(251 days)
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.
| Performance Metric | Implied Acceptance Criteria (Inferred from Industry Standards/Predicate) | Reported Device Performance (INNOVANCE Anti-Xa) |
|---|---|---|
| Precision (Within-Device/Lab CV%) | Generally low CV% (e.g., < 10% for clinical assays) | Plasma Pool 1: CV% not reported, SD = 2.0 ng/mLPlasma Pool 2: CV% not reported, SD = 1.1 ng/mLINNOVANCE Apixaban Control 1: 2.48%Plasma Pool 3: 2.03%INNOVANCE Apixaban Control 2: 2.57%Plasma Pool 3: 2.09% |
| Reproducibility (Combined sites CV%) | Generally low CV% across sites | < 65 ng/mL: ≤ 4.6 CV% (SD) / CV% not reported≥ 65 ng/mL: ≤ 6.68% |
| Limit of Blank (LoB) | Very low, ideally close to 0 ng/mL | 1.0 ng/mL |
| Limit of Detection (LoD) | Low enough to detect clinically relevant concentrations | 3.3 ng/mL |
| Method Linearity | Acceptable linearity across the measuring range | Linear over 10.5 ng/mL to 378 ng/mL |
| Measuring Interval (Range) | Clinically appropriate range for therapeutic monitoring | 20 to 350 ng/mL (extendable up to 700 ng/mL with dilution) |
| Interference | No significant interference from common endogenous/exogenous substances at specified concentrations | No interference observed up to stated concentrations for Bilirubin, Hemoglobin, Lipids, Danaparoid sodium, Edoxaban, Fondaparinux, LMWH, UFH, Rivaroxaban, Atorvastatin, Ticagrelor, Acetylsalicylic acid, Warfarin, Isosorbide dinitrate. |
| Method Comparison (Correlation (r) and Regression equation) | High correlation (e.g., r > 0.95) and close to y=x for agreement with predicate. | Overall (n=301): r = 0.989, y = 1.026x - 8.590 ng/mL (across 3 sites) |
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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Image /page/0/Picture/0 description: The image shows the logo of the U.S. Food and Drug Administration (FDA). On the left is the Department of Health & Human Services logo. To the right of that is the FDA logo, which is a blue square with the letters "FDA" in white. To the right of the blue square is the text "U.S. FOOD & DRUG ADMINISTRATION" in blue.
October 10, 2024
Siemens Healthcare Diagnostics Products GmbH Anja Wilhelm Manager Regulatory Affairs Emil-von-Behring-Strasse 76 Marburg, HE 35041 Germany
Re: K240315
Trade/Device Name: INNOVANCE Anti-Xa Regulation Number: 21 CFR 864.7295 Regulation Name: Heparin And Direct Oral Factor Xa Inhibitor Drug Test System Regulatory Class: Class II Product Code: QLU Dated: September 10, 2024 Received: September 10, 2024
Dear Anja Wilhelm:
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 mediation-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 contains the text "Min Wu-S) A". The text is written in a simple, sans-serif font. The letters are black, and the background is white. The text appears to be a name or a title, with the "-S) A" possibly indicating a suffix or abbreviation.
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) K240315
Device Name INNOVANCE Anti-Xa
Indications for Use (Describe)
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.
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 quidance 'The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)]', issued July 28, 2014.
1. Applicant
| Siemens Healthcare Diagnostics Products GmbH | |
|---|---|
| Emil-von-Behring-Str. 76 | |
| 35041 Marburg, Germany | |
| Contact Person: | Anja Wilhelm |
| Email: | anja.wilhelm@siemens-healthineers.com |
| Phone: | +49 172 3428316 |
| 2. Device | |
| Name of Device: | INNOVANCE Anti-Xa |
| Regulation Number: | 21 CFR 864.7295 |
| Regulation Description: | Heparin And Direct Oral Factor Xa Inhibitor Drug Test System |
| Product Code: | QLU |
| Device Classification Name: | Anti-Factor Xa Activity Test System, Apixaban |
| Regulatory Class: | Class II |
| 510(k) Review Panel | Hematology (81) |
| 3. Predicate Device | |
| Name of Device / 510(k): | HemosIL Liquid Anti-Xa / DEN190032, K213464, K223187 |
| Regulation Number: | 21 CFR 864.7295 |
| Regulation Description: | Heparin And Direct Oral Factor Xa Inhibitor Drug Test System |
| Product Code: | QLU |
| Device Classification Name: | Anti-Factor Xa Activity Test System, Apixaban |
| Regulatory Class: | Class II |
| 510(k) Review Panel | Hematology (81) |
A Class 2 Device Recall HemosIL Liquid Anti-Xa was issued on October 19, 2021. The recall topic was related to labeled On-board instrument stability issue for current and future lots, reduced On-board Instrument Stability from 7 days. Furthermore, in K213464 Instrumentation Laboratory Company cleared the reduced on-board stability claims of 4 days for the ACL TOP Family/ACL TOP Family 50 Series.
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No reference devices were used in this submission.
4. Device Description / Test Principle
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.
5. Intended Use / Indications for Use
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-5100 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 Standards 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.
6. Special Conditions for Use Statements
For in-vitro diagnostic use only.
For laboratory professional use.
For prescription use only.
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7. Special instrument requirements:
When used with INNOVANCE Heparin Calibrator:
- BCS XP System •
- . Automated Blood Coagulation Analyzer CA-600 series (CA-600 series)
- AUTOMATED BLOOD COAGULATION ANALYZER CS-2500 (CS-2500 System)
- . AUTOMATED BLOOD COAGULATION ANALYZER CS-5100 (CS-5100 System)
When used with INNOVANCE Apixaban Standards:
- . AUTOMATED BLOOD COAGULATION ANALYZER CS-2500 (CS-2500 System)
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 Anti-Xa and the predicate device HemosIL Liquid Anti-Xa including their dedicated calibrator and control materials.
| Item | Predicate DeviceHemosIL Liquid Anti-Xa | Subject DeviceINNOVANCE Anti-Xa |
|---|---|---|
| Intended Use /Indication for Use | 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 | 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 Standards 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 |
| Item | Predicate Device | Subject Device |
| HemosIL Liquid Anti-Xa | INNOVANCE Anti-Xa | |
| therapy in the following situations wheremeasurement of apixaban levels couldbe useful to have as additionalinformation:- Patients at risk for major bleeding- Patients experiencing a bleedingepisodeWhen used with HemosILRivaroxaban Calibrators:Quantitative determination ofrivaroxaban on the ACL TOP Family andACL TOP Family 50 Series throughmeasurement of factor Xa activity, whichis inversely proportional to therivaroxaban level. With HemosILRivaroxaban Calibrators, the assay isintended to measure rivaroxabanconcentrations in patients onrivaroxaban therapy in the followingsituations where measurement ofrivaroxaban levels could be useful tohave as additional information:- Patients at risk for major bleeding- Patients experiencing a bleedingepisodeThe assay is not a stand-alone test andthe results should be used in conjunctionwith other clinical and laboratoryfindings.For use in adult population. Forprescription use only | with plasma from patients undergoinganticoagulant therapy with apixaban insituations where quantification ofapixaban levels may be indicated:- Patient with bleeding- Patient with risk for bleeding(e.g. during perioperativemanagement)- Patient with conditions affectingpharmacokinetics (e.g.deteriorating renal function,extremes of body weight,treatment with other drugsknown to affectpharmacokinetics of apixaban).The performance of this device has notbeen established in neonate andpediatric patient populations. | |
| Sample Type | 3.2% citrated human plasma | Same |
| Measurement | Quantitative | Same |
| TestingMethodology | Chromogenic | Same |
| Reporting Unit | ng/mL | Same |
| Item | Predicate DeviceHemosIL Liquid Anti-Xa | Subject DeviceINNOVANCE Anti-Xa |
| Instrument type | Automated Coagulation analyzer | Same |
Similarities of the Reagents
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Similarities of the Calibrator Material
| Item | Predicate DeviceHemosIL Apixaban Calibrators | Subject DeviceINNOVANCE Apixaban Standards |
|---|---|---|
| Intended Use | HemosIL Apixaban Calibrators areintended for the calibration of theHemosIL Liquid Anti-Xa assay whentesting for apixaban on the ACL TOPFamily and ACL TOP Family 50 Series. | For calibration of the INNOVANCE Anti-Xaassay for the quantitativedetermination of the concentration ofapixaban in citrated human plasma. |
| used by the instrument to automaticallyprepare a calibration curve | used to establish a reference curve(calibration curve) | |
| Matrix | human citrated plasma | human plasma, citrated |
| Physical status | lyophilized | lyophilized |
| Concentrationlevels | 2Calibrator 1: no apixaban Calibrator 2:lot-specific | 2Standard 0: no apixaban Standard 1: lot-specific |
Similarities of the Control Material
| Item | Predicate Device | Subject Device |
|---|---|---|
| HemosIL Apixaban Controls | INNOVANCE Apixaban Controls | |
| Intended Use | HemosIL Apixaban Controls are for the quality control of the HemosIL Liquid Anti-Xa assay when testing for apixaban on the ACL TOP Family and ACL TOP Family 50 Series.Apixaban Low Control: Assayed control intended for the assessment of precision and accuracy of the assay at the low concentration of apixaban.Apixaban High Control: Assayed control intended for the assessment of precision and accuracy of the assay at the high concentration of apixaban. | For quality control of the INNOVANCE Anti-Xa assay for the quantitative determination of apixaban in citrated human plasma. |
| Matrix | human citrated plasma | human plasma, citrated |
| Physical status | lyophilized | lyophilized |
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| Item | Predicate DeviceHemosIL Apixaban Controls | Subject DeviceINNOVANCE Apixaban Controls |
|---|---|---|
| Concentrationlevels | 2 (concentrations lot-specific) | 2 (concentrations lot-specific) |
Differences of the Reagents
| Item | Predicate DeviceHemosIL Liquid Anti-Xa | Subject DeviceINNOVANCE Anti-Xa |
|---|---|---|
| Instrumentation | ACL TOP Family (K160276)ACL TOP Family 50 Series (K150877) | AUTOMATED BLOOD COAGULATIONANALYZER CS-2500 (CS-2500System) (K172286) |
| On-boardStability | 4 days | 72 hours |
| Open ReagentStability | 1 month | 8 weeks |
| Composition | The HemosIL Anti-Xa kit includes thefollowing components: | The INNOVANCE Anti-Xa kit includesthe following components: |
| Factor Xa reagent: Liquid preparationcontaining purified bovine Factor Xa(approximately 5.5 nkat/mL),Tris-Buffer, EDTA, dextransulfate, sodium chloride andbovine serum albumin.Chromogenic substrate: liquidchromogenic substrate S-2732(approximately 1.2 mg/mL) andbulking agent. | Ready to use liquid containing:FXa, bovine (~0.7 IU/mL)buffers/stabilizers, preservativespH 8Ready to use liquid containing:Suc-lle-Glu(piperidin-1-yl)-Gly-Arg-pNA.HCl (1.25 mg/mL)buffers/stabilizers, preservativespH 5 | |
| Limit of Detection | 9 ng/mL for apixaban | 3.3 ng/mL for apixaban |
| Linearity | 20 to 1000 ng/mL for apixaban | 20 to 700 ng/mL for apixaban |
| KitSizeConfigurations | 4 mL Kit Vial Size (Size 1):Factor Xa reagent (Cat. No.0020302612): 5 x 2.5 mL vial of aliquid preparation containing purifiedbovine Factor Xa (approximately 5.5nkat/mL), Tris- Buffer, EDTA, dextransulfate, sodium chloride and bovineserum albumin. | INNOVANCE Anti-Xa (Only 1 Size):INNOVANCE Anti-Xa Reagent:5 x 3.2 mL vial of a liquid preparation.INNOVANCE Anti-Xa Substrate:5 x 4.0 mL vial of liquid chromogenicsubstrate. |
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| Item | Predicate DeviceHemosIL Liquid Anti-Xa | Subject DeviceINNOVANCE Anti-Xa |
|---|---|---|
| Chromogenic substrate (Cat. No.0020302622): 5 x 3 mL vial of liquidchromogenic substrate S-2732(approximately 1.2 mg/mL) andbulking agent.10 mL Kit Vial Size (Size 2): | ||
| Factor Xa reagent (Cat. No.0020303610): 5 x 5 mL vial of a liquidpreparation containing purifiedbovine Factor Xa (approximately 5.5nkat/mL), Tris-Buffer, EDTA, dextransulfate, sodium chloride and bovineserum albumin.Chromogenic substrate (Cat. No.0020303620): 5 x 6 mL vial of liquidchromogenic substrate S-2732(approximately 1.2 mg/mL) and bulkingagent | ||
| Calibrators (SoldSeparately) | HemosIL Apixaban Calibrators TargetLevels: 0 and ~500 ng/mL | INNOVANCE Apixaban StandardsTarget Levels: 0 and ~420 ng/mL |
| Controls (SoldSeparately) | HemosIL Apixaban ControlsTarget Levels: ~75 and ~300 ng/mL | INNOVANCE Apixaban ControlsTarget Levels: ~70 and ~260 ng/mL |
Differences of the Calibrator Material
| Item | Predicate Device | Subject Device |
|---|---|---|
| HemosIL Apixaban Calibrators | INNOVANCE Apixaban Standards | |
| Stabilityafterreconstitution | 7 days at 2-8°C in the closed originalvial, | 2-8 °C: reconstituted, 40 hours (closed original vial) |
| 8 hours at 15-25°C on-board the ACLTOP Family/ACL TOP Family 50 Seriesor | 15-25 °C: reconstituted, 12 hours (closed original vial) | |
| 60 days at -20°C in the closed originalvial (single thaw only). | ||
| Traceability | There are no international standards for apixaban. Calibrator value assignments are traceable to apixaban supplied by the manufacturer and quantitated in plasmas assayed by Liquid Chromatography - tandem Mass Spectrometry (LC-MS/MS). | There are no international standards for apixaban. The concentration of apixaban is calibrated against an internal reference preparation and is lot specific. |
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Differences of the Control Material
| Item | Predicate DeviceHemosIL Apixaban Controls | Subject DeviceINNOVANCE Apixaban Controls |
|---|---|---|
| Stabilityafterreconstitution | 7 days at 2-8°C in the closed originalvial8 hours at 15-25°C on-board the ACLTOP Family/ACL TOP Family 50 Series60 days at -20°C in the closed originalvial (single thaw only). | 2-8 °C: reconstituted, 48 hours (closedoriginal vial)15-25 °C: reconstituted, 20 hours(closed original vial)≤-18 °C: reconstituted, 4 weeks(closed original vial) |
| Traceability | There are no international standards forapixaban. Control value assignmentsare traceable to apixaban supplied bythe manufacturer and quantitated inplasmas assayed by LiquidChromatography – tandem MassSpectrometry (LC-MS/MS). | There are no international standards forapixaban. The concentrationofapixaban is calibrated against aninternal reference preparation |
The differences between the predicate device and proposed device do not result in a change to the intended use of apixaban method, 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 in support of the substantial equivalence determination.
Precision
Precision studies were conducted with the CS-2500 System as described in the CLSI document EP05-A3, using INNOVANCE Apixaban Control 1, INNOVANCE Apixaban Control 2 and 4 plasma pools.
| Repeatability | Within-Device/LabPrecision | |||||
|---|---|---|---|---|---|---|
| Sample | n | Meanng/mL | SDhng/mL | CVi% | SDhng/mL | CVi% |
| Plasma pool 1 | 240 | 31.4 | 0.9 | - | 2.0 | - |
| Plasma Pool 2 | 240 | 50.1 | 0.7 | - | 1.1 | - |
| INNOVANCE Apixaban Control 1 | 240 | 74.9 | - | 1.58 | - | 2.48 |
| Plasma pool 3 | 240 | 95.8 | - | 1.25 | - | 2.03 |
| INNOVANCE Apixaban Control 2 | 240 | 277.6 | - | 2.20 | - | 2.57 |
| Plasma pool 3 | 240 | 320.5 | - | 1.24 | - | 2.09 |
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Reproducibility
Reproducibility was assessed based on internally conducted studies, including site, laboratory, operator and lot variability factors.
| Combined sites | Combined assay lots | |||
|---|---|---|---|---|
| Sample concentration | SDhng/mL | CVi% | SDhng/mL | CVi% |
| < 65 ng/mL | ≤ 4.6 | - | ≤ 2.0 | - |
| ≥ 65 ng/mL | - | ≤ 6.68 | - | ≤ 4.05 |
^ SD: Standard Deviation
1 CV: Coefficient of Variation
Limit of Blank (LoB), Limit of Detection (LoD) and Limit of Quantitation (LoQ)
The LoB for INNOVANCE Anti-Xa on the SYSMEX CS-2500 was successfully calculated from measurements of samples with an assigned value of 0 ng/mL apixaban. The LoB for the measurement procedure was set to 1.0 ng/mL.
The LoD for INNOVANCE Anti-Xa on the SYSMEX CS-2500 was successfully calculated from measurements of samples with an assigned value of 2, 4, 6, 8 and 10 ng/mL apixaban (approximately 1fold, 2-fold, 3-fold, 4-fold and 5-fold of the measured LoB value (1.0 nq/mL)). The LoD for the measurement procedure was set to 3.3 ng/mL.
The LoQ for INNOVANCE Anti-Xa on the SYSMEX CS-2500 was successfully calculated from measurements of samples with an assigned value of 16, 18, 20, 22 and 24 ng/mL apixaban (20 ng/mL ± 20 %) allowing a maximum TE of ≤ 7 ng/mL. The LoQ for the measurement procedure was set to 15.8 ng/mL. The TE was <7 ng/mL for both reagent lots.
Linearity
The method 'Apixaban with INNOVANCE Anti-Xa on the SYSMEX CS-2500' demonstrates acceptable linearity over the range of 10.5 ng/mL to 378 ng/mL.
Measuring Interval
Based on the outcome of the LoQ and linearity studies the measuring interval is provided to the users of INNOVANCE Anti-Xa as follows:
Apixaban: 20 to 350 ng/mL
For the quantitative determination of the concentration of apixaban the upper limit of the measuring interval can be extended up to 700 ng/mL by manual 1:2 dilution of the sample with Standard Human Plasma (e.g. 200 µL Sample with 200 µL Standard Human Plasma) and subsequent measurement of the diluted sample. The result of the manually diluted sample must be multiplied by the dilution factor of 2 prior to reporting. To confirm extended measuring range The dilution recovery study was carried out in accordance with the CLSI document EP34-ED1:2018 'Establishing and Verifying an Extended Measuring Interval Through Specimen Dilution and Spiking.'
Interference
The INNOVANCE Anti-Xa assay was evaluated for interference on the CS-2500 System (Apixaban) according to CLSI document EP07-A2 and CLSI document EP07-ED3.
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Following concentrations of listed endogenous substances were found to cause no interference up to the indicated concentrations:
| Substance | No Interference up to... |
|---|---|
| Bilirubin (unconjugated)* | 17 mg/dL |
| Bilirubin (conjugated)* | 31 mg/dL |
| Hemoglobin* | 191 mg/dL |
| Lipids** | 150 mg/dL |
*According to CLSI guideline EP07-A2
**Evaluated with INTRALIPID equivalent (LIPOVENOES) spiked samples.
In addition, no interferences up to the indicated activities/concentrations of following exogenous substances were observed:
| Substance | No Interference up to... |
|---|---|
| Danaparoid sodium* | 0.05 U/mL |
| Edoxaban* | 5.8 ng/mL |
| Fondaparinux* | 60.0 ng/mL |
| LMWH* | 0.07 IU/mL |
| UFH* | 0.06 IU/mL |
| Rivaroxaban* | 5.3 ng/mL |
| Atorvastatin*** | 0.077 mg/dL |
| Ticagrelor*** | 0.190 mg/dL |
| Acetylsalicylic acid*** | 3.00 mg/dL |
| Warfarin*** | 5.34 mg/dL |
| Isosorbide dinitrate*** | 0.600 mg/dL |
*according to CLSI guideline EP07-A2
***according to CLSI guideline EP07-ED3
Method Comparison
A study was performed according to CLSI document EP09-A3 with fresh and frozen samples to compare the INNOVANCE Anti-Xa assay on the CS-2500 System to the HemosIL Liquid Anti-Xa on the ACL TOP for the measurement of apixaban. The results from the Passing-Bablock regression analysis are summarized in the following table:
| n | Concentration range of plasmasamples investigated | Coefficient ofcorrelation | Regression equation |
|---|---|---|---|
| 301 | 23–602 ng/mL | 0.989 | $y = 1.026 \times - 8.590$ ng/mL |
The summary of multicentric study is given below:
Siemens Healthcare Diagnostics Products GmbH
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| N | r | Slope | Intercept | |||||
|---|---|---|---|---|---|---|---|---|
| Value | 95% CI | Value | 95% CI | |||||
| Site 1 | 94 | 0.994 | 1.042 | 1.014 | 1.070 | -2.568 | -6.562 | 1.376 |
| Site 2 | 94 | 0.990 | 0.991 | 0.956 | 1.030 | -9.048 | -14.670 | -3.346 |
| Site 3 | 113 | 0.987 | 1.001 | 0.970 | 1.034 | -9.299 | -14.621 | -5.552 |
| Multicenter | 301 | 0.989 | 1.026 | 1.006 | 1.047 | -8.590 | -11.593 | -5.677 |
10. Conclusion
Based on the nonclinical and clinical performance studies as documented in this 510k, INNOVANCE Anti-Xa was found to have a safety and effectiveness profile that is substantially equivalent to the predicate device for use of apixaban method (legally marketed predicate device, HemosIL Liquid Anti-Xa, with initial FDA marketing authorization under DEN190032 for apixaban measurement and FDA cleared under K213464 with modified on-board instrument stability claims as well as addition of rivaroxaban claim under K223187 device clearance).
§ 864.7295 Heparin and direct oral factor Xa inhibitor drug test system.
(a)
Identification. A heparin and direct oral factor Xa inhibitor drug test system is intended for the detection of heparin and direct oral factor Xa inhibitors in human specimens collected from patients taking heparin or direct oral factor Xa inhibitors. This device is intended to aid in the management of therapy in conjunction with other clinical and laboratory findings.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Design verification and validation must include the following:
(i) Detailed documentation of analytical device performance studies and results demonstrating acceptable analytical performance with a sufficient number of specimens tested in order to obtain unbiased estimates of analytical performance. This documentation shall include the following as appropriate to the technology, specimen types tested, and intended use of the device:
(A) Studies and results for that demonstrate device precision including repeatability and reproducibility, using quality controls and clinical samples, when appropriate. Precision studies must assess specimens for each indicated drug at concentrations throughout the measuring range of the device including near clinically relevant levels, as appropriate. The study must evaluate different sources of variability including, as appropriate, between-run, between-operator, between-lot, between-instrument, between-day, and between-site;
(B) Studies and results that demonstrate that the device is free from clinically significant interference, from endogenous and exogenous interferents associated with the target population(s), and interferents that are specific for, or related to, the technology or methodology of the device;
(C) Data to demonstrate appropriate specimen stability for the intended sample matrices under the intended conditions for specimen collection, handling, and storage described in the device labeling;
(D) Studies and results that demonstrate the linear range, limit of blank (LoB), limit of detection (LoD), and limit of quantitation (LoQ), as applicable to the technology of the device; and
(E) For any devices intended for use for near patient testing, studies and results that demonstrate the robustness of the device in the hands of the intended user, including the entire testing procedure, pre-analytical specimen processing steps, and results interpretation.
(ii) Detailed documentation of clinical performance testing in which the performance is analyzed relative to a comparator that FDA has determined is appropriate. Specimens must be representative of the intended use population(s) and must cover the full range of the device output and any clinically relevant decision points as appropriate.
(2) The labeling required under § 809.10(b) of this chapter must include:
(i) Identification of any known interferents, including all endogenous, exogenous, technology-specific, and patient population-specific interferents, specific to the test outputs. The information must include the concentration(s) or level(s) of the interferent at which clinically significant interference was found to occur, and the concentration range or levels at which interference was not found to occur;
(ii) A prominent statement that the device is not intended for use in monitoring patients taking heparin or direct oral factor Xa inhibitors; and
(iii) Limiting statements indicating, as applicable:
(A) That the device should only be used in conjunction with information available from clinical evaluations and other diagnostic procedures; and
(B) That the device is not specific to the direct oral factor Xa inhibitor that has been evaluated and may detect the presence of other direct factor Xa inhibitors that have not been evaluated.