(70 days)
For in vitro diagnostic use in the quantitative, serial determination of CA 125 in human serum and plasma (EDTA and lithium heparin) and to aid in the management of patients with ovarian carcinoma using the ADVIA Centaur® XP and ADVIA Centaur® XPT systems. The test is intended for use as an aid in monitoring patients previously treated for ovarian cancer. Serial testing for CA 125 in the serum and plasma of patients who are clinically free of disease should be used in conjunction with other clinical methods used for the early detection of cancer recurrence. The test is also intended for use as an aid in the management of ovarian cancer patients with metastatic disease by monitoring the progression or regression of disease in response to treatment. It is recommended that the ADVIA Centaur CA 125II assay be used under the order of a physician trained in the management of gynecological cancers. This assay is not intended for screening or diagnosis of ovarian cancer or for use on any other system.
The ADVIA Centaur CA 125II assay is comprised of the following reagents: CA 125II Lite Reagent (monoclonal mouse anti-M11 antibody labeled with acridinium ester and monoclonal mouse anti-OC 125 labeled with fluorescein in phosphate buffer with bovine serum albumin and preservatives) and CA 125II Solid Phase Reagent (monoclonal mouse anti-fluorescein antibody coupled to paramagnetic particles in phosphate buffer with bovine serum albumin and preservatives).
Here's an analysis of the provided text regarding the acceptance criteria and study for the ADVIA Centaur CA 125II assay.
Acceptance Criteria and Device Performance for ADVIA Centaur CA 125II Assay
The Siemens Healthcare Diagnostics Inc. ADVIA Centaur CA 125II Assay is an in vitro diagnostic device for the quantitative, serial determination of CA 125 in human serum and plasma (EDTA and lithium heparin) to aid in the management of patients with ovarian carcinoma. The submission K200199 primarily focused on adding plasma as an accepted sample type.
Table of Acceptance Criteria and Reported Device Performance
| Performance Characteristic | Acceptance Criteria (Implicit for predicate device or general industry standards) | Reported Device Performance (Candidate Device) |
|---|---|---|
| Detection Limits | ||
| Limit of Blank (LoB) | N/A (Previous Analytical Sensitivity: 2 U/mL) | 2.0 U/mL |
| Limit of Detection (LoD) | N/A (Previously Not Applicable) | 3.0 U/mL |
| Limit of Quantitation (LoQ) | N/A (Previously Not Applicable) | 3.0 U/mL (within-laboratory CV ≤ 20%) |
| Measuring Interval | 2 - 600 U/mL (Predicate Device) | 3.0 – 600 U/mL |
| Method Comparison (vs. Bayer Immuno 1® CA 125II assay) | Strong correlation expected (e.g., r > 0.95) | Correlation coefficient (r) = 0.992 |
| Equation (slope ideally close to 1, intercept close to 0) | N/A | ADVIA Centaur CA 125II = 1.025 (Bayer Immuno 1) + 1.15 U/mL |
| Specimen Equivalence (vs. Serum) | Slopes close to 1.0, intercepts close to 0, strong correlation (e.g., r close to 1.0) | |
| Dipotassium EDTA plasma (y) vs. Serum (x) | N/A | Slope: 0.95 (0.92-0.98), Intercept: -0.4 U/mL (-1.5-0.7 U/mL), Correlation: 1.00 |
| Lithium Heparin plasma (y) vs. Serum (x) | N/A | Slope: 1.03 (0.97-1.08), Intercept: -0.2 U/mL (-1.8-1.4 U/mL), Correlation: 1.00 |
| Interferences (EDTA and Heparin) | Bias within an acceptable range (e.g., typically +/- 10% or +/- 20%) | |
| Dipotassium EDTA (9.0 mg/mL) | N/A | 3.7% bias (at 39.6 U/mL), 1.3% bias (at 526.5 U/mL) |
| Heparin (75 U/mL) | N/A | 3.2% bias (at 42.4 U/mL), -0.9% bias (at 471.4 U/mL) |
Study Details:
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Sample size used for the test set and the data provenance:
- Method Comparison: 224 samples (range 3.1 to 466.6 U/mL). Data provenance is not explicitly stated (country, retrospective/prospective).
- Specimen Equivalence:
- Dipotassium EDTA plasma vs. Serum: 162 sample pairs.
- Lithium Heparin plasma vs. Serum: 119 sample pairs.
- Data provenance is not explicitly stated (country, retrospective/prospective).
- Interferences: 2 tested analyte concentration levels for each substance (EDTA and Heparin) with "Analyte Concentration" values given. Sample size per level is not specified, but typically multiple replicates are used. Data provenance is not explicitly stated.
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Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
This device is an in vitro diagnostic (IVD) assay for measuring CA 125 levels. The "ground truth" for this type of device is typically established by reference methods or predicate devices (as seen in the method comparison and specimen equivalence studies), not by expert consensus on image interpretation or clinical diagnosis. Therefore, this question is not directly applicable in the context of this IVD device. The validation relies on the quantitative measurement accuracy against established methods. -
Adjudication method (e.g., 2+1, 3+1, none) for the test set:
Not applicable, as this is an IVD assay measuring an analyte, not requiring human adjudication of results in the way image interpretation or clinical diagnosis would. -
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 IVD laboratory assay, not an AI-powered diagnostic imaging or clinical decision support system involving human readers. -
If a standalone (i.e., algorithm only without human-in-the loop performance) was done:
Yes, the performance characteristics (detection limits, method comparison, specimen equivalence, interferences) represent the standalone performance of the ADVIA Centaur CA 125II assay. It's a fully automated immunoassay, so its performance is inherently "algorithm only" (the biochemical reaction and detection system). While results are used by clinicians, the measurement itself is standalone. -
The type of ground truth used (expert consensus, pathology, outcomes data, etc.):
For method comparison, the "ground truth" was established by the Bayer Immuno 1® CA 125II assay, which served as the reference method. For specimen equivalence, human serum served as the reference matrix against which plasma samples were compared. For detection limits, it's based on statistical analysis of blank and low-concentration samples. -
The sample size for the training set:
Not applicable in the AI sense. This is a traditional immunoassay, not a machine learning model that requires a "training set." The assay principle, design, and reagent formulation were established through standard laboratory development and validation processes, not machine learning training. -
How the ground truth for the training set was established:
Not applicable for the reason stated above. The "ground truth" for developing and calibrating an immunoassay involves extensive analytical chemistry, antibody development, and optimization of reaction conditions, with reference to known standards and established methods, rather than a "training set" with established ground truth labels in the machine learning context.
Summary of the Study that Proves the Device Meets Acceptance Criteria:
The study detailed in the 510(k) submission K200199 focused on demonstrating the substantial equivalence of the ADVIA Centaur CA 125II assay with the expanded sample type (EDTA and lithium heparin plasma) to its predicate device, which only accepted serum.
The key studies presented to support this included:
- Detection Limit determination: Performed in accordance with CLSI Document EP17-A2, establishing LoB, LoD, and LoQ. These values were provided and indicate the analytical sensitivity of the assay.
- Method Comparison: The assay's performance was compared against the Bayer Immuno 1® CA 125II assay using 224 samples. A strong correlation (r = 0.992) and a regression equation (ADVIA Centaur CA 125II = 1.025 (Bayer Immuno 1) + 1.15 U/mL) were reported, demonstrating agreement with a commonly used predicate.
- Specimen Equivalence: This crucial study, performed in accordance with CLSI Document EP09-A3, compared results from EDTA plasma and lithium heparin plasma against serum samples. The reported slopes (0.95 for EDTA, 1.03 for lithium heparin) and intercepts (-0.4 U/mL for EDTA, -0.2 U/mL for lithium heparin) with corresponding 95% confidence intervals falling close to the ideal (slope=1, intercept=0) and high correlation coefficients (1.00 for both) indicate that plasma matrices yield comparable results to serum. This directly supports the safety and effectiveness of using plasma samples.
- Interference testing: Performed per CLSI Document EP07-ed3, demonstrating that high concentrations of EDTA and Heparin do not significantly interfere with the assay's results (bias within low single digits).
The submission argues that "The assay principle, design and reagent formulation has not changed from the original device, therefore, the analytical performance studies and data previously reviewed under 510(K) K020828 continues to apply to this assay." The additional studies specifically addressed the change in sample type (plasma), showing that the device performs equivalently with these new sample types as it does with serum, thus meeting the requirements for substantial equivalence.
§ 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.