(205 days)
The Bayer Immuno 1™ CA 125 II™ Assay is an in vitro device for the quantitative measurement of OC 125 reactive determinants associated with a high molecular weight glycoprotein in serum of women with primary epithelial invasive ovarian cancer. The Bayer Immuno 1™ CA 125 II™ Assay is indicated as an aid in the management (monitoring) of ovarian cancer patients when used in conjunction with other diagnostic procedures. The CA 125 II™ Assay is also indicated as a one time test for use as an aid in the detection of residual ovarian carcinoma in patients who have undergone first line therapy and would be considered for diagnostic second look procedures. An assay value of greater than or equal to 35 U/mL is predictive of residual disease, provided that alternative causes of an elevated CA 125 II™ assay value can be excluded. It is recommended that the Bayer Immuno 1 CA 125 II assay be used under the order of a physician trained and experienced in management of gynecological cancers.
The Bayer Immuno 1™ CA 125 II™ Assay utilizes a well-established immunoassay technology in which one monoclonal antibody (M11) is conjugated to fluorescein (R1) and a second monoclonal antibody (OC 125) is conjugated to alkaline phosphatase (R2). An Immuno 1 Magnetic Particle coated with anti-fluorescein antibody, the R1 conjugate, and patient sample, calibrator, or control are mixed simultaneously and incubated at 37℃ on the system. The R2 conjugate is then added, and binds to the immobilized CA 125 to form a sandwich immunocomplex on the solid phase. The magnetic particles complexed with the immunological sandwich are then washed to separate unbound molecules, and a colorimetric substrate is added. The rate of conversion of substrate to a compound with absorbance at 405 or 450 nm is measured rate is proportional to the concentration of CA 125 antigen in the sample. A cubic-through-zero curve fitting algorithm is used to generate standard curves.
The assay has a range of 0 to 500 UmL. The Bayer Immuno 1™ CA 125 II™ Assay Calibrators consist of a set of six calibrator levels at 0, 15, 30, 80, 200, and 500 U/mL.
Here's a breakdown of the acceptance criteria and the study that proves the device meets them, based on the provided text:
Acceptance Criteria and Device Performance
| Acceptance Criteria | Reported Device Performance |
|---|---|
| Imprecision (Reproducibility) | Within-run imprecision: Ranged from 1.4% to 3.6% CV across products and sites. |
| Total imprecision: Ranged from 2.2% to 4.1% CV across products and sites. | |
| Maximum inter-assay % CV (pooled over reagent lots and clinical sites): 4.1% over the range of the assay. | |
| Clinical Utility for Monitoring (Longitudinal) | Sensitivity to change in clinical condition: 79% (58 out of 73 evaluable patients showed correspondence between CA 125 II levels and clinical course). This was based on: |
- Increase ≥ 100% into or within the abnormal range (> 35 U/mL) for clinical progression.
- Decrease ≥ 50% for clinical response.
Positive Predictive Value (of an increase/decrease in assay values matching clinical change): 96% (50 out of 52 instances where CA 125 II values changed as expected with clinical status). |
| Other Performance Characteristics | The previous 510(k) (K964098) reported and confirmed acceptance for: - Analytical sensitivity
- Assay specificity
- Cross-reactivity
- Linear range
- Parallelism (sample dilution)
- Hook effect
- Reagent lot-to-lot variation
- Method comparison to the Centocor CA 125 II™ RIA. These met accepted specifications set for an assay of this type. |
| Safety and Effectiveness | Confirmed as an aid in the management of ovarian cancer patients. The correlation between Immuno 1 CA 125 II™ concentrations and the patients' clinical course of disease demonstrates its utility, in conjunction with other clinical indicators, to confirm disease progression and response to therapy. |
Study Details
1. Sample sizes used for the test set and the data provenance:
- Imprecision Study Test Set:
- Products: BioRad 1 (n=667 observations), MD Pool (n=677 observations), BioRad 2 (n=680 observations), Calibrator 1 (n=275 observations), Calibrator 2 (n=456 observations), Calibrator 3 (n=454 observations), Calibrator 4 (n=458 observations), Calibrator 5 (n=447 observations), Calibrator 6 (n=245 observations).
- Provenance: US (Bayer Corporation, Tarrytown, NY), Finland (Helsinki University Central Hospital), Canada (Hopital Saint-Luc, Montreal). This was part of the previous 510(k) (K964098).
- Clinical Study (Management/Monitoring) Test Set:
- Sample Size: 78 ovarian cancer patients (Stages I - IV). 5 patients were eventually deemed "Indeterminate" and not used in the analysis, resulting in 73 evaluable patients.
- Provenance: All patient samples were studied retrospectively. Samples were collected and stored (-70°C) in specimen banks prior to the study. The study was conducted at two US clinical trial sites: Johns Hopkins Hospital (Site JH) and M. D. Anderson Cancer Center (Site MDA).
2. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- The document implies clinical status was determined by standard diagnostic procedures and clinical assessment. While it states "clinical data to confirm their clinical status" and "qualified experts," it does not specify the number or specific qualifications of experts who established the ground truth (e.g., individual doctors, oncology boards, etc.). It mentions "accepted diagnostic procedures" and that "clinical data were gathered during well controlled investigations conducted by qualified experts," but no details on their specific roles or qualifications are provided.
3. Adjudication method for the test set:
- The document does not explicitly state an adjudication method for the test set in terms of multiple reviewers for the clinical status. The clinical course of disease and response to therapy were based on "hard clinical data" and "accepted diagnostic procedures." The interpretation of the CA 125 II levels against clinical course was evaluated similar to Bast et al.(16) using predefined criteria (doubling for progression, 50% decrease for response).
4. 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, this was an in-vitro diagnostic device (IVD) assay. MRMC studies are typically for imaging devices or AI algorithms where human readers interpret and classify images. This device measures a biomarker in serum. Therefore, this section is not applicable.
5. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:
- Yes, this was a standalone device. The Immuno 1 CA 125 II™ Assay itself performs the quantitative measurement of the biomarker. Its performance was evaluated on its own, and its utility is explicitly stated as "an aid in the management (monitoring) of ovarian cancer patients when used in conjunction with other diagnostic procedures." This indicates it's meant to be interpreted by a physician, not replace clinical judgment, but it's not an "AI algorithm with human-in-the-loop" performance study type.
6. The type of ground truth used (expert consensus, pathology, outcomes data, etc.):
- The ground truth for the clinical utility study was clinical status/course of disease (e.g., disease progression, response to therapy, stable persistent disease, no clinical evidence of disease). This clinical status would have been determined through various accepted diagnostic procedures and medical evaluations, which can include imaging, physical examination, pathology (from biopsies or surgeries), and other clinical markers, leading to an overall assessment by treating physicians or review boards. The phrase "hard clinical data to confirm their clinical status" supports this.
7. The sample size for the training set:
- The document does not explicitly mention a separate "training set" for the development of the current expanded intended use. The 510(k) is for an expanded indication for an existing assay. The original assay received clearance in 1997 (K964098) with "clinical data demonstrating assay values in the target ovarian cancer population as well as expected values in healthy individuals and patients with related benign and malignant diseases" which would have served a development/training purpose for establishing initial performance characteristics. This submission focuses on validating the expanded intended use using the 78 patients in the clinical study.
8. How the ground truth for the training set was established:
- As a training set is not explicitly detailed for this specific expanded indication submission, specific ground truth establishment methods for a training set are not described. However, for the initial assay development (prior to K964098), the ground truth for "assay values in the target ovarian cancer population as well as expected values in healthy individuals and patients with related benign and malignant diseases" would have been established through clinical diagnosis (e.g., biopsy-confirmed cancer, healthy volunteer screening, diagnosis of benign conditions).
§ 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.