(445 days)
In-vitro diagnostic automated assay for the quantitative determination of the von Willebrand antigen (VWF:Ag) in human plasma collected from venous blood samples in 3.2% sodium citrated tubes on the SYSMEX® CS-2500 analyzer.
As an aid used in the evaluation of patients aged 4 weeks and older with suspected or confirmed von Willebrand factor disorders and intended for prescription use.
Results of this test should always be interpreted in conjunction with the patient's medical history, clinical presentation and other laboratory findings.
The vWF Ag is an immunoturbidimetric assay for the quantitative, WHO-standardized determination of von Willebrand factor (VWF) antigen concentration.
The vWF Aq kit consist of a Latex Reagent (4 x 2 mL) which is a suspension of small polystyrene particles (latex) coated with rabbit anti-human VWF antibodies. The Reagent Diluent (4 x 4 mL) is provided within the kit which is a solution containing glycine. The Reagent Diluent is intended for dilution of the Latex Reagent. The vWF Ag kit is completed by the Buffer (4 x 5 mL) which is a glycine buffer. All components contain sodium azide (< 1 g/L) as preservative.
The small polystyrene particles to which rabbit anti-human VWF antibodies have been attached by covalent bonding are aggregated when mixing with samples containing von Willebrand antigen. This aggregation is then detected turbidimetrically via the increase in turbidity, which is proportional to the antigen level present in the test sample.
Here's an analysis of the acceptance criteria and study details for the vWF Ag device, based on the provided text:
Acceptance Criteria and Device Performance
The document doesn't explicitly state "acceptance criteria" as a single, consolidated table with pass/fail values. Instead, it details performance characteristics established through various studies. I will present the reported device performance for several key metrics:
| Metric | Acceptance Criteria (Implied by Study Design) | Reported Device Performance (vWF Ag on SYSMEX® CS-2500) |
|---|---|---|
| Measuring Interval (LoQ) | Accurate measurement at lower limit | LoQ established as 3.12% of norm; lower limit of 4% of norm is accurately measured. |
| Measuring Interval (Linearity) | Predefined maximum deviation: ≤ 20% absolute (for measured range ≤ 20% of norm), ±10.0% relative (for measured range > 20% of norm) | Linear across 3.6 to 399.7% of norm; met predefined maximum deviation criteria. |
| Endogenous Interferents | No interference up to indicated concentrations | No interference observed up to: Hemoglobin 712 mg/dL, Bilirubin (unconjugated) 30 mg/dL, Bilirubin (conjugated) 100 mg/dL, Lipids 549 mg/dL, Rheumatoid Factors 23 IU/mL |
| Exogenous Interferents | No interference up to indicated concentrations (various drugs) | No interference observed up to indicated concentrations for 23 listed drugs (e.g., Acetaminophen 156 µg/mL, Emicizumab 300 µg/mL) - See full list in original text |
| Heterophilic Antibodies | No susceptibility | No susceptibility observed towards human anti-mouse antibodies (HAMAs) or lupus anticoagulant. |
| High Dose Hook Effect | No high dose hook effect | No high dose hook effect up to 1213% of norm VWF:Ag. |
| Sample Carryover | No cross-contamination | No cross-contamination caused by one sample into another. |
| Reagent Carryover | No cross-contamination | No cross-contamination caused by one application into another. |
| Reproducibility (Total CV) | Not explicitly stated as a single value, but evaluated against established clinical laboratory standards (CLSI EP05-A3) | 2.03 – 5.96% (Multicenter, USA) |
| Method Comparison (Passing-Bablok Regression) | Proposed and predicate devices provide equivalent results. | Sites Combined: y=1.04x - 4.60% of norm, r=0.982 (r²=0.965) - Meets equivalence criteria against predicate. |
Study Details
2. Sample Sizes and Data Provenance
- Measuring Interval (LoQ): Five independent low-analyte plasma pools.
- Measuring Interval (Linearity): Not explicitly stated, but "a dilution series was prepared using a high plasma sample pool and a low plasma sample pool to equal 12 different dilutions."
- Specificity (Interference): "Individual native samples with and without interferent" for paired-difference experiments. "Single native plasmas" for Rheumatoid factors. The number of samples per interferent testing is not specified.
- Reference Interval:
- Blood group O: n = 147
- Blood group non-O: n = 159
- Blood group independent: n = 306
- Data Provenance: Three clinical study sites in the United States. The study involved apparently healthy subjects.
- Pediatric Population Measurements:
- Blood group O: n = 21
- Blood group non-O: n = 26
- Total pediatric (independent of ABO blood group): n = 47
- Data Provenance: "healthy pediatric subjects".
- Precision/Reproducibility:
- External Reproducibility (Multicenter): Three (3) external sites in the USA (Sites 1, 2, and 3). Test samples included three plasma pools and three control materials. Each site used 5 days, 2 runs/day, 3 replicates/run (3x5x2x3).
- Internal Precision (Single Site, Germany - Reagent Variability): One (1) site in Germany. 20 days, 2 runs/day, 2 replicates/run (20x2x2) with 3 different reagent lots.
- Internal Precision (Single Site, Germany - Calibrator Variability): One (1) site in Germany. 20 days, 2 runs/day, 2 replicates/run (20x2x2) with 3 different calibrator lots.
- Internal Precision (Single Site, Germany - Instrument Variability): One (1) site in Germany. 5 days, 2 runs/day, 4 replicates/run (5x2x4) on 3 SYSMEX® CS-2500 analyzers.
- Data Provenance: Mixed (USA and Germany), all prospective measurements for the study.
- Method Comparison:
- Site 1 (Germany): N = 107
- Site 2 (United States): N = 115
- Site 3 (United States): N = 117
- Overall (Combined Sites): N = 339
- Data Provenance: One external site in Germany (Site 1) and two external sites in the United States (Site 2 and Site 3). The samples tested "ensured the intended use population was tested". This implies a mix of patient samples. Retrospective or prospective nature is not explicitly stated but generally for method comparison, collected clinical samples are used.
3. Number of Experts and Qualifications (for Ground Truth)
The document describes in-vitro diagnostic assay performance, which typically relies on laboratory measurements rather than expert human interpretation of images or clinical findings where "ground truth" and "experts" as in radiology studies would be directly relevant.
- For the "Reference Interval" and "Pediatric Population" studies: These likely involved general medical professionals or phlebotomists for sample collection, and laboratory technicians for running the assays. The "ground truth" here is the biological sample itself and the reference standard used (WHO standard for calibration traceability). No "experts" in the sense of adjudicating findings (e.g., radiologists) were explicitly mentioned.
4. Adjudication Method (for Test Set)
Not applicable. This is an in-vitro diagnostic assay, not a device requiring human interpretation of results requiring adjudication for a test set. The performance is assessed based on quantitative measurements against predefined analytical performance metrics and comparison to a predicate device.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No. This is an in-vitro diagnostic device (an assay), not an imaging or diagnostic AI system that aids human readers. The document details a method comparison study between the proposed device and a predicate device, which is a different type of comparative effectiveness.
6. Standalone Performance (i.e., algorithm only without human-in-the-loop performance)
Yes, the studies reported are for the standalone performance of the vWF Ag assay on the SYSMEX® CS-2500 analyzer. This is an automated assay, meaning it operates without human-in-the-loop performance for result generation. Interpretations of historical context or other lab findings are mentioned as necessary in conjunction with the test results, but the test itself is standalone.
7. Type of Ground Truth Used
- Measuring Interval, Specificity, Precision/Reproducibility: The "ground truth" for these analytical performance studies is based on:
- Known concentrations in prepared samples (e.g., dilutions from plasma pools, spiked samples with interferents).
- Reference materials (e.g., control materials, calibrators).
- WHO Standard (reagents traceable to WHO 6th International Standard Factor VIII / Von Willebrand Factor (07/316)).
- Reference Interval & Pediatric Population: The "ground truth" is derived from empirically measuring VWF:Ag levels in a defined population of "apparently healthy subjects" using the device itself.
- Method Comparison: The "ground truth" for comparison is the performance of the legally marketed predicate device (STA® - Liatest® VWF:Ag on the STA R Max® analyzer).
8. Sample Size for the Training Set
Not applicable. This document describes the performance of a VWF Ag assay, which is an immunoturbidimetric test, not an AI/ML algorithm that requires a training set in the conventional sense. The "training" for such a system would involve optimizing the assay's chemical reagents and instrument parameters, which is part of the development process but not disclosed as a distinct "training set" of data.
9. How the Ground Truth for the Training Set Was Established
Not applicable, as there's no explicitly defined "training set" for an AI/ML algorithm. The assay's analytical performance and calibration are established using reference materials and pooled samples with known or established values, as described in point 7.
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Image /page/0/Picture/0 description: The image contains the logo of the U.S. Food and Drug Administration (FDA). On the left is the Department of Health & Human Services logo. To the right of that is the FDA logo, which consists of the letters "FDA" in a blue square, followed by the words "U.S. FOOD & DRUG" in a larger, bold blue font. Below that is the word "ADMINISTRATION" in a smaller, bold blue font.
June 2, 2023
Siemens Healthcare Diagnostics Products GmbH % Petra Dissmann Regulatory Affairs Manager Emil-von-Behring Strasse 76 Marburg, Hesse 35041 Germany
Re: K220728
Trade/Device Name: vWF Ag Regulation Number: 21 CFR 864.7290 Regulation Name: Factor Deficiency Test Regulatory Class: Class II Product Code: GGP Dated: February 10, 2023 Received: February 10, 2023
Dear Petra Dissmann:
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
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Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely.
Min Wu -S
Min Wu, Ph.D. Branch Chief Division of Immunology and Hematology Devices OHT7: Office of In Vitro Diagnostics Office of Product Evaluation and Quality Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known) K220728
Device Name vWF Ag
Indications for Use (Describe)
In-vitro diagnostic automated assay for the quantitative determination of the von Willebrand antigen (VWF:Ag) in human plasma collected from venous blood samples in 3.2% sodium citrated tubes on the SYSMEX® CS-2500 analyzer.
As an aid used in the evaluation of patients aged 4 weeks and older with suspected or confirmed von Willebrand factor disorders and intended for prescription use.
Results of this test should always be interpreted in conjunction with the patient's medical history, clinical presentation and other laboratory findings.
| Type of Use (Select one or both, as applicable) | |
|---|---|
| ------------------------------------------------- | -- |
X Prescription Use (Part 21 CFR 801 Subpart D)
| Over-The-Counter Use (21 CFR 801 Subpart C)
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Image /page/3/Picture/0 description: The image contains the logos for Siemens and Healthineers. The word "SIEMENS" is in teal, and the word "Healthineers" is in orange. To the right of the word "Healthineers" is a graphic of orange dots arranged in a circular pattern.
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. Applicant
| Siemens Healthcare Diagnostics Products GmbH | |
|---|---|
| Emil-von-Behring-Str. 76 | |
| 35041 Marburg, Germany | |
| Contact Person: | Dr. Petra M. Dissmann |
| Email: | petra.dissmann@siemens-healthineers.com |
| Phone: | + 49 172 369 245 9 |
| Date Prepared: | June 02, 2023 |
2. Device
| Name of Device: | vWF Ag |
|---|---|
| Regulation Number: | 21 CFR 864.7290 |
| Regulation Description: | Factor deficiency test |
| Product Code: | GGP |
| Device Classification Name: | Test, Qualitative And Quantitative Factor Deficiency |
| Regulatory Class: | Class II |
| 510(k) Review Panel | Hematology (81) |
3. Predicate Device
| Name of Device: | STA® - Liatest® VWF:Ag (K962675) |
|---|---|
| Regulation Number: | 21 CFR 864.7290 |
| Regulation Description: | Factor deficiency test |
| Product Code: | GJT |
| Device Classification Name: | Plasma, Coagulation Factor Deficient |
| Regulatory Class: | Class II |
| 510(k) Review Panel | Hematology (81) |
One recall associated with the predicate were found on the FDA Medical Device Recalls database. However, this recall from 2013 was specific to the software design of the affected product (analyzer) and customers were informed by the manufacturer Diagnostica Stago Inc. (original applicant was American Bioproducts Company) how to deal with the problem. The recall topic has no bearing on the studies and content of this premarket notification. No reference devices were used in this submission.
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4. Device Description / Test Principle
The vWF Ag is an immunoturbidimetric assay for the quantitative, WHO-standardized determination of von Willebrand factor (VWF) antigen concentration.
The vWF Aq kit consist of a Latex Reagent (4 x 2 mL) which is a suspension of small polystyrene particles (latex) coated with rabbit anti-human VWF antibodies. The Reagent Diluent (4 x 4 mL) is provided within the kit which is a solution containing glycine. The Reagent Diluent is intended for dilution of the Latex Reagent. The vWF Ag kit is completed by the Buffer (4 x 5 mL) which is a glycine buffer. All components contain sodium azide (< 1 g/L) as preservative.
The small polystyrene particles to which rabbit anti-human VWF antibodies have been attached by covalent bonding are aggregated when mixing with samples containing von Willebrand antigen. This aggregation is then detected turbidimetrically via the increase in turbidity, which is proportional to the antigen level present in the test sample.
5. Intended Use / Indications for Use
In-vitro diagnostic automated assay for the quantitative determination of the von Willebrand antigen (VWF:Ag) in human plasma collected from venous blood samples in 3.2% sodium citrated tubes on the SYSMEX® CS-2500 analyzer.
As an aid used in the evaluation of patients aged 4 weeks and older with suspected or confirmed yon Willebrand factor disorders and intended for prescription use.
Results of this test should always be interpreted in conjunction with the patient's medical history, clinical presentation and other laboratory findings.
| Similarities between vWF Ag and STA®-Liatest® VWF:Ag | ||
|---|---|---|
| Item | Proposed Device vWF Ag | Predicate Device (K962675) STA®-Liatest® VWF:Ag |
| Regulation Number | 21 CFR 864.7290 | Same |
| Regulation Description | Factor deficiency test | Same |
| Intended Use | In-vitro diagnostic automated assay for the quantitative determination of the von Willebrand antigen (VWF:Ag) in human plasma collected from venous blood samples in 3.2% sodium citrated tubes on the SYSMEX® CS-2500 analyzer. | The STA® - Liatest® VWF:Ag kit is intended for use with STA-R® and STA Compact®, for the quantitative determination of von Willebrand factor antigen (VWF:Ag) in plasma by the immuno-turbidimetric method. |
| Similarities between vWF Ag and STA®-Liatest® VWF:Ag | ||
| Item | Proposed DevicevWF Ag | Predicate Device (K962675)STA®-Liatest® VWF:Ag |
| Indications forUse | As an aid used in the evaluation ofpatients aged 4 weeks and older withsuspected or confirmed von Willebrandfactor disorders and intended forprescription use.Results of this test should always beinterpreted in conjunction with thepatient's medical history, clinicalpresentation and other laboratoryfindings. | Information not given in instructions foruse |
| VWF analyte | VWF:Ag | Same |
| Unit | % of norm(100% of norm equals 1.00 IU) | %(100% equals 1.00 IU) |
| Test Principleanalyzermeasuringprinciple(wavelength) | Immuno-turbidimetry(660 nm) | Immuno-turbidimetry(540 nm) |
| Test Principle(biochemicalprinciple ofreagent) | Small polystyrene particles to whichspecific antibodies have been attachedby covalent bonding are aggregatedwhen mixing with samples containingvon Willebrand antigen. This aggregationis then detected turbidimetrically via theincrease in turbidity, which isproportional to the antigen level presentin the test sample. | This assay is based on the change inturbidity of a microparticle suspensionthat is measured by photometry. Asuspension of latex microparticles,coated by covalent bonding withantibodies specific for VWF, is mixedwith the test plasma whose VWFantigen level is to be assayed. Anantigen-antibody reaction takes place,leading to an agglutination of the latexmicroparticles which induces anincrease in turbidity of the reactionmedium. This increase in turbidity isreflected by an increase in absorbance,the latter being measuredphotometrically. The increase inabsorbance is a function of the VWFlevel present in the test sample. |
| Form | Liquid Suspension | Same |
| Similarities between vWF Ag and STA®-Liatest® VWF:Ag | ||
| Item | Proposed DevicevWF Ag | Predicate Device (K962675)STA®-Liatest® VWF:Ag |
| Sample Type | Citrated human plasma from venousbloodCitrated platelet poor human plasmaTo obtain plasma, carefully mix 9parts venous blood with 1 part sodiumcitrate solution (0.11 mol/L, 3.2%),avoiding the formation of foam. Anevacuated tube system or syringemay be used. Centrifuge the blood specimen toachieve platelet poor plasma tube assoon as possible for no less than 15minutes at ≥ 1500 x g. Plasma can be stored on the cells or itcan be removed from the cellularcomponent and stored in unopenedtube at room temperature. Pleaserefer to CLSI guideline H21-A5 forfurther details. The manufacturer'sinstructions for the samplingequipment must also be followed. | SameBlood (9 vol.) is collected in 0.109 M(i.e., 3.2%) trisodium citrateanticoagulant (1 vol.) (in the USAfollow CLSI guideline documentsH3-A6 and H21-A5). Centrifugation: 15 minutes at2000 - 2500 g |
| Reagents | vWF Ag Buffer:Glycine buffer Sodium azide (< 1 g/L) | Reagent 1:Glycine buffer Sodium azide (< 1 g/L) |
| vWF Ag Latex Reagent:Suspension of small polystyreneparticles coated with rabbit anti-human VWF antibodies. Sodium azide (< 1 g/L) | Reagent 2:Suspension of microlatexparticles coated with rabbitantihuman VWF antibodies Sodium azide (< 1 g/L) | |
| vWF Ag Diluent for Latex Reagent:Solution containing glycineintended for dilution of the LatexReagent Sodium azide (< 1 g/L) | Reagent 3:Solution containing glycine fordilution of Latex reagent(Reagent 2) Sodium azide (< 1 g/L) | |
| Buffer | Dade® Owren's Veronal Buffer | STA® - Owren-Koller |
| Storage | Until expiration date (indicated on eachvial and the box label) when stored at2 - 8°C | Until expiration date indicated on thebox label, when stored at2 - 8°C |
| Stability / ShelfLife | 18 months | 18 months |
| Differences between vWF Ag and STA®-Liatest® VWF:Ag | ||
| Item | Proposed DevicevWF Ag | Predicate Device (K962675)STA®-Liatest® VWF:Ag |
| ClassificationProduct Code | GGP | GJT |
| Device | Test, Qualitative and QuantitativeFactor Deficiency | Plasma, Coagulation Factor Deficient |
| Measuring Interval | 4 – 300% of norm | 3 - 420% |
| Instructions for use information:- Performance Characteristics:The detection threshold of STA®- Liatest® VWF:Ag on the STA®is 3% VWF:Ag. The STA® -Liatest® VWF:Ag procedure onthe STA® is linear up to 105%.- Procedure, Assay: If any of thepatient results falls outside theworking range of the assay, theinstrument automatically reteststhe sample in question at anappropriate dilution provided thatthis option has been entered inmemory in the test definition(see Reference Manual). | ||
| Explanation of retest option: Eachsample is routinely diluted 1:2, if theresult is > 105% the test setting allowsre-dilution 1:8 (upper linear range105%, 4 x $105% = 420%$ ). | ||
| Control Level | 3 Control levels(sold separately from the assay): | 2 Control levels(sold separately from the assay): |
| Control Plasma N(K042333, normal range) | STA®-Liatest® Control N(normal range) | |
| Control Plasma P andControl Plasma P 1:6 diluted(K042209, pathological range) | STA®-Liatest® Control P(pathological range) | |
| Stability OnceOpened | 4 weeks at 2 – 8°C | Not specified in package insert |
| On Board Stability | In original vials the vWF Ag Reagentand vWF Ag Buffer may be left onboard the instrument for 100 hours.The reagent vials can staycontinuously on board or be removedand stored closed at 2 to 8 °C beforethe next placement on board.' | With STA® - mini Reducer andperforated cap in place the stability ofReagent 2 after dilution is 15 days onSTA-R® and STA Compact® |
| Differences between vWF Ag and STA®-Liatest® VWF:Ag | ||
| Item | Proposed DevicevWF Ag | Predicate Device (K962675)STA®-Liatest® VWF:Ag |
| AmbientTemperature | The 510(k) data confirms that thecorrectness of the measured resultsfor the vWF Ag assay is assuredwithin the operating rangetemperatures of the SYSMEX CS-2500 analyzer.(8 - 12 °C). | Not specified in package insert |
| Sample Stability | • Maximal storage at 15 to 25 °C inprimary cups(plasma stored over cells) =4 hours• Maximal storage at 15 to 25 °C insecondary cup(plasma siphoned from cells) =4 hours• Maximal storage at ≤ -20 °C insecondary cups(plasma siphoned from cells) =3 months• Maximal storage at ≤ -74 °C insecondary cups(plasma siphoned from cells) =6 monthsFurthermore, the 510(k) data confirmsthat once frozen samples can bemeasured within 4 hours after thawing. | • 8 hours at 20 ± 5 °C• 24 hours at 2 - 8 °C• 1 month at -20 °C. |
| High Dose HookEffect | The vWF Ag assay on theSYSMEX® CS-2500 systemshows no high dose hook effectup to 1213% of norm VWF:Ag. | If there is a dose-hook effect, the testsetup takes it into account. |
| Sample Carryover | The 510(k) data confirms thatthere is no cross-contaminationcaused by one sample intoanother. | Not specified in package insert |
| Reagent Carryover | The 510(k) data confirms thatthere is no cross-contaminationcaused by one application intoanother. | Not specified in package insert |
| Comparison between Calibrators | ||
| Item | Proposed DevicevWF Ag | Predicate Device (K962675)STA®-Liatest® VWF:Ag |
| Intended Use | Standard Human Plasma is used forthe calibration of the followingcoagulation and fibrinolysis tests:1. Prothrombin time (PT)2. Fibrinogen (Clauss method)3. Coagulation factors II, V, VII, VIII,IX, X, XI, XII and VWF4. Inhibitors: Antithrombin III, proteinC, protein S, α2-antiplasmin5. PlasminogenThe percentage values given in theenclosed table of values relate to apool of fresh citrated human plasma,which by definition, exhibits 100 %of the norm for all the factors.Coagulation factors and inhibitorsfor which a WHO Standard isavailable are referenced to thisstandard and the values are given inInternational Units (IU). | Unknown |
| Matrix | Normal human plasma (lyophilized) | Unknown |
| Directly traceable toWHO Standard | Yes, traceable toWHO 6th International StandardFactor VIII / Von Willebrand Factor(07/316) | Unknown |
| Calibration Concept | Calibrator including analytical value(sold separately):Standard Human PlasmaA standard curve is generated byautomatic determination of differentdilutions of Standard HumanPlasma and Dade® Owren'sVeronal Buffer.The respective levels are defined bythe actual concentration of theStandard Human Plasma lot asprovided in the enclosed Table ofAnalytical Values, and by thesystem-specific dilution settings forcalibration. | Calibrator including analytical value(sold separately):STA® - VWF:Ag CalibratorAssay calibration is performed withSTA® - VWF:Ag Calibrator. PrepareSTA® - VWF:Ag Calibrator and scanthe information contained in thebarcode of the Assay Value insertto the instrument. The standardsare automatically prepared by theanalyzer by dilution with STA®Owren-Koller according to theparameters entered in theinstrument for the assay.STA® - Owren-Koller alonerepresents the 0 %-point. |
| Comparison between Calibrators | ||
| Item | Proposed DevicevWF Ag | Predicate Device (K962675)STA®-Liatest® VWF:Ag |
| Stability / Shelf Life | 24 months | Unknown |
| On Board Stability | Because calibrators are intended tobe used immediately, Siemens doesnot claim the on-board stability ofStandard Human Plasma in thelabeling. | Unknown |
| Stability afterReconstitution | 4 hours stored at 15 to 25 °C and4 weeks stored at -20 °C | Unknown |
6. Comparison of Technological Characteristics with the Predicate Device
- A) Assay
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B) Calibrator
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The above described differences do not raise new questions as to safety and effectiveness of the new device.
7. Performance Data
The following performance data were provided in support of the substantial equivalence determination.
Non-Clinical Studies 7.1.
7.1.1 Measuring Interval (Limit of Quantitation and Linearity)
The measuring interval of the application was established with respect to the limit of quantitation (LoQ) and the linearity study.
The LoQ study was carried out in accordance with the CLSI document EP17-A2 'Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures: Approved Guideline-Second Edition'. The verification of the LoQ was performed with five independent low-analyte plasma pools. Normal plasma pools were diluted with von Willebrand factor (VWF) deficient plasma. The LoQ was defined as 3.12% of norm. The greatest observed total error was 2.09% of norm. The study result confirms that the lower limit of the measuring interval of the vWF Ag assay (4% of norm) can be accurately measured with the proposed device.
The linearity study was performed in accordance with the CLSI document EP06 2nd ed. 'Evaluation of Linearity of Quantitative Measurement Procedures'. The linearity of the application was evaluated for three (3) lots of the vWF Ag assay across the measuring range (4 to 300% of norm). A dilution series was prepared using a high plasma sample pool and a low plasma sample pool to equal 12 different dilutions spanning a VWF:Ag concentration of 3.6 to 399.7% of norm. The deviation from linearity according to EP06 2nd ed. was calculated for each concentration of the dilution series investigated. The predefined maximum deviation in the measured range of ≤ 20% of norm (absolute). The highest predefined maximum deviation in the measured range of > 20% of norm was ±10.0% (relative).
Based on the results of the LoQ and linearity study, the measuring interval for the VWF Ag assay was established as 4 to 300% of norm.
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7.1.2. Specificity
The effects of potentially interfering substances were investigated in interference studies according to CLSI document EP07 'Interfering Testing in Clinical Chemistry. 3rd ed.'. Siemens investigated the test concentrations as recommended in CLSI document EP37 'Supplemental Tables for Interference Testing in Clinical Chemistry, 1st Edition'.
Dose-response experiments were carried out to determine the degree of interference as a function of the interferent concentration for endogenous interferents (hemoglobin, unconjugated bilirubin, conjugated bilirubin, lipids, and rheumatoid factors).
Paired-difference experiments were carried out to evaluate the amount of interferent up to which no interference is to be expected. Individual native samples with and without interferent were compared within the studies. Such interference testing was performed with a panel of exogenous substances including Over the Counter and Prescription Drugs.
The interferent test concentrations were investigated regarding four (4) different von Willebrand factor (VWF) antigen levels: Low level, medical decision levels (30% of norm, 50% of norm), and high level. The evaluation regarding the endogenous interferents rheumatoid factors was carried out with single native plasmas.
Following concentrations of listed endogenous substances were found to cause no interference up to the indicated concentrations:
| Interferent | No interference up to: |
|---|---|
| Hemoglobin | 712 mg/dL |
| Bilirubin ( unconjugated) | 30 mg/dL |
| Bilirubin (conjugated) | 100 mg/dL |
| Lipids* | 549 mg/dL |
| Rheumatoid Factors | 23 IU/mL |
| Interferent | No interference up to: |
| Acetaminophen (Paracetamol) | 156 µg/mL |
| Acetyl salicylic acid | 30 µg/mL |
| Amitriptyline hydrochloride | 543 ng/mL |
| Atorvastatin calcium salt trihydrate | 812 ng/mL |
| Budesonide | 6.3 ng/mL |
| Carbimazol | 3.6 µg/mL |
| Ciprofloxacin | 12 µg/mL |
| Cisplatin | 33 µg/mL |
| Citalopram hydrobromide | 6.79 µg/mL |
| Clopidogrel hydrogensulfate | 24 ng/mL |
| Diclofenac sodium salt | 26 µg/mL |
| Emicizumab | 300 µg/mL |
| Estradiol | 7.5 pg/mL |
| Ibuprofen sodium salt | 240 µg/mL |
| Lenalidomide | 2.13 µg/mL |
| Lisinopril dihydrate | 268 ng/mL |
| L-Thyroxin | 180 ng/mL |
| Metformin Hydrochloride | 15.4 µg/mL |
| Pantoprazole sodium sesquihydrate | 34 µg/mL |
| Progesterone | 540 ng/mL |
| Ramipril | 156 ng/mL |
| RFVIIa: NovoSeven® (Eptacog alfa activated) | 4.5 µg/mL |
| RFVIII: ELOCTA® (Efmoroctocog alfa) | 1.875 IU/mL |
| RFVIII: Esperoct® (Turoctocog alfa pegol) | 1.875 IU/mL |
| Tetracycline | 24 µg/mL |
| Theophylline | 60 µg/mL |
| Thiouracil (2-Thiouracil) | 15.9 µg/mL |
| Ticagrelor | 108 µg/mL |
| Tranexamic Acid | 162.9 µg/mL |
| Valproic Acid | 318 µg/mL |
| Valsartan | 11.7 µg/mL |
- Evaluated with Intralipid® equivalent (Lipovenoes®) spiked samples.
Patient samples may contain heterophilic antibodies that could react in immunoassays to give a falsely elevated or depressed result.
No susceptibility of the vWF Ag assay was observed towards human anti-mouse antibodies (HAMAs) or the potential interference by antibodies (lupus anticoagulant, named Lupus in the following) caused by the autoimmune disease lupus erythematosus.
The presence of rheumatoid factors may lead to an overestimation of VWF:Ag. The diagnosis or exclusion of any type of von Willebrand disease (VWD) should therefore never be based solely on the vWF Ag assay's result.
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In addition, no interferences up to the indicated concentrations of following exogenous substances were observed:
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7.2. Clinical Studies
7.2.1. Reference Interval
A reference interval study was conducted at three (3) clinical study sites in the United States with apparently healthy subjects following the guidance of CLSI document EP28-A3c 'Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline – Third Edition'. Fresh plasma specimens obtained from apparently healthy donors were tested with the following results:
| Reference Interval Study | ||||
|---|---|---|---|---|
| ABO | n | Median(% of norm) | 2.5th - 97.5th percentile(% of norm) | |
| Blood group O | 147 | 92.9 | 46.6 - 202.1 | |
| Blood group non-O | 159 | 135.5 | 54.3 — 293.6 | |
| Blood group independent* | 306 | 111.3 | 50.6 – 271.2 |
- The blood group independent reference range is calculated from pooled sample results (n = 147 blood group O and n = 159 blood group non-O).
7.2.2. Measurements of VWF:Ag in healthy pediatric population
For the 'measurements of VWF:Ag in a healthy pediation' apparently healthy subjects > 4 weeks to < 18 years of age were investigated. Blood donors regarding two (2) different blood-group types were investigated.
A study with n = 21 pediatric, healthy subjects with blood group O in the age range from > 4 weeks to < 18 years demonstrated values from 40.8 to 160.8% of norm. 19 out of 21 tested subjects had values within the reference interval established for individuals ≥ 18 years of age with blood group O.
A further study with n = 26 pediatric, healthy subjects with blood group non-O in the age range from > 4 weeks to < 18 years demonstrated values from 73.2 to 200.0% of norm. All of the 26 tested subjects had values within the reference interval established for individuals ≥ 18 years of age with blood group non-0.
Independent from the ABO blood group, the tested n = 47 pediatric, healthy subjects in the age range between > 4 weeks to < 18 years demonstrated values from 40.8 to 200.0% of norm. 45 out of 47 tested subjects had values within the reference interval established for individuals ≥ 18 years of age.
Note: This information cannot be used as a pediatric reference interval.
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7.2.3. Precision / Reproducibility
Precision (single site) studies and a reproducibility (multi-site) study were performed in accordance with the CLSI document EP05-A3 'Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline - Third Edition' to investigate the precision performance characteristics of the WF Ag assay on the SYSMEX® CS-2500 analyzer. The reproducibility investigation was performed in a multicenter study, including three (3) study sites in the USA (Sites 1, 2, and 3). The precision investigation was performed internally at the Siemens company site in Germany (Site 4). Three (3) plasma pools as well as three (3) control materials (Control Plasma P, and Control Plasma P 1:6 diluted) were investigated as test samples were chosen to cover the measuring interval of the WVF Ag assay (4 to 300% of norm) and the medical decision levels (30% of norm, 50% of norm). The plasma pools were prepared at the Siemens company site and sent frozen to the external study sites for testing with the three (3) control materials following routine operation and calibration. The order of samples and control materials for each run and day varied to avoid an inherent bias to the study.
The external reproducibility study was carried out at three (3) external sites, on five (5) days, with two (2) runs per day and three (3) replicates of each sample per run (3x5x2x3). All external sites performed the reproducibility study with the same reagent/calibrator lot combination.
An internal precision study was carried out on twenty (20) days, with two (2) runs per day and two (2) replicates of each sample per run (20x2x2) on one (1) SYSMEX® CS-2500 analyzer. The study investigated three (3) different reagent lots in combination with one (1) calibrator lot, in addition three (3) calibrator lots were investigated in combination with one (1) reagent lot.
A further internal precision study was carried out on five (5) days, with two (2) runs per day and four (4) replicates of each sample per run (5x2x4) on three (3) SYSMEX® CS-2500 analyzers. The study investigated one (1) reagent/calibrator lot combination on all three (3) SYSMEX® CS-2500 analyzers.
The results are presented in the following tables:
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| Evaluation of 3x5x2x3 Reproducibility Study (Multicenter, USA) | ||||
|---|---|---|---|---|
| CV (%) | ||||
| Repeatability(Within-Run) | Between-Run | Between-Day | Between-Site | Total(combinedSites) |
| 1.14 – 4.28 | 0.00 – 1.42 | 0.00 – 1.65 | 0.81 – 3.79 | 2.03 – 5.96 |
| Evaluation of 3x5x2x3 Precision Study at Single Sites (USA) | ||||
|---|---|---|---|---|
| CV (%) | ||||
| Study Site | Repeatability(Within-Run) | Between-Run | Between-Day | Total(Within-Site) |
| Site 1 | 0.73 - 3.08 | 0.00 - 1.21 | 0.00 - 1.89 | 0.83 - 3.48 |
| Site 2 | 1.11 - 4.32 | 0.00 - 1.56 | 0.00 - 2.48 | 1.30 - 4.99 |
| Site 3 | 1.42 - 5.16 | 0.00 - 1.89 | 0.00 - 2.09 | 1.95 - 5.44 |
| Evaluation of 3x20x2x2 Precision Study at Single Site (Germany)Investigation of reagent variability (reagent lots combined) | ||||
|---|---|---|---|---|
| CV (%) | ||||
| Repeatability(Within-Run) | Between-Run | Between-Day | Between-Reagent Lot | Total(combinedreagent lots) |
| 1.32 – 6.68 | 0.00 - 2.67 | 0.00 – 1.88 | 0.87 - 3.22 | 2.53 - 7.37 |
| Evaluation of 3x20x2x2 Precision Study at Single Site (Germany)Investigation of calibrator variability (calibrator lots combined) | ||||
|---|---|---|---|---|
| CV (%) | ||||
| Repeatability(Within-Run) | Between-Run | Between-Day | Between-Calibrator Lot | Total(combinedcalibrator lots) |
| 1.11 – 6.06 | 0.00 – 2.94 | 0.00 - 1.55 | 1.09 - 4.73 | 2.55 - 6.88 |
| Evaluation of 3x5x2x4 Precision Study at Single Site (Germany)Investigation of instrument variability | |||||
|---|---|---|---|---|---|
| CV (%) | |||||
| Repeatability(Within-Run) | Between-Run | Between-Day | Between-Instrument | Total(combinedinstruments) | |
| 1.47 – 3.16 | 0.0 - 0.94 | 0.33 - 1.56 | 0.00 - 4.08 | 1.77 - 5.30 |
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7.2.4. Method comparison
Method comparison studies designed according to EP09c CLSI Guideline 'Measurement Procedure Comparison and Bias Estimation Using Patient Samples; Approved Guideline-Third Edition' were conducted at one (1) external site in Germany (Site 1) and two (2) external sites in the United States (Site 2 and Site 3). All sites used the same protocol but only Site 3 performed measurements on the predicate device.
Samples were measured on both the predicate device (STA® Liatest® VWF:Ag on the STA R Max® analyzer) as well as on the proposed device (the vWF Ag assay on the Sysmex® CS-2500 analyzer). The samples tested ensured the intended use population was tested. Results were compared by Passing-Bablok regression analysis. Results from each application met the predetermined acceptance criteria. The following summary of Passing-Bablok regression shows that the proposed and predicate devices provide equivalent results when used in a clinical setting.
| Method Comparison Results (Passing-Bablok Regression):Proposed Device = vWF Ag on the Sysmex® CS-2500 analyzer andPredicate Device = STA® Liatest® VWF:Ag on the STA R Max® analyzer | |||
|---|---|---|---|
| Site 1 | Site 2 | Site 3 | Sites Combined |
| N = 107 | N = 115 | N = 117 | N = 339 |
| y = 1.07x - 4.67% of norm | y = 1.07x - 5.56% of norm | y = 0.99x - 4.36% of norm | y =1.04x - 4.60% of norm |
| r = 0.996 | r = 0.972 | r = 0.978 | r = 0.982 |
| (r2 = 0.992) | (r2 = 0.944) | (r2 = 0.956) | (r2 = 0.965) |
8. Conclusion
The non-clinical and clinical data support the safety of the proposed device, the vWF Ag assay.
The clinical data demonstrates that the vWF Ag assay on the SYSMEX® CS-2500 analyzer performs comparably to the predicate device (STA® Liatest® VWF:Ag on the STA R Max®) that is currently marketed for the same intended use.
The data submitted for this premarket notification demonstrates that the device raises no concerns with regard to safety and effectiveness.
§ 864.7290 Factor deficiency test.
(a)
Identification. A factor deficiency test is a device used to diagnose specific coagulation defects, to monitor certain types of therapy, to detect coagulation inhibitors, and to detect a carrier state (a person carrying both a recessive gene for a coagulation factor deficiency such as hemophilia and the corresponding normal gene).(b)
Classification. Class II (performance standards).