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INNOVANCE Anti-Xa assay in combination with INNOVANCE Heparin Calibrator is an In-vitro diagnostic automated chromogenic assay for the quantitative determination of unfractionated heparin (UFH) and low molecular weight heparin (LMWH) activity in human plasma collected from venous blood samples in 3.2 % sodium citrated tubes in the clinical laboratory. The quantitative determination of UFH and LMWH can be performed on the BCS XP System, CS-2500 System, CS-5100 System and the CA-660 System. For use with plasma from patients undergoing anticoagulant therapy with either UFH or LMWH.

INNOVANCE Anti-Xa assay in combination with INNOVANCE Apixaban Standard provides quantitative determination of the concentration of apixaban in human plasma collected from venous blood samples in 3.2 % sodium citrated tubes in the clinical laboratory. The quantitative determination of apixaban can be performed on CS-2500 System. For use with plasma from patients undergoing anticoagulant therapy with apixaban in situations where quantification of apixaban levels may be indicated:

· Patient with bleeding,

· Patient with risk for bleeding (e.g. during perioperative management),

· Patient with conditions affecting pharmacokinetics (e.g. deteriorating renal function, extremes of body weight, treatment with other drugs known to affect pharmacokinetics of apixaban).

The performance of this device has not been established in neonate and pediatric patient populations.

INNOVANCE Anti-Xa assay is a one stage chromogenic assay. The reagent kit consists of two components. One component (Reagent) contains Xa. the other (Substrate) a chromogenic substrate specific for Xa. Upon mixing of INNOVANCE Anti-Xa Reagent and INNOVANCE Anti-Xa Substrate, Xa converts the chromogenic substrate into two products, one of them is paranitroaniline. The formation of paranitroaniline can be quantified by the coaqulation analyzer employing light absorption at a specific wavelength (405 nm).

In the presence of a heparin containing sample the formation of paranitroaniline will be reduced in a time dependent manner. This is due to inhibition of Xa by the heparin/AT complex is formed in the patient's plasma and competes with the substrate conversion by Xa. The concentration of the complex is not only dependent on the concentration of heparin but also on the availability of the patient's endogenous antithrombin. By comparison to a reference curve the heparin activity of the sample can be quantified.

To reduce the influence from heparin antagonists, such as platelet factor 4 (PF4), dextran sulfate is included in the reaction mixture.

In the presence of an apixaban containing sample factor Xa is inhibited directly by this inhibitor. Comparison to an inhibitor specific reference curve allows quantification of the inhibitor concentration in the sample.

The provided text describes the performance data for the INNOVANCE Anti-Xa assay, a device for quantitative determination of anticoagulants. As the request is about acceptance criteria and study proving it, and this document is an FDA 510(k) summary, specific acceptance criteria would be internal to the manufacturer's validation plan and not explicitly stated as "acceptance criteria" in this public summary. However, the performance data presented (Precision, Reproducibility, LoB, LoD, LoQ, Linearity, Measuring Interval, Interference, and Method Comparison) implicitly demonstrate that the device meets the necessary performance characteristics for its intended use, making it "substantially equivalent" to a predicate device.

Here's an attempt to extract and infer the information based on the provided document:

1. Table of Acceptance Criteria (Inferred from Performance Data) and Reported Device Performance

Since explicit acceptance criteria are not stated as pass/fail thresholds in this summary, they are inferred based on the presented results which led to substantial equivalence. The predicate device's performance often sets the benchmark for substantial equivalence.

2. Sample Size and Data Provenance:

• Test Set Sample Size:
  • Precision: 240 measurements for each of the 6 samples (INNOVANCE Apixaban Control 1 & 2, and 4 plasma pools).
  • LoB, LoD, LoQ: Not explicitly stated as a single number, but calculation involves measurements of multiple samples (e.g., "samples with an assigned value of 0 ng/mL apixaban" for LoB; "samples with an assigned value of 2, 4, 6, 8 and 10 ng/mL apixaban" for LoD; "samples with an assigned value of 16, 18, 20, 22 and 24 ng/mL apixaban" for LoQ).
  • Linearity & Measuring Interval: Not explicitly stated as a single number, but likely involves multiple spike levels and measurements.
  • Interference: Not explicitly stated, but involves testing various interfering substances.
  • Method Comparison: 301 fresh and frozen plasma samples (multicentric study across 3 sites).
• Data Provenance: The document does not specify the country of origin for the data. It refers to "internally conducted studies" and a "multicentric study" for reproducibility and method comparison, implying clinical laboratories. Since the applicant is Siemens Healthcare Diagnostics Products GmbH, Marburg, Germany, it's highly probable that some or all studies were conducted in Germany or other European countries, though this is not explicitly stated. The studies are described as conforming to CLSI (Clinical and Laboratory Standards Institute) guidelines, which are international standards. The samples for method comparison were "fresh and frozen plasma samples." It is a prospective study in terms of testing the device performance against established samples/methods.

3. Number of Experts and Qualifications for Ground Truth:

This device is an in-vitro diagnostic assay that measures the concentration of substances (heparin, apixaban) in blood plasma directly. Therefore, the "ground truth" is typically defined by:

• Reference Methods: For method comparison, it refers to the results obtained from the predicate device (HemosIL Liquid Anti-Xa) on the ACL TOP system.
• Assigned Values: For calibrators and controls, the "assigned value" is based on the manufacturer's preparation and testing, often traceable to internal reference preparations or qualified methods like LC-MS/MS for substances like apixaban, as stated in the traceability sections for calibrators and controls.

There is no mention of human "experts" (e.g., radiologists, pathologists) establishing ground truth, as this is a quantitative laboratory assay, not an imaging device requiring expert interpretation.

4. Adjudication Method for the Test Set:

Not applicable. This is a quantitative laboratory assay, not a device where interpretation or human reading requires adjudication. The ground truth for method comparison is the measurement from the predicate device (HemosIL Liquid Anti-Xa).

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study:

Not applicable. This is an in-vitro diagnostic device for quantitative chemical analysis, not an imaging device or AI algorithm with human-in-the-loop performance component.

6. Standalone (Algorithm Only) Performance:

This device is a standalone diagnostic assay (reagent kit used with specific automated analyzers). Its performance data, as detailed, represents its standalone performance. There is no separate "algorithm" in the sense of AI that needs to be evaluated independently of the assay system.

7. Type of Ground Truth Used:

• Reference Method Comparison: For method comparison, the ground truth was established by the predicate device (HemosIL Liquid Anti-Xa), which is a legally marketed device, providing a comparative ground truth.
• Internal Reference/Assigned Values: For precision, LoB, LoD, LoQ, linearity, and interference studies, the ground truth for samples (e.g., controls, plasma pools, spiked samples) was established by their assigned values, internal reference preparations, or spiked concentrations. The traceability section explicitly mentions that for apixaban, calibration values are "traceable to apixaban supplied by the manufacturer and quantitated in plasmas assayed by Liquid Chromatography - tandem Mass Spectrometry (LC-MS/MS)" for the predicate, and for the subject device, "calibrated against an internal reference preparation."

8. Sample Size for the Training Set:

This document describes the analytical validation of a diagnostic assay (a chemical reagent system) rather than an AI/ML algorithm. Therefore, the concept of a "training set" for an algorithm doesn't directly apply in the traditional sense. The development of such assays involves extensive R&D, formulation, and preliminary testing, but these are not referred to as "training sets" in the context of typical regulatory submissions for IVDs. The closest equivalent would be the R&D samples used during the development and optimization phase of the reagent and its performance on the instruments. No specific numbers are provided for this.

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

As above, the concept of a "training set" is not relevant here. For the analytical studies presented, "ground truth" (or reference values) for various samples (calibrators, controls, patient samples, spiked samples) were established through recognized methods:

• Predicate Device Measurements: For comparative studies, the measurements from the legally marketed predicate device served as a comparative reference.
• LC-MS/MS (Liquid Chromatography - tandem Mass Spectrometry): This highly accurate analytical technique is explicitly mentioned for establishing traceability and quantifying apixaban in calibrators for the predicate device, and the subject device uses an "internal reference preparation" which would likely also be validated against similar high-accuracy methods.
• Gravimetric/Volumetric Spiking: For linearity, LoD, and LoQ studies, samples are often prepared by precisely adding known concentrations of the analyte (apixaban) to a matrix, making the spiked concentration the ground truth.

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HemosIL Liquid Anti-Xa is an automated chromogenic assay for in vitro diagnostic use by laboratory professionals in clinical laboratories. The assay provides quantitative results on 3.2% citrated human plasma for the following analytes based on the calibrators used:

· When used with HemosIL Heparin Calibrators:

Quantitative determination of unfractionated heparin (UFH) and low molecular weight heparin (LMWH) activity on the ACL TOP Family and ACL TOP Family 50 Series.

· When used with HemosIL Apixaban Calibrators:

Quantitative determination of apixaban on the ACL TOP Family 50 Series through measurement of factor Xa activity, which is inversely proportional to the apixaban level. With HemosIL Apixaban Calibrators, the assay is intended to measure apixaban concentrations in patients on apixaban therapy in the following situations where measurement of apixaban levels could be useful to have as additional information:

• Patients at risk for major bleeding

• Patients experiencing a bleeding episode

· When used with HemosIL Rivaroxaban Calibrators:

Quantitative determination of rivaroxaban on the ACL TOP Family and ACL TOP Family 50 Series through measurement of factor Xa activity, which is inversely proportional to the rivaroxaban level. With HemosL Rivaroxaban Calibrators, the assay is intended to measure rivaroxaban concentrations in patients on rivaroxaban therapy in the following situations where measurement of rivaroxaban levels could be useful to have as additional information:

• Patients at risk for major bleeding

• Patients experiencing a bleeding episode

The assay is not a stand-alone test and the results should be used in conjunction with other clinical and laboratory findings. For use in adult population. For prescription use only.

HemosIL Liquid Anti-Xa is a one stage chromogenic assay based on a synthetic chromogenic substrate and on Factor Xa inactivation. The assay provides quantitative rivaroxaban results on 3.2% citrated human plasma as follows: Rivaroxaban levels in patient plasma are measured automatically on ACL TOP Family and ACL TOP Family 50 Series when this assay is calibrated with HemosIL Rivaroxaban Calibrators. Rivaroxaban directly inhibits Factor Xa activity independent of the antithrombin present. The Factor Xa activity measured by the assay is exogenous. Factor Xa is neutralized directly by rivaroxaban. Residual Factor Xa is quantified with a synthetic chromogenic substrate. The paranitroaniline released is monitored kinetically at 405 nm and is inversely proportional to the rivaroxaban level in the sample.

HemosIL Liquid Anti-Xa is an automated chromogenic assay for in vitro diagnostic use by laboratory professionals in clinical laboratories. The assay provides quantitative results on 3.2% citrated human plasma for the following analytes based on the calibrators used:

When used with HemosIL Heparin Calibrators:
• Quantitative determination of unfractionated heparin (UFH) and low molecular weight heparin (LMWH) activity on the ACL TOP Family and ACL TOP Family 50 Series.

When used with HemosIL Apixaban Calibrators:
• Quantitative determination of apixaban on the ACL TOP Family and ACL TOP Family 50 Series through measurement of factor Xa activity, which is inversely proportional to the apixaban level. With HemosIL Apixaban Calibrators, the assay is intended to measure apixaban concentrations in patients on apixaban therapy in the following situations where measurement of apixaban levels could be useful to have as additional information:

• Patients at risk for major bleeding
• Patients experiencing a bleeding episode

When used with HemosIL Rivaroxaban Calibrators:
• Quantitative determination of rivaroxaban on the ACL TOP Family and ACL TOP Family 50 Series through measurement of factor Xa activity, which is inversely proportional to the rivaroxaban level. With HemosIL Rivaroxaban Calibrators, the assay is intended to measure rivaroxaban concentrations in patients on rivaroxaban therapy in the following situations where measurement of rivaroxaban levels could be useful to have as additional information:

• Patients at risk for major bleeding
• Patients experiencing a bleeding episode

The assay is not a stand-alone test and the results should be used in conjunction with other clinical and laboratory findings.

For use in adult population. For prescription use only.

This appears to be a 510(k) summary for a medical device called "HemosIL Liquid Anti-Xa," which is an in vitro diagnostic assay. The document details the device's technical specifications and performance studies to demonstrate substantial equivalence to a predicate device.

Here's an analysis of the acceptance criteria and the study that proves the device meets them, based on the provided text:

Important Note: The document focuses on demonstrating substantial equivalence for the HemosIL Liquid Anti-Xa assay for rivaroxaban measurement, comparing it to an existing HemosIL Liquid Anti-Xa device for apixaban measurement. Therefore, the "acceptance criteria" table below will reflect the performance characteristics the manufacturer is demonstrating for the new rivaroxaban application, and how its performance stacks up against those established for the predicate or against generally accepted analytical performance standards for such assays. It's not about a specific "AI" device as might be implied by some questions in the prompt, but rather a diagnostic assay.

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state "acceptance criteria" in a separate section with specific numerical targets. Instead, it presents various performance study results (Precision, Reproducibility, LoB/LoD/LoQ, Linearity, Interferences, Stability, Method Comparison) which collectively demonstrate the device's analytical performance. The acceptance is implied by the successful completion of these studies and the presented data.

Here's a table summarizing the reported device performance for the HemosIL Liquid Anti-Xa for rivaroxaban measurement. The implicit acceptance criteria are that these performance characteristics are adequate for the intended use and comparable to or better than the predicate device/industry standards.

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HemosIL Liquid Anti-Xa is an automated chromogenic assay for in vitro diagnostic use by laboratory professionals in clinical laboratories. The assay provides quantitative results on 3.2% citrated human plasma for the following analytes based on the calibrators used:

. When used with HemosIL Heparin Calibrators:

Quantitative determination of unfractionated heparin (UFH) and low molecular weight heparin (LMWH) activity on the ACL TOP Family, ACL TOP Family 50 Series, and ACL Elite/Elite Pro.

· When used with HemosIL Apixaban Calibrators:

Quantitative determination of apixaban on the ACL TOP Family and ACL TOP Family 50 Series through measurement of Factor Xa activity, which is inversely proportional to the apixaban level. With HemosIL Apixaban Calibrators, the assay is intended to measure apixaban concentrations in patients on apixaban therapy in the following situations where measurement of apixaban levels could be useful to have as additional information:

• Patients at risk for major bleeding
• Patients experiencing a bleeding episode

The assay is not a stand-alone test and the results should be used in conjunction with other clinical and laboratory findings.

For use in adult population. For prescription use only.

HemosIL Liquid Heparin and HemosIL Liquid Anti-Xa are one stage chromogenic assays based on a synthetic chromogenic substrate and on Factor Xa inactivation. The assay provides quantitative apixaban results on 3.2% citrated human plasma when used with HemosIL Heparin Calibrators and/or HemosIL Apixaban Calibrators.

The assay contains:

• Factor Xa reagent purified bovine Factor Xa, Tris-Buffer, EDTA, dextran sulfate, . sodium chloride, and bovine serum albumin
• Chromogenic substrate liquid chromogenic substrate S-2732 and bulking agent .

The assay requires the following components which are not included in the assay kit:

• HemosIL Apixaban Calibrators two levels ( and ( ( ng/mL) of lyophilized calibrators . prepared from human citrated plasma containing apixaban, buffers, and stabilizers.
• HemosIL Apixaban Controls two levels (1) and (1) of lyophilized controls . prepared from human citrated plasma containing apixaban, buffers, and stabilizers,
• HemosIL Heparin Calibrator three levels (0, 0.8 and 2.0 IU/mL) of lyophilized . calibrators prepared from human citrated plasma containing heparin, buffer and stablizers.
• HemosIL LMW Heparin Controls two levels (low and high) of lyophilized controls . prepared from human citrated plasma containing low molecular weight (LMW) heparin, buffers and stabilizers. Each lot of LMW Heparin Controls is traceable to the 3rd International WHO Standadrd 11/176 for LMW heparin.
• Hemos IL UF Heparin Controls two levels (low and high) of lyophilized controls . prepared from human citrated plasma containing unfractionated (UF) heparin, buffers and stabilizers. Each lot of UF Heparin Controls is traceable to the 6th International WHO standard 07/328 for UF heparin.
• Cleaning solution .
• Cleaning agent .
• Factor diluent .

The HemosIL Liquid Anti-Xa assay is an automated chromogenic assay designed for in vitro diagnostic use to quantitatively determine unfractionated heparin (UFH), low molecular weight heparin (LMWH) activity, and apixaban levels in citrated human plasma.

Here's an analysis of its acceptance criteria and the study that proves its performance:

1. Table of Acceptance Criteria and Reported Device Performance

The document primarily focuses on analytical performance for apixaban, as heparin performance was previously reported. The key performance criteria evaluated for apixaban are precision, linearity/reportable range, traceability, stability, detection limits, and analytical specificity.

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

• Precision Studies (Test Set):
  • Study 1: 240 determinations (80 per reagent lot).
  • Study 2: Total number of determinations not fully specified, but involved multiple instrument models and reagent lots.
  • Study 3: No specific number of determinations given, states "prodeterminations".
  • Study 4: 270 determinations (multisite).
  • Study 5: 270 determinations (multisite).
• Linearity Studies (Test Set): Normal pooled plasma (NPP) spiked with known concentrations of apixaban, tested in four replicates.
• Detection Limit Studies (Test Set):
  • LoB: n=60 determinations per reagent lot per instrument model (using four citrated plasma pools).
  • LoD: n=60 determinations per reagent lot per instrument model (using four citrated plasma pools).
  • LoQ: n=40 determinations per reagent lot per instrument model (using four citrated plasma pools).
• Analytical Specificity/Interference Studies (Test Set): Test samples (spiked with apixaban) and control samples, tested in a minimum of four replicates.
• Clinical Accuracy (Method Comparison Study Test Set): 367 clinical samples collected from patients receiving apixaban.
• Data Provenance: The method comparison study involved clinical samples collected from three different U.S. clinical sites. This indicates the data is prospective or retrospective clinical data, collected in a real-world setting.
  • For the analytical studies (precision, linearity, detection limits, interference), these were laboratory-controlled studies using spiked or pooled plasma samples.

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

For the clinical accuracy study, the ground truth was established by a validated apixaban LC-MS/MS method. The document does not specify the number or qualifications of experts involved in running or validating this LC-MS/MS method, as LC-MS/MS is a highly sensitive and precise analytical technique typically performed by trained laboratory personnel.

4. Adjudication Method for the Test Set

Not applicable. The ground truth for the clinical accuracy study was established by a quantitative instrumental method (LC-MS/MS), not through expert consensus requiring adjudication.

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

No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done. This device is an automated in vitro diagnostic assay, not an imaging or diagnostic interpretation device that would typically involve human readers. Therefore, the concept of human readers improving with AI vs. without AI assistance does not apply.

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

Yes, the studies reported are standalone performance evaluations of the HemosIL Liquid Anti-Xa assay (an automated algorithm/instrument system). The performance characteristics presented are for the device itself, generating quantitative results. While the device results are intended to be used by laboratory professionals and clinicians, the performance of the device is measured directly, not in conjunction with human interpretation for accuracy.

7. The Type of Ground Truth Used

• Analytical Performance Studies (Precision, Linearity, Detection Limits): Ground truth was established by known concentrations of apixaban used to spike samples, or intrinsic properties of control materials and pooled plasma.
• Clinical Accuracy (Method Comparison Study): Ground truth was established by a validated apixaban Liquid Chromatography - tandem Mass Spectrometry (LC-MS/MS) method. LC-MS/MS is considered a gold standard for drug quantification.

8. The Sample Size for the Training Set

The document does not explicitly mention a "training set" in the context of machine learning. The HemosIL Liquid Anti-Xa is a chromogenic assay based on biochemical reactions and factor Xa inactivation, not a machine learning algorithm that requires specific training data in the traditional sense. The development of such assays involves extensive R&D, reagent optimization, and calibration curve generation, which could be seen as analogous to "training" but is not reported with a distinct sample size for "training set" in this context.

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

As noted above, a traditional "training set" as understood in machine learning is not applicable here. The assay relies on established biochemical principles and calibration against known standards.

• Calibration: For apixaban, calibrator value assignments are traceable to apixaban supplied by the manufacturer and quantitated in plasma assayed by LC-MS/MS. This process ensures the assay accurately measures apixaban concentrations.

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