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HemosIL AcuStar HIT-IgG(PF4-H) is a qualitative, fully automated, chemiluminescent immunoassay (CIA) for the detection of IgG antibodies that react with Platelet Factor 4 (PF4) when complexed to heparin. The assay is for use in human 3.2% or 3.8% citrated plasma and serum on the ACL AcuStar instrument in a laboratory setting.

The result provided by the assay should be interpreted as either positive or negative based on the assay cut-off (1.00 U/ mL). The positive or negative result aids in determining the risk for heparin induced thrombocytopenia (HIT) when used in conjunction with other laboratory and clinical findings.

Anti-PF4/Heparin antibodies are commonly found in patients with HIT. For use in adult population suspected of HIT. Not for use in isolation to exclude HIT.

HemosIL AcuStar HIT Controls are for the quality control of the HemosIL AcuStar HIT-IgG(PF4-H) assay as performed on the ACL AcuStar.

For prescription use.

The HemosIL AcuStar HIT-IgG(PF4-H) assay is a chemiluminescent two-step immunoassay consisting of magnetic particles coated with PF4 complexed to polyvinyl sulfonate (PVS) which capture, if present, the PF4/Heparin antibodies from the sample. After incubation, magnetic separation, and a wash step, a tracer consisting of an isoluminol-labeled anti-human IgG antibody is added and may bind with the captured PF4/Heparin IgG on the particles. After a second incubation, magnetic separation, and a wash step, reagents that trigger the luminescent reaction are added, and the emitted light is measured as relative light units (RLUs) by the ACL AcuStar optical system. The RLUs are directly proportional to the PF4/Heparin IgG concentration in the sample.

The HemosIL AcuStar HIT-IgG(PF4-H) kit consists of:
R HIT-IgG(PF4-H) Cartridge for 25 determinations: Cartridge containing 1 vial of magnetic particle suspension coated with PF4/PVS complex, 1 vial of assay buffer, 1 vial of tracer consisting of an mAb anti-human IgG antibody labeled with isoluminol, and 1 vial of sample diluent used for the regular predilution of the sample. The reagents are in a phosphate or Tris buffer containing bovine serum albumin, bovine fetal serum, PF4/PVS complex, mouse monoclonal IgG, stabilizers, and preservative.

C1 HIT-IgG(PF4-H) Calibrator 1: Barcoded tube of a solution with humanized mAb anti-PF4-Heparin in Tris buffer containing bovine serum albumin, stabilizers and preservative.

C2 HIT-IgG(PF4-H) Calibrator 2: Barcoded tube of a solution with humanized mAb anti-PF4-Heparin in Tris buffer containing bovine serum albumin, stabilizers, and preservative.

The calibrators are lot specific and they cannot be used with other lots of reagents.

Controls:
The Low and High HIT Controls are prepared by means of a dedicated process and contain different concentrations of humanized monoclonal anti-PF4-Heparin.

Low HIT Control: Control intended for the assessment of precision and accuracy of the HemosIL AcuStar HIT-IgG(PF4-H) assay below the cut-off.

High HIT Control: Control intended for the assessment of precision and accuracy of the HemosIL AcuStar HIT-IgG(PF4-H) assay above the cut-off.

Use of both controls is recommended for a complete quality control program.

Here's a breakdown of the acceptance criteria and the study details for the HemosIL AcuStar HIT-IgG(PF4-H) device, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state "acceptance criteria" for all performance metrics in a pass/fail format. However, by comparing the device to the predicate and the SRA, and given the FDA clearance, a reasonable inference of acceptable performance can be made from the reported results. The critical performance metrics are related to agreement with the predicate device and a reference method (SRA).

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

• Multicenter Method Comparison (vs. Predicate and SRA):
  • Sample Size:
    • N=802 for comparison to predicate (Zymutest HIA IgG).
    • N=790 for comparison to Serotonin Release Assay (SRA). (12 samples removed due to invalid/indeterminate SRA results).
  • Data Provenance: Samples were obtained from patients exposed to heparin and showing HIT-related symptoms. The study was conducted at three (3) external clinical sites (hospitals). This indicates a prospective clinical study environment across multiple locations, likely within the country where the study was performed (not explicitly stated, but typically FDA submissions refer to studies conducted in, or acceptable to, the US or EU). The status is prospective in the sense that these were newly tested samples within the framework of this study, even if collected from ongoing patient care.
• Precision and Reproducibility Studies: Sample pools and native patient samples were used. Actual number of unique patient samples used for these studies is not explicitly stated, but the studies involve repeated testing of these samples.
• Cut-off Determination: 87 citrated plasma samples from hospitalized patients exposed to heparin and with clinical signs consistent with HIT.
• Reference Intervals:
  • Heparin Exposed, Non-HIT Suspected: 91 citrated plasma samples.
  • Healthy Donors: 154 citrated plasma samples.

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

• For Cut-off Determination: The Serotonin Release Assay (SRA) served as the reference method (ground truth). It is implied that the SRA results themselves were established by experts in the hospitals where the samples were tested. No specific number or qualifications of experts are given in this document.
• For Multicenter Method Comparison: The SRA was again used as the primary reference method ("gold standard"). The results of the SRA are taken as the ground truth. There is no mention of an expert panel specifically adjudicating the SRA results or the clinical diagnoses used in the study.

4. Adjudication Method for the Test Set

• No explicit adjudication method (e.g., 2+1) is described for the test set of the primary clinical study.
• The comparison relies directly on the results of the Serotonin Release Assay (SRA) as the reference standard, and the predicate device.
• The "cut-off determination" section mentions that the 87 samples were tested by the hospital with SRA, and these results (45 SRA positive, 42 SRA negative) were used to perform ROC analysis to establish the device's cut-off. This suggests the SRA results are considered the definitive truth.

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

• No, an MRMC comparative effectiveness study was not done. This device is an in vitro diagnostic (IVD) immunoassay, not an imaging or interpretive device that typically involves human readers in the output interpretation directly. The output is a numerical value (U/mL) and a categorical interpretation (Positive/Negative) which is then used by clinicians. There is no "human-in-the-loop" component in the sense of interpreting the AI's output in comparison to interpreting raw data.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done

• Yes, the provided performance data represents the standalone performance of the HemosIL AcuStar HIT-IgG(PF4-H) assay. This is an automated immunoassay where the instrument and reagents perform the analytical steps and output the result (U/mL) and interpretation (Positive/Negative). There is no "human-in-the-loop" interaction with the algorithm's immediate output that would alter its performance metrics as presented here.

7. The Type of Ground Truth Used

• Serotonin Release Assay (SRA) results were used as the primary reference method or "gold standard" for establishing clinical performance (e.g., PPV, NPV, and cut-off determination).
• The predicate device (Zymutest HIA IgG) was also used as a comparator for demonstrating substantial equivalence.

8. The Sample Size for the Training Set

• The document does not explicitly mention a "training set" in the context of machine learning or AI algorithm development. This device is an IVD immunoassay, and its development follows more traditional analytical validation processes rather than AI model training.
• However, the "Cut-Off Determination" study, which involved 87 samples with known SRA results, effectively served a similar purpose to a training/validation set in establishing an optimal operating point (the 1.00 U/mL cut-off) for the device. These patients had been exposed to heparin and displayed clinical signs consistent with HIT.
• The "Reference Interval" studies (healthy donors and heparin-exposed non-HIT suspected patients) also contribute to understanding the assay's behavior in different populations, which could be seen as part of foundational data.

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

• As noted above, for the "Cut-Off Determination" study (serving a similar role to a training set), the ground truth for the 87 samples was established by Serotonin Release Assay (SRA) results performed by the hospital. The results were categorized as SRA positive (45 samples) and SRA negative (42 samples). These SRA classifications then allowed for Receiver Operating Characteristics (ROC) analysis to determine the optimal assay cut-off.

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