(68 days)
For the in vitro quantitative measurement of 1116-NS-19-9 defined antigen in human serum and plasma (EDTA or heparin). The VITROS CA19-9 assay is to be used to aid in the management of patients diagnosed with cancers of the exocrine pancreas. The VITROS CA19-9 assay can be used to monitor the disease status in patients with confirmed pancreatic cancer who show measurable CA19-9 values over the course of their disease. Serial CA 19-9 test results should be used in conjunction with all other available clinical and laboratory data before a medical decision is determined.
The VITROS CA 19-9 assay is performed using the VITROS CA 19-9 Reagent Kit and the VITROS Immunodiagnostic System. An immunometric assay is performed. CA 19-9 antigen present in the sample reacts with a biotinylated antibody (mouse monoclonal anti-1116-NS-19-9 defined antigen). The antigen-biotinylated antibody complex binds to the wells, unbound materials are removed by washing. In a second incubation a horseradish peroxidase (HRP)-labeled antibody Conjugate (mouse monoclonal anti-1116-NS-19-9 defined antigen) binds to the immobilized complex. Unbound conjugate is removed by washing. The bound HRP conjugate is measured by a luminescent reaction. A reagent containing luminogenic Substrates (a luminol derivative and a peracid salt) and an electron transfer agent, is added to the wells. The HRP Conjugate catalyzes the oxidation of the luminol derivative, producing light. The electron transfer agent (a substituted acetanilide) increases the level of light produced and prolongs the emission. The light signals are read by the system. The light produced is directly proportional to the concentration of 1116-NS-19-9 defined antigen present.
The system is comprised of three main elements:
- The VITROS Immunodiagnostic Products (in this case VITROS Immunodiagnostic Products CA 19-9 Reagent Pack, VITROS Immunodiagnostic Products CA 19-9 Calibrator Kit, and the VITROS Immunodiagnostic Products CA 19-9 Range Verifier Kit, which are used by the VITROS Immunodiagnostic System to perform the VITROS CA 19-9 assay).
- The VITROS Immunodiagnostic System instrumentation, which provides automated use of the immunoassay kits. The VITROS Immunodiagnostic System was cleared for market by a separate 510(k) premarket notification (K962919).
- Common Reagent Products Signal Reagent and VITROS Immunodiagnostic Products Universal Wash Reagent, which were cleared as part of the VITROS Immunodiagnostic Products Total T3 510(k) premarket notification (K964310).
The VITROS System and common reagents are dedicated specifically only for use with the VITROS Immunodiagnostic Products range of immunoassay products.
Here's an analysis of the provided text, outlining the acceptance criteria and the study that proves the device meets those criteria, structured as requested:
1. Table of Acceptance Criteria and Reported Device Performance
The document provided does not explicitly state formal "acceptance criteria" in a quantitative, pre-defined manner for the device's performance in clinical application (e.g., specific sensitivity/specificity targets). Instead, it focuses on demonstrating substantial equivalence to a predicate device and showing an association between changes in marker value and changes in disease state.
The "reported device performance" section focuses on the concordance between changes in the VITROS CA 19-9 assay and changes in the disease state for pancreatic cancer patients.
| Area of Evaluation | Reported Device Performance (%/Value) |
|---|---|
| Comparison Study (vs. Predicate Device) | |
| Passing-Bablok Regression | Slope: 0.83 (95% CI: 0.80, 0.88) |
| Intercept: -4.02 (95% CI: -4.3, 0.27) | |
| Pearson's Correlation (r) | 0.93 (95% CI: 0.91, 0.95) |
| Pancreatic Cancer Serial Specimens Study | |
| Association between Change in Marker Value and Change in Disease State (per observation pair) | |
| Total Concordance ($C$) | 59.4% (111/187 observation pairs) |
| Positive Concordance ($C_+$) | 45.5% (15/33 observation pairs where disease progressed and marker increased) |
| Negative Concordance ($C_-$) | 62.3% (96/154 observation pairs where disease did not progress and marker did not increase) |
| Per-Patient Analysis of Concordance | |
| Total Concordance ($C$) | Estimate: 66.22% (95% CI: 54.28% - 76.81%) |
| Positive Concordance ($C_+$) | Estimate: 68.18% (95% CI: 45.13% - 86.14%) (Proportion of patients with disease progression also showing CA 19-9 increase) |
| Negative Concordance ($C_-$) | Estimate: 65.38% (95% CI: 50.91% - 78.03%) (Proportion of patients with no disease progression also showing no CA 19-9 increase) |
2. Sample Size Used for the Test Set and Data Provenance
- Comparison Study (vs. Predicate):
- Sample Size: 176 specimens.
- Data Provenance: Not explicitly stated, but given the context of a 510(k) summary for a US submission, it is likely to be a combination of retrospective samples or samples collected specifically for this validation. The document does not specify country of origin.
- Pancreatic Cancer Serial Specimens Study:
- Sample Size: 74 patients, yielding 261 evaluable observations (average 3.5 observations per patient) and 187 observation pairs for the change analysis.
- Data Provenance: Not explicitly stated, but inferred to be clinical data. The document does not specify country of origin or if it's retrospective/prospective. It mentions "staging was available from the chart," suggesting retrospective chart review.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
The document does not mention the use of experts to establish the ground truth for the test set in either the comparison study or the pancreatic cancer serial specimens study.
- In the comparison study, the ground truth is implicitly the result from the predicate device (Fujirebio Diagnostics, Inc. CA 19-9 RIA).
- In the pancreatic cancer serial specimens study, the "Change in Disease State (Progression / No Progression)" is the ground truth. The method for determining this change is not detailed but would typically come from clinical assessments (e.g., imaging, clinical symptoms, physician's diagnosis), not expert consensus based on re-reading.
4. Adjudication Method for the Test Set
No adjudication method (e.g., 2+1, 3+1) is mentioned or implied for either study to establish ground truth or assess discrepancies.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done
No MRMC comparative effectiveness study was done. The device is an in vitro diagnostic assay, not an imaging device typically evaluated with MRMC studies or human reader performance. The "effectiveness" is shown through clinical correlation and substantial equivalence to a predicate, not through human reader improvement.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done
Yes, the studies presented are standalone performance evaluations of the assay itself. The device is a laboratory assay (VITROS CA 19-9), and its performance is measured directly, without human interpretation or adjustment influencing the assay's output. The output (CA 19-9 value) is then interpreted by clinicians in conjunction with other data.
7. The Type of Ground Truth Used
- Comparison Study: The "ground truth" was the results obtained from the predicate device (Fujirebio Diagnostics, Inc. CA 19-9 RIA).
- Pancreatic Cancer Serial Specimens Study: The "ground truth" was the clinical determination of disease state change (Progression vs. No Progression). This likely came from a composite of clinical factors, imaging, and physician assessment, rather than a single direct measure like pathology at every time point for all patients.
8. The Sample Size for the Training Set
The document does not specify a separate "training set" sample size. For an IVD assay like this, development typically involves method development and verification using various samples, but a formally defined "training set" in the machine learning sense is not applicable. The studies described are performance validation studies.
9. How the Ground Truth for the Training Set Was Established
Since no explicit training set is mentioned in the context of machine learning, this question is not directly applicable. For the development and verification of the assay itself, the ground truth would have been established through well-characterized reference materials, known concentrations, and comparisons to established methods during the research and development phases.
§ 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.