(184 days)
INNOVANCE Antithrombin is a chromogenic assay for the automated quantitation of functionally active antithrombin in human citrated plasma and can be used as an aid in the diagnosis of antithrombin deficiency.
INNOVANCE Antithrombin is indicated as an aid in monitoring antithrombin activity to support QFITLIA (fitusiran) dosing in adult and pediatric patients aged 12 years and older with hemophilia A or B with or without factor VIII or IX inhibitors.
The INNOVANCE Antithrombin assay is suitable for the determination of physiologically active antithrombin on automatic analyzers and enables the diagnosis of inherited or acquired antithrombin deficiencies. The INNOVANCE Antithrombin assay utilizes a chromogenic measuring principle. An excess of human factor Xa is added to citrated plasma. In the presence of heparin, a portion of the enzyme is complexed and inactivated by the antithrombin present in the sample. Excess, uninhibited factor Xa then cleaves a specific chromogenic substrate, causing the release of a dye. The substrate cleavage is determined by the increase in the absorbance value at 405 nm. The release of dye is inversely proportional to the inhibiting activity of antithrombin in the plasma sample, i.e., the smaller the concentration of functionally active antithrombin, the higher the absorbance signal per time unit.
The provided text describes the analytical and clinical performance of the INNOVANCE Antithrombin assay, particularly in relation to guiding QFITLIA (fitusiran) dosing. It's important to note that this document is for an in vitro diagnostic (IVD) device (an assay), not a software-based AI/ML device that typically involves human readers and image analysis. Therefore, some of the requested information (like number of experts for ground truth, adjudication methods, MRMC studies, or training set details for an AI algorithm) are not directly applicable or found in this type of submission.
However, I will extract and infer the closest applicable information based on the provided text.
Here's a breakdown of the acceptance criteria and study details:
Acceptance Criteria and Reported Device Performance
For an IVD device like the INNOVANCE Antithrombin, acceptance criteria are typically related to analytical performance characteristics that demonstrate the assay's reliability and accuracy. The document highlights precision (repeatability/reproducibility), analytical specificity (interference), and detection capabilities (limit of quantitation).
| Acceptance Criteria Category | Specific Acceptance Criterion (Implicit/Explicit) | Reported Device Performance (INNOVANCE Antithrombin) |
|---|---|---|
| Precision | Repeatability (within-run precision) | Pathological Plasma Pool 1 (mean: 15.73 % of norm): Repeatability CV: 8.77 % |
| Pathological Plasma Pool 2 (mean: 9.75 % of norm): Repeatability SD: 1.36 % of Norm | ||
| Within-device/lab precision | Pathological Plasma Pool 1 (mean: 15.73 % of norm): Within-Device/Lab CV: 9.65 % | |
| Pathological Plasma Pool 2 (mean: 9.75 % of norm): Within-Device/Lab SD: 1.59 % of Norm | ||
| Total precision (combined lots) | Pathological Plasma Pool 1 (mean: 15.73 % of norm): Total combined lots CV: 9.95 % | |
| Pathological Plasma Pool 2 (mean: 9.75 % of norm): Total combined lots SD: 1.59 % of Norm | ||
| Reproducibility (multi-site/between-lab) | Pathological Plasma Pool 1 (mean: 15.54 % of norm): Reproducibility CV: 8.85 % | |
| Pathological Plasma Pool 2 (mean: 11.05 % of norm): Reproducibility Lab SD: 2.19 % of Norm | ||
| Analytical Specificity | Interference (from common substances & therapeutics) | No interference up to: |
- Triglycerides 211 mg/dL
- Hemoglobin 1000 mg/dL
- Bilirubin 60 mg/dL
No interferences from therapeutics up to: - Desmopressin: 0.0144 µg/mL
- Tranexamic Acid: 0.48 mg/mL
- Recombinant Factor VIIa: 2.16 µg/mL
- Coagulation Factor VIII: 0.96 IU/mL
- Coagulation Factor IX: 1.44 IU/mL
- Activated Prothrombin Complex Concentrate (aPCC): 2.4 IU/mL |
| Detection Capabilities | Limit of Quantitation (LoQ) | LoQ was determined as 7.32% of norm. (Calculated based on a Total Error goal of not exceeding 4% of norm). |
| Clinical Performance | Aid in monitoring AT activity for QFITLIA dosing to achieve target range | Clinical data from the ATLAS-OLE study demonstrated that individualized QFITLIA AT-DR using the INNOVANCE Antithrombin assay was successful at achieving AT levels within the targeted AT activity range of 15-35%. Median observed annualized bleeding rate (IQR) for treated bleeds was 3.7 (0.0; 7.5) overall, 1.9 (0.0; 5.6) in inhibitor patients and 3.8 (0.0; 11.2) in non-inhibitor patients. This supports its use for safe and effective dosing. |
Study Information
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Sample sizes used for the test set and the data provenance:
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Analytical Performance Studies (Test Set):
- Precision (Single Site): n=240 determinations (3 reagent lots, 20 days, 2 runs/day, 2 samples/run for 2 pathological plasma pools).
- Reproducibility (Multi-Site): Each of the three internal study sites performed 5 runs per day with 3 replicates of each of the two pathological plasma pools per run (3x5x2x3). The total number of unique samples or determinations isn't given as a single 'n' for the entire reproducibility study, but it involves multiple runs and replicates across sites.
- Analytical Specificity/Interference: Panel of exogenous substances tested on two plasma pools (low AT activity ~10-15% of norm, and high AT activity ~90% of norm). Specific 'n' values for samples tested per interferent are not given, but described as "paired-difference experiments".
- Limit of Quantitation (LoQ): n=120 determinations (4 replicates of 5 patient samples, run once per day for 3 days using 2 reagent lots on one BCS XP System).
- Data Provenance: The analytical studies were performed "internally at the Siemens company site in Germany (Site 1)" and "three (3) internal study sites (Sites 1, 2, and 3)". This implies prospective data collection for these specific validation studies. The clinical data used for drug dosing came from a multicenter clinical trial (ATLAS-OLE study).
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Clinical Validation Data (Test Set for new indication):
- QFITLIA ATLAS-OLE Study: A total of 227 patients were treated with QFITLIA. Of these, 213 patients were transitioned to an AT-DR (Antithrombin-based Dosing Regimen) with the target AT activity range of 15-35%. 199 patients started at the 50 mg dose every other month with dosing guided by INNOVANCE Antithrombin.
- Data Provenance: This was a multicenter, open-label extension study (ATLAS-OLE, ClinicalTrials.gov Identifier NCT03754790). The text indicates AT activity was measured "at baseline (prior to QFITLIA initiation) as well as after QFITLIA exposure throughout the ATLAS-OLE study". This is prospective clinical trial data. The country of origin for the patient data is not explicitly stated but is typically international for large clinical trials.
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Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- This is an IVD assay clearance, not an AI/ML device in image analysis. Therefore, there are no "experts" in the sense of human readers interpreting clinical data for an algorithm's ground truth.
- The "ground truth" for an IVD device's performance is typically established by:
- Reference Methods: Highly accurate, established laboratory methods.
- Clinical Outcomes/Patient Status: For the clinical validation, the "ground truth" is the patient's actual antithrombin activity level using the assay itself, and subsequently, the clinical outcomes related to bleeding rates and successful maintenance of AT levels within the therapeutic range under QFITLIA dosing. The QFITLIA clinical trial (ATLAS-OLE) provides this clinical outcome data.
- The expertise lies in the chemists, biochemists, and clinical laboratory scientists who designed and ran the analytical validation studies, and the clinical investigators (e.g., hematologists) involved in the QFITLIA clinical trial who managed patient care and assessed clinical outcomes. Their qualifications are inherent to conducting such studies, but not explicitly detailed as "experts establishing ground truth" in the same way as for AI.
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Adjudication method (e.g. 2+1, 3+1, none) for the test set:
- Not applicable for this type of IVD device. Adjudication methods like 2+1 (two readers agree, third resolves discrepancy) are common in AI/ML clinical validation studies involving human interpretation (e.g., radiology reads). For an assay, measurements are quantitative and discrepancies would be resolved through re-testing, calibration checks, or instrument troubleshooting, not human adjudication of a qualitative decision.
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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 as this is an IVD assay, not an AI/ML device assisting human readers.
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If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:
- The core "performance" of this device is its analytical measurement. The "standalone" performance here refers to the assay's ability to accurately quantify antithrombin activity itself, which is what the analytical performance studies (precision, interference, LoQ) demonstrate. There isn't an "algorithm" in the typical AI sense; it's a chemical reaction and spectrophotometric measurement. The clinical validation then shows that this standalone measurement (AT activity) is useful in guiding QFITLIA dosing, which is "without human-in-the-loop performance" of the assay itself, though humans still perform the dosing decisions based on the assay output.
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The type of ground truth used (expert consensus, pathology, outcomes data, etc.):
- Analytical Ground Truth: For precision, the "ground truth" samples were "pathological plasma pools" with known/target mean AT activities. For interference, the "ground truth" for "no interference" was defined by comparing results with and without interferent, with acceptance based on a predefined allowable difference (e.g., within X% of the control). For LoQ, calibration standards and accepted statistical methods (CLSI document EP17-A2) were used to determine the lowest reliable measurable concentration.
- Clinical Ground Truth: For the clinical validation, the "ground truth" for the device's utility in QFITLIA dosing was clinical outcomes data from the ATLAS-OLE study, specifically:
- The ability to achieve and maintain AT activity levels within the target therapeutic range (15-35%).
- The observed annualized bleeding rates in patients whose dosing was guided by the assay.
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The sample size for the training set:
- This is an IVD assay, not an AI/ML algorithm that requires a "training set" in the machine learning sense. The assay works based on established chemical principles, not on being trained on a dataset.
- The closest analogy might be the samples used for initial assay development, calibration, and internal optimization, but these are not referred to as a "training set" in this context.
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How the ground truth for the training set was established:
- Not applicable, as there is no "training set" for this IVD assay in the AI/ML sense.
§ 864.7060 Antithrombin III assay.
(a)
Identification. An antithrombin III assay is a device that is used to determine the plasma level of antithrombin III (a substance which acts with the anticoagulant heparin to prevent coagulation). This determination is used to monitor the administration of heparin in the treatment of thrombosis. The determination may also be used in the diagnosis of thrombophilia (a congenital deficiency of antithrombin III).(b)
Classification. Class II (performance standards).