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The Access BR Monitor assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of CA 15-3 antigen levels in human serum and plasma (heparin) using the Access Immunoassay Systems. This device is indicated for use in the measurement of CA 15-3 antigen to aid in the management of breast cancer patients. Serial testing for CA 15-3 antigen concentrations should be used in conjunction with other clinical methods for monitoring breast cancer.

The Access BR Monitor assay, Access BR Monitor Calibrators, and the Access Immunoassay analyzers comprise the Dxl 9000 Access Immunoassay Amalyzer for the quantitative determination of CA 15-3 antigen levels in human serum and plasma (heparin) using the Dxl 9000 Access Immunoassay Analyzer.

Here's a breakdown of the acceptance criteria and study information for the Access BR Monitor device, based on the provided FDA document:

1. Table of Acceptance Criteria and Reported Device Performance

• Slope: 0.95 (95% CI: 0.94 - 0.96)
• Intercept: 0.70 (95% CI: 0.31 - 1.4)
• Correlation Coefficient (R): 1.00
  (Implied acceptance if comparable to predicate) |
  | Imprecision (Within-Laboratory) | - SD ≤ 1.5 U/mL at concentrations ≤ 15 U/mL
• CV ≤ 10.0% at concentrations ≥ 15 U/mL | Met acceptance criteria.
• Sample 1 (4.2 U/mL): SD 0.1, CV 3.4%
• Sample 2 (19 U/mL): CV 2.9%
• Sample 3 (34 U/mL): CV 3.2%
• Sample 4 (79 U/mL): CV 3.0%
• Sample 5 (105 U/mL): CV 3.0%
• Sample 6 (425 U/mL): CV 3.2%
• Sample 7 (825 U/mL): CV 4.0% |
  | Linearity | Not explicitly stated numerically, but stated as being linear throughout the analytical measuring interval. | Met acceptance criterion, indicating linearity throughout the analytical measuring interval (0.8 – 1,000 U/mL). |
  | Limit of Blank (LoB) | 0.4 U/mL | Met acceptance criterion. LoB estimate: 0.1 U/mL. |
  | Limit of Detection (LoD) | 0.5 U/mL | Met acceptance criterion. LoD estimate: 0.3 U/mL. |
  | Limit of Quantitation (LoQ) | Not explicitly stated numerically, but two different LoQ definitions are provided. | - 20% CV LoQ estimate: 0.3 U/mL
• LoQ at 20% within-laboratory imprecision estimate: 0.8 U/mL |

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

• Method Comparison: N = 163 samples.
  • Data Provenance: Not specified in the provided text (e.g., country of origin, retrospective or prospective).
• Imprecision:
  • Sample 1, 2: N = 126
  • Sample 3, 4, 5, 6, 7: N = 120
  • Data Provenance: Not specified.
• Linearity, LoB, LoD, LoQ: Sample sizes not explicitly stated for these specific studies, beyond the "N" for method comparison and imprecision.
  • Data Provenance: Not specified.

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

There is no mention of experts or ground truth establishment for the test set in the provided document. The studies described are analytical performance studies (method comparison, imprecision, linearity, limits) of an immunoassay device, which typically compare the device's measurements against a reference method or predetermined values, not against expert consensus on clinical diagnoses.

4. Adjudication Method for the Test Set

Not applicable, as the studies are analytical performance assessments of an immunoassay, not studies involving human interpretation or adjudication of clinical cases.

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 immunoassay for measuring CA 15-3 antigen levels, not an AI-assisted diagnostic imaging or interpretation tool that would involve human readers.

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

Yes, the studies described (Method Comparison, Imprecision, Linearity, LoB, LoD, LoQ) are all examples of standalone performance evaluations of the immunoassay system. The device itself (Access BR Monitor on the Dxl 9000 Access Immunoassay Analyzer) operates as an "algorithm only" in the sense that it automates the measurement of the analyte; there is no human-in-the-loop for the measurement process itself.

7. The Type of Ground Truth Used

The "ground truth" for these analytical studies is either:

• Reference method/Predicate device results: For the method comparison study, the Access 2 Immunoassay System served as the reference (predicate) for comparison.
• Known concentrations/values: For studies like Imprecision, Linearity, LoB, LoD, and LoQ, calibrated samples or controls with known or expected analyte concentrations are used as the reference against which the device's measurements are assessed. The document refers to "predetermined values" or "calculated estimates" based on established statistical methods (e.g., CLSI guidelines).

8. The Sample Size for the Training Set

Not applicable. This device is an immunoassay, not a machine learning or AI model that requires a "training set." Its calibration is established through a stored calibration curve, as mentioned in the "Comparison of Technological Characteristics" table.

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

Not applicable, as there is no "training set" in the context of an AI/ML model for this immunoassay device. The "calibration curve" for the immunoassay is established using calibrators, which are materials with known concentrations of the analyte, manufactured and tested according to quality control standards.

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For in vitro diagnostic use with the IMMULITE® 2000 Systems Analyzers - for the quantitative measurement of CA15-3 antigen in human serum and plasma, as an aid in the detection of recurrence in previously treated stage III breast cancer patients, and in the management of metastatic breast cancer patients by monitoring disease progression or response to treatment. Serial testing for patient CA15-3 values should be used in conjunction with other clinical methods used for detecting early recurrence in stage III disease and for monitoring response to treatment in patients with metastatic breast cancer.

The IMMULITE® 2000 BR-MA assay was cleared under K013984. The components of the cleared assay were modified to reduce biotin interference. The modified IMMULITE® 2000 BR-MA Assay is comprised of the following components: BR-MA Bead Pack (L2BR12), BR-MA Reagent Wedge (L2BRA2) - Well 1, BR-MA Reagent Wedge (L2BRA2) - Well 2, and BR-MA Adjustors (LBRL, LBRH). The IMMULITE 2000 BR-MA is a solid-phase, two-step chemiluminescent immunometric assay. There are two incubation cycles of 30 minutes each. During the initial 30-minute cycle, the patient sample is incubated with biotinylated antibody coated bead (bead pack) and a buffer (reagent wedge well 1). The biotinylated antibody on the bead captures the antigen in the patient sample. On completion of the first 30-minute cycle, unbound sample/buffer are then removed via a centrifugal wash. During the second 30-minute cycle, alkaline phosphatase antibody conjugate in buffer (reagent wedge well 2) is added to complete the bead pair immunocomplex sandwich consisting of capture Ab-antigen-detection Ab. On completion of the second 30-minute cycle, unbound conjuqate is removed by centrifugal wash. The amount of alkaline phosphatase bound is directly proportional to the patient sample. Following the two 30-minute incubation periods. IMMULITE chemiluminescent substrate (L2SUBM) is added for a further 5-minute incubation period to generate the luminogenic reaction. The chemiluminescent substrate undergoes hydrolysis in the alkaline phosphatase to yield an unstable intermediate, which then emits photons. The sustained emissions are measured by the luminometer. The resulting relative light units are proportional to the concentration of CA15-3 in the sample, which is expressed as U/mL.

The retrieved document describes the acceptance criteria and performance of the IMMULITE 2000 BR-MA assay, which is a tumor-associated antigen immunological test system for CA15-3. The modifications to the device primarily focus on reducing biotin interference.

Here's a breakdown of the requested information based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly list "acceptance criteria" against "reported device performance" in a single table. Instead, it presents performance characteristic studies that implicitly demonstrate the device meets certain standards. I've aggregated these into a table format below, using typical performance metrics for such devices. The "Acceptance Criteria" are implied by common laboratory standards (e.g., CLSI guidelines) and the successful outcome of the tests.

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

• Detection Limits (LoB, LoD, LoQ): The specific sample size for determining LoB, LoD, and LoQ is not explicitly stated as a number of individual patient samples, but the study was conducted "in accordance with CLSI EP17-A2," which provides methodologies for these determinations.
• Linearity/Measuring Interval: A high and low sample pool were used to prepare a panel of ten levels. The number of individual patient samples contributing to these pools is not specified.
• Method Comparison: 274 patient samples.
• Assay Precision: Five serum samples. Each tested in duplicate over 20 days, two runs per day (total 80 replicates per sample). Total N for data points is 400 (5 samples * 80 replicates).
• Assay Reproducibility: Five serum samples. Each tested over 5 days, with 5 replicates per sample (total 25 replicates per sample) across 3 reagent lots. Total N of data points is 375 (5 samples * 25 replicates * 3 reagent lots).
• Recovery: 5 neat samples spiked with 3 different concentrations of CA15-3 solution.
• Interference: Not specified as a number of patient samples, but various compounds were tested.
• Hook Effect: Not specified as a number of patient samples.
• Reference Range Verification: 69 apparently healthy female samples across 3 lots (total 207 results).
• Matrix Comparison: Not explicitly specified, but "comparable values to serum samples" were demonstrated across SST, Lithium Heparin, and EDTA tube types.

Data Provenance: The document does not specify the country of origin of the data or whether the studies were retrospective or prospective. It refers to human serum and plasma samples and "patient samples" and "apparently healthy female samples" without further geographical or temporal details.

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

This information is not applicable to this type of device. The IMMULITE 2000 BR-MA is an in vitro diagnostic assay that quantitatively measures CA15-3 antigen. Its performance characteristics are established through analytical studies (e.g., precision, linearity, interference) and comparisons to a predicate device or established laboratory methods, rather than through expert interpretation of outputs to establish a "ground truth" (as might be seen in imaging AI, for example). The ground truth for this device is the actual concentration of the analyte, verified through reference methods or spiked samples with known concentrations.

4. Adjudication Method for the Test Set

Not applicable. As described above, this device's performance is not evaluated through expert adjudication of results but rather by comparing its quantitative measurements to known values or to a predicate device, and assessing its analytical characteristics.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and Effect Size of How Much Human Readers Improve with AI vs. Without AI Assistance

Not applicable. This is an in vitro diagnostic assay, not an AI-assisted diagnostic imaging or interpretation system requiring human "readers." The "human reader" concept is not relevant here.

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

The device is an automated in vitro diagnostic assay. Its primary function is to perform quantitative measurements of CA15-3. The performance studies described (detection limits, linearity, precision, etc.) are all standalone performance evaluations of the assay itself, without a "human-in-the-loop" component in the sense of interpreting an output that then needs human review for diagnosis. The device provides a quantitative result (U/mL), which is then used by a clinician in conjunction with other clinical methods. So, yes, the performance data presented are for the standalone analytical performance of the device.

7. The Type of Ground Truth Used

The ground truth used in the performance studies includes:

• Known concentrations: For linearity, recovery, interference, and hook effect studies, samples are often prepared with known concentrations of the analyte or interferents.
• Reference methods/Predicate device: For method comparison, results from the candidate device are compared against results from the legally marketed predicate device.
• Statistical methods: Established CLSI (Clinical and Laboratory Standards Institute) guidelines provide the statistical framework and generally accepted methodologies for determining metrics like LoB, LoD, LoQ, precision, and linearity.
• Clinically defined healthy populations: For reference range verification, samples from "apparently healthy female samples" are used.

8. The Sample Size for the Training Set

The document describes performance studies for a modified in vitro diagnostic assay. These studies are typically for verification and validation, not for "training" an algorithm in the sense of machine learning. There is no mention of a "training set" in the context of algorithm development or machine learning. The studies primarily evaluate the analytical performance of the modified assay components.

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

As there is no mention of a "training set" for an algorithm, this question is not applicable. The device's mechanism is based on immunometric assay principles using chemical reactions, not on training data for a machine learning model.

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Lumipulse G CA15-3 is a Chemiluminescent Enzyme Immunoassay (CLEIA) for the quantitative determination of CA 15-3 in human serum or plasma (sodium heparin, lithium heparin, or dipotassium EDTA) on the LUMPULSE G System.

The assay is to be used as an aid in the management of patients previously diagnosed with stage II and III breast cancer. Serial testing for patient CA15-3 assay values should be used in conjunction with other clinical methods used for monitoring breast cancer.

WARNING: The concentration of CA 15-3 in a given specimen, as determined by assays from different manufacturers, can vary due to differences in assay methods and reagent specificity. The results reported by the laboratory to the physician must include the identity of the assay for CA 15-3 used. Values obtained with different assay methods cannot be used interchangeably. If, in the course of monitoring a patient, the assay method used of CA 15-3 is changed, the laboratory must perform additional serial testing to confirm baseline values. Prior to changing assays, the laboratory MUST confirm baseline values for patients being serially monitored. Lumipulse G CA 15-3 should not be used for cancer screening or diagnosis.

Lumipulse G CA15-3 is an assay system, including a set of immunoassay reagents, for the quantitative measurement of CA 15-3 in specimens based on CLEIA technology by a two-step sandwich immunoassay method on the LUMIPULSE G System.

Lumipulse G CA15-3 Immunoreaction Cartridges: REF 235102 The Lumipulse G CA15-3 Immunoreaction Cartridges consists of 3 x 14 tests. Each kit contains the following:

1.) Antibody-Coated Particle Solution (Liquid when used, 250 µL/Immunoreaction Cartridge) Contains 150 µg/mL anti-CA 15-3 monoclonal antibody (mouse)-coated particles, protein stabilizers (bovine and mouse) and chemical stabilizers in 0.15 M sodium chloride/Tris buffer. This solution contains gelatin and turns into gel at 15°C or lower. Preservative: sodium azide.

2.) Enzyme-Labeled Antibody Solution (Liquid, 350 µL/Immunoreaction Cartridge) Contains 0.2 µg/mL alkaline phosphatase (ALP: calf)-labeled anti-CA 15-3 monoclonal antibody (mouse), protein stabilizers (bovine and calf) and chemical stabilizers in 0.1 M sodium chloride/MES buffer. Preservative: sodium azide.

Here's an analysis of the acceptance criteria and study detailed in the provided document, restructured to answer your specific questions:

1. A table of acceptance criteria and the reported device performance

The document primarily focuses on validating the Lumipulse G CA15-3 assay as "substantially equivalent" to a predicate device (ARCHITECT CA 15-3) and demonstrating its analytical and clinical performance. The acceptance criteria are largely implicit, based on meeting established guidelines (CLSI) and demonstrating satisfactory performance within defined ranges or against a predicate.

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The ADVIA Centaur® BR assay is an in vitro diagnostic test for the quantitative serial determination of cancer antigen CA 27.29 in human serum and plasma (EDTA) using the ADVIA Centaur XP, and ADVIA Centaur XPT systems. The test is intended for use as an aid in monitoring patients previously treated for Stage III breast cancer. Serial testing for CA 27.29 in the serum and plasma of patients who are clinically free of disease should be used in conjunction with other clinical methods used for the early detection of cancer recurrence. The test is also intended for use as an aid in the management of breast cancer patients with metastatic disease by monitoring the progression or regression of disease in response to treatment.

The ADVIA Centaur BR assay is a fully automated, competitive immunoassay using direct, chemiluminescent technology. Results are determined using a calibration curve that is generated specifically on each instrument by a 2-point calibration and a master curve with the reagent bar code. The ADVIA Centaur BR assay is intended for use on the ADVIA Centaur family of analyzers. The ADVIA Centaur Calibrator G is a set of 2 level calibrators for the assay. Siemens recommends the use of commercially available quality control materials with at least two levels (low and high).

The ADVIA Centaur BR reagent kit contains the following:

• ADVIA Centaur BR ReadyPack primary reagent pack contains Lite Reagent and Solid Phase ● Reagent.
• Materials Required but Not provided:
• ADVIA Centaur Calibrator G: consists of 2 levels (low and high) of CA 27.29 calibrators in equine serum with sodium azide (0.1%) and preservatives; lyophilized.
• ADVIA Centaur BR Pretreatment Reagent: consists of sodium hydroxide (0.24 N) Optional Reagents:
• ADVIA Centaur Multi-Diluent 1: consists of equine serum with sodium azide (0.1%) and preservatives.
• . ADVIA Centaur BR Master Curve Material: consists of a set of 7 levels of CA 27.29 (MCM1-7) spiked in lyophilized equine serum with sodium azide (0.1% after reconstitution) and preservatives.

The Siemens Healthcare Diagnostics Inc. ADVIA Centaur BR assay, with updated claims for plasma (EDTA) sample and detection capability (LoB, LoD, and LoQ), was determined to be substantially equivalent to the predicate device (K982680). The purpose of this submission was to add the plasma (EDTA) sample claim and update the detection capability claims.

1. Table of Acceptance Criteria and Reported Device Performance

Comparisons of Candidate and Predicate Device for Specimen Equivalence (Dipotassium EDTA Plasma vs. Serum):

Interference Testing (Dipotassium EDTA):

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

• Specimen Equivalence by Method Comparison:

  • Sample Size: 101 samples (N=101)
  • Data Provenance: Not explicitly stated (e.g., country of origin, retrospective or prospective). The study used patient samples.

• Detection Capability (LoB, LoD, LoQ): The specific sample sizes for LoB, LoD, and LoQ determination are not provided in this summary, but the determination was performed in accordance with CLSI Document EP17-A2.

• Interferences: EDTA: The specific number of samples tested for interference is not provided, but tests were performed at two analyte concentrations.

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

This type of immunoassay (measuring tumor-associated antigen CA 27.29) does not typically involve expert review of images or clinical data for establishing ground truth in the same way imaging devices do. The ground truth for analytical performance studies is established by the known concentration of the analyte in the samples, or by comparison to a reference method, rather than through expert consensus.

4. Adjudication Method for the Test Set

Not applicable for this type of analytical performance study. Adjudication methods (e.g., 2+1) are typically used in studies involving subjective interpretation of data, such as medical images, where discrepancies between readers need to be resolved. This study involves quantitative measurements.

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 MRMC comparative effectiveness study was conducted as this device is an in vitro diagnostic test for quantitative serial determination of a cancer antigen, not an AI-based imaging or diagnostic tool requiring human reader interpretation in that context.

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

This is a standalone in vitro diagnostic assay. Its performance is evaluated based on its ability to accurately measure the target analyte (CA 27.29) in patient samples. Human intervention is limited to sample handling, loading, and interpreting the quantitative results per clinical guidelines, not in generating the test result itself.

7. The Type of Ground Truth Used (expert consensus, pathology, outcomes data, etc.)

The ground truth for the performance characteristics was established by:

• Detection Capability: Defined statistically based on measured values from blank and low-concentration samples (in accordance with CLSI EP17-A2).
• Specimen Equivalence: Comparison of results from plasma (EDTA) samples to serum samples using Deming linear regression, implying serum results (from the predicate device/established method) serve as the reference.
• Interferences: Known concentrations of interferents and analyte spiked into samples.

8. The Sample Size for the Training Set

No training set information is provided in the summary. Immunoassays are generally optimized and validated during development, and the performance studies presented reflect the validation of the finalized assay.

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

Not applicable, as no training set information is provided as per point 8.

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The ADVIA Centaur CA 15-3 assay is an in vitro diagnostic test for the quantitative serial determination of cancer antigen CA 15-3 in human serum and plasma (EDTA and lithium heparin) using the ADVIA Centaur XP, and ADVIA Centaur XPT systems. When used in conjunction with other clinical and diagnostic procedures, serial testing with the ADVIA Centaur CA 15-3 assay is useful for monitoring the course of disease and therapy in metastatic breast cancer patients, and for detection of recurrence in previously treated Stage II, with greater than two positive lymph nodes, or Stage III breast cancer patients. This assay is not intended for use on any other system.

The ADVIA Centaur CA 15-3 assay reagents come in the following configurations: 5 ReadyPack primary reagent packs containing ADVIA Centaur CA 15-3 Lite Reagent, Solid Phase, and Conjugate Reagent, and ADVIA Centaur CA 15-3 Master Curve card (500 tests); 1 ReadyPack primary reagent pack containing ADVIA Centaur CA 15-3 Lite Reagent, Solid Phase, and Conjugate Reagent, and ADVIA Centaur CA 15-3 Master Curve card (100 tests). The ReadyPack consists of ADVIA Centaur CA 15-3 ReadyPack primary reagent pack; Lite Reagent (monoclonal mouse anti-DF3 antibody labeled with acridinium ester), ADVIA Centaur CA 15-3 ReadyPack primary reagent pack; Solid Phase Reagent (monoclonal mouse capture antibody covalently coupled to paramagnetic particles), and ADVIA Centaur CA 15-3 ReadyPack primary reagent pack: Conjugate Reagent (monoclonal mouse anti-115D8 antibody labeled with a thiocarbamate of fluorescein).

Here's a breakdown of the acceptance criteria and the study that proves the device meets them, based on the provided text:

Device: ADVIA Centaur CA 15-3 assay

1. Table of acceptance criteria and the reported device performance:

Note: The document states "The analytical performance data previously reviewed for the ADVIA Centaur CA 15-3 assay continues to apply to this assay." This implies that the change from the predicate device was primarily the addition of plasma sample types, and the acceptance criteria for the original analytical performance characteristics (like assay range, precision within serum, etc.) were already met and considered valid for this modified device. The studies presented here focus on demonstrating equivalence for the new sample types and re-affirming key analytical specifications. The specific numerical acceptance criteria themselves are not explicitly listed but are implied by the successful results of the studies.

2. Sample sized used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective):

• Detection Capability: No specific sample size is provided for LoB, LoD, and LoQ determination. The methodology followed CLSI Document EP17-A2. Data provenance is not specified.
• Precision: 80 results per specimen type (Serum A, Serum B, Plasma EDTA, Plasma Heparin, Control 1, 2, 3). No information on data provenance (country, retrospective/prospective).
• Specimen Equivalency:
  • Dipotassium EDTA plasma vs. Serum: 129 samples
  • Lithium Heparin plasma vs. Serum: 108 samples
    No information on data provenance (country, retrospective/prospective).
• Interferences: No specific sample size is given per substance, but results are provided for Dipotassium EDTA and Heparin at two different analyte concentrations. No information on data provenance.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:

This is an in vitro diagnostic test for measuring a tumor marker (CA 15-3). The ground truth for such devices is typically established through reference methods or quantitative chemical analysis, not by human expert interpretation of images or clinical cases. Therefore, the concept of "experts establishing ground truth" in the way it applies to imaging AI or diagnostic algorithms based on interpretation is not relevant here.

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set:

Not applicable. This is an in vitro diagnostic assay, not a device requiring interpretation or adjudication by multiple human readers.

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:

Not applicable. This is an in vitro diagnostic assay, not an AI-powered diagnostic imaging or clinical decision support system that would involve human readers.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:

Yes, the studies presented are for the standalone performance of the ADVIA Centaur CA 15-3 assay. While it is intended for use "in conjunction with other clinical and diagnostic procedures" and for use by healthcare professionals, the performance characteristics tested (precision, detection capability, specimen equivalency, interference) represent the analytical performance of the automated assay itself, without human interpretation as part of the core performance measurement.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.):

The ground truth for this type of quantitative assay would inherently be established by the concentration of the analyte (CA 15-3) as measured by a reference method or highly accurate, precisely calibrated laboratory standard. For specimen equivalency, the ground truth is the concentration in serum measured by the same assay, to which the plasma measurements are compared. For interference, it is the known concentration of the analyte without the interferent.

8. The sample size for the training set:

The document describes performance data for the modified device. It states that "The analytical performance data previously reviewed for the ADVIA Centaur CA 15-3 assay continues to apply to this assay." This implies that prior internal validation and possibly external studies for the original device (K012357) served as the "training" or development data. No specific sample size for a training set dedicated to the modified device is provided, as the modifications were largely related to sample types, not a complete re-development of the assay's core principle or algorithm that would necessitate a new, extensive training dataset for an AI model.

9. How the ground truth for the training set was established:

Given this is an in vitro diagnostic assay, the "ground truth" for the training set (or rather, the development and verification phases of the original assay) would have been established through a rigorous process of:

• Reference materials: Using certified reference materials with known concentrations of CA 15-3.
• Primary reference methods: Comparing to established, highly accurate analytical methods.
• Spiking studies: Adding known amounts of CA 15-3 to samples to assess analytical recovery.
• Clinical correlation: While not a "ground truth" in the analytical sense, the selection of the analyte (CA 15-3) and its clinical cut-offs are derived from extensive clinical studies correlating CA 15-3 levels with disease status and progression in breast cancer patients. This would involve a large number of patient samples with confirmed clinical diagnoses, pathology reports, and known treatment outcomes.

The document primarily focuses on the validation studies performed to support the modified device (addition of plasma sample types) rather than the original development or "training" phases, which would have occurred prior to the predicate device's clearance.

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Immunological in vitro assay for quantitative determination of CA 15-3 in human serum, Li-heparin and EDTA plasma to aid in the management of breast cancer patients. In conjunction with other clinical and diagnostic procedures, serial testing with this assay is an aid

• · in the early detection of recurrence in previously treated stage II and III breast cancer patients
• · for monitoring response to therapy in metastatic breast cancer patients
  The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.

The Elecsys CA 15-3 II Test System is a two-step sandwich immunoassay with streptavidin microparticles and electrochemiluminescence detection for the quantitative determination of CA 15-3 in human serum, Li-heparin plasma and EDTA plasma. It is intended for use on the cobas e 801 immunoassay analyzer. The cobas e family of analyzers employs the electrochemiluminescence "ECLIA" technology. Results are determined using a calibration curve that is generated specifically on each instrument by a 2-point calibration and a master curve provided via the cobas link.

The provided text describes a 510(k) premarket notification for the Elecsys CA 15-3 II device, which is an immunological in vitro assay for the quantitative determination of CA 15-3. The primary purpose of this specific submission (K181492) is to extend the allowable sample type to include K2-EDTA plasma, in addition to serum and Li-heparin plasma already cleared under a previous submission (K171605).

Therefore, the acceptance criteria and study specifically relate to demonstrating the comparability of K2-EDTA plasma samples to serum samples for this assay. Most other performance characteristics (precision, analytical sensitivity, hook effect, linearity, endogenous interferences, method comparison to another analyzer, and stability) were demonstrated in the prior K171605 submission and are simply referenced, not re-evaluated in detail here, as the core assay technology remains the same.

Here's the breakdown of the information requested, focusing on the K2-EDTA plasma extension:

1. Table of Acceptance Criteria and Reported Device Performance

Note: The exact numerical acceptance criteria (e.g., specific ranges for slope and intercept) for Passing/Bablok regression are not explicitly stated in this document but are implied by the "fulfilled the acceptance criteria" statement. Typically, these would be pre-defined limits for non-inferiority or equivalence.

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

• Sample Size: 44 serum/plasma paired samples.
• Data Provenance: The document does not explicitly state the country of origin for the samples. It is a retrospective study using existing samples, as they were "tested in singleton" for this specific comparison.

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

• This study does not involve expert human readers or ground truth established by subjective expert consensus (like in imaging studies). Instead, it's a quantitative immunoassay comparing instrument measurements from different sample types.
• The "ground truth" for this type of test is the measured value of the analyte (CA 15-3) in the serum sample, which is the established and currently accepted sample type. The study aims to show that the K2-EDTA plasma sample provides a comparable measurement.

4. Adjudication Method for the Test Set

• None. Adjudication methods (like 2+1, 3+1) are typically used in clinical or imaging studies where subjective interpretation is involved and consensus among multiple experts is needed to establish a definitive ground truth. This is a quantitative analytical performance study.

5. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study was Done

• No. This is an analytical performance study of an in vitro diagnostic (IVD) device, not a multi-reader, multi-case clinical effectiveness study. It assesses the device's ability to measure an analyte accurately and comparably across different sample types, not how it impacts human reader performance or diagnostic accuracy in a clinical setting.

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

• Yes, this is a standalone analytical performance study. The Elecsys CA 15-3 II assay itself provides a quantitative result. The study evaluated the direct output of the assay on the cobas e 801 analyzer for different sample types. There is no "human-in-the-loop" component in the direct measurement or comparison being assessed here.

7. The Type of Ground Truth Used

• The "ground truth" for comparison in this study is the measured CA 15-3 value in human serum, which is the currently accepted and validated sample matrix for this assay. The K2-EDTA plasma samples are being compared against these serum measurements to determine if they yield equivalent results. This implicitly relies on the established analytical accuracy of the device when using serum.

8. The Sample Size for the Training Set

• Not applicable / Not explicitly specified for this K2-EDTA plasma validation. This is an analytical validation study of a reagent/instrument system, not a machine learning model that requires a "training set" in the conventional sense. The "training" of the assay system itself comes from its development and standardization processes (e.g., against reference methods, master curves), which would have used numerous samples but are not detailed as a distinct "training set" in this context. The K171605 submission would have contained more foundational validation data.

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

• Not applicable in the context of machine learning training data. For an IVD assay like this, the "ground truth" for its development and standardization (analogous to "training") is established through:
  • Traceability to international standards or reference methods: The document states the method has been standardized against other established CA 15-3 methods (Enzymun-Test CA 15-3, CA 15-3 RIA from Fujirebio Diagnostics), indicating a chain of traceability to agreed-upon CA 15-3 values.
  • Analytical precision and accuracy studies: Extensive studies are performed during development to ensure the assay consistently and accurately measures the target analyte over its dynamic range using known concentrations and reference materials.
  • Clinical correlation: While not the focus of this specific K181492 submission, initial device development and validation (e.g., for K171605) would have involved clinical studies to correlate CA 15-3 levels with patient outcomes, disease status, and therapy response.

In summary, this 510(k) submission (K181492) is a targeted analytical validation to expand the Indications for Use for an existing immunoassay by demonstrating the analytical equivalence of an additional sample matrix (K2-EDTA plasma) to the previously cleared serum samples. The validation relies on quantitative comparisons rather than subjective human interpretation.

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Immunological in vitro assay for quantitative determination of CA 15-3 in human serum and Li-heparin plasma to aid in the management of breast cancer patients. In conjunction with other clinical and diagnostic procedures, serial testing with this assay is an aid

• · in the early detection of recurrence in previously treated stage II and III breast cancer patients
• · for monitoring response to therapy in metastatic breast cancer patients
  The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.

The Elecsys CA 15-3 II Test System is a two-step sandwich immunoassay with streptavidin microparticles and electrochemiluminescence detection for the quantitative determination of CA 15-3 in human serum and plasma. It is intended for use on the cobas e 411 immunoassay analyzer. The cobas e family of analyzers employs the electrochemiluminescence "ECLIA" technology.
Results are determined using a calibration curve that is generated specifically on each instrument by a 2-point calibration and a master curve provided with the reagent barcode.

The provided text describes the 510(k) Premarket Notification for the Elecsys CA 15-3 II diagnostic test system. This is an in vitro immunoassay designed to quantitatively determine CA 15-3 in human serum and Li-heparin plasma to aid in the management of breast cancer patients. It is not an AI/ML powered device, therefore many of the requested elements pertaining to AI/ML specific studies (e.g., MRMC studies, training set details, expert ground truth establishment for AI) are not applicable.

However, I can extract information related to the performance studies conducted to prove the device meets acceptance criteria, focusing on the analytical performance characteristics relevant to an immunoassay.

Acceptance Criteria and Reported Device Performance

The document doesn't explicitly present a single "acceptance criteria" table with corresponding "reported device performance" values in a concise format. Instead, it describes various non-clinical performance evaluations and states that "specification was met" or "deviations were within predetermined acceptance criteria" for each. I will summarize the key performance parameters and the general findings related to meeting criteria.

Note: For each study, the acceptance criteria are implied by the statement that the "specification was met" or "deviations were within predetermined acceptance criteria." The document does not provide the numerical thresholds for these criteria.

Study Details:

1. Sample Size Used for the Test Set and Data Provenance:

   • Precision: 2 replicates of controls and 5 pooled human sera samples per run, 2 runs per day for 21 days.
   • LoB/LoD: 60 total blank replicates per reagent lot (LoB) and 60 total replicates per sample per reagent lot (LoD).
   • LoQ: 25 replicates per sample per reagent lot.
   • High-Dose Hook Effect: 2 samples.
   • Linearity: 3 high analyte serum samples and 3 high analyte plasma samples, diluted to 15 concentrations.
   • Endogenous Interferences: For each interfering substance, three human serum samples (low, mid, high CA 15-3 concentrations).
   • Exogenous Interferences (Anticoagulants): 49 native samples (serum and Li-Heparin plasma).
   • Method Comparison: 190 human serum samples (single donors, native samples).
   • Reagent Stability:
     • Onboard: Six human serum samples.
     • Real-time: PreciControl Tumor Marker Level 1 and 2 (3 lot numbers over various time points).
   • Sample Stability: 10 samples for each sample type (Serum, Li-Heparin plasma) for each storage condition.
   • Calibration Stability:
     • Lot: Five human serum samples.
     • On-board: Six human serum samples.
   • Data Provenance: The document states "human serum" and "human plasma" samples were used, and refers to Roche Diagnostics GmbH in Mannheim, Germany, and Penzberg, Germany for establishment registration. It appears to be primarily laboratory-generated data for analytical validation, not specific patient cohorts with country of origin. The term "native samples" implies real patient samples, but no specifics on their origin are given beyond being "human." The studies are retrospective analytical investigations to characterize the device's technical performance.

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

   • This is an in vitro diagnostic (IVD) immunoassay, not an AI/ML device relying on interpretation of medical images or clinical data by experts. The "ground truth" for these analytical studies is the quantitative concentration of CA 15-3 in the sample, measured using reference methods or established spiked concentrations. No human experts were involved in establishing the "ground truth" in the way it would be for an AI device. The ground truth for analytical performance is based on the inherent properties of the samples and reference materials.

3. Adjudication Method for the Test Set:

   • Not applicable. This is an IVD immunoassay, not an AI/ML interpretation study requiring human adjudication.

4. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done:

   • No, an MRMC study was not done. This is an IVD immunoassay. MRMC studies are typically performed for imaging interpretation/AI devices to assess the impact of AI on human reader performance.

5. If a Standalone (i.e., Algorithm Only Without Human-in-the-Loop Performance) Was Done:

   • Yes, the entire study is essentially a "standalone" performance evaluation of the immunoassay system (Elecsys CA 15-3 II on cobas e analyzers). Its output is a quantitative value (CA 15-3 concentration), not an interpretation that a human would then use as "assistance." The performance metrics evaluated (precision, linearity, limits, interference, method comparison) are intrinsic to the device's analytical function without human interaction for result generation.

6. The Type of Ground Truth Used:

   • The ground truth for this device's performance studies is based on:
     • Reference materials/controls: For precision, stability studies (e.g., PreciControl Tumor Marker).
     • Known (spiked) concentrations: For linearity, hook effect, interference studies, where samples are prepared with precisely known amounts of analyte or interfering substances.
     • Native samples: For method comparison and sample type evaluations, where the "ground truth" is established by the predicate device or a trusted reference measurement.
     • Blank samples: For Limit of Blank determination.

7. The Sample Size for the Training Set:

   • Not applicable in the context of an AI/ML algorithm. This device is a biochemical immunoassay. Its "training" or "calibration" involves internal calibration procedures (e.g., 2-point calibration and master curve provided with reagent barcode), which are distinct from the data-driven training of a machine learning model. The reference to "calibration curve" and "master curve" relates to the instrument's operational setup, not a machine learning training dataset.

8. How the Ground Truth for the Training Set Was Established:

   • Not applicable in the AI/ML sense. Calibration is performed using "CalSet" (calibration materials) and is standardized against previous Elecsys CA 15-3 assays, which were in turn standardized against Enzymun Test CA 15-3 and CA 15-3 RIA by Fujirebio Diagnostics. This establishes traceability to recognized reference methods for the quantitative measurement.

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The LOCI CA15-3 method is an in vitro diagnostic test for the quantitative measurement of CA 15-3 in human serum and lithium heparin and EDTA plasma on the Dimension Vista® System. When used in conjunction with other clinical and diagnostic procedures, serial testing with the LOCI CA 15-3 assay may be used as an aid in the management of previously treated stage II and III breast cancer patients and for monitoring response to therapy in metastatic breast cancer patients.

The LOCI 7 CAL is an in vitro diagnostic product for the calibration of Cancer Antigen 15-3 (CA 15-3) and Cancer Antigen 19-9 (CA 19-9) methods on the Dimension Vista® system.

The LOCI CA 15-3 (CA 15-3) method is a homogeneous, sandwich chemiluminescent immunoassay based on LOCI® technology. The LOCI® reagents include two synthetic bead reagents and a biotinylated anti-CA 15-3 monoclonal antibody (DF3) fragment. The first bead reagent (Chemibeads) is coated with an anti-CA15-3 monoclonal antibody (115DB) and contains a chemiluminescent dye. The second bead reagent (Sensibeads) is coated with streptavidin and contains a photosensitizer dye. Sample is incubated with biotinylated antibody and Chemibeads to form bead-CA 15-3-biotinylated antibody sandwiches. Sensibeads are added and bind to form bead-pair immunocomplexes. Illumination of the complex at 680 nm generates singlet oxygen from Sensibeads which diffuses into the Chemibeads, triggering a chemiluminescent reaction. The resulting signal is measured at 612 nm and is a direct function of the CA 15-3 concentration in the sample.

The LOCI 7 calibrator is a liguid, frozen, bovine serum albumin, based product containing CA 15-3 from human cell culture. The kit consists of ten vials two vials per level (A-E), 2.0 mL per vial. Description of the manufacturing, value assignment and stability testing process are provided in this submission report.

The provided document is a 510(k) summary for an in vitro diagnostic device (IVDD), the LOCI CA 15-3 Flex® Reagent Cartridge, and its associated calibrator. IVDDs, particularly those for tumor markers, are typically evaluated through analytical performance studies rather than clinical studies with patient outcomes as endpoints, which are more common for AI/ML devices or therapeutic interventions.

The document does not contain the information requested in the prompt regarding acceptance criteria and performance data from a "study that proves the device meets the acceptance criteria." Specifically, it lacks:

• A table of acceptance criteria and reported device performance: The document compares the intended use, sample type, measuring range, sample size, and measurement method of the new device to its predicate, but these are not "acceptance criteria" in the sense of performance metrics (like sensitivity, specificity, accuracy, precision, etc.) and their corresponding measured values.
• Sample size, data provenance, number of experts, adjudication method, MRMC studies, standalone performance, type of ground truth, training set size, and how training ground truth was established: These details are typical for studies involving diagnostic algorithms, particularly those using AI/ML, and are not found in this 510(k) summary for a traditional immunoassay and calibrator.

Instead, this document focuses on demonstrating substantial equivalence to existing legally marketed devices, as is standard for 510(k) submissions. The substantial equivalence is argued based on similarities in intended use, technology, and analytical characteristics (though specific performance metrics are not detailed here beyond measuring range).

Therefore, I cannot fulfill the request to provide acceptance criteria and study details based on the provided text.

The document primarily states:

• The LOCI CA 15-3 method is a quantitative measurement of CA 15-3 using a homogeneous, sandwich chemiluminescent immunoassay.
• Its intended use is as an aid in the management of previously treated stage II and III breast cancer patients and for monitoring response to therapy in metastatic breast cancer patients, in conjunction with other clinical and diagnostic procedures.
• The LOCI 7 CAL is for the calibration of CA 15-3 and CA 19-9 methods.
• Substantial equivalence is claimed against the ADVIA Centaur CA 15-3 assay (K012357) for the reagent cartridge and the Access® BR Monitor Assay (K072612) for the calibrator.

To obtain the detailed performance data (e.g., precision, accuracy, linearity, analytical sensitivity, etc.) and acceptance criteria that were likely part of the original 510(k) submission, one would need to access the full 510(k) submission packet, which is generally not publicly available in its entirety beyond the summary.

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The Access BR Monitor assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of CA 15-3 antigen levels in human serum and plasma using the Access Immunoassay Systems. This device is indicated for use in the measurement of CA 15-3 antigen to aid in the management of breast cancer patients. Serial testing for patient CA 15-3 antigen concentrations should be used in conjunction with other clinical methods for monitoring breast cancer.

The Access BR Monitor Calibrators are intended to calibrate the Access BR Monitor assay for the quantitative determination of CA 15-3 antigen levels in human serum and plasma using the Access Immunoassay Systems.

The Access BR Monitor assay and the Access Immunoassay Analyzers comprise the Access Immunoassay Systems for the quantitative determination of CA 15-3 antigen levels in human serum and plasma.

Acceptance Criteria and Device Performance Study for Access® BR Monitor Assay (K072612)

This submission describes the modified Access® BR Monitor assay, an immunoassay for the quantitative determination of CA 15-3 antigen levels in human serum and plasma. The study focuses on demonstrating substantial equivalence to the previously cleared Access® BR Monitor assay (K033036) by verifying that the modified device meets specified acceptance criteria, particularly concerning imprecision.

1. Table of Acceptance Criteria and Reported Device Performance

Assessment of Imprecision Performance:

The reported total imprecision (7.7% - 10.8% CV) falls largely within the acceptance criteria of ≤ 10% for concentrations between 15 and 500 U/mL.
The statement "Total imprecision ranged from 7.7% CV to 10.8% CV" suggests that within the tested range (18 to 513 U/mL), there might be some values slightly exceeding 10% CV, likely towards the upper end of the 500 U/mL range or slightly above it. The acceptance criteria for concentrations greater than 500 U/mL is ≤ 12%. The summary states that "Imprecision above 500 U/mL was the only performance characteristic revised," implying the device does meet the ≤ 12% criterion for concentrations > 500 U/mL, even if not explicitly detailed in the reported values. The overall conclusion states that the modification to imprecision above 500 U/mL "was not found to impact the safety and efficacy of the device."

2. Sample size used for the test set and the data provenance

The document provides a "Summary of Precision Study" which states:

• Within-run assay imprecision was tested for concentrations from approximately 18 to 513 U/mL.
• Data Provenance: Not explicitly stated, but clinical precision studies for diagnostic devices are typically conducted in a controlled laboratory setting (e.g., in-house or contract research organization). It's reasonable to infer this was a prospective study designed to assess the performance of the modified device. The country of origin is not specified.

The exact number of samples (individual patient samples or spiked control samples) used to generate these imprecision ranges is not provided. Usually, imprecision studies involve running multiple replicates of control samples at different concentrations across various runs and days.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts

Not applicable. This is an in-vitro diagnostic (IVD) device for quantitative antigen determination, not a device requiring human expert interpretation of images or other subjective data for ground truth establishment. The "ground truth" for precision studies relies on the known or reference values of the control materials used.

4. Adjudication method for the test set

Not applicable. As described above, this is an IVD device for quantitative measurement. There is no subjective interpretation requiring adjudication among experts.

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

Not applicable. This device is an IVD immunoassay, not an AI-assisted diagnostic tool requiring human reader studies or MRMC analyses.

6. If a standalone (i.e. algorithm only without human-in-the loop performance) was done

Yes, the precision study evaluates the performance of the Access® BR Monitor assay as a standalone algorithm/device. The results (CV percentages) reflect the inherent performance of the instrument and reagents in measuring CA 15-3 antigen levels without human subjective interpretation.

7. The type of ground truth used

The ground truth for the imprecision study is based on the known or reference concentrations of the control samples used. These control samples are typically manufactured to contain specific, verified concentrations of the CA 15-3 antigen.

8. The sample size for the training set

Not applicable. This is not a machine learning or AI-based device that requires a distinct "training set" in the conventional sense. The device's operational parameters (e.g., reagent formulation, calibration curves) are established through manufacturing and assay development processes, not through a 'training set' of data in the AI context.

9. How the ground truth for the training set was established

Not applicable, as explained in point 8. The "ground truth" for establishing the assay's operational characteristics would stem from analytical characterization during development, using reference materials and established analytical methods.

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The ARCHITECT CA 15-3 assay is a Chemiluminescent Microparticle Immunoassay (CMIA) for the quantitative determination of DF3 defined antigen in human serum and plasma on the ARCHITECT i System. The ARCHITECT CA 15-3 assay is to be used as an aid in the management of Stage II and Stage III breast cancer patients. Serial testing for patient CA 15-3 assay values should be used in conjunction with other clinical methods for monitoring breast cancer.

The ARCHITECT CA 15-3 assay is a two-step immunoassay to determine the presence of DF3 reactive determinants in human serum or plasma, using Chemiluminescent Microparticle Immunoassay (CMIA) technology with flexible assay protocols, referred to as Chemiflex™. In the first step, sample, wash buffer and 115D8 coated paramagnetic microparticles are combined. DF3 reactive determinants present in the sample bind to the 115D8 coated microparticles. After washing, DF3 acridinium-labeled conjugate is added in the second step. Pre-Trigger and Trigger Solutions are then added to the reaction mixture; the resulting chemiluminescent reaction is measured as relative light units (RLUs). A direct relationship exists between the amount of DF3 reactive determinants in the sample and the RLUs detected by the ARCHITECT i optical system.

Acceptance Criteria and Device Performance Study for ARCHITECT® CA 15-3® Assay

This document summarizes the acceptance criteria and the study performed to demonstrate that the ARCHITECT® CA 15-3® Assay meets these criteria, based on the provided 510(k) summary.

1. Table of Acceptance Criteria and Reported Device Performance

The provided document details various performance characteristics, which serve as the acceptance criteria for the device. The reported performance for the ARCHITECT CA 15-3 Assay is compared against these criteria.

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