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ImmunoCAP Tryptase is an in vitro semi-quantitative assay for measurement of tryptase in human serum or plasma (EDTA, lithium heparin or sodium heparin). It is intended for in vitro diagnostic use as an aid in the clinical diagnosis of patients with a suspicion of systemic mastocytosis in conjunction with other clinical and laboratory findings. ImmunoCAP Tryptase is to be used with the instruments Phadia 100 and Phadia 250.

ImmunoCAP Tryptase reagents are modular in concept and are available individually in different package sizes dependent on instrument system used.

The reagents needed to perform the ImmunoCAP Tryptase assay are listed below. ImmunoCAP Tryptase/ImmunoCAP Tryptase Conjugate 50 (10-9525-02/10-9522-02) ImmunoCAP Tryptase Calibrators/ImmunoCAP Tryptase Calibrator Strip (10-9526-01/10-9523-01) ImmunoCAP Tryptase Curve Control/ImmunoCAP Tryptase Curve Control Strip (10-9527-01/10-9524-01) ImmunoCAP Tryptase Anti-Tryptase (14-4518-01), ImmunoCAP Tryptase Control (10-9370-01)

The Phadia AB ImmunoCAP Tryptase assay is an in vitro semi-quantitative assay for measuring tryptase in human serum or plasma. It is intended for in vitro diagnostic use to aid in the clinical diagnosis of patients suspected of systemic mastocytosis, in conjunction with other clinical and laboratory findings. This submission is an update due to changes in raw materials for the ImmunoCAP Tryptase Conjugate and ImmunoCAP Tryptase Calibrators, but these changes do not affect the intended or indications for use.

1. Acceptance Criteria and Reported Device Performance

The provided document does not explicitly state numerical acceptance criteria in a table format. However, it indicates that the analytical and clinical performance of the updated ImmunoCAP Tryptase was "verified through studies" and concluded to be "substantially equivalent" to the currently cleared product. This implies that the performance in these studies met the thresholds established for substantial equivalence.

The performance characteristics verified include:

• Precision
• Lot-to-lot reproducibility
• Linearity
• Limit of detection
• Hook effect
• Analytical specificity
• Interference of HAMA
• Recovery
• Sample matrix compatibility
• Clinical performance

The document states that "The results showed that the clinical performance of ImmunoCAP Tryptase has not changed when used as an aid in the routine clinical diagnosis of systemic mastocytosis according to WHO criteria."

2. Sample Sizes and Data Provenance

• Test Set Sample Size: The clinical performance was verified through studies performed at two sites, including a total of 138 patients.
• Data Provenance: The document does not explicitly state the country of origin for the clinical samples. The phrase "samples with and without clinical documentation, as well as samples from healthy individuals" suggests a mix, likely from clinical settings where the studies were conducted. It is a prospective clinical evaluation, given the context of verifying performance for a device update.
• Training Set Sample Size: Not explicitly stated. The document describes an update to an existing device rather than a new algorithm development, so a distinct 'training set' for the algorithm in the sense of AI/ML models is not directly applicable here. The focus is on verifying that the material changes do not alter performance.

3. Number and Qualifications of Experts for Ground Truth

Not applicable. This device is a semi-quantitative assay for a biomarker (tryptase), not an imaging or diagnostic AI device requiring expert adjudication of images or clinical cases for ground truth establishment. The ground truth for clinical performance would be the definitive diagnosis of systemic mastocytosis based on WHO criteria, which involves a combination of clinical, laboratory, and histopathological findings.

4. Adjudication Method for the Test Set

Not applicable. As this is not an AI/ML algorithm requiring human interpretation of outputs, there is no adjudication method in the traditional sense for a test set. Clinical diagnosis based on WHO criteria would be the reference.

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

Not applicable. This is not a device that involves human readers interpreting diagnostic outputs. It is a laboratory assay.

6. Standalone Performance Study

Yes, a standalone performance study was done for the device. The document details the analytical performance characteristics (precision, linearity, limit of detection, etc.) and states that the updated ImmunoCAP Tryptase was compared to the currently cleared ImmunoCAP Tryptase using samples. This inherently describes a standalone performance evaluation of the updated device.

7. Type of Ground Truth Used

For the clinical performance verification, the ground truth was "routine clinical diagnosis of systemic mastocytosis according to WHO criteria." This indicates a comprehensive set of diagnostic guidelines, which would typically involve expert consensus, clinical symptoms, laboratory markers (including tryptase levels), and potentially bone marrow biopsy results.

For the analytical performance verification, the ground truth would be based on established analytical methods and reference materials to assess accuracy, precision, linearity, etc.

8. Sample Size for the Training Set

Not applicable. This is not an AI/ML algorithm that undergoes a training phase with a specific training set of data. The submission is for an update to an existing in vitro diagnostic assay due to raw material changes.

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

Not applicable, as there is no training set in the context of an AI/ML model for this device.

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ImmunoCAP Tryptase is an in vitro semi-quantitative assay for measurement of tryptase in human serum or plasma (EDTA, lithium heparin or sodium heparin). It is intended for in vitro diagnostic use as an aid in the clinical diagnosis of patients with a suspicion of systemic mastocytosis in conjunction with other clinical and laboratory findings.

ImmunoCAP Tryptase is to be used with the instruments Phadia 100, Phadia 250, or Phadia 1000.

ImmunoCAP Tryptase is a fluorescence immunoassay for the measurement of human tryptase based on ImmunoCAP solid phase. ImmunoCAP Tryptase measures the total tryptase levels including all forma of a-tryptase and B-tryptase. ImmunoCAP Tryptase concentrations are quantitatively reported in microgram/L (ug/L).

ImmunoCAP Tryptase consists of assay specific reagents to be used as part of Phadia Laboratory Systems along with already cleared instruments (including instrument and data management software) and system reagents (system reagents were cleared in K051218).

ImmunoCAP Tryptase kits (for the Phadia 100, Phadia 250, and Phadia 1000) contain the following reagents:

• ImmunoCAP Tryptase Conjugate
• ImmunoCAP Tryptase Anti-Tryptase bound to ImmunoCAP carrier
• Development solution
• Stop solution
• Washing solution
• IgE/ECP/Tryptase sample diluent (available separately, not included in the ImmunoCAP Tryptase kit)
• ImmunoCAP Tryptase Control (prepared from selected pooled human serum and lyophilized)

In addition, the Phadia 100 kit includes the following reagents:

• Tryptase calibrators (1, 5, 12.5, 50, and 200 µg/L human tryptase in buffer)
• Tryptase Curve Control 1 (single dose vials of human tryptase in buffer)

In addition, the Phadia 250 and Phadia 1000 kits include the following reagents:

• ImmunoCAP Tryptase Calibrator Strip (1, 5, 12.5, 50, and 200 µg/L human tryptase in buffer)
• Tryptase Curve Control Strip (human tryptase in buffer)

The IMMUNOCAP TRYPTASE device is a fluorescence immunoassay for the measurement of human tryptase, intended as an aid in the clinical diagnosis of patients with a suspicion of systemic mastocytosis. The device's performance was evaluated through various studies, including precision, linearity, recovery, stability, detection limit, hook effect, analytical specificity, and clinical studies for sensitivity and specificity.

1. Acceptance Criteria and Reported Device Performance

The acceptance criteria for precision were defined as a maximum total CVtotal% that would be met for all samples. The exact numerical criteria are obscured in the provided document (b)(4).

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

• Precision (Phadia 100): 10 serum samples.
• Precision (Phadia 250): 16 serum samples.
• Precision (Phadia 1000): 15 serum samples.
• Linearity: 6 serum samples.
• Hook Effect: 5 samples (two serum, one EDTA plasma, one lithium heparin plasma, one sodium heparin plasma).
• Analytical Specificity: Two studies each with two serum samples (13.2 µg/L and 1.8 µg/L tryptase) and three serum samples (with tryptase levels (b)(4)). Heparin interference tested with blank and tryptase-spiked samples. HAMA tested with serum samples.
• Matrix Comparison:
  • Serum and EDTA Plasma: 21 healthy patients.
  • Serum, Lithium Heparin Plasma, and Sodium Heparin Plasma: 20 healthy patients.
• Instrument Comparison: 50 individual samples, 3 pooled internal control samples, and two lots of ImmunoCAP Tryptase Control.
• Clinical Studies (Adults): 138 adult patients. Data provenance: Samples collected at one site in Spain over a 3-year period (retrospective/prospective not explicitly stated, but "over a 3-year period" suggests collection over time).
• Clinical Studies (Pediatric): 156 pediatric patients. Data provenance: Samples collected at one site in Spain over an eight-year period (2003-2011).
• Expected Values/Reference Range: 124 healthy individuals (89 adults, rest children).

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

The ground truth for the clinical studies (systemic mastocytosis diagnosis) was established based on the WHO recommendations for mastocytosis, primarily the 4th edition of "WHO classification of tumors of hematopoietic and lymphoid tissues from 2008".

The studies mention the "Spanish Network on Mastocytosis" coordinated sample collection and patient classification. The WHO criteria themselves are based on a consensus proposal from "a large number of patients with established mastocytosis in different centers of Europe and North America" and involved a "consensus meeting 'Year 2000 Working Conference on Mastocvtosis'".

It is not specified how many individual experts established the ground truth for the specific 138 adult and 156 pediatric cases used in these studies, nor their individual qualifications (e.g., specific years of experience for radiologists). However, the ground truth is anchored in an internationally recognized consensus process and WHO classification, indicating a high level of expert involvement in developing the criteria.

4. Adjudication Method for the Test Set

The diagnostic classification for systemic mastocytosis was done "according to the WHO recommendations for mastocytosis, without consideration of the fourth minor criterion of tryptase levels persistently exceeding 20 ug/L" for the initial analysis. A reanalysis then included tryptase results to see the impact on classification.

This indicates an adjudication method based on an established medical guideline (WHO criteria), where the device's output (tryptase level) was initially excluded from the diagnosis to evaluate its standalone performance against the other criteria, and then included to reflect its intended use. There is no mention of a traditional reader adjudication method like 2+1 or 3+1 involving human readers explicitly reviewing cases to establish ground truth for each test case. Instead, the ground truth is derived from a set of clinical and laboratory findings interpreted by clinicians/pathologists following WHO guidelines.

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

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. The studies evaluate the analytical performance of the automated ImmunoCAP Tryptase assay and its clinical effectiveness (sensitivity and specificity) in diagnosing systemic mastocytosis based on a WHO-defined cutoff, not the improvement of human readers with AI assistance. This device is an in vitro diagnostic test, not an AI-powered image analysis tool that assists human readers.

6. If a Standalone Study Was Done

Yes, standalone (algorithm only) performance was done. The precision, linearity, recovery, detection limit, hook effect, analytical specificity, and matrix/instrument comparison studies all assess the analytical performance of the ImmunoCAP Tryptase assay system itself, independent of human interpretation or assistance.

The clinical studies also present the device's performance (sensitivity and specificity) using a predefined cut-off (20 ug/L) against a clinical diagnosis established by other WHO criteria, which can be considered a standalone evaluation of its diagnostic utility.

7. The Type of Ground Truth Used

The ground truth used for the clinical studies was expert consensus / clinical diagnosis based on established guidelines. Specifically, the diagnosis of Systemic Mastocytosis was classified "according to the WHO recommendations for mastocytosis." These recommendations are themselves based on a consensus proposal developed from extensive clinical and laboratory data, and reviewed scientific literature. The criteria include major criteria (e.g., mast cell infiltrates in organs) and minor criteria (e.g., abnormal mast cell morphology, C-kit mutation, CD2/CD25 expression), excluding tryptase levels for the initial evaluation of the device.

8. The Sample Size for the Training Set

The document does not explicitly state a sample size for a training set. This is a diagnostic assay, and its performance characteristics (precision, linearity, etc.) are typically established through analytical studies using characterized samples rather than a "training set" in the machine learning sense. The clinical studies used patient samples for validation.

The "Traceability" section mentions that "The original reference standard was produced in-house and its concentration determined by the supplier. Each subsequent lot is standardized against reference standards." This implies an internal process for calibrating and standardizing the assay, which might involve a form of internal "training" or calibration, but not a distinct "training set" of patient data for algorithm development as seen in AI/ML products.

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

As there is no explicitly defined "training set" for an algorithm in the context of an FDA submission for a fluorescence immunoassay, the concept of establishing ground truth for a training set is not directly applicable here. The assay relies on a biochemical reaction and a predefined calibration curve. The reference standards mentioned in the traceability section are used to standardize the assay, and their concentrations are determined by the supplier, implying analytical validation rather than expert-labeled ground truth in a clinical context.

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