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Reagent Kit:

The ARCHITECT Galectin-3 assay is a chemiluminescent microparticle immunoassay (CMIA) for the quantitative determination of galectin-3 in human serum and EDTA plasma.

The ARCHITECT Galectin-3 assay may be used in conjunction with clinical evaluation as an aid in assessing the prognosis of patients diagnosed with chronic heart failure (HF). The ARCHITECT Galectin-3 assay is used with the ARCHITECT i System with STAT protocol capability.

Calibrators:

The ARCHITECT Galectin-3 Calibrators are for the calibration of the ARCHITECT i System when used for the quantitative determination of galectin-3 in human serum and EDTA plasma.

Controls:

The ARCHITECT Galectin-3 Controls are for the verification of the ARCHITECT i System when used for the quantitative determination of galectin-3 in human serum and EDTA plasma.

The ARCHITECT Galectin-3 assay is a two-step immunoassay for the guantitative determination of galectin-3 in human serum or EDTA plasma using CMIA technology with flexible assay protocols, referred to as Chemiflex.

In the first step, sample and M3/38 anti-galectin-3 coated paramagnetic microparticles are combined. Galectin-3 present in the sample binds to the anti-galecin-3 coated microparticles. After washing, 87B5 anti-galectin-3 acridinium-labeled conjugate is added to create a reaction mixture in the second step. Following another wash cycle, pre-trigger solutions are added to the reaction mixture. The resulting chemiluminescent reaction is measured as relative light units (RLUs).

A direct relationship exists between the amount of galectin-3 in the sample and the RLUs detected by the ARCHITECT i System optics. The kit is composed of the following:

ARCHITECT Galectin-3 Reagent Kit (5P03)
ARCHITECT Galectin-3 Calibrators (5P03-01)
ARCHITECT Galectin-3 Controls (5P03-10)

Here's the information about 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

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

• Precision (Analytical):

  • Test Set Description: 3 levels of controls and 5 levels of human serum and plasma panels.
  • Sample Size: Minimum of two replicates at two separate times per day for 20 different days (for one lot study) and for 10 different days (for two lots study), for a total of 40 replicates for each lot in the reproducibility study.
  • Data Provenance: Human serum and plasma samples. Retrospective (implied, as samples were collected and then tested for the study). Country of origin is not specified but implied to be US since the submission is to FDA.

• Linearity/Assay Reportable Range:

  • Test Set Description: Two serum samples (one low, one high) and two plasma samples (one low, one high).
  • Sample Size: Neat and diluted panels tested in replicates of three.
  • Data Provenance: Serum and plasma samples. Retrospective (implied). Country of origin not specified.

• Detection Limit:

  • Test Set Description: 7 normal human serum samples in ARCHITECT Galectin-3 Calibrator A, and Low Level Panel Set.
  • Sample Size: Replicates of five, twice per day over three days on two systems with two reagent lots (N= 120).
  • Data Provenance: Normal human serum samples. Retrospective (implied). Country of origin not specified.

• Analytical Specificity (Cross-Reactivity):

  • Test Set Description: Four serum and four plasma samples.
  • Sample Size: The 8 prepared samples were tested in replicates of three.
  • Data Provenance: Human serum and plasma samples. Retrospective (implied). Country of origin not specified.

• Analytical Specificity (Therapeutic Interference):

  • Test Set Description: Serum and plasma samples with various therapeutic agents spiked in.
  • Sample Size: Each galectin-3 sample pool was split into 2 equal aliquots for each therapeutic tested (test and control).
  • Data Provenance: Serum and plasma samples. Retrospective (implied). Country of origin not specified.

• Analytical Specificity (Endogenous Substance Interference):

  • Test Set Description: Serum and plasma samples with various endogenous substances spiked in.
  • Sample Size: Each galectin-3 sample was split into two aliquots for each endogenous substance tested (test and control).
  • Data Provenance: Serum and plasma samples. Retrospective (implied). Country of origin not specified.

• Clinical Study (Prognosis in HF):

  • Test Set Description: Specimens from a multicenter cohort of outpatients with chronic heart failure (HF).
  • Sample Size: 405 serum specimens.
  • Data Provenance: Human serum specimens from a multicenter cohort. Retrospective clinical study ("obtained at time of study entry"). Country of origin is not specified but the submission is to the US FDA.

• Expected Values/Reference Range:

  • Test Set Description: Plasma samples from apparently healthy subjects without known heart disease.
  • Sample Size: 274 plasma samples (133 females, 141 males).
  • Data Provenance: Plasma samples from an observational study. Retrospective (implied). Country of origin not specified.

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

• No information is provided about experts establishing ground truth for the analytical performance studies. These studies typically use pre-defined concentrations or reference materials.
• For the clinical study evaluating prognosis in HF: The ground truth (primary endpoint: hospitalization due to worsening HF, ventricular assist device placement, cardiac transplantation, or all-cause mortality) is based on outcome data. This would typically be recorded clinical events, not established by an adjudication panel of experts in the same way an imaging study would be. The clinical evaluation and diagnosis of heart failure, and classification of events, would be performed by treating physicians/specialists, but the specific process for confirming these outcomes for the study is not detailed as involving a separate panel of experts for ground truth establishment.

4. Adjudication Method for the Test Set

• Not applicable for the analytical performance studies as they rely on quantitative measurements against known standards or reference methods.
• For the clinical study, an explicit adjudication method (e.g., 2+1, 3+1) is not described for the primary endpoint events. The primary endpoint (hospitalization due to worsening HF, ventricular assist device placement, cardiac transplantation, or all-cause mortality) are events recorded during patient follow-up. While clinical judgments are involved in diagnosing and reporting these events, the document doesn't indicate a separate, independent adjudication panel for confirming these outcomes specifically for the study data.

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. This device is an in vitro diagnostic (IVD) assay that quantitatively measures galectin-3 from patient samples. MRMC studies are typically used for imaging devices or AI algorithms that assist human readers in interpreting complex images or data. The ARCHITECT Galectin-3 assay provides a numerical value, which is then used in conjunction with clinical evaluation, rather than assisting a human reader in a diagnostic task that involves pattern recognition.

6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) Was Done

• Yes, the ARCHITECT Galectin-3 assay operates as a standalone algorithm (device only). It produces a quantitative value (ng/mL) of galectin-3 from a patient sample. The performance characteristics described (precision, linearity, detection limit, analytical specificity) are all based on the device's ability to accurately and precisely provide this numerical output. The "human-in-the-loop" aspect comes during the interpretation of the result in conjunction with clinical evaluation, but the assay itself functions independently to generate the measurement. The clinical study demonstrates its effectiveness in its standalone capacity to provide a prognostic indicator.

7. The Type of Ground Truth Used

• Analytical Studies: The ground truth for analytical performance studies (precision, linearity, detection limit, analytical specificity) generally relies on reference materials, known concentrations, or established standard methods. For instance, precision is measured against the device's own reported values, linearity against expected dilutions, and detection limits against known low-concentration samples.
• Clinical Study: The ground truth for the clinical validation study was outcomes data. Specifically, the primary endpoint was a composite of hospitalization due to worsening HF, ventricular assist device placement, cardiac transplantation, or all-cause mortality. These are objective clinical events recorded during patient follow-up.

8. The Sample Size for the Training Set

• This is an in vitro diagnostic (IVD) assay, not typically an AI/ML algorithm that requires a distinct "training set" in the conventional sense of supervised machine learning.
• The "training" equivalent for an IVD kit would be the internal development and optimization work, including the choice of reagents, antibodies, and manufacturing processes. The document does not specify a "training set" size. The calibrators and controls (6 levels for calibrators, 3 levels for controls) are used for routine calibration and quality control of the instrument and assay, not a training set for an AI model.

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

• As explained above, there isn't a "training set" for an AI/ML model for this type of IVD device.
• The calibrators' concentrations (0.0 ng/mL to 114.0 ng/mL) and controls' target concentrations (9.1 ng/mL, 20.5 ng/mL, 74.1 ng/mL) are established. The text states that "The primary calibrators for the ARCHITECT Galectin-3 assay were manufactured gravimetrically and produced based on protein content." This means their concentrations are determined by a highly precise gravimetric (weighing) method and based on the amount of recombinant human galectin-3 protein added. This serves as the "ground truth" for calibrating the assay.

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BGM Galectin-3 is an in vitro diagnostic device that quantitatively measures galectin-3 in serum or EDTA-plasma by enzyme-linked immunosorbant assay (ELISA) on a microtiter plate platform to be used in conjunction with clinical evaluation as an aid in assessing prognosis of patients diagnosed with chronic heart failure (HF). BGM Galectin-3 is indicated for prescription use only.

BGM Galectin-3 is a microtiter plate-based sandwich enzyme-linked immunosorbant assay (ELISA) for the quantitative determination of galectin-3 levels in human serum and plasma. BGM Galectin-3 consists of a rat monoclonal anti-mouse galectin-3 antibody coated microtiter plate serving as the solid phase capture antibody and a horseradish peroxidase (HRP)-labeled mouse monoclonal anti-human galectin-3 antibody functioning as the liquid phase tracer antibody for detecting bound galectin-3.

In the testing procedure, galectin-3 in the standard, control, or patient specimen binds to the immobilized capture antibody; after a wash step, bound galectin-3 is detected by the addition of HRP-labeled anti-galectin-3 antibody. Following a second wash step, the presence of bound galectin-3 is demonstrated by an enzymatic blue color development resulting from the addition of tetramethylbenzidene (TMB) solution as the substrate. Color development is stopped by adding sulfuric acid, changing the color to yellow. Color intensity is read at an absorbance of 450 nm using a colorimetric reader. The absorbance is proportional to the galectin-3 levels in the samples, and test results of the samples are determined using a calibration curve derived from the standards.

BGM Galectin-3 contains the microtiter plate, reagents, assayed quality control materials and standards required to perform analyses on serum or EDTA-plasma samples.

This document describes the analytical and clinical performance of the BGM Galectin-3™ assay.

1. Table of Acceptance Criteria and Reported Device Performance:

The document doesn't explicitly state "acceptance criteria" for all tests in a single table, but the "Summary of Performance Data" section describes various tests and their outcomes. For clinical performance, the focus is on hazard ratios and cumulative probabilities.

Here's an integrated table derived from the provided text, using reported outcomes as evidence of meeting implicit acceptance criteria:

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

• Analytical Performance Studies (Precision, Linearity, Matrix Equivalence, Detection Limit, Cross-Reactivity, Interfering Substances): The sample sizes vary per test. For example:
  • Precision: Six (6) EDTA-plasma pools for internal precision, and three (3) EDTA-plasma pools tested at three (3) CLIA labs.
  • Matrix Equivalence: Forty-nine (49) matched serum and EDTA-plasma samples.
  • Detection Limit: Forty-eight (48) replicate measurements for LoB, and four (4) serum samples (each 16 replicates, total 64 measurements) for LoD.
  • Cross-reactivity/Interference: Multiple substances tested, typically at a single concentration, within a small set of samples. The exact number of samples for each interfering substance test is not explicitly stated beyond "purified hemoglobin (up to 500 mg/dL)" or "conjugated bilirubin (up to 16.8 mg/dL)."
• Clinical Validation Study (Test Set):
  • Sample Size: 895 banked EDTA-plasma samples.
  • Data Provenance: From patients in the United States and Canada, representing a controlled multi-center clinical study (HF-ACTION study). This is retrospective data (banked samples).

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

The clinical validation study uses "endpoints" (all-cause mortality, all-cause hospitalization, cardiovascular mortality, heart failure-related hospitalization) which are typically objective, adjudicated events based on patient records. The document does not specify an "expert" panel that retrospectively established a ground truth label for each patient's galectin-3 level outside of the outcomes data. The study validates the assay's ability to predict these objective outcomes.

4. Adjudication Method for the Test Set:

Not applicable in the context of this device. The "ground truth" for the clinical validation is based on objective clinical outcomes (mortality, hospitalization), not expert agreement on an image or diagnosis. The HF-ACTION study itself would have had protocols for determining these outcomes.

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:

Not applicable. This is an in vitro diagnostic (IVD) assay that measures a biomarker, not an imaging device or AI algorithm requiring human reader interpretation or assistance.

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

The BGM Galectin-3 assay is an entirely standalone device. It quantitatively measures galectin-3 levels from patient samples. There is no human-in-the-loop component for the measurement itself; the clinician interprets the device's numerical output.

7. The Type of Ground Truth Used:

• Analytical Studies: The ground truth is based on reference materials, known concentrations, and established methods for assessing analytical performance (e.g., CLSI guidelines).
• Clinical Validation Study: The ground truth for the clinical validation of the assay's prognostic aid claims is outcomes data, specifically:
  • All-cause mortality
  • All-cause hospitalization
  • Cardiovascular mortality
  • Heart failure-related hospitalization

8. The Sample Size for the Training Set:

The document describes two main groups of samples related to clinical performance:

• Reference Range Determination (healthy population): 1,099 banked plasma samples from apparently healthy subjects. This set was used to establish the expected values for galectin-3 in a normal population.
• Cutoff Value Derivation (HF patients): 582 individuals with HF. This set was used to establish the initial cutoff values for risk stratification (≤ 17.8 ng/mL, 17.8-25.9 ng/mL, > 25.9 ng/mL).

These two sets effectively serve as the "training" or "derivation" sets for the clinical interpretation of the assay.

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

• Reference Range: Established from 1,099 apparently healthy subjects. "Healthy" implies the absence of known heart disease. The exact methods for confirming "healthy" status are not detailed but would typically involve medical history, physical examination, and possibly other diagnostic tests.
• Cutoff Value Derivation: Derived from 582 individuals with HF. The document implies these cutoffs were determined by analyzing the association between galectin-3 levels and adverse outcomes within this derivation cohort. The specific methodology for deriving these cutoffs (e.g., statistical methods like ROC curve analysis or survival analysis) is not explicitly detailed in this summary, but they are subsequently validated in a separate, larger cohort. "HF" diagnosis would be established by clinical criteria, but the specific validation method for that diagnosis is not given.

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