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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).

• 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

1. Sample sizes used for the test set and the data provenance:

   • 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).

   • 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

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CP3000 analyzer: The CP3000 is a fully automated, random-access in vitro blood coagulation analyzer intended for use by healthcare professionals in the clinical laboratory. The CP3000 analyzer is designed to process plasma samples photometrically using chromogenic assays.

Coagpia AT Reagent: Coagpia AT Reagent is intended for the quantitative determination (AT) activity in human 3.2% citrated venous plasma. The reagent is intended for use on Sekisui CP3000 analyzers by trained laboratory personnel in clinical laboratories. For in vitro diagnostic use.

Coagpia Calibrator: The Coagpia Calibrator is intended for use as a calibration plasma for the following Sekisui coagulation assay on Sekisui CP3000 analyzers by trained laboratory personnel in clinical laboratories. For in vitro diagnostic use. - Coagpia AT Reagent

Coagpia Control Set: The Coagpia Control Set contains 2 levels of assaved plasma intended for the following Sekisui coagulation assay on Sekisui CP3000 analyzers by trained laboratory personnel. For in vitro diagnostic use. - Coagpia AT Reagent

CP3000: The CP3000 is designed for easy-to-use, rapid in-vitro blood coagulation testing on citrated human plasma. The CP3000 system is capable of performing the chromogenic methodologic assay, giving the user the ability to perform analysis for both direct hemostasis measurements and calculated parameters. For these assay methodologies, the analyzers employs two photometric detection methods: light scattering and absorbance. The light scattering method uses light emitting diodes at a wavelength of 660 nm, and the absorbance method uses a halogen lamp with filters providing wavelengths at 405/570/730 nm.

Coagpia AT Reagent: Coagpia AT Reagent is intended for the quantitative determination of antithrombin (AT) activity in human plasma on the CP3000 analyzers. The reagent is supplied in a kit of 2 x 10 mL of Reagent 1 and 1 x 10mL of Reagent 2. Both reagents are liquid and do not require any preparation prior to use.

Coagpia Calibrator: The Coagpia Calibrator is supplied as 10 vials of lyophilized human plasma and is suitable for the calibration of the antithrombin activity assay using Coagpia AT Reagent on the CP3000 coagulation analyzers.

Coagpia Control Set: The Coagpia Control Set is supplied as10 vials of lyophilized human plasma; 5 vials of Level 1 Control and 5 vials of Level 2 Control and is suitable for use with the antithrombin activity assay using Coagpia AT Reagent on the CP3000 analyzers.

Here's a breakdown of the acceptance criteria and study information for the CP3000 Coagulation analyzer, Coagpia AT Reagent, Coagpia Calibrator, and Coagpia Control Set, based on the provided FDA 510(k) summary:

1. Table of Acceptance Criteria and Reported Device Performance

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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.

The INNOVANCE™ Antithrombin assay utilizes a chromogenic measuring principle. An excess of 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 rate of the substrate cleavage is determined by the increase in the absorbance value at 405 nm.

Acceptance Criteria and Device Performance for INNOVANCE™ Antithrombin

This response summarizes the acceptance criteria and study details for the INNOVANCE™ Antithrombin device, as presented in the provided 510(k) summary.

1. Table of Acceptance Criteria and Reported Device Performance

The 510(k) summary primarily focuses on demonstrating substantial equivalence to a predicate device. Therefore, the "acceptance criteria" are implied by the performance of the predicate device and the desired correlation and precision statistics.

Table 1: Performance Characteristics of INNOVANCE™ Antithrombin

Study Proving Device Meets Acceptance Criteria:

The study involved comparing the INNOVANCE™ Antithrombin reagent to the legally marketed predicate device, Dade Behring Berichrom™ Antithrombin III (A) reagent (K933125), on the BCS®/BCS® XP System.

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

• Test Set Sample Size:
  • Method Comparison: n = 284 plasma samples.
  • Precision:
    • Control Plasma N: Tested 80 times (reported as N=80 for precision).
    • Control Plasma P: Tested 80 times.
    • Pathological Plasma Pool: Tested 80 times.
• Data Provenance: The document does not explicitly state the country of origin or whether the data was retrospective or prospective. Given it's a 510(k) submission for a device manufactured in Germany (Dade Behring Marburg GmbH), some data might originate from Germany, but this is not confirmed. It is also not specified if the data was retrospective or prospective.

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

Not applicable. This device is an in vitro diagnostic (IVD) assay that quantifies a specific analyte (functionally active antithrombin) through a chromogenic reaction. The "ground truth" for the test samples is established by the validated results from the predicate device and the known concentrations of the control plasmas, not through expert human interpretation.

4. Adjudication Method for the Test Set

Not applicable. As described above, the "ground truth" for this IVD device is based on quantifiable measurements and a predicate device's performance, not on subjective expert assessment requiring adjudication.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and the Effect Size of How Much Human Readers Improve with AI vs. Without AI Assistance

Not applicable. This is an in vitro diagnostic assay, not an imaging or diagnostic AI device that involves human readers or AI assistance in interpretation.

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

Yes, the performance data presented (method comparison and precision) represents the standalone performance of the INNOVANCE™ Antithrombin assay without human intervention influencing the assay's quantitative result. The device is automated, and its performance is assessed independently.

7. The Type of Ground Truth Used

The ground truth for the method comparison study was established by the results obtained from the legally marketed predicate device, Dade Behring Berichrom™ Antithrombin III (A) reagent, when run on the same plasma samples. For precision studies, the ground truth was the known concentrations of the control plasmas (Control Plasma N, Control Plasma P, and a pathological plasma pool). This is an example of an established reference method/device and certified controls.

8. The Sample Size for the Training Set

Not applicable. This device is a chromogenic assay; it is not based on a machine learning or AI algorithm that requires a "training set" in the conventional sense. Its performance is based on chemical reactions and optical detection.

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

Not applicable, as there is no "training set" for this type of IVD device.

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HemosIL Antithrombin is an in vitro diagnostic test for the quantitative determination of Antithrombin in human plasma to monitor the administration of heparin in the treatment of thrombosis and as an aid in the diagnosis of thrombophilia (a congenital deficiency of Antithrombin).

HemosIL Antithrombin is an in vitro diagnostic test for the quantitative determination of Antithrombin in human plasma to monitor the administration of heparin in the treatment of thrombosis and as an aid in the diagnosis of thrombophilia (a congenital deficiency of Antithrombin).

This 510(k) submission (K070301) for HemosIL Antithrombin is a re-submission to modify the "Expected Values" section of the product insert. It explicitly states that the device itself is not materially different from the previously FDA-cleared predicate device (K980499 HemosIL Antithrombin).

Therefore, this document does not contain a new study demonstrating the device meets acceptance criteria. Instead, it relies on the substantial equivalence to the predicate device, whose previous clearance would have involved studies meeting acceptance criteria. The information provided is primarily focused on the regulatory process for a labeling change, rather than a new performance study.

Given this, I cannot provide a detailed answer to your request in the format you specified, as the document does not contain the required information about a new performance study.

However, I can extract the following information that is present in the provided text:

• Device Name: HemosIL Antithrombin
• Intended Use: Quantitative determination of Antithrombin in human plasma to monitor heparin administration in thrombosis treatment and as an aid in diagnosing thrombophilia (congenital Antithrombin deficiency).
• Regulatory Information:
  • Regulation Number: 21 CFR 864.7060
  • Regulation Name: Antithrombin III Assay
  • Product Code: JBQ
  • Regulatory Class: Class II
• Predicate Device: K980499 HemosIL Antithrombin
• Reason for Submission: Modification of the "Expected Values" section in the product insert to reference published literature and emphasize the need for each laboratory to establish its own normal range.
• Statement on Technological Characteristics: "HemosIL Antithrombin with the modified Expected Values section in the product insert is not materially different from the FDA cleared device."
• Expected Values (Modified Section): "Antithrombin activity levels in healthy individuals are approximately in the range of 83 - 128%. Antithrombin levels are low in neonates/infants and increase to adult levels by approximately 1 year of age; levels are then slightly higher than in adults up to age 16 year. Due to many variables which may affect results, each laboratory should establish its own normal range." This section references: Kottke-Marchant K, Duncan A. Antithrombin Deficiency: Issues in Laboratory Diagnosis, Arch Pathol Lab Med. 2002; 126:1326-1336.

To answer your request, one would need to access the original 510(k) submission for the predicate device (K980499 HemosIL Antithrombin), as that is where the performance data and acceptance criteria would have been established and demonstrated. This current document does not provide any of the requested study details (sample size, data provenance, expert ground truth, adjudication, MRMC study, standalone performance, training set size, etc.) because it is not a submission for a new device or significant modification requiring new performance data.

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HemosIL Liquid Antithrombin is an automated chromogenic assay for the quantitative determination of Antithrombin in human citrated plasma as an aid in the diagnosis of hereditary and acquired Antithrombin deficiency and to monitor Antithrombin substitution therapy.

HemosIL Liquid Antithrombin is an automated chromogenic assay for the quantitative determination of Antithrombin in human citrated plasma as an aid in the diagnosis of hereditary and acquired Antithrombin deficiency and to monitor Antithrombin substitution therapy. This in vitro diagnostic test is based on a synthetic chromogenic substrate and on Factor Xa inactivation. As a consequence, it is specific and not influenced by Heparin Cofactor II. Antithrombin levels in patient plasma are measured automatically on IL Coagulation Systems.

This 510(k) submission (K062431) for HemosIL Liquid Antithrombin is a "Special 510(k)" which indicates that the device being submitted is not materially different from a previously cleared device. The purpose of this submission is to modify the "Expected Values" section of the product inserts to reference a normal range from published literature and reinforce the need for each laboratory to establish its own normal reference range.

Therefore, the submission does not contain new performance studies or data to prove the device meets acceptance criteria. Instead, it relies on the substantial equivalence to the predicate device (K033775 HemosIL Liquid Antithrombin) and the update to labeling information.

Because no new performance study data is presented, much of the requested information cannot be provided. However, based on the provided document, here's what can be inferred or explicitly stated:

Acceptance Criteria and Reported Device Performance

Since this is a Special 510(k) for a labeling change and not a new device or significant modification requiring new performance data, there are no specific acceptance criteria or reported device performance metrics presented in this document. The device relies on the performance validated for the predicate device, K033775 HemosIL Liquid Antithrombin.

Details of the Study

As this is a Special 510(k) for a labeling change, no new study proving device performance is included in this document. The submission focuses on updating the "Expected Values" section based on published literature and clarifying the need for local laboratory validation of normal ranges.

Therefore, the following points cannot be answered from the provided text:

2. Sample size used for the test set and the data provenance: Not applicable, no new test set data presented.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts: Not applicable, no new ground truth established for a test set.
4. Adjudication method (e.g. 2+1, 3+1, none) for the test set: Not applicable, no new test set data presented.
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 device, not an AI-assisted diagnostic product.
6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done: Not applicable, this is an in vitro diagnostic device, not an algorithm.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc): For the predicate device, the ground truth would typically be established through method comparisons to recognized reference methods or clinical outcomes studies, but this information is not present in this document. The current submission updates expected values based on published literature.
8. The sample size for the training set: Not applicable, no new model training is performed.
9. How the ground truth for the training set was established: Not applicable, no new model training is performed.

Summary of Changes and Basis for Clearance:

The core of this submission is the modification of the "Expected Values" section in the product inserts. The change is:

• From: Implied standard normal ranges.
• To: Explicitly stating that "Antithrombin activity levels in healthy individuals are approximately in the range of 83 – 128%," and more importantly, adding the directive "Due to many variables which may affect results, each laboratory should establish its own normal range." This statement is supported by a published literature reference: "Kottke-Marchant K, Duncan A. Antithrombin Deficiency: Issues in Laboratory Diagnosis, Arch Pathol Lab Med. 2002; 126:1326-1336."

The FDA's clearance (SEP - 1 2006) for this Special 510(k) indicates that they determined the device with this modified labeling is "substantially equivalent" to the previously cleared HemosIL Liquid Antithrombin (K033775). This is because the underlying device formulation and performance characteristics are unchanged, and the modification is limited to ensuring appropriate interpretation of results by emphasizing localized validation of reference ranges, a common best practice in clinical laboratory diagnostics.

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BIOPHEN Antithrombin 2.5 and 5 kit, is an in vitro diagnostic test for the quantitative determination of Antithrombin in human plasma, as an aid in the diagnosis of thrombophilia (a congenital deficiency of Antithrombin).

Biophen Antithrombin 2.5 and 5 kit, an in vitro diagnostic test for the quantitative determination of Antithrombin in human plasma to monitor the Antithrombin concentration in human plasma, in instances of recurrent thrombosis resulting from a congenital or acquired deficiency of Antithrombin.

The provided text describes the Biophen Antithrombin device and its performance relative to a predicate device, Coamatic® Antithrombin. The study presented here is focused on demonstrating substantial equivalence to the predicate device, not on establishing de novo clinical utility or a standalone performance against a clinical ground truth.

Here's an analysis based on your questions:

1. Table of Acceptance Criteria and Reported Device Performance

The core acceptance criterion for substantial equivalence in this context is a strong correlation with the predicate device and acceptable reproducibility (intra-assay and inter-assay variability).

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

• Sample Size for Test Set: 21 samples
• Data Provenance: The plasma samples were "received from hospital," implying they are clinical samples. The country of origin is not explicitly stated, but the submission is from Hyphen Biomed, France, and the FDA review process is for the US market. It is retrospective as samples were "received from hospital" and tested.

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

This type of study does not involve establishing ground truth by human experts in the typical sense for diagnostic imaging or subjective assessments. Instead, the performance of the new device (Biophen Antithrombin) is compared to the results obtained by a predicate device (Coamatic® Antithrombin), which serves as the "reference" or "ground truth" for the comparison of analytic performance. Therefore, no human experts were used to establish the "ground truth" for the test set in this context. The "truth" is established by the measurements of the predicate device.

4. Adjudication Method for the Test Set

Not applicable. As described in point 3, there was no expert adjudication process. The comparison was directly between the quantitative results of two laboratory devices.

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) device for quantitative determination of Antithrombin, not an imaging AI or a device that assists human readers. Therefore, an MRMC study or assessment of human reader improvement with AI assistance is not relevant.

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

Yes, in a way. The "performance data" provided clearly represents the standalone analytical performance of the Biophen Antithrombin device. It measures the Antithrombin concentration directly from plasma samples. There is no human "in the loop" impacting the quantitative measurement itself, beyond handling the samples and operating the automated system (ACL, BCS). The comparison to the predicate device is also a standalone comparison of two device-generated results.

7. The Type of Ground Truth Used

The "ground truth" for this study is not a clinical outcome or pathology report, but rather the results obtained from the legally marketed predicate device, Coamatic® Antithrombin. The study aims to demonstrate that Biophen Antithrombin produces results substantially equivalent to an already approved device.

8. The Sample Size for the Training Set

The document does not provide information about a "training set" for the Biophen Antithrombin device itself. This is an IVD kit, not a machine learning algorithm that requires a training set in the conventional sense. The development of such a kit would involve internal validation and optimization, but these details are not part of this 510(k) summary.

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

Not applicable, as there is no mention of a training set for a machine learning algorithm. The "training" of an IVD device like this would involve internal R&D to define reagents and protocols, but this is not disclosed in the summary.

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CHROMOPEP AT is intended for use as an in vitro chromogenic assay for the quantitative determination of antithrombin activity in citrated human plasma.
CHROMOPEP PC is intended for use as an in vitro chromogenic assay for the quantitative determination of Protein C activity in citrated human plasma.

Chromopep PC is a chromogenic assay consisting of a synthetic substrate and Protein C activator.
Chromopep AT is a chromogenic assay consisting of a synthetic substrate, Factor Xa, and a Tris Heparin Buffer.

The provided text is a 510(k) Premarket Notification Summary for two devices, Chromopep PC and Chromopep AT, which are chromogenic assays for quantitative determination of Protein C and Antithrombin activity, respectively. These are IVD devices and the provided summary focuses on demonstrating their substantial equivalence to predicate devices, rather than establishing de novo performance criteria. Therefore, several of the requested categories are not applicable or cannot be extracted from this document, as they typically apply to studies evaluating new medical devices and their performance against clinical endpoints or ground truth.

Here's an analysis based on the information available:

1. A table of acceptance criteria and the reported device performance:

Since this is a substantial equivalence submission for IVD assays, the "acceptance criteria" are implied by demonstrating that the new devices perform comparably to their legally marketed predicate devices. The document does not specify quantitative acceptance criteria (e.g., minimum sensitivity, specificity, or accuracy targets) or directly report performance metrics in the way a clinical study for a treatment device might. Instead, the performance is demonstrated through comparison to the predicate devices, implying that if they are "substantially equivalent" in design and intended use, their performance will also be equivalent and acceptable.

2. Sample size used for the test set and the data provenance:

The document does not provide details of specific test sets, sample sizes, or data provenance. The submission focuses on the design and intended use equivalence to predicate devices. It is typical for IVD submissions regarding substantial equivalence to include performance data (e.g., accuracy, precision, linearity, interference studies), but this specific summary does not present those details.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g., radiologist with 10 years of experience):

Not applicable. For IVD assays, "ground truth" often refers to a reference method or known concentration/activity of the analyte. The summary does not describe any expert adjudication for establishing ground truth.

4. Adjudication method (e.g., 2+1, 3+1, none) for the test set:

Not applicable. Expert adjudication methods are typically used in imaging or clinical diagnostic studies where subjective interpretation is involved. This document pertains to quantitative laboratory assays.

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. MRMC studies and AI assistance are not relevant to this type of IVD chromogenic assay.

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

Not applicable. These are laboratory reagents for quantitative assays, not AI algorithms.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.):

The document does not explicitly state the "ground truth" used for performance assessment. For quantitative IVD assays, ground truth typically refers to:

• Reference methods (e.g., gold standard laboratory tests).
• Certified reference materials with known analyte concentrations.
• Spiked samples with known amounts of the analyte.

The summary emphasizes the comparison to predicate devices, implying that their established performance serves as a benchmark rather than a separate ground truth study outlined here.

8. The sample size for the training set:

Not applicable. These are chemical reagents for performing assays, not machine learning or AI models that require training sets.

9. How the ground truth for the training set was established:

Not applicable, as there is no training set for these types of IVD devices.

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HemosIL Liquid Antithrombin XL is a modified version of HemosIL Liquid Antithrombin (K994238) with optimized reagent volumes for use on specific IL Coagulation Systems, such as the ACL Futura (K951891) and ACL Advance (K002400). This modification does not alter the fundamental scientific technology of the device or its intended use as an automated chromogenic assay for the quantitative determination of Antithrombin in human citrated plasma as an aid in the diagnosis of hereditary and acquired Antithrombin deficiency and to monitor Antithrombin substitution therapy. For in vitro diagnostic use.

HemosIL Liquid Antithrombin XL is a modified version of HemosIL Liquid Antithrombin (K994238) with optimized reagent volumes for use on specific IL Coagulation Systems, such as the ACL Futura (K951891) and ACL Advance (K002400). This modification does not alter the fundamental scientific technology of the device or its intended use as an automated chromogenic assay for the quantitative determination of Antithrombin in human citrated plasma as an aid in the diagnosis of hereditary and acquired Antithrombin deficiency and to monitor Antithrombin substitution therapy.

The HemosIL Liquid Antithrombin XL device is a modified version of the HemosIL Liquid Antithrombin (K994238) with optimized reagent volumes. The modification does not alter the fundamental scientific technology or its intended use as an automated chromogenic assay for the quantitative determination of Antithrombin in human citrated plasma. It is intended as an aid in the diagnosis of hereditary and acquired Antithrombin deficiency and to monitor Antithrombin substitution therapy.

1. Table of acceptance criteria and the reported device performance:

The provided document describes performance metrics related to precision and method comparison but does not explicitly state pre-defined acceptance criteria (e.g., "CV must be Y%"). Instead, it presents the results of these studies. For the method comparison, the results are presented in a highly obfuscated and unreadable table due to OCR errors.

However, based on standard laboratory practice for diagnostic assays, the reported precision (CV%) values demonstrate acceptable performance for an Antithrombin assay, especially given the range of AT levels tested. The predicate device (HemosIL Antithrombin K980499) serves as the benchmark for substantial equivalence.

2. Sample size used for the test set and the data provenance:

• Precision Studies:
  • For Normal, Low Abnormal, and High Abnormal control levels, the sample size (n) for each level was 60.
  • Data provenance: Not explicitly stated (e.g., country of origin). The studies appear to be laboratory-based performance evaluations, likely retrospective as they involve control plasmas rather than patient samples for the precision part.
• Method Comparison Study:
  • The sample size for the method comparison study is not explicitly stated in the readable portion of the provided text. The table intended to present this data is corrupted.
  • Data provenance: Not explicitly stated.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:

This information is not provided in the document. For an in vitro diagnostic device like this, "ground truth" often refers to reference methods or clinically established values for the analytes in the control or patient samples. The document focuses on comparing the new device to a predicate device and evaluating its precision, not on new clinical diagnoses established by experts.

4. Adjudication method for the test set:

This information is not applicable to this type of study for an in vitro diagnostic device where the "truth" is typically laboratory-derived values or predicate device results, not expert consensus on interpretations.

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:

This is not applicable. The HemosIL Liquid Antithrombin XL is an automated chromogenic assay, not an imaging device or AI-driven diagnostic tool that relies on human readers or interpretations. Therefore, an MRMC study and AI assistance are not relevant to its evaluation.

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

The device itself is an automated laboratory assay, which by its nature operates in a "standalone" fashion (algorithm/reagent/instrument only) to produce a quantitative result. The performance data provided, specifically precision and method comparison, represent this standalone performance. There isn't a "human-in-the-loop" component in the sense of a human interpreting the primary output of the assay.

7. The type of ground truth used:

• Precision Studies: The "ground truth" for precision is the mean Antithrombin (% AT) value established for each control level (Normal, Low Abnormal, High Abnormal). This is typically determined through repeated measurements and confirmation with established methods.
• Method Comparison Study: The "ground truth" for the modified device (HemosIL Liquid Antithrombin XL) was the results obtained from the legally marketed predicate device (HemosIL Antithrombin K980499). The study aimed to show substantial equivalence to this predicate.

8. The sample size for the training set:

For an in vitro diagnostic assay like this, there isn't typically a "training set" in the machine learning sense. The assay is based on chemical reactions and photometric detection. The development and optimization of the reagent volumes and assay parameters would involve extensive experimentation and optimization, but not a distinct "training set" of data in the way an AI algorithm is trained. The reported values for precision are from performance studies, not "training."

9. How the ground truth for the training set was established:

As indicated above, the concept of a "training set" and associated "ground truth" in the machine learning context does not directly apply to the development and validation of this chemical assay. The "ground truth" for optimizing the assay parameters would be the known concentrations of Antithrombin in reference materials and controls, used to ensure accuracy and precision.

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ChromoCheck™ Antithrombin is intended for use as an in vitro chromogenic assay for the quantitative determination of antithrombin activity in citrated human plasma.

ChromoCheck™ Antithrombin is a chromogenic assay consisting of a synthetic substrate, Factor Xa, and a Tris Heparin Buffer

ChromoCheck™ Antithrombin Acceptance Criteria and Study Details

1. Acceptance Criteria and Reported Device Performance

The provided document does not explicitly state pre-defined acceptance criteria for the ChromoCheck™ Antithrombin device. Instead, it demonstrates substantial equivalence to a predicate device (Coamatic Antithrombin) through a correlation study. The performance of ChromoCheck™ Antithrombin is assessed by its correlation with this predicate device.

Conclusion: The reported R² values of 0.992 and 0.989, and slopes close to 1 (0.988 and 1.036) indicate a very strong linear correlation with the predicate device, suggesting the device meets an implicit acceptance criterion of high concordance with an established method.

2. Sample Size and Data Provenance for Test Set

• Sample Size: 50 normal and pathological patient samples.
• Data Provenance: Not explicitly stated, but given the submitter's location (Dartmouth, Nova Scotia, Canada), it is likely to be from Canada or a mix of sources. The study is retrospective as it compares with an existing predicate.

3. Number and Qualifications of Experts for Ground Truth

Not applicable. The ground truth for this study is the measurement obtained from the predicate device, Coamatic Antithrombin, not expert consensus.

4. Adjudication Method for Test Set

Not applicable. The study involves direct comparison of quantitative measurements from two devices, not expert adjudication of subjective assessments.

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

Not applicable. This is not an AI/human-in-the-loop study. It is a comparison of two quantitative in-vitro diagnostic assays.

6. Standalone Performance Study

Yes, a standalone performance study was done for the ChromoCheck™ Antithrombin in the sense that its measurements were recorded independently. However, its effectiveness was determined by comparison to a predicate, rather than against an 'absolute' ground truth. The study demonstrates the device's ability to produce quantitative antithrombin activity results.

7. Type of Ground Truth Used

The "ground truth" for this study was the quantitative antithrombin activity results obtained from the predicate device, Coamatic® Antithrombin.

8. Sample Size for Training Set

Not applicable. This device is an in vitro diagnostic assay, not a machine learning or AI algorithm that requires a training set.

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

Not applicable, as there is no training set for this device.

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Coamatic® LR Antithrombin is intended for the quantitative determination of the heparin cofactor activity of antithrombin (AT) in human citrated plasma. All components of the kit are in liquid formulation (LR = Liquid Reagents).

Coamatic® LR Antithrombin is intended for the quantitative determination of the heparin cofactor activity of antithrombin (AT) in human citrated plasma. All components of the kit are in liquid formulation (LR = Liquid Reagents).

Antithrombin is the most important natural inhibitor of the coagulation cascade. By inhibiting the coagulation proteases, especially thrombin, factor Xa and factor IXa, antithrombin prevents uncontrolled coagulation and thrombosis. Plasma is incubated with an excess of Factor Xa (FXa) in the presence of heparin. The residual activity of FXa is determined by the rate of hydrolysis of the chromogenic substrate S-2772. The pNA release measured at 405 nm is inversely proportional to the AT level in the range 15-125% of normal plasma.

Here's a breakdown of the acceptance criteria and study details for the Coamatic® LR Antithrombin device, based on the provided text:

Acceptance Criteria and Device Performance

Note: The document does not explicitly state pre-defined numerical "acceptance criteria" for the slope, intercept, r-value, or CV%. Instead, it presents the results from which the FDA made a substantial equivalence determination based on the overall performance compared to the predicate device. The values presented here are the "reported device performance."

Study Details

2. Sample Size and Data Provenance

• Sample Size for Test Set: 61 citrated plasma samples.
• Data Provenance: Not specified in the provided text (e.g., country of origin, retrospective or prospective).

3. Number of Experts and Qualifications for Ground Truth

• Not Applicable (N/A): This type of information is usually relevant for medical imaging or AI diagnostic devices where human experts interpret data. For an in vitro diagnostic (IVD) assay like this, the "ground truth" is typically established by a reference method or validated analytical procedure rather than human expert consensus. The comparison is made against the predicate device.

4. Adjudication Method for Test Set

• Not Applicable (N/A): Adjudication methods (like 2+1, 3+1) are used to resolve discrepancies in human expert interpretations, which is not relevant for this type of IVD device study. The comparison is objective, based on analytical measurement.

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

• No, an MRMC study was not done. This type of study is primarily for medical imaging devices where different human readers evaluate cases with and without AI assistance. This device is an automated IVD assay.

6. Standalone (Algorithm Only) Performance Study

• Yes, a standalone study was done. The "Method Comparison" section directly assesses the performance of the Coamatic® LR Antithrombin assay on the ACL Futura against the predicate device (IL Test™ Liquid AT) on the ACL 9000. This is a direct measurement of the device's performance as an algorithm/test system. The "Precision" study also assesses the standalone analytical performance of the device on the ACL Futura.

7. Type of Ground Truth Used

• Predicate Device/Reference Method: The "ground truth" or reference for comparison was the IL Test™ Liquid Antithrombin on the ACL 9000, which is the legally marketed predicate device. This implies that the predicate device is considered the established method for determining Antithrombin levels in this context.

8. Sample Size for Training Set

• Not Applicable (N/A): The document describes a traditional analytical validation for an IVD assay, not a machine learning or AI-driven device that requires a training set. The device itself is a reagent kit and instrument system.

9. How Ground Truth for Training Set Was Established

• Not Applicable (N/A): As there is no training set mentioned or implied for a machine learning algorithm, this question is not relevant.

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