(53 days)
The ADVIA Centaur® CA 19-9 Assay is an in vitro immunoassay for the quantitative measurement of the CA 19-9 tumor-associated antigen, in human serum, using the ADVIA Centaur System. This assay is indicated for the serial measurement of CA 19-9 to aid in the management of patients diagnosed with cancers of the exocrine pancreas. The test is useful as an aid in monitoring of disease status in those patients having confirmed pancreatic cancer who have levels of serum CA 19-9 at some point in their disease process exceeding the median concentration determined for the apparently healthy cohort. CA 19-9 values must be interpreted in conjunction with all other clinical and laboratory data before a medical decision is determined. This assay is not intended for use on any other system.
The ADVIA Centaur CA 19-9 assay is a fully automated, two-step sandwich immunoassay using direct, chemiluminescent technology. The method utilizes a single monoclonal antibody (Mab), 116-NS-19-9, for both the Solid Phase and the Lite Reagent. The Mab is both covalently coupled to paramagnetic particles in the Solid Phase as well as labeled with acridinium ester in the Lite Reagent.
The sample and Solid Phase are first incubated at 37℃ for 7.5 minutes. This step is followed by a wash step to remove excess unbound antigen. The Lite Reagent is then reacted with the Solid Phase that is bound to CA 19-9 antigen for an additional 20-minute incubation. This two-step protocol eliminates any high-dose hook effect in this assay.
Here's a breakdown of the acceptance criteria and study information for the Bayer HealthCare Diagnostics Division ADVIA Centaur® CA 19-9 Assay, based on the provided document:
1. Table of Acceptance Criteria and Reported Device Performance
The submission does not explicitly state "acceptance criteria" in a quantified format that one would typically find for a diagnostic test. Instead, it compares the performance characteristics of the new device (ADVIA Centaur CA 19-9 Immunoassay) to those of the predicate device (Fujirebio Diagnostics CA 19-9 RIA). The implication is that the new device's performance should be comparable or superior to the predicate for features where direct comparison is feasible. For clinical concordance, the new device's performance is presented on its own.
| Feature | Acceptance Criteria (Implied by Predicate/Desired Performance) | Reported Device Performance (ADVIA Centaur CA 19-9 Immunoassay) |
|---|---|---|
| Precision | Values for duplicates should be within 15% of the mean (for predicate). New device should be comparable. | Within-run 4.3 – 11.3 %CV from 7.2 – 386.7 Units/mL. Total 5.5 – 14.5 %CV from 7.2 – 386.7 Units/mL. (Considered acceptable for substantial equivalence). |
| Hook Effect | None up to 1,250,000 Units/mL (for predicate). New device should be comparable or better. | No high dose effect up to 5,800,000 Units/mL. (Considered superior to predicate). |
| Analytical Sensitivity | 0.9 Units/mL (for predicate). New device should be comparable. | 1.2 Units/mL. (Slightly less sensitive than predicate, but considered substantially equivalent). |
| **Clinical Concordance | ||
| (with disease progression - Per-Visit Analysis)** | Not explicitly stated as a concrete acceptance criterion, but demonstrated clinical agreement with disease status. | Concordance = (39+47)/131 = 65.7% (95% CI of 54.9% to 76.3%). |
| Predictive Value (No Progression) = 47/74 = 63.5% (95% CI of 52.9% to 77.4%). | ||
| Predictive Value (Progression) = 39/57 = 68.4% (95% CI of 56.6% to 80.1%). | ||
| Method Comparison (Correlation with Predicate) | Strong correlation (r) to the predicate device. | Relationship: ADVIA Centaur CA 19-9 = 0.97 (Fujirebio RIA) + 0.13 Units/mL. |
| Correlation coefficient (r) = 0.88. |
2. Sample Sizes Used for the Test Set and Data Provenance
- Clinical Concordance Test Set: 131 clinical samples (patients with pancreatic cancer, monitored serially for changes in disease status).
- Method Comparison Test Set: 360 samples in the assay range of 1.2 - 700 Units/mL.
- Data Provenance: The document does not explicitly state the country of origin or whether the data was retrospective or prospective. Given the nature of a 510(k) submission, it's highly likely that these were prospective or a mix of prospective and retrospectively collected clinical samples, but this is not definitively stated.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
The document states that the clinical concordance studies compare "changes in CA 19-9 value relative to disease progression." However, it does not provide details on:
- The number of experts.
- Their qualifications.
- The specific method used to establish the "Change in Disease State" (i.e., "Progression" or "No Progression"). This clinical status would serve as the ground truth.
4. Adjudication Method for the Test Set
The document does not describe any adjudication method used to establish the ground truth ("Change in Disease State") for the clinical concordance study.
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
- No, an MRMC comparative effectiveness study was not done.
- This device is an in vitro diagnostic (IVD) immunoassay, not an AI-powered image analysis or interpretation tool that assists human readers. Therefore, the concept of "human readers improve with AI vs without AI assistance" does not apply here. The study focuses on the performance of the assay itself and its correlation with clinical status and a predicate device.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was done
- Yes, a standalone study was done. This entire submission describes the standalone performance of the ADVIA Centaur CA 19-9 Assay, an automated in vitro diagnostic device, without human intervention in the result generation process once the sample is loaded. The "clinical concordance" section assesses the direct relationship between the assay's output and clinical disease progression.
7. The Type of Ground Truth Used
- Clinical Outcomes/Disease State: For the clinical concordance study, the ground truth was "Change in Disease State" (Progression or No Progression), which is derived from a patient's overall clinical presentation and likely involves various clinical and diagnostic assessments over time. The document does not specify the exact methods or criteria used to define "Progression" or "No Progression."
- Predicate Device Measurements: For the method comparison study, the ground truth for measuring CA 19-9 values was essentially the measurement obtained from the Fujirebio Diagnostics CA 19-9 RIA predicate device.
8. The Sample Size for the Training Set
The document does not specify a separate training set size for the development of the ADVIA Centaur CA 19-9 Assay. This is common for traditional immunoassays, where the "training" involves optimizing reagents, chemistry, and instrument parameters rather than iterative machine learning on a distinct dataset. Clinical and analytical performance studies are typically conducted on independent samples after the assay development is complete.
9. How the Ground Truth for the Training Set Was Established
As there's no explicitly defined "training set" in the context of machine learning, the question of its ground truth establishment is not applicable in the same way. The development of an immunoassay involves extensive biochemical research, optimization of antibody performance, fluorogenic labels, reaction kinetics, and calibration curves using known standards, rather than establishing a ground truth for a dataset to "train" an algorithm.
§ 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.