The cassette Roche COBAS INTEGRA Carbon Dioxide (CO2-S) contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative determination of the carbon dioxide concentration in serum and plasma. Determination of carbon dioxide concentration in blood is most commonly performed as an initial test in the cvaluation of the body's ability to control blood pH by appropriate removal of metabolism byproducts via the lung and kidneys.

The cassette Roche COBAS INTEGRA Glucose HK Liquid contains an in vitro diagnostic reagent system intended for use on the COBAS INTEGRA for the quantitative determination of the glucose concentration in serum, plasma, urine and cerebrospinal fluid (CSF). In addition, an optional glucose "fast application" for serum and plasma is available. Glucose measurements are used in the diagnosis and treatment of carbohydrate metabolism disorders including diabetes mellitus and idiopathic hypoglycemia.

Device Description

The COBAS INTEGRA test applications contained in this submission are 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℃. 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

The provided text describes two devices, COBAS INTEGRA Carbon Dioxide (CO2-S) and COBAS INTEGRA Glucose HK Liquid (GLULF), in a 510(k) submission. Here's an analysis of the acceptance criteria and supporting studies for each:

Device 1: COBAS INTEGRA Carbon Dioxide (CO2-S)

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state "acceptance criteria." However, substantial equivalence is determined by comparing the performance characteristics of the proposed device against a legally marketed predicate device. The values presented for the proposed device imply the performance achieved for each characteristic, and the aim is to demonstrate that these are equivalent to or better than the predicate.

Performance Characteristic	Acceptance Criteria (Predicate)	Reported Device Performance (CO2-S)
Assay Range	0 - 40 mmol/L	0 - 50 mmol/L
Sensitivity	$5.2 \times 10^{-2} \Delta A$ per mmol/L	$1.5 \times 10^{-2} \Delta A$ per mmol/L
Precision:
Level 1 Mean (mmol/L)	18.9	19.5
Level 2 Mean (mmol/L)	33.0	33.8
% CV (within-run)	Level 1: 1.2; Level 2: 1.1	Level 1: 1.1; Level 2: 1.2
% CV (total)	Level 1: 2.5; Level 2: 1.9	Level 1: 3.1; Level 2: 2.5
Accuracy:
Sample size (n)	200	220
Corr. Coefficient (r)	0.997	0.999
Linear Regression	1.04x + 0.4 mmol/L	1.01x - 0.8 mmol/L

Note: The reported sensitivity for the proposed device (1.5 x 10^-2 ΔA per mmol/L) is lower than the predicate (5.2 x 10^-2 ΔA per mmol/L). In immunoassay terms, a lower ΔA indicates lower sensitivity, which could be a point of divergence. However, the FDA's clearance implies that the overall performance was deemed substantially equivalent, often considering the clinical impact and other strong performance metrics like accuracy and precision. The assay range of the proposed device is wider, which is generally an improvement. The precision and accuracy metrics are comparable or slightly better in some aspects for the proposed device.

2. Sample size used for the test set and the data provenance

Sample size for accuracy test set (n): 220
Data provenance: Not explicitly stated (e.g., country of origin, retrospective or prospective). The document uses generic terms like "clinical and nonclinical studies." Given the context of a 510(k) submission to the US FDA, it's highly probable the data was collected under controlled conditions to support regulatory approval, likely in a prospective manner, but this is not explicitly confirmed.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts

Not applicable. This is an in vitro diagnostic device measuring a quantitative analyte. The "ground truth" (or reference values) for comparison are established by a reference method or legally marketed predicate device, not by expert interpretation of images or other qualitative data. Therefore, no experts were used in this manner.

4. Adjudication method for the test set

Not applicable for this type of in vitro diagnostic device. Adjudication methods like 2+1 or 3+1 are typically used for qualitative assessments, often in imaging studies where multiple readers interpret results and discrepancies need resolution. For quantitative measurements, comparisons are made against established reference methods or predicate devices.

5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

Not applicable. This is not an AI/imaging device. It is an in vitro diagnostic reagent system for quantitative determination of a chemical analyte.

6. If a standalone (i.e. algorithm only without human-in-the loop performance) was done

Yes, the performance characteristics provided (assay range, sensitivity, precision, accuracy) represent the standalone performance of the COBAS INTEGRA Carbon Dioxide (CO2-S) reagent on the COBAS INTEGRA Analyzer. This is typical for in vitro diagnostic devices where the analytical performance of the assay itself is validated.

7. The type of ground truth used

The ground truth for the analytical accuracy (correlation and linear regression) is based on comparison against a reference method or a predicate device. The linearity and correlation coefficients indicate how well the proposed device's measurements align with these established methods. The predicate device "COBAS INTEGRA Carbon Dioxide (CO2)" (K954992) serves as the primary comparator.

8. The sample size for the training set

Not provided. For in vitro diagnostic devices like this, there isn't typically a "training set" in the machine learning sense. Method development and optimization (which might be analogous to training) would involve various samples, but the specific number is not disclosed in the 510(k) summary, which focuses on validation/test data.

9. How the ground truth for the training set was established

Not applicable as there is no explicitly defined "training set" with ground truth in the traditional sense for this type of device in the provided document. Method development and optimization would use samples with known CO2 concentrations, but the specific process for establishing these values for internal development is not detailed.

Device 2: COBAS INTEGRA Glucose HK Liquid (GLULF) (fast application)

1. Table of Acceptance Criteria and Reported Device Performance

Similar to CO2-S, the document presents performance characteristics for the proposed GLULF "fast application" in comparison to its predicate (standard application).

Performance Characteristic	Acceptance Criteria (Predicate)	Reported Device Performance (GLULF - fast application)
Assay Range	0 - 40 mmol/L	0 - 30 mmol/L
Sensitivity	$5.4 \times 10^2 \Delta A$ per mmol/L	$5.4 \times 10^2 \Delta A$ per mmol/L
Precision:
Level 1 Mean (mmol/L)	5.3	4.7
Level 2 Mean (mmol/L)	33.2	27.7
% CV (within-run)	Level 1: 1.7; Level 2: 0.72	Level 1: 1.4; Level 2: 0.5
% CV (total)	Level 1: 2.6; Level 2: 1.5	Level 1: 2.4; Level 2: 1.2
Accuracy:
Sample size (n)	220	216
Corr. Coefficient (r)	0.999	0.999
Linear Regression	1.05x - 0.2 mmol/L	0.99x + 0.01 mmol/L

Note: The reported assay range for the "fast application" is narrower (0-30 mmol/L) compared to the standard application (0-40 mmol/L). However, precision for the fast application appears slightly better (lower %CVs), and the sensitivity is identical. The accuracy metrics (correlation coefficient and linear regression) are highly comparable, indicating substantial equivalence in performance for the intended use and specified range.

2. Sample size used for the test set and the data provenance

Sample size for accuracy test set (n): 216
Data provenance: Not explicitly stated (e.g., country of origin, retrospective or prospective). Similar to CO2-S, the data would likely be from controlled studies, presumably prospective, but this is not explicitly confirmed.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts

Not applicable. This is an in vitro diagnostic device measuring a quantitative analyte. The "ground truth" for comparison is established by a reference method or legally marketed predicate device.

4. Adjudication method for the test set

Not applicable for this type of in vitro diagnostic device.

5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

Not applicable. This is not an AI/imaging device.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done

Yes, the performance characteristics provided represent the standalone analytical performance of the COBAS INTEGRA Glucose HK Liquid (GLULF) fast application reagent on the COBAS INTEGRA Analyzer.

7. The type of ground truth used

The ground truth for the analytical accuracy is based on comparison against a reference method (enzymatic reference method with hexokinase) or a predicate device (COBAS INTEGRA Glucose HK Liquid - standard application, K972250).

8. The sample size for the training set

Not provided. Similar to CO2-S, "training set" in the machine learning sense is not applicable or detailed in the document.

9. How the ground truth for the training set was established

Not applicable as there is no explicitly defined "training set" with ground truth in the traditional sense for this type of device in the provided document. Method development and optimization would use samples with known glucose concentrations, but the specific process for establishing these values for internal development is not detailed.

Summary

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K980996

5 1998 JUN

Image /page/0/Picture/2 description: The image shows the Roche logo. The logo consists of the word "Roche" in bold, sans-serif font, enclosed within a hexagon shape. The hexagon is oriented horizontally, with the word "Roche" centered inside it.

510(k) Summary

Roche COBAS® INTEGRA Reagent Cassettes

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:________________________________________________________________________________________________________________________________________________

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 March 16, 1997

Contact: James W. Haynes Regulatory Affairs Associate Phone: (908) 253-7569 (908) 253-7547 Fax:

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Device Name: II.

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

Table 1

Proprietary Name	Classification Name	ProductCode	RegulationNumber
COBAS INTEGRA Carbon Dioxide(CO2-S)	Bicarbonate / carbon dioxidetest system	KHS	862.1160
COBAS INTEGRA Glucose HK Liquid(GLULF)	Glucose test system	CFR	862.1345

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

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

Product Name	Predicate Product Name	K number	Date ofsubstantialequivalence
COBAS INTEGRA Carbon Dioxide(CO2-S)	COBAS INTEGRA Carbon Dioxide(CO2)	K954992	1/25/96
COBAS INTEGRA Glucose HK Liquid(GLULF)	COBAS INTEGRA Glucose HK Liquid(GLUCL)	K972250	8/12/97

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-----------------	--

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

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℃. 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).

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Through this submission, it is the intention of Roche to gain clearance for one additional COBAS Reagent Cassette and one optional application for a previously approved COBAS Reagent These are the COBAS INTEGRA Carbon Dioxide (CO2-S) and the COBAS Cassette, INTEGRA Glucose (GLULF), respectively.

COBAS INTEGRA Carbon Dioxide (CO2-S):

The cassette COBAS INTEGRA Carbon Dioxide (CO2-S) contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative determination of the carbon dioxide concentration in serum and plasma.

COBAS INTEGRA Glucose HK Liquid (GLULF):

The cassette COBAS INTEGRA Glucose HK Liquid contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative determination of the glucose concentration in serum, plasma. urine and cerebrospinal fluid (CSF). In addition, an optional glucose "fast application" for serum and plasma is available.

The intended use, clinical utility and methodology of each reagent cassette are further described in the test specific COBAS INTEGRA Method Manual sheets, contained in the test specific sections of this submission.

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

Tables 3-4 outline the technological characteristics (methodologies) of the COBAS INTEGRA Reagents in comparison to those of legally marketed predicate products.

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

Tables 3-4 demonstrate the results of clinical and nonclinical studies performed using the COBAS INTEGRA Reagent Cassettes. 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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	COBAS INTEGRA CarbonDioxide (CO2-S)(proposed)	COBAS INTEGRA CarbonDioxide (CO2)(cleared)
Intended Use	quantitative determination of thecarbon dioxide concentration inserum and plasma	quantitative determination of thecarbon dioxide concentration inserum and plasma
Methodology	enzymatic methodology withphosphoenolpyruvate carboxylaseand malate dehydrogenase	enzymatic methodology withphosphoenolpyruvate carboxylaseand malate dehydrogenase
Sample type	Serum and Plasma	Serum and Plasma
Calibrator	Roche Ammonia / Ethanol / CO2Calibrator (K952282)	Roche Ammonia / Ethanol / CO2Calibrator
Controls	Roche Ammonia / Ethanol / CO2Control Normal and Abnormal(K942048)	Roche Ammonia / Ethanol / CO2Control Normal and Abnormal
Reagents	Mono reagent in vial B (granulate)	Substrates in vial A (liquid)Enzymes in vial C (liquid)
Performance Characteristics:
Assay range	0 - 50 mmol/L	0 - 40 mmol/L
Sensitivity	$1.5 x 10-2 ΔΑ$ per mmol/L ofcarbon dioxide	$5.2 x 10-2 AA$ per mmol/L ofcarbon dioxide
Precision:	Level 1	Level 2
Mean (mmol/L)	19.5	33.8
	Level 1	Level 2
	18.9	33.0
% CV (within-run)	1.1	1.2
% CV (total)	3.1	2.5
	2.5	1.9
	1.2	1.1
Accuracy:
Sample size (n)	220	200
Corr. Coefficient (r)	0.999	0.997
	1.01x - 0.8 mmol/L	1.04x + 0.4 mmol/L

Table 3 - COBAS INTEGRA Carbon Dioxide (CO2-S)

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: .

	COBAS INTEGRA GlucoseHK Liquid (GLULF)(fast application)(modification)		COBAS INTEGRA GlucoseHK Liquid (GLUL)(standard application)(cleared)
Methodology	Enzymatic reference method withhexokinase		Enzymatic reference method withhexokinase
Sample type	Serum and plasma		Serum, plasma, urine and CSF
Calibrator	Roche Calibrator (human)(K942706)		Roche Calibrator (human)
Controls	Roche Control Serum N and P(human) (K972214)		Roche Control Serum N and P(human)
Reagents	Mono reagent in vial A and B(liquid)		Mono reagent in vial A and B(liquid)
Performance Characteristics:
Assay range	0 - 30 mmol/L		0 - 40 mmol/L
Sensitivity	5.4 x 102 ΔA per mmol/L ofglucose		5.4 x 102 ΔA per mmol/L ofglucose
Precision:Mean (mmol/L)	Level 14.7	Level 227.7	Level 15.3	Level 233.2
% CV (within-run)	1.4	0.5	1.7	0.72
% CV (total)	2.4	1.2	2.6	1.5
Accuracy:Sample size (n)	216		220
Corr. Coefficient (r)	0.999		0.999
Linear regression	0.99x + 0.01 mmol/L		1.05x - 0.2 mmol/L

Table 4 - COBAS INTEGRA Glucose HK Liquid (GLULF)

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Image /page/6/Picture/1 description: The image shows the seal of the Department of Health & Human Services (HHS) of the United States. The seal features a stylized eagle with its wings spread, symbolizing protection and service. The words "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" are arranged in a circular pattern around the eagle.

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

5 1898 JUN

James W. Haynes . Requlatory Affairs Associate Roche Diagnostic Systems 1080 U.S. Highway 202 Somerville, New Jersey 08876-3771

K980996 Re: Roche COBAS® INTEGRA Carbon Dioxide Reagent Cassette and Roche COBAS® INTEGRA Glucose HK Liquid Reagent Regulatory Class: II Product Code: KHS, CFR March 16, 1998 Dated: Received: March 17, 1998

Dear Mr. Haynes:

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 The general controls provisions of the Act 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. ಗ substantially equivalent determination assumes compliance with 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 regulatory 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 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 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 Bitman

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) Number (if known)

Roche COBAS INTEGRA Carbon Dioxide-(CO2-S) Reagent Cassette Device Name:

Roche COBAS INTEGRA Glucosc HK Liquid Reagent Cassette

Indications for Use:

(Division Sign-Off)
Division of Clinical Laboratory Devices
510(k) Number. 980996

(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

§ 862.1160 Bicarbonate/carbon dioxide test system.

(a)
Identification. A bicarbonate/carbon dioxide test system is a device intended to measure bicarbonate/carbon dioxide in plasma, serum, and whole blood. Bicarbonate/carbon dioxide measurements are used in the diagnosis and treatment of numerous potentially serious disorders associated with changes in body acid-base balance.(b)
Classification. Class II.