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INNOVANCE Anti-Xa assay in combination with INNOVANCE Heparin Calibrator is an In-vitro diagnostic automated chromogenic assay for the quantitative determination of unfractionated heparin (UFH) and low molecular weight heparin (LMWH) activity in human plasma collected from venous blood samples in 3.2 % sodium citrated tubes in the clinical laboratory. The quantitative determination of UFH and LMWH can be performed on the BCS XP System, CS-2500 System, CS-5100 System and the CA-660 System. For use with plasma from patients undergoing anticoagulant therapy with either UFH or LMWH.

INNOVANCE Anti-Xa assay in combination with INNOVANCE Apixaban Standard provides quantitative determination of the concentration of apixaban in human plasma collected from venous blood samples in 3.2 % sodium citrated tubes in the clinical laboratory. The quantitative determination of apixaban can be performed on CS-2500 System. For use with plasma from patients undergoing anticoagulant therapy with apixaban in situations where quantification of apixaban levels may be indicated:

· Patient with bleeding,

· Patient with risk for bleeding (e.g. during perioperative management),

· Patient with conditions affecting pharmacokinetics (e.g. deteriorating renal function, extremes of body weight, treatment with other drugs known to affect pharmacokinetics of apixaban).

The performance of this device has not been established in neonate and pediatric patient populations.

INNOVANCE Anti-Xa assay is a one stage chromogenic assay. The reagent kit consists of two components. One component (Reagent) contains Xa. the other (Substrate) a chromogenic substrate specific for Xa. Upon mixing of INNOVANCE Anti-Xa Reagent and INNOVANCE Anti-Xa Substrate, Xa converts the chromogenic substrate into two products, one of them is paranitroaniline. The formation of paranitroaniline can be quantified by the coaqulation analyzer employing light absorption at a specific wavelength (405 nm).

In the presence of a heparin containing sample the formation of paranitroaniline will be reduced in a time dependent manner. This is due to inhibition of Xa by the heparin/AT complex is formed in the patient's plasma and competes with the substrate conversion by Xa. The concentration of the complex is not only dependent on the concentration of heparin but also on the availability of the patient's endogenous antithrombin. By comparison to a reference curve the heparin activity of the sample can be quantified.

To reduce the influence from heparin antagonists, such as platelet factor 4 (PF4), dextran sulfate is included in the reaction mixture.

In the presence of an apixaban containing sample factor Xa is inhibited directly by this inhibitor. Comparison to an inhibitor specific reference curve allows quantification of the inhibitor concentration in the sample.

The provided text describes the performance data for the INNOVANCE Anti-Xa assay, a device for quantitative determination of anticoagulants. As the request is about acceptance criteria and study proving it, and this document is an FDA 510(k) summary, specific acceptance criteria would be internal to the manufacturer's validation plan and not explicitly stated as "acceptance criteria" in this public summary. However, the performance data presented (Precision, Reproducibility, LoB, LoD, LoQ, Linearity, Measuring Interval, Interference, and Method Comparison) implicitly demonstrate that the device meets the necessary performance characteristics for its intended use, making it "substantially equivalent" to a predicate device.

Here's an attempt to extract and infer the information based on the provided document:

1. Table of Acceptance Criteria (Inferred from Performance Data) and Reported Device Performance

Since explicit acceptance criteria are not stated as pass/fail thresholds in this summary, they are inferred based on the presented results which led to substantial equivalence. The predicate device's performance often sets the benchmark for substantial equivalence.

2. Sample Size and Data Provenance:

• Test Set Sample Size:
  • Precision: 240 measurements for each of the 6 samples (INNOVANCE Apixaban Control 1 & 2, and 4 plasma pools).
  • LoB, LoD, LoQ: Not explicitly stated as a single number, but calculation involves measurements of multiple samples (e.g., "samples with an assigned value of 0 ng/mL apixaban" for LoB; "samples with an assigned value of 2, 4, 6, 8 and 10 ng/mL apixaban" for LoD; "samples with an assigned value of 16, 18, 20, 22 and 24 ng/mL apixaban" for LoQ).
  • Linearity & Measuring Interval: Not explicitly stated as a single number, but likely involves multiple spike levels and measurements.
  • Interference: Not explicitly stated, but involves testing various interfering substances.
  • Method Comparison: 301 fresh and frozen plasma samples (multicentric study across 3 sites).
• Data Provenance: The document does not specify the country of origin for the data. It refers to "internally conducted studies" and a "multicentric study" for reproducibility and method comparison, implying clinical laboratories. Since the applicant is Siemens Healthcare Diagnostics Products GmbH, Marburg, Germany, it's highly probable that some or all studies were conducted in Germany or other European countries, though this is not explicitly stated. The studies are described as conforming to CLSI (Clinical and Laboratory Standards Institute) guidelines, which are international standards. The samples for method comparison were "fresh and frozen plasma samples." It is a prospective study in terms of testing the device performance against established samples/methods.

3. Number of Experts and Qualifications for Ground Truth:

This device is an in-vitro diagnostic assay that measures the concentration of substances (heparin, apixaban) in blood plasma directly. Therefore, the "ground truth" is typically defined by:

• Reference Methods: For method comparison, it refers to the results obtained from the predicate device (HemosIL Liquid Anti-Xa) on the ACL TOP system.
• Assigned Values: For calibrators and controls, the "assigned value" is based on the manufacturer's preparation and testing, often traceable to internal reference preparations or qualified methods like LC-MS/MS for substances like apixaban, as stated in the traceability sections for calibrators and controls.

There is no mention of human "experts" (e.g., radiologists, pathologists) establishing ground truth, as this is a quantitative laboratory assay, not an imaging device requiring expert interpretation.

4. Adjudication Method for the Test Set:

Not applicable. This is a quantitative laboratory assay, not a device where interpretation or human reading requires adjudication. The ground truth for method comparison is the measurement from the predicate device (HemosIL Liquid Anti-Xa).

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

Not applicable. This is an in-vitro diagnostic device for quantitative chemical analysis, not an imaging device or AI algorithm with human-in-the-loop performance component.

6. Standalone (Algorithm Only) Performance:

This device is a standalone diagnostic assay (reagent kit used with specific automated analyzers). Its performance data, as detailed, represents its standalone performance. There is no separate "algorithm" in the sense of AI that needs to be evaluated independently of the assay system.

7. Type of Ground Truth Used:

• Reference Method Comparison: For method comparison, the ground truth was established by the predicate device (HemosIL Liquid Anti-Xa), which is a legally marketed device, providing a comparative ground truth.
• Internal Reference/Assigned Values: For precision, LoB, LoD, LoQ, linearity, and interference studies, the ground truth for samples (e.g., controls, plasma pools, spiked samples) was established by their assigned values, internal reference preparations, or spiked concentrations. The traceability section explicitly mentions that for apixaban, calibration values are "traceable to apixaban supplied by the manufacturer and quantitated in plasmas assayed by Liquid Chromatography - tandem Mass Spectrometry (LC-MS/MS)" for the predicate, and for the subject device, "calibrated against an internal reference preparation."

8. Sample Size for the Training Set:

This document describes the analytical validation of a diagnostic assay (a chemical reagent system) rather than an AI/ML algorithm. Therefore, the concept of a "training set" for an algorithm doesn't directly apply in the traditional sense. The development of such assays involves extensive R&D, formulation, and preliminary testing, but these are not referred to as "training sets" in the context of typical regulatory submissions for IVDs. The closest equivalent would be the R&D samples used during the development and optimization phase of the reagent and its performance on the instruments. No specific numbers are provided for this.

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

As above, the concept of a "training set" is not relevant here. For the analytical studies presented, "ground truth" (or reference values) for various samples (calibrators, controls, patient samples, spiked samples) were established through recognized methods:

• Predicate Device Measurements: For comparative studies, the measurements from the legally marketed predicate device served as a comparative reference.
• LC-MS/MS (Liquid Chromatography - tandem Mass Spectrometry): This highly accurate analytical technique is explicitly mentioned for establishing traceability and quantifying apixaban in calibrators for the predicate device, and the subject device uses an "internal reference preparation" which would likely also be validated against similar high-accuracy methods.
• Gravimetric/Volumetric Spiking: For linearity, LoD, and LoQ studies, samples are often prepared by precisely adding known concentrations of the analyte (apixaban) to a matrix, making the spiked concentration the ground truth.

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In-vitro diagnostic reagents for the quantitative determination of immunoglobulins (IgG. IgA and IgM) in human serum, heparinized and EDTA plasma, and IgG in human urine and cerebrospinal fluid (CSF) by means of immunonephelometry on the BN II and BN ProSpec® System. Measurements of IgG aid in the diagnosis of abnormal protein metabolism and the body's lack of ability to resist infectious agents.

The N Antiserum to Human IgG reagent containing animal serum, produced by immunization of rabbits with highly purified human immunoglobulin (

The provided text describes a special 510(k) premarket notification for a modified device, "N Antisera to Human Immunoglobulins (IgG, IgA, and IgM)". The sole modification is the addition of a High Dose Hook (HDH) effect claim for IgG in cerebrospinal fluid (CSF) samples.

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

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

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

• Sample Size: The study used a "CSF high sample pool." The exact number of individual patient samples contributing to this pool (if multiple were pooled) is not specified. However, the study involved a dilution scheme with twelve (12) individual dilution levels, including the neat sample.
• Data Provenance: Not explicitly stated. The manufacturer is Siemens Healthcare Diagnostics Products GmbH, located in Marburg, Germany, which suggests the study was likely conducted in Germany or a similar geographic region. It is implicitly a prospective study designed to evaluate the HDH effect for the modified device.

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 section is not applicable as the device is an in-vitro diagnostic reagent for quantitative determination, not an imaging or interpretive device that would typically require expert ground truth establishment in the described manner. The "ground truth" for this type of test is the quantitatively measured concentration of IgG in a sample, established through laboratory methods and comparison to known standards.

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

This section is not applicable. Adjudication methods like 2+1 or 3+1 are typically used for establishing ground truth in interpretive studies (e.g., radiologists reviewing images). For a quantitative in-vitro diagnostic test, the "ground truth" is determined by the analytical method itself against known standards.

5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

This is not applicable. The device is an in-vitro diagnostic reagent, not an AI-assisted diagnostic tool or an imaging device requiring human reader interpretation. No MRMC study was performed.

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

This refers to the performance of the analytical system (N Antisera reagent on BN II System) without human intervention in the measurement process. The HDH study performed is a standalone performance evaluation of the reagent/instrument system. The acceptance criteria and performance data in the table above demonstrate this standalone performance.

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

For this in-vitro diagnostic device, the "ground truth" for the High Dose Hook study was established by creating known dilutions of a high-concentration CSF sample, which were then measured by the device. The reported concentrations for these dilutions serve as the reference. The ultimate analytical ground truth for the quantitative measurement itself is tied to international standards like ERM-DA470k/IFCC (as stated in the "Traceability/Standardization" section).

8. The sample size for the training set

This document does not describe the development or training of a machine learning model, so there is no training set in the typical sense. The "training" for such a diagnostic test involves method development, optimization, and validation using various samples and controls, but these are not referred to as a "training set" for an algorithm.

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

As there is no training set for an algorithm, this question is not applicable.

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In-vitro diagnostic automated assay for the quantitative determination of the von Willebrand antigen (VWF:Ag) in human plasma collected from venous blood samples in 3.2% sodium citrated tubes on the SYSMEX® CS-2500 analyzer.

As an aid used in the evaluation of patients aged 4 weeks and older with suspected or confirmed von Willebrand factor disorders and intended for prescription use.

Results of this test should always be interpreted in conjunction with the patient's medical history, clinical presentation and other laboratory findings.

The vWF Ag is an immunoturbidimetric assay for the quantitative, WHO-standardized determination of von Willebrand factor (VWF) antigen concentration.

The vWF Aq kit consist of a Latex Reagent (4 x 2 mL) which is a suspension of small polystyrene particles (latex) coated with rabbit anti-human VWF antibodies. The Reagent Diluent (4 x 4 mL) is provided within the kit which is a solution containing glycine. The Reagent Diluent is intended for dilution of the Latex Reagent. The vWF Ag kit is completed by the Buffer (4 x 5 mL) which is a glycine buffer. All components contain sodium azide (

Here's an analysis of the acceptance criteria and study details for the vWF Ag device, based on the provided text:

Acceptance Criteria and Device Performance

The document doesn't explicitly state "acceptance criteria" as a single, consolidated table with pass/fail values. Instead, it details performance characteristics established through various studies. I will present the reported device performance for several key metrics:

Study Details

2. Sample Sizes and Data Provenance

• Measuring Interval (LoQ): Five independent low-analyte plasma pools.
• Measuring Interval (Linearity): Not explicitly stated, but "a dilution series was prepared using a high plasma sample pool and a low plasma sample pool to equal 12 different dilutions."
• Specificity (Interference): "Individual native samples with and without interferent" for paired-difference experiments. "Single native plasmas" for Rheumatoid factors. The number of samples per interferent testing is not specified.
• Reference Interval:
  • Blood group O: n = 147
  • Blood group non-O: n = 159
  • Blood group independent: n = 306
  • Data Provenance: Three clinical study sites in the United States. The study involved apparently healthy subjects.
• Pediatric Population Measurements:
  • Blood group O: n = 21
  • Blood group non-O: n = 26
  • Total pediatric (independent of ABO blood group): n = 47
  • Data Provenance: "healthy pediatric subjects".
• Precision/Reproducibility:
  • External Reproducibility (Multicenter): Three (3) external sites in the USA (Sites 1, 2, and 3). Test samples included three plasma pools and three control materials. Each site used 5 days, 2 runs/day, 3 replicates/run (3x5x2x3).
  • Internal Precision (Single Site, Germany - Reagent Variability): One (1) site in Germany. 20 days, 2 runs/day, 2 replicates/run (20x2x2) with 3 different reagent lots.
  • Internal Precision (Single Site, Germany - Calibrator Variability): One (1) site in Germany. 20 days, 2 runs/day, 2 replicates/run (20x2x2) with 3 different calibrator lots.
  • Internal Precision (Single Site, Germany - Instrument Variability): One (1) site in Germany. 5 days, 2 runs/day, 4 replicates/run (5x2x4) on 3 SYSMEX® CS-2500 analyzers.
  • Data Provenance: Mixed (USA and Germany), all prospective measurements for the study.
• Method Comparison:
  • Site 1 (Germany): N = 107
  • Site 2 (United States): N = 115
  • Site 3 (United States): N = 117
  • Overall (Combined Sites): N = 339
  • Data Provenance: One external site in Germany (Site 1) and two external sites in the United States (Site 2 and Site 3). The samples tested "ensured the intended use population was tested". This implies a mix of patient samples. Retrospective or prospective nature is not explicitly stated but generally for method comparison, collected clinical samples are used.

3. Number of Experts and Qualifications (for Ground Truth)

The document describes in-vitro diagnostic assay performance, which typically relies on laboratory measurements rather than expert human interpretation of images or clinical findings where "ground truth" and "experts" as in radiology studies would be directly relevant.

• For the "Reference Interval" and "Pediatric Population" studies: These likely involved general medical professionals or phlebotomists for sample collection, and laboratory technicians for running the assays. The "ground truth" here is the biological sample itself and the reference standard used (WHO standard for calibration traceability). No "experts" in the sense of adjudicating findings (e.g., radiologists) were explicitly mentioned.

4. Adjudication Method (for Test Set)

Not applicable. This is an in-vitro diagnostic assay, not a device requiring human interpretation of results requiring adjudication for a test set. The performance is assessed based on quantitative measurements against predefined analytical performance metrics and comparison to a predicate device.

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

No. This is an in-vitro diagnostic device (an assay), not an imaging or diagnostic AI system that aids human readers. The document details a method comparison study between the proposed device and a predicate device, which is a different type of comparative effectiveness.

6. Standalone Performance (i.e., algorithm only without human-in-the-loop performance)

Yes, the studies reported are for the standalone performance of the vWF Ag assay on the SYSMEX® CS-2500 analyzer. This is an automated assay, meaning it operates without human-in-the-loop performance for result generation. Interpretations of historical context or other lab findings are mentioned as necessary in conjunction with the test results, but the test itself is standalone.

7. Type of Ground Truth Used

• Measuring Interval, Specificity, Precision/Reproducibility: The "ground truth" for these analytical performance studies is based on:
  • Known concentrations in prepared samples (e.g., dilutions from plasma pools, spiked samples with interferents).
  • Reference materials (e.g., control materials, calibrators).
  • WHO Standard (reagents traceable to WHO 6th International Standard Factor VIII / Von Willebrand Factor (07/316)).
• Reference Interval & Pediatric Population: The "ground truth" is derived from empirically measuring VWF:Ag levels in a defined population of "apparently healthy subjects" using the device itself.
• Method Comparison: The "ground truth" for comparison is the performance of the legally marketed predicate device (STA® - Liatest® VWF:Ag on the STA R Max® analyzer).

8. Sample Size for the Training Set

Not applicable. This document describes the performance of a VWF Ag assay, which is an immunoturbidimetric test, not an AI/ML algorithm that requires a training set in the conventional sense. The "training" for such a system would involve optimizing the assay's chemical reagents and instrument parameters, which is part of the development process but not disclosed as a distinct "training set" of data.

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

Not applicable, as there's no explicitly defined "training set" for an AI/ML algorithm. The assay's analytical performance and calibration are established using reference materials and pooled samples with known or established values, as described in point 7.

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CardioPhase® hsCRP is an in-vitro diagnostic reagent for the quantitative determination of C-reactive protein (CRP) in human serum, and heparin and EDTA plasma by means of particle enhanced immunonephelometry using the BN II and BN ProSpec® System. In acute phase response, increased levels of plasma proteins, including C-reactive protein, is observed. Measurement of CRP is useful for the detection and evaluation of infection, tissue injury, inflammatory disorders and associated diseases. High sensitivity CRP (hsCRP) measurements may be used as an independent risk marker for the identification of individuals at risk for future cardiovascular disease. Measurements of hsCRP, when used in conjunction with traditional clinical laboratory evaluation of acute coronary syndromes, may be useful as an independent marker of prognosis for recurrent events, in patients with stable coronary disease or acute coronary syndromes.

The CardioPhase hsCRP assay is an in vitro diagnostic reagent for the quantitative determination C-reactive protein, in human serum, and heparinized and EDTA plasma by means of particle-enhanced immunoassay determination. Polystyrene particles coated with monoclonal antibodies specific to human CRP are aggregated when mixed with samples containing CRP. These aggregates scatter a beam of light passed through the sample. The intensity of the scattered light is proportional to the concentration of the relevant protein in the sample. The result is evaluated by comparison with a standard of known concentration.

This document describes the CardioPhase® hsCRP device, a C-reactive protein immunological test system, and a Special 510(k) submission for a change in its reference standard material from ERM-DA470 to ERM-DA474/IFCC.

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

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state numerical acceptance criteria for all performance characteristics, but rather describes the studies performed and their satisfactory outcomes which imply meeting internal acceptance limits. For instance, for linearity, the stated ranges confirm the measuring range, implying that the observed linearity falls within acceptable deviations. For matrix comparison, high correlation coefficients and slopes close to 1 with intercepts close to 0 indicate acceptable equivalence.

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In-vitro diagnostic automated assay for the quantitative determination of the von Willebrand factor-GPIb-binding activity in human plasma collected from venous blood samples in 3.2% sodium citrate tubes on the BCS XP System.

As an aid used in the evaluation of patients with suspected or confirmed von Willebrand factor disorders.

Results of this test should always be interpreted in conjunction with the patient's medical history, clinical presentation and other laboratory findings.

The INNOVANCE VWF Ac assay is a particle enhanced turbidimetric assay based on binding of VWF to the recombinant GPIb (two gain-of-function mutations included). The assay provides quantitative VWF activity results on 3.2% citrated human plasma when used with Standard Human Plasma Calibrators (K023141).

The reagent kit consists of three components: Reagent I (containing polystyrene particles coated with anti-GPIb mouse monoclonal antibodies). Reagent II (buffer containing heterophilic blocking reagent) and Reagent III (containing recombinant GPIb).

The INNOVANCE VWF Ac assay is a device for the quantitative determination of von Willebrand factor-GPIb-binding activity. The device is intended to aid in the evaluation of patients with suspected or confirmed von Willebrand factor disorders.

Here's an analysis of its acceptance criteria and supporting studies:

1. Acceptance Criteria and Reported Device Performance

• Study 2 (Multi-site reproducibility): Total CVs ranged from 3.48% to 6.29%. All values for multi-site reproducibility were within acceptable limits.
• Study 3 (Instrument/operator variability): Total CVs ranged from 2.86% to 6.01%. All values were within acceptable limits. |
  | Linearity | - Assay should demonstrate linearity across the claimed reportable range (4 to 300% of norm). | - Linearity studies (using spiked and native samples) demonstrated linearity from 4 to 300% of norm on the BCS XP System. |
  | Analytical Specificity/Interference | - No clinically significant interference from specified endogenous or exogenous substances at tested concentrations. | - Endogenous Interference: No clinically significant interference from Hemoglobin (up to 1000 mg/dL), Bilirubin (unconjugated) (up to 60 mg/dL), Bilirubin (conjugated) (up to 40 mg/dL), Triglycerides (up to 726 mg/dL), and Rheumatoid Factors (up to 438 IU/mL).
• Exogenous Interference: No clinically significant interference from a panel of 30 common drugs tested at specific concentrations.
• Heterophilic blocking reagent included to minimize interference from heterophile antibodies. |
  | High Dose Hook | - No high dose hook effect observed up to a specified VWF activity level. | - No high dose hook effect observed up to a VWF activity of 656% of norm. |
  | Traceability | - INNOVANCE VWF Ac results should be traceable to the WHO 6th International Standard (IS) Factor VIII / Von Willebrand Factor. | - INNOVANCE VWF Ac results are traceable to the WHO 6th International Standard (IS) Factor VIII / Von Willebrand Factor (NIBSC code 07/316), with an observed bias of +2.3% (relative). |
  | Stability (Shelf-life, In-use, Reconstituted, Sample, Transportation, Freeze/Thaw) | - Reagent and calibrator shelf-life stability.
• On-board stability.
• Once opened stability.
• Reconstituted stability (calibrator).
• Ambient temperature operating range.
• Transportation stability.
• Freeze/thaw tolerance for reagent and calibrator.
• Sample stability under various storage conditions.
• Equivalence between fresh and frozen samples. | - Reagent Shelf-Life: 12 months at 2-8°C.
• Calibrator Shelf-Life: 12 months at 2-8°C.
• On-Board Stability (Reagent): 36 hours at 18-32°C. Accumulated on-board stability: 24 hours for Reagents I & II, 36 hours for Reagent III.
• On-Board Stability (Calibrator): 6 hours at 18-32°C (not recommended in labeling due to immediate use intent).
• Once Opened Stability (Reagent): 37 days for Reagents I & II, 113 days for Reagent III when stored at 2-8°C.
• Reconstituted Stability (Calibrator): 4 hours at 15-25°C; 4 weeks at -20°C; 2 hours at 15-25°C after freeze/thaw.
• Ambient Temperature: Correctness assured within 18-32°C operating range.
• Transportation Stability: All tested conditions met acceptance criteria.
• Freeze/Thaw Tolerance: Stable for one freeze/thaw cycle for both reagent and calibrator.
• Sample Stability: 3 months at ≤ -20℃; 12 months at 300.0% of norm (not for establishing reference interval). |
  | Carry-Over (Sample & Reagent) | - No significant carryover from one sample to the next or from one reagent application to another. | - Sample Carryover: No carryover observed.
• Reagent Carryover: No cross-contamination observed. |
  | Diagnostic Accuracy (Method Comparison) | - Acceptable comparability to predicate devices (BC von Willebrand Reagent, HemosIL VWF).
• Passing-Bablok analysis results (slope, intercept, predicted bias, Pearson correlation coefficient) should meet predefined acceptance criteria. | - Vs. BC von Willebrand Reagent (current study): Combined sites (N=102) showed Pearson r = 0.916, Slope = 1.037, Intercept = 3.497. Predicted bias at MDP1 (30% norm) = 4.60% norm; at MDP2 (50% norm) = 10.14% (relative). All met acceptance criteria.
• Vs. HemosIL VWF: Combined sites (N=97) showed Pearson r = 0.971, Slope = 0.955, Intercept = -0.552. Predicted bias at MDP1 (30% norm) = -1.90% norm; at MDP2 (50% norm) = -5.76% (relative). All met acceptance criteria.
• Vs. BC von Willebrand Reagent (Patzke et al., 2014 re-analysis): Combined sites (N=556, 4-300% of norm) showed Pearson r = 0.985, Slope = 0.955, Intercept = 1.110. Predicted bias at MDP1 (30% norm) = -0.23% norm; at MDP2 (50% norm) = -2.26% (relative). All met acceptance criteria and confirmed acceptable comparability. |
  | Diagnostic Concordance | - Overall percent agreement, positive percent agreement (any type of VWD), and negative percent agreement (VWD excluded) should demonstrate acceptable concordance with existing standard of care (SOC) VWF-activity assays. | - Overall Percent Agreement: 83.33% (95% CI: 76.23 - 88.63).
• Positive Percent Agreement ('any type' VWD): 74.29% (95% CI: 57.93 - 85.84).
• Negative Percent Agreement ('VWD excluded'): 95.77% (95% CI: 88.30 - 98.55).
• "Overall percentage agreement of more than 80%… demonstrates that for the majority of patients (> 80%), use of the subject device instead of currently available assays to measure VWF activity will not alter diagnosis." The PPA at low VWF (52.63%) was accepted with clinical justifications. |

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

• Precision (Single Site):

  • Study 1 (reagent variability): 5 plasma pools + 2 control materials = 7 samples. Each tested 240 times (20 days x 2 runs x 2 replicates x 3 reagent lots or 3 calibrator lots for a total of 240 determinations, 80 per lot).
  • Study 2 (reproducibility multi-site): 5 plasma pools + 2 control materials = 7 samples. Each tested 90 times (3 external sites x 5 days x 2 runs x 3 replicates for a total of 90 determinations, 30 per site).
  • Study 3 (instrument/operator variability): 5 plasma pools + 2 control materials = 7 samples. Each tested 120 times (5 days x 2 runs x 4 replicates x 3 systems for a total of 120 determinations, 40 per system).
  • Provenance: Single site precision studies were conducted in Germany. Multi-site reproducibility and instrument/operator variability studies were conducted across three external sites (locations not specified for multi-site reproducibility study, but internal site for instrument/operator variability implies one location).

• Linearity (Test Sets):

  • Spiked Sample Linearity: 10 different concentrations of spiked samples.
  • Native Sample Linearity: 12 different concentrations of native samples.
  • Provenance: High pool for spiked samples prepared by spiking normal plasma with VWF concentrate. Low pool with VWF deficient plasma (internally produced). Native samples from contract blood plasma provider. Locations not specified but implied to be part of the testing facilities.

• Analytical Specificity/Interference (Test Sets):

  • Endogenous Interference: 4 VWF activity levels (low, 2 medical decision levels, high) tested with 5 test samples each. 80 measurements overall (4 VWF levels x 5 test samples x 4 replicates). Each sample prepared with native plasma and dilution/spiking.
  • Exogenous Interference: 4 VWF activity levels for each of the 30 interferent drugs. 32 measurements per interferent (4 VWF levels x 4 aliquots x 2 conditions - spiked/control).
  • Provenance: Samples prepared with native plasma and VWF deficient plasma or VWF concentrate.

• High Dose Hook (Test Set): 10 different dilution samples from a high VWF Ac activity plasma pool. Measured in 6 replicates.

  • Provenance: High pool prepared by spiking normal plasma with VWF concentrate, diluted with VWF deficient plasma.

• Traceability (Test Set): Three vials of WHO 6th International Standard for Factor VIII / von Willebrand Factor. Measured in single determination.

• Stability (Test Sets):

  • Reagent/Calibrator Shelf-Life: 5 plasma pools + 3 control materials. Measured 6-12 replicates at each of 6 time points over 15 months.
  • On-Board Stability: 5 plasma pools + 3 control materials. Measured 6 replicates at each of 5 time points.
  • Once Opened Stability: 5 plasma pools + 3 control materials. Measured 6-12 replicates at multiple time points (2,4,6 weeks for reagent I/II; 6,12,18 weeks for reagent III).
  • Reconstituted Stability (Calibrator): Aliquots of Standard Human Plasma (SHP) measured 6-12 replicates at various time points and conditions.
  • Ambient Temperature: 8 test samples. Each tested in 8 replicates on 3 days.
  • Transportation Study: 5 plasma pools + 3 control materials. Tested 3-6 replicates at various temperature stress conditions.
  • Freeze/Thaw Tolerance: 5 plasma pools + 3 control materials. Tested 3 replicates under stressed and unstressed conditions.
  • Sample Stability: At least 20 samples. Tested in quadruplicate over various time points and storage conditions.
  • Frozen vs. Fresh Samples: 60 fresh samples. Measured one replicate fresh, then one replicate after frozen storage.
  • Provenance: Plasma pools, control materials, patient samples. Specific origins (e.g., country) not detailed for all stability studies, but likely conducted at manufacturer's internal labs or controlled external sites.

• Detection Limit (Test Sets):

  • LoB: 5 analyte-free samples. n=60 determinations per reagent lot per instrument.
  • LoD: 5 low-analyte samples. n=50 determinations per sample.
  • LoQ: 5 low-analyte samples. n=60 determinations per reagent lot per instrument.
  • Provenance: Samples prepared with VWF deficient plasmas and dilutions of normal plasma pools.

• Normal Range / Reference Interval (Test Set):

  • Adults: 302 apparently healthy individuals (150 blood group O, 152 blood group non-O) ≥ 18 years of age.
  • Pediatrics: 85 apparently healthy pediatric individuals (44 blood group O, 41 blood group non-O) > 4 weeks to

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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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In-vitro diagnostic reagents for the quantitative determination of free light chains (FLC), type kappa or type lambda in human serum and EDTA-plasma by means of particle-enhanced immunonephelometry using the BN Systems. 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.

In-vitro diagnostic reagents for the quantitative determination of free light chains (FLC), type kappa or type lambda in human serum and EDTA-plasma by means of particle-enhanced immunonephelometry using the BN Systems. 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 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 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. The devices in this submission have not materially changed since clearance under K171742. The purpose for this submission is to add monitoring of multiple myeloma (MM) to the intended use.

Here's a breakdown of the requested information based on the provided text, focusing on the expanded indication for monitoring Multiple Myeloma (MM) with the N Latex FLC kappa and N Latex FLC lambda assays:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are not explicitly stated as numerical targets in the document beyond the performance metrics themselves. However, the study aims to demonstrate substantial equivalence to the predicate device and satisfactory agreement with clinical status for MM monitoring. The reported performance is as follows:

Note: The document states "For the predicate device similar data were obtained when compared to clinical status," suggesting the 26% sensitivity for progression is considered acceptable in this context given the device's role as an "aid" in diagnosis and monitoring.

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

• Sample Size for Test Set:
  • Clinical Status Comparison: 391 patients (divided into 47 with Progression and 344 with No Progression).
  • Agreement with Clinical Assessment: 391 patients.
  • Comparison to Predicates (Response Category): 391 patients.
  • Comparison to Predicates (Follow-up Graphs): 102 patients.
• Data Provenance: The study was a "multi-center study." The country of origin is not explicitly stated, but the submission is from Siemens Healthcare Diagnostics Products GmbH, based in Germany. The study appears to be retrospective as it compares results with existing clinical assessments and predicate device results.

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

The document does not specify the number of experts or their qualifications for establishing the ground truth. It mentions "clinical assessment provided by the physician in charge within the Case Report Form (CRF)."

4. Adjudication Method for the Test Set

The document does not explicitly describe an adjudication method. "Clinical assessment provided by the physician in charge" suggests a singular clinical judgment rather than a consensus or adjudicated process among multiple experts for the ground truth.

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

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not performed. This device is an in-vitro diagnostic assay, not an imaging AI system that would typically involve human readers.

6. Standalone Performance

Yes, a standalone performance analysis was done. The N Latex FLC assays were evaluated independently in comparison to clinical status and then compared to the predicate devices. The sensitivity and specificity values are derived from the algorithm's performance in categorizing patient status.

7. Type of Ground Truth Used

The ground truth used was clinical assessment based on IMWG FLC criteria, taking into account IFE (immunofixation electrophoresis) and serum FLC measurements in conjunction with "other clinical findings" and "further information in addition to serum testing" as provided by the treating physician in the Case Report Form.

8. Sample Size for the Training Set

The document does not mention a training set. This is a diagnostic assay, and the study focuses on evaluating its performance (validation) rather than training an algorithm. The "training set" concept is more applicable to machine learning-based AI devices.

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

Not applicable, as no training set is described for this device.

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