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N Latex FLC kappa and lambda are in-vitro diagnostic reagents for the quantitative determination of free light chains (FLC), type kappa or type lambda in human serum and EDTA-plasma. N Latex FLC kappa and lambda assays are used: • as an aid in the diagnosis and monitoring of multiple myeloma (MM) on the BN Systems and Atellica® CH Analyzer. • as an aid in the diagnosis of immunoglobulin light-chain amyloidosis (AL) on the BN Systems and Atellica® CH Analyzer. • as an aid in the monitoring of immunoglobulin light-chain amyloidosis (AL) on the BN Systems. · as an aid in the evaluation of Monoclonal Gammopathy of Undetermined Significance (MGUS) on the BN Systems and Atellica® CH Analyzer. Results of FLC measurements should always be interpreted in conjunction with other laboratory and clinical findings.

The N Latex FLC (free light chain) assays are in vitro diagnostic reagents for the quantitative determination of free light chains, type kappa or type lambda, in human serum and EDTA plasma by means of particle-enhanced immunoassay determination. Used in conjunction with other clinical and laboratory findings, FLC measurements are used as an aid in the diagnosis and monitoring of multiple myeloma (MM), as an aid in the diagnosis of amyloidosis (AL) on the BN Systems and Atellica® CH Analyzer; as an aid in the monitoring of amyloidosis (AL) on the BN Systems and as an aid in the evaluation of MGUS on the BN Systems. The FLC test systems on the Atellica® CH Analyzer are based upon the principles of particle-enhanced turbidimetry. Polystyrene particles coated with antibodies to human free light chains, type kappa or lambda, respectively, are agglutinated with samples containing FLC. Monitoring the agglutination by measuring the increase in turbidity, a concentration curve is obtained. The actual change in absorbance is proportional to the concentration of the respective protein in the sample. The result is evaluated by comparison with a standard of known concentration.

The provided text describes the acceptance criteria and performance study for the Siemens Healthcare Diagnostics Products GmbH N Latex FLC kappa and N Latex FLC lambda assays when applied to the Atellica® CH Analyzer, specifically for the added indication as an aid in the evaluation of Monoclonal Gammopathy of Undetermined Significance (MGUS).

Here's a breakdown of the requested information:

1. Table of Acceptance Criteria and Reported Device Performance

The device performance is assessed through a method comparison study between the N Latex FLC kappa and N Latex FLC lambda assays on the Atellica® CH Analyzer (candidate device) and the N Latex FLC kappa and N Latex FLC lambda assays on the BN ProSpec System (predicate device).

Note on MGUS Specific Results: While the overall study meets the acceptance criteria for slope and predicted bias, the separate analysis for MGUS patients only for N Latex FLC lambda shows predicted biases of -15.7% and -16.9% at the lower and upper limit reference intervals respectively, and a slope of 0.841. These specific MGUS-only results for lambda do not meet the stated acceptance criteria of ≤ +/- 10% bias and a slope of 0.9-1.1. However, the document's general conclusion states "Acceptance criteria fulfilled" based on the overall results (Table 7.3.1-2 and 7.3.1-3). The separate MGUS-only table (7.3.1-4 and 7.3.1-5) is presented as a sub-analysis, and the acceptance criteria for this sub-analysis are not explicitly re-stated or modified from the general criteria. The FDA’s acceptance of this submission implies that the overall performance was considered sufficient.

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

• Sample Size (Overall):
  • N Latex FLC kappa: 212 samples
  • N Latex FLC lambda: 202 samples
• Sample Size (MGUS-specific analysis):
  • N Latex FLC kappa: 38 MGUS samples
  • N Latex FLC lambda: 35 MGUS samples
• Data Provenance: The method comparison study was conducted internally at the Siemens Healthcare Diagnostics Products GmbH site in Marburg, Germany. It incorporated "samples derived from MGUS patients." The text for the clinical performance study for MGUS evaluation mentions "121 MGUS samples (89 Non-IgM, 21 IqM and 11 LC MGUS) and 102 polyclonal immunostimulation samples," but it's important to differentiate these from the test set numbers used in the method comparison study (212/202 and 38/35). The specific type (retrospective/prospective) is not explicitly stated for the source of these samples, but the mention of "derived from MGUS patients" suggests pre-existing samples, which would typically be retrospective.

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

This information is not provided in the given text. The device is an in-vitro diagnostic reagent for quantitative determination of free light chains, and the "ground truth" for the method comparison study is established by comparison to a legally marketed predicate device (N Latex FLC assays on the BN ProSpec System).

4. Adjudication Method for the Test Set

This information is not applicable as the ground truth is established by a predicate diagnostic device, not by expert consensus or adjudication. The study is a method comparison, not a reader study.

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

No, an MRMC comparative effectiveness study was not done. This device is an in-vitro diagnostic assay, not an imaging AI device that relies on human reader interpretation. The study evaluates the analytical performance of the assay compared to a predicate, not how human readers improve with AI assistance.

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

Yes, in essence. This is a standalone performance study of the diagnostic assay on a new instrument platform (Atellica® CH Analyzer) compared to its performance on a predicate instrument (BN ProSpec System). The "algorithm" here refers to the analytical process of the in-vitro diagnostic test.

7. The Type of Ground Truth Used

The ground truth for the method comparison study is the performance of the predicate device (N Latex FLC kappa and N Latex FLC lambda assays on the BN ProSpec System). This is a comparative study aiming to show equivalence to an already legally marketed and accepted diagnostic method.

8. The Sample Size for the Training Set

This information is not provided in the text. The document describes a study to support a 510(k) submission for a diagnostic assay, which typically involves validation studies rather than "training sets" in the context of machine learning (unless the underlying technology uses machine learning, which is not indicated here). If there was any internal development or calibration process that could be considered "training," the sample size used for that is not disclosed.

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

This information is not applicable/not provided as there is no mention of a "training set" in the context of machine learning. If the question refers to how the "predicate device" performance (which acts as the reference for this study) was originally established, that information is outside the scope of this particular 510(k) submission document. The predicate device itself has been cleared under previous 510(k)s (K171742, K182098, K193047, K201496).

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N Latex FLC kappa and lambda are in-vitro diagnostic reagents for the quantitative determination of free light chains (FLC), type kappa or type lambda in human serum and EDTA plasma. N Latex FLC kappa and lambda assays are used:
• as an aid in the diagnosis and monitoring of multiple myeloma (MM) on the BN Systems and Atellica® CH Analyzer.
• as an aid in the diagnosis of immunoglobulin light-chain amyloidosis (AL) on the BN Systems and Atellica® CH Analyzer.
· as an aid in the monitoring of immunoglobulin light-chain amyloidosis (AL) on the BN Systems.
· as an aid in the evaluation of Monoclonal Gammopathy of Undetermined Significance (MGUS) on the BN Systems.
Results of FLC measurements should always be interpreted in conjunction with other laboratory and clinical findings.

N Latex FLC kappa and lambda are in-vitro diagnostic reagents for the quantitative determination of free light chains (FLC), type kappa or type lambda in human serum and EDTAplasma. N Latex FLC kappa and lambda assays are used as an aid in the diagnosis and monitoring of multiple myeloma (MM) and immunoglobulin light-chain amyloidosis (AL) and as an aid in the evaluation of Monoclonal Gammopathy of Undetermined Significance (MGUS). Monitoring of immunoglobulin light-chain amyloidosis (AL) and evaluation of MGUS are cleared for use only on the BN Systems.
The N Latex FLC test systems are based upon the principles of particle-enhanced immunonephelometry. Polystyrene particles coated with monoclonal antibodies to human free light chains, type kappa or lambda, respectively, are agglutinated when mixed with samples containing free light chains. These aggregates scatter a beam of light passed through the sample. The intensity of the scattered light is proportional to the concentration of the respective protein in the sample. The result is evaluated by comparison with a standard of known concentration.

This document describes the N Latex FLC kappa and N Latex FLC lambda assays, in vitro diagnostic reagents used for the quantitative determination of free light chains (FLC), type kappa or type lambda, in human serum and EDTA plasma. This submission seeks to add "monitoring of immunoglobulin light-chain amyloidosis (AL) on the BN Systems" to the device's indications for use.

1. Acceptance Criteria and Reported Device Performance

The acceptance criteria are implicitly derived from the comparative studies presented, aiming to demonstrate substantial equivalence to the predicate device and acceptable concordance with clinical status. The reported performance is summarized in the tables below, using Evaluation Mode 2 as favored by Siemens.

Comparison of N Latex FLC versus Freelite (Predicate Device) - Evaluation Mode 2

Concordance of N Latex FLC versus Clinical Status - Evaluation Mode 2

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

The test set for the comparative effectiveness study included data from a multi-center study on immunoglobulin light-chain amyloidosis (AL) patients.

• Sample Size: The N Latex FLC versus Freelite comparison involves a total of 241 observations based on initial and consecutive blood draws. The comparison to clinical status involves 222 observations.
• Data Provenance: The document does not explicitly state the country of origin. The study is retrospective, comparing changes between an initial sample draw and each consecutive blood draw, and then comparing these results to both a predicate device and clinical response.

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

The "clinical response" used as ground truth was "provided by the physician taking into account all available clinical and laboratory information."

• Number of Experts: Not explicitly stated, but it implies individual physicians for each patient.
• Qualifications: "Physician" is the qualification mentioned. No specific experience levels (e.g., years of experience or specialization in oncology/hematology) are provided for these physicians.

4. Adjudication Method for the Test Set

The document mentions that clinical response was "provided by the physician taking into account all available clinical and laboratory information." There is no mention of a formal adjudication panel or process (e.g., 2+1, 3+1). The response evaluation criteria are derived from NCCN Response Criteria for serum M protein/IFE and FLC levels/ratios.

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

No MRMC study was conducted. This device is an in-vitro diagnostic assay, not an imaging AI device that would typically involve human readers. The comparative effectiveness assessment focuses on the agreement between the new device and a predicate device, and the concordance of both devices with physician-determined clinical status.

6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study

Yes, the studies presented are standalone performance assessments of the N Latex FLC kappa and lambda assays. The device itself is an automated assay, and its performance is evaluated directly (algorithm only). The comparison to clinical status is essentially an evaluation of the algorithm's output versus an established clinical truth.

7. Type of Ground Truth Used

The ground truth for the clinical comparison was based on clinical status/physician assessment, which encompasses "all available clinical and laboratory information" including NCCN Response Criteria. This is closer to an "outcomes data" or "expert consensus" type of ground truth in a clinical context.

8. Sample Size for the Training Set

The document does not provide information on the training set size. This submission focuses on performance data for an extended indication for monitoring AL. It refers to previous submissions (K171742, K182098, K193047) for established analytical and clinical studies, implying that the device was already developed and validated. The current submission's study used a distinct set of AL patients for evaluating the new monitoring claim.

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

Not applicable/provided. As this submission is for an extended indication and refers to previous clearances for the device, details on the ground truth establishment for the initial training set (if any for algorithm development) are not included in this document. The focus of the provided text is on demonstrating performance for the new monitoring claim.

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N Latex FLC kappa and lambda are in-vitro diagnostic reagents for the quantitative determination of free light chains (FLC), type kappa or type lambda in human serum and EDTA-plasma. N Latex FLC kappa and lambda assays are used:
• as an aid in the diagnosis and monitoring of multiple myeloma (MM) on the BN Systems and Atellica® CH Analyzer,
• as an aid in the diagnosis of amyloidosis (AL) on the BN Systems and Atellica® CH Analyzer,
• as an aid in the evaluation of Monoclonal Gammopathy of Undetermined Significance (MGUS) on the BN Systems.
Results of FLC measurements should always be interpreted in conjunction with other laboratory and clinical findings.

The N Latex FLC (free light chain) assays are in vitro diagnostic reagents for the quantitative determination of free light chains, type kappa or type lambda, in human serum and EDTA plasma by means of particle-enhanced immunoassay determination. Used in conjunction with other clinical and laboratory findings, FLC measurements are used as an aid in the diagnosis and monitoring of multiple myeloma (MM), as an aid in the diagnosis of amyloidosis (AL) and on the BN Systems, as an aid in the evaluation of MGUS.
Polystyrene particles coated with antibodies to human free light chains, type kappa or lambda, are agglutinated when mixed with samples containing FLC. These aggregates scatter a beam of light passed through the sample. The intensity of the scattered light is proportional to the concentration of the respective protein in the sample. The result is evaluated by comparison with a standard of known concentration.

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

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implicitly defined by the concordance percentages achieved in various patient cohorts. The document does not explicitly state numerical thresholds as "acceptance criteria" but rather presents the performance results.

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

• MGUS Concordance:
  • Test Set Sample Size: 121 MGUS samples (89 Non-IgM, 21 IgM, 11 LC MGUS)
  • Data Provenance: Not explicitly stated, but the study was described as a "multi-center study," suggesting samples were collected from various clinical sites. It is implied to be retrospective as they are described as "clinically defined samples" and patients with "diagnosed" MGUS or polyclonal immunostimulation.
• LC MGUS Concordance:
  • Test Set Sample Size: 11 LC MGUS samples (subset of the 121 MGUS samples).
  • Data Provenance: Same as above (multi-center, implied retrospective).
• Polyclonal Immunostimulation Concordance:
  • Test Set Sample Size: 102 specimens.
  • Data Provenance: Same as above (multi-center, implied retrospective).
• Evaluation of MGUS Patients (Stable Cohort):
  • Test Set Sample Size: 61 patients.
  • Data Provenance: Not explicitly stated, but patients were "initially diagnosed for MGUS" and "evaluated over different time periods" with "at least 4 sample draws at various time intervals," indicating a prospective or longitudinal study design over time.
• Evaluation of MGUS Patients (Progressive Cohort):
  • Test Set Sample Size: 4 patients.
  • Data Provenance: Same as above (prospective/longitudinal).

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

The document does not specify the number or qualifications of experts used to establish the ground truth for the test set. It refers to "clinically defined samples" and "clinical diagnosis," implying that the ground truth was based on a comprehensive clinical assessment, likely by medical professionals (e.g., oncologists, hematologists), but the details are not provided.

4. Adjudication Method for the Test Set

The document does not describe an adjudication method for establishing the ground truth of the test set (e.g., 2+1, 3+1). The ground truth appears to be based on pre-existing "clinical diagnosis" or "clinically defined samples."

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

• No, an MRMC comparative effectiveness study was not done. This device is an in-vitro diagnostic reagent, which provides quantitative measurements, not an imaging device that human readers interpret. Therefore, the concept of "human readers improve with AI vs without AI assistance" is not applicable in this context.

6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study

• Yes, a standalone performance study was done. The studies described (concordance and evaluation of stable/progressive patients) assessed the performance of the N Latex FLC assays (the "device" or "algorithm" in this context) directly against clinical diagnoses and criteria. The results are reported as the "N Latex FLC κ/λ Ratio Concordance" and "N Latex FLC results," indicating an assessment of the device's output without direct human-in-the-loop interpretation of the assay results during the diagnostic process itself (though human interpretation of the FLC results in conjunction with other clinical findings is part of the intended use).

7. Type of Ground Truth Used

The ground truth used was expert consensus / clinical diagnosis / outcomes data.

• "Clinically defined samples" with diagnoses of MGUS or polyclonal immunostimulation.
• "Clinical diagnosis of MGUS" and "change in clinical diagnosis of MGUS to MM" for the stable and progressive cohorts, respectively. This implies that the ground truth was established by medical professionals using a combination of clinical findings, established diagnostic criteria, and other laboratory results, which could be considered a form of expert consensus or clinical outcomes.

8. Sample Size for the Training Set

The document does not report on a separate training set or its sample size. The performance data provided is for the evaluation of the device, implying the device was already developed. For an in-vitro diagnostic assay like this (which is a reagent test and analytical system), the "training" typically refers to the development and optimization of the assay's chemical and biological components, calibration, and establishment of analytical performance characteristics, rather than machine learning model training on a distinct labeled dataset. The document refers to prior submissions (K171742 and K182098) for "previously documented analytical and clinical studies," which likely covered the initial development and analytical validation.

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

As no explicit "training set" for an AI/ML model is mentioned, this question is not directly applicable. For a traditional diagnostic assay, the "ground truth" during development involves rigorous analytical validation (e.g., using reference materials, spiked samples, and comparison to established methods) and initial clinical studies to define normal ranges and characteristic responses in different disease states. These would have been established through standard laboratory and clinical practices, likely involving certified reference materials, reference methods, and clinical expert assessment of patient samples.

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In-vitro diagnostic reagents for the quantitative determination of free light chains (FLC), type kappa or type lambda in human serum and EDTA-plasma. FLC measurements are used as an aid in the diagnosis and monitoring of multiple myeloma (MM) and as an aid in the diagnosis of amyloidosis (AL) in conjunction with other laboratory and clinical findings.

The response category assignment of 'Complete Response' for the monitoring of MM, is reliant upon the combination of clinical history and other tests including protein electrophoresis, immunofixation and bone marrow, imaging and urine assessments.

The N Latex FLC (free light chain) assays are in vitro diagnostic reagents for the quantitative determination of free light chains, type kappa or type lambda, in human serum and EDTA plasma by means of particle-enhanced immunoassay determination. Used in conjunction with other clinical and laboratory findings, FLC measurements are used as an aid in the diagnosis and monitoring of multiple myeloma (MM) and as an aid in the diagnosis of amyloidosis (AL).

Polystyrene particles coated with antibodies to human free light chains, type kappa or lambda, respectively, are agglutinated with samples containing FLC. A concentration curve is obtained by monitoring agglutination and measuring the increase in turbidity. The actual change in absorbance is proportional to the concentration of the respective protein in the sample. The result is evaluated by comparison with a standard of known concentration.

The provided text describes the submission for a 510(k) premarket notification for the N Latex FLC kappa and N Latex FLC lambda assays, adapted for use on the Atellica® CH Analyzer. The submission aims to demonstrate substantial equivalence to previously cleared devices.

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

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

The document states that "The test methods and acceptance criteria used for N Latex FLC kappa and lambda on the Atellica® CH Analyzer are equivalent to those used for the predicate device." However, specific numerical acceptance criteria and reported device performance (e.g., accuracy, precision, sensitivity, specificity values) are not detailed in the provided text. The text mentions "comparative testing was performed, and the results obtained demonstrate substantial equivalent performance," but does not present the direct results of these tests against specific acceptance criteria.

The only comparative performance aspect mentioned specifically is the "Analytical Measuring Range":

Note: Without the specific performance study results (e.g., accuracy, precision, limit of detection, linearity) and their corresponding acceptance criteria, a complete table cannot be generated from the given text.

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

The text mentions "comparative testing" and "verification activities" but does not specify the sample size used for these test sets.
Data provenance (country of origin, retrospective/prospective) is also not specified.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)

This product is an in-vitro diagnostic reagent for quantitative determination, not an imaging device requiring expert interpretation for ground truth. The "ground truth" for such devices typically relies on reference methods or spiked samples with known concentrations. The text does not mention the involvement of experts or their qualifications for establishing ground truth, as it's not applicable in the same way it would be for an image-based diagnostic.

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

Adjudication methods like 2+1 or 3+1 are typically used in studies involving human interpretation (e.g., radiologists reading images). For an in-vitro diagnostic device that provides quantitative results, an adjudication method in this sense is not applicable and therefore not mentioned.

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

There is no mention of a multi-reader multi-case (MRMC) comparative effectiveness study. This type of study is specifically relevant for imaging devices or AI-assisted diagnostic tools that involve human readers. The N Latex FLC assays are IVD reagents that provide quantitative measurements, meaning human "readers" don't interact with the device in the same way they would with an imaging AI. The submission focuses on the performance of the assay on a new instrument platform.

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

The N Latex FLC assays are standalone in the sense that they provide a quantitative result without human "interpretation" of the analytical output in the way an imaging AI would be interpreted. It's a fully automated analytical process on the Atellica® CH Analyzer. The entire study implicitly focuses on the standalone analytical performance of the combined reagent/analyzer system. The results generated by the device are numerical values, which are then used by clinicians in conjunction with other findings.

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

The text does not explicitly state the type of ground truth used. For quantitative laboratory assays, ground truth is typically established through:

• Reference methods: Comparing results to a well-established, often more complex or gold-standard analytical method.
• Certified reference materials: Using samples with accurately known concentrations of the analyte.
• Commutability studies: Ensuring that control materials behave similarly to patient samples.

The document mentions "Traceability: Internal Reference Plasma Pool," which suggests that internal standards are used to calibrate and ensure consistency, contributing to the establishment of reliable measurements which act as the 'ground truth' for the assay's performance claims.

8. The sample size for the training set

The provided text describes a 510(k) submission for an in-vitro diagnostic reagent system, not an AI/ML algorithm. Therefore, the concept of a "training set" in the context of machine learning does not apply. The assays are based on established immunoassay principles, not on learned patterns from a training dataset.

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

As explained in point 8, the concept of a "training set" for an AI/ML algorithm is not applicable here.

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