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The CRYOcheck FVIII Inhibitor Kit is for clinical laboratory use in conjunction with a Factor VIII activity assay to enable the performance of a modified Nijmegen-Bethesda assay using 3.2% citrated human plasma. It enables the determination of a functional FVIII inhibitor titer to aid in the clinical management of congenital hemophilia A in individuals aged 2 years or older. For in vitro diagnostic use.

Device Description

The FVIII Inhibitor Kit is used in the CDC modification of the Nijmegen-Bethesda assay and contains the following components:
Imidazole Buffered Pooled Normal Plasma (IB-PNP): Pooled normal plasma from a minimum of twenty donors with a factor VIII activity value of 95-113% and buffered with imidazole to a pH of 7.3 – 7.5.
Imidazole Buffered Bovine Serum Albumin (IB-BSA): A 4% BSA solution buffered with imidazole to a pH of 7.3-7.5.
Negative Factor VIII Inhibitor Control: Pooled normal plasma from a minimum of five donors buffered with HERES to a pH of 6.2-8.2
Positive Factor VIII Inhibitor Control: HEPES buffered (pH 6.2-8.2) immunodepleted FVIII deficient plasma to which anti-human FVIII antibodies have been added.

AI/ML Overview

The document provided describes the performance characteristics and studies for the CRYOcheck FVIII Inhibitor Kit, rather than an AI/ML-driven medical device. Therefore, a direct mapping to all the requested criteria for AI/ML device acceptance (such as MRMC studies, number of experts for ground truth, adjudication methods, and training set details) is not possible.

However, I can extract and present the information relevant to the device's performance and the studies conducted to demonstrate its effectiveness, aligning with the spirit of the acceptance criteria for a diagnostic kit.

Device: CRYOcheck™ FVIII Inhibitor Kit

Intended Use: For clinical laboratory use in conjunction with a Factor VIII activity assay to enable the performance of a modified Nijmegen-Bethesda assay using 3.2% citrated human plasma. It enables the determination of a functional FVIII inhibitor titer to aid in the clinical management of congenital hemophilia A in individuals aged 2 years or older. For in vitro diagnostic use.

Acceptance Criteria and Reported Device Performance

Since this is an in-vitro diagnostic kit and not an AI/ML device, the "acceptance criteria" are related to standard analytical performance characteristics. The table below summarizes the key performance metrics and the reported results.

Acceptance Criterion (Performance Metric)	Reported Device Performance
Precision (Multi-Reagent Lot)	- Kit Negative Control: SD 0.1 BU/mL (304.1% CV) - Kit Positive Control: 9.4% CV - Negative Plasma Sample: SD 0.1 BU/mL (24.4% CV) - Low Plasma Sample: 8.2% CV - Mid Plasma Sample: 9.9% CV - High Plasma Sample: 6.7% CV (Aggregated Data for all 3 lots) - Negative Plasma Sample: SD 0.1 BU/mL (29.0% CV) - Low Plasma Sample: 8.2% CV - Mid Plasma Sample: 8.3% CV - High Plasma Sample: 8.4% CV
Reproducibility (Multi-Reagent Lot Site to Site)	- Kit Negative Control: SD 0.1 BU/mL (422.7% CV) - Kit Positive Control: 16.0% CV - Negative Plasma Sample: SD 0.1 BU/mL (28.4% CV) - Low Plasma Sample: 10.6% CV - Mid Plasma Sample: 8.3% CV - High Plasma Sample: 13.2% CV (Pooled 3-Site Data) The results demonstrated a pooled reproducibility of ≤16% CV for the positive samples and 0.1 BU/mL SD for the negative plasma sample.
Linearity/Assay Reportable Range	Linearity Range: 0.2 to 1402.9 BU/mL.
Shelf-Life Stability	Supported a 12-month shelf-life stability claim when stored at <-70°C.
In-Use Stability	Supported a 4-hour in-use stability of the product when maintained at room temperature (18–25 °C) or at 2-8 °C post thaw.
Detection Limit	- Limit of Blank (LoB): 0.1 BU/mL - Limit of Detection (LoD): 0.2 BU/mL - Limit of Quantitation (LoQ): 0.2 BU/mL
Interference	No interference found with: hemoglobin (≤ 500mg/dL), bilirubin (≤ 500mg/dL), Intralipid (≤ 29mg/dL), vWF (≤ 20 µg/mL). Lupus anticoagulant autoantibodies may interfere with the quantification of low titer FVIII inhibitors. Rheumatoid Factor at ≥ 82 IU/mL showed interference.
Method Comparison	- Positive Agreement: 100% (95% Cl, 97-100%) - Negative Agreement: 99% (95% CI, 93-100%) Regression statistics showed equivalent performance to comparator method. Overall Pearson Correlation Coefficient: 0.970 ($r^2$ = 0.940).
Sample Integrity	- Robustness demonstrated for FVIII measurements in fresh and frozen plasma samples, including after multiple freeze/thaw cycles (-80°C to 2-8°C, -80°C to -20°C for up to 15 days, and up to three freeze/thaw cycles at -20°C and -80°C). - Sample stability of 12 months when stored frozen at <-70°C.

Study Details (Relevant to an In-Vitro Diagnostic Kit)

The document describes a series of analytical performance studies for the CRYOcheck FVIII Inhibitor Kit.

Sample Size and Data Provenance:
- Precision and Reproducibility Studies: Four plasma samples from congenital hemophilia A patients (negative, low, mid, high levels of FVIII inhibitor) and the kit's Positive and Negative Controls were used.
  - Precision: 80 replicates per sample per lot (3 lots).
  - Reproducibility: 30 replicates per sample per site (3 sites).
  - Data provenance: Implied to be from internal and external laboratories, likely within North America given the submitter and FDA context. The studies are retrospective analyses of samples.
- Linearity Study: Twelve sample dilutions (0 to 100 BU/mL) created from FVIII inhibitor positive plasma and FVIII inhibitor-negative plasma. An expanded study used eighteen sample dilutions (0 to 1402.9 BU/mL) from a high titer contrived sample.
- Stability Studies: Five to six replicates of kit Positive/Negative Controls and four or three plasma samples (negative, low, mid, high FVIII inhibitor levels).
- Detection Limit Studies: Four blank plasma samples from normal healthy donors (for LoB), and four low titer plasma samples from congenital hemophilia A donors (for LoD). Measured in triplicate using three lots over five days.
- Interference Studies: Patient plasma samples spiked with possible interferents. 10 replicates tested alongside 10 replicates of blank matrix control.
- Method Comparison Studies (Test Set): 210 human plasma samples from individuals with congenital hemophilia A. Aliquots distributed across three sites.
  - Data Provenance: Not explicitly stated, but samples are from congenital hemophilia A patients, suggesting clinical samples from a relevant population. The study is prospective in terms of testing collected samples, but the samples themselves are retrospective in terms of their collection relative to the study.
- Sample Integrity Studies: Three test plasma samples created by spiking anti-FVIII monoclonal antibody into immunodepleted FVIII deficient plasma (negative, low, high FVIII inhibitor levels). A retrospective analysis on four plasma samples from congenital hemophilia A patients.
Number of Experts and Qualifications: Not applicable for this type of IVD kit study. The performance is assessed against a comparator method or internal validation standards, not through expert interpretation of images or other subjective data.
Adjudication Method (for Test Set): Not applicable. This is a quantitative diagnostic test where results are numerical values. The comparison is done against a "central reference laboratory using a chromogenic CDC-Modified Nijmegen-Bethesda Assay which has been implemented as a validated Laboratory-Developed Test."
Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study: Not applicable to an in-vitro diagnostic kit where human interpretation is not the primary output being evaluated. The kit measures a biomarker, and its performance is evaluated based on analytical characteristics.
Standalone Performance: The performance data presented (precision, linearity, detection limits, stability, interference, and method comparison) represent the "algorithm only" or "device only" performance without human-in-the-loop performance, as it's an automated laboratory test.
Type of Ground Truth:
- For analytical performance (precision, linearity, stability, detection limits): "Ground truth" is established by the known concentrations/characteristics of controls, spiked samples, or by reference to established metrological protocols (e.g., CLSI guidelines).
- For method comparison studies: The ground truth was established by a "validated Laboratory-Developed Test" (LDT) based on a chromogenic CDC-Modified Nijmegen-Bethesda Assay performed at a central reference laboratory. This serves as the reference method.
- For sample integrity studies: The "ground truth" for the spiked samples was their known composition or assigned values based on fresh measurements. For the retrospective analysis, the true values would be the FVIII inhibitor titers measured by the established method.
Sample Size for Training Set: Not applicable. This is not an AI/ML device that undergoes a "training" phase. The kit's components and assay methodology are developed through R&D, not machine learning from a specific dataset.
How Ground Truth for Training Set Was Established: Not applicable (see point 7).

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