated. The COBAS INTEGRA HDL - Cholesterol Direct, however, allows for the

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direct specific determination of HDL cholesterol in the presence of LDL. VLDL and chylomicrons without any sample pretreatment. Therefore, lending itself to automated routine analysis.

V. Summary of the technological characteristics of the new device in comparison to those of the predicate.

The COBAS INTEGRA HDL-D reagent cassette is similar to the COBAS INTEGRA HDL reagent system in that HDL cholesterol is quantitated using an enzymatic, colorimetric method (CHOD/PAP).

The differences are that the current COBAS INTEGRA HDL application requires pretreatment of the sample with a separating reagent prior to analysis whereas the COBAS INTEGRA HDL-D reagent cassette measures the HDL cholesterol concentration directly in the sample.

The current COBAS INTEGRA HDL reagent application is used in conjunction with the Roche HDL Cholesterol Precipitating Reagent and the COBAS INTEGRA Cholesterol reagent cassette (K951595). The Roche HDL Cholesterol Precipitating Reagent uses phosphotungstic acid and magnesium ions to precipitate the chylomicrons, VLDL, and LDL. After centrifugation, HDL remaining in the supernatant is quantitated by its cholesterol content using an enzymatic. colorimetric method (CHOD/PAP).

A summary of the similarities, differences and performance characteristics between the COBAS INTEGRA HDL-D reagent cassette and the COBAS INTEGRA HDL reagent system are listed in Table 2.

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Table 2

	COBAS INTEGRA HDL-D reagentcassette	COBAS INTEGRA HDL reagentsystem
Intended Use	quantitative determination of HDLcholesterol	quantitative determination of HDLcholesterol
Methodology	Selective inhibition colorimetricassay (no pretreatment required)	Phosphotungstic acid pretreatmentused with colorimetric method(CHOD/PAP)
Sample type	Serum and plasma	Serum and plasma
Calibrator	Roche HDL Calibrator Directlyophilized human serumAssigned value ~1.58 mmol/L(61 mg/dL)	Roche Calibrator (human)Assigned value ~4.08 mmol/L (158 mg/dL) (undiluted)
Controls	Roche Control Serum N and P(human)	Roche Control Serum N and P(human)
Reagent type	Liquid	Granulate
Reagent (activeingredients)	R1: MOPSPolyanions4 - Amino-antipyrineMg ClR2: N,N-bis-m-toluidineCholesterol esteraseCholesterol oxidaseHorseradish	Pretreatment: Phosphotungstic acidR: HEPESSodium cholate4 - Chlorophenol4 - Amino-antipyrineCholesterol esteraseCholesterol oxidaseHorseradish
On-board Stability	12 weeks	8 weeks
PerformanceCharacteristics:
Assay range	0.01 - 4.0 mmol/L(0.386 - 155 mg/dL)	0 - 5.0 mmol/L(0 - 193 mg/dL)

Precision:	Level 1	Level 2	Level 1	Level 2
Mean (mmol/L)	0.60 mmol/L(23.2 mg/dL)	1.41 mmol/L(54.6 mg/dL)	0.82(31.7 mg/dL)	1.42(54.9 mg/dL)
% CV (within run)	1.4	1.1	1.2	0.85
% CV (total)	2.2	2.3	2.7	5.5
Sensitivity	$8.2 X 10^{-2}$ ΔA per mmol/L( $2.1 X 10^{-3}$ ΔA per mg/dL)	$6.4 X 10^{-2}$ ΔA per mmol/L( $1.7 X 10^{-3}$ ΔA per mg/dL)
Accuracy:
Sample size (n)	258	232
Corr. Coefficient	0.901	0.998
Linear regression	$0.77x + 0.33$ mmol/L( $0.77x + 12.8$ mg/dL)	$0.99x - 0.05$ mmol/L( $0.99x - 1.93$ mg/dL)

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Brief discussion of the clinical and nonclinical tests relied on for a determination of VI. substantial equivalence:

Table 2 shows the clinical and nonclinical performance characteristics of the COBAS INTEGRA HDL-D Reagent Cassette. This information demonstrates that the performance of this device is substantially equivalent to the currently marketed COBAS INTEGRA HDL reagent system.

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Image /page/6/Picture/1 description: The image shows the logo for the Department of Health & Human Services - USA. The logo consists of a stylized eagle with three tail feathers, and the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" arranged in a circular fashion around the eagle. The logo is black and white.

Public Health Service

DEC 18 1997

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

Maria Feijoo . Manager, Regulatory Affairs Roche Diagnostic Systems, Inc. 1080 U.S. Highway 202 Somerville, New Jersey 08876-3771

Re : K973284 COBAS INTEGRA HDL-D Requlatory Class: I Product Code: LBR, CHH Dated: November 25, 1997 Received: November 26, 1997

Dear Ms. Feijoo:

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 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 Requlations, Title 21, Parts 800 to 895. ਕੇ substantially equivalent determination assumes compliance with the Current Good Manufacturing Practice requirements, as set forth in the Quality System Regulation (QS) for Medical General regulation (21 CFR Part 820) and that, Devices: through periodic QS inspections, the Food and Drug Administration (FDA) will verify such assumptions. Failure to comply with the GMP regulation may result in requlatory action. In addition, FDA may publish further 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 requlations.

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Page 2

Under the Clinical Laboratory Improvement Amendments of 1988 (CLIA-88), this device may require a CLIA complexity categorization. To determine if it does, you should contact the Centers for Disease Control and Prevention (CDC) at (770) 488-7655.

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 regulation (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/dsmamain.html".

Sincerely yours,
Steven Litman

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

Enclosure

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Page__________________________________________________________________________________________________________________________________________________________________________

510(k) Number (if known)

Device Name: Roche COBAS INTEGRA HDL-D Reagent Cassette

Indications for Use:

L. Mitchell Chappell for A.W. Montgomery

(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

§ 862.1175 Cholesterol (total) test system.

(a)
Identification. A cholesterol (total) test system is a device intended to measure cholesterol in plasma and serum. Cholesterol measurements are used in the diagnosis and treatment of disorders involving excess cholesterol in the blood and lipid and lipoprotein metabolism disorders.(b)
Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 862.9.