(254 days)
Not Found
No
The description details a standard chromogenic assay and its performance characteristics, with no mention of AI or ML algorithms for data analysis, interpretation, or decision support.
No.
This device is an in vitro diagnostic (IVD) assay designed to quantify concentrations of certain substances (heparin, apixaban, rivaroxaban) in human plasma. It provides information for diagnostic or monitoring purposes, but it does not directly treat or prevent a disease or condition.
Yes
The "Intended Use / Indications for Use" section explicitly states "for in vitro diagnostic use." Additionally, it describes how the assay provides quantitative results for various analytes (heparin, apixaban, rivaroxaban) to provide "additional information" for patient management, particularly in situations like "patients at risk for major bleeding" or "patients experiencing a bleeding episode," which are diagnostic scenarios.
No
The device is an in vitro diagnostic assay which involves chemical reagents and is used on specific hardware platforms (ACL TOP Family and ACL TOP Family 50 Series). It is not solely software.
Yes, this device is an IVD (In Vitro Diagnostic).
The "Intended Use / Indications for Use" section explicitly states: "HemosIL Liquid Anti-Xa is an automated chromogenic assay for in vitro diagnostic use by laboratory professionals in clinical laboratories."
This statement directly identifies the device as intended for use outside of the body to diagnose or aid in the diagnosis of a condition.
N/A
Intended Use / Indications 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 50 Series through measurement of factor Xa activity, which is inversely proportional to the apixaban level. With HemosIL Apixaban Calibrators, the assay is intended to measure apixaban concentrations in patients on apixaban therapy in the following situations where measurement of apixaban levels could be useful to have as additional information:
- Patients at risk for major bleeding
- Patients experiencing a bleeding episode
When used with HemosIL Rivaroxaban Calibrators:
Quantitative determination of rivaroxaban on the ACL TOP Family and ACL TOP Family 50 Series through measurement of factor Xa activity, which is inversely proportional to the rivaroxaban level. With HemosL Rivaroxaban Calibrators, the assay is intended to measure rivaroxaban concentrations in patients on rivaroxaban therapy in the following situations where measurement of rivaroxaban levels could be useful to have as additional information:
- Patients at risk for major bleeding
- Patients experiencing a bleeding episode
The assay is not a stand-alone test and the results should be used in conjunction with other clinical and laboratory findings. For use in adult population. For prescription use only.
Product codes (comma separated list FDA assigned to the subject device)
QLU
Device Description
HemosIL Liquid Anti-Xa is a one stage chromogenic assay based on a synthetic chromogenic substrate and on Factor Xa inactivation. The assay provides quantitative rivaroxaban results on 3.2% citrated human plasma as follows: Rivaroxaban levels in patient plasma are measured automatically on ACL TOP Family and ACL TOP Family 50 Series when this assay is calibrated with HemosIL Rivaroxaban Calibrators.Rivaroxaban directly inhibits Factor Xa activity independent of the antithrombin present. The Factor Xa activity measured by the assay is exogenous. Factor Xa is neutralized directly by rivaroxaban.Residual Factor Xa is quantified with a synthetic chromogenic substrate. The paranitroaniline released is monitored kinetically at 405 nm and is inversely proportional to the rivaroxaban level in the sample.
Mentions image processing
Not Found
Mentions AI, DNN, or ML
Not Found
Input Imaging Modality
Not Found
Anatomical Site
Not Found
Indicated Patient Age Range
adult population
Intended User / Care Setting
laboratory professionals in clinical laboratories.
Description of the training set, sample size, data source, and annotation protocol
Not Found
Description of the test set, sample size, data source, and annotation protocol
Not Found
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
Type of study: Precision
Sample size: 80/instrument/lot (for each sample level)
Key results: Within-run and total precision assessed in accordance with CLSI EP05-A3 for 20 days.
ACL TOP Family: Rivaroxaban Low Control (Mean 77.2 ng/mL, CV% Within-run 3.3, CV% Total 4.1), Rivaroxaban High Control (Mean 284.0 ng/mL, CV% Within-run 1.4, CV% Total 2.4).
ACL TOP Family 50 Series: Rivaroxaban Low Control (Mean 80.9 ng/mL, CV% Within-run 2.5, CV% Total 4.9), Rivaroxaban High Control (Mean 283.9 ng/mL, CV% Within-run 1.4, CV% Total 2.4).
Type of study: Reproducibility
Sample size: 30 replicates per level
Key results: Reproducibility studies conducted at 3 sites using 1 operator per site on 3 different ACL TOP Family systems, using 3 lots of HemosIL Liquid Anti-Xa and 1 lot of HemosIL Rivans (Low and High).
Pooled 3 Site Data: Rivaroxaban Low Control (Mean 72.6 ng/mL, Total SD 3.00, Total %CV 4.1), Rivaroxaban High Control (Mean 281 ng/mL, Total SD 6.51, Total %CV 2.3).
Type of study: Limit of Blank (LoB), Limit of Detection (LoD), and Limit of Quantitation (LoQ)
Key results: Performed in accordance with CLSI EP17-A2. LoB = 2.4 ng/mL, LoD = 8 ng/mL, LoQ = 20 ng/mL.
Type of study: Linearity
Key results: Performed in accordance with CLSI EP06, 2nd Edition. Analytical Measuring Interval (AMI) for 18-550 ng/mL. Extended Measuring Interval (EMI) for 425-1100 ng/mL. Supports a reportable linear range for rivaroxaban on the ACL TOP Family 50 Series of 20 to 1000 ng/mL.
Type of study: Interferences
Key results: Performed in accordance with CLSI EP07, 3rd Edition. Rivaroxaban results not affected by listed interferents up to specified concentrations (e.g., Hemoglobin 600 mg/dL, Bilirubin 40 mg/dL, Triglycerides 921 mg/dL). Note: Rivaroxaban results may be falsely elevated in samples tested post-andexanet alfa administration.
Type of study: In-Use Stability and Shelf-life
Key results: Performed in accordance with CLSI EP25-A. Open Vial stability: 1 Month at 2-8°C. On-Board Instrument stability: 4 Days at 15-25°C. Shelf-life: 30 Months at 2-8°C.
Type of study: Method Comparison
Sample size: 337 samples (from patients treated with rivaroxaban, including 12 from bleeding patients and 261 from patients at risk of major bleeding)
Key results: Multicenter study at 3 laboratory sites comparing Liquid Anti-Xa for rivaroxaban on ACL TOP HemosIL Family to LC-MS/MS.
Pooled data: r = 0.995, Slope = 0.971, Intercept = -0.697, Mean Bias = -2.8%.
Internal method comparison study comparing ACL TOP Family 50 Series to ACL TOP Family for rivaroxaban showed a slope of 0.972, intercept of 0.810, and r of 0.999.
Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)
Not Found. Precision: CV% (Within-run), CV% (Total). Reproducibility: SD, %CV. Method Comparison: r, Slope, Intercept, Mean Bias.
Predicate Device(s): If the device was cleared using the 510(k) pathway, identify the Predicate Device(s) K/DEN number used to claim substantial equivalence and list them here in a comma separated list exactly as they appear in the text. List the primary predicate first in the list.
Reference Device(s): Identify the Reference Device(s) K/DEN number and list them here in a comma separated list exactly as they appear in the text.
Not Found
Predetermined Change Control Plan (PCCP) - All Relevant Information for the subject device only (e.g. presence / absence, what scope was granted / cleared under the PCCP, any restrictions, etc).
Not Found
§ 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.
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Image /page/0/Picture/0 description: The image shows the logo of the U.S. Food and Drug Administration (FDA). The logo consists of two parts: a symbol on the left and the FDA name and title on the right. The symbol on the left is a stylized representation of a human figure, while the text on the right reads "FDA U.S. FOOD & DRUG ADMINISTRATION" in blue letters.
June 23, 2023
Instrumentation Laboratory Co. Carol Marble Senior Regulatory Affairs Director 180 Hartwell Road Bedford, Massachusetts 01730
Re: K223187
Trade/Device Name: HemosIL Liquid 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: Mav 23, 2023 Received: May 24, 2023
Dear Carol Marble:
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 (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 located 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.
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
1
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 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (OS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-
542 of the Act); 21 CFR 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 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).
Sincerely,
Image /page/1/Picture/6 description: The image contains the text "Min Wu -S". The text is written in a simple, sans-serif font. The letters are black against a white background. The text appears to be a name or a title.
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) K223187
Device Name HemosIL Liquid Anti-Xa
Indications for Use (Describe)
HemosIL Liquid Anti-Xa is an automated chromogenic assay for in vitro diagnostic use by laboratory professionals in clinical laboratories. The assay provides quantitative results on 3.2% citrated human plasma for the following analytes based on the calibrators used:
· When used with HemosIL Heparin Calibrators:
Quantitative determination of unfractionated heparin (UFH) and low molecular weight heparin (LMWH) activity on the ACL TOP Family and ACL TOP Family 50 Series.
· When used with HemosIL Apixaban Calibrators:
Quantitative determination of apixaban on the ACL TOP Family 50 Series through measurement of factor Xa activity, which is inversely proportional to the apixaban level. With HemosIL Apixaban Calibrators, the assay is intended to measure apixaban concentrations in patients on apixaban therapy in the following situations where measurement of apixaban levels could be useful to have as additional information:
-
Patients at risk for major bleeding
-
Patients experiencing a bleeding episode
· When used with HemosIL Rivaroxaban Calibrators:
Quantitative determination of rivaroxaban on the ACL TOP Family and ACL TOP Family 50 Series through measurement of factor Xa activity, which is inversely proportional to the rivaroxaban level. With HemosL Rivaroxaban Calibrators, the assay is intended to measure rivaroxaban concentrations in patients on rivaroxaban therapy in the following situations where measurement of rivaroxaban levels could be useful to have as additional information:
-
Patients at risk for major bleeding
-
Patients experiencing a bleeding episode
The assay is not a stand-alone test and the results should be used in conjunction with other clinical and laboratory findings. For use in adult population. For prescription use only.
Type of Use (Select one or both, as applicable)
X Prescription Use (Part 21 CFR 801 Subpart D)
Over-The-Counter Use (21 CFR 801 Subpart C)
CONTINUE ON A SEPARATE PAGE IF NEEDED.
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510(k) Summary
This 510(k) Summary of Safety and Effectiveness is being submitted in accordance with the requirements of the Safe Medical Device Act of 1990 and 21 CFR 807.92.
| Submitter's
Information | Instrumentation Laboratory (IL) Co.
180 Hartwell Road
Bedford, MA 01730, USA | | |
|----------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------|------------------------|
| Contact Person | Carol Marble, Senior Regulatory Affairs Director
Phone: 781-861-4467
Fax: 781-861-4207
Email: cmarble@werfen.com | | |
| Preparation Date | June 22, 2023 | | |
| Device Trade Name | HemosIL Liquid Anti-Xa | | |
| Regulatory
Information | Regulation No. | 21 CFR 864.7295 | |
| | Regulation Description | Anti-Factor Xa Activity Test System | |
| | Classification | Class II | |
| | Product Code | QLU | |
| | Classification Panel | Hematology (81) | |
| Predicate Device Nos. | DEN190032
K213464 | Predicate Device Name | HemosIL Liquid Anti-Xa |
| Device Description | HemosIL Liquid Anti-Xa is a one stage chromogenic assay based on a synthetic
chromogenic substrate and on Factor Xa inactivation. The assay provides
quantitative rivaroxaban results on 3.2% citrated human plasma as follows:
Rivaroxaban levels in patient plasma are measured automatically on ACL TOP
Family and ACL TOP Family 50 Series when this assay is calibrated with
HemosIL Rivaroxaban Calibrators.Rivaroxaban directly inhibits Factor Xa activity independent of the antithrombin
present. The Factor Xa activity measured by the assay is exogenous. Factor Xa
is neutralized directly by rivaroxaban.Residual Factor Xa is quantified with a synthetic chromogenic substrate. The
paranitroaniline released is monitored kinetically at 405 nm and is inversely
proportional to the rivaroxaban level in the sample. | | |
5
| | HemosIL Liquid Anti-Xa is an automated chromogenic assay for in vitro
diagnostic use by laboratory professionals in clinical laboratories. The assay
provides quantitative results on 3.2% citrated human plasma for the following
analytes based on the calibrators used: | |
|---------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| | When used with HemosIL Heparin Calibrators:
• Quantitative determination of unfractionated heparin (UFH) and low
molecular weight heparin (LMWH) activity on the ACL TOP Family and
ACL TOP Family 50 Series. | |
| | When used with HemosIL Apixaban Calibrators:
• Quantitative determination of apixaban on the ACL TOP Family and ACL
TOP Family 50 Series through measurement of factor Xa activity, which is
inversely proportional to the apixaban level. With HemosIL Apixaban
Calibrators, the assay is intended to measure apixaban concentrations in
patients on apixaban therapy in the following situations where measurement
of apixaban levels could be useful to have as additional information:
- Patients at risk for major bleeding
- Patients experiencing a bleeding episode | |
| Intended Use /
Indications for Use | | |
| | When used with HemosIL Rivaroxaban Calibrators:
• Quantitative determination of rivaroxaban on the ACL TOP Family and ACL
TOP Family 50 Series through measurement of factor Xa activity, which is
inversely proportional to the rivaroxaban level. With HemosIL Rivaroxaban
Calibrators, the assay is intended to measure rivaroxaban concentrations in
patients on rivaroxaban therapy in the following situations where
measurement of rivaroxaban levels could be useful to have as additional
information: - Patients at risk for major bleeding
- Patients experiencing a bleeding episode | |
| | The assay is not a stand-alone test and the results should be used in conjunction
with other clinical and laboratory findings. | |
| | For use in adult population. For prescription use only. | |
| Item | Predicate Device | Subject Device |
| Trade Name and
Measurand | HemosIL Liquid Anti-Xa
for apixaban measurement | HemosIL Liquid Anti-Xa
for rivaroxaban measurement |
| Manufacturer | Instrumentation Laboratory Co. | Same |
| Intended Use /
Indications for Use | See updated intended use / indications for use on previous page. | |
| Similarities | | |
| Item | Predicate Device | Subject Device |
| Trade Name and
Measurand | HemosIL Liquid Anti-Xa
for apixaban measurement | HemosIL Liquid Anti-Xa
for rivaroxaban measurement |
| Regulation No. | 21 CFR 864.7295 | Same |
| Regulation
Description | Anti-Factor Xa Activity Test System | Same |
| Classification | Class II | Same |
| Product Code | QLU | Same |
| Review Panel | Hematology (81) | Same |
| Technical Method | The test detects residual factor Xa using
a chromogenic substrate. The signal or
optical density is compared to a drug-
specific calibration curve and results are
reported as nanograms per milliliter
(ng/mL). | Same |
| Sample Type | 3.2% citrated human plasma | Same |
| Measurement | Quantitative | Same |
| Testing Methodology | Chromogenic | Same |
| Reporting Unit | ng/mL | Same |
| Similarities (Cont.) | | |
| Item | Predicate Device | Subject Device |
| Composition | The HemosIL Anti-Xa kit includes the following components:
• Factor Xa reagent: Liquid preparation containing purified bovine Factor Xa (approximately 5.5 nkat/mL), Tris-Buffer, EDTA, dextran sulfate, sodium chloride and bovine serum albumin.
• Chromogenic substrate: liquid chromogenic substrate S-2732 (approximately 1.2 mg/mL) and bulking agent. | Same |
| Instrumentation | ACL TOP Family (K160276)
ACL TOP Family 50 Series (K150877) | Same |
| On-board Stability | 4 days | Same |
| Open Reagent Stability | 1 month | Same |
| Differences | | |
| Item | Predicate Device | Subject Device |
| Measurand | apixaban | rivaroxaban |
| Limit of
Detection | 9 ng/mL for apixaban | 8 ng/mL for rivaroxaban |
| Linearity | 20 to 1000 ng/mL for apixaban | 20 to 1000 ng/mL for rivaroxaban |
| Kit Size
Configurations | 4 mL Kit Vial Size (Only 1 Size):
Factor Xa reagent (Cat. No.
0020302612): 5 x 2.5 mL vial of a
liquid preparation containing
purified bovine Factor Xa
(approximately 5.5 nkat/mL), Tris-
Buffer, EDTA, dextran sulfate,
sodium chloride and bovine serum
albumin. Chromogenic substrate (Cat. No.
0020302622): 5 x 3 mL vial of
liquid chromogenic substrate S-
2732 (approximately 1.2 mg/mL)
and bulking agent. | 4 mL Kit Vial Size (Size 1):
Factor Xa reagent (Cat. No. 0020302612): 5
x 2.5 mL vial of a liquid preparation
containing purified bovine Factor Xa
(approximately 5.5 nkat/mL), Tris-Buffer,
EDTA, dextran sulfate, sodium chloride and
bovine serum albumin. Chromogenic substrate (Cat. No.
0020302622): 5 x 3 mL vial of liquid
chromogenic substrate S-2732
(approximately 1.2 mg/mL) and bulking
agent. 10 mL Kit Vial Size (Size 2):
Factor Xa reagent (Cat. No. 0020303610): 5
x 5 mL vial of a liquid preparation containing
purified bovine Factor Xa (approximately 5.5
nkat/mL), Tris-Buffer, EDTA, dextran
sulfate, sodium chloride and bovine serum
albumin. Chromogenic substrate (Cat. No.
0020303620): 5 x 6 mL vial of liquid
chromogenic substrate S-2732
(approximately 1.2 mg/mL) and bulking
agent |
| Calibrators
(Sold
Separately) | HemosIL Apixaban Calibrators
Target Levels: 0 and ~500 ng/mL | HemosIL Rivaroxaban Calibrators
Target Levels: 0 and ~500 ng/mL |
| Controls
(Sold
Separately) | HemosIL Apixaban Controls
Target Levels: ~75 and ~300 ng/mL | HemosIL Rivaroxaban Controls
Target Levels: ~80 and ~300 ng/mL |
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Substantial Equivalence Discussion
Following is a description of the similarities and differences between the predicate device, the currently marketed HemosIL Liquid Anti-Xa for apixaban measurement under DEN190032, with modified on-board instrument stability claims under K213464, compared to the subject device with the expanded intended use for rivaroxaban measurement.
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8
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Performance Summary
Precision
Within-run and total precision was assessed in accordance with CLSI EP05-A3 for 20 days, with 2 runs per day and 2 replicates per run for each sample level (n=80/instrument/lot), using 3 lots of HemosIL Liquid Anti-Xa on representative members of the ACL TOP Family and ACL TOP Family 50 Series. To span the assay range, 6 citrated plasma samples were tested, as well as HemosIL Rivaroxaban Controls.
| ACL TOP Family | Mean (ng/mL) | CV% (Within-run) | CV% (Total) |
|---|---|---|---|
| Rivaroxaban Low Control | 77.2 | 3.3 | 4.1 |
| Rivaroxaban High Control | 284.0 | 1.4 | 2.4 |
| Sample 1 | 49.3 | 3.9 | 5.5 |
| Sample 2 | 762.1 | 1.4 | 2.5 |
| Sample 3 | 904.0 | 1.3 | 2.8 |
| Sample 4 | 125.0 | 1.3 | 1.6 |
| Sample 5 | 32.0 | 4.1 | 5.2 |
| Sample 6 | 428.0 | 0.9 | 1.0 |
The tables below include data for representative systems each with 1 reagent lot.
| ACL TOP Family 50 Series | Mean (ng/mL) | CV% (Within-run) | CV% (Total) |
|---|---|---|---|
| Rivaroxaban Low Control | 80.9 | 2.5 | 4.9 |
| Rivaroxaban High Control | 283.9 | 1.4 | 2.4 |
| Sample 1 | 51.0 | 2.7 | 3.2 |
| Sample 2 | 798.7 | 1.6 | 1.6 |
| Sample 3 | 943.7 | 1.1 | 1.2 |
| Sample 4 | 130.4 | 1.0 | 1.5 |
| Sample 5 | 33.0 | 3.4 | 4.5 |
| Sample 6 | 445.0 | 1.2 | 1.2 |
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Reproducibility
Reproducibility studies were conducted at 3 stes using (1 operator per site) on 3 different ACL TOP Family systems (1 system per site), using 3 lots of HemosIL Liquid Anti-Xa and 1 lot of HemosIL Rivans (Low and High). Five citrated plasma samples were also tested across the 3 sites. Each material was tested in triplicate, twice a day for 5 days, for a total of 30 replicates per level.
The pooled 3 site data is presented below.
| Pooled 3 Site Data | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Level | Mean | |||||||||||||
| (ng/mL) | N | Repeatability | ||||||||||||
| (Within-Run) | Between-Run | Between-Day | Between-Site | Between-Lot | Reproducibility | |||||||||
| (Total) | ||||||||||||||
| SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | |||
| Rivaroxaban Low Control | 72.6 | 270 | 2.28 | 3.1% | 1.03 | 1.4% | 0.00 | 0.0% | 1.44 | 2.0% | 0.80 | 1.1% | 3.00 | 4.1% |
| Rivaroxaban High Control | 281 | 270 | 4.58 | 1.6% | 4.10 | 1.5% | 0.00 | 0.0% | 2.15 | 0.8% | 0.17 | 0.1% | 6.51 | 2.3% |
| Sample 1 | 45.0 | 270 | 2.55 | 5.7% | 0.88 | 2.0% | 0.56 | 1.3% | 3.38 | 7.5% | 0.66 | 1.5% | 4.41 | 9.8% |
| Sample 2 | 750 | 270 | 19.68 | 2.6% | 1.44 | 0.2% | 6.30 | 0.8% | 22.12 | 3.0% | 5.26 | 0.7% | 30.76 | 4.1% |
| Sample 3 | 939 | 270 | 25.49 | 2.7% | 3.43 | 0.4% | 7.41 | 0.8% | 22.98 | 2.4% | 8.83 | 0.9% | 36.36 | 3.9% |
| Sample 4 | 51.8 | 270 | 2.46 | 4.7% | 1.30 | 2.5% | 0.84 | 1.6% | 1.55 | 3.0% | 0.83 | 1.6% | 3.39 | 6.5% |
| Sample 5 | 118 | 270 | 3.71 | 3.1% | 4.29 | 3.6% | 2.76 | 2.3% | 5.71 | 4.8% | 1.64 | 1.4% | 8.67 | 7.3% |
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Limit of Blank (LoB), Limit of Detection (LoD) and Limit of Quantitation (LoQ)
LoB, LoD and LoQ studies for rivaroxaban were performed in accordance with CLSI EP17-A2, using 3 lots of HemosIL Liquid Anti-Xa on a representative ACL TOP Family model and a representative ACL TOP Family 50 Series model. The following maximum limits were determined:
| Limit of Blank (LoB) | Limit of Detection (LoD) | Limit of Quantitation (LoQ) |
|---|---|---|
| 2.4 ng/mL | 8 ng/mL | 20 ng/mL* |
*Note: The reportable value for the LoQ will be 20 ng/mL as the lower limit of the linear range.
Linearity
Linearity studies for rivaroxaban were performed in accordance with CLSI EP06, 2nd Edition, using 3 lots of HemosIL Liquid Anti-Xa on a representative ACL TOP Family model and a representative ACL TOP Family 50 Series model.
- Analytical Measuring Interval (AMI): The AMI was performed over the range of 18-550 ng/mL for 13 . rivaroxaban concentrations. Each rivaroxaban level was tested in quadruplicate on both instrument models with each reagent lot.
- Extended Measuring Interval (EMI): The EMI was performed over the range of 425-1100 ng/mL for 9 ● rivaroxaban concentrations. Each rivaroxaban level was tested in quadruplicate on both instrument models with each reagent lot.
The studies support a reportable linear range for rivaroxaban on the ACL TOP Family 50 Series of 20 to 1000 ng/mL.
Interferences and Limitations
Interference studies for rivaroxaban were performed in accordance with CLSI EP07, 34 Edition, using 1 lot of HemosIL Liquid Anti-Xa on a representative ACL TOP Family model. The studies support that rivaroxaban results on the ACL TOP Family and ACL TOP Family 50 Series are not affected by the following interferents up to:
| Hemoglobin | 600 mg/dL |
|---|---|
| Bilirubin (unconjugated) | 40 mg/dL |
| Bilirubin (conjugated) | 40 mg/dL |
| Triglycerides | 921 mg/dL |
| Acetylsalicylic acid | 3.00 mg/dL |
| Atorvastatin | 0.075 mg/dL |
| Isosorbide dinitrate | 0.600 mg/dL |
| Ticagrelor | 0.188 mg/dL |
| Warfarin | 7.50 mg/dL |
| Lupus anticoagulant | dRVVT Screen/Confirm Ratio 2.47 |
Rivaroxaban results may be falsely elevated in samples tested post-andexanet alfa administration.
The assay is not intended for the monitoring and dosage adjustment of rivaroxaban.
Administer a reversal agent based on current clinical guidance, and take into consideration other clinical and laboratory findings including the Factor Xa inhibitor dose and time since last dose. For additional information, refer to current clinical guidance and reversal agent prescribing information.
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In-Use Stability and Shelf-life
In-use stability and shelf-life studies for rivaroxaban were performed in accordance with CLSI EP25-A, using multiple lots of HemosIL Liquid Anti-Xa on a representative ACL TOP Family model. The studies support the following rivaroxaban claims on the ACL TOP Family and ACL TOP Family 50 Series:
| Study Type | Storage Condition | Claim |
|---|---|---|
| Open Vial | 2-8°C | 1 Month |
| On-Board Instrument | 15-25°C | 4 Days |
| Shelf-life | 2-8°C | 30 Months |
Method Comparison
A multicenter study was performed in accordance with CLSI EP09c, 3rd Edition, at 3 laboratory sites comparing Liquid Anti-Xa for the measurement of rivaroxaban oon the ACL TOP HemosIL Family to LC-MS/MS. Samples were from patients treated with rivaroxaban, including 12 samples from bleeding patients and 261 samples from patients at risk of major bleeding. A summary of the individual site and pooled 3-site results on 337 samples is shown below.
| N | r | Slope | Intercept | Mean Bias | ||||
|---|---|---|---|---|---|---|---|---|
| Value | 95% CI | Value | 95% CI | |||||
| Site 1 | 111 | 0.995 | 0.947 | 0.927 0.966 | -3.872 | -5.922 | -1.822 | -8.7% |
| Site 2 | 107 | 0.995 | 0.981 | 0.944 1.019 | 2.374 | -2.750 | 7.497 | 2.0% |
| Site 3 | 119 | 0.995 | 0.994 | 0.962 1.025 | -1.376 | -5.114 | 2.362 | -1.6% |
| Pooled | 337 | 0.995 | 0.971 | 0.953 0.990 | -0.697 | -3.087 | 1.692 | -2.8% |
An internal method comparison study was performed comparing the performance of the ACL TOP Family 50 Series to the ACL TOP Family using representative systems from both families. Representative results are shown below.
| System | Analyte | Slope | Intercept | r | Comparator method |
|---|---|---|---|---|---|
| ACL TOP Family 50 Series | Rivaroxaban | 0.972 | 0.810 | 0.999 | ACL TOP Family |
Conclusion
HemosIL Liquid Anti-Xa for rivaroxaban measurement is substantially equivalent to the legally marketed predicate device, HemosIL Liquid Anti-Xa, FDA marketing authorized under DEN190032 for apixaban measurement and FDA cleared under K213464 with modified on-board instrument stability claims.