K Number

Device Name

INNOVANCE VWF Ac

Manufacturer

Siemens Healthcare Diagnostics Products GmbH

Date Cleared

2022-09-29

(701 days)

Product Code

QTY

Regulation Number

864.7293

Intended Use

In-vitro diagnostic automated assay for the quantitative determination of the von Willebrand factor-GPIb-binding activity in human plasma collected from venous blood samples in 3.2% sodium citrate tubes on the BCS XP System. As an aid used in the evaluation of patients with suspected or confirmed von Willebrand factor disorders. Results of this test should always be interpreted in conjunction with the patient's medical history, clinical presentation and other laboratory findings.

Device Description

The INNOVANCE VWF Ac assay is a particle enhanced turbidimetric assay based on binding of VWF to the recombinant GPIb (two gain-of-function mutations included). The assay provides quantitative VWF activity results on 3.2% citrated human plasma when used with Standard Human Plasma Calibrators (K023141). The reagent kit consists of three components: Reagent I (containing polystyrene particles coated with anti-GPIb mouse monoclonal antibodies). Reagent II (buffer containing heterophilic blocking reagent) and Reagent III (containing recombinant GPIb).

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Type

Center

Panel

Date Received

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Subsequent Product Codes

Applicant Name (Manufacturer)

Device Name

Decision

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Street 2

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Class Advise Committee

SSP Indicator

Third Party Reviewed

Expedited Review

Predicate Devices

K972116, K200033

Reference Devices

K013114, K023141, K042333, K042209, K050928, K924124, K972116, K200033, K160276

AI/ML (Artificial Intelligence / Machine Learning)

No
The summary describes a standard turbidimetric assay and its performance characteristics. There is no mention of AI, ML, or any related computational techniques used for analysis or interpretation. The "Mentions AI, DNN, or ML" field is explicitly marked as "Not Found".

Therapeutic

No.
This device is an in-vitro diagnostic assay used to determine the quantitative level of von Willebrand factor-GPIb-binding activity. It is an aid in the evaluation of patients with suspected or confirmed von Willebrand factor disorders, providing diagnostic information, rather than directly treating or preventing a disease.

Diagnostic

Yes

The "Intended Use / Indications for Use" section explicitly states that the device is an "In-vitro diagnostic automated assay" and is used "As an aid used in the evaluation of patients with suspected or confirmed von Willebrand factor disorders." This clearly indicates its role in diagnosing or aiding in the diagnosis of medical conditions.

SaMD (Software as a Medical Device)

The device is an in-vitro diagnostic assay that includes reagent components (Reagent I, Reagent II, and Reagent III) which are physical substances used in the test. This indicates it is not a software-only device.

IVD (In Vitro Diagnostic)

Yes, this device is an IVD (In Vitro Diagnostic).

Here's why:

Intended Use/Indications for Use: The intended use explicitly states it is an "In-vitro diagnostic automated assay" for the quantitative determination of a substance (von Willebrand factor-GPIb-binding activity) in a human sample (plasma collected from venous blood). It also states it is used "as an aid used in the evaluation of patients with suspected or confirmed von Willebrand factor disorders." This clearly indicates it is used to diagnose or aid in the diagnosis of a disease or condition using a sample taken from the human body.
Device Description: The description details a "particle enhanced turbidimetric assay" that uses reagents to measure the binding activity in human plasma. This is a typical description of an in vitro diagnostic test.
Performance Studies: The document includes extensive performance studies such as precision, linearity, analytical specificity, interference, stability, detection limit, normal range, and clinical studies (method comparison and diagnostic concordance). These are all standard types of studies performed to validate the performance of an IVD.
Key Metrics: The inclusion of metrics like Positive Percent Agreement, Negative Percent Agreement, and Overall Percent Agreement from the diagnostic concordance study further confirms its use in a diagnostic context.

All of these elements align with the definition and characteristics of an In Vitro Diagnostic device.

PCCP (Predetermined Change Control Plan) Authorized

N/A

Overview

Intended Use / Indications for Use

As an aid used in the evaluation of patients with suspected or confirmed von Willebrand factor disorders.

Results of this test should always be interpreted in conjunction with the patient's medical history, clinical presentation and other laboratory findings.

Product codes

QTY

Device Description

The reagent kit consists of three components: Reagent I (containing polystyrene particles coated with anti-GPIb mouse monoclonal antibodies). Reagent II (buffer containing heterophilic blocking reagent) and Reagent III (containing recombinant GPIb).

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

The diagnostic concordance study included patient samples with various demographics including age. The reference interval study for the general population included individuals >= 18 years of age. A separate study for healthy pediatric individuals included ages > 4 weeks to = 1000% of norm.

Key results: No high dose hook effect observed up to a VWF activity of 656% of norm.

5. Traceability, Stability, Expected Values (Controls, Calibrators, or Methods):

Traceability: Study performed on one BCS XP System with three lots of INNOVANCE VWF Ac reagent and three Standard Human Plasma lots. Results traceable to WHO 6th International Standard (NIBSC code 07/316).
Value assignment: Calibration concept/value assignment process for Standard Human Plasma. Confirmed stability of calibration curve to WHO IS.
Expected Values Controls: Control Plasma N and Control Plasma P used as normal and pathologic controls.
Shelf-Life Stability (Reagent): Evaluated according to CLSI EP25-A. Stable for 12 months when stored at 2-8°C.
Shelf-Life Stability (Calibrator): Evaluated according to CLSI EP25-A. Stable for 12 months when stored at 2-8°C.
In-Use Stability (Reagent): Classical on-board stability (18 to 32°C) and accumulated on-board stability (2 to 8°C). Stable up to 36 hours opened and maintained on-board at 18 to 32 ℃. Maximum accumulated on board stability is 24 hours for Reagents I and II and 36 hours for Reagent III.
In-Use Stability (Calibrator): On-board stability of 6 hours (18 to 32°C).
Once Opened Stability (Reagent): Reagent I and II stable for 37 days, Reagent III for 113 days when stored open vial at 2-8°C.
Reconstituted Stability of the Calibrator: 4 hours when stored at 15 to 25°C, 4 weeks when stored at -20°C, and 2 hours at 15 to 25°C once frozen and thawed.
Ambient Temperature: Correctness of results assured within 18°C to 32°C.
Transportation Study: All measurements meet predefined acceptance criteria for transportation stability.
Freeze/thaw tolerance Study: Stable for one freeze/thaw cycle.
Sample Stability: Stable for 3 months at = 18 years of age.
- Key results: Generic VWF activity reference interval (pooled data): 50.7 to 203.5% of norm.
  - Blood group O: 49.0 to 178.9% of norm.
  - Blood group non-O: 60.7 to 214.1% of norm.
  - Female: 55.4 to 181.3% of norm.
  - Male: 48.8 to 210.7% of norm.
Measurements of VWF in healthy pediatric population:
- Study type: VWF activity in healthy pediatric population study.
- Sample size: 85 apparently healthy pediatric individuals (44 blood group O and 41 blood group non-O) with > 4 weeks to 300.0% of norm. 78 out of 85 within the reference interval for individuals >= 18 years of age.

8. Carry-Over:

Sample Carryover: No carryover caused by one sample into another.
Reagent Carryover: No cross-contamination caused by one application into another.

B. Clinical Studies:

1. Diagnostic Accuracy:

Method Comparison with the BC von Willebrand Assay
- Study type: Method comparison at four clinical laboratory sites in U.S.
- Sample size: 144 samples (17 fresh, 124 frozen, 3 diluted). 102 samples included in statistical evaluation (within measuring interval of both devices).
- Key results: Passing-Bablok regression (combined sites): Slope 1.037, Intercept 3.497, Pearson Correlation Coefficient (r) 0.916. Predicted bias at MDP1 (30% of norm) 4.60% of norm. Predicted bias at MDP2 (50% of norm) 10.14% (relative). Met predefined acceptance criteria.
Method Comparison with HemosIL von Willebrand Assay
- Study type: Method comparison.
- Sample size: 144 samples (17 fresh, 124 frozen, 3 diluted). 97 samples included in statistical evaluation (within measuring interval of both devices).
- Key results: Passing-Bablok regression (combined sites): Slope 0.955, Intercept -0.552, Pearson Correlation Coefficient (r) 0.971. Predicted bias at MDP1 (30% of norm) -1.90% of norm. Predicted bias at MDP2 (50% of norm) -5.76% (relative). Met predefined acceptance criteria.
Method Comparison Study (Patzke et al. (2014) data re-analysis)
- Study type: Re-analysis of method comparison from published study.
- Sample size: 618 samples; 580 samples included in statistical evaluation.
- Key results:
  - For samples with INNOVANCE VWF Ac results from 20 to 150% of norm (N=417): Slope 0.954, Intercept 2.505, r 0.972. Predicted bias at MDP1 1.14% of norm, at MDP2 0.45% (relative).
  - For samples with INNOVANCE VWF Ac results from 4 to 300% of norm (N=556): Slope 0.955, Intercept 1.110, r 0.985. Predicted bias at MDP1 -0.23% of norm, at MDP2 -2.26% (relative).
- Confirmed acceptable comparability.

2. Diagnostic Concordance:

Study type: Comparison with site specific standard of care (SOC) VWF-activity assay.
Sample size: 138 patients (108 tested by Beckman Coulter von Willebrand Reagent, 30 by HemosIL VWF Activity Reagent).
Key results:
- Positive Percent Agreement 'any type': 74.29% (57.93%, 85.84%)
- Positive Percent Agreement 'low' VWF: 52.63% (31.71%, 72.67%)
- Negative Percent Agreement 'VWD excluded': 95.77% (88.30%, 98.55%)
- Overall Percent Agreement: 83.33% (76.23%, 88.63%)
- Overall agreement > 80% shows use of subject device will not alter diagnosis for majority of patients.

3. Real-world evidence

Study type: Comprehensive review of published scientific literature describing studies evaluating the subject device.
Key results: Provided real-world evidence of safety and effectiveness, demonstrating method comparison data between INNOVANCE VWF Ac and other VWF activity assays.

Key Metrics

Imprecision (CV):
- Single site total CVs: 1.54% to 7.24%
- Multi-site total CVs: 2.83% to 6.29%
Reportable Range: 4 to 300% of norm
High Dose Hook: No hook effect up to 656% of norm
Limit of Blank (LoB): 1.131% of norm
Limit of Detection (LoD): 1.738% of norm
Limit of Quantitation (LoQ): 3.72% of norm
Reference Interval (pooled): 50.7 to 203.5% of norm
Method Comparison (INNOVANCE VWF Ac vs BC von Willebrand Reagent):
- Pearson Correlation Coefficient (r): 0.916
- Slope: 1.04
- Intercept: 3.50% of norm
- Predicted bias at MDP1 (30% of norm): 4.60% of norm
- Predicted bias at MDP2 (50% of norm): 10.14% (relative)
Method Comparison (INNOVANCE VWF Ac vs HemosIL VWF):
- Pearson Correlation Coefficient (r): 0.971
- Slope: 0.96
- Intercept: -0.55% of norm
- Predicted bias at MDP1 (30% of norm): -1.90% of norm
- Predicted bias at MDP2 (50% of norm): -5.76% (relative)
Diagnostic Concordance:
- Positive Percent Agreement 'any type': 74.29%
- Positive Percent Agreement 'low' VWF: 52.63%
- Negative Percent Agreement 'VWD excluded': 95.77%
- Overall Percent Agreement: 83.33%

Predicate Device(s)

Not Found

Reference Device(s)

BCS XP System (K013114), Standard Human Plasma Calibrators (K023141), Control Plasma N (K042333), Control Plasma P (K042209), Dade Owren's Veronal Buffer (K050928), Washing Solution for Coagulation Analyzers (K924124), BC von Willebrand Reagent (K972116), HemosIL VWF (K200033), ACL TOP 500 CTS (K160276)

Predetermined Change Control Plan (PCCP) - All Relevant Information

Not Found

Regulation Number and Section

N/A

Summary

Image /page/0/Picture/0 description: The image shows the logo of the U.S. Food & Drug Administration (FDA). The logo consists of two parts: a symbol on the left and the text on the right. The symbol is a circular emblem with abstract shapes. The text reads "FDA U.S. FOOD & DRUG ADMINISTRATION" in blue lettering, with "FDA" in a larger, bolder font and "ADMINISTRATION" in a smaller font.

EVALUATION OF AUTOMATIC CLASS III DESIGNATION FOR INNOVANCE VWF Ac DECISION SUMMARY

I Background Information:

A De Novo Number

DEN200067

B Applicant

Siemens Healthcare Diagnostics Products GmbH

C Proprietary and Established Names

INNOVANCE VWF Ac

D Regulatory Information

| Product
Code(s) | Classification | Regulation
Section | Panel |
|--------------------|--------------------------------|-----------------------|-----------------|
| QTY | Von Willebrand factor
assay | 21 CFR 864.7293 | 81 - Hematology |

II Submission/Device Overview:

A Purpose for Submission:

De Novo request for evaluation of automatic class III designation for INNOVANCE VWF Ac assay

B Measurand:

von Willebrand factor activity

C Type of Test:

Quantitative test of the von Willebrand factor-GPIb-binding activity

III Indications for Use:

A Intended Use(s):

Food and Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20993-0002 www.fda.gov

See Indications for Use below.

B Indication(s) for Use:

As an aid used in the evaluation of patients with suspected or confirmed von Willebrand factor disorders.

Results of this test should always be interpreted in conjunction with the patient's medical history, clinical presentation and other laboratory findings.

C Special Conditions for Use Statement(s):

Rx - For Prescription Use Only

D Special Instrument Requirements:

BCS XP System (K013114)

IV Device/System Characteristics:

A Device Description:

| INNOVANCE VWF Ac
assay kit components | Description | Vials provided in
the assay kit |
|------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------|
| INNOVANCE VWF Ac
Reagent I | Ready to use liquid containing:
Buffer
Sucrose
Polystyrene particles coated
with anti-GPIb mouse
monoclonal antibodies (2.2 g/L)
Amphotericin B
Gentamicin sulfate | 3 x 2.0 mL |
| INNOVANCE VWF Ac
Reagent II | Ready to use liquid containing:
Buffered saline
Heterophilic blocking reagent
Polyvinylpyrrolidone
Detergent
Sodium azide ( 300 % of norm).

The gender specific reference intervals are: 55.4 to 181.3% of norm for female and 48.8 to 210.7% of norm for male.

Descriptive statistics of the reference interval study of INNOVANCE VWF Ac on the BCS XP System pooled over all sites (n=3); specific analysis for females and males.

| Gender | n | Unit | 2.5th Percentile (95%
confidence range) | 97.5th Percentile (95%
confidence range) |
|--------------------|-----|-----------|--------------------------------------------|---------------------------------------------|
| Gender
combined | 302 | % of norm | 50.7
(46.8, 57.5) | 203.5
(189.1, 220.6) |
| Female | 154 | % of norm | 55.4
(49.5, 61.6) | 181.3
(164.7, 220.6) |
| Male | 148 | % of norm | 48.8
(42.9, 57.1) | 210.7
(199.0 - *) |

The upper 95% confidence limit for the 97.5th percentile cannot be stated for this subgroup, because corresponding to the sample size of n=148, the highest observation represents the upper limit of the 95% confidence range for the 97.5th percentile. The highest observation in this subgroup was above the measuring interval of INNOVANCE VWF Ac (> 300% of norm).

Measurements of VWF in healthy pediatric population

The VWF activity in healthy pediatric population study for the two subgroups investigated (blood group O and non-O) was conducted at two U.S. clinical sites. Citrated plasma samples were obtained from 85 apparently healthy pediatric individuals (44 blood group O and 41 blood group non-O) with > 4 weeks to 4 weeks to 300.0% of norm (78 out of 85 within the reference interval for individuals ≥ 18 years of age). A statement indicating that the outcome of the study is not to be used as a pediatric reference interval is provided in the labeling.

8. Carry-Over:

a. Sample Carryover

To evaluate whether a sample could cause contamination by being carried over into the subsequent test sample, two plasma pools with low VWF concentrations were investigated as acceptor samples (low analyte sample 1 and low analyte sample 2). The low analyte sample 1 was investigated using the BCS XP System's Medium-Setting (used for samples of > 20 to 150% of norm VWF activity) of the INNOVANCE VWF Ac test setting (no sample dilution is used). The low analyte sample 2 was investigated using the Low-Setting (used for samples of 4 to 20% of norm VWF activity) of the INNOVANCE VWF Ac test setting on the BCS XP System (higher volume of the sample is pipetted onto the reaction mixture). Both low analyte samples were prepared by diluting a normal plasma pool with VWF deficient plasma that was internally produced by immunoaffinity chromatography. A plasma pool with a high VWF concentration (high carryover test sample) was prepared by spiking a normal plasma pool with VWF concentrate and 1:4 dilution was carried out with dilution buffer when the target range of the donor test sample was beyond the measuring range interval (MRI). The study was conducted by using one reagent lot and one calibrator lot on one instrument. The study data shows that there is no carryover caused by one sample into another.

b. Reagent Carryover

To evaluate the accuracy bias from reagent carryover via the analyzer dispensers on the BCS XP System, the INNOVANCE VWF Ac carryover study was performed on one BCS XP System, with one respective reagent lot and one calibrator lot. To investigate INNOVANCE VWF Ac as acceptor assay, four different samples were determined to investigate the measuring interval adequately: A low sample (~10% of norm), a sample representing the medical decision level (~30% of norm). a normal plasma pool (~100% of norm) and a high pool (~170% of norm). When investigating the other assays (PT seconds with Dade Innovin, APTT with Dade Actin FSL, Antithrombin with INNOVANCE Antithrombin and D-dimer with INNOVANCE D-Dimer) as acceptor assays two different samples were determined- a normal sample and a pathologic sample. The reagent carryover study data shows that there is no cross-contamination caused by one application into another.

B. Clinical Studies:

1. Diagnostic Accuracy:
  Method Comparison with the BC von Willebrand Assay

Method comparison studies were performed at four clinical laboratory sites located in the U.S. to compare the performance of the INNOVANCE VWF Ac assay with the BC von Willebrand Reagent (K972116) on the BCS XP System (K013114). The studies were performed with fresh and frozen samples (17 fresh samples, 124 frozen samples, 3 diluted samples, total N=144). To support the intended use population, patient samples with various demographics (i.e., race, gender, and age), were included in the study. The patient cohort included patients previously diagnosed with von Willebrand disease (VWD) (VWD type 1. VWD type 2 (type 2A, 2B, 2M and 2N), VWD type 3, and patients with acquired VWD), patients with hemophilia A, patient with platelet dysfunction and patients without final VWD related diagnosis at the time of enrollment. All samples were collected in 3.2% sodium citrate anticoagulant and tested in singlet with both methods (subject and comparator). Patient sample demographics included 103 females and 41 males, ≥ 6 months of age. Based on the inclusion and exclusion criteria for the method comparison, 140 patient samples were included into the study. From these. 102 (14 fresh samples, 88 frozen samples) were inside the measuring interval of the BC von Willebrand Reagent and the subject device and thus included in the statistical evaluation. Linear regression analyses were performed for the dataset collected for each site.

Passing-Bablok regression analysis was performed for all sites combined (results summarized below).

| Site | N | Pearson
Correlation
Coefficient
(r) | Coefficient of
Determination
(r²) | Slope
(95%
confidence
interval (CI) | Intercept
(95% CI) |
|-------------------|-----|----------------------------------------------|-----------------------------------------|----------------------------------------------|--------------------------|
| Combined
Sites | 102 | 0.916 | 0.839 | 1.037
(0.959, 1.137) | 3.497
(-2.893, 8.257) |

A summary of device performance at different medical decision points throughout the reportable range for the combined dataset is shown below.

| Method
Comparison,
all sites
combined | n | Slope | Intercept
(% of
norm) | Predicted bias
at MDP1
(30% of norm) | Predicted bias
at MDP2
(50% of norm) | Pearson
correlation
coefficient
(r) |
|------------------------------------------------|-----|-------|-----------------------------|--------------------------------------------|--------------------------------------------|----------------------------------------------|
| | 102 | 1.04 | 3.50 | 4.60% of norm | 10.14%
(relative) | 0.916 |

The observed predicted bias at the medical decision points for all sites combined met the predefined acceptance criteria. The result demonstrates that INNOVANCE VWF Ac shows acceptable comparability to the BC von Willebrand Reagent on the BCS XP System.

Method Comparison with HemosIL von Willebrand Assay

An additional method comparison evaluation between the INNOVANCE VWF Ac on the BCS XP System versus HemosIL VWF (K200033) on the ACL TOP 500 CTS (K160276)

was conducted. Test results from the INNOVANCE VWF activity test performed at four different clinical sites were compared with the results from the HemosIL VWF test performed at one external site (Duke University Health Systems). A total of 144 samples (17 fresh samples, 124 frozen samples, 3 diluted samples, total N=144) were included in this study. The patient cohort included patients previously diagnosed with VWD (VWD type 1, VWD type 2 (type 2A, 2B, 2M and 2N), VWD type 3, and patients with acquired VWD), patients with hemophilia A, patient with platelet dysfunction and patients without final VWD related diagnosis at the time of enrollment. A total of 97 samples were inside the measuring interval of both devices (19-300% of norm) and thus included in the statistical evaluation. Linear regression analyses were performed for the dataset collected for each site.

Passing-Bablok regression analysis was performed for all sites combined (results summarized below).

| Site | N | Pearson
Correlation
Coefficient
(r) | Coefficient of
Determination
(r²) | Slope
(95% CI) | Intercept
(95% CI) |
|-------------------|----|----------------------------------------------|-----------------------------------------|-----------------------|-------------------------|
| Combined
Sites | 97 | 0.971 | 0.943 | 0.955
(0.89, 1.02) | -0.552
(-4.83, 3.84) |

A summary of device performance at different medical decision points throughout the reportable range for the combined dataset is shown below.

| Method
Comparison, all sites
combined | n | Slope | Intercept
(% of norm) | Predicted bias
at MDP1
(30% of norm) | Predicted bias
at MDP2
(50% of norm) | Pearson
correlation
coefficient
(r) |
|---------------------------------------------|----|-------|--------------------------|--------------------------------------------|--------------------------------------------|----------------------------------------------|
| | 97 | 0.96 | -0.55 | -1.90% of norm | -5.76%
(relative) | 0.971 |

The observed predicted bias at the medical decision points for all sites combined met the predefined acceptance criteria. The result demonstrates that INNOVANCE VWF Ac on the BCS XP System shows acceptable comparability to the HemosIL VWF on the ACL TOP 500 CTS.

Method Comparison Study (Patzke et al. (2014) data re-analysis)

The method comparison study INNOVANCE VWF Ac versus BC von Willebrand Reagent on the BCS XP System presented in Patzke et al. (2014) was performed at three clinical sites (Germany, Switzerland and USA). A total of 618 samples were included in the method comparison study, and n=580 samples (n=29 diluted samples, no spiked samples) were included in the statistical evaluation. The patient cohort included patients previously diagnosed with VWD (VWD type 1, VWD type 2 (type 2A, 2B, 2M and 2N), and patients with acquired VWD), patients before or after treatment with DDAVP (Desmopressin) and patients without final VWD related diagnosis at the time of enrollment. The statistical evaluation of the method comparison INNOVANCE VWF Ac versus BC von Willebrand Reagent on the BCS XP System (Passing-Bablok regression analysis) presented in Patzke et

al. (2014) included all samples with results found within the AMI for INNOVANCE VWF Ac (AMI outside the U.S. = 4 to 600% of norm) and within the AMI for BC von Willebrand Reagent (AMI outside the U.S. = 10 to 600% of norm). Linear regression analyses were performed for the dataset collected for each site.

Passing-Bablok regression of Method Comparison INNOVANCE VWF Ac versus BC von Willebrand Reagent on the BCS XP for samples with INNOVANCE VWF Ac results from 20 to 150% of norm.

| Site | N | Pearson
Correlation
Coefficient
(r) | Coefficient of
Determination
(r²) | Slope
(95% CI) | Intercept
(95% CI) |
|-------------------|-----|----------------------------------------------|-----------------------------------------|-------------------------|-------------------------|
| Combined
Sites | 417 | 0.972 | 0.944 | 0.954
(0.936, 0.974) | 2.505
(1.147, 3.558) |

A summary of device performance at different medical decision points throughout the reportable range for the combined dataset is shown below.

| Method
Comparison,
all sites
combined | n | Slope | Intercept
(% of
norm) | Predicted bias
at MDP1
(30% of norm) | Predicted bias
at MDP2
(50% of norm) | Pearson
correlation
coefficient
(r) |
|------------------------------------------------|-----|-------|-----------------------------|--------------------------------------------|--------------------------------------------|----------------------------------------------|
| | 417 | 0.97 | 2.51 | 1.14% of norm | 0.45%
(relative) | 0.972 |

Passing-Bablok regression of Method Comparison INNOVANCE VWF Ac versus BC von Willebrand Reagent on the BCS XP for samples with INNOVANCE VWF Ac results from 4 to 300% of norm.

| Site | N | Pearson
Correlation
Coefficient
(r) | Coefficient of
Determination
(r²) | Slope
(95% CI) | Intercept
(95% CI) |
|-------------------|-----|----------------------------------------------|-----------------------------------------|-------------------------|-------------------------|
| Combined
Sites | 556 | 0.985 | 0.970 | 0.955
(0.940, 0.971) | 1.110
(0.349, 2.018) |

A summary of device performance at different medical decision point throughout the reportable range for the combined dataset is shown below.

| Method
Comparison,
all sites
combined | n | Slope | Intercept
(% of
norm) | Predicted bias
at MDP1
(30% of norm) | Predicted bias
at MDP2
(50% of norm) | Pearson
correlation
coefficient
(r) |
|------------------------------------------------|------|-------|-----------------------------|--------------------------------------------|--------------------------------------------|----------------------------------------------|
| 556 | 0.96 | 1.11 | -0.23% of norm | -2.26%
(relative) | 0.985 | |

The results demonstrate that the additional evaluations of the method comparison INNOVANCE VWF Ac versus BC von Willebrand Reagent on the BCX XP System (for the

ranges from 20 to 150% of norm and 4 to 300% of norm) confirm the acceptable comparability between the devices shown in the publication of Patzke et al. (2014) for the entire U.S. AMI (4 to 300% of norm).

2. Diagnostic Concordance:

The diagnostic concordance study was conducted to compare the use of the subject device instead of using the study site specific standard of care (SOC) VWF-activity assay within the initial evaluation of VWF disorders. A total of 138 patients were included in the diagnostic concordance study of which 108 patients were tested by Beckman Coulter von Willebrand Reagent as the SOC VWF activity assay at three sites, and 30 patients were tested by HemosIL VWF Activity Reagent as its SOC VWF activity assay at one site. This initial evaluation is most commonly accomplished using the following assays (NIH Publication No 08-5832): VWF antigen (VWF:Ag), VWF activity and coagulation factor VIII (FVIII) activity (called 'initial VWD testing panel'). The overall percent agreement, the positive percent agreement (PPA: any type of VWD) and the negative percent agreement (NPA: VWD excluded) with 95% Confidence Limits were calculated.

Agreement Measures	Agreement (%)	Lower Limit of 95% Score Confidence Interval	Upper Limit of 95% Score Confidence Interval
Positive Percent Agreement
'any type'	74.29	57.93	85.84
Positive Percent Agreement
'low' VWF	52.63	31.71	72.67
Negative Percent Agreement
'VWD excluded'	95.77	88.30	98.55
Overall Percent Agreement	83.33	76.23	88.63

Diagnostic Concordance: Percent Agreements and 95% Confidence Limits.

An overall percentage agreement of more than 80% between the INNOVANCE VWF Ac and the SOC activity assays was found. This result demonstrates that for the majority of patients (> 80%), use of the subject device instead of currently available assays to measure VWF activity will not alter diagnosis.

3. Real-world evidence

A comprehensive review of published scientific literature describing studies evaluating the subject device is presented in this De Novo classification request to provide real-world evidence (RWE) from literature. The original publications (no reviews) include method comparison data between INNOVANCE VWF Ac and other VWF activity assays performed by independent research or clinical organizations. The real-world evidence further demonstrates the safety and effectiveness of the new device INNOVANCE VWF Ac.

VII Proposed Labeling:

The labeling supports the decision to grant the De Novo request for this device.

Identified Risks to Health	Mitigation Measures
Falsely elevated von Willebrand factor (VWF)
activity results may lead to delayed diagnosis
and delayed patient management of von
Willebrand disease (VWD). Patients with
delayed diagnosis and resulting delayed patient
management of VWD are at increased risk of
bleeding due to the withholding of appropriate
treatment.	Certain design verification and validation
identified in special control (1), including
documentation of certain analytical studies
and clinical studies.
Certain labeling information identified in
special control (2), including limitations and
performance information identified in special
control (1).
Falsely depressed von Willebrand factor
(VWF) activity results may lead the physician
to suspect von Willebrand disease (VWD) in
patients who do not have the disease. As a
result, the patients may receive unnecessary
follow-up testing and unnecessary treatment as
well as delays in receiving a correct diagnosis
and appropriate patient management. In
addition, affected patients may experience
mental anxiety because of the erroneous
diagnosis.	Certain design verification and validation
identified in special control (1), including
documentation of certain analytical studies
and clinical studies.
Certain labeling information identified in
special control (2), including limitations and
performance information identified in special
control (1).
No results may lead to delayed patient
management.	Certain design verification and validation
identified in special control (1), including
documentation of certain analytical studies
and clinical studies.
Certain labeling information identified in
special control (2), including limitations and
performance information identified in special
control (1).

VIII Identified Risks and Mitigations:

IX Benefit/Risk Assessment:

A Summary of the Assessment of Benefit:

The INNOVANCE® VWF Ac assay is intended for the quantitative determination of the von Willebrand factor-GPIb-binding activity in patients with suspected or confirmed von Willebrand factor disorders. It is an automated, particle enhanced turbidimetric assay that measures the binding between VWF and gain-of-function mutants of platelet receptor GPIb. The reagents do

not contain ristocetin and platelets, which may affect assay performance due to sourcing variability.

The performance characteristics of the assay are evaluated in analytical studies. In single site internal precision study, the total within-site CVs range from 1.54 to 7.24%. In external multicenter reproducibility study, the total CVs for combined sites range from 2.83 to 6.29%. The CVs for both precision and reproducibility studies meet the predefined acceptance criteria. Although samples around medical decision levels and within normal range are contrived, the sponsor has provided line data and results demonstrating comparability between contrived samples (spiked plasma pool) and native patient samples.

The performance characteristics of the assay are also evaluated in clinical validation studies. In the comparison study between INNOVANCE® VWF Ac assay and BC von Willebrand Reagent, Passing-Bablok evaluation of pooled data (all site combined) show that slope, intercept, predicted bias at medical decision points and Pearson correlation coefficient meet the predefined acceptance criteria. However, samples at individual sites do not adequately cover the AMI. To address the Agency's concern and provide additional comparison data, the sponsor reanalyzed the line data from a published study that compared INNOVANCE® VWF Ac assay to BC von Willebrand Reagent with an additional 580 samples. Passing-Bablok analysis of the additional data shows acceptable performance.

The diagnostic concordance between the INNOVANCE® VWF Ac assay and site-specific standard of care assay is evaluated and shows an overall percent agreement of 83.3% and a negative percent agreement of 95.8%. For low VWF, the positive percent agreement (PPA) is 52.6%. The sponsor has provided benefit risk analysis and clinical justifications for the acceptability of the PPA at low VWF.

Data from above studies show favorable analytical and clinical performance for the proposed indications for use.

B Summary of the Assessment of Risk:

Falsely elevated VWF activity results may lead to delayed diagnosis and treatment of von Willebrand disease (VWD). The patients are at increased risk for bleeding because of the potential delayed appropriate treatment. Falselv depressed VWF activity results may lead the physician to suspect VWD in patients who do not have the disease. As a result, the patients may receive unnecessary follow-up testing and possibly unnecessary treatment as well as delays in receiving a correct diagnosis and appropriate patient management. In addition, the patients may experience unnecessary anxiety because of the erroneous diagnosis. Failed results may cause delayed diagnosis of VWD. Further, no results may lead to delayed patient management.

C Patient Perspectives:

This submission did not include specific information on patient perspectives for this device.

D Summary of the Assessment of Benefit-Risk:

The proposed special controls include requiring device labeling include a statement that results should be used in conjunction with the patient's medical history, clinical presentation, and other laboratory findings. Device labeling addresses the risk of interference (including endogenous and exogeneous substances, HAMA and RF) and includes information on the possibility of failed results possibly caused by interference. Device labeling also contains information on expected values (results of reference interval studies) and characteristics of analytical and clinical performance. Given the performance characteristics, applicable general controls and proposed special controls, including labeling mitigations, the probable benefits outweigh the probable risks of this device.

X Conclusion:

The De Novo request is granted and the device is classified under the following and subject to the special controls identified in the letter granting the De Novo request:

Product Code(s): QTY Device Type: Von Willebrand factor assay Class: II Regulation: 21 CFR 864.7293