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The BÜHLMANN fCAL turbo is an in vitro diagnostic assay intended for the quantitative measurement of fecal calprotectin, a neutrophilic protein that is a marker of inflammation, in human stool. The BÜHLMANN fCAL turbo aids in the diagnosis of inflammatory bowel disease (IBD), specifically Crohn's disease (CD) and ulcerative colitis (UC) and aids in the differentiation of IBD from irritable bowel syndrome (IBS) in conjunction with other laboratory and clinical findings.

The BÜHLMANN CALEX Cap is a single use tube intended for the preparation of human stool samples to be used with the BÜHLMANN fCAL turbo.

The BÜHLMANN fCAL® turbo, a particle-enhanced turbidimetric immunoassay (PETIA), is performed using patient stool extracts collected without preservatives. Calprotectin within the sample extract mediates immunoparticle agglutination; sample turbidity is proportional to calprotectin concentration. The detected light absorbance allows quantification of calprotectin concentration via interpolation of an established calibration curve. The assay is validated for use on clinical chemistry analyzers such as the Roche cobas® c501/c502 platforms.

The BÜHLMANN fCAL® turbo Reagent Kit is to be used in conjunction with the BÜHLMANN fCAL® turbo Calibrator Kit and BÜHLMANN fCAL® turbo Control Kit, which are available separately.

Sample extracts may be prepared using manual weighing extraction methods or the CALEX® Cap.

The CALEX® Cap is a single use tilled with extraction buffer. The sampling pin houses a dosing tip which is used to obtain sufficient stool sample for the extraction process. The extraction method leads to stool specimen extracts which can be measured directly using the BÜHLMANN fCAL® turbo assay.

This document describes the validation of the BÜHLMANN fCAL® turbo and CALEX® Cap device, an in vitro diagnostic assay for measuring fecal calprotectin.

1. Table of Acceptance Criteria (Implied) and Reported Device Performance

The document doesn't explicitly list "acceptance criteria" in a separate table, but the performance data sections demonstrate that the device meets various analytical and clinical performance standards. The key performance metrics are presented as results from studies.

2. Sample Size and Data Provenance

• Test Set Sample Sizes:

  • Precision Studies: 80 replicates per sample for Single-Site and Extraction Reproducibility, 75 replicates per sample for Multi-Site and Lot-to-Lot precision.
  • Linearity: Not explicitly stated as a number of unique patient samples, but involves two dilution series with "various mixing ratios" and 4 replicates per dilution.
  • Accuracy/Recovery: 7 samples.
  • Interfering Substances: Stool specimen extracts with 4 approximate calprotectin concentrations; specific number of runs not explicitly stated.
  • Method Comparison (vs. predicate ELISA): 248 clinical study samples.
  • Extraction Method Comparison (CALEX® Cap vs. Manual): 241 clinical study samples.
  • Clinical Sensitivity/Specificity: 265 samples for IBD vs. IBS analysis, 337 samples for IBD vs. non-IBD analysis.
  • Expected Values/Reference Range: 141 apparently healthy normal adults.

• Data Provenance: The document does not explicitly state the country of origin for the clinical study data or whether it was retrospective or prospective. Given the submitter's location (Switzerland), it's possible some or all studies were conducted there or internationally. The term "clinical study samples" usually implies prospective collection, but it's not explicitly stated.

3. Number of Experts and Qualifications for Ground Truth

• This document is for an in vitro diagnostic (IVD) assay, specifically an immunological test system for fecal calprotectin. The "ground truth" for such devices often relies on established laboratory methods, clinical diagnoses based on a constellation of evidence (e.g., endoscopy, histology, imaging, other lab findings), or consensus among clinicians.
• No "experts" in the sense of human readers for images are mentioned or used for establishing ground truth. Instead, the device's performance is compared against:
  • Itself (for precision, linearity, recovery, sensitivity).
  • A legally marketed predicate device (for method comparison).
  • External clinical diagnoses (for clinical sensitivity/specificity).
• For clinical diagnosis (e.g., IBD, IBS, non-IBD), the ground truth is implicitly established by clinical findings, which would typically involve qualified physicians (e.g., gastroenterologists) and pathologists, but their specific number or qualifications are not detailed as this is standard for IVD test validation.

4. Adjudication Method for the Test Set

• Adjudication methods (like 2+1, 3+1) are typically used for studies involving human interpretation of complex data (e.g., medical images) where a consensus is needed to define the ground truth for equivocal cases.
• This is an IVD device, not an image-based AI system. Therefore, there is no "adjudication method" as described in the context of human reader studies. The "ground truth" for clinical sensitivity/specificity would be the established clinical diagnosis for each patient, determined by standard medical practice, not by expert adjudication of the test results themselves.

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

• No MRMC study was done. MRMC studies are designed to compare the diagnostic performance of human readers, often with and without AI assistance, on a set of medical cases.
• This document describes the validation of an in vitro diagnostic (IVD) test kit, which is a laboratory assay. It does not involve human readers interpreting images or any AI assistance for human interpretation.

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

• Yes, this entire submission effectively represents a standalone performance study of the BÜHLMANN fCAL® turbo and CALEX® Cap device.
• As an IVD assay, its core function is to produce quantitative results based on the chemical reaction. The performance data (precision, linearity, accuracy, analytical sensitivity, method comparison) demonstrate its intrinsic performance independent of human interpretation of its raw output. The subsequent clinical sensitivity and specificity studies evaluate the diagnostic accuracy of the device's numerical output against clinical diagnoses. There is no "human-in-the-loop" in the direct operation or result generation of the assay itself, apart from standard laboratory procedures and subsequent clinical interpretation of the numerical calprotectin values.

7. Type of Ground Truth Used

• Analytical Ground Truths:
  • Known concentrations: For linearity, analytical sensitivity (LoB, LoD, LoQ), accuracy/recovery, and interfering substances, the ground truth involves samples with known or spiked concentrations of calprotectin or interferents.
  • Reference Methods/Predicate Device: For method comparison, the predicate BÜHLMANN fCAL® ELISA assay serves as a comparative ground truth.
• Clinical Ground Truths:
  • Clinical Diagnosis: For clinical sensitivity and specificity, the ground truth for patients was their established clinical diagnosis (e.g., IBD, IBS, non-IBD). This diagnosis is typically based on an aggregation of clinical findings, endoscopic results, histological reports, and other laboratory tests, representing the best available clinical determination.
  • Healthy Normal Cohort: For expected values/reference range, the ground truth was a cohort of "apparently healthy normal adults" based on lack of symptoms or signs of gastrointestinal disease, implying a clinical assessment.

8. Sample Size for the Training Set

• This document describes the validation studies for a pre-market submission (510(k)) for an IVD device. For such devices, particularly those based on immunoassay technology, the concept of a "training set" like that used in machine learning (ML) is generally not applicable in the same way. The device's underlying immunoassay methodology is laboratory-based and its parameters are established through extensive analytical development rather than data-driven "training" in the ML sense.
• The document presents performance data from verification and validation studies, which are essentially "test sets" for the final device. There is no mention of a separate "training set" of patient data for model development as one would see with a deep learning algorithm. The analytical parameters and performance characteristics of the immunoassay are developed and optimized by the manufacturer.

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

• As explained above, the concept of a distinct "training set" and associated ground truth establishment in the context of an ML algorithm is not directly applicable to this immunoassay device's validation as described in the 510(k) summary. The development of such assays relies on biochemical principles, calibration curves established with known standards, and analytical validation experiments performed on various matrices and samples. The "ground truth" for developing the assay itself would be the precisely measured values of known calprotectin standards.

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The BÜHLMANN fCAL turbo is an in vitro diagnostic assay intended for the quantitative measurement of fecal calprotectin, a neutrophilic protein that is a marker of intestinal mucosal inflammation, in human stool. The BÜHLMANN fCAL turbo aids in the diagnosis of inflammatory bowel disease (IBD), specifically Crohn's disease (CD) and ulcerative colitis (UC) and aids in the differentiation of IBD from irritable bowel syndrome (IBS) in conjunction with other laboratory and clinical findings.

The BÜHLMANN fCAL® turbo, a particle-enhanced turbidimetric immunoassay (PETIA), is performed using patient stool extracts collected without preservatives. Calprotectin within the sample extract mediates immunoparticle agglutination; sample turbidity is proportional to calprotectin concentration. The detected light absorbance allows quantification of calprotectin concentration via interpolation of an established calibration curve. The assay is validated for use on clinical chemistry analyzers such as the Roche cobas® c501/c502 platforms.

The BÜHLMANN fCAL® turbo Reagent Kit is to be used in conjunction with the BÜHLMANN fCAL® turbo Calibrator Kit and BÜHLMANN fCAL® turbo Control Kit, which are available separately.

The provided document describes the 510(k) premarket notification for the BÜHLMANN fCAL® turbo device, an in vitro diagnostic assay. It details the device's indications for use, its technological characteristics compared to a predicate device, and the performance data collected to demonstrate its safety and effectiveness.

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

Acceptance Criteria and Device Performance

The core of the acceptance criteria for the BÜHLMANN fCAL® turbo, as a new device seeking substantial equivalence to a legally marketed predicate (BÜHLMANN fCAL® ELISA), is demonstrated through various performance studies. The primary goal is to show that, despite technological differences, the new device performs comparably to the predicate and is safe and effective for its stated indications.

The document implicitly defines acceptance criteria through the successful outcomes of its performance studies, demonstrating analytical parity and comparable clinical utility. Explicit numerical thresholds for acceptance are not always stated outright as "acceptance criteria" but are demonstrated by the presented results falling within acceptable ranges or showing strong correlation/agreement with the predicate.

Here's a table summarizing the key performance metrics presented, which serve as the de facto acceptance criteria and the device's reported performance:

• 8 samples tested (S01-S08).
• Mean values ranged from 42.9 µg/g to 5405.6 µg/g.
• Within-run %CV ranged from 0.7% to 8.3%.
• Within-laboratory %CV ranged from 1.4% to 9.1%.
  Multi-Site Reproducibility Study:
• 8 samples tested (S01-S08).
• Mean values ranged from 47.2 µg/g to 5475.6 µg/g.
• Total Precision %CV ranged from 3.2% to 11.3%.
  Lot-to-Lot Precision Study:
• 8 samples tested (S1-S8).
• Mean values ranged from 45.2 µg/g to 5303.1 µg/g.
• Total Precision %CV ranged from 3.6% to 11.3%.
  Extraction Reproducibility Study:
• 10 samples tested (S1-S10).
• Mean values ranged from 47.7 µg/g to 3330.4 µg/g.
• Total Precision %CV for extraction ranged from 1.4% to 13.0%. |
  | Linearity/Analytical Measuring Range (R² close to 1, small intercept, slope close to 1) | Linearity Study:
• Two dilution series analyzed.
• Dilution Series 1: Covered 37.6 – 12,216.0 µg/g. Regression: Intercept=5.7 (95% C.I. 1.6, 16.9), Slope=1.057 (95% C.I. 1.044, 1.075), R²=0.9983.
• Dilution Series 2: Covered 33.5 – 13,339.5 µg/g. Regression: Intercept=3.8 (95% C.I. -0.4, 13.3), Slope=1.031 (95% C.I. 1.014, 1.042), R²=0.9984.
  Claimed Analytical Measuring Range: Direct: 30 - 2000 µg/g. With automatic dilution: 30 - 10,000 µg/g. (Supported by data) |
  | High Dose Hook Effect (No significant effect at high concentrations) | High Dose Hook Effect Study:
• No high dose hook effect observed up to 45,715 µg/g. |
  | Accuracy/Recovery (Total Recovery % close to 100%) | Accuracy/Recovery Study:
• 7 spiked samples (varied baselines).
• Total recovery ranged from 93.6% to 102.0%. |
  | Analytical Sensitivity (Low LoB, LoD, LoQ) | Analytical Sensitivity Studies:
• LoB (Limit of Blank) = 16.7 µg/g.
• LoD (Limit of Detection) = 23.7 µg/g.
• LoQ (Limit of Quantitation) = 30 µg/g.
  Supports claimed direct measuring range of 30 - 2000 µg/g, and 30 - 10,000 µg/g with automatic dilution. |
  | Interfering Substances (No significant interference) | Interfering Substances Study:
• Tested various analytes (e.g., Iron, Prednisone, Mesalamine, Vancomycin, antibiotics, vitamins, hemoglobin) and common enteropathological microorganisms (e.g., E. coli, Salmonella, Klebsiella, Shigella, Yersinia) at specified concentrations.
• Confirmed no interference. |
  | Method Comparison with Predicate (Strong correlation, low bias, high PPA/NPA) | Method Comparison Study:
• Statistical Comparison (Passing-Bablok):
  • Slope = 1.025 (95% CI: 0.990, 1.058) (close to 1).
  • Intercept = -4.5 µg/g (95% CI: -8.7, 0.3) (close to 0).
  • Bias at 80 µg/g = -3.1% (95% CI: -7.2%, 0.5%).
  • Bias at 160 µg/g = -0.3% (95% CI: -2.4%, 2.7%).
  • Correlation (r) = 0.972 (strong positive correlation).
• Clinical Agreement (PPA/NPA):
  • All subjects combined: PPA (lower cutoff) = 93.6% (88.5%, 96.9%), NPA (lower cutoff) = 91.3% (83.6%, 96.2%).
  • PPA (upper cutoff) = 93.9% (87.1%, 97.7%), NPA (upper cutoff) = 95.3% (90.6%, 98.1%).
    (High PPA/NPA values indicate good agreement with the predicate across various patient subgroups and diagnostic cutoffs). |
    | Clinical Sensitivity/Specificity (Clinically meaningful diagnostic performance for IBD vs. IBS/non-IBD) | Clinical Sensitivity/Specificity Study:
• IBD vs. IBS:
  • Borderline considered Positive: Sensitivity = 91.1%, Specificity = 76.2%.
  • Borderline considered Negative: Sensitivity = 80.0%, Specificity = 87.7%.
• IBD vs. Non-IBD:
  • Borderline considered Positive: Sensitivity = 91.1%, Specificity = 74.3%.
  • Borderline considered Negative: Sensitivity = 80.0%, Specificity = 85.1%.
    (Demonstrates ability to differentiate IBD from IBS and non-IBD conditions). |
    | Expected Values/Reference Range (Distribution in healthy population) | Expected Values/Reference Range Study:
• Tested 141 healthy normal adults.
• Distribution: 75.2% 160 µg/g.
  (Provides population data for interpretation). |

Study Details Proving Device Meets Acceptance Criteria

1. Sample Size and Data Provenance:

   • Precision Studies (Single-site, Multi-site, Lot-to-Lot): For each sample (typically 8 different concentration levels), n=80 (Single-site) or n=75 (Multi-site, Lot-to-Lot) measurements were performed. This refers to the number of replicates / runs, not distinct clinical samples. These are analytical performance studies using spiked samples or controls.

   • Extraction Reproducibility Study: n=80 for each of the 10 samples (again, replicates/runs).

   • Linearity Study: Each dilution was tested in 4 replicates. Number of unique stool specimens used for creating dilution series is not explicitly stated but implied to be at least two (one high, one low).

   • Accuracy/Recovery Study: 7 clinical samples were spiked and tested.

   • Interfering Substances Study: Stool extracts with 4 different calprotectin concentrations were used for analytes/pharmaceuticals/supplements. Microorganism interference was tested at given cell counts, presumably across various stool extracts. The exact number of distinct stool samples used for interference testing is not specified.

   • Method Comparison Study: A total of 248 clinical study samples were tested. 220 had valid results within the linear measuring range for both devices.

   • Clinical Sensitivity/Specificity Study: 337 clinical samples were included for IBD vs. non-IBD analysis, and 265 clinical samples for IBD vs. IBS.

   • Expected Values/Reference Range Study: 141 apparently healthy normal adults provided stool samples.

   • Data Provenance: Not explicitly stated but typically for an FDA 510(k) submission, these studies would be conducted in the country of origin of the manufacturer (Switzerland, in this case) or in clinical sites compliant with GCLP/GCP, often with diverse patient populations to support generalizability (though not explicitly stated as multi-national for every study). The studies are inherently prospective in nature, as they involve newly generated data from specified experimental designs for device validation.

2. Number of Experts and Qualifications for Ground Truth of Test Set:

   • This section is not applicable for this type of in-vitro diagnostic device (IVD). The device measures a biomarker (fecal calprotectin). The "ground truth" for the test set is either:
     • Analytical True Value: For analytical studies (precision, linearity, accuracy, analytical sensitivity, interference), the ground truth is established by the known concentrations of spiked samples, reference materials, or highly accurate reference methods.
     • Clinical Diagnosis: For the method comparison and clinical sensitivity/specificity studies, the ground truth for "IBD," "IBS," and "non-IBD" is based on the clinical diagnosis of the patient from whom the stool sample was collected. This diagnosis is established by healthcare professionals (e.g., gastroenterologists) using a combination of clinical findings, endoscopy, histology, and other laboratory tests, not by a panel of independent "experts" adjudicating images or cases for the purpose of a study (which is common in AI/Imaging studies).

3. Adjudication Method for the Test Set:

   • Not applicable in the context of expert adjudication for diagnostic calls, as this is an IVD measuring a biomarker.
   • For the clinical ground truth, it's based on the established clinical diagnosis by treating physicians. There is no mention of a separate adjudication process (e.g., 2+1 or 3+1 reader consensus) for these clinical diagnoses for the purpose of this device study.

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

   • No, an MRMC study was not done. This type of study is specifically relevant for image-based diagnostic aids where the output of the AI directly influences a human reader's interpretive performance. The BÜHLMANN fCAL® turbo is a laboratory-based immunoassay that quantifies a biomarker. Its output is a numerical concentration, not an image interpretation requiring multiple readers. The "comparative effectiveness" is demonstrated against the predicate device's performance, not how it assists human readers in interpreting complex visual information.

5. Standalone (Algorithm Only) Performance:

   • Yes, this entire submission effectively describes a standalone performance. The BÜHLMANN fCAL® turbo is an automated analyzer/reagent system that directly measures fecal calprotectin concentration from a stool sample extract. The reported results (e.g., precision, linearity, accuracy, clinical sensitivity/specificity) are the direct output of the device itself, without human-in-the-loop interpretation of its primary numerical output. The device "aids in the diagnosis" in conjunction with other findings, meaning the numerical output is used by clinicians, but the device itself functions as a standalone measurement tool.

6. Type of Ground Truth Used:

   • Analytical Ground Truth: For the analytical performance studies (Precision, Linearity, Accuracy, Analytical Sensitivity, Interfering Substances), the ground truth is established through known concentrations of reference materials, spiked samples, or comparison to established reference methods.
   • Clinical Ground Truth: For the Method Comparison and Clinical Sensitivity/Specificity studies, the ground truth for patient classification (IBD, IBS, non-IBD, normal) is based on clinical diagnosis, which would typically include outcomes data, endoscopic findings, histological results, and the overall clinical picture as determined by a treating physician. It is not expert consensus of independent reviewers explicitly for the study, nor is it pathology in the sense of a single definitive pathology report for every case, but rather a comprehensive clinical workup.

7. Sample Size for the Training Set:

   • Not applicable / Not explicitly stated as a separate "training set" in the context of traditional machine learning. This device is an in vitro diagnostic (IVD) immunoassay, not an AI/ML algorithm that is "trained" on a large dataset of patient samples in the same way a deep learning model for image analysis is. The "training" here refers to the internal development and calibration of the assay (e.g., establishing the standard curve, optimizing reagent concentrations), which is part of the product development process, not a distinct "training set" like in AI/ML validation studies. The analytical performance and clinical validation studies presented here are akin to a "test set" and "validation set" in AI/ML terminology, but the concept of a separate "training set" for the device itself (rather than the general scientific knowledge used in developing the immunoassay) is not present.

8. How Ground Truth for Training Set Was Established:

   • As noted above, the concept of a "training set" for this type of IVD device is different from AI/ML models. The ground truth for developing and calibrating the assay (which could be loosely considered "training") involves:
     • Reference materials with known concentrations of calprotectin.
     • Standard curves generated using defined calibrators.
     • Analytical methods and clinical literature informing the selection of antibodies, detection methods, and clinical cut-offs.
     • Internal validation and optimization processes during product development.

In summary, the document thoroughly details the analytical and clinical performance of the BÜHLMANN fCAL® turbo, demonstrating substantial equivalence to its predicate by meeting rigorous criteria in terms of precision, linearity, accuracy, analytical sensitivity, and demonstrating comparable clinical utility in differentiating IBD from other gastrointestinal conditions. The nature of the device (an immunoassay) means certain aspects typically found in AI/ML performance studies (like MRMC or reader adjudication) are not applicable.

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The BÜHLMANN fCAL® ELISA is an in vitro diagnostic assay intended for the quantitative measurement of fecal calprotectin in human stool. The BÜHLMANN fCAL® ELISA aids in the diagnosis of inflammatory bowel disease (IBD), specifically Crohn's disease (CD) and ulcerative colitis (UC) and aids in the differentiation of IBD from irritable bowel syndrome (IBS) in conjunction with other laboratory and clinical findings.

The BÜHLMANN fCAL® ELISA is an enzyme-linked immunosorbent assay (ELISA) performed using patient stool extracts collected without preservatives. Calprotectin within the extract binds to protein specific antibodies coated on the well surface. An enzyme conjugated antibody detects the captured antigen. Incubation of the complex with substrate results in a colored product which reflects the amount of calprotectin in the sample. Quantification of calprotectin concentration is achieved using standard plate readers.

The provided document describes the BÜHLMANN fCAL® ELISA, an in vitro diagnostic assay for the quantitative measurement of fecal calprotectin in human stool. The device aids in the diagnosis of inflammatory bowel disease (IBD) and differentiation of IBD from irritable bowel syndrome (IBS).

Here's an analysis of the acceptance criteria and study information:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are not explicitly stated as distinct, quantifiable targets in the provided text. Instead, the document presents performance study results. The "Clinical Thresholds" section (page 7) outlines the device's interpretation zones, which serve as criteria for classifying results.

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

• Clinical Study (IBD vs. non-IBD):
  • Sample Size: 337 total samples (135 IBD, 202 non-IBD).
  • Data Provenance: Not explicitly stated (e.g., country of origin, retrospective/prospective).
• Clinical Study (IBD vs. IBS):
  • Sample Size: 265 total samples (135 IBD, 130 IBS).
  • Data Provenance: Not explicitly stated.

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

This information is not provided in the document. The method for establishing ground truth (e.g., clinical diagnosis by a panel of specialists) is not detailed.

4. Adjudication method for the test set

This information is not provided in the document.

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

A multi-reader multi-case (MRMC) comparative effectiveness study was not done. This device is a diagnostic assay (ELISA), not an AI-assisted imaging device requiring human-in-the-loop interpretation.

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

The entire performance evaluation described for the BÜHLMANN fCAL® ELISA is inherently a standalone (algorithm only) performance study. The device provides a quantitative measurement of fecal calprotectin without human interpretive input in the assay process itself. The clinical sensitivity and specificity evaluate the performance of this standalone measurement against a clinical diagnosis.

7. The type of ground truth used

The ground truth for the clinical studies appears to be clinical diagnosis. The sections "Clinical Sensitivity/Specificity of IBD vs. non-IBD" and "Clinical Sensitivity/Specificity of IBD vs. IBS" compare the device's results to "IBD," "non-IBD," and "IBS" classifications, which are clinical diagnoses.

8. The sample size for the training set

This information is not provided in the document. As this is a diagnostic assay, not a machine learning model, the concept of a "training set" in the typical sense of AI model development may not directly apply. However, method development and optimization would have involved internal samples, but their size and nature are not disclosed as a "training set."

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

This information is not provided in the document.

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