(675 days)
For in vitro diagnostic use with the IMMULITE® 1000 Analyzers - for the quantitative measurement of CA125 antigen in serum, as an aid in monitoring the response to therapy for patients with epithelian ovarian cancer, and in detecting residual ovarian cancer in patients who have undergone first-line therapy and would be considered for diagnostic second look procedures.
For in vitro diagnostic use with the IMMULITE® 2000 Systems Analyzers - for the quantitative measurement of CA125 antigen in serum, as an aid in monitoring the response to therapy for patients with epithelian ovarian cancer, and in detecting residual ovarian cancer in patients who have undergone first-line therapy and would be considered for diagnostic second-look procedures.
The IMMULITE®/IMMULITE 1000 OM-MA Assay is comprised of OM-MA Test Units (beads coated with murine monoclonal anti-CA125 antibody), OM-MA Cycle 1 Reagent Wedge (alkaline phosphatase conjugated to rabbit polyclonal anti-CA125 antibody in buffer), OM-MA Cycle 2 Reagent Wedge (buffer), and OM-MA Adjustors (Low and High, CA125 in a nonhuman protein/buffer matrix).
The IMMULITE® 2000 OM-MA Assay is a newer generation instrument that dispenses an individual bead from a pack into a separate reaction tube. It is comprised of OM-MA Bead Pack (beads coated with murine monoclonal anti-CA125 antibody), OM-MA Reagent Wedge (Well 1: alkaline phosphatase conjugated to rabbit polyclonal anti-CA125 antibody in buffer; Well 2: buffer), and OM-MA Adjustors (Low and High, CA125 in a nonhuman protein/buffer matrix).
Both assays are solid-phase, two-site chemiluminescent immunometric assays that measure CA125 antigen quantitatively in serum.
The Siemens Healthcare Diagnostics Products Ltd IMMULITE/IMMULITE 1000 OM-MA and IMMULITE 2000 OM-MA assays are intended for the quantitative measurement of CA125 antigen in serum. The devices aid in monitoring the response to therapy for patients with epithelial ovarian cancer and in detecting residual ovarian cancer in patients who have undergone first-line therapy.
Here's an analysis of the acceptance criteria and study proving device meets these criteria:
1. Table of Acceptance Criteria and Reported Device Performance
For IMMULITE/IMMULITE 1000 OM-MA Assay (modified):
| Acceptance Criteria | Reported Device Performance |
|---|---|
| Detection Limit (LoB) | 0.14 U/mL |
| Detection Limit (LoD) | 0.38 U/mL |
| Detection Limit (LoQ) | 2 U/mL |
| Assay Measuring Interval | 2 - 500 U/mL (confirmed by linearity with overall recovery bias ≤20%) |
| Method Comparison (Regression) | y = 0.995x - 0.199, y = 0.999x - 0.047, y = 1.022x - 0.821 (for Lot 1, 2, 3 respectively, against predicate IMMULITE 1000) |
| Precision (%CV) | Within-run: 2.9-4.5%, Within-Lab: 3.0-5.3% |
| Reproducibility (%CV) | Between-Lot: 5.25-6.45%, Total Reproducibility: 7.55-9.37% |
| Hook Effect (U/mL) | Detects >500 U/mL for concentrations as high as 84,500 U/mL |
| Biotin Interference | Specimens with biotin at 3500 ng/mL demonstrate ≤10% change in results. |
| Reference Range | 93%-94% of healthy individuals ≤ 21 U/mL (verified) |
| Shelf-life | Exceeded 365 days (estimated ty an: 665 to 30011 days) |
For IMMULITE 2000 OM-MA Assay (modified):
| Acceptance Criteria | Reported Device Performance |
|---|---|
| Detection Limit (LoB) | 0.18 U/mL |
| Detection Limit (LoD) | 0.43 U/mL |
| Detection Limit (LoQ) | 3 U/mL |
| Assay Measuring Interval | 3 - 500 U/mL (confirmed by linearity with overall recovery bias ≤15%) |
| Method Comparison (Regression) | y = 1.032x + 0.086, y = 0.955x - 0.256, y = 0.976x - 0.142 (for Lot 1, 2, 3 respectively, against predicate IMMULITE 2000) |
| Precision (%CV) | Within-run: 4.4-6.1%, Within-Lab: 5.1-7.7% |
| Reproducibility (%CV) | Lot-to-Lot: 1.89-4.94%, Total Reproducibility: 6.19-7.85% |
| Hook Effect (U/mL) | Detects >500 U/mL for concentrations as high as 80,000 U/mL |
| Biotin Interference | Specimens with biotin at 3500 ng/mL demonstrate ≤10% change in results. |
| Reference Range | 94% of healthy individuals ≤ 21 U/mL (verified) |
| Shelf-life | Exceeded 365 days (estimated ty an: 665 to 30011 days) |
2. Sample Size and Data Provenance
- Method Comparison Test Set: A total of 253 patient samples were used for method comparison studies for both the IMMULITE 1000 and IMMULITE 2000 assays. The documentation does not specify the country of origin of the data or whether it was retrospective or prospective.
- Precision Test Set: Five serum samples were tested for each assay (IMMULITE 1000 and IMMULITE 2000). The samples were tested in duplicate over 20 days, two runs per day, for a total of 80 replicates per sample level.
- Reproducibility Test Set: Five serum samples were tested for each assay (IMMULITE 1000 and IMMULITE 2000) using a 5x5x3 experimental design (5 days, 5 replicates, 3 reagent lots).
- Recovery Test Set: 19 samples were used for spike and recovery studies.
- Reference Range Verification Test Set: For each assay (IMMULITE 1000 and IMMULITE 2000), "apparently healthy female samples" were used. Specifically, for IMMULITE 1000, n=50 for Lot 1 and Lot 2, and n=45 for Lot 3. For IMMULITE 2000, n=50 for all three lots. The provenance is not explicitly stated beyond "healthy female samples."
- Stability Test Set: Native patient samples were used for accelerated stability studies, but the exact number of unique samples is not specified.
3. Number of Experts and Qualifications for Ground Truth
This device is an in vitro diagnostic (IVD) assay for quantitative measurement of a biomarker (CA125). The performance claims are based on analytical performance characteristics, not on interpretation of images or clinical outcomes by experts in the typical sense of a diagnostic imaging AI device. Therefore, the concept of "experts" to establish a ground truth for a test set, like radiologists or pathologists, is not directly applicable here. The "ground truth" for analytical performance studies is established by the assay's ability to accurately and precisely measure the analyte concentrations.
4. Adjudication Method for the Test Set
Not applicable. As an IVD assay measuring an analyte concentration, there is no adjudication process similar to that for subjective diagnostic interpretations. Performance is assessed through statistical analysis of quantitative results against established analytical methods and specifications.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No. An MRMC study is relevant for diagnostic imaging devices where multiple human readers interpret cases. This document describes an in vitro diagnostic assay that quantitatively measures a biomarker, not a device requiring human interpretation for diagnosis. Therefore, the concept of "how much human readers improve with AI vs without AI assistance" does not apply.
6. Standalone Performance Measurement
Yes, the studies described are essentially standalone performance studies of the IMMULITE/IMMULITE 1000 OM-MA and IMMULITE 2000 OM-MA assays. The device (the assay) itself generates the quantitative measurement. The "human-in-the-loop" aspect, for this type of device, would be the clinician interpreting the numerical results in the context of a patient's treatment and disease status, a step downstream from the device's analytical performance. The studies focus on the analytical accuracy, precision, linearity, and interference of the assay itself.
7. Type of Ground Truth Used
The ground truth used for these analytical studies is primarily:
- Quantitative Reference Values / Expected Values:
- For Detection Limits (LoB, LoD, LoQ), ground truth is based on the statistical determination of the lowest measurable concentrations.
- For Linearity, ground truth is established by preparing samples with known, serially diluted concentrations (expected values).
- For Method Comparison, the predicate device's results are used as the comparative "ground truth" (or reference method) to assess equivalence.
- For Precision and Reproducibility, the ground truth is the inherent variability of the measurements around a mean dose.
- For Spike Recovery, ground truth is the "expected" concentration after spiking known amounts of analyte into samples.
- For Specificity (Cross-reactivity), ground truth is the known concentration of potentially cross-reacting substances.
- For Interference, ground truth is the known concentration of potentially interfering substances.
- For Reference Range, ground truth is derived from the established reference interval for healthy individuals (≤ 21 U/mL).
8. Sample Size for the Training Set
This document does not specify a separate "training set" or its size in the context of artificial intelligence or machine learning. The studies described are analytical performance validations for an in vitro diagnostic assay, which typically involve testing samples to verify performance against pre-defined specifications rather than training a machine learning model.
9. How the Ground Truth for the Training Set Was Established
As there is no mention of a "training set" in the context of AI/ML for this device, information on how its ground truth was established is not provided or applicable. The ground truth for the performance validation studies, as described in point 7, is based on established analytical methods and known concentrations.
§ 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.