(53 days)
The ADVIA Centaur CA 15-3 assay is an in vitro diagnostic test for the quantitative serial determination of cancer antigen CA 15-3 in human serum and plasma (EDTA and lithium heparin) using the ADVIA Centaur XP, and ADVIA Centaur XPT systems. When used in conjunction with other clinical and diagnostic procedures, serial testing with the ADVIA Centaur CA 15-3 assay is useful for monitoring the course of disease and therapy in metastatic breast cancer patients, and for detection of recurrence in previously treated Stage II, with greater than two positive lymph nodes, or Stage III breast cancer patients. This assay is not intended for use on any other system.
The ADVIA Centaur CA 15-3 assay reagents come in the following configurations: 5 ReadyPack primary reagent packs containing ADVIA Centaur CA 15-3 Lite Reagent, Solid Phase, and Conjugate Reagent, and ADVIA Centaur CA 15-3 Master Curve card (500 tests); 1 ReadyPack primary reagent pack containing ADVIA Centaur CA 15-3 Lite Reagent, Solid Phase, and Conjugate Reagent, and ADVIA Centaur CA 15-3 Master Curve card (100 tests). The ReadyPack consists of ADVIA Centaur CA 15-3 ReadyPack primary reagent pack; Lite Reagent (monoclonal mouse anti-DF3 antibody labeled with acridinium ester), ADVIA Centaur CA 15-3 ReadyPack primary reagent pack; Solid Phase Reagent (monoclonal mouse capture antibody covalently coupled to paramagnetic particles), and ADVIA Centaur CA 15-3 ReadyPack primary reagent pack: Conjugate Reagent (monoclonal mouse anti-115D8 antibody labeled with a thiocarbamate of fluorescein).
Here's a breakdown of the acceptance criteria and the study that proves the device meets them, based on the provided text:
Device: ADVIA Centaur CA 15-3 assay
1. Table of acceptance criteria and the reported device performance:
| Performance Characteristic | Acceptance Criteria (from context) | Reported Device Performance |
|---|---|---|
| Detection Capability | ||
| Limit of Blank (LoB) | Not explicitly stated, implied to be <= 1.0 U/mL | 1.0 U/mL |
| Limit of Detection (LoD) | Not explicitly stated, implied to be <= 2.0 U/mL | 2.0 U/mL |
| Limit of Quantitation (LoQ) | Within-laboratory CV <= 20% | 3.0 U/mL (at which CV is <= 20%) |
| Precision | Within-laboratory CV for controls/specimens (typically <5-10% for clinical assays) | |
| Serum B (175.54 U/mL) | Not explicitly stated | CV: 3.2% |
| Plasma, EDTA (107.13 U/mL) | Not explicitly stated | CV: 3.6% |
| Plasma, Heparin (34.79 U/mL) | Not explicitly stated | CV: 3.8% |
| Control 1 (25.53 U/mL) | Not explicitly stated | CV: 4.8% |
| Control 2 (59.28 U/mL) | Not explicitly stated | CV: 4.4% |
| Control 3 (115.82 U/mL) | Not explicitly stated | CV: 4.8% |
| Specimen Equivalency | Strong correlation (r > 0.95 or 0.98) and acceptable slope/intercept (close to 1 and 0 respectively) vs. serum | |
| Dipotassium EDTA plasma vs. Serum | Not explicitly stated | Slope: 0.96, Intercept: 0.46 U/mL, r: 1.00 |
| Lithium Heparin plasma vs. Serum | Not explicitly stated | Slope: 1.02, Intercept: -0.72 U/mL, r: 1.00 |
| Interferences | Bias due to interferents within acceptable limits (typically +/- 10%) | |
| Dipotassium EDTA (5.4 mg/mL) @ 15.85 U/mL | Not explicitly stated | Bias: 3.3% |
| Dipotassium EDTA (5.4 mg/mL) @ 107.66 U/mL | Not explicitly stated | Bias: 4.9% |
| Heparin (75 U/mL) @ 9.71 U/mL | Not explicitly stated | Bias: 0.8% |
| Heparin (75 U/mL) @ 106.18 U/mL | Not explicitly stated | Bias: 1.2% |
Note: The document states "The analytical performance data previously reviewed for the ADVIA Centaur CA 15-3 assay continues to apply to this assay." This implies that the change from the predicate device was primarily the addition of plasma sample types, and the acceptance criteria for the original analytical performance characteristics (like assay range, precision within serum, etc.) were already met and considered valid for this modified device. The studies presented here focus on demonstrating equivalence for the new sample types and re-affirming key analytical specifications. The specific numerical acceptance criteria themselves are not explicitly listed but are implied by the successful results of the studies.
2. Sample sized used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective):
- Detection Capability: No specific sample size is provided for LoB, LoD, and LoQ determination. The methodology followed CLSI Document EP17-A2. Data provenance is not specified.
- Precision: 80 results per specimen type (Serum A, Serum B, Plasma EDTA, Plasma Heparin, Control 1, 2, 3). No information on data provenance (country, retrospective/prospective).
- Specimen Equivalency:
- Dipotassium EDTA plasma vs. Serum: 129 samples
- Lithium Heparin plasma vs. Serum: 108 samples
No information on data provenance (country, retrospective/prospective).
- Interferences: No specific sample size is given per substance, but results are provided for Dipotassium EDTA and Heparin at two different analyte concentrations. No information on data provenance.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
This is an in vitro diagnostic test for measuring a tumor marker (CA 15-3). The ground truth for such devices is typically established through reference methods or quantitative chemical analysis, not by human expert interpretation of images or clinical cases. Therefore, the concept of "experts establishing ground truth" in the way it applies to imaging AI or diagnostic algorithms based on interpretation is not relevant here.
4. Adjudication method (e.g. 2+1, 3+1, none) for the test set:
Not applicable. This is an in vitro diagnostic assay, not a device requiring interpretation or adjudication by multiple human readers.
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 an in vitro diagnostic assay, not an AI-powered diagnostic imaging or clinical decision support system that would involve human readers.
6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:
Yes, the studies presented are for the standalone performance of the ADVIA Centaur CA 15-3 assay. While it is intended for use "in conjunction with other clinical and diagnostic procedures" and for use by healthcare professionals, the performance characteristics tested (precision, detection capability, specimen equivalency, interference) represent the analytical performance of the automated assay itself, without human interpretation as part of the core performance measurement.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.):
The ground truth for this type of quantitative assay would inherently be established by the concentration of the analyte (CA 15-3) as measured by a reference method or highly accurate, precisely calibrated laboratory standard. For specimen equivalency, the ground truth is the concentration in serum measured by the same assay, to which the plasma measurements are compared. For interference, it is the known concentration of the analyte without the interferent.
8. The sample size for the training set:
The document describes performance data for the modified device. It states that "The analytical performance data previously reviewed for the ADVIA Centaur CA 15-3 assay continues to apply to this assay." This implies that prior internal validation and possibly external studies for the original device (K012357) served as the "training" or development data. No specific sample size for a training set dedicated to the modified device is provided, as the modifications were largely related to sample types, not a complete re-development of the assay's core principle or algorithm that would necessitate a new, extensive training dataset for an AI model.
9. How the ground truth for the training set was established:
Given this is an in vitro diagnostic assay, the "ground truth" for the training set (or rather, the development and verification phases of the original assay) would have been established through a rigorous process of:
- Reference materials: Using certified reference materials with known concentrations of CA 15-3.
- Primary reference methods: Comparing to established, highly accurate analytical methods.
- Spiking studies: Adding known amounts of CA 15-3 to samples to assess analytical recovery.
- Clinical correlation: While not a "ground truth" in the analytical sense, the selection of the analyte (CA 15-3) and its clinical cut-offs are derived from extensive clinical studies correlating CA 15-3 levels with disease status and progression in breast cancer patients. This would involve a large number of patient samples with confirmed clinical diagnoses, pathology reports, and known treatment outcomes.
The document primarily focuses on the validation studies performed to support the modified device (addition of plasma sample types) rather than the original development or "training" phases, which would have occurred prior to the predicate device's clearance.
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November 22, 2019
Siemens Healthcare Diagnostics, Inc. Anoop Jov Regulatory Affairs Specialist 511 Benedict Avenue Tarrytown, New York 10591
Re: K192777
Trade/Device Name: ADVIA Centaur CA 15-3 assay Regulation Number: 21 CFR 866.6010 Regulation Name: Tumor-Associated Antigen Immunological Test System Regulatory Class: Class II Product Code: MOI Dated: September 27, 2019 Received: September 30, 2019
Dear Anoop Joy:
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. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. 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. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. 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
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requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (OS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely,
Takeesha Taylor-Bell Acting Deputy Division Director Division of Immunology and Hematology Devices OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Ouality Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known) K192777
Device Name ADVIA Centaur CA 15-3 assay
Indications for Use (Describe)
The ADVIA Centaur CA 15-3 assay is an in vitro diagnostic test for the quantitative serial determination of cancer antigen CA 15-3 in human serum and plasma (EDTA and lithium heparin) using the ADVIA Centaur XP, and ADVIA Centaur XPT systems. When used in conjunction with other clinical and diagnostic procedures, serial testing with the ADVIA Centaur CA 15-3 assay is useful for monitoring the course of disease and therapy in metastatic breast cancer patients, and for detection of recurrence in previously treated Stage II, with greater than two positive lymph nodes, or Stage III breast cancer patients. This assay is not intended for use on any other system.
| Type of Use (Select one or both, as applicable) | |
|---|---|
| ☑ Prescription Use (Part 21 CFR 801 Subpart D) | ☐ Over-The-Counter Use (21 CFR 801 Subpart C) |
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510(k) Summary of Safety and Effectiveness
ADVIA Centaur CA 15-3 assay
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.
The assigned 510(k) Number: K192777
. APPLICANT
Siemens Healthcare Diagnostics Inc. 511 Benedict Avenue, Tarrytown, NY 10591 USA
| Contact: | Anoop Joy |
|---|---|
| Regulatory Clinical Affairs Specialist | |
| Phone: | (914) 524-2273 |
| Fax: | (914) 524-2101 |
| E-mail: | anoop.joy@siemens-healthineers.com |
Date Prepared: November 21, 2019
II. Regulatory Information
Name of Device: ADVIA Centaur CA 15-3 Classification: Class II Regulation Section: 21 CFR § 866.6010 Product Code: MOI Panel: Immunology
lll. PREDICATE DEVICE
Name of Device: ADVIA Centaur CA 15-3 assay 510 (k): K012357
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DEVICE DESCRIPTION IV.
The ADVIA Centaur CA 15-3 assay reagents come in the following configurations:
| Contents | Number of Tests |
|---|---|
| 5 ReadyPack primary reagent packs containing ADVIA CentaurCA 15-3 Lite Reagent, Solid Phase, and Conjugate ReagentADVIA Centaur CA 15-3 Master Curve card | 500 |
| 1 ReadyPack primary reagent pack containing ADVIA CentaurCA 15-3 Lite Reagent, Solid Phase, and Conjugate ReagentADVIA Centaur CA 15-3 Master Curve card | 100 |
The ReadyPack consists of the following:
ADVIA Centaur CA 15-3 ReadyPack® primary reagent pack; Lite Reagent
5.0 mL/reagent pack monoclonal mouse anti-DF3 antibody (~ 2.0 µg/mL) labeled with acridinium ester in buffered saline with bovine serum albumin, sodium azide (< 0.1%), and preservatives.
ADVIA Centaur CA 15-3 ReadyPack primary reagent pack; Solid Phase Reagent
25.0 ml /reagent pack monoclonal mouse capture antibody (~30 µg/mL) covalently coupled to paramagnetic particles in buffer with bovine serum albumin, sodium azide (< 0.1%), and preservatives.
ADVIA Centaur CA 15-3 ReadyPack primary reagent pack: Conjugate Reagent
5.0 mL/reagent pack monoclonal mouse anti-115D8 antibody (~12.5 µg/mL) labeled with a thiocarbamate of fluorescein in buffered saline with bovine serum albumin and preservatives
INTENDED USE V.
The ADVIA Centaur® CA 15-3 assay is an in vitro diagnostic test for the quantitative serial determination of cancer antigen CA 15-3 in human serum and plasma (EDTA and lithium heparin) using the ADVIA Centaur®, ADVIA Centaur XP, and ADVIA Centaur XPT systems. When used in conjunction with other clinical and diagnostic procedures, serial testing with the ADVIA Centaur CA 15-3 assay is useful for monitoring the course of disease and therapy in metastatic breast cancer patients, and for detection of recurrence in previously treated Stage II. with greater than two positive Ivmph nodes, or Stage III breast cancer patients. This assav is not intended for use on any other system.
INDICATIONS FOR USE VI.
Same as Intended use
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COMPARISION OF TECHNOLOGICAL CHARACTERISTICS WITH THE VII. PREDICATE DEVICE
The following table provides a comparison between the predicate and candidate device.
| Item | Predicate Device | Candidate Device (Modified Device) |
|---|---|---|
| ADVIA Centaur CA 15-3 | ADVIA Centaur CA 15-3 | |
| Intended Use | The ADVIA Centaur® CA 15-3 assay is an in vitro diagnostic test for the quantitative serial determination of cancer antigen CA 15-3 in human serum using the ADVIA Centaur, ADVIA Centaur XP, and ADVIA Centaur XPT systems. When used in conjunction with other clinical and diagnostic procedures, serial testing with the ADVIA Centaur CA 15-3 assay is useful for monitoring the course of disease and therapy in metastatic breast cancer patients, and for detection of recurrence in previously treated Stage II, with greater than two positive lymph nodes, or Stage III breast cancer patients. This assay is not intended for use on any other system. | The ADVIA Centaur® CA 15-3 assay is an in vitro diagnostic test for the quantitative serial determination of cancer antigen CA 15-3 in human serum and plasma (EDTA and lithium heparin) using the ADVIA Centaur®, ADVIA Centaur XP, and ADVIA Centaur XPT systems. When used in conjunction with other clinical and diagnostic procedures, serial testing with the ADVIA Centaur CA 15-3 assay is useful for monitoring the course of disease and therapy in metastatic breast cancer patients, and for detection of recurrence in previously treated Stage II, with greater than two positive lymph nodes, or Stage III breast cancer patients. This assay is not intended for use on any other system. |
| Measurement | Quantitative | Same |
| Assay Range | 0.5-200 U/mL | 3.0-200 U/mL |
| Assay Principle | Sandwich immunoassay | Same |
| Technology | Direct chemiluminescent | Same |
| Sample Type | Serum | Serum and plasma (EDTA and lithium heparin) |
| Sample Volume | 20 µL | same |
| Reagent Volume | 50 µL of Conjugate Reagent and 250 µL of Solid Phase | same |
| Incubation Time | 20 minutes at 37°C. | same |
| Standardization | traceable to an internal standard manufactured using highly purified material. | Same |
| Calibration | 2-point | Same |
| Calibrators | ADVIA Centaur CA 15-3Calibrator | Same |
| Number ofCalibratorLevels | Two levels | Same |
| Controls | Commercial Controls | Same |
| Number ofControl Levels | 2 | Same |
| DetectionAntibody | monoclonal mouse anti-DF3antibody labeled with acridiniumester | Same |
| CaptureAntibody | monoclonal mouse captureantibody covalently coupled toparamagnetic particles | Same |
Table 1: Substantial Equivalence Comparison
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PERFORMANCE CHARACTERISTICS DATA VIII.
Addition of plasma sample type claim was demonstrated by performing specimen equivalency studies, precision studies and interference studies using EDTA and Heparin. Since the assay principle, design or formulation not changed from original device, the analytical performance data previously reviewed for the ADVIA Centaur CA 15-3 assay continues to apply to this assay.
Detection Capability
Detection capability was determined in accordance with CLSI Document EP17-A2.
| Limit of Blank (LoB) | 1.0 U/mL |
|---|---|
| Limit of Detection (LoD) | 2.0 U/mL |
| Limit of Quantitation (LoQ) | 3.0 U/mL |
The LoB corresponds to the highest measurement likely to be observed for a blank sample with a probability of 95%.
The LoD corresponds to the lowest concentration of cancer antigen CA 15-3 that can be detected with a probability of 95%.
The LoQ corresponds to the lowest amount of cancer antigen CA 15-3 in a sample at which the within laboratory CV is ≤ 20%.
Precision
Precision was determined in accordance with CLSI Document EP05-A3. Samples were assayed in duplicate in 2 runs per day for 20 days. The following results were obtained:
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| Repeatability | Within-Laboratory Precision | |||||
|---|---|---|---|---|---|---|
| Specimen Type | Na | Mean(U/mL) | SDb(U/mL) | CVc (%) | SD(U/mL) | CV (%) |
| Serum A | 80 | 7.80 | 0.24 | N/Ad | 0.39 | N/A |
| Serum B | 80 | 175.54 | 2.32 | 1.3 | 5.62 | 3.2 |
| Plasma, EDTA | 80 | 107.13 | 2.21 | 2.1 | 3.84 | 3.6 |
| Plasma, Heparin | 80 | 34.79 | 0.79 | 2.3 | 1.32 | 3.8 |
| Control 1 | 80 | 25.53 | 0.48 | 1.9 | 1.23 | 4.8 |
| Control 2 | 80 | 59.28 | 1.70 | 2.9 | 2.64 | 4.4 |
| Control 3 | 80 | 115.82 | 2.06 | 1.8 | 5.54 | 4.8 |
a Number of results.
b Standard deviation.
c Coefficient of variation.
d Not applicable.
Specimen Equivalency
Specimen equivalency was determined with the Deming linear regression model in accordance with CLSI Document EP09-A3. The following results were obtained:
| Tube (y) vs. Serum (x) | Na | Sample Interval | Slope | Intercept | rb |
|---|---|---|---|---|---|
| Dipotassium EDTA plasma | 129 | 3.43-199.49 U/mL | 0.96 | 0.46 U/mL | 1.00 |
| Lithium heparin plasma | 108 | 3.13-196.11 U/mL | 1.02 | -0.72 U/mL | 1.00 |
a Number of samples tested.
b Correlation coefficient.
Interferences
Interference testing was performed in accordance with CLSI Document EP07-ed3. The following results were obtained:
| Substance | Substance Test Concentration | Analyte Concentration(U/mL) | Bias (%) |
|---|---|---|---|
| Dipotassium EDTA | 5.4 mg/mL | 15.85 | 3.3 |
| 107.66 | 4.9 | ||
| Heparin | 75 U/mL | 9.71 | 0.8 |
| 106.18 | 1.2 |
X. CONCLUSION
Comparative testing of the modified ADVIA Centaur CA 15-3 assay is substantially equivalent in principle and performance to the Predicate Device - ADVIA Centaur CA 15-3 assay cleared under 510(k) K012357.
Siemens Healthcare Diagnostics Inc. Traditional 510(k): ADVIA Centaur CA 15-3 assay
§ 866.6010 Tumor-associated antigen immunological test system.
(a)
Identification. A tumor-associated antigen immunological test system is a device that consists of reagents used to qualitatively or quantitatively measure, by immunochemical techniques, tumor-associated antigens in serum, plasma, urine, or other body fluids. This device is intended as an aid in monitoring patients for disease progress or response to therapy or for the detection of recurrent or residual disease.(b)
Classification. Class II (special controls). Tumor markers must comply with the following special controls: (1) A guidance document entitled “Guidance Document for the Submission of Tumor Associated Antigen Premarket Notifications (510(k)s) to FDA,” and (2) voluntary assay performance standards issued by the National Committee on Clinical Laboratory Standards.