INNOVANCE(r) Heparin Reagents, INNOVANCE(r) Heparin Calibrator, INNOVANCE(r) Heparin UF and Heparin LMW Controls
Device Facts
| Record ID | K162540 |
|---|---|
| Device Name | INNOVANCE(r) Heparin Reagents, INNOVANCE(r) Heparin Calibrator, INNOVANCE(r) Heparin UF and Heparin LMW Controls |
| Applicant | Siemens Healthcare Diagnostics Prodcts GmbH |
| Product Code | KFF · Hematology |
| Decision Date | Aug 22, 2017 |
| Decision | SESE |
| Submission Type | Traditional |
| Regulation | 21 CFR 864.7525 |
| Device Class | Class 2 |
Intended Use
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.
Device Story
One-stage chromogenic assay; measures unfractionated heparin (UFH) and low molecular weight heparin (LMWH) activity in citrated human plasma. Input: venous blood plasma samples. Principle: Coagulation Factor Xa and chromogenic substrate mixed with patient plasma; heparin/antithrombin complex inhibits Xa; residual Xa converts substrate to paranitroaniline; light absorption measured at 405 nm. Output: heparin activity (IU/mL) quantified via reference curve. Used in clinical laboratories on BCS® XP System; operated by laboratory personnel. Dextran sulfate included to minimize interference from heparin antagonists like platelet factor 4. Output assists clinicians in monitoring heparin anticoagulant therapy.
Clinical Evidence
No clinical trials; analytical performance only. Method comparison study performed at three sites (1 US, 2 internal) using 165 UFH and 155 LMWH patient samples. Compared INNOVANCE Heparin Assay on BCS® XP to Coamatic Heparin assay on ACL TOP. Passing-Bablok regression showed high correlation (r=0.98-0.99). Precision studies (repeatability/reproducibility) followed CLSI EP05-A2; total CVs generally <5%. Linearity established 0.10–1.50 IU/mL per CLSI EP06-A.
Technological Characteristics
Chromogenic assay; liquid reagent containing Factor Xa and chromogenic substrate. Measures light absorption at 405 nm. Automated on BCS® XP System. Traceable to WHO International Standards for UFH (07/328) and LMWH (05/112). Includes dextran sulfate to mitigate PF4 interference. Shelf-life 24 months at 2–8°C.
Indications for Use
Indicated for quantitative determination of UFH and LMWH activity in citrated human plasma from patients undergoing heparin anticoagulant therapy. Performance not established in neonate or pediatric populations.
Regulatory Classification
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).
Predicate Devices
- Coamatic Heparin Assay (K983178)
Related Devices
- K111822 — STA(R) - LIQUID ANTI-XA, MULTI HEP CALIBRATOR, QUALITY HNF / UFH, QUALITY HBPM / LMWH · Diagnostica Stago, Inc. · Oct 26, 2011
- K090209 — HEMOSIL LIQUID HEPARIN, HEPARIN CALIBRATORS AND LMW AND UF HEPARIN CONTROLS · Instrumentation Laboratory CO · Jun 2, 2009
Submission Summary (Full Text)
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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)
| <span> ☑ Prescription Use (Part 21 CFR 801 Subpart D) </span> |
|--------------------------------------------------------------------|
| <span> ☐ Over-The-Counter Use (21 CFR 801 Subpart C) </span> |
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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<br>(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 Device<br>INNOVANCE® Heparin Assay | Predicate Device<br>Coamatic Heparin - K983178 |
|------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| | | |
| Intended Use | In-vitro diagnostic automated<br>chromogenic assay for the quantitative<br>determination of unfractionated heparin<br>(UFH) and low molecular weight heparin<br>(LMWH) activity in human plasma<br>collected from venous blood samples in<br>3.2% sodium citrate tubes on the BCS®<br>XP System in the clinical laboratory. | For the quantitative determination of<br>unfractionated heparin (UF Heparin) or<br>low molecular weight heparin (LMW<br>Heparin) in human citrated plasma using<br>automated and microplate methods. |
| Indications for<br>Use | For use with plasma from patients<br>undergoing heparin anticoagulant therapy<br>with 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 Device<br>INNOVANCE® Heparin Assay | Predicate Device<br>Coamatic Heparin – K983178 |
|---------------------------|----------------------------------------------------------------------|------------------------------------------------|
| Units | IU/mL | Same |
| Storage | Until expiration date printed on each vial<br>and carton at 2 - 8 °C | Same |
| Measuring<br>Range | 0.10 to 1.50 IU/mL | 0 to 1.5 IU/mL |
| Composition | Liquid<br>(Factor Xa and chromogenic substrate) | Lyophilized<br>(Factor Xa and S-2732) |
| Calibration<br>Curve | Single calibration curve for UFH and<br>LMWH | Same |
| Stability / Shelf<br>Life | 24 months at 2-8 °C | Not available from package insert |
| Stability once<br>opened | 8 weeks at 2-8 °C | 3 months at 2-8 °C in the original vial |
| On Board<br>Stability | 24 hours in cooled positions on the<br>BCS® XP System | Not available from package insert. |
### 6.2 Comparison of Calibrator Features
| Item | Proposed Device<br>INNOVANCE® Heparin Calibrator | Predicate Device<br>3rd International Standard for LMWH<br>6th International Standard for UFH |
|---------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------|
| Intended Use | For the calibration of the<br>INNOVANCE® Heparin assay for the<br>quantitative determination of the<br>activity of unfractionated heparin<br>(UFH) and low molecular weight<br>heparin (LMWH) in citrated human<br>plasma. | International Standard for LMWH<br>International 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 below<br>UFH: Not available |
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| Stability after<br>Reconstitution | 24 hours at 15-25 °C<br>48 hours at 2-8 °C | Not available |
|-----------------------------------|--------------------------------------------|-------------------------------------------------------------------|
| Calibrator Levels | 5 levels | 1 level; to be reconstituted and diluted<br>in plasma, as needed. |
### 6.3 Comparison of Control Features
| Item | Device (K162540)<br>INNOVANCE Heparin UF and LMW<br>Controls | Coamatic Heparin Control |
|-----------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------|
| Intended Use | For quality control of the<br>INNOVANCE® Heparin assay for the<br>quantitative determination of the activity<br>of unfractionated heparin (UFH) and<br>low molecular weight heparin (LMWH)<br>in citrated human plasma. | Not Available |
| Matrix | Human Plasma (Lyophilized) | Not Available |
| Traceability to WHO | Yes | Not Available |
| Number of Control | 2 levels for LMWH<br>2 levels for UFH | Not Available |
| Reconstitution<br>Stability | 24 hours at 15-25°C<br>48 hours at 2-8ºC<br>4 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<br>(IU/mL) | Within-Run<br>(SD, %CV) | Between-<br>Run<br>(SD, %CV) | Between-<br>Day<br>(SD, %CV) | Between-Site<br>(SD, %CV) | Total<br>(SD, %CV) |
|--------------------------|-----|-----------------|-------------------------|------------------------------|------------------------------|---------------------------|--------------------|
| LMW CO 1<br>(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<br>(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<br>(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<br>(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<br>(IU/mL) | Within-Run<br>(SD, %CV) | Between-<br>Run<br>(SD, %CV) | Between-<br>Day<br>(SD, %CV) | Between-<br>Lot<br>(SD, %CV) | Total<br>(SD, %CV) |
|--------------------------|-----|-----------------|-------------------------|------------------------------|------------------------------|------------------------------|--------------------|
| LMW CO 1<br>(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<br>(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<br>(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<br>(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<br>(IU/mL) | Within-Run<br>(SD, %CV) | Between-<br>Run<br>(SD, %CV) | Between-<br>Day<br>(SD, %CV) | Between-<br>Site<br>(SD, %CV) | Total<br>(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<br>(IU/mL) | Within-Run<br>(SD, %CV) | Between-<br>Run<br>(SD, %CV) | Between-<br>Day<br>(SD, %CV) | Between-<br>Lot<br>(SD, %CV) | Total<br>(SD, %CV) |
|--------------------------------------|-----|-----------------|-------------------------|------------------------------|------------------------------|------------------------------|--------------------|
| Calibrator 2<br>(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<br>(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<br>(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<br>(IU/ml) | Within-Run<br>(SD, %CV) | Between-<br>Run<br>(SD, %CV) | Between-<br>Day<br>(SD, %CV) | Between-<br>Site<br>(SD, %CV) | Total<br>(SD, %CV) |
|----------------------|-----|-----------------|-------------------------|------------------------------|------------------------------|-------------------------------|--------------------|
| LMW CO 1<br>(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<br>(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<br>(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<br>(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.
{12}------------------------------------------------
| Sample | N | Mean<br>(IU/ml) | Within-Run<br>(SD, %CV) | Between-<br>Run<br>(SD, %CV) | Between-<br>Day<br>(SD, %CV) | Between-<br>Lot<br>(SD, %CV) | Total<br>(SD, %CV) |
|----------------------------------|-----|-----------------|-------------------------|------------------------------|------------------------------|------------------------------|--------------------|
| LMW CO 1<br>(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<br>(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<br>(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<br>(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.
{13}------------------------------------------------
| N | Slope | Intercept<br>(IU/mL) | r | r2 | MDP<br>(IU/mL) | Predicted<br>Bias<br>(IU/mL) | Predicted<br>Bias<br>(%) |
|----|-------|----------------------|-------|-------|----------------|------------------------------|--------------------------|
| 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 | Correlation<br>Coefficient<br>(r) |
|--------------------------------------------------------------------------------------------------------------------|-----|-------|-----------|-----------------------------------|
| INNOVANCE®<br>Heparin on BCS® XP<br>System vs.<br>Coamatic® Heparin<br>on ACL TOP System<br>(UFH samples only) | 165 | 0.93 | 0.03 | 0.98 |
| INNOVANCE®<br>Heparin on BCS® XP<br>System vs.<br>Coamatic® Heparin<br>on ACL TOP System<br>(LMWH samples<br>only) | 155 | 1.06 | -0.01 | 0.99 |
INNOVANCE® Heparin on BCS XP vs. Coamatic® Heparin on the ACL TOP
{14}------------------------------------------------
#### 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.
