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.

Device Description

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.

AI/ML Overview

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

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.
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.
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.
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.
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.
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.
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.
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.

Summary

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March 28, 2025

Siemens Healthcare Diagnostic Products GmbH Martina Pfeiff Regulatory Affairs Manager Emil-von-Behring Strasse 76 Marburg, Hessen 35041 Germany

Re: K242952

Trade/Device Name: INNOVANCE Antithrombin Regulation Number: 21 CFR 864.7060 Regulation Name: Antithrombin III Assay Regulatory Class: Class II Product Code: JBQ Dated: September 20, 2024 Received: September 25, 2024

Dear Martina Pfeiff:

We have reviewed your section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (the Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database available at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Additional information about changes that may require a new premarket notification are provided in the FDA guidance documents entitled "Deciding When to Submit a 510(k) for a Change to an Existing Device"

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(https://www.fda.gov/media/99812/download) and "Deciding When to Submit a 510(k) for a Software Change to an Existing Device" (https://www.fda.gov/media/99785/download).

Your device is also subject to, among other requirements, the Quality System (QS) regulation (21 CFR Part 820), which includes, but is not limited to, 21 CFR 820.30. Design controls; 21 CFR 820.90. Nonconforming product; and 21 CFR 820.100, Corrective and preventive action. Please note that regardless of whether a change requires premarket review, the OS regulation requires device manufacturers to review and approve changes to device design and production (21 CFR 820.30 and 21 CFR 820.70) and document changes and approvals in the device master record (21 CFR 820.181).

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR Part 803) for devices or postmarketing safety reporting (21 CFR Part 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safetyreporting-combination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR Part 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR Parts 1000-1050.

All medical devices, including Class I and unclassified devices and combination product device constituent parts are required to be in compliance with the final Unique Device Identification System rule ("UDI Rue"). The UDI Rule requires, among other things, that a device bear a unique device identifier (UDI) on its label and package (21 CFR 801.20(a)) unless an exception or alternative applies (21 CFR 801.20(b)) and that the dates on the device label be formatted in accordance with 21 CFR 801.18. The UDI Rule (21 CFR 830.300(a) and 830.320(b)) also requires that certain information be submitted to the Global Unique Device Identification Database (GUDID) (21 CFR Part 830 Subpart E). For additional information on these requirements, please see the UDI System webpage at https://www.fda.gov/medical-devices/device-advicecomprehensive-regulatory-assistance/unique-device-identification-system-udi-system.

Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.

For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

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Sincerely,

Image /page/2/Picture/3 description: The image shows the text "Min Wu-SA" in a large, bold, sans-serif font. The text is black against a white background. There is a watermark in the background that is light blue.

Min Wu, Ph.D. Branch Chief Division of Immunology and Hematology Devices OHT7: Office of In Vitro Diagnostics Office of Product Evaluation and Quality Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K242952

Device Name INNOVANCE Antithrombin

Indications for Use (Describe)

INNOVANCE Antithrombin is a chromogenic assay for the automated quantitation of functionally active antitirombin in human citrated plasma and can be used as an aid in the diagnosis of antithrombin deficiency.

Type of Use (Select one or both, as applicable)
× Prescription Use (Part 21 CFR 801 Subpart D)	Over-The-Counter Use (21 CFR 801 Subpart C)

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510(k) Summary

This summary of 510(k) safety and effectiveness information is submitted in accordance with the requirements of 21 CFR §807.92, the Safe Medical Act of 1990, and follows the FDA guidance 'The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)]', issued July 28, 2014.

The assigned 510(k) number is: K242952

1. Applicant

Siemens Healthcare Diagnostics Products GmbH

Emil-von-Behring-Str. 76
35041 Marburg, Germany
Contact Person:	Martina Pfeiff
Email:	martina.pfeiff@siemens-healthineers.com
Phone:	+ 49 (174) 3319336
Date Prepared:	September 20, 2024

2. Device

Name of Device:	INNOVANCE® Antithrombin / K242952
Regulation Number:	21CFR 864.7060
Regulation Description:	Antithrombin III assay
Product Code:	JBQ
Device Classification Name:	Antithrombin III Quantitation
Regulatory Class:	Class II
510(k) Review Panel	Hematology

3. Predicate Device

Name of Device / 510(k):	Berichrom® Antithrombin III (A) / K933125
Regulation Number:	21CFR 864.7060
Regulation Description:	Antithrombin III assay
Product Code:	JPE
Device Classification Name:	Antithrombin III, Two Stage Clotting Time Assay
Regulatory Class:	Class II
510(k) Review Panel	Hematology

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No recalls are listed in FDA's Medical device recall database for the predicate device.

No reference devices were used in this submission.

4. Device Description / Test Principle

Antithrombin (AT) is a main inhibitor of enzymatic activity in the coaqulation processes and is synthesized in the liver. This serine protease inhibits different coaqulation factors, with thrombin and factor Xa being the primary target enzymes. The inhibition of thrombin and factor Xa by antithrombin is amplified approximately 1,000-fold in the presence of heparin.

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. A genetically caused antithrombin deficiency leads to reduced antithrombin activity with reduced protein concentration (type I deficiency) or normal protein concentration (type II deficiency). Acquired antithrombin deficiency occurs as a result of reduced synthesis, increased protein consumption, or as a result of protein loss in conditions such as DIC (disseminated intravascular coagulation), sepsis, acute hemolytic transfusion reaction, increased protein loss in nephrotic syndrome, thrombotic microangiopathies, malignant diseases, acute thrombotic episodes and asparaginase therapy. The INNOVANCE Antithrombin assay enables the detection of patients with antithrombin deficiency.

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.

antithrombin + heparin -------------------------------------------------------------------------------------------------------------------------------------------------------
[antithrombin • heparin] + FXa (excess) — > [antithrombin • heparin • FXa] + FXa (residual)
chromogenic FXa substrate

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.

5. Intended Use / Indications for Use

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6. Special Conditions for Use Statements

For in-vitro diagnostic use only. For laboratory professional use. For prescription use only.

7. Special instrument requirements*

. Siemens BCS® XP System
SYSMEX® Automated Coagulation Analyzer, MODEL CA-1500 ●
SYSMEX Automated Coagulation Analyzer, MODEL CA-500
Siemens Healthineers Automated Blood Coagulation Analyzer CA-620 ●
Sysmex Automated Blood Coagulation Analyzer CA-620 .
. Siemens Healthineers Automated Blood Coagulation Analyzer CA-660
Sysmex Automated Blood Coagulation Analyzer CA-660
Siemens Healthineers Automated Blood Coagulation Analyzer CS-2500
Sysmex Automated Blood Coagulation Analyzer CS-2500
Siemens Healthineers Automated Blood Coagulation Analyzer CS-5100 ●
. Sysmex Automated Blood Coagulation Analyzer CS-5100

*The intended use related to QFITLIA (fitusiran) is available currently for the BCS XP System only.

8. Comparison of Technological Characteristics with the Predicate Device

The following table presents a comparison of the similarities and differences between the proposed device INNOVANCE Antithrombin (K242952) and the predicate device Berichrom Antithrombin III (A) (K933125).

Item	Proposed Device (K242952)	Predicate Device (K933125)
	INNOVANCE Antithrombin	Berichrom Antithrombin III (A)
Regulation Number	864.7060	same
Regulation Description	Antithrombin III assay	same
510(k) Review Panel	Hematology	same
Regulatory Class	Class II	same
Product Code	JBQ	JPE
Device Classification Name	Antithrombin III quantitation	Antithrombin III, two stage clotting time assay
Indications for Use / Intended Use	INNOVANCE Antithrombin is a chromogenic assay for the automated quantitation of functionally active antithrombin in human citrated plasma and can be	For the quantitative determination of the functional activity of antithrombin III (AT III) in plasma using automated analyzers for diagnosing reduced AT III synthesis
Item	Proposed Device (K242952)	Predicate Device (K933125)
	INNOVANCE Antithrombin	Berichrom Antithrombin III (A)
	used as an aid in the diagnosis ofantithrombin deficiency.INNOVANCE Antithrombin isindicated as an aid in monitoringantithrombin activity to supportQFITLIA (fitusiran) dosing in adultand pediatric patients aged 12years and older with hemophilia Aor B with or without factor VIII or IXinhibitors.	or increased consumption and formonitoring substitution therapy.
Sample Type	Human citrated plasma	same
Analyte	Antithrombin III	same
Units	% of the norm	same
Measurement	Quantitative	same
Test Principle	Chromogenic (405 nm)	same
Instrument Type	automated coagulation analyzers	automated coagulation analyzers ormanually
Storage	up to the expiry date at 2-8 °C	same
Calibrator (soldseparately)	Standard Human Plasma	same
Controls (soldseparately)	Control Plasma N,Control Plasma P	same
Linearity	7.3 - 127.9% AT	3.7 - 120% AT
Precision	Control N- Repeatability CV: 2.8 %- Within-Device/Lab CV: 3.7 %Control P- Repeatability CV: 2.6 %- Within-Device/Lab CV: 4.5 %Pathological plasma pool (mean:61.7 % of norm)- Repeatability CV: 1.9 %- Within-Device/Lab CV: 3.5 %Additional DataPathological Plasma Pool 1 (mean:15.73 % of norm)- Repeatability CV: 8.77 %	Control N:- Within Run CV: 2.4 %- Run to Run CV: 2.2 %- Total CV: 3.1 %Control P:- Within Run CV: 4.7 %- Run to Run CV: 0.8 %- Total CV: 4.5 %
Item	Proposed Device (K242952)	Predicate Device (K933125)
	INNOVANCE Antithrombin	Berichrom Antithrombin III (A)
	- Within-Device/Lab CV: 9.65 %- Total combined lots CV: 9.95 %
	Pathological Plasma Pool 1 (mean: 15.54 % of norm)- Reproducibility CV: 8.85 %
	Pathological Plasma Pool 2 (mean: 9.75 % of norm)- Repeatability SD: 1.36 % of Norm- Within-Device/Lab SD: 1.59 % of Norm- Total combined lots SD: 1.59 % of norm
	Pathological Plasma Pool 2 (mean: 11.05 % of norm)- Reproducibility Lab SD: 2.19 % of Norm
Reagent Composition	Reagent	Thrombin Reagent
	- human FXa- salts, stabilizers bovine serum albumin- sodium glutamate, aprotinin, heparin, hirudin in Tris/HCI, pH 8.0- preservatives: 5-chloro-2-methyl-2H-isothiazol-3-one and 2-methyl-2H- isothiazol-3-one	- Thrombin, bovine- Heparin sodium, porcine- Aprotinin
	Substrate	Substrate
	- benzyloxycarbonyl-D-Leu-Gly-Arg-ANBA-methylamide-acetate in sodium acetate buffer pH 5.6	- Tos-Gly-Pro-Arg-ANBA-IPA
	- preservatives: 5-chloro-2-methyl-2-Hisothiazol-3-one and 2-methyl-2H-isothiazol- 3-one	Buffer Solution
	Buffer	- TRIS/HCI- NaCl- Preservative: Sodium azide
	- salts in Tris/HCl, pH 8.0- preservatives: 5-chloro-2-methyl-2-Hisothiazol-3-one
Item	Proposed Device (K242952)	Predicate Device (K933125)
	INNOVANCE Antithrombin	Berichrom Antithrombin III (A)
	and 2-methyl-2H-isothiazol- 3-one
Physical Form	Liquid (all components)	Lyophilized (Thrombin Reagent, Substrate)
		Liquid (Buffer Solution)
On-board stability	48 hours	24 hours
Sample stability	Please refer to the instructions inthe CLSI document H21-A52 forfrozen storage conditions andsample stability.4 hours at 15 to 25 °CFrozen plasma specimens shouldbe rapidly thawed at 37 °C; thengently mixed and testedimmediately. Do not freeze multipletimes. Use the plasma undiluted.	1 month at -20 °C2 days at 2 to 8 °C6 hours at 15 to 25 °CPlasma stored at -20 °C is to bethawed within 10 minutes at 37 °C,after which the assay is to beperformed within 2 hours. Do notfreeze multiple times. Use theplasma undiluted.
Interference ofbilirubin, hemoglobin,triglycerides	No interference up to:- Triglycerides 211 mg/dL- Hemoglobin 1000 mg/dL- Bilirubin 60 mg/dL	No interference up to:- Triglycerides 600 mg/dL- Hemoglobin 800 mg/dL- Bilirubin 60 mg/dL

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Items shown for the proposed device derive from K081769 (initial clearance) and K242952. Information indicated in italics refers to new claims introduced with K242952.

The differences between the predicate device and proposed device do not result in a change to the intended use, the indications for use, or to safety and efficacy when used according to the product labeling.

9. Performance Data

The following performance data were provided to support the intended use and in support of the substantial equivalence determination to Berichrom AT.

Based on the results of the risk analysis, precision study and interference studies were identified as verification activity and acceptance criteria established. Clinical validation for the added claim was done by the legal manufacturer of the therapeutic drug QFITLIA (fitusiran), Sanofi.

9.1. Analytical Performance Studies

Repeatability/Reproducibility, analytical specificity and Limit of Quantification studies were performed for the extension of the intended use of INNOVANCE Antithrombin. All Performance claims cleared under K081769 remain valid.

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9.1.1 Repeatability/Reproducibility

A precision (single site) study and a reproducibility (multi-site) study were performed in accordance with the CLSI document EP05-A3 Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline - Third Edition' to investigate the precision performance characteristics in the lower measuring range of INNOVANCE Antithrombin on the BCS XP System.

The reproducibility investigation was performed in a multi-site study, including three (3) internal study sites (Sites 1, 2, and 3). The precision investigation was performed internally at the Siemens company site in Germany (Site 1). Two (2) pathological plasma pools were investigated as test samples. These two pools were chosen to cover the lower AT activity measuring interval of INNOVANCE Antithrombin (<20% of norm) and the medical decision point for QFITLIA (fitusiran) dosing (15% of norm). The order of samples and control materials for each run and day varied to avoid an inherent bias to the study. The internal reproducibility study was carried out at three (3) internal sites, on five (5) runs per day and three (3) replicates of each sample per run (3x5x2x3). All internal sites performed the reproducibility study with the same reagent/calibrator lot combination.

A single-site precision study was carried out on one (1) BCS XP System in twenty (20) days, with two (2) runs per day, two (2) samples per run, in combination with three (3) reagent lots and one (1) calibrator lot (3x20x2x2x1x1; i.e., n=240). The results are presented in the following tables:

	Precision (n = 240)
	Repeatability		Within-device/lab		Total (combined lots)
Sample	Mean[% of Norm]	SD1[% of Norm]	CV2[%]	SD1[% of Norm]	CV2[%]	SD1[% of Norm]	CV2[%]
Pathological Plasma Pool 1	15.73	-	8.77	-	9.65	-	9.95
Pathological Plasma Pool 2	9.75	1.36	-	1.59	-	1.59	-

			Combined laboratories
Sample	n	Mean[% of Norm]	SD1[% of Norm]	CV2[%]
Pathological Plasma Pool 1	90	15.54	-	8.85
Pathological Plasma Pool 2	90	11.05	2.19	-

1 SD: Standard Deviation

2 CV: Coefficient of Variation

9.1.2 Analytical Specificity/Interference

The effects of potentially interfering substances were investigated in an interference study according to CLSI document EP07 'Interfering Testing in Clinical Chemistry. 3rd ed.'. Paired-difference experiments were carried out to evaluate the amount of interferent up to which no interference is to be expected. The

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concentration of the different interferents used was calculated in accordance with CLSI EP7-A3 based on the highest expected interferent concentration in plasma. For desmopressin and Tranexamic acid, the recommended dose for hemophilia patients was used as given in their respective US Prescribing Information. For Recombinant Factor VIIa, Coagulation Factor VIII, Coagulation Factor IX and activated Prothrombin Complex Concentrate (aPCC) doses tested in the interference study were based on the highest doses recommended for bleed management for subjects on QFITLIA (fitusiran).

Samples with and without interferent were compared within the studies. Such interference testing was performed with a panel of exogenous substances. Two (2) plasma pools, a low plasma pool at approximately 10-15 % of norm Antithrombin activity and a high plasma pool at approximately 90 % of norm Antithrombin activity were used.

No interferences up to the indicated concentrations of following therapeutics were observed:

Therapeutic	No interference 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

9.1.3 Detection Capabilities

The limit of quantitation (LoQ) was determined according to the CLSI document EP17-A2:2012, Evaluation of Detection Capability for Clinical CLSI Laboratory Measurement Procedures; Approved Guideline - Second Edition.

To determine the LoQ, plasma samples with concentrations ranging from approximately 6 - 10 % of normal Antithrombin activity were prepared. Four replicates of five patient samples were run once per day for three days using two (2) INNOVANCE Antithrombin reagent lots on one BCS XP System totaling in n=120 determinations. The LoQ estimates were evaluated separately for each reagent lot.

The LoQ was calculated according to CLSI document based on an Total Error goal of not exceed 4% of norm. The LoQ was set to 7.32% of norm as the maximum of the reagent lot specific LoQ values.

9.2. Clinical Validation Data

The safety and effectiveness of the INNOVANCE Antithrombin assay as an aid in monitoring the antithrombin (AT) activity in patients on QFITLIA (fitusiran) was demonstrated through testing of specimens from hemophilia A and B patients with and without inhibitors enrolled in the clinical trial program for QFITLIA. In particular, INNOVANCE Antithrombin assay on the BCS XP analyzer was used to guide AT-based dosing of QFITLIA (AT-based dose regimen, AT-DR) in the ATLAS-OLE study (ClinicalTrials.gov Identifier NCT03754790). Please refer to the QFITLIA drug labeling at Drugs@FDA for more details.

A total of 227 patients were treated with QFITLIA in this multicenter study which was initiated as an openlabel extension study to evaluate the long-term safety and efficacy of QFITLIA in adult and pediatric

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510(k) Summary of INNOVANCE Antithrombin

patients aged ≥12 years with hemophilia A or B, with or without inhibitory antibodies to FVIII or FIX. Eligible patients initially received QFITLIA 80 mg subcutaneously (SC) once monthly. The study was amended to evaluate the efficacy and safety of the AT-DR. A total of 213 patients were subsequently transitioned to an AT-DR with the target AT activity range of 15-35%.

The INNOVANCE Antithrombin assay was used to measure AT activity at baseline (prior to QFITLIA initiation) as well as after QFITLIA exposure throughout the ATLAS-OLE study (AT activity was measured monthly for 12 months after first dose or after dose adjustment, and every 4 months thereafter). The dose of QFITLIA was adjusted based on AT activity levels, if needed, to target AT activity range of 15-35%. Of the total AT-DR population, 199 patients started at the 50 mg dose every other month with dosing guided by the INNOVANCE Antithrombin assay.

In the AT-DR, the QFITLIA starting dose was 50 mg every two months and the dosing was individually adjusted based on AT activity level. The dose could be increased to 50 mg every month or 80 mg every month, or decreased to 20 mg every two months or 20 mg every month, or treatment discontinued if AT activity was <15% at the lowest dose. No patients required escalation to 80 mg every month to achieve the target AT range. The dose required to maintain AT activity 15-35% in patients who initiated dosing on 50 mg every two months was as follows: 35.8% received 50 mg every two months, 15.7% received 50 mg every month, 30.9% received 20 mg every two months, 2.9% received 20 mg every month, and 14.7% discontinued due to more than one AT activity <15%.

Efficacy of QFITLIA was evaluated for a duration of 7 months (primary efficacy period) following a 6month dose adjustment period. 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.

Clinical data from the ATLAS-OLE study demonstrate 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% and can thus be used for supporting the safe and effective dosing of QFITLIA. In conclusion, INNOVANCE Antithrombin assay can be used 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.

10. Comments on Substantial Equivalency

The Siemens Healthcare Diagnostics Products GmbH believes that the data presented in this 510(k) premarket notification as well as the descriptions of similarities and differences support a decision of substantial equivalence between the INNOVANCE Antithrombin assay and the predicate device, Berichrom Antithrombin III (A) (K933125). These two medical devices have equivalent intended uses, technology and performance specifications. Therefore, a premarket clearance is supported based on the performance testing data provided in this submission and in NDA 219019 from Sanofi.

11.Conclusion

Based on the analytical and clinical performance data as documented in this 510(k), in K081769 and NDA 219019, INNOVANCE Antithrombin was found to have a safety and effectiveness profile that is substantially equivalent to the predicate device Berichrom Antithrombin III (A) (K933125). In addition, the data submitted for this premarket notification demonstrates that the modified device raises no concerns regarding safety and effectiveness.

Regulation Number and Section

§ 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).