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Elecsys CA 125 II is an immunoassay for the in vitro quantitative determination of OC 125 reactive determinants in human serum, Li heparin, K2-EDTA, as well as Li-heparin plasma tubes containing separating gel on the cobas e 411 analyzer.

These determinants are associated with a high molecular weight glycoprotein in serum and plasma of women with primary epithelial invasive ovarian cancer (excluding those with cancer of low malignant potential).

This immunoassay is indicated for use as an aid in the detection of recurrent ovarian carcinoma. This immunoassay is further indicated for use in monitoring patients for disease progress or response to therapy.

The electrochemiluminescence immunoassay "ECLIA" is intended for use on the cobas e 411 immunoassay analyzers.

For use in the verification of the callbration established by the Elecsys CA 125 II reagent on the Elecsys and cobas e immunoassay analyzers.

The CA 125 II assay employs a sandwich test principle using biotinylated monoclonal CA 125-specific antibody and a monoclonal CA 125-specific antibody labeled with a ruthenium complex to form a sandwich complex. The use of streptavidin-coated microparticles serves as the solid phase for the electrochemiluminescence detection.

Results are determined using a calibration curve that is generated specifically on each instrument by a 2 point calibration and a master curve (5-point-calibration) provided with the reagent bar code.

The CA 125 II application is identical to the predicate assay (K972162). This submission is being done to modernize the labeling by adding the LoB, LoD and LoQ data and to change the sample:reagent ratio from 40:60μL to 20:70μL. Additionally, based on internal stability data the calibration frequency has been extended from 4 to 8 weeks.

The Elecsys CA 125 II CalCheck is a lyophilized product consisting of equine serum in level 1 and human serum matrix for levels 2 and 3. During manufacture, the analyte is spiked into the matrix at the desired concentration levels.

Here's a breakdown of the acceptance criteria and the study details for the Elecsys CA 125 II Assay, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document provides a comparison table (Table 1) between the predicate device (Elecsys CA 125 II, K972162) and the candidate device (Elecsys CA 125 II Assay), highlighting both similarities and differences, including labeled performance characteristics. Since explicit "acceptance criteria" are not given in a numerical form that can be directly compared to "reported performance" for each item, I will present the key performance characteristics detailed for the candidate device as its reported performance, implicitly indicating what was demonstrated to FDA for substantial equivalence.

2. Sample Sizes Used for the Test Set and Data Provenance

The document details various studies performed, each with its own sample size and type:

• Precision: 4 serum samples + 2 additional serum samples for testing.
• Limit of Blank (LoB): 5 analyte-free human samples.
• Limit of Detection (LoD): 5 human samples with low analyte concentration.
• Limit of Quantitation (LoQ): 3 human sample pools.
• Linearity: 6 dilution series from 6 different spiked human samples (3 serum, 3 plasma), each with 15 dilutions.
• Dilution: 3 human samples spiked to concentrations above the measuring range.
• High Dose Hook Effect: 2 samples spiked with analyte to 50,000 U/mL, each with a dilution series.
• HAMA Effect: 1 HAMA serum and 1 basic serum (both spiked with analyte).
• Endogenous Interference: 5 interfering substances (Intralipid, Biotin, Bilirubin, Rheumatic Factor, Hemolysis) tested using 3 spiked human samples (low, medium, high) to prepare 11 dilutions.
• Exogenous Interference (Drugs): 16 common and 23 additional pharmaceutical compounds, each spiked into 2 human samples (low and high CA125 concentration).
• Exogenous Interference (Anticoagulants): 51 or 52 serum/plasma pairs for each sample material type (Serum, Li-Heparin, K2-EDTA-, K3-EDTA-plasma, Li-Heparin Plasma Separation Tubes).
• Method Comparison (Sample/Reagent Ratio Change): 80 human serum samples (native single donors).
• Method Comparison (CalSet Change): 111 human serum samples (native single donors).
• Reagent Stability:
  • After first opening: 5 human serum samples (native single donors) and 2 controls.
  • On-board: 5 human samples (pooled and single donor) and 2 controls.
  • Shelf-life: PreciControl Tumor Marker 1 and 2, using 3 reagent lots (154355-Lot, 157240, 158725).
• Sample Stability:
  • 2 to 8°C: 10 human samples for each of 4 sample types (Serum, K2-EDTA-plasma, K3-EDTA-plasma, Li-Heparin-plasma).
  • Room Temperature: 10 human samples for each of 4 sample types.
  • -20°C: 10 human samples for each of 4 sample types.
  • Freeze/Thaw: 10 human samples for each of 4 sample types.
• Calibration Stability:
  • Lot calibration: 4 human serum samples (pooled patient samples) and 2 controls.
  • On-board calibration: 5 human serum samples (pooled and single donor) and 2 controls.

Data Provenance: The document generally refers to "human samples," "human serum samples," "pooled patient samples," and "native single donors." It does not explicitly state the country of origin, but given the submitter (Roche Diagnostics) and the nature of the device (in vitro diagnostic), it's highly likely to be a combination of commercially available human samples and samples collected in clinical settings in regions where such studies are commonly performed, potentially including the US or Europe. All studies appear to be prospective for the purpose of device validation, as they involve specific experimental designs to evaluate performance characteristics.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts

This information is not provided in the document. For an immunoassay like Elecsys CA 125 II, "ground truth" typically refers to the true concentration of the analyte (CA 125) in the samples. This is usually established through reference methods, certified reference materials, or highly characterized control materials, rather than expert consensus on diagnostic images or clinical outcomes. The document mentions standardization against the Enzymun-Test CA 125 II method, which in turn was standardized against the CA 125 II RIA from Fujirebio Diagnostics. This implies a chain of reference methods rather than expert panels establishing ground truth for individual samples.

4. Adjudication Method for the Test Set

This information is not applicable/not provided as the device is an immunoassay for quantitative determination of CA 125, not a device requiring interpretation or adjudication by multiple experts (like radiology images). The "ground truth" for quantitative assays is typically established through analytical methods and reference standards, not by an adjudication process.

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

This information is not applicable/not provided. The Elecsys CA 125 II Assay is an in vitro diagnostic immunoassay that quantifies a biomarker. It does not involve human readers interpreting cases or AI assistance in the context of image analysis.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done

This information is not applicable/not provided in the context of an "algorithm only" as generally understood for AI/imaging devices. The device is a standalone automated immunoassay system (Elecsys CA 125 II Assay on the cobas e 411 analyzer) that provides quantitative results. Its "performance" is inherently "standalone" in the sense that the analyzer directly processes samples and generates results without human diagnostic interpretation input into the result generation itself. However, a clinician then interprets these results in conjunction with other clinical findings.

7. The Type of Ground Truth Used (Expert Consensus, Pathology, Outcomes Data, etc.)

The ground truth for the quantitative measurement of CA 125 in the test samples is implicitly established by:

• Reference Methods/Standardization: The method has been standardized against the Enzymun-Test CA 125 II method, which in turn was standardized against the CA 125 II RIA from Fujirebio Diagnostics. This indicates that the "true" values used for comparison (e.g., in method comparison studies) are derived from these established reference methods.
• Spiking: For studies like linearity, dilution, hook effect, and interference, samples were "spiked" with known concentrations of the analyte, establishing a known "ground truth" for the added analyte.
• Assigned Values: For controls (e.g., PreciControl Tumor Marker), "assigned values" are used, which are derived from comprehensive characterization processes.

8. The Sample Size for the Training Set

This information is not explicitly provided in the document. For an immunoassay, "training set" might refer to data used during the assay development phase to optimize reagent concentrations, reaction times, and calibration algorithms. This type of data is usually part of internal R&D and not typically detailed in 510(k) summaries as a "training set" in the same way it would be for a machine learning model. The document primarily focuses on validation/verification studies.

9. How the Ground Truth for the Training Set Was Established

Since the document does not explicitly mention a "training set" in the context of a machine learning algorithm, the establishment of ground truth for such a set is not applicable/not provided. If an analogous "training set" were considered to be the samples used during assay development for parameter optimization, the ground truth would likely be established using similar methods as noted in point 7 (reference methods, spiking, assigned values for controls).

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The Roche Elecsys Anti-HAV immunoassay is used for the in vitro qualitative detection of total antibodies (IgM and IgG) to hepatitis A virus in human serum and plasma (K2-EDTA). The assay is intended for use as an aid in the laboratory diagnosis of past or acute/recent hepatitis A infection.

Assay results, in conjunction with other laboratory results and clinical information, may be used to provide presumptive evidence of infection with hepatitis A virus in persons with signs or symptoms of hepatitis and in persons at risk for hepatitis A infection, or used as an aid to determine the presence of antibody response to HAV in vaccine recipients.

The electrochemiluminescence immunoassay "ECLIA" is intended for use on Elecsys and cobas e immunoassav analyzers.

Elecsys PreciControl Anti-HAV is used for the quality control of the Elecsys Anti-HAV immunoassay on the Elecsys and cobas e immunoassay analyzers.

The Elecsys anti-HAV test is a qualitative assay based on electrochemiluminescence immunoassay "ECLIA" technology. The Elecsys anti-HAV test utilizes a competitive immunoassay format in which sample anti-HAV antibody competes with biotinylated and ruthenvlated anti-HAV monoclonal antibodies for a limited amount of cell culture-derived HAV antigen. The sample antibody and the HAV antigen react in the first incubation. The biotinylated antibodies and ruthenium complex® -labeled antibodies specific for HAV antigen are added in the second incubation together with streptavidin-coated magnetic microparticles. The unbound HAV antigen reacts with the modified antibodies and the resulting immune complexes are bound to the solid phase through a biotinstreptavidin interaction. If all HAV antigens are complexed by sample anti-HAV antibody during the first incubation, no modified/labeled immune complexes are formed and captured during the second incubation.

Following the second incubation, the reaction mixture is aspirated into the measuring cell where the microparticles are magnetically captured onto the surface of the electrode. Unbound substances are removed by elution with ProCell. Application of a voltage to the electrode induces chemiluminescent emission from the captured immune complexes which is measured by a photomultiplier. The level of signal detected by the system decreases as the concentration of the anti-HAV antibody target present in a patient sample increases.

Results are determined via a calibration curve which is generated by 2-point calibration on the instrument and a master curve provided via the reagent barcode. The calibration process converts the output so that low levels of sample anti-HAV antibodies are expressed by low output and high levels of antibody are expressed by high output. These outputs are finally interpreted on a qualitative basis around the established cut-off output.

Here's a breakdown of the acceptance criteria and study information for the Elecsys® Anti-HAV Assay, based on the provided 510(k) summary:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are generally implied by the performance metrics reported, as the submission concludes that the information "supports a substantial equivalence decision." This means the reported performance met the FDA's expectations for equivalence to the predicate device.

2. Sample Sizes Used for the Test Set and Data Provenance

• Clinical Performance Study (Comparison with Predicate):
  • Total Samples: 1050 samples (after excluding one concordantly equivocal sample).
  • Cohort Breakdown:
    • Subjects for whom routine hepatitis A testing had been ordered.
    • Hospitalized patients.
    • Subjects at increased risk for hepatitis.
    • Subjects with signs and symptoms of hepatitis.
    • Subjects characterized with acute hepatitis A.
    • Subjects below the age of 21 years (pediatric/adolescents).
    • Specific numbers per cohort are detailed in the tables (e.g., 197 for Routine HAV Testing, 219 for Hospitalized, etc., summing to the overall total).
  • Data Provenance: Multi-center study conducted in the U.S. (across 3 sites: BW, WU, JH). Samples were a mix of prospective and retrospective collections. All samples stored frozen before shipment.
• Analytical Specificity (Cross-reactivity): 177 samples from 15 potentially cross-reactive subgroups.
• Analytical Specificity (Interference): Native human serum pools, and 18 commonly used pharmaceuticals and folic acid.
• Prevalence Study (Expected Values): 602 patients (300 from high prevalence region, Western U.S. (New Mexico); 302 from low prevalence region, Eastern U.S. (Indiana)). This was a prospective study.
• Seroconversion Sensitivity: 3 seroconversion panels.
• Method Comparison (between platforms): 202 samples (100 non-reactive from prevalence cohort, 53 reactive from clinical cohorts, 49 reactive from Roche R&D archive).

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts

This information is not explicitly provided in the summary. The "ground truth" for clinical performance is established by comparing the Elecsys Anti-HAV assay results against an "FDA-cleared reference method" (the predicate device, Abbott AxSym HAVAB® 2.0). However, the summary does not specify if or how many human experts were involved in interpreting results from either the new device or the predicate to establish a "ground truth" in cases of discordance, or to confirm clinical status. The study relies on the predicate device's established performance and classification of samples.

4. Adjudication Method for the Test Set

The summary does not explicitly describe an adjudication method involving human experts for the test set. The clinical performance section states that the assay's performance was determined by agreement with the predicate device, which indicates a direct comparison rather than a human adjudication process to "resolve" discordant results. For "borderline" results from the Elecsys Anti-HAV assay (18.0 < IU/L < 22.0), the protocol involves retesting in duplicate and interpreting based on the majority of the three results (initial + 2 retests). This is an internal retesting protocol, not an external expert adjudication.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

• No, an MRMC comparative effectiveness study was not done. This document describes the performance of an in vitro diagnostic (IVD) assay, not the performance of human readers using an AI device. Therefore, the effect size of human readers improving with AI vs without AI assistance is not applicable.

6. Standalone Performance

• Yes, standalone performance was done. The entire submission details the performance of the Elecsys Anti-HAV assay (the algorithm/device) as a standalone diagnostic tool for detecting total antibodies to hepatitis A virus. All performance metrics reported (precision, detection limits, analytical specificity, and clinical agreement with the predicate device) reflect the device's performance without human interpretation or intervention in the diagnostic output itself (though a human ultimately uses the result for clinical decision-making).

7. The Type of Ground Truth Used

The primary "ground truth" used for evaluating the clinical performance of the Elecsys Anti-HAV assay was the results from an FDA-cleared reference method: the Abbott AxSym HAVAB® 2.0 assay. The submission explicitly states: "The performance of the Elecsys anti-HAV assay was determined by percent agreement among negative samples and percent agreement among positive samples, against a consensus comparator method. The main predicate (Abbott AxSym HAV AB- 2.0) was used as sole comparator/reference."
For seroconversion, vendor data from the predicate device was also used.

8. The Sample Size for the Training Set

The summary does not explicitly specify a "training set" sample size in the context of an AI/machine learning model. This is an immunoassay, which typically relies on established chemical and biological reactions and calibration curves rather than an iterative learning process with a "training set" in the modern AI sense. The assay uses a master curve provided via a reagent barcode and 2-point instrument calibration. The master standard curve is established by diluting an anti-HAV positive human serum with an analyte free human serum matrix, with concentration values assigned by reading from a reference calibrator curve using multiple instruments and replicates. The "training" in this context would be the development and optimization of the assay itself and its reagents.

9. How the Ground Truth for the Training Set Was Established

As noted above, there isn't a "training set" in the AI sense for this immunoassay. However, the calibration process (which is analogous to establishing the basis for decision-making) works as follows:

• The device is standardized against the "Second International Standard for Anti-Hepatitis A, Immunoglobulin, Human, NIBSC code: 97/646" of the NIBSC.
• Calibrators: Two calibrators are used: Calibrator 1 (anti-HAV negative serum) and Calibrator 2 (anti-HAV positive serum with approx. 46 IU/L).
• Master Standard Curve: A reagent lot-specific master standard curve is provided on the barcode. This curve is established by diluting an anti-HAV positive human serum with an analyte free human serum matrix. The concentration value is assigned by reading the concentration from the reference calibrator curve using four Elecsys 2010 and four MODULAR ANALYTICS E170 instruments with 2 runs and 2 replicates per run and per instrument.
• The calibration data ensures the assay's output signal can be accurately converted into a quantitative reading (IU/L) and then interpreted qualitatively (Reactive, Equivocal, Non-Reactive) based on the established cut-off.

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