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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.

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).

The INNOVANCE VWF Ac assay is a device for the quantitative determination of von Willebrand factor-GPIb-binding activity. The device is intended to aid in the evaluation of patients with suspected or confirmed von Willebrand factor disorders.

Here's an analysis of its acceptance criteria and supporting studies:

1. Acceptance Criteria and Reported Device Performance

• Study 2 (Multi-site reproducibility): Total CVs ranged from 3.48% to 6.29%. All values for multi-site reproducibility were within acceptable limits.
• Study 3 (Instrument/operator variability): Total CVs ranged from 2.86% to 6.01%. All values were within acceptable limits. |
  | Linearity | - Assay should demonstrate linearity across the claimed reportable range (4 to 300% of norm). | - Linearity studies (using spiked and native samples) demonstrated linearity from 4 to 300% of norm on the BCS XP System. |
  | Analytical Specificity/Interference | - No clinically significant interference from specified endogenous or exogenous substances at tested concentrations. | - Endogenous Interference: No clinically significant interference from Hemoglobin (up to 1000 mg/dL), Bilirubin (unconjugated) (up to 60 mg/dL), Bilirubin (conjugated) (up to 40 mg/dL), Triglycerides (up to 726 mg/dL), and Rheumatoid Factors (up to 438 IU/mL).
• Exogenous Interference: No clinically significant interference from a panel of 30 common drugs tested at specific concentrations.
• Heterophilic blocking reagent included to minimize interference from heterophile antibodies. |
  | High Dose Hook | - No high dose hook effect observed up to a specified VWF activity level. | - No high dose hook effect observed up to a VWF activity of 656% of norm. |
  | Traceability | - INNOVANCE VWF Ac results should be traceable to the WHO 6th International Standard (IS) Factor VIII / Von Willebrand Factor. | - INNOVANCE VWF Ac results are traceable to the WHO 6th International Standard (IS) Factor VIII / Von Willebrand Factor (NIBSC code 07/316), with an observed bias of +2.3% (relative). |
  | Stability (Shelf-life, In-use, Reconstituted, Sample, Transportation, Freeze/Thaw) | - Reagent and calibrator shelf-life stability.
• On-board stability.
• Once opened stability.
• Reconstituted stability (calibrator).
• Ambient temperature operating range.
• Transportation stability.
• Freeze/thaw tolerance for reagent and calibrator.
• Sample stability under various storage conditions.
• Equivalence between fresh and frozen samples. | - Reagent Shelf-Life: 12 months at 2-8°C.
• Calibrator Shelf-Life: 12 months at 2-8°C.
• On-Board Stability (Reagent): 36 hours at 18-32°C. Accumulated on-board stability: 24 hours for Reagents I & II, 36 hours for Reagent III.
• On-Board Stability (Calibrator): 6 hours at 18-32°C (not recommended in labeling due to immediate use intent).
• Once Opened Stability (Reagent): 37 days for Reagents I & II, 113 days for Reagent III when stored at 2-8°C.
• Reconstituted Stability (Calibrator): 4 hours at 15-25°C; 4 weeks at -20°C; 2 hours at 15-25°C after freeze/thaw.
• Ambient Temperature: Correctness assured within 18-32°C operating range.
• Transportation Stability: All tested conditions met acceptance criteria.
• Freeze/Thaw Tolerance: Stable for one freeze/thaw cycle for both reagent and calibrator.
• Sample Stability: 3 months at ≤ -20℃; 12 months at 300.0% of norm (not for establishing reference interval). |
  | Carry-Over (Sample & Reagent) | - No significant carryover from one sample to the next or from one reagent application to another. | - Sample Carryover: No carryover observed.
• Reagent Carryover: No cross-contamination observed. |
  | Diagnostic Accuracy (Method Comparison) | - Acceptable comparability to predicate devices (BC von Willebrand Reagent, HemosIL VWF).
• Passing-Bablok analysis results (slope, intercept, predicted bias, Pearson correlation coefficient) should meet predefined acceptance criteria. | - Vs. BC von Willebrand Reagent (current study): Combined sites (N=102) showed Pearson r = 0.916, Slope = 1.037, Intercept = 3.497. Predicted bias at MDP1 (30% norm) = 4.60% norm; at MDP2 (50% norm) = 10.14% (relative). All met acceptance criteria.
• Vs. HemosIL VWF: Combined sites (N=97) showed Pearson r = 0.971, Slope = 0.955, Intercept = -0.552. Predicted bias at MDP1 (30% norm) = -1.90% norm; at MDP2 (50% norm) = -5.76% (relative). All met acceptance criteria.
• Vs. BC von Willebrand Reagent (Patzke et al., 2014 re-analysis): Combined sites (N=556, 4-300% of norm) showed Pearson r = 0.985, Slope = 0.955, Intercept = 1.110. Predicted bias at MDP1 (30% norm) = -0.23% norm; at MDP2 (50% norm) = -2.26% (relative). All met acceptance criteria and confirmed acceptable comparability. |
  | Diagnostic Concordance | - Overall percent agreement, positive percent agreement (any type of VWD), and negative percent agreement (VWD excluded) should demonstrate acceptable concordance with existing standard of care (SOC) VWF-activity assays. | - Overall Percent Agreement: 83.33% (95% CI: 76.23 - 88.63).
• Positive Percent Agreement ('any type' VWD): 74.29% (95% CI: 57.93 - 85.84).
• Negative Percent Agreement ('VWD excluded'): 95.77% (95% CI: 88.30 - 98.55).
• "Overall percentage agreement of more than 80%… 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." The PPA at low VWF (52.63%) was accepted with clinical justifications. |

2. Sample sizes used for the test set and data provenance:

• Precision (Single Site):

  • Study 1 (reagent variability): 5 plasma pools + 2 control materials = 7 samples. Each tested 240 times (20 days x 2 runs x 2 replicates x 3 reagent lots or 3 calibrator lots for a total of 240 determinations, 80 per lot).
  • Study 2 (reproducibility multi-site): 5 plasma pools + 2 control materials = 7 samples. Each tested 90 times (3 external sites x 5 days x 2 runs x 3 replicates for a total of 90 determinations, 30 per site).
  • Study 3 (instrument/operator variability): 5 plasma pools + 2 control materials = 7 samples. Each tested 120 times (5 days x 2 runs x 4 replicates x 3 systems for a total of 120 determinations, 40 per system).
  • Provenance: Single site precision studies were conducted in Germany. Multi-site reproducibility and instrument/operator variability studies were conducted across three external sites (locations not specified for multi-site reproducibility study, but internal site for instrument/operator variability implies one location).

• Linearity (Test Sets):

  • Spiked Sample Linearity: 10 different concentrations of spiked samples.
  • Native Sample Linearity: 12 different concentrations of native samples.
  • Provenance: High pool for spiked samples prepared by spiking normal plasma with VWF concentrate. Low pool with VWF deficient plasma (internally produced). Native samples from contract blood plasma provider. Locations not specified but implied to be part of the testing facilities.

• Analytical Specificity/Interference (Test Sets):

  • Endogenous Interference: 4 VWF activity levels (low, 2 medical decision levels, high) tested with 5 test samples each. 80 measurements overall (4 VWF levels x 5 test samples x 4 replicates). Each sample prepared with native plasma and dilution/spiking.
  • Exogenous Interference: 4 VWF activity levels for each of the 30 interferent drugs. 32 measurements per interferent (4 VWF levels x 4 aliquots x 2 conditions - spiked/control).
  • Provenance: Samples prepared with native plasma and VWF deficient plasma or VWF concentrate.

• High Dose Hook (Test Set): 10 different dilution samples from a high VWF Ac activity plasma pool. Measured in 6 replicates.

  • Provenance: High pool prepared by spiking normal plasma with VWF concentrate, diluted with VWF deficient plasma.

• Traceability (Test Set): Three vials of WHO 6th International Standard for Factor VIII / von Willebrand Factor. Measured in single determination.

• Stability (Test Sets):

  • Reagent/Calibrator Shelf-Life: 5 plasma pools + 3 control materials. Measured 6-12 replicates at each of 6 time points over 15 months.
  • On-Board Stability: 5 plasma pools + 3 control materials. Measured 6 replicates at each of 5 time points.
  • Once Opened Stability: 5 plasma pools + 3 control materials. Measured 6-12 replicates at multiple time points (2,4,6 weeks for reagent I/II; 6,12,18 weeks for reagent III).
  • Reconstituted Stability (Calibrator): Aliquots of Standard Human Plasma (SHP) measured 6-12 replicates at various time points and conditions.
  • Ambient Temperature: 8 test samples. Each tested in 8 replicates on 3 days.
  • Transportation Study: 5 plasma pools + 3 control materials. Tested 3-6 replicates at various temperature stress conditions.
  • Freeze/Thaw Tolerance: 5 plasma pools + 3 control materials. Tested 3 replicates under stressed and unstressed conditions.
  • Sample Stability: At least 20 samples. Tested in quadruplicate over various time points and storage conditions.
  • Frozen vs. Fresh Samples: 60 fresh samples. Measured one replicate fresh, then one replicate after frozen storage.
  • Provenance: Plasma pools, control materials, patient samples. Specific origins (e.g., country) not detailed for all stability studies, but likely conducted at manufacturer's internal labs or controlled external sites.

• Detection Limit (Test Sets):

  • LoB: 5 analyte-free samples. n=60 determinations per reagent lot per instrument.
  • LoD: 5 low-analyte samples. n=50 determinations per sample.
  • LoQ: 5 low-analyte samples. n=60 determinations per reagent lot per instrument.
  • Provenance: Samples prepared with VWF deficient plasmas and dilutions of normal plasma pools.

• Normal Range / Reference Interval (Test Set):

  • Adults: 302 apparently healthy individuals (150 blood group O, 152 blood group non-O) ≥ 18 years of age.
  • Pediatrics: 85 apparently healthy pediatric individuals (44 blood group O, 41 blood group non-O) > 4 weeks to

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