(345 days)
For in vitro diagnostic use in the quantitative determination of total billrubin in human serum and plasma on the ADVIA Chemistry Systems. Such measurements are used in the diagnosis and treatment of hemolytic, biliary, and liver disorders, including hepatitis and cirrhosis.
The ADVIA Chemistry Total Bilirubin_2 is used for the in vitro quantitative determination of total bilirubin in human serum and plasma on the ADVIA® Chemistry Systems. The proposed labeling indicates the ADVIA Chemistry Total Bilirubin_2 reagents can be used on the ADVIA Chemistry Systems 1650, 1800, 2400, and 1200. The Total Bilirubin_2 assay is based on a chemical oxidation method, utilizing vanadate as the oxidizing agent. Total bilirubin (conjugated and unconjugated) is oxidized by vanadate at about pH 2.9 to produce biliverdin. In the presence of detergent and vanadate, both conjugated and unconjugated bilirubin are oxidized. This oxidation causes a decrease in optical density of the yellow color, which is specific to bilirubin. The decrease in optical density at 451/545 nm is proportional to the total bilirubin concentration in the sample. The concentration is measured as an endpoint reaction.
Here's an analysis of the provided 510(k) summary regarding the ADVIA® Chemistry Total Bilirubin_2 device, focusing on acceptance criteria and supporting studies:
1. Table of Acceptance Criteria and Reported Device Performance
The 510(k) summary does not explicitly state formal "acceptance criteria" in terms of pre-defined thresholds for performance metrics. Instead, it demonstrates "substantial equivalence" to a predicate device (ADVIA® IMS Total Bilirubin) by comparing performance characteristics. The implied acceptance criterion is that the new device's performance is comparable to or better than the predicate device's performance, and within generally accepted analytical standards for clinical laboratory assays.
| Performance Characteristic | Stated Acceptance Criteria (Implied) | Reported Device Performance (ADVIA Chemistry Total Bilirubin_2) | Predicate Device Performance (ADVIA IMS Total Bilirubin) |
|---|---|---|---|
| Imprecision (Total CV) | Comparable to predicate and generally acceptable for clinical assays. | ADVIA 1650/1800: 1.1% - 3.2% | ADVIA IMS: 2.1% - 8.2% |
| ADVIA 2400: 1.0% - 4.7% | (comparable levels) | ||
| ADVIA 1200: 1.3% - 3.6% | |||
| Correlation (Method Comparison) | Regression statistics (slope, intercept, r) to indicate strong linear correlation with predicate/comparison methods, and low Syx. | ADVIA 1650 vs ADVIA IMS: $y=0.925x + 0.12$, Syx=0.42, r=0.998 | N/A (predicate itself) |
| ADVIA 2400 vs ADVIA 1650: $y=0.999x - 0.02$, Syx=0.19, r=1.000 | |||
| ADVIA 1200 vs ADVIA 1650: $y=1.036x - 0.05$, Syx=0.21, r=1.000 | |||
| Interfering Substances | Minimal clinically significant interference (e.g., within a predefined percentage change or acceptable clinical limits). | Ascorbic acid (50 mg/dL): -1.16% to 0.00% change | Not explicitly stated in the summary, implied acceptable. |
| Hemoglobin (1000 mg/dL): -2.1% to 7.0% change | |||
| Lipids (Triglycerides, 750 mg/dL): 6.8% to 8.6% change | |||
| Analytical Range | Comparable to predicate and suitable for clinical diagnosis. | ADVIA 1650/1800: 0.1 - 35.0 mg/dL | Not explicitly stated in summary, implied covered. |
| ADVIA 2400: 0.1 - 35.0 mg/dL | |||
| ADVIA 1200: 0.1 - 35.0 mg/dL |
2. Sample Size and Data Provenance for the Test Set
-
Imprecision Study (Test Set):
- The sample size for the imprecision study is not explicitly stated as a single "test set" size. Instead, it reports CVs at multiple bilirubin levels. The common practice for imprecision studies involves running samples (controls or patient pools) multiple times over several days. The table shows 3-5 different bilirubin levels tested on each of the four ADVIA Chemistry Systems.
- Data Provenance: Not specified in the summary (e.g., country of origin). The studies appear to be prospective as they were conducted specifically for this 510(k) submission to evaluate the performance of the new device.
-
Correlation (Method Comparison) Study (Test Set):
- Sample Size:
- Serum, ADVIA 1650 vs ADVIA IMS: 118 samples (N=118)
- Serum, ADVIA 2400 vs ADVIA 1650: 119 samples (N=119)
- Serum, ADVIA 1200 vs ADVIA 1650: 119 samples (N=119)
- Data Provenance: Not specified (e.g., country of origin). Appears to be prospective as these studies would have been designed to compare the new device against existing methods.
- Sample Size:
-
Interfering Substances Study (Test Set):
- The sample size for the interfering substances experiment is not explicitly stated. Typically, a small number of samples (e.g., one or two per interference level) are spiked with the interfering substance and tested.
- Data Provenance: Not specified. Appears to be prospective.
-
Analytical Range Study (Test Set):
- The sample size used to establish the analytical range (linearity) is not explicitly stated. These studies typically use a series of diluted/spiked samples to cover the claimed range.
- Data Provenance: Not specified. Appears to be prospective.
3. Number of Experts and Qualifications for Ground Truth
- No external "experts" (e.g., radiologists) were explicitly used to establish ground truth for these analytical performance studies.
- For an in vitro diagnostic (IVD) device like a bilirubin assay, "ground truth" is typically established by:
- Reference Methods: The "AACC Reference Method" is stated as the standardization method for both the new device and the predicate. This is a highly standardized and validated analytical method.
- Predicate Device: The predicate device itself (ADVIA IMS Total Bilirubin) serves as a gold standard or "truth" for comparison in the method correlation studies. Its results are assumed to be accurate.
- Known Concentrations: For studies like imprecision, interfering substances, and analytical range, commercial controls or spiked samples with known, verified concentrations are used.
4. Adjudication Method for the Test Set
- Not applicable. This product is an in vitro diagnostic (IVD) lab assay. Adjudication, particularly multi-reader methods (e.g., 2+1, 3+1), is typically relevant for interpretative devices like imaging diagnostics where human readers make a judgment, and their discrepancies need to be resolved. For a quantitative chemical assay, the measurement itself is the output, and any discrepancies would be resolved through re-testing, calibration checks, or investigation into analytical errors, rather than expert adjudication of a qualitative result.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
- No MRMC study was done. This type of study is for interpretative devices involving human perception (e.g., radiology AI). The ADVIA Chemistry Total Bilirubin_2 is a quantitative analytical device that produces numerical results, not images or qualitative interpretations that a human reads. Therefore, the concept of "how much human readers improve with AI vs without AI assistance" does not apply here.
6. Standalone (Algorithm Only) Performance Study
- Yes, this entire submission is a standalone performance study in the context of an IVD. The device is the algorithm/reagent system that performs the measurement without human interpretation of the primary data (other than reading the final numerical output). The performance data (imprecision, correlation, etc.) reflects the algorithm/reagent system's capabilities without human-in-the-loop directly influencing the outputted bilirubin concentration. Human interaction is limited to operating the instrument, loading samples, and interpreting the final numerical result in a clinical context.
7. Type of Ground Truth Used
- Reference Methods and Predicate Device:
- For standardization, the AACC Reference Method is explicitly stated as the ground truth.
- For method comparison/correlation, the ADVIA IMS Total Bilirubin assay (predicate device) served as the comparison method, implicitly representing the accepted "truth" for validating the new device's accuracy.
- For imprecision, analytical range, and interfering substances, the ground truth would have been established using calibrated materials, known-concentration controls, and carefully prepared spiked samples.
8. Sample Size for the Training Set
- Not applicable / Not explicitly stated for algorithm training. This device is a traditional chemical assay, not an AI/ML-based device that undergoes a distinct "training" phase with a large dataset in the sense of machine learning algorithms. The development of such an assay involves chemical formulation, optimization, and extensive analytical validation in a laboratory setting, but not typically "training data" as would be used for neural networks or similar AI.
9. How the Ground Truth for the Training Set Was Established
- Not applicable. As explained above, this is not an AI/ML device with a training set in the conventional sense. The "ground truth" for the device's development and optimization would have been established through standard chemical and laboratory practices, utilizing reference methods, standards, and control materials to ensure the reagents and measurement principles were accurate and robust.
{0}------------------------------------------------
510(k) Summary
DEC 0 7 2007
| Submitter information Contact person: | Philip LiuManager, Regulatory Affairs & Compliance |
|---|---|
| Address: | Siemens Medical Solutions Diagnostics(formerly Bayer HealthCare, LLC, Diagnostics Division)511 Benedict AvenueTarrytown, NY 10591 |
| Phone: | 914-524-2443914-524-2500 (fax) |
| Date summary prepared: | November 30, 2007 |
| Device Trade or Proprietary Name: | ADVIA® Chemistry Total Bilirubin_2 |
| Device Common/Usual Name or Classification Name: | Total Bilirubin Reagent/Test System |
| Classification Number/Class: | JFM/Class II |
This 510(k) summary of safety and effectiveness is being submitted in accordance with the requirements of 21 CFR 807.92.
The assigned 510(k) number is: K063845
Predicate Devices:
| Predicate Device | |
|---|---|
| Device Name | ADVIA® IMS |
| Common name | Total Bilirubin |
| 510(k) Number | K992399 |
| Manufacturer | Bayer HealthCare LLC |
Device Description:
The ADVIA Chemistry Total Bilirubin_2 is used for the in vitro quantitative determination of total bilirubin in human serum and plasma on the ADVIA® Chemistry Systems. The proposed labeling indicates the ADVIA Chemistry Total Bilirubin_2 reagents can be used on the ADVIA Chemistry Systems 1650, 1800, 2400, and 1200.
{1}------------------------------------------------
The Total Bilirubin_2 assay is based on a chemical oxidation method, utilizing vanadate r no Toxidizing agent. Total bilirubin (conjugated and unconjugated) is oxidized by vanadate at about pH 2.9 to produce biliverdin. In the presence of detergent and vanadate, both conjugated and unconjugated bilirubin are oxidized. This oxidation vanadato, both conjudical and the optical density of the yellow color, which is specific to roudon badded a accease in optical density at 451/545 nm is proportional to the total bilirubin concentration in the sample. The concentration is measured as an endpoint reaction.
Statement of Intended Use:
The ADVIA Chemistry Total Bilirubin_2 assay is for in vitro diagnostic use in the THE ADVIA Onemination of total bilirubin in human serum and plasma on the ADVIA® Chemistry Systems. Such measurements are used in the diagnosis and treatment of hemolytic, biliary, and liver disorders, including hepatitis and cirrhosis.
Comparison to the Predicate Device:
Similarities
| ADVIA Chemistry TotalBilirubin_2 | ADVIA IMS(predicate device) | |
|---|---|---|
| Intended Use | For the quantitativedetermination of total bilirubin | For the quantitativedetermination of total bilirubin |
| Specimen Type | Human serum or plasma(lithium heparin) | Human serum or plasma(lithium heparin) |
| Reaction Type | Colorimetric endpoint | Colorimetric endpoint |
| Calibration | Single point | Single point |
| Expected Values* | 0.2 – 1.2 mg/dL | 0.2 - 1.2 mg/dL |
- Tietz NW, Clinical Guide to Laboratory Tests. 3th ed. Philadelphia, PA: WB Saunders Company, 1995:88-91
Differences
| ADVIA Chemistry TotalBilirubin_2 | ADVI IMS(predicate device) | |
|---|---|---|
| Principle | Vanadate oxidation | Diazotized sulfanilic acid withblank |
| Reagents | Two liquid reagents containedin system specific packaging | One lyophilized reagent,diluent, and one liquid reagentcontained in system specificpackaging |
| Standardization | AACC Reference Method | AACC Reference Method |
Siemens Medical Solutions Diagnostics (formerly Bayer HealthCare, LLC) ADVIA Chemistry Total Bilirubin 2 Premarket Notification 510(k) Attachment #1- Revised 510(k) Summary November 30, 2007
{2}------------------------------------------------
Performance:
Substantial equivalence was demonstrated by testing several performance characteristics including imprecision, method comparison, interfering substances, serum/plasma equivalency, and analytical range. The following tables summarize the precision (total), interfering substances, analytical range, and method comparison results.
All of the evaluation studies gave acceptable results compared to the predicate device. These studies support that the ADVIA Chemistry Total Bilirubin_2 assay is substantially equivalent to the ADVIA IMS Total Bilirubin assay that is currently marketed.
Imprecision (Serum)
| ADVIA Chemistry1650/1800 | ADVIA Chemistry2400 | ADVIA Chemistry1200 | ADVIA IMS | ||||
|---|---|---|---|---|---|---|---|
| Level(mg/dL) | Total CV(%) | Level(mg/dL) | Total CV(%) | Level(mg/dL) | Total CV(%) | Level(mg/dL) | Total CV(%) |
| 1.0 | 2.0 | 1.0 | 4.7 | 1.1 | 3.6 | 0.8 | 8.2 |
| 7.1 | 2.6 | 7.2 | 2.3 | 7.6 | 1.3 | 6.7 | 2.1 |
| 15.4 | 3.2 | 15.5 | 1.6 | 14.7 | 1.4 | 16.7 | 2.4 |
| 22.1 | 1.2 | 21.8 | 1.0 | 22.1 | 1.4 | -- | -- |
| 27.5 | 1.1 | 27.1 | 1.5 | 27.6 | 1.7 | -- | -- |
Correlation (y = ADVIA Chemistry Total Bilirubin_2, x = comparison system)
| Specimen type,System (y) | ComparisonSystem (x) | N | RegressionEquation | Syx(mg/dL) | r | Sample Range(mg/dL) |
|---|---|---|---|---|---|---|
| Serum, ADVIA 1650 | ADVIA IMS | 118 | $y= 0.925x + 0.12$ | 0.42 | 0.998 | 0.2 - 26.8 |
| Serum, ADVIA 2400 | ADVIA 1650 | 119 | $y= 0.999x - 0.02$ | 0.19 | 1.000 | 0.3 - 24.4 |
| Serum, ADVIA 1200 | ADVIA 1650 | 119 | $y= 1.036x - 0.05$ | 0.21 | 1.000 | 0.3 - 24.4 |
Interfering Substances
| InterferingSubstance | InterferingSubstanceConc.(mg/dL) | Total Bilirubin Conc. (mg/dL) | Effect(% change) | ||||
|---|---|---|---|---|---|---|---|
| ADVIA1650/1800 | ADVIA2400 | ADVIA1200 | ADVIA1650/1800 | ADVIA2400 | ADVIA1200 | ||
| Ascorbic acid | 50 | 1.30 | 1.29 | 1.33 | -1.16 | -4.65 | 0.00 |
| Hemoglobin | 1000 | 1.18 | 1.22 | 1.36 | 6.80 | -2.1 | 7.0 |
| Lipids (Triglycerides) | 750 | 1.11 | 1.11 | 1.12 | 8.6 | 6.8 | 7.2 |
Siemens Medical Solutions Diagnostics (formerly Bayer HealthCare, LLC) ADVIA Chemistry Total Bilirubin_2 Premarket Notification 510(k) Attachment #1- Revised 510(k) Summary November 30, 2007
{3}------------------------------------------------
Analytical Range (Serum/Plasma)
| ADVIA 1650/1800 | 0.1 - 35.0 mg/dL |
|---|---|
| ADVIA 2400 | 0.1 - 35.0 mg/dL |
| ADVIA 1200 | 0.1 - 35.0 mg/dL |
Conclusions:
The ADVIA Chemistry Total Bilirubin_2 assay is substantially equivalent to other products in commercial distribution intended for similar use. Most notably, it is substantially equivalent to the Bayer ADVIA IMS Total Bilirubin method (K992399).
{4}------------------------------------------------
Image /page/4/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo features a stylized eagle with its wings spread, and the words "DEPARTMENT OF HEALTH & HUMAN SERVICES USA" are arranged in a circular pattern around the eagle. The logo is black and white.
Public Health Service
Food and Drug Administration 2098 Gaither Road Rockville MD 20850
DEC 0 7 2007
Baver Healthcare, LLC c/o Dr. Philip Liu Manager, Regulatory Affairs and Compliance 511 Benedict Avenue Tarrytown, NY 10591-5097
Re: K063845 Trade Name: Advia Chemistry Total Bilirubin 2 Regulation Number: 21 CFR 862.1110 Regulation Name: Bilirubin (Total or Direct) Test System. Regulatory Class: Class II Product Code: JFM Dated: November 30, 2007 Received: December 04, 2007
Dear Dr. Liu:
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and 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) that do not require approval of a premarket approval application (PMA). 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 (PMA), it may be subject to such additional controls. Existing major regulations affecting your device can be found in Title 21, Code of Federal Regulations (CFR), Parts 800 to 895. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); and good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820).
{5}------------------------------------------------
Page 2 -
This letter will allow you to begin marketing your device as described in your Section 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 information about the application of labeling requirements to your device, or questions on the promotion and advertising of your device, please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at (240) 276-0490. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807.97). You may obtain other general information on your responsibilities under the Act from the Division of Small Manufacturers, International and Consumer Assistance at its toll-free number (800) 638-2041 or (240) 276-3150 or at its Internet address at http://www.fda.gov/cdrh/industry/support/index.html.
Sincerely yours,
Jean M. Cooper, M.S., D.V.M.
Jéan M. Cooper, M.S., D.V.M. Director Division of Chemistry and Toxicology Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health
Enclosure
{6}------------------------------------------------
Indications for Use
510(k) Number (if known): K063845
Device Name: ADVIA CHEMISTRY TOTAL BILIRUBIN_2
Indications For Use:
For in vitro diagnostic use in the quantitative determination of total billrubin in human serum and plasma on the ADVIA Chemistry Systems. Such measurements are used in the diagnosis and treatment of hemolytic, biliary, and liver disorders, including hepatitis and cirrhosis.
Prescription Use × (Part 21 CFR 801 Subpart D) AND/OR
Over-The-Counter Use (21 CFR 801 Subpart C)
(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF NEEDED)
Concurrence of CDRH, Office of In Vitro Diagnostic Devices (OIVD)
Carol C. Benson
Division Sign-Off
Division Sign-Off
Office of In Vitro Diagnostic Device Postuation and Safety
Page 1 of 1
§ 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.