For in vitro diagnostic use with the CARESIDE Analyzer™ to measure direct bilirubin from whole blood, serum or plasma specimens to aid in the diagnosis and treatment of patients with hepatic, hemolytic hematologic, and metabolic diseases, including hepatitis and gall bladder blockage.

Device Description

CARESIDE™ Direct Bilirubin cartridges are used with the CARESIDE Analyzer™ to measure direct bilirubin in whole blood, plasma or serum specimens. The CARESIDE™ Direct Bilirubin cartridge, a single use disposable in vitro diagnostic test cartridge, delivers a measured volume of plasma or serum to a dry film to initiate the measurement of direct bilirubin. The film cartidge (patent pending) contains all reagents necessary to measure direct bilirubin. Each CARESIDE™ Direct Bilirubin cartridge consists of a direct bilirubin-specific multi-layer reagent film mounted in a plastic base with a hinged lid. The user introduces the specimen into the cartridge Sample Well, closes the lid and inserts the cartridge into the CARESIDE Analyzer™. Once loaded, the CARESIDE Analyzer™ scans the cartridge barcode, brings the cartridge and the contained specimen to 37℃, and spins the cartridge to move the sample from the Sample Well into the cartridge channels and chambers. 8.5 microliters of sample remains in the metering passage. Any excess sample flows into an overflow well. The 8.5 microliters of sample is automatically dispensed onto the multi-layer reagent film. The spreading layer distributes the specimen uniformly before it passes through to the absorption layer. The color intensity of the resulting bluish dye, as measured by the amount of reflected light at 570 nanometers, directly relates to the direct bilirubin concentration of the specimen.

AI/ML Overview

Here's a breakdown of the acceptance criteria and the study details for the CARESIDE™ Direct Bilirubin device, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implied through the comparison with the predicate device and the stated performance characteristics.

Acceptance Criterion	Predicate Device Performance (Trace Direct Bilirubin)	CARESIDE™ Direct Bilirubin Performance
Intended Use	To aid in the diagnosis and treatment of patients with hepatic, hemolytic hematological, and metabolic disease, including hepatitis and gall bladder blockage.	Same (Substantially Equivalent)
Indications	For in vitro diagnostic use	For in vitro diagnostic use, For point of care use
Measurement	Quantitative	Quantitative (Substantially Equivalent)
Method Principle	Acid diazo method	Dry film, diazo method
Materials	Sulphanilic acid, sodium nitrite	Sulfanilic acid, sodium nitrite (Substantially Equivalent)
Detection Limit	Depends on instrumentation	0.2 mg/dL
Reportable Range	Up to 20 mg/dL	0.1 to 16 mg/dL
Accuracy	Not provided	Mean recovery 97%
Precision	Total CV, 1.2 mg/dL, 8.7%	Total CV, 2.2 mg/dL, 3.1%
Linearity	Linear up to 20 mg/dL	Linear up to 16 mg/dL
Interference	No reported interference	No significant interference observed at tested concentrations (Ascorbic Acid, Hemoglobin, Total Protein, Triglycerides)
Test time	10 minutes	Approx. 4 minute warm-up + 5 minute test time
Sample Type	Serum	Anti-coagulated whole blood, plasma, or serum plasma.
Specimen volume	10 µl	8.5 µl test volume (90 ± 10 µl applied volume)

Notes on Acceptance Criteria:

The document doesn't explicitly state "acceptance criteria" but rather presents a comparative performance table against a legally marketed predicate device. The underlying assumption is that the CARESIDE™ device must perform as well as or better than the predicate for these parameters to be considered substantially equivalent.
For "Reportable Range," the CARESIDE™ device has a slightly lower upper limit (16 mg/dL vs 20 mg/dL) but this is still within clinically relevant ranges and the overall performance is deemed equivalent.
For "Precision," the CARESIDE™ device demonstrates better precision (3.1% vs 8.7% CV).

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

The document does not explicitly state the sample size used for the test set or the data provenance (e.g., country of origin, retrospective/prospective). It only provides the performance characteristics determined from studies.

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

This information is not provided in the document. The type of device (in vitro diagnostic for bilirubin) suggests that the ground truth would likely be established through a reference method or laboratory standard, rather than expert consensus on interpretation.

4. Adjudication Method for the Test Set

This information is not applicable/provided as the "test set" and "ground truth establishment" would refer to analytical performance studies, not human expert interpretation of images or other subjective data.

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

This information is not applicable/provided. The CARESIDE™ Direct Bilirubin is an in vitro diagnostic device, operating independently to measure a biomarker. It does not involve human readers interpreting output that would be assisted by AI.

6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study

The entire study described is essentially a standalone (algorithm only) performance assessment, as the device directly measures bilirubin concentration without requiring human subjective interpretation during the measurement process. The device's performance characteristics (detection limit, reportable range, accuracy, precision, linearity, interference) are all measures of its standalone analytical capability.

7. Type of Ground Truth Used

The ground truth for this type of in vitro diagnostic device would be established by:

Method Comparison: Comparing the CARESIDE™ device's results against a well-established, legally marketed predicate device (BM/Hitachi 902 Direct Bilirubin) or a recognized reference method. The document states:
- "CARESIDETM = 0.99 (BM/Hitachi 902 Direct Bilirubin) + 0.019 mg/dL, r = 0.997"
Reference Standards/Calibrators: For accuracy, linearity, and detection limits, the performance would be verified against known concentrations of bilirubin in control materials or calibrators.

8. Sample Size for the Training Set

This information is not provided in the document. For an in vitro diagnostic device like this, "training set" doesn't typically apply in the same way it would for an AI/machine learning algorithm that learns from data. Device development involves establishing reagent formulations, reaction kinetics, and optical measurement parameters, which are validated through analytical studies.

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

Since a "training set" in the machine learning sense is not applicable here, the question of how its ground truth was established is also not applicable. The underlying chemical reactions and spectrophotometric measurements are based on established scientific principles. The "calibration information bar-coded on each cartridge" and the "lot-specific standard curve" mentioned in the device description imply that internal reference materials and procedures are used to establish the device's measurement accuracy for each manufacturing lot.

Summary

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CARESIDE, Inc. Page 10

DEC 27 1999

510(K) SUMMARY: CARESIDE™ DIRECT BILIRUBIN V. SAFETY AND EFFECTIVENESS

I. Applicant Information

A. Applicant Name
Applicant/Manufacturer Address B.
C. Telephone Number
D. Contact Person
E. FAX Number
e-Mail Address F.
Date 510(k) Summary prepared G.

Device Information II.

A. Device Name (Trade)
B. Device Name (Classification)
C. Device Classification

CARESIDE, Inc. 6100 Bristol Parkway Culver City, CA 90230 310-338-6767 Kenneth B. Asarch, Pharm.D., Ph.D. 310-338-6789 AsarchK@CARESIDE.com November 5, 1999

CARESIDE™ Direct Bilirubin

Direct bilirubin test system Clinical chemistry panel Bilirubin (total or direct) test system Regulation Number: 21 CFR 862.1110 Regulatory Class 2 Classification Number: 75CIG None applicable

D. Special controls and performance standards

III. Substantial Equivalence Claim

A. General equivalency claim
The ability to monitor analyte-specific biochemical reactions in dry film and other formats is widely recognized and has gained widespread acceptance for use in chemistry assays. As well, the ability to measure direct bilirubin via reaction with sodium nitrite and sulfanilic acid is used in other commercial methods.

Direct billrubin in vitro diagnostic products are already on the U.S. market, including spectrophotometric methods from Trace America, Inc. and from Boehringer Mannheim/Hitachi 902.

B. Specific equivalency claim
This CARESIDE™ Direct Bilirubin test is substantially equivalent in intended use and clinical performance to the currently marketed reagents for the quantitative measurement of direct bilirubin.on the Trace America Direct Bilirubin. Both are based on the diazo method; however, the Trace America method is based upon liquid reagents while the CARESIDE method is based dry reagents.

Name of Predicate Device:	Trace America, Inc. Direct Bilirubin.
Predicate Device 510K number:	K870365
Product Code:	75CIW

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IV. Device Description

A. Explanation of Device Function
Each CARESIDE™ Direct Bilirubin cartridge consists of a direct bilirubin-specific multi-layer reagent film mounted in a plastic base with a hinged lid. The user introduces the specimen into the cartridge Sample Well, closes the lid and inserts the cartridge into the CARESIDE Analyzer™.

Once loaded, the CARESIDE Analyzer™ scans the cartridge barcode, brings the cartridge and the contained specimen to 37℃, and spins the cartridge to move the sample from the Sample Well into the cartridge channels and chambers. 8.5 microliters of sample remains in the metering passage. Any excess sample flows into an overflow well.

The 8.5 microliters of sample is automatically dispensed onto the multi-layer reagent film. The spreading layer distributes the specimen uniformly before it passes through to the absorption layer. The color intensity of the resulting bluish dye, as measured by the amount of reflected light at 570 nanometers, directly relates to the direct bilirubin concentration of the specimen.

Test Reaction Sequence:

Sodium Nitrite + Sulfanilic Acid ---------------------------------------------------------------------------------------------------------------------------------------------

Conjugated Bilirubin + 4-sulfo-benzenediazonium ------------------------------------------------------------------------------------------------------------------------------

As the cartridges spin, a photodiode measures reflectance of light emitted by a wavelength-specific light emitting diode (LED) over a fixed time period. The instrument uses the reflectance measurements and the lot-specific standard curve to calculate direct bilirubin concentration.

B. Test Summary
Bilirubin is formed by the reticuloendothelial system as a by-product of the breakdown of hemoglobin. Bilirubin circulates in multiple forms: (1) unconjugated bilirubin. sometimes referred to as indirect bilirubin, which circulates non-covalently bound to albumin, (2) conjugated or direct bilirubin which is covalently bound to glucuronic acid and circulates freely, and (3) covalently protein bound. Conjugated bilirubin, excreted into the bile by the liver, imparts to bile its major pigmentation.

In healthy individuals, a small amount of bilirubin is found in the serum. An increase in unconjugated bilirubin is more frequently associated with increased destruction of red blood cells (hemolysis); and an increase in conjugated bilirubin is more likely seen in dysfunction of the liver or bile ducts.

Total bilirubin is commonly measured as part of a routine examination. A normal level of total bilirubin rules out any significant impairment of the excretory function of the liver or excessive hemolysis of red blood cells. If the total bilirubin level is elevated, the direct bilirubin level may be measured in order to discriminate between the levels of conjugated and unconjugated bilirubin.

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V. Intended Use

A. Intended Use

The CARESIDE™ Direct Bilirubin cartridge is intended for in vitro diagnostic use in conjunction with the CARESIDE Analyzer™ to quantitatively measure direct bilirubin in whole blood, plasma or serum.

B. Indications for Use
This product is indicated for use in the diagnosis and treatment of patients with hepatic, hemolytic hematological, and metabolic disease, including hepatitis and gall bladder blockage.

VI. Technological Characteristics

A. Similarities

	CARESIDE™ DirectBilirubin	Trace Direct Bilirubin
Intended Use	Primarily to aid in thediagnosis and treatment ofpatients with hepatic,hemolytic hematological, andmetabolic disease, includinghepatitis and gall bladderblockage.	Same
Indications	For in vitro diagnostic use.For point of care use	For in vitro diagnostic use
Measurement	Quantitative	Same
Method Principle	Dry film, diazo method	Acid diazo method
Materials	Sulfanilic acid, sodium nitrite	Sulphanilic acid, sodiumnitrite
Detector	Reflectance photometer (570nm)	Spectrophotometer (550 nm)
Test time	Approx. 4 minute warm-up(on-board) plus approximately5 minute test time.	10 minutes
Sample Type	Anti-coagulated whole blood,plasma, or serum plasma.	Serum
Specimen volume	8.5 µl test volume(90 ± 10 µl applied volume)	10 µl
Calibration	Calibration information bar-coded on each cartridge.Calibration information maychange with each lot.	Calibration required.
Quality Control	2 levels	Same
Reporting Units	mg/dL	Same
Reaction Temp.	37 °C	Constant

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B. Differences

	CARESIDE™ DirectBilirubin	Trace Direct Bilirubin
SpecimenProcessing	Not required	Required
Accuratepipetting	Not required	Required
Reagent pre-warming	Not required	Required

C. Comparative Performance Characteristics

	CARESIDE™ DirectBilirubin	Trace Direct Bilirubin
Detection limit	0.2 mg/dL	Depends on instrumentation
Reportable range	0.1 to 16 mg/dL	to 20 mg/dL
Accuracy	Mean recovery 97%	Not provided
Precision	Total CV, 2.2 mg/dL, 3.1%	Total CV, 1.2 mg/dL, 8.7%
Methodcomparison	CARESIDETM = 0.99 (BM/Hitachi 902 Direct Bilirubin) + 0.019 mg/dL, r = 0.997
Linearity	Linear up to 16 mg/dL.	Linear up to 20 mg/dL
Interference	No significant interference observed at tested concentration of interferent:Ascorbic Acid,......... 10 mg/dLHemoglobin,......... 300 mg/dLTotal Protein,......... 9 g/dLTriglycerides .........3000 mg/dL	No reported interference

D. Conclusion

The nonclinical and clinical data provided demonstrate that the CARESIDE™ Direct Bilirubin product is as safe, effective, and performs as well as or better than the legally marketed predicate device

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Image /page/4/Picture/1 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 image of three wavy lines, which are meant to represent the human form.

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

DEC 2 7 1999

Kenneth B. Asarch, Ph.D. VP Quality Systems and Regulatory Affairs CARESIDE, Inc. 6100 Bristol Parkway Culver City. California 90230

Re: K993771 Trade Name: CARESIDE™ Direct Bilirubin Regulatory Class: II Product Code: CIG Dated: November 5, 1999 Received: November 8, 1999

Dear Dr. Asarch:

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 Ouality System Regulation (OS) 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/dsma/dsmamain.html".

Sincerely yours,

Steven Routman

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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VII. INDICATIONS FOR USE

510(k) Number:

Device Name:

CARESIDE™ Direct Bilirubin

Indications for use:

Sean Cooper

(Division Sign-Off)
Division of Clinical Laboratory Devices
510(k) Number K963771

(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

§ 862.1110 Bilirubin (total or direct) test system.

(a)
Identification. A bilirubin (total or direct) test system is a device intended to measure the levels of bilirubin (total or direct) in plasma or serum. Measurements of the levels of bilirubin, an organic compound formed during the normal and abnormal distruction of red blood cells, if used in the diagnosis and treatment of liver, hemolytic hematological, and metabolic disorders, including hepatitis and gall bladder block.(b)
Classification. Class II.