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The Tosoh ST AIA-PACK BNP assay is designed for IN VITRO DIAGNOSTIC USE ONLY for the quantitative measurement of BNP in human (K2EDTA) plasma on Tosoh AIA System Analyzers. BNP is used as an aid in the diagnosis of heart failure (HF) in patients presenting to the emergency department (ED) with clinical suspicion of new onset HF, acutely decompensated or exacerbated HF.

The ST AIA-PACK BNP is a two-site immunoenzymometric assay which is performed entirely in the ST AIA-PACK BNP test cups. BNP present in the test sample is bound with monoclonal antibody immobilized on magnetic beads and enzyme-labeled monoclonal antibody. The magnetic beads are washed to remove unbound enzyme-labeled monoclonal antibody and are then incubated with a fluorogenic substrate, 4-methylumbelliferyl phosphate (4MUP). The amount of enzyme-labeled monoclonal antibody that binds to the beads is directly proportional to the BNP concentration in the test sample. A standard curve is constructed, and unknown sample concentrations are calculated using the curve.

The Tosoh ST AIA-PACK BNP Assay aims to extend its measuring interval beyond 2,000 pg/mL through manual and automated 1:5 and 1:10 dilutions. This is a special 510(k) submission, meaning it refers to a device that has already been cleared (K192380) and modifications were made to it that do not significantly alter its performance or safety (e.g., modified firmware, revised labeling, minor material changes, etc.). Since this is a Special 510(k) and not a de novo submission, this document is a justification for substantial equivalence to its predicate device (K192380), and does not contain detailed information for how the predicate device was evaluated.

Therefore, the study summary below only refers to the performance of the modified device compared to its predicate device, and not a full evaluation of the predicate device's performance.

1. Acceptance Criteria and Reported Device Performance

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

The document does not specify the sample sizes used for the manual and automated dilution studies, nor does it specify the country of origin or whether the data was retrospective or prospective.

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

Not applicable. The ground truth method does not involve human experts; it relies on direct measurement.

4. Adjudication method for the test set

Not applicable. The ground truth method does not involve human experts.

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 versus without AI assistance

Not applicable. This is not an AI-assisted diagnostic device, but an in vitro diagnostic assay.

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

Not applicable. This device is an in vitro diagnostic assay, not an algorithm.

7. The type of ground truth used

The ground truth used for both manual and automated dilution studies is the recovery value of the BNP concentration after dilution, indicating the accuracy of the dilution process. This is a direct measurement based on the expected concentration after dilution.

8. The sample size for the training set

Not applicable. This device is an in vitro diagnostic assay and does not involve machine learning or a training set.

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

Not applicable. This device is an in vitro diagnostic assay and does not involve machine learning or a training set.

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The Tosoh ST AIA-PACK BNP assay is designed for IN VITRO DIAGNOSTIC USE ONLY for the quantitative measurement of BNP in human K2EDTA plasma on Tosoh AIA System analyzers. BNP is used as an aid in the diagnosis of heart failure (HF) in patients presenting to the emergency department (ED) with clinical suspicion of new onset HF, acutely decompensated or exacerbated HF.

The ST AIA-PACK BNP is a two-site immunoenzymometric assay which is performed entirely in the ST AIA-PACK BNP test cups. BNP present in the test sample is bound with monoclonal antibody immobilized on magnetic beads and enzyme-labeled monoclonal antibody. The magnetic beads are washed to remove unbound enzyme-labeled monoclonal antibody and are then incubated with a fluorogenic substrate, 4-methylumbelliferyl phosphate (4MUP). The amount of enzyme-labeled monoclonal antibody that binds to the beads is directly proportional to the BNP concentration in the test sample. A standard curve is constructed, and unknown sample concentrations are calculated using the curve.

The provided text describes the performance characteristics and clinical study results for the ST AIA-PACK BNP assay, an in vitro diagnostic device. This device is intended for the quantitative measurement of BNP in human K2EDTA plasma as an aid in the diagnosis of heart failure (HF).

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

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

The document does not explicitly state "acceptance criteria" in a table format with pass/fail thresholds. Instead, it presents performance data from various analytical and clinical studies. We can infer performance parameters that would typically be subject to acceptance criteria in such a submission.

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

• Test Set Sample Size:
  • Analytical Performance:
    • Precision: 6 K2EDTA plasma samples tested, each at n=80 per lot across 3 lots (total n=240 for combined lot analysis).
    • Linearity: 14 samples ranging from 3.1 - 2271.5 pg/mL.
    • Detection/Quantitation Limit: 11 low-level samples tested in 10 replicates each (2 replicates over 5 days).
    • Interference: K2EDTA samples with known BNP concentrations spiked with various interferents/cross-reactants. Specific N for each interferent test not explicitly stated but implied multiple samples.
  • Clinical Performance:
    • Number of samples assayed: 825
    • Number of samples used for analysis (test set): 724 (101 excluded due to hemolysis, severe renal insufficiency, etc.)
• Data Provenance:
  • Country of Origin: Not explicitly stated for analytical samples. For clinical study: Samples were collected from patients presenting to Emergency Departments (EDs) at 8 clinical sites. The specific country is not mentioned, but given the FDA submission, it is likely the US or a region adhering to similar clinical trial standards.
  • Retrospective or Prospective:
    • Analytical performance: Appears to be prospective testing (e.g., precision study conducted at one site with specified reagents/analyzers, linearity study explicitly designed).
    • Clinical Performance: Prospective study, as it states "The prospective study enrolled male and female patients from 8 clinical sites comprised of Emergency Departments (ED)."

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

• Number of Experts: An independent central adjudication panel comprised of 4 expert cardiologists and 1 ER physician.
• Qualifications of Experts: Expert Cardiologists and an ER Physician. Their specific years of experience are not stated, but their designation as "expert" and the role in an adjudication panel for a clinical trial implies significant experience and qualifications in their respective fields related to heart failure diagnosis.

4. Adjudication method for the test set

• Adjudication Method: Diagnosis of HF or non-HF was determined by an independent central adjudication panel. The panel had access to patient CRFs and clinical information (including echocardiography, other cardiac/thoracic imaging, and standard of care BNP or NT-proBNP results if available). They were blinded to the attending physician's final diagnosis and NYHA classification. The document states that the adjudication was done "to ensure standardization and accuracy of diagnosis per 2013 ACCF/AHA Guidelines for Management of HF." This indicates a consensus-based approach based on comprehensive clinical data, supervised by multiple blinded experts.

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

• No, an MRMC comparative effectiveness study was not done. This submission is for an in vitro diagnostic (IVD) device (a blood test for BNP), not an AI-assisted diagnostic imaging device. Therefore, the concept of "human readers improving with AI vs without AI assistance" does not apply in this context. The study evaluates the performance of the assay itself compared to a ground truth established by clinical adjudication.

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

• Yes, a standalone performance was done. The clinical study evaluates the performance of the "ST AIA-PACK BNP assay" itself to quantitatively measure BNP and its ability to aid in the diagnosis of HF. The results (sensitivity, specificity, AUC) are presented as the performance of the device at the given cutoff, without human interpretation of the device's output influencing the performance metrics being reported. The human element (adjudication panel) was used to establish the ground truth for diagnosis, against which the device's measurements were compared.

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

• Type of Ground Truth: The ground truth for the clinical study was established by expert consensus based on comprehensive clinical information and per established guidelines. Specifically, the "Diagnosis of HF or non- HF was determined by an independent central adjudication panel (comprised of 4 expert cardiologists and 1 ER physician) ... per 2013 ACCF/AHA Guidelines for Management of HF." They had access to patient CRFs, echocardiography, other cardiac/thoracic imaging, and standard of care BNP/NT-proBNP results. This represents a robust form of expert consensus based on extensive clinical data.

8. The sample size for the training set

• The document does not explicitly mention a separate "training set" for the device's development. The "Performance Characteristics" section details analytical and clinical validation studies. For a quantitative IVD like this, the "training" aspect is typically related to the assay's development, calibration, and optimization of reagents and protocols, rather than an explicit "training set" used in machine learning. The clinical study described is a validation study (test set).

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

• As a specific "training set" for algorithmic learning is not mentioned (as this is a biochemical assay), the concept of ground truth for a training set in that sense does not apply directly. However, the development of such an assay involves extensive work to ensure its accuracy and reliability across the dynamic range, linearity, precision, and minimizing interference. This often uses well-characterized, sometimes synthetic or spiked, samples with known concentrations to inform the assay's design and calibration. The "Traceability" section mentions that "The ST AIA-PACK BNP CALIBRATOR SET contains assigned concentrations of BNP. The assigned value is determined on a lot-by-lot basis and is designed to provide an assay calibration range of 4.0 to 2,000 pg/mL of BNP. The calibrators in this set are prepared gravimetrically and are compared to internal reference standards." This implies the "ground truth" for the internal calibration and ongoing quality control of the assay is established through gravimetric preparation and comparison to internal reference standards.

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