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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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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):

For IMMULITE 2000 OM-MA Assay (modified):

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.

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For in vitro diagnostic use with the IMMULITE® 2000 Systems Analyzers — for the quantitative measurement of cortisol (hydrocortisone, Compound F) in serum, as an aid in the clinical assessment of adrenal status.

The IMMULITE 2000 Cortisol assay is comprised of the following components: Cortisol Bead Pack (solid phase) containing Polyclonal rabbit anti-cortisol antibody; Cortisol Reagent Wedge (liquid phase) containing Alkaline phosphatase (bovine calf intestine) conjugated to cortisol in buffer, with preservative; and Cortisol Adjustors (Low and High) containing Cortisol in processed human serum, with preservative.

The provided document describes the IMMULITE® 2000 Cortisol device, a chemiluminescence immunoassay for the quantitative measurement of cortisol in serum, used as an aid in the clinical assessment of adrenal status. This submission (K202826) is for a modified device due to a new supplier of the antibody, with the predicate device being the IMMULITE® 2000 Cortisol (K931409).

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

Executive Summary:

The study aims to demonstrate substantial equivalence of the modified IMMULITE® 2000 Cortisol assay to the predicate device. The performance characteristics evaluated included detection limits, linearity, precision, spike recovery, method comparison, and analysis of interfering and cross-reactive substances. All evaluated studies produced acceptable results compared to the predicate device.

1. Table of Acceptance Criteria and Reported Device Performance:

The document doesn't explicitly state "acceptance criteria" for each performance characteristic in a quantifiable manner (e.g., "linearity must have an R-squared > 0.98"). Instead, it states that the studies "produced acceptable results when compared to the Predicate device and were deemed verified" or that information "has not changed and are as per K931409." For method comparison, a regression equation and correlation coefficient are provided.

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

• Method Comparison:

  • Sample Size: 149 native patient samples.
  • Data Provenance: Not explicitly stated, but "native patient samples" implies clinical samples, likely from a hospital or lab. Retrospective or prospective is not specified. Country of origin not specified.

• Linearity:

  • Sample Size: Not explicitly stated as a number of unique patient samples, but 9 levels of dilutions were prepared from high and low human serum pools.
  • Data Provenance: Human serum pools. Retrospective or prospective, and country of origin are not specified.

• Specificity (Cross-Reactivity):

  • Sample Size: Not explicitly stated, but multiple cross-reactant solutions were prepared and spiked into "a blank sample (charcoal-adsorbed human serum)."
  • Data Provenance: Charcoal-adsorbed human serum.

• Interference:

  • Sample Size: 5 patient samples.
  • Data Provenance: Not explicitly stated, but "patient samples" implies clinical samples. Retrospective or prospective, and country of origin are not specified.

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

This information is not provided in the document. For in vitro diagnostic assays measuring specific analytes, the "ground truth" is typically the measured value itself, often established by a validated reference method or the predicate device, rather than expert interpretation of images or clinical findings.

4. Adjudication Method for the Test Set:

This is not applicable in the context of an in vitro diagnostic assay like this. Adjudication methods (e.g., 2+1, 3+1) are common in studies involving subjective assessments, such as imaging interpretation by multiple readers. For quantitative measurements, the "truth" is typically derived from the measurement itself.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done, and the effect size of how much human readers improve with AI vs without AI assistance:

This is not applicable. The device is an in vitro diagnostic assay, not an AI or imaging device that assists human readers.

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

This is not applicable. The device is a laboratory instrument (IMMULITE® 2000 System Analyzers) that performs a chemiluminescent immunoassay. It does not involve a "standalone algorithm" in the same sense as an AI diagnostic software. Its performance is inherent to the assay and instrument.

7. The Type of Ground Truth Used:

For this type of in vitro diagnostic device, the "ground truth" is established by:

• Reference Methods/Predicate Device: For method comparison, the "truth" is implicitly the values obtained from the predicate device (unmodified IMMULITE® 2000 Cortisol assay).
• Known Concentrations: For linearity, detection limits, specificity, and interference studies, the "ground truth" is based on precisely prepared samples with known concentrations of cortisol, cross-reactants, or interferents, or "spiked" samples where the added amount is known. These are often prepared from certified reference materials or highly pure substances.

8. The Sample Size for the Training Set:

This is not applicable. This is an immunoassay device, not a machine learning or AI model that requires a "training set" in the conventional sense. The development and optimization of the assay chemistry, reagents, and instrument operation are based on laboratory experiments and validation processes, not data training.

9. How the Ground Truth for the Training Set was Established:

This is not applicable as there is no "training set" for this type of device. The accuracy of the assay is established through extensive analytical validation using prepared controls, reference materials, and patient samples compared against established methods.

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For in vitro diagnostic use with the IMMULITE® and IMMULITE 1000 Analyzers - for the quantitative measurement of cortisol (hydrocortisone, Compound F) in serum, as an aid in the clinical assessment of adrenal status.

The IMMULITE/IMMULITE® 1000 Cortisol assay is comprised of the following components: Cortisol Test Unit (solid phase) - 1 bead/Test unit, Polyclonal rabbit anti-cortisol antibody. Cortisol Reagent Wedge (liquid phase) - 7.5 mL, Alkaline phosphatase (bovine calf intestine) conjugated to cortisol in buffer, with preservative. Cortisol Adjustors (Low and High) - 3 mL, Cortisol in processed human serum, with preservative.

The document describes the performance characteristics of the IMMULITE/IMMULITE® 1000 Cortisol assay, which is an in vitro diagnostic device. This device measures cortisol in serum to aid in the clinical assessment of adrenal status. The submission is for a modified device with a new supplier for the antibody, maintaining the same intended use.

Here's an analysis of the acceptance criteria and the study proving the device meets them:

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

The document doesn't explicitly present a table labeled "acceptance criteria." Instead, it describes performance characteristics that were evaluated to demonstrate substantial equivalence to a predicate device. The implied acceptance criterion for each characteristic is that the performance of the modified device should be comparable to or within acceptable limits of the predicate device, or meet established clinical laboratory standards (e.g., CLSI guidelines).

Here's a table based on the provided "Performance Characteristics" section, showing the evaluated parameters and their reported outcomes:

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

• Detection Limits (LoB, LoD, LoQ): The sample sizes are not explicitly stated for the determination of LoB, LoD, and LoQ, but these are typically determined using multiple replicates of blank and low-concentration samples. The study was conducted in accordance with CLSI EP17-A2.
• Linearity: The study involved combining a high human serum pool with a low human serum pool to create 9 levels of dilutions. The number of individual samples within these pools is not specified. The provenance is "human serum."
• Method Comparison:
  • Sample Size: A total of 152 native patient samples.
  • Data Provenance: "native patient samples," indicating human origin. The country of origin is not specified, but the applicant's address is in the UK. The study was retrospective or prospective is not explicitly stated, but "patient samples" typically implies retrospectively collected samples for this type of comparison study.

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 (IVD) assay measuring a biomarker (cortisol). The "ground truth" for such devices is established by reference methods or validated higher-order methods, not typically by expert human interpretation (like in imaging AI).

• For Method Comparison, the ground truth is simply the measurement obtained from the predicate device (unmodified IMMULITE 1000 Cortisol Assay), which is presumed to be the accepted standard. No human experts are used for ground truth establishment in this context.
• For Detection Limits, Linearity, Specificity, and Interference, the ground truth is based on the precise preparation of known concentrations of analytes, cross-reactants, or interfering substances, and comparison to the assay's ability to accurately measure them. This does not involve expert human interpretation.

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

Not applicable. As an IVD assay measuring a quantitative biomarker, adjudication by human experts is not part of the ground truth establishment or performance evaluation process. The measurements are objective.

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 not an AI-assisted diagnostic imaging device for human interpretation, but rather an automated in vitro diagnostic assay measuring a chemical compound. Therefore, MRMC studies are not relevant.

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

Yes, the performance characteristics described are indeed standalone performance of the device (IMMULITE/IMMULITE® 1000 Cortisol assay) itself. It evaluates the accuracy, precision, limits, and specificity of the biochemical measurement system, without human involvement in the direct measurement or interpretation of the assay's output for diagnostic purposes in the study. The human role is in operating the instrument and interpreting the numerical result in the clinical context, but the study focuses on the analytical performance of the device.

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

The ground truth used for this IVD device is primarily:

• Reference measurements/Predicate device measurements: For the method comparison study, the measurements from the legally marketed predicate device (IMMULITE/IMMULITE® 1000 Cortisol, K931409) serve as the reference or "ground truth" for comparison.
• Prepared known concentrations: For studies like linearity, detection limits, specificity (cross-reactivity), and interference, the ground truth is established by preparing samples with precisely known concentrations of the analyte, cross-reactants, or interfering substances.
• Standardized methods/guidelines: Compliance with CLSI (Clinical and Laboratory Standards Institute) guidelines (e.g., EP17-A2, EP06-A, EP09c, EP07) implies that the ground truth methodology follows accepted laboratory standards for analytical performance.

8. The sample size for the training set:

Not applicable. This document describes a traditional in vitro diagnostic immunoassay, not a machine learning or artificial intelligence algorithm that requires a "training set." The development of such assays involves chemical and biological optimization, not data-driven model training.

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

Not applicable, as there is no "training set" for this type of device.

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