The cassette COBAS INTEGRA LDL Direct (LDL-D) contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA 700 for the quantitative determination of LDL-cholesterol direct concentration in serum and plasma. Low density lipoprotein cholesterol measurement, in conjunction with other lipid determinations, has been shown to be useful in assessing the risk of coronary heart disease.

The Roche Calibrator LDL Direct is intended for use as calibrator in quantitative Low Density Lipoprotein cholesterol assays. It is recommended for use with LDL Direct reagents on COBAS® chemistry systems. A calibrator is a device intended for medical purposes for use in a test system to establish points of reference that are used in the determination of values in the measurement of substances in human specimens.

Device Description

The COBAS INTEGRA test applications contained in this submission are intended for use with the COBAS INTEGRA Analyzer, which is also known as the COBAS INTEGRA 700. 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.

AI/ML Overview

Here's a breakdown of the acceptance criteria and study information for the Roche COBAS® INTEGRA LDL Direct and Roche Calibrator LDL Direct, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state "acceptance criteria" as a separate, pre-defined set of thresholds. Instead, it presents performance characteristics of the new device and compares them to those of predicate devices to demonstrate substantial equivalence. The implication is that if the new device's performance aligns with or is comparable to the predicate devices, it meets the "acceptance criteria" for substantial equivalence.

Performance Characteristic	Acceptance Criteria (Implied by Predicate Performance)	Reported Device Performance (COBAS INTEGRA LDL Direct)
Intended Use (Reagent)	Quantitative determination of LDL-cholesterol direct concentration in serum or plasma, useful in assessing coronary heart disease risk.	Quantitative determination of LDL-cholesterol direct concentration in serum and plasma, useful in assessing coronary heart disease risk.
Intended Use (Calibrator)	Calibrator for quantitative Low Density Lipoprotein cholesterol assays.	Calibrator for quantitative Low Density Lipoprotein cholesterol assays on COBAS chemistry systems.
Matrix (Calibrator)	Human serum	Human serum
Approx. Value (Calibrator)	51.4 mg/dL	2.85 mmol/L (110 mg/dL)
Precision (Level 1 Mean)	Not explicitly stated (predicate data not available for direct comparison)	2.72 mmol/L (105 mg/dL)
Precision (Level 1 Within Run CV)	Not explicitly stated	1.4
Precision (Level 1 Total CV)	Not explicitly stated	1.9
Precision (Level 2 Mean)	Not explicitly stated	5.12 mmol/L (198 mg/dL)
Precision (Level 2 Within Run CV)	Not explicitly stated	1.8
Precision (Level 2 Total CV)	Not explicitly stated	2.1
Linearity	500 mg/dL	14.0 mmol/L (540 mg/dL)
Accuracy (Correlation Coefficient vs. COBAS MIRA)	Not explicitly stated (predicate comparison is to Beta-quantification or Friedewald)	0.964
Accuracy (Linear Regression vs. COBAS MIRA)	Not explicitly stated	y = 0.85x + 0.7 mmol/L

Note: For accuracy, the new device is compared to COBAS MIRA, Beta-quantification, and Friedewald formula. The predicate device's accuracy is provided against Beta-quantification. The document implies that a strong correlation (e.g., r > 0.95) and a linear regression close to y=x would be acceptable for accuracy.

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

The document refers to "clinical and nonclinical studies."

Test Set Sample Size for Accuracy:
- Against COBAS MIRA: n = 276
- Against Beta-quantification: n = 150
- Against Friedewald formula: n = 276
Data Provenance: The document does not explicitly state the country of origin or whether the data was retrospective or prospective.

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

This type of information is not provided in the document. For an in vitro diagnostic device like this, ground truth is typically established through reference methods or established laboratory procedures, not by human experts in the way it would be for an imaging AI.

4. Adjudication Method for the Test Set

This information is not applicable and therefore not provided. Adjudication methods (like 2+1, 3+1) are common in clinical trials involving subjective interpretations (e.g., imaging reads) to resolve discrepancies. For a quantitative diagnostic test like LDL-cholesterol, discrepancies would typically be resolved by retesting, using a definitive reference method, or investigating pre-analytical/analytical errors.

5. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study Was Done, and Effect Size of Human Readers Improvement with AI vs. Without AI Assistance

This information is not applicable and therefore not provided. MRMC studies are relevant for imaging devices or AI tools where human readers are interpreting data, and the AI's role is to assist or augment their performance. The Roche COBAS INTEGRA LDL Direct is a laboratory diagnostic assay, not one that involves human interpretation of "cases" in an MRMC context.

6. If a Standalone Study (Algorithm Only Without Human-in-the-Loop Performance) Was Done

Yes, this is essentially a standalone study. The document describes the performance of the COBAS INTEGRA LDL Direct system itself (the reagent cassette + analyzer) in measuring LDL-cholesterol directly. There isn't a human-in-the-loop component described for the function of this diagnostic device.

7. The Type of Ground Truth Used

The ground truth for the accuracy studies was established by comparing the COBAS INTEGRA LDL Direct results against:

COBAS MIRA: Another automated chemistry analyzer, likely acting as a comparative reference method.
Beta-quantification: A established reference method for lipoprotein analysis, considered highly accurate for LDL-cholesterol.
Friedewald formula: A calculated estimate of LDL-cholesterol based on other lipid measurements (total cholesterol, HDL-cholesterol, triglycerides).

8. The Sample Size for the Training Set

The document does not mention a "training set". This is an in vitro diagnostic device, not an AI/machine learning algorithm in the typical sense that would require a distinct training set for model development. The development process for an IVD involves formulation, optimization, and verification, rather than "training" with a dataset for an algorithm.

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

Since there is no "training set" mentioned or implied for this type of device, this information is not applicable.

Summary

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OCT 1 1998

Image /page/0/Picture/1 description: The image contains the number 982848 at the top. Below the number is a hexagon with the word "Roche" inside. The text and hexagon are black and the background is white.

510(k) Summary

Roche COBAS® INTEGRA LDL Direct and Roche Calibrator LDL Direct

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

The assigned 510(k) number is: K982848

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 6, 1998

Rita Smith Contact: Senior Regulatory Affairs Associate

Phone: (908) 253-7545 (908) 253-7547 Fax:

Branchburg Township 1080 U.S. Highway 202 Somerville, New Jersey 08876-3771

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II. Device Name:

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

Table 1

Product Name	ClassificationName	ProductCode	CFRNumber andRegulatory Class
COBAS INTEGRALDL Direct (LDL-D)	Low Density Lipoprotein testsystem	MRR	862.1475Class I
Roche Calibrator LDL Direct	Calibrator, Secondary	JIT	862.1150Class II

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

The following table identifies the legally marketed devices to which Roche Diagnostic Systems, Inc. claims equivalence.

Table 2

Product Name	Predicate ProductName	DatePredicateCleared	Predicate510(k)Number
COBAS INTEGRALDL Direct (LDL-D)	Roche Reagent for LDL Direct	1/6/93	K924674
Roche Calibrator LDL Direct	Roche Calibrator Serum	6/16/92	K922043

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

Tables 3 demonstrates the results of clinical and nonclinical studies performed using the COBAS INTEGRA LDL Direct Reagent Cassette. The significant performance characteristics relied upon for a determination of substantial equivalence are summarized in this chart. This information concludes that the performance of this device is essentially equivalent to other legally marketed devices of a similar kind.

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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 to gain clearance for the new reagent cassette, COBAS INTEGRA LDL Direct and its associated calibrator, Roche Calibrator LDL Direct.

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

Tables 3 outlines the technological characteristics (methodologies) of the COBAS INTEGRA LDL Direct in comparison to those of legally marketed predicate products.

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COBAS INTEGRA LDL DIRECT

The cassette COBAS INTEGRA LDL Direct (LDL-D) contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA 700 for the quantitative determination of LDLcholesterol direct concentration in serum and plasma. Low density lipoprotein cholesterol measurement, in conjunction with other lipid determinations, has been shown to be useful in assessing the risk of coronary heart disease.

ROCHE CALIBRATOR LDL DIRECT

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Table 3

COBAS INTEGRA LDL DirectandRoche Calibrator LDL Direct		Roche Reagents for LDL Direct(K924674)andRoche Calibrator Serum (K922043)
Intended Use:
Reagent	for the quantitative determination of LDL-cholesterol direct concentration in serum andplasma	intended for use in direct, quantitativedetermination of low-density lipoprotein(LDL) cholesterol in serum or plasma
Calibrator	intended for use as calibrator in quantitativeLow Density Lipoprotein cholesterol assays onCOBAS chemistry systems	calibrator intended for use on COBASchemistry instruments with Roche clinicalchemistry reagents
Reagents	Enzymes and detergent (liquid)Coupler and detergent (liquid)	a suspension of polystyrene beadscoated with goat polyclonal antibodiesto human apolipoproteins in buffer with0.1% sodium azide.controls, 2 levelscholesterol separation tubes
Principle	HDL, VLDL and chylomicrons are specificallyhydrolyzed by a detergent. Through a series ofchemical reactions only a colorless product isproduced from these particles. During this firststep, LDL particles remain intact and a seconddetergent with a coupler is added to releasecholesterol in the LDL particles. Thischolesterol then undergoes an enzymaticreaction in the presence of coupler to producecolor.	Affinity purified goat polyclonal antisera tospecific human apolipoproteins facilitatesthe removal of HDL and VLDL in thespecimen. After centrifugation, LDLremains in the filtrate solution.
Calibrator
Matrix:	human serum	human serum
Approx. Value:	2.85 mmol/L (110 mg/dL)	51.4 mg/dL
Performance Characteristics:
Precision:	Level 1	Level 2
Mean	2.72 mmol/L(105 mg/dL)	5.12 mmol/L(198 mg/dL)
Within Run CV	1.4	1.8
Total CV	1.9	2.1
Linearity	14.0 mmol/L (540 mg/dL)	500 mg/dL
Accuracy:	COBASMIRA	Beta-quant-ification	Friedewaldformula	Beta-quantification
Sample size (n)	276	150	276	74
Corr. Coefficient (r)	0.964	0.954	0.963	0.96
Linear regression	y = 0.85x +0.7 mmol/L	y= 0.95x +0.1 mmol/L	y = 0.97x +0.5 mmol/L	y = 1.05x + 4.8 mg/dL

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Image /page/6/Picture/2 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a circular seal with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" around the perimeter. Inside the circle is a stylized symbol of three human profiles facing right, stacked on top of each other.

OCT 1 1998 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 : K982848 COBAS® INTEGRA LDL Direct Reagent Cassette Roche® Calibrator LDL Direct Regulatory Class: I & II Product Code: MRR, JIT August 11, 1998 Dated: Received: August 12, 1998

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. A substantially equivalent determination assumes compliance with and e the Current Good Manufacturing Practice requirements, as set forth in the Quality System Regulation (QS) for Medical Devices: General regulation (21 CFR Part 820) and that, 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 . .... In addition, FDA may publish further announcements action. 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

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 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 Radiological Health

Enclosure

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Page 1 of 1

1982848 510(k) Number (if known)

Device Name:

COBAS INTEGRA LDL Direct Reagent Cassette (LDL-D), Art. No. 07 6674 7

Roche Calibrator LDL Direct , Art. No. 07 6675 5

Indications for Use:

(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)

(Division Sign-Off)
Division of Clinical Laboratory Devices
510(k) Number 982848

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

Regulation Number and Section

§ 862.1475 Lipoprotein test system.

(a)
Identification. A lipoprotein test system is a device intended to measure lipoprotein in serum and plasma. Lipoprotein measurements are used in the diagnosis and treatment of lipid disorders (such as diabetes mellitus), atherosclerosis, and various liver and renal diseases.(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.