(50 days)
The CARESIDE™ Total Bilirubin cartridge is intended for in vitro diagnostic use in conjunction with the CARESIDE™ Analyzer to quantitatively measure the total concentration of bilirubin in anti-coagulated whole blood, plasma or serum. The CARESIDE™ Total Bilirubin test aids in the diagnosis and treatment of patients with liver, hemolytic, hematological, and metabolic disorders, including hepatitis and gall bladder blockage.
This product is for in vitro diagnostic use with the CARESIDE™M Analyzer to quantitatively measure total bilirubin concentration in anti-coagulated whole blood, plasma or serum specimens to aid in the diagnosis and treatment of patients with liver, hemolytic, hematological, and metabolic disorders, including hepatitis and gall bladder blockage. It is intended for professional laboratory use: not for point of care use or physician office laboratory use.
CARESIDE™ Total Bilirubin cartridges are used with the CARESIDE™ Analyzer to quantitatively measure the total concentration of bilirubin in anti-coagulated whole blood, plasma or serum specimens. The CARESIDE™ Total Bilirubin cartridge, a single use disposable in vitro diagnostic test cartridge, aids in specimen separation and delivers a measured volume of plasma or serum to a dry film to initiate the measurement of the total concentration of bilirubin. The film cartridge (patent pending) contains all reagents necessary to measure the total concentration of bilirubin.
Each CARESIDE™ Total Bilirubin cartridge consists of a bilirubin-specific multi-layer reagent film mounted in a plastic base with a hinged lid. The user introduces the anticoagulated whole blood, serum, or plasma specimen into the cartridge sample deposition 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 deposition well into the cartridge channels and chambers. As the cartridge continues to spin, the blood cells are separated from the plasma/serum and the cells accumulate in the separation well. Approximately ten microliters of plasma (or serum, as applicable) remain in the metering passage. Excess sample flows into an overflow well.
The plasma (or serum, as applicable) is automatically dispensed onto the multi-layer reagent film. The spreading and reaction layer distributes the sample evenly on the film and dissociates the unconjugated bilirubin from albumin. Conjugated and unconjugated bilirubin reacts with 2,4-dichlorobenzene diazonium salt to form a red azo dye. The color intensity, as measured by the amount of light reflected at 505 nanometers, directly relates to the total concentration of bilirubin in the specimen.
As the cartridge spins, a photodiodes measures reflectance of light emitted from a wavelength-specific light emitting diode (LED) at a fixed time. The analyzer uses the reflectance measurements and the lot-specific standard curve to calculate the total bilirubin concentration.
The provided document describes the CARESIDE™ Total Bilirubin device and its comparison to a predicate device, the Vitros TBIL DT Slides, for the purpose of seeking 510(k) clearance. The information provided focuses on demonstrating substantial equivalence, rather than a detailed clinical study with predefined acceptance criteria and a comprehensive study report to "prove" the device meets them in a formal sense. However, we can extract the comparative performance characteristics that serve as the basis for the equivalence claim.
Based on the information, the acceptance criteria are implicitly defined by the comparative performance against the predicate device, Vitros TBIL DT Slides. The study conducted is a comparative performance study.
Here's an analysis of the provided information:
1. Table of Acceptance Criteria and Reported Device Performance
Since this is a 510(k) submission focusing on substantial equivalence, explicit "acceptance criteria" are not stated in a numerical form that the device must strictly meet. Instead, the performance of the CARESIDE™ Total Bilirubin device is compared directly to the predicate device, the Vitros TBIL DT Slides. The implicit "acceptance" is that the CARESIDE™ device performs as well as or better than the predicate device, as concluded in Section IV.D.
| Performance Characteristic | Acceptance Criteria (Implicit from Predicate Device) | CARESIDE™ Total Bilirubin Performance |
|---|---|---|
| Detection Limit | Not explicitly provided for predicate | 0.2 mg/dL |
| Reportable Range | 0.1 to 20 mg/dL | 0.2 to 24 mg/dL |
| Accuracy (Mean Recovery) | Not provided for predicate | 96% |
| Precision (Total CV) | 1.2 mg/dL, 6% | 1.1 mg/dL, 12% |
| Method Comparison | r = 0.96 (correlation with another method) | CARESIDE™ = 1.04 (Vitros TBIL DT) + 1.0 mg/dL, r = 0.96 |
| Linearity | Not provided for predicate | Yielded results within acceptable limits |
| Interference | Not provided for predicate | No significant interference observed at tested concentration of interferents: Ascorbic Acid (20 mg/dL), Hemoglobin (100 mg/dL), Protein (9 mg/dL) |
| Specimen Types & Anticoagulants | No clinical difference between serum, heparin plasma, or EDTA plasma. Whole blood unsuitable. | No clinically significant difference between anti-coagulated whole blood, serum, sodium heparin plasma, and EDTA plasma. |
| Expected Values (Reference Range) | 0.1-1.4 mg/dL (male) Central 95% interval | 0.2 to 1.3 mg/dL Central 95% interval |
2. Sample Size Used for the Test Set and Data Provenance
The document does not explicitly state the sample sizes for the studies, nor the data provenance (e.g., country of origin, retrospective/prospective) for each specific performance characteristic study (e.g., accuracy, precision, method comparison, interference). The information provided is a summary of the comparative performance.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
This type of information is not applicable and not provided in the document. The "ground truth" for a quantitative diagnostic device like a total bilirubin test is typically established through reference methods (e.g., diazotized sulfanilic acid reaction in the presence of caffeine-benzoate-acetate, as mentioned for the CARESIDE™ device as its reference method) or comparison to a cleared predicate device, not by expert consensus or interpretation of images/cases.
4. Adjudication Method for the Test Set
This is not applicable since the device measures a quantitative analyte and doesn't involve subjective interpretation that would require an adjudication method.
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?
This is not applicable. The CARESIDE™ Total Bilirubin device is an in vitro diagnostic (IVD) device for quantitative measurement of a biochemical analyte. It does not involve human readers interpreting cases, nor does it incorporate artificial intelligence for image analysis or diagnostic assistance.
6. If a Standalone (i.e. algorithm only without human-in-the loop performance) was done
The device itself is a standalone analytical system (CARESIDE™ Analyzer with CARESIDE™ Total Bilirubin cartridges) for quantitative measurement. Its performance characteristics listed are inherently "standalone" in the sense of the analytical measurement. There is no "human-in-the-loop" component for the measurement itself, beyond proper specimen collection, loading, and result interpretation by laboratory professionals.
7. The Type of Ground Truth Used
The ground truth for evaluating the CARESIDE™ Total Bilirubin device's performance is established by:
- Comparison to a legally marketed predicate device: Vitros TBIL DT Slides for the Vitros DT 60 II.
- Comparison to a candidate reference method: The document states that the CARESIDE™ device uses "Diazotized sulfanilic acid reaction in the presence of caffeine-benzoate-acetate (candidate ref. method for serum total bilirubin determination)" as its reference method. This is a common and accepted reference method in clinical chemistry for bilirubin measurement.
8. The Sample Size for the Training Set
The document does not provide information on a "training set" or its sample size. For an IVD device like this, the development typically involves analytical validation studies rather than machine learning model training sets.
9. How the Ground Truth for the Training Set Was Established
As there is no mention of a "training set" in the context of machine learning, this question is not applicable. The analytical performance of the device is assessed against a predicate device and established reference methods.
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CARESIDE, Inc. Page 6
CARESIDE™ Total Bilirubin (K981588) CO Premarket Notification Addendum June 11, 1998
JUN 23 1998
Attachment 3
(Revised 510(k) Summary)
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CARESIDE™ TOTAL BILIRUBIN 510(K) SUMMARY: SAFETY AND EFFECTIVENESS
I. Applicant Information
- A. Applicant Name
- Applicant/Manufacturer Address B.
- C. Telephone Number
- Contact Person D.
- FAX Number E.
- F. e-Mail Address
- G. Date 510(k) Summary prepared
II. Device Information
- 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 @ worldnet.att.net June 11, 1998
CARESIDE™ Total Bilirubin
Total Bilirubin test system Clinical chemistry panel Total Bilirubin test system Regulation Number: 21 CFR 862.1110 Regulatory Class II Classification Number: 75CIG None applicable
- D. Special controls and performance standards
III. Substantial Equivalence Claim
- General equivalency claim A.
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.
Total bilirubin in vitro diagnostic products, in both dry film and other formats, are already on the U.S. market, including total bilirubin products which utilize diphylline to dissociate conjugated bilirubin and diazonium salts to combine with bilirubin to form an azo dye.
B. Specific equivalency claim
This CARESIDE™ Total Bilirubin test is substantially equivalent in principle, intended use, and clinical performance to the currently marketed Vitros slides for the quantitative measurement of total bilirubin on the Vitros DT 60 II.
| Name of Predicate Device: | Johnson and Johnson's (formerly Eastman Kodak, Inc.) Vitros TBIL Slides for Johnson and Johnson's Vitros DT 60 (formerly Eastman Kodak's DT 60 II). |
|---|---|
| Predicate Device 510K number: | K912844/A |
| Product Code: | 75CIG |
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IV. Device Description
CARESIDE™ Total Bilirubin cartridges are used with the CARESIDE™ Analyzer to quantitatively measure the total concentration of bilirubin in anti-coagulated whole blood, plasma or serum specimens. The CARESIDE™ Total Bilirubin cartridge, a single use disposable in vitro diagnostic test cartridge, aids in specimen separation and delivers a measured volume of plasma or serum to a dry film to initiate the measurement of the total concentration of bilirubin. The film cartridge (patent pending) contains all reagents necessary to measure the total concentration of bilirubin.
Explanation of Device Function A.
Each CARESIDE™ Total Bilirubin cartridge consists of a bilirubin-specific multi-layer reagent film mounted in a plastic base with a hinged lid. The user introduces the anticoagulated whole blood, serum, or plasma specimen into the cartridge sample deposition 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 deposition well into the cartridge channels and chambers. As the cartridge continues to spin, the blood cells are separated from the plasma/serum and the cells accumulate in the separation well. Approximately ten microliters of plasma (or serum, as applicable) remain in the metering passage. Excess sample flows into an overflow well.
The plasma (or serum, as applicable) is automatically dispensed onto the multi-layer reagent film. The spreading and reaction layer distributes the sample evenly on the film and dissociates the unconjugated bilirubin from albumin. Conjugated and unconjugated bilirubin reacts with 2,4-dichlorobenzene diazonium salt to form a red azo dye. The color intensity, as measured by the amount of light reflected at 505 nanometers, directly relates to the total concentration of bilirubin in the specimen.
Test Reaction Sequence:
Image /page/2/Figure/9 description: This image shows a reaction scheme. Direct bilirubin and indirect bilirubin react with 2,4-dichlorobenzen diazonium salt in a reaction of diazo. This reaction produces a red azo dye. Dyphilline is also present in the reaction.
As the cartridge spins, a photodiodes measures reflectance of light emitted from a wavelength-specific light emitting diode (LED) at a fixed time. The analyzer uses the reflectance measurements and the lot-specific standard curve to calculate the total 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, also known as indirect, bilirubin which circulates non-covalently bound to albumin, (2) direct or conjugated bilirubin that is covalently bound to glucuronic acid, and (3) covalently protein bonded bilirubin. Conjugated bilirubin, excreted into the bile by the liver, gives the 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 may be 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. Only when the total bilirubin levels are elevated is it indicated to determine the direct bilirubin level in order to discriminate between the
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relative levels of conjugated and unconjugated bilirubin levels above 2.5 mg/dL are associated with jaundice.
v. Intended Use
- A. Intended Use
The CARESIDE™ Total Bilirubin cartridge is intended for in vitro diagnostic use in conjunction with the CARESIDE™ Analyzer to quantitatively measure the total concentration of bilirubin in anti-coagulated whole blood, plasma or serum. The CARESIDE™ Total Bilirubin test aids in the diagnosis and treatment of patients with liver, hemolytic, hematological, and metabolic disorders, including hepatitis and gall bladder blockage.
Indications for Use B.
This product is for in vitro diagnostic use with the CARESIDE™M Analyzer to quantitatively measure total bilirubin concentration in anti-coagulated whole blood, plasma or serum specimens to aid in the diagnosis and treatment of patients with liver, hemolytic, hematological, and metabolic disorders, including hepatitis and gall bladder blockage. It is intended for professional laboratory use: not for point of care use or physician office laboratory use.
VI. Technological Characteristics
- A. Similarities
| CARESIDE™ Total Bilirubin | Vitros TBIL DT Slides | |
|---|---|---|
| Intended Use | Primarily to aid in the diagnosis andtreatment of patients with liver,hemolytic, hematological andmetabolic disorders. | Same |
| Indications | For in vitro diagnostic use.For professional laboratory use: notfor point of care or physician officelaboratory use. | For in vitro diagnostic use |
| Measurement | Quantitative | Same |
| Method Principle | Dry film based diazo reaction. | Same |
| Specimen dilution | Not required | Same |
| Materials | Dyphilline2,4-dichlorobenzene diazonium salt | Dyphilline[4-(N-carboxymethylsulfamyl)- benzene diazoniumhexafluorophosphate] |
| Detector | Reflectance (505 nm) | Reflectance (555 nm) |
| Test time | Approximately 4 minute warm-up(on-board) plus 5 minute test time. | 15 minutes slide warm-up (off-line)plus 5 minutes test time. |
| Reference Method | Diazotized sulfanilic acid reaction inpresence of caffeine-benzoate-acetate(candidate ref. method for serum totalbilirubin determination) | Unknown |
| Sample Type | Serum, plasma, anti-coagulatedwhole blood (wb) [wb appliedsample, plasma test sample] | serum, plasma |
| Specimen volume | 10 μl test volume(85 ± 15 μl applied volume) | 10 μl |
| Calibration | Calibration information bar-coded oneach cartridge. Calibrationinformation may change with eachlot. | Run Vitros DT II calibratorswhenever a new slide lot is used orwhen necessary. |
| Quality Control | 2 levels | Same |
| Reporting Units | mg/dL or mmol/L | Same |
| Reaction Temp. | 37 °C | Same |
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B. Differences
| CARESIDE™ TotalBilirubin | Vitros TBIL DT Slides | |
|---|---|---|
| Direct bloodspecimen | Yes, whole blood | No, requires separation ofwhole blood prior to sampleapplication |
| Reportable range | 0.2 to 24 mg/dL | 0.1 to 20 mg/dL |
| Accuratepipetting | Not required | Required |
| Reagent pre-warming | Not required | Required |
C. Comparative Performance Characteristics
| CARESIDE™ TotalBilirubin | Vitros TBIL DT Slides | |
|---|---|---|
| Detection limit | 0.2 mg/dL | Not provided |
| Reportable range | 0.2 to 24 mg/dL | 0.1 to 20 mg/dL |
| Accuracy | Mean recovery 96% | Not provided |
| Precision | Total CV, 1.1 mg/dL, 12% | Total CV, 1.2 mg/dL, 6% |
| Method comparison | CARESIDE™ = 1.04 (Vitros TBIL DT) + 1.0 mg/dL, | r = 0.96 |
| Linearity | Linearity by mixing and bydilution yielded results withinacceptable limits | Not provided |
| Interference | No significant interferenceobserved at testedconcentration of interferent:Ascorbic Acid, 20 mg/dLHemoglobin, 100 mg/dLProtein, 9 mg/dL | Not provided |
| Specimen Types& Anticoagulants | No clinically significantdifference between anti-coagulated whole blood,serum, sodium heparinplasma, and EDTA plasma. | No clinically significantdifference between serum,heparin plasma, or EDTAplasma. Whole blood isunsuitable. |
| Expected Values | 0.2 to 1.3 mg/dLCentral 95% interval | 0.1-1.4 mg/dL (male)Central 95% interval |
D. Conclusion
The nonclinical and clinical data provided demonstrate that the CARESIDE™ Total 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/5/Picture/1 description: The image shows the logo for the Department of Health & Human Services - USA. The logo is circular and contains the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" around the perimeter. In the center of the logo is an abstract symbol that resembles a stylized caduceus or a representation of human figures.
Food and Drug Administration 2098 Gaither Road Rockville MD 20850
JUN 23 1998
Kenneth B. Asarch, Ph.D. VP Quality Systems and Regulatory Affairs Exigent Diagnostics Inc. 6100 Bristol Parkway Culver City, California 90230
K981588 Re : CareSide™ Total Bilirubin Regulatory Class: II CIG Product Code: Dated: April 30, 1998 Received: May 4, 1998
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 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. A substantially equivalent determination assumes compliance with the Current Good Manufacturing Practice requirements, as set forth in the Quality System Requlation (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 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 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 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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CARESIDE, Inc. Page 5
INDICATIONS FOR USE VI.
510(k) Number: K981588
CARESIDE™ Total Bilirbuin Device Name:
with the diagnostic use for in vitro product is Indications for use: This CARESIDE™ Analyzer to quantitatively measure total bilirubin concentration in anti-coagulated whole blood, plasma or serum specimens to aid in the diagnosis and treatment of patients with liver, hemolytic, hematological, and metabolic disorders, including hepatitis and gall bladder blockage. It is intended for professional laboratory use: not for point of care use or physician office laboratory use.
Division Sign-Off)
Vivision of Clinical Laboratory Devices
(k) Number K981588
(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)
OR
Over-The-Counter Use _ (Optional Format 1-2-96)
§ 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.