(76 days)
For in vitro diagnostic use in the quantitative measurement of carcinoembryonic antigen (CEA) in serum and plasma (EDTA and lithium heparin) to aid in the management of cancer patients in whom changing concentrations of CEA are observed using the ADVIA Centaur® XP and ADVIA Centaur® XPT systems.
The assay reagents come in the following configurations:
5 ReadyPack primary reagent packs containing ADVIA Centaur CEA Lite Reagent and Solid Phase ADVIA Centaur CEA Master Curve card (500 Tests)
1 ReadyPack primary reagent pack containing ADVIA Centaur CEA Lite Reagent and Solid Phase ADVIA Centaur CEA Master Curve card (100 Tests)
The ReadyPack consists of the following:
ADVIA Centaur® CEA ReadyPack® primary reagent pack; Lite Reagent: 5.0 mL/reagent pack polyclonal rabbit anti-CEA antibody (~400 ng/mL) labeled with acridinium ester in phosphate buffered saline with protein stabilizers, sodium azide (0.12%), and preservatives
ADVIA Centaur® CEA ReadyPack® primary reagent pack; Solid Phase Reagent: 25.0 mL/reagent pack monoclonal mouse anti-CEA antibody (~120 µg/mL) covalently coupled to paramagnetic particles in phosphate buffered saline with protein stabilizers, sodium azide (0.11%), and preservatives
ADVIA Centaur® CEA ReadyPack® ancillary reagent pack; CEA Diluent: 5.0 mL/reagent pack bicine buffer, gelatin, and BSA with preservatives and sodium azide (0.1%)
ADVIA Centaur® CEA Diluent: 10.0 mL/reagent vial bicine buffer, gelatin, and BSA with preservatives and sodium azide (0.1%)
This document describes the acceptance criteria and the study proving that the ADVIA Centaur® CEA assay meets these criteria, specifically for the addition of plasma (EDTA and lithium heparin) sample claims.
1. Table of Acceptance Criteria and Reported Device Performance
The acceptance criteria are implicitly defined by the reported performance characteristics, especially for specimen equivalence and interference, as the submission focuses on demonstrating equivalence to a previously cleared device.
| Performance Characteristic | Acceptance Criteria (Implicit) | Reported Device Performance (Candidate Device) |
|---|---|---|
| Detection Capability | LoB: 0.50 ng/mL (µg/L) | |
| LoD: 1.00 ng/mL (µg/L) | ||
| LoQ: 2.00 ng/mL (µg/L) | ||
| Accuracy / Method Comparison | Correlation (r) close to 1.00; Slope (ADVIA Centaur CEA vs ACS:180 CEA) close to 1.00; Intercept close to 0.00 | Correlation (r) = 1.00; Slope = 0.97; Intercept = 0.11 ng/mL |
| Specimen Equivalence | Slope (alternate tube types vs serum) = 0.90–1.10 | Dipotassium EDTA plasma vs Serum: Slope = 0.95, Intercept = 0.20 ng/mL (µg/L), r = 1.00 Lithium Heparin plasma vs Serum: Slope = 0.99, Intercept = 0.19 ng/mL (µg/L), r = 1.00 |
| Interferences | Bias due to interferents within acceptable limits (not explicitly stated, but implied by data presentation) | Dipotassium EDTA (9.0 mg/mL): 5.78 ng/mL: -0.3% Bias 55.62 ng/mL: 4.6% Bias Heparin (75 U/mL): 5.83 ng/mL: -0.6% Bias 61.23 ng/mL: 0.9% Bias |
2. Sample Sizes Used for the Test Set and Data Provenance
- Accuracy/Method Comparison: 201 samples (range of 2.00 to 78.93 ng/mL).
- Specimen Equivalence:
- Dipotassium EDTA plasma vs. Serum: 64 samples (range of 2.08-97.10 ng/mL).
- Lithium Heparin plasma vs. Serum: 46 samples (range of 2.11-97.10 ng/mL).
- Interferences: Analyte concentrations were tested at 5-6 ng/mL and 55-61 ng/mL for each interferent (Dipotassium EDTA and Heparin). The exact number of samples per concentration is not specified, but it implies a controlled experimental setup.
The document does not explicitly state the country of origin of the data or whether the studies were retrospective or prospective. However, given the context of a 510(k) submission for a diagnostic device, the data would typically be derived from controlled, prospective studies conducted in a clinical or laboratory setting.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
This information is not applicable. The device measures a quantitative analyte (CEA) in blood samples. The "ground truth" for the test set is established by the reference method (ACS:180 CEA assay for accuracy/method comparison, or the serum sample itself for specimen equivalence) and the intrinsic concentration of the analyte, rather than expert consensus on interpretive tasks.
4. Adjudication Method (for the test set)
Not applicable, as the "ground truth" is based on quantitative measurements by a reference method or direct comparison, not subjective interpretation requiring adjudication.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No MRMC study was done. This type of study is typical for imaging or interpretive AI devices comparing human performance with and without AI assistance. The ADVIA Centaur® CEA assay is an in vitro diagnostic device for quantitative chemical measurement, not an AI-powered interpretive tool.
6. Standalone Performance
Yes, a standalone performance study was done. The document reports the detection capability (LoB, LoD, LoQ), method comparison, specimen equivalence, and interference studies of the ADVIA Centaur® CEA assay as a standalone device. These studies evaluate the assay's characteristics directly without a human-in-the-loop component for interpretation.
7. Type of Ground Truth Used
- Accuracy/Method Comparison: The ground truth was established by comparison to a legally marketed predicate device, the ACS:180 CEA assay. This essentially uses the measurements from an established, accepted method as the reference.
- Specimen Equivalence: The ground truth was the CEA concentration measured in serum samples, against which plasma samples (EDTA and lithium heparin) were compared.
- Detection Capability and Interferences: The ground truth for these studies would be based on known concentrations of CEA and interferents in control samples, which are objectively measurable.
8. Sample Size for the Training Set
No information is provided regarding a separate "training set" for the assay itself. For in vitro diagnostic devices like this, the development process involves extensive calibration, reagent optimization, and verification using various samples, but these are generally considered part of development and verification, not a distinct "training set" in the machine learning sense. The clinical studies described (method comparison, specimen equivalence) serve as external validation of the device's performance.
9. How the Ground Truth for the Training Set was Established
Not applicable, as there is no explicitly defined "training set" in the context of machine learning for this in vitro diagnostic assay. The device's performance is driven by the biochemical interactions of the reagents, not by a learned model from a training set. The calibration and standardization of the assay are traceable to an internal standard manufactured using highly purified material, as stated in the "Standardization" section of Table 1.
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April 13, 2020
Siemens Healthcare Diagnostics Inc. Mey Lyn Vasquez Regulatory Clinical Affairs Specialist 511 Benedict Ave. Tarrytown, NY 10591
Re: K200215
Trade/Device Name: ADVIA Centaur CEA Assay Regulation Number: 21 CFR 866.6010 Regulation Name: Tumor-associated antigen immunological test system Regulatory Class: Class II Product Code: DHX Dated: January 27, 2020 Received: January 28, 2020
Dear Mey Lyn Vasquez:
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 requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part
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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 (QS) 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,
Carolina Kagan Acting Chief Division of Immunology and Hematology Devices OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Quality Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known) K200215
Device Name ADVIA Centaur® CEA assay
Indications for Use (Describe)
For in vitro diagnostic use in the quantitative measurement of carcinoembryomic antigen (CEA) in serum and plasma (EDTA and lithium heparin) to aid in the management of cancer patients in whom changing concentrations of CEA are observed using the ADVIA Centaur® XP and ADVIA Centaur® XPT systems.
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
Introduction: According to the requirements of SMDA 1990 and 21 CFR 807.92, the following information provides sufficient details to understand the basis for determination of substantial equivalence.
The assigned 510(k) Number: k200215_______________
APPLICANT 1.
Siemens Healthcare Diagnostics Inc. 511 Benedict Avenue, Tarrytown, NY 10591 USA
| Contact: | Mey Vasquez |
|---|---|
| Regulatory Clinical Affairs Specialist | |
| Phone: | (914) 524-2458 |
| Fax: | (914) 524-3579 |
| E-mail: | mey.vasquez@siemens-healthineers.com |
Date Prepared: April 09, 2020
Regulatory Information 2.
Assay
| Trade Name | ADVIA Centaur® CEA assay |
|---|---|
| Device | system, test, carcinoembryonic antigen |
| Regulation Description | Tumor-associated antigen immunological test system |
| FDA Classification | Class II |
| Review Panel | Immunology |
| Product Code | DHX |
| Regulation Number | 21 CFR 866.6010 |
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3. PREDICATE DEVICE
Assay
Name of Device: ADVIA Centaur® CEA assay
510 (k): K981478
4. DEVICE DESCRIPTION
The assay reagents come in the following configurations:
| Contents | Numberof Tests |
|---|---|
| 5 ReadyPack primary reagent packs containing ADVIA CentaurCEA Lite Reagent and Solid PhaseADVIA Centaur CEA Master Curve card | 500 |
| 1 ReadyPack primary reagent pack containing ADVIA CentaurCEA Lite Reagent and Solid PhaseADVIA Centaur CEA Master Curve card | 100 |
The ReadyPack consists of the following:
ADVIA Centaur® CEA ReadyPack® primary reagent pack; Lite Reagent
5.0 mL/reagent pack polyclonal rabbit anti-CEA antibody (~400 ng/mL) labeled with acridinium ester in phosphate buffered saline with protein stabilizers, sodium azide (0.12%), and preservatives
ADVIA Centaur® CEA ReadyPack® primary reagent pack; Solid Phase Reagent
25.0 mL/reagent pack monoclonal mouse anti-CEA antibody (~120 µg/mL) covalently coupled to paramagnetic particles in phosphate buffered saline with protein stabilizers, sodium azide (0.11%), and preservatives
ADVIA Centaur® CEA ReadyPack® ancillary reagent pack; CEA Diluent
5.0 mL/reagent pack bicine buffer, gelatin, and BSA with preservatives and sodium azide (0.1%)
ADVIA Centaur® CEA Diluent
10.0 mL/reagent vial bicine buffer, gelatin, and BSA with preservatives and sodium azide (0.1%)
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5. INDICATIONS FOR USE
For in vitro diagnostic use in the quantitative measurement of carcinoembryonic antigen (CEA) in serum and plasma (EDTA and lithium heparin) to aid in the management of cancer patients in whom changing concentrations of CEA are observed using the ADVIA Centaur® XP and ADVIA Centaur® XPT systems.
6. INTENDED USE
Same as Indications for Use
Purpose of the Submission 7.
The purpose of this submission is for the addition of plasma (EDTA and lithium heparin) sample claim for the ADVIA Centaur® CEA assay.
COMPARISION OF TECHNOLOGICAL CHARACTERISTICS WITH THE 8. PREDICATE DEVICE
The following table demonstrates substantial equivalence between the ADVIA Centaur® CEA assay (Candidate Device) that has modified Instructions for Use (Package Inserts) with the addition of the plasma (EDTA and lithium) sample claim and the currently marketed ADVIA Centaur® CEA assay (Predicate Device) that was cleared under 510(k) K981478.
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| Assay | ||||
|---|---|---|---|---|
| ltem | Predicate Device | Candidate Device | ||
| ADVIA Centaur® CEA assay | ADVIA Centaur® CEA assay | |||
| Intended Use | For in vitro diagnostic use in the quantitativemeasurement of carcinoembryonic antigen (CEA)in serum to aid in the management of cancerpatients in whom changing concentrations of CEAare observed using the ADVIA Centaur®, ADVIACentaur XP, and ADVIA Centaur XPT systems. | For in vitro diagnostic use in the quantitative measurementof carcinoembryonic antigen (CEA) in serum and plasma(EDTA and lithium heparin) to aid in the management ofcancer patients in whom changing concentrations of CEAare observed using the ADVIA Centaur® XP and ADVIACentaur® XPT systems. | ||
| Measurement | Quantitative | Same | ||
| Assay Range | 0.5-100 ng/mL (µg/L) | 2.00-100 ng/mL (µg/L) | ||
| Assay Principle | Sandwich immunoassay | Same | ||
| Technology | Direct chemiluminescent | Same | ||
| Sample Type | Serum | Serum or plasma (EDTA orlithium heparin) | ||
| Sample Volume | 50 µL | Same | ||
| ReagentVolume | 50 µL of Lite Reagent and 250 µL of Solid Phase | Same | ||
| IncubationTime | 7.5 minutes at 37°C. | Same | ||
| Standardization | The ADVIA Centaur CEA assay is traceable to aninternal standard manufactured using highlypurified material. Assigned values for calibratorsare traceable to this standardization. | Same | ||
| Calibration | 2-point | Same | ||
| Calibrators | ADVIA Centaur Calibrator D | Same |
Table 1: Substantial Equivalence Comparison
Siemens Healthcare Diagnostics Inc.
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| Assay | ||
|---|---|---|
| Item | Predicate Device | Candidate Device |
| ADVIA Centaur® CEA assay | ADVIA Centaur® CEA assay | |
| Number ofCalibratorLevels | Two levels | Same |
| Controls | Commercial Controls | Same |
| Number ofControl Levels | 2 | Same |
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PERFORMANCE CHARACTERISTICS DATA 9.
Detection Capability
Detection capability was determined in accordance with CLSI Document EP17-A2. 11
| Limit of Blank (LoB) | 0.50 ng/mL (µg/L) |
|---|---|
| Limit of Detection (LoD) | 1.00 ng/mL (µg/L) |
| Limit of Quantitation (LoQ) | 2.00 ng/mL (µg/L) |
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 carcinoembryonic antigen that can be detected with a probability of 95%.
The LoQ corresponds to the lowest amount of carcinoembryonic antigen in a sample at which the within laboratory CV is ≤ 20%.
Precision
Cleared under premarket submission K981478
Method Comparison
Method comparison data and regression analysis was revised in K200215.
Accuracy / Method Comparison
For 201 samples in the range of 2.00 to 78.93 ng/mL (µg/L), the relationship between the ADVIA Centaur CEA assay and the ACS:180 CEA assay is described by the equation:
ADVIA Centaur CEA = 0.97 (ACS:180 CEA) + 0.11 ng/mL Correlation coefficient (r) = 1.00
Specimen Equivalence
Specimen equivalency was determined using 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 | 64 | 2.08-97.10 ng/mL (µg/L) | 0.95 | 0.20 ng/mL (µg/L) | 1.00 |
| Lithium heparin plasma | 46 | 2.11-97.10 ng/mL (µg/L) | 0.99 | 0.19 ng/mL (µg/L) | 1.00 |
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The assay is designed to have a slope of 0.90–1.10 for alternate tube types versus serum.
Agreement of the specimen types may vary depending on the study design and sample population used. Assay results obtained at individual laboratories may vary from the data presented.
Interferences
Interference testing was performed in accordance with CLSI Document EP07-ed3. The following results were obtained:
| Substance | Substance Test Concentration | Analyte Concentrationng/mL (µg/L) | Bias (%) |
|---|---|---|---|
| Dipotassium EDTA | 9.0 mg/mL | 5.78 | -0.3 |
| 55.62 | 4.6 | ||
| Heparin | 75 U/mL | 5.83 | -0.6 |
| 61.23 | 0.9 |
Assay results obtained at individual laboratories may vary from the data presented.
Expected Values
Cleared under premarket submission K981478
X. CONCLUSION
Comparative testing of the ADVIA Centaur® CEA assay is substantially equivalent in principle and performance to the Predicate Device – ADVIA Centaur® CEA assay cleared under 510(k) K981478.
§ 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.