(344 days)
INNOVANCE® Heparin Assay
In vitro diagnostic automated chromogenic assay for the quantitative determination of unfractionated heparin (UFI) and low molecular weight heparin (LMWH) activity in human plasma collected from venous blood samples in 3.2% sodium citrate tubes on the BCS® XP System in the clinical laboratory. For use with plasma from patients undergoing heparin anticoagulant therapy with either UFH or LMWH. The performance of this device has not been established in neonate and pediatric patient populations.
INNOVANCE® Heparin Calibrator
For calibration of the INNOVANCE® Heparin assay for the quantitative determination of the activity of unfractionated heparin (UFH) and low molecular weight heparin (LMWH) in citrated human plasma.
INNOVANCE® Heparin UF and LMW Controls
For quality control of the INNOVANCE® Heparin assay for the quantitative determination of the activity of unfractionated heparin (UFH) and low molecular weight heparin (LMWH) in citrated human plasma.
The INNOVANCE® Heparin assay is a one stage chromogenic assay. The reagent kit consists of two components. One component (INNOVANCE Heparin Reagent) contains Coagulation Factor Xa (Xa), the other (INNOVANCE Heparin Substrate) a chromogenic substrate specific for Xa. Upon mixing of INNOVANCE Heparin Reagent and INNOVANCE Heparin 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/antithrombin (AT) complex. This 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.
The INNOVANCE® Heparin Calibrator consists of 5 calibrator levels. INNOVANCE® Heparin Calibrator 1 represents plasma containing no heparin. INNOVANCE® Heparin Calibrator 2, 3, 4 and 5 contain defined activities of LMWH and are calibrated against the World Health Orqanization (WHO) International Standards for UFH and LMWH. The calibrator levels are used to establish a reference curve (calibration curve) which then can be employed to quantify the heparin activity of UFH and LMWH containing plasmas.
The INNOVANCE® Heparin Controls consist of plasmas containing defined activities of either UFH or LMWH. Recovery of these controls within their assigned ranges indicates proper functionality of the assay system.
This document describes the performance data for the INNOVANCE® Heparin Assay, INNOVANCE® Heparin Calibrator, and INNOVANCE® Heparin UF and LMW Controls. The information provided focuses on the analytical performance of the device rather than a clinical study involving human readers and AI assistance. Therefore, some requested information related to human expert involvement, MRMC studies, and AI-specific ground truth establishment cannot be extracted from this document.
Here's an analysis of the acceptance criteria and study proving the device meets them, based on the provided text:
1. A table of acceptance criteria and the reported device performance
The document provides extensive data on linearity, specificity (interference), reproducibility, and repeatability. Specific acceptance criteria are mentioned as "pre-established acceptance criteria" or inferred from the "no interference up to..." statements. Since the exact numerical acceptance criteria are not explicitly listed in a consolidated table, I will present the reported performance and note that the studies "met pre-established acceptance criteria" or "were found to cause no interference."
Acceptance Criteria and Reported Device Performance for INNOVANCE® Heparin Assay System
| Performance Metric | Acceptance Criteria (Implicit/Explicit) | Reported Device Performance |
|---|---|---|
| Measuring Range (Linearity & LoQ) | - Established Limit of Quantitation (LoQ) | - Assay range established as 0.10 - 1.50 IU/mL. |
| - Linearity verified across specified range | - Linearity study performed with 21 different dilutions for UFH and LMWH (0.00 to 1.90 IU/mL). | |
| Specificity (Interference) | - No interference up to specified concentrations for various endogenous and exogenous substances. | No interference observed up to: |
| - Ascorbic Acid: 176 mg/dL | ||
| - Bilirubin (unconjugated): 60 mg/dL | ||
| - Bilirubin (conjugated): 40 mg/dL | ||
| - Hemoglobin: 347 mg/dL | ||
| - Platelet Factor 4: 0.7 µg/mL | ||
| - Triglycerides: 807 mg/dL | ||
| - Rheumatoid Factor: 220 IU/mL | ||
| - Apixaban: 4.1 ng/mL | ||
| - Danaparoid Sodium: 0.03 IU/mL | ||
| - Fondaparinux: 35.5 ng/mL | ||
| - Rivaroxaban: 7.1 ng/mL | ||
| Reproducibility & Repeatability (Reagent) | - Meets CLSI EP05-A2 guidelines. | - Reproducibility (Table 1): Total %CVs for LMW controls ranged from 2.97% to 4.40%, for UFH controls from 3.29% to 7.30%. For LMWH plasma pools, total %CVs ranged from 3.47% to 21.15%. For UFH plasma pools, total %CVs ranged from 4.30% to 20.60%. |
| - Repeatability (Table 2): Total %CVs for LMW controls ranged from 1.85% to 3.12%, for UFH controls from 3.58% to 3.71%. For LMWH plasma pools, total %CVs ranged from 2.83% to 9.30%. For UFH plasma pools, total %CVs ranged from 3.21% to 7.58%. | ||
| Reproducibility & Repeatability (Calibrator) | - Total %CV for reproducibility (Table 3) and repeatability (Table 4) within specified limits. | - Reproducibility (Table 3): Total %CVs for calibrator levels ranged from 2.23% to 3.36%. |
| - Repeatability (Table 4): Total %CVs for calibrator levels ranged from 2.53% to 3.74%. | ||
| Reproducibility & Repeatability (Control) | - Total %CV for reproducibility (Table 5) and repeatability (Table 6) within specified limits. | - Reproducibility (Table 5): Total %CVs ranged from 2.97% to 7.30%. |
| - Repeatability (Table 6): Total %CVs ranged from 2.45% to 3.67%. | ||
| Frozen vs. Fresh Method Comparison | - Passing-Bablok regression slope, intercept, and correlation coefficient meet pre-established criteria. | - Slope: 1.00, Intercept: -0.01 IU/mL, r: 0.996, r2: 0.993. Predicted bias for MDP (0.3, 0.4 IU/mL) was -0.01 IU/mL. Percent bias for MDP (0.6, 0.7, 1.0 IU/mL) ranged from -1.00% to -1.67%. All acceptance criteria were met. |
| Method Comparison (vs. predicate device) | - Passing-Bablok regression slope, intercept, and correlation coefficient meet pre-established criteria. | - UFH samples: Slope: 0.93, Intercept: 0.03, Correlation Coefficient (r): 0.98. |
| - LMWH samples: Slope: 1.06, Intercept: -0.01, Correlation Coefficient (r): 0.99. | ||
| - Results met the pre-established acceptance criteria. |
2. Sample size used for the test set and the data provenance (e.g., country of origin of the data, retrospective or prospective)
- Measuring Range (Linearity): 21 different dilutions per heparin type (UFH and LMWH). Uses plasma pools spiked with standards.
- Specificity (Interference): Base pools of UFH and LMWH were prepared. Specific sample count not provided, but implies multiple samples to establish "no interference up to..." levels.
- Reproducibility and Repeatability:
- Reagent (reproducibility): 240 measurements (N=240) per sample type (LMW/UF controls, LMWH/UFH plasma pools).
- Conducted at three external sites and one internal site (Siemens Marburg site prepared pools). Data provided is multicenter.
- Plasma pools were prepared at Siemens Marburg and sent frozen to external sites, implying retrospective analysis of these prepared samples.
- Reagent (repeatability): 240 measurements (N=240) per sample type.
- Conducted at one site (Bad Oeynhausen).
- Calibrator (reproducibility): 120 measurements (N=120) per calibrator level.
- Conducted at three internal sites.
- Calibrator (repeatability): 240 measurements (N=240) per calibrator level.
- Conducted at one site.
- Controls (reproducibility): 240 measurements (N=240) per control level.
- Conducted at three sites.
- Controls (repeatability): 240 measurements (N=240) per control level.
- Conducted at one site.
- Reagent (reproducibility): 240 measurements (N=240) per sample type (LMW/UF controls, LMWH/UFH plasma pools).
- Frozen vs. Fresh Method Comparison: 69 samples (N=69).
- Conducted at one study site in Germany.
- This study involved both fresh samples (measured within 4 hours) and frozen aliquots of the same samples (measured after at least one week of -70°C storage), making it a comparison of sample handling rather than purely retrospective vs. prospective patient data collection.
- Method Comparison (vs. predicate device):
- UFH samples: 165 samples (N=165).
- LMWH samples: 155 samples (N=155).
- Conducted at three sites, including one external US site. All sites used the same protocol.
- Frozen samples were thawed and measured, indicating a retrospective use of collected samples.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)
This document describes the analytical performance of an in-vitro diagnostic device for quantifying heparin activity. The "ground truth" in this context is established by reference methods, international standards (WHO International Standards for UFH and LMWH), and analytical accuracy/precision measurements, not by human expert interpretations of images or clinical outcomes. Therefore, there are no human experts involved in establishing the "ground truth" as described for medical imaging AI devices.
4. Adjudication method (e.g. 2+1, 3+1, none) for the test set
Not applicable. This is an analytical performance study for an in-vitro diagnostic assay. Adjudication methods like 2+1 or 3+1 are typical for subjective human interpretation tasks, such as radiology reads, which are not relevant here.
5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance
Not applicable. This document is about an in-vitro diagnostic device, not an AI-assisted diagnostic tool that involves human readers interpreting cases.
6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done
Yes, the studies presented (linearity, specificity, reproducibility, repeatability, frozen vs. fresh comparison, method comparison) are effectively "standalone algorithm" performance evaluations, as they assess the device's analytical measurement capabilities directly, without human interpretation of results as a variable. The "algorithm" here refers to the biochemical reactions and instrument logic that produce the quantitative heparin activity measurement.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc)
The ground truth for this device is based on:
- International Standards: The INNOVANCE® Heparin Calibrators and Controls are traceable to the World Health Organization (WHO) International Standards for UFH and LMWH. This is the primary reference for accuracy and calibration.
- Reference Methods/Predicate Devices: The method comparison studies demonstrate equivalence to an established, legally marketed predicate device (Coamatic Heparin assay on the IL ACL TOP®), which itself would have been validated against accepted reference methods and standards.
- Known Concentrations: Linearity and interference studies use samples spiked with known concentrations of UFH, LMWH, and potential interferents.
- Statistical Analysis: CLSI guidelines (e.g., EP06-A, EP07-A2, EP05-A2, EP09-A3) are used for statistical evaluation of analytical performance, ensuring robust and validated methodologies for assessing precision and accuracy.
8. The sample size for the training set
This document does not specify a "training set" in the context of machine learning. The device is a traditional in-vitro diagnostic assay, not an AI/ML algorithm that undergoes a distinct training phase on a large dataset. The "training" for such devices typically involves the development and optimization of the reagent formulations, instrument parameters, and calibration procedures, which is an engineering and chemistry development process rather than a data-driven training of a model.
9. How the ground truth for the training set was established
As there is no "training set" in the AI/ML sense, this question is not applicable. The development and calibration of the assay components (reagents, calibrators, controls) are established through rigorous analytical chemistry and metrology principles, tracing back to international reference standards and validated against known concentrations and predicate devices.
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Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002
August 22, 2017
Siemens Healthcare Diagnostics Products GmbH Rose Marinelli Regulatory Clinical Affairs Specialist Emil-von-Behring Str 76 Marburg, Germany 35041
Re: K162540 Trade/Device Name: INNOVANCE® Heparin Assay INNOVANCE® Heparin Calibrator INNOVANCE® Heparin UF and LMW Controls Regulation Number: 21 CFR 864.7525 Regulation Name: Heparin assay Regulatory Class: Class II Product Code: KFF, JIS, GGN Dated: August 10, 2017 Received: August 14, 2017
Dear Ms. Marinelli:
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. 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
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all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); medical device reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
If you desire specific advice for your device on our labeling regulation (21 CFR Part 801), please contact the Division of Industry and Consumer Education at its toll-free number (800)638-2041 or (301)796-7100 or at its Internet address http://www.fda.gov/MedicalDevices/ResourcesforYou /Industry/default.htm. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to http://www.fda.gov /MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.
You may obtain other general information on your responsibilities under the Act from the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address http://www.fda.gov/MedicalDevices/ResourcesforYou/ Industry/default.htm.
Sincerely.
Leonthena R. Carrington -S
Lea Carrington Director Division of Immunology and Hematology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known) K162540
Device Name INNOVANCE® Heparin Assay INNOVANCE® Heparin Calibrator INNOVANCE® Heparin UF and LMW Controls
Indications for Use (Describe)
INNOVANCE® Heparin Assay
In vitro diagnostic automated chromogenic assay for the quantitative determination of unfractionated heparin (UFI) and low molecular weight heparin (LMWH) activity in human plasma collected from venous blood samples in 3.2% sodium citrate tubes on the BCS® XP System in the clinical laboratory. For use with plasma from patients undergoing heparin anticoagulant therapy with either UFH or LMWH. The performance of this device has not been established in neonate and pediatric patient populations.
INNOVANCE® Heparin Calibrator
For calibration of the INNOVANCE® Heparin assay for the quantitative determination of the activity of unfractionated heparin (UFH) and low molecular weight heparin (LMWH) in citrated human plasma.
INNOVANCE® Heparin UF and LMW Controls
For quality control of the INNOVANCE® Heparin assay for the quantitative determination of the activity of unfractionated heparin (UFH) and low molecular weight heparin (LMWH) in citrated human plasma.
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 and follows the FDA guidance "The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)]", issued July 28, 2014.
1 Submitter
Siemens Healthcare Diagnostics Products GmbH Emil-von-Behring-Str. 76 35041 Marburg, Germany
| Contact Person: | Rose Marinelli |
|---|---|
| Email: | rose.t.marinelli@siemens-healthineers.com |
| Phone: | 302-631-8805 |
| Facsimile: | 302-631-6299 |
| Date: | Prepared: September 9, 2016 |
2 Device
| Name of Device: | INNOVANCE® Heparin Assay |
|---|---|
| Common or Usual Name: | Heparin |
| Classification Name: | Heparin assay (21 CFR 864.7525) |
| Regulatory Class: | Class II |
| Product Code: | KFF |
| 510(k) Review Panel: | Hematology |
| Name of Device: | INNOVANCE® Heparin Calibrator |
| Common or Usual Name: | Calibrator, primary |
| Classification Name: | Calibrator (21 CFR 862.1150) |
| Regulatory Class: | Class II |
| Product Code: | JIS |
| 510(k) Review Panel: | Hematology |
| Name of Device: | INNOVANCE® Heparin UF and LMW Controls INNOVANCE® Heparin UF Control 1 INNOVANCE® Heparin UF Control 2 INNOVANCE® Heparin LMW Control 1 INNOVANCE® Heparin LMW Control 2 |
| Common or Usual Name: | Heparin Controls |
| Classification Name: | Plasma, Coagulation Control(21 CFR 864.5425) |
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| Regulatory Class: | Class II |
|---|---|
| Product Code: | GGN |
| 510(k) Review Panel: | Hematology |
3 Predicate Device
Coamatic Heparin Assay, K983178 (UFH and LMWH)
A method comparison study for the above listed device was performed with the Coamatic Heparin assay on the Instrumentation Laboratory (IL) ACL TOP®. To the best of our knowledge, the predicate device has not been subject to a design-related recall for any of the applications associated with this Premarket Notification.
4 Device Description / Test Principle
The INNOVANCE® Heparin assay is a one stage chromogenic assay. The reagent kit consists of two components. One component (INNOVANCE Heparin Reagent) contains Coagulation Factor Xa (Xa), the other (INNOVANCE Heparin Substrate) a chromogenic substrate specific for Xa. Upon mixing of INNOVANCE Heparin Reagent and INNOVANCE Heparin 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/antithrombin (AT) complex. This 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.
The INNOVANCE® Heparin Calibrator consists of 5 calibrator levels. INNOVANCE® Heparin Calibrator 1 represents plasma containing no heparin. INNOVANCE® Heparin Calibrator 2, 3, 4 and 5 contain defined activities of LMWH and are calibrated against the World Health Orqanization (WHO) International Standards for UFH and LMWH. The calibrator levels are used to establish a reference curve (calibration curve) which then can be employed to quantify the heparin activity of UFH and LMWH containing plasmas.
The INNOVANCE® Heparin Controls consist of plasmas containing defined activities of either UFH or LMWH. Recovery of these controls within their assigned ranges indicates proper functionality of the assay system.
5 Intended Use / Indications for Use
INNOVANCE® Heparin Assay
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 citrate tubes on the BCS® XP System in the clinical laboratory. For use with plasma from patients undergoing heparin anticoagulant therapy with either UFH or LMWH. The performance of this device has not been established in neonate and pediatric patient populations.
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INNOVANCE® Heparin Calibrator
For calibration of the INNOVANCE® Heparin assay for the quantitative determination of the activity of unfractionated heparin (UFH) and low molecular weight heparin (LMWH) in citrated human plasma.
INNOVANCE® Heparin UF and LMW Controls
For quality control of the INNOVANCE® Heparin assay for the quantitative determination of the activity of unfractionated heparin (UFH) and low molecular weight heparin (LMWH) in citrated human plasma.
Comparison of Technological Characteristics 6
| ltem | Proposed DeviceINNOVANCE® Heparin Assay | Predicate DeviceCoamatic Heparin - K983178 |
|---|---|---|
| Intended Use | In-vitro diagnostic automatedchromogenic assay for the quantitativedetermination of unfractionated heparin(UFH) and low molecular weight heparin(LMWH) activity in human plasmacollected from venous blood samples in3.2% sodium citrate tubes on the BCS®XP System in the clinical laboratory. | For the quantitative determination ofunfractionated heparin (UF Heparin) orlow molecular weight heparin (LMWHeparin) in human citrated plasma usingautomated and microplate methods. |
| Indications forUse | For use with plasma from patientsundergoing heparin anticoagulant therapywith either UFH or LMWH. | Not available from package insert. |
| Heparin Type | UFH and LMWH | Same |
| Test Principle | Chromogenic | Same |
| Sample Type | 3.2% Citrated human plasma | Same |
| Antithrombin | None | Same |
| Control Level | 2 levels for UFH and 2 levels for LMWH | Same |
6.1 Comparison of Reagent Features
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| Item | Proposed DeviceINNOVANCE® Heparin Assay | Predicate DeviceCoamatic Heparin – K983178 |
|---|---|---|
| Units | IU/mL | Same |
| Storage | Until expiration date printed on each vialand carton at 2 - 8 °C | Same |
| MeasuringRange | 0.10 to 1.50 IU/mL | 0 to 1.5 IU/mL |
| Composition | Liquid(Factor Xa and chromogenic substrate) | Lyophilized(Factor Xa and S-2732) |
| CalibrationCurve | Single calibration curve for UFH andLMWH | Same |
| Stability / ShelfLife | 24 months at 2-8 °C | Not available from package insert |
| Stability onceopened | 8 weeks at 2-8 °C | 3 months at 2-8 °C in the original vial |
| On BoardStability | 24 hours in cooled positions on theBCS® XP System | Not available from package insert. |
6.2 Comparison of Calibrator Features
| Item | Proposed DeviceINNOVANCE® Heparin Calibrator | Predicate Device3rd International Standard for LMWH6th International Standard for UFH |
|---|---|---|
| Intended Use | For the calibration of theINNOVANCE® Heparin assay for thequantitative determination of theactivity of unfractionated heparin(UFH) and low molecular weightheparin (LMWH) in citrated humanplasma. | International Standard for LMWHInternational Standard for UFH |
| Matrix | Human Plasma (Lyophilized) | Porcine Mucosa |
| Components | LMWH | UFH and LMWH |
| Traceability to WHO | Yes | WHO Standard |
| On-Board Stability | 4 Hours (BCS XP) | Not Available |
| Shelf-life | 24 Months at 2-8°C | LMWH: 6 months at -40°C or belowUFH: Not available |
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| Stability afterReconstitution | 24 hours at 15-25 °C48 hours at 2-8 °C | Not available |
|---|---|---|
| Calibrator Levels | 5 levels | 1 level; to be reconstituted and dilutedin plasma, as needed. |
6.3 Comparison of Control Features
| Item | Device (K162540)INNOVANCE Heparin UF and LMWControls | Coamatic Heparin Control |
|---|---|---|
| Intended Use | For quality control of theINNOVANCE® Heparin assay for thequantitative determination of the activityof unfractionated heparin (UFH) andlow molecular weight heparin (LMWH)in citrated human plasma. | Not Available |
| Matrix | Human Plasma (Lyophilized) | Not Available |
| Traceability to WHO | Yes | Not Available |
| Number of Control | 2 levels for LMWH2 levels for UFH | Not Available |
| ReconstitutionStability | 24 hours at 15-25°C48 hours at 2-8ºC4 weeks at < - 18ºC | Not Available |
| Stability | On-Board: 4 hours (BCS® XP) | Not Available |
| Stability | Shelf-life: 24 months at 2-8ºC | Not Available |
The differences between the predicate devices and proposed reagents and calibrators do not result in a change to the intended use, the indications for use, or the safety and efficacy when used according to the product labeling. There were no differences found for the controls.
7 Performance Data
The following performance data were provided in support of the substantial equivalence determination.
7.1 Non-Clinical Studies
7.1.1 Measuring Range (Linearity and LoQ)
The analytical measuring range of the INNOVANCE Heparin assay was confirmed by establishment of the Limit of Quantitation (LoQ) for the low end and by a linearity study. The linearity study was performed by using normal plasma (pool) spiked with increasing activities (0.00 to 1.90 IU/mL) of the International Standard for Unfractionated Heparin (IS UFH) and normal plasma (pool spiked with increasing activities (0.00 to 1.90 IU/mL) of the International Standard for Low Molecular Weight Heparin (IS LMWH). Plasma pools containing no heparin were spiked with each respective heparin (UFH and LMWH) to equal 21 different dilutions per heparin with 3 lots of reagents. The testing was in accordance with CLSI: EP06-A, Evaluation of
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the Linearity of Quantitative Measurement Procedures: A Statistical Approach; Approved Guide/ine in which the mean of four replicates from each dilution were plotted versus the assigned values. Differences between the predicted value from the best fitting polynomial and the predicted value from the 1st order regression were calculated for each dilution level for each heparin type. Based on the results of these two studies, the assay range for the INNOVANCE Heparin assay was established as 0.10 - 1.50 IU/mL.
Specificity 7.1.2
Interference testing was performed according to CLSI: EP7-A2, Interference Testing in Clinical Chemistry; Approved Guideline-Second Edition. Testing included endogenous interferents (bilirubin (unconiuqated), bilirubin (coniuqated), hemoglobin, platelet factor 4 (PF4) and triglycerides), known exogenous interferents (Rivaroxaban, Apixaban, Fondaparinux, Danaparoid Sodium) and other Over the Counter and Prescription drugs. Base pools of UFH and LMWH were prepared to span the assay range and to cover medical decision points and these base pools were used to perform the interference testing. Information about interference will be included in the Instructions for Use for INNOVANCE Heparin and in the application sheet.
Following concentrations of listed endogenous substances were found to cause no interference up to the indicated concentrations:
| Interferent | No Interference up to... |
|---|---|
| Ascorbic Acid | 176 mg/dL |
| Bilirubin (unconjugated) | 60 mg/dL |
| Bilirubin (conjugated) | 40 mg/dL |
| Hemoglobin | 347 mg/dL |
| Platelet Factor 4 | 0.7 μg/mL |
| Triglycerides | 807 mg/dL |
| Rheumatoid Factor | 220 IU/mL |
In addition, no interferences up to the indicated concentrations of following exogenous substances were observed:
| Interferent | No Interference up to... |
|---|---|
| Apixaban | 4.1 ng/mL |
| Danaparoid Sodium | 0.03 IU/mL |
| Fondaparinux | 35.5 ng/mL |
| Rivaroxaban | 7.1 ng/mL |
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7.2 Clinical Studies
Reproducibility and Repeatability Studies 7.2.1
A multicenter reproducibility study was performed in accordance with CLSI: EP05-A2, Evaluation of Precision Performance of Quantitative Measurement Methods: Approved Guideline-Second Edition with the INNOVANCE® Heparin assay on the BCS® XP System.
The study was conducted at three external sites for both UFH and LMWH. Plasma pools spanning the assay range were prepared at the Siemens Marburg site and sent frozen to the external study sites for testing along with appropriate controls for LMWH and UFH. See Table 1.
For reagent repeatability study, the testing data of the three lots at one site (Bad Oeynhausen) of INNOVANCE® Heparin reagent with LMWH/UFH controls (level 1 and 2) and heparin plasma pool samples was included. Table 2 provides a summary of the data.
| Sample | N | Mean(IU/mL) | Within-Run(SD, %CV) | Between-Run(SD, %CV) | Between-Day(SD, %CV) | Between-Site(SD, %CV) | Total(SD, %CV) |
|---|---|---|---|---|---|---|---|
| LMW CO 1(Lot 553304) | 240 | 0.448 | 0.010* / 2.17 | 0.005 / 1.07 | 0.006 / 1.34 | 0.015 / 3.42 | 0.020 / 4.40 |
| LMW CO 2(Lot 553404) | 240 | 1.045 | 0.013 / 1.24 | 0.010 / 1.00 | 0.009 / 0.89 | 0.024 / 2.34 | 0.031 / 2.97 |
| PP LMWH 1 | 240 | 0.160 | 0.009 / 5.56 | 0.010 / 6.33 | 0.000 / 0.00 | 0.031 / 19.40 | 0.034 / 21.15 |
| PP LMWH 2 | 240 | 0.717 | 0.010 / 1.35 | 0.010 / 1.33 | 0.008 / 1.14 | 0.019 / 2.67 | 0.025 / 3.47 |
| PP LMWH 3 | 240 | 1.425 | 0.014 / 0.97 | 0.014 / 1.02 | 0.018 / 1.26 | 0.042 / 2.94 | 0.050 / 3.49 |
| UF CO 1(Lot 553504) | 240 | 0.330 | 0.007 / 2.16 | 0.003 / 0.85 | 0.006 / 1.96 | 0.022 / 6.64 | 0.024 / 7.30 |
| UF CO 2(Lot 553604) | 240 | 0.731 | 0.008 / 1.13 | 0.007 / 0.93 | 0.009 / 1.30 | 0.019 / 2.64 | 0.024 / 3.29 |
| PP UFH 1 | 240 | 0.161 | 0.009 / 5.31 | 0.002 / 1.06 | 0.006 / 3.50 | 0.031 / 19.57 | 0.033 / 20.60 |
| PP UFH 2 | 240 | 0.719 | 0.009 / 1.30 | 0.008 / 1.13 | 0.009 / 1.30 | 0.027 / 3.72 | 0.031 / 4.30 |
| PP UFH 3 | 240 | 1.403 | 0.012 / 0.86 | 0.018 / 1.26 | 0.013 / 0.92 | 0.062 / 4.44 | 0.067 / 4.79 |
Table 1: INNOVANCE® Heparin Reagent Reproducibility Study
*Note: Bolded values indicate whether a SD or %CV is used for acceptance criteria
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| Sample | N | Mean(IU/mL) | Within-Run(SD, %CV) | Between-Run(SD, %CV) | Between-Day(SD, %CV) | Between-Lot(SD, %CV) | Total(SD, %CV) |
|---|---|---|---|---|---|---|---|
| LMW CO 1(Lot 553304) | 240 | 0.443 | 0.010 / 2.25 | 0.004 / 1.00 | 0.007 / 1.60 | 0.005 / 1.06 | 0.014 / 3.12 |
| LMW CO 2(Lot 553404) | 239 | 1.024 | 0.013 / 1.23 | 0.007 / 0.66 | 0.012 / 1.15 | 0.004 / 0.36 | 0.019 / 1.85 |
| PP LMWH 1 | 240 | 0.151 | 0.009 / 5.71 | 0.006 / 4.05 | 0.008 / 4.97 | 0.005 / 3.60 | 0.014 / 9.30 |
| PP LMWH 2 | 240 | 0.703 | 0.010 / 1.37 | 0.011 / 1.54 | 0.011 / 1.60 | 0.008 / 1.11 | 0.020 / 2.83 |
| PP LMWH 3 | 240 | 1.409 | 0.017 / 1.19 | 0.021 / 1.50 | 0.023 / 1.64 | 0.008 / 0.54 | 0.036 / 2.58 |
| UF CO 1(Lot 553504) | 240 | 0.315 | 0.007 / 2.34 | 0.002 / 0.58 | 0.008 / 2.48 | 0.004 / 1.34 | 0.012 / 3.71 |
| UF CO 2(Lot 553604) | 240 | 0.699 | 0.009 / 1.35 | 0.009 / 1.29 | 0.010 / 1.41 | 0.019 / 2.70 | 0.025 / 3.58 |
| PP UFH 1 | 240 | 0.152 | 0.006 / 4.18 | 0.004 / 2.84 | 0.008 / 5.09 | 0.004 / 2.45 | 0.012 / 7.58 |
| PP UFH 2 | 240 | 0.677 | 0.009 / 1.35 | 0.007 / 1.01 | 0.013 / 1.86 | 0.014 / 1.99 | 0.022 / 3.21 |
| PP UFH 3 | 240 | 1.327 | 0.016 / 1.18 | 0.022 / 1.64 | 0.012 / 0.92 | 0.032 / 2.44 | 0.044 / 3.30 |
Table 2: INNOVANCE® Heparin Reagent Repeatability Study
*Note: Bolded values indicate whether a SD or %CV is used for acceptance criteria.
Table 3 and Table 4 show the precision information for the calibration material. The
reproducibility and repeatability of INNOVANCE® Heparin Calibrators was tested. A 5-day study with two runs per day testing of four replicates was performed.
Table 3 (below) shows data for a reproducibility study using one lot of calibrator levels were run as samples on three internal sites by three operators on three BSC XP systems.
| Sample | N | Mean(IU/mL) | Within-Run(SD, %CV) | Between-Run(SD, %CV) | Between-Day(SD, %CV) | Between-Site(SD, %CV) | Total(SD, %CV) |
|---|---|---|---|---|---|---|---|
| 553803 | 120 | 0.431 | 0.011 / 2.65 | 0.002 / 0.41 | 0.009 / 2.03 | 0.00 / 0.00 | 0.014 / 3.36 |
| 553903 | 120 | 0.829 | 0.013 / 1.58 | 0.002 / 0.20 | 0.013 / 1.57 | 0.00 / 0.00 | 0.019 / 2.23 |
| 559303 | 120 | 1.221 | 0.016 / 1.29 | 0.006 / 0.51 | 0.029 / 2.40 | 0.00 / 0.00 | 0.034 / 2.77 |
Table 3: INNOVANCE® Heparin Calibrator Reproducibility Study (IU/mL)
*Note: Bolded values indicate whether a SD or %CV is used for acceptance criteria.
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In addition, Table 4 shows the data for repeatability. Three lots of calibrator were used in the study design and run as samples at one site.
| Sample | N | Mean(IU/mL) | Within-Run(SD, %CV) | Between-Run(SD, %CV) | Between-Day(SD, %CV) | Between-Lot(SD, %CV) | Total(SD, %CV) |
|---|---|---|---|---|---|---|---|
| Calibrator 2(553802 / -03 / -04) | 240 | 0.420 | 0.010 / 2.49 | 0.004 / 1.00 | 0.007 / 1.64 | 0.009 / 2.02 | 0.016 / 3.74 |
| Calibrator 3(553902 / -03 / -04) | 240 | 0.816 | 0.011 / 1.37 | 0.008 / 1.00 | 0.012 / 1.42 | 0.010 / 1.23 | 0.021 / 2.53 |
| Calibrator 4(559302 / -03 / -04) | 240 | 1.224 | 0.016 / 1.28 | 0.016 / 1.31 | 0.012 / 0.98 | 0.021 / 1.71 | 0.033 / 2.69 |
| Table 4: INNOVANCE® Heparin Calibrator Repeatability Study (IU/mL) | ||
|---|---|---|
| -------------------------------------------------------------------- | -- | -- |
*Note: Bolded values indicate whether a SD or %CV is used for acceptance criteria.
For reproducibility of the controls (20x2x2) the data of one lot of control at three sites was measured and is shown in Table 5 (below).
| Sample | N | Mean(IU/ml) | Within-Run(SD, %CV) | Between-Run(SD, %CV) | Between-Day(SD, %CV) | Between-Site(SD, %CV) | Total(SD, %CV) |
|---|---|---|---|---|---|---|---|
| LMW CO 1(553304) | 240 | 0.448 | 0.010 / 2.17 | 0.005 / 1.07 | 0.006 / 1.34 | 0.015 / 3.42 | 0.020 / 4.40 |
| LMW CO 2(553404) | 240 | 1.045 | 0.013 / 1.24 | 0.010 / 1.00 | 0.009 / 0.89 | 0.024 / 2.34 | 0.031 / 2.97 |
| UF CO 1(553504) | 240 | 0.330 | 0.007 / 2.16 | 0.003 / 0.85 | 0.006 / 1.96 | 0.022 / 6.64 | 0.024 / 7.30 |
| UF CO 2(553604) | 240 | 0.731 | 0.008 / 1.13 | 0.007 / 0.93 | 0.009 / 1.30 | 0.019 / 2.64 | 0.024 / 3.29 |
*Note: Bolded values indicate whether a SD or %CV is used for acceptance criteria.
The data of three lots of controls at one site is summarized in Table 6.
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| Sample | N | Mean(IU/ml) | Within-Run(SD, %CV) | Between-Run(SD, %CV) | Between-Day(SD, %CV) | Between-Lot(SD, %CV) | Total(SD, %CV) |
|---|---|---|---|---|---|---|---|
| LMW CO 1(553302 / -03 / -04) | 240 | 0.468 | 0.011 / 2.41 | 0.000 / 0.00 | 0.005 / 1.06 | 0.003 / 0.75 | 0.013 / 2.74 |
| LMW CO 2(553402 / -03 / -04) | 240 | 1.053 | 0.014 / 1.35 | 0.009 / 0.82 | 0.007 / 0.64 | 0.019 / 1.76 | 0.026 / 2.45 |
| UF CO 1(553502 / -03 / -04) | 240 | 0.356 | 0.008 / 2.37 | 0.002 / 0.68 | 0.003 / 0.73 | 0.009 / 2.61 | 0.013 / 3.67 |
| UF CO 2(553602 / -03 / -04) | 240 | 0.730 | 0.011 / 1.49 | 0.010 / 1.37 | 0.003 / 0.41 | 0.020 / 2.79 | 0.025 / 3.47 |
Table 6: INNOVANCE® Heparin Control Repeatability Study (IU/mL)
*Note: Bolded values indicate whether a SD or %CV is used for acceptance criteria.
7.2.2 Frozen vs. Fresh Method Comparison Study
The objective of this study was to perform a method comparison study to confirm comparability of results obtained when using either fresh or frozen samples. Per study design, a minimum of 60 samples covering the clinically reportable range was to compare fresh samples to those stored at -70°C after a minimum of one week.
Fresh samples were measured within four (4h) after blood collection. Within this timeframe one aliquot of all samples was prepared and stored at -70°C. After at least one week of storage time, the aliquot was thawed within ten (10) minutes at 37°C in a water bath, gently mixed and measured immediately within two (2) hours.
The study was performed at one study site in Germany. To ensure the study did not introduce bias, one reagent lot was used to exclude reagent lot- to-lot variability.
Results were analyzed by both Passing-Bablok regression analysis and Bland Altman analysis. All results met pre-established acceptance criteria for both Passing-Bablok and Bland Altman.
The results for Frozen vs. Fresh Method Comparison are presented below.
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| N | Slope | Intercept(IU/mL) | r | r2 | MDP(IU/mL) | PredictedBias(IU/mL) | PredictedBias(%) |
|---|---|---|---|---|---|---|---|
| 69 | 1.00 | -0.01 | 0.996 | 0.993 | 0.3 | -0.01 | N/A |
| 0.4 | -0.01 | N/A | |||||
| 0.6 | N/A | -1.67 | |||||
| 0.7 | N/A | -1.43 | |||||
| 1.0 | N/A | -1.00 |
All acceptance criteria were met.
7.2.3 Method comparison
Method comparison studies designed according to CLSI: EP09-A3: Measurement Procedure Comparison and Bias Estimation Using Patient Samples; Approved Guideline-Third Edition and were conducted at three sites including one external US site, where all sites used the same protocol. Frozen samples were thawed and measured on both the predicate device, Coamatic® Heparin assay on the ACL TOP, as well as the new device, INNOVANCE® Heparin assay on the BCS® XP, in random order. Results from all sites combined were compared by Passing-Bablok regression analysis. Results met the pre-established acceptance criteria for slope, intercept and correlation coefficient. The following summary of Passing-Bablok regression analysis proves substantial equivalence between the INNOVANCE® Heparin assay and the predicate device.
| N | Slope | Intercept | CorrelationCoefficient(r) | |
|---|---|---|---|---|
| INNOVANCE®Heparin on BCS® XPSystem vs.Coamatic® Heparinon ACL TOP System(UFH samples only) | 165 | 0.93 | 0.03 | 0.98 |
| INNOVANCE®Heparin on BCS® XPSystem vs.Coamatic® Heparinon ACL TOP System(LMWH samplesonly) | 155 | 1.06 | -0.01 | 0.99 |
INNOVANCE® Heparin on BCS XP vs. Coamatic® Heparin on the ACL TOP
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Traceability 8
8.1 Calibrator Traceability
INNOVANCE® Heparin Calibrator is traceable to the WHO Standard for UFH as well as the WHO Standard for LMWH.
8.2 Calibrator Stability
Unopened vials of INNOVANCE® Heparin Calibrator are stored at 2-8 °C until the expiration date printed on each carton. After reconstitution, calibrators are stable for 24 hours at 15-25 °C and 48 hours at 2-8 °C.
8.3 Control Traceability
INNOVANCE® Heparin Controls are traceable to the WHO Standard for UFH as well as to the WHO Standard for LMWH.
8.4 Control Stability
Unopened vials of INNOVANCE® Heparin UF and LMW Controls are stored at 2-8 °C until the expiration date printed on each carton. After reconstitution, controls are stable for 24 hours at 15-25 °C, 48 hours at 2-8 °C and for 4 weeks at ≤ -18°C.
9 Conclusion
The differences between the predicate devices and proposed reagents and calibrators do not result in a change to the intended use, the indications for use, or the safety and efficacy when used according to the product labeling. There were no differences found for the controls.
§ 864.7525 Heparin assay.
(a)
Identification. A heparin assay is a device used to determine the level of the anticoagulant heparin in the patient's circulation. These assays are quantitative clotting time procedures using the effect of heparin on activated coagulation factor X (Stuart factor) or procedures based on the neutralization of heparin by protamine sulfate (a protein that neutralizes heparin).(b)
Classification. Class II (performance standards).