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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 Elecsys CA 15-3 II CalCheck 5 is an assayed control for use in calibration verification and for use in the verification of the assay range established by the Elecsys CA 15-3 II reagent on the indicated Elecsys and cobas e immunoassay analyzers. For in vitro diagnostics use only.

The Elecsys CA 15-3 II CalCheck 5 is a lyophilized product consisting of CA 15-3 in equine serum matrix (Level 1) or human serum matrix (Levels 2-5). 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 that proves the device meets them, based on the provided text:

Device: Elecsys CA 15-3 II CalCheck 5

Intended Use: An assayed control for use in calibration verification and for use in the verification of the assay range established by the Elecsys CA 15-3 II reagent on the indicated Elecsys and cobas e immunoassay analyzers. For in vitro diagnostics use only.

1. Table of Acceptance Criteria and Reported Device Performance

• Level 1 assigned value: ≤ 2.5 U/mL.
• % CV: 5% for levels 2-5.
• Median value on additional analyzers (Elecsys 2010, cobas e 411, cobas e 601, and cobas e 602) must be within 10% of the master platform (MODULAR ANALYTICS E170) assigned value. | - Value assignment testing was conducted and passed pre-defined acceptance criteria (specific numerical results for each level are not detailed, but the summary states they passed).
• Assigned values from the master platform (MODULAR ANALYTICS E170) were deemed valid for the other platforms (Elecsys 2010, cobas e 411, cobas e 601, and cobas e 602). |
  | Open-Vial Stability (after reconstitution) | Reconstituted Elecsys CA 15-3 II CalCheck 5 must be stable for up to 4 hours at 20-25°C. | Real-time testing was performed, and the data support the claim of stability for up to 4 hours at 20-25°C. |
  | Shelf-Life Stability | - Initial shelf-life claim: 18 months at 2-8°C.
• Long-term shelf-life claim: 36 months at 2-8°C (supported by ongoing real-time testing). | - Accelerated stability testing at 35°C supports an initial shelf-life claim of 18 months at 2-8°C.
• Real-time testing at 2-8°C is ongoing to support a claim of 36 months. |

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

• Sample Size (Value Assignment): For each CalCheck lot, the CalChecks are run in duplicate on at least three E170 analyzer measuring cells. The assigned value is the median of at least 6 determinations. This process is repeated for each of the five CalCheck levels (levels 1-5). The same procedure is performed on four additional analyzers (Elecsys 2010, cobas e 411, cobas e 601, and cobas e 602) for comparison.
• Sample Size (Stability): Not explicitly stated, but "real-time and accelerated stability tests were conducted."
• Data Provenance: Not explicitly stated, but presumably from internal laboratory studies conducted by Roche Diagnostics in the context of their in vitro diagnostic device development. This would be considered prospective data generation for regulatory submission. The country of origin is not specified but Roche Diagnostics is based in Indianapolis, IN, USA.

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

• Not applicable for this type of device. The "ground truth" for in vitro diagnostic control materials is established through extensive analytical validation (value assignment, stability, precision) against reference methods or established procedures, rather than expert interpretation of results. The "truth" is the analytically determined value and its expected performance characteristics.

4. Adjudication Method for the Test Set

• Not applicable. As this device is an assayed control for calibration verification, there is no subjective adjudication of results by experts. Results are evaluated against predefined analytical precision and accuracy criteria. The median value from multiple determinations is used as the assigned value.

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

• No. This type of study (MRMC) is relevant for diagnostic imaging or interpretation tasks where human readers (interpreters) are involved. The Elecsys CA 15-3 II CalCheck 5 is an in vitro diagnostic control material used to verify instrument performance, not to aid in the interpretation of patient samples by human readers.

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

• Yes, in essence. The performance characteristics (value assignment, stability) are determined for the control material itself, independent of immediate human intervention in the result determination process for patient samples. The evaluation described is of the analytical performance of the control material on specified automated immunoassay analyzers.

7. The Type of Ground Truth Used

• Analytically Determined/Assigned Values: The ground truth for the CalChecks are their "assigned values," which are determined through a rigorous internal testing process involving multiple runs on multiple analyzer measuring cells. These assigned values are then used as the reference points for subsequent quality control and calibration verification by end-users. The stability data are also based on analytically measured changes in concentration over time.

8. The Sample Size for the Training Set

• Not applicable. This device is an assayed control material, not a machine learning algorithm that requires a "training set." The development of the product and its performance characteristics rely on analytical validation studies, not on training data in the context of AI/ML.

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

• Not applicable, as it's not an AI/ML device requiring a training set.

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