(104 days)
The VITROS®CA 15-3 is an in vitro assay intended for the quantitative measurement of DF3 defined antigen in serum or plasma (EDTA or heparin) from patients previously treated for stage II or stage III breast cancer. Serial test results obtained with the VITROS CA 15-3 assay, in patients who are clinically free of disease, should be used in conjunction with all relevant information derived from diagnostic test, physical examination and full medical history in accordance with appropriate patient management procedures used for early detection of recurrence. The test is also intended for use as an aid in the management of breast cancer patients with metastatic disease by monitoring progression or response to treatment.
The VITROS Immunodiagnostic System uses luminescence as the signal in the quantitative and semi-quantitative determination of selected analytes in human body fluids, commonly serum and plasma. Coated microwells are used as the solid phase separation system. The system is comprised of three main elements: 1. The VITROS Immunodiagnostic Products (in this case VITROS Immunodiagnostic Products CA 15-3 Reagent Pack, VITROS Immunodiagnostic Products CA 15-3 Calibrators, which are combined by the VITROS Immunodiagnostic System to perform the VITROS CA 15-3 assay). 2. The VITROS Immunodiagnostic System instrumentation, which provides automated use of the immunoassay kits. 3. Common reagents used by the VITROS System in each assay.
The provided text does not contain acceptance criteria in the traditional sense of performance metrics (e.g., sensitivity, specificity, accuracy thresholds) for a diagnostic device.
Instead, the document focuses on demonstrating substantial equivalence to a previously cleared predicate device (Centocor CA 15-3 RIA) for regulatory approval (510(k)). This means the study aims to show that the new device performs similarly and is as safe and effective as the existing one, rather than meeting specific predefined performance targets set independently.
Here's an analysis based on the information provided, addressing as many of your points as possible:
1. Table of Acceptance Criteria and Reported Device Performance
As noted, explicit acceptance criteria (e.g., "sensitivity must be >X%") are not provided in the document. The primary criterion is demonstrating substantial equivalence to the predicate device.
| Device Characteristic | Acceptance Criteria (Implied by Substantial Equivalence) | Reported Device Performance (VITROS CA 15-3 assay) |
|---|---|---|
| Calibration Range | Should be comparable to or improve upon the predicate device for clinical utility. | 0 - 500 U/mL (Predicate: 0 - 200 U/mL, showing an expanded range) |
| Basic Principle | Similar immunoassay principle. | Solid phase immunoassay (Predicate: Solid phase radioimmunoassay - similar but different tracer) |
| Tracer | Functionally equivalent to quantify the analyte. | Enzyme labeled (Predicate: Radioactive tracer - different, but deemed equivalent in function) |
| Sample Type | Same or broader range of clinically relevant sample types. | Serum, plasma (heparin or EDTA) (Predicate: Serum, plasma - broader for plasma type) |
| Antibody | Should detect the same antigen (DF3) effectively. | 1) Mouse monoclonal anti-DF3 antigen antibody in biotinylated antibody reagent; 2) Mouse monoclonal anti-DF3 antigen antibody in conjugate reagent (Predicate: 1) Mouse monoclonal 115D8 antibody coated onto beads; 2) Mouse monoclonal DF3 antibody labeled with I125 - different antibodies but target same antigen) |
| Sample Volume | Clinically reasonable and practical. | 10 µL (Predicate: 20 µL - improvement in sample efficiency) |
| Incubation Time & Temp | Clinically reasonable and practical, ideally improving throughput. | First incubation 16 minutes at 37°C with shaking; Second incubation 16 minutes at 37°C with shaking (Predicate: First incubation 2 hours at room temperature; Second incubation 3 hours at room temperature - significant improvement in speed) |
| Correlation | Strong positive correlation (e.g., correlation coefficient > 0.9) with the predicate. | Bablock Passing regression: VITROS CA 15-3 assay = 0.945 x [Centocor CA 15-3 RIA] + 1.55 (U/mL); Correlation coefficient: 0.978 |
| Clinical Utility | Expected to demonstrate similar clinical utility for monitoring recurrence and treatment response. | "The serial monitoring study demonstrated the clinical utility of the VITROS CA 15-3 assay for monitoring for recurrence of disease in patients previously treated for stage II or stage III breast cancer and for monitoring response to treatment of breast cancer patients with metastatic disease." |
2. Sample Size Used for the Test Set and Data Provenance
- Sample Size: The document states that comparisons were performed with "samples from a variety of clinical categories" and "patient specimens from patients who are normal, undergoing therapeutic and/or undergoing diagnostic evaluation." However, specific sample sizes for the test set are not provided in the excerpt.
- Data Provenance: The document does not specify the country of origin of the data. The data appears to be retrospective as it involves "patient specimens" and "clinical studies of apparently healthy individuals, patients with cancer and patients with a variety of non-malignant diseases," indicating samples collected prior to the study for the VITROS assay.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
There is no mention of experts being used to establish ground truth in the context of this diagnostic assay. For an in vitro diagnostic test that measures a biomarker (CA 15-3 antigen), the "ground truth" is typically the quantitative value obtained from the reference method (the predicate device) or from established analytical assays. The study aims to correlate the new device's measurements with those of the predicate.
4. Adjudication Method for the Test Set
Not applicable. As described above, this is a quantitative in vitro diagnostic assay comparing its results to a predicate device, not a qualitative assessment requiring expert adjudication.
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 device, not an AI or imaging device involving human readers/interpreters.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was Done
This device is a standalone diagnostic kit/system. Its performance is evaluated directly through its quantitative measurements, rather than as an assistant to a human. The "standalone" performance is essentially what the comparability study demonstrates.
7. The Type of Ground Truth Used (expert consensus, pathology, outcomes data, etc.)
The primary ground truth/reference standard used for comparison is the results obtained from the legally marketed predicate device, the Centocor CA 15-3 RIA. This is implicitly considered the "truth" for establishing substantial equivalence. Additionally, "clinical utility" was demonstrated via a "serial monitoring study" for recurrence and response to treatment, which would likely involve outcomes data (e.g., disease recurrence, treatment response status) but the methodology for determining these outcomes is not detailed.
8. The Sample Size for the Training Set
Not applicable. This document describes a traditional in vitro diagnostic assay, not a machine learning or AI-based device that typically has a distinct "training set." The development of such assays often involves optimization and calibration using various samples, but these are not usually referred to as a "training set" in the context of AI.
9. How the Ground Truth for the Training Set Was Established
Not applicable, as there is no mention of a "training set" for an AI or machine learning model. The assay's development would involve establishing accurate measurements against known standards and optimizing chemical/biological parameters, but this is a different process than establishing "ground truth" for machine learning training.
§ 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.