(268 days)
The T-TAS 01 Instrument is intended for use with T-TAS reagent chips in the clinical laboratory.
The T-TAS 01 PL chip is intended for use in the clinical laboratory for the analysis of the platelet thrombus formation process (primary hemostatic function) in patients age 21 and older with a history of conditions associated with impaired primary hemostatic function or use of antiplatelet therapy. The test uses BAPA-anticoagulated whole blood specimens to measure platelet adhesion to a thrombogenic collagen-coated surface and aggregation, which causes an increase in flow pressure inside the PL chip. The test measures primary hemostatic function as the area under the pressure-time curve (AUC), with AUC < 260 suggesting abnormal primary hemostatic function. Additional testing may be necessary to identify the cause(s) of abnormal primary hemostatic function. The test has been evaluated in patients taking antiplatelet therapy, in patients with von Willebrand disease, and in patients with Glanzmann's thrombasthenia. Other primary hemostasis disorders have not been evaluated.
The BAPA tube for T-TAS 01 is intended to be used for the collection, transport, and storage of blood specimens for use with the T-TAS 01 system.
The T-TAS 01 system is an in vitro diagnostic device that is comprised of tabletop instrument controlled by a dedicated PC and a disposable, single-use flow chamber. The PL Chip for T-TAS 01 is designed to specifically measure platelet thrombus formation (PTF) under physiological conditions on a collagen-coated analytical path consisting of 26 microcapillary channels. Platelet thrombus formation is a direct indicator of the patient's primary hemostatic function. The assay is performed under arterial flow conditions using benzylsulfonyl-D-Arg-Pro-4-amidinobenzylamide (BAPA)-anticoagulated whole blood samples. BAPA is an anticoagulant that inhibits thrombin and factor Xa, blocking the coagulation cascade and allowing the PL assay to specifically measure only the platelet thrombus formation process (primary hemostasis). During the assay, the blood sample is exposed to arterial shear stresses at 1,500 s-1 in the presence of a collagen-coated surface, which causes platelet attachment to collagen mediated by von Willebrand factor (vWF), and platelet activation. Platelet activation causes the release of endogenous factors contained within the platelets that recruit and activate other platelets and cause aggregation, and platelet thrombus formation. The growing platelet thrombus causes occlusion of the microcapillary channels, which increases the flow pressure within the assay chip. The process of platelet thrombus formation in the flow chamber is continuously monitored by a pressure sensor that tracks pressure changes in the flow path. Results are calculated automatically within 10 minutes or when the pressure a reading reaches 60 kPa above the baseline pressure, whichever occurs first. Results are displayed as AUC, which is the flow pressure curve over 10 minutes.
AUC results less than 260 are associated with abnormal primary hemostatic function.
The provided text is a 510(k) Summary for the T-TAS 01 System with PL Chip, an automated platelet aggregation system. It details the device's intended use, comparison to a predicate device, and non-clinical and clinical performance data.
Here's an analysis to extract the requested information, noting that this document describes a diagnostic test, not an AI model. Therefore, some questions related to AI-specific studies (e.g., human-in-the-loop, AI effect size, training data ground truth establishment) are not directly applicable or answerable from this document.
Device Name: T-TAS 01 System with PL Chip
Device Type: Automated Platelet Aggregation System (In Vitro Diagnostic, IVD)
Acceptance Criteria for Performance (based on clinical performance data):
The device's performance is demonstrated through its ability to differentiate between individuals with normal primary hemostatic function and those with impaired function due to specific conditions. The key metric is the Area Under the Pressure-Time Curve (AUC), with a cutoff of < 260 AUC suggesting abnormal primary hemostatic function.
Since this is a diagnostic device comparison to a predicate, the "acceptance criteria" are implicitly met by demonstrating substantial equivalence to the predicate device (Dade Behring PFA-100) and by providing clinical performance metrics (negative agreement and sensitivity) for various target populations. The document does not explicitly state pre-defined quantitative acceptance criteria thresholds for these metrics that were required for clearance, but rather presents the results.
1. Table of Acceptance Criteria and Reported Device Performance
Given that explicit "acceptance criteria" (thresholds for success) are not stated in the document as typical for AI/ML performance metrics, we will present the key performance indicators reported and their values. The underlying "acceptance" is the FDA's determination of substantial equivalence based on these results.
| Performance Metric | Implicit Acceptance Criteria (based on predicate equivalence & clinical utility) | Reported Device Performance (T-TAS 01 AUC < 260 cutoff) |
|---|---|---|
| Precision | CV ≤ 15% or SD ≤ 39 (as stated in the document) | Met (e.g., Total CV for High: 2.8%, Middle: 14.3%, Low: 19.6% - note: Low is slightly above 15% CV but acceptable given SD ≤ 39, as 25.7 is less than 39 for low signal values) |
| Negative Agreement (Healthy Donors) | High agreement expected, comparable to predicate's ability to identify normal. | 95.8% (95% CI: 91.1-98.0%) |
| Sensitivity (Aspirin Monotherapy) | Clinically meaningful detection of impairment due to aspirin. | 68.4% (95% CI: 55.5-79.0%) |
| Sensitivity (Clopidogrel + ASA DAPT) | Clinically meaningful detection of impairment. | 100.0% (95% CI: 81.5-100.0%) |
| Sensitivity (Prasugrel + ASA DAPT) | Clinically meaningful detection of impairment. | 100.0% (95% CI: 78.2-100.0%) |
| Sensitivity (Ticagrelor + ASA DAPT) | Clinically meaningful detection of impairment. | 100.0% (95% CI: 76.8-100.0%) |
| Sensitivity (von Willebrand Disease) | Clinically meaningful detection of impairment. | 72.0% (95% CI: 50.6-87.9%) |
| Sensitivity (Glanzmann's Thrombasthenia) | Clinically meaningful detection of impairment. | 100.0% (95% CI: 43.9-100.0%) |
| Interference | No significant effect on AUC results at specific concentrations of tested compounds | Met (list of tested compounds provided, some known to affect platelet activity still acceptable as device measures their effect) |
| Stability (PL chip & blood samples) | Demonstrated stability for declared durations. | Met (Closed pouch PL chip: 12 months; Open pouch PL chip: 8 hours; BAPA tube: 10 months; Blood sample: 6 hours) |
2. Sample Size Used for the Test Set and Data Provenance
- Clinical Performance Test Set Sample Size:
- Healthy Donors: 142 individuals
- Aspirin Monotherapy: 57 patients
- Clopidogrel + ASA DAPT: 18 patients
- Prasugrel + ASA DAPT: 15 patients
- Ticagrelor + ASA DAPT: 14 patients
- von Willebrand Disease: 25 patients (12 Type 1, 10 Type 2, 3 Type 3)
- Glanzmann's Thrombasthenia: 3 patients
- Total Clinical Subjects: 142 + 57 + 18 + 15 + 14 + 25 + 3 = 274 subjects across 6 investigational sites.
- Data Provenance: The study was conducted at 6 investigational sites. The document does not explicitly state the country of origin, but given it's an FDA submission, the primary data likely comes from the US. It is a prospective collection of data for the purpose of this clinical evaluation, as it refers to "subjects enrolled at ... investigational sites."
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
This is a diagnostic device for measuring a physiological parameter (platelet thrombus formation) based on direct blood sample analysis. The "ground truth" is established by the patient's diagnosed medical condition or medication use (e.g., "healthy donor," "patients taking antiplatelet therapy," "patients with von Willebrand disease," "patients with Glanzmann's thrombasthenia") and, in some cases, by other laboratory tests (e.g., PFA-100 results, vWF activity, FVIII:C levels to confirm vWD).
Therefore, the concept of "experts establishing ground truth" in the sense of image annotation or AI model output review by multiple radiologists is not directly applicable here. The "experts" are the physicians who diagnosed the patients and the laboratory personnel who performed confirmatory tests. The document does not specify the number or qualifications of these individuals directly, as their role is standard medical practice for diagnosis.
4. Adjudication Method for the Test Set
Not applicable in the context of this diagnostic device study. Ground truth is based on clinical diagnosis and other objective laboratory parameters, not on interpretation requiring adjudication among human readers/experts.
5. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study Was Done, If So, What Was the Effect Size of How Much Human Readers Improve with AI vs Without AI Assistance
Not applicable. This is not an AI-based device, nor does it involve human readers interacting with an AI system. It is an automated in vitro diagnostic test.
6. If a Standalone (i.e. Algorithm Only Without Human-in-the-Loop Performance) Was Done
The T-TAS 01 System is a standalone automated diagnostic device. Its performance, as measured by AUC, is the "algorithm only" or "device only" performance. The results (AUC values) are automatically calculated by the instrument when the pressure reading reaches 60 kPa or after 10 minutes.
7. The Type of Ground Truth Used (Expert Consensus, Pathology, Outcomes Data, etc.)
The ground truth was established by:
- Clinical Diagnosis: Patients with a history of conditions associated with impaired primary hemostatic function (e.g., Von Willebrand disease, Glanzmann's thrombasthenia) or those confirmed to be taking antiplatelet therapy (aspirin, clopidogrel, prasugrel, ticagrelor).
- Absence of Diagnosis/Conditions: For the healthy control group, individuals without a history of inherited or acquired platelet dysfunction, and without laboratory evidence of von Willebrand disease.
- Confirmatory Laboratory Tests: For von Willebrand disease patients, comparison to PFA-100 Col/EPI and Col/ADP sensitivity, and reference to vWF activity and FVIII:C results.
8. The Sample Size for the Training Set
This document describes the validation of a lab diagnostic device, not an AI/ML model. Therefore, the concept of a "training set" for model development is not explicitly discussed. The device's underlying principles (measuring pressure changes due to platelet adhesion and aggregation) are based on established physiological and engineering principles, not on learned patterns from a training dataset in the AI sense.
9. How the Ground Truth for the Training Set Was Established
Not applicable, as this is not an AI/ML device relying on a training set in the typical AI sense. The device is designed and validated based on known biological mechanisms and engineering specifications.
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Image /page/0/Picture/0 description: The image shows 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, with the letters "FDA" in a blue square. To the right of the blue square is the text "U.S. FOOD & DRUG ADMINISTRATION" in blue.
February 14, 2020
Fujimori Kogyo Co., Ltd. Jeffrey Dahlen Project Leader 11435 Merritage Court San Diego, California 92131
Re: K191364
Trade/Device Name: T-TAS 01 System with PL Chip Regulation Number: 21 CFR 864.5700 Regulation Name: Automated platelet aggregation system Regulatory Class: Class II Product Code: JOZ Dated: May 20, 2019 Received: May 22, 2019
Dear Jeffrey Dahlen:
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.
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
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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 (OS) 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 mediation-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,
Takeesha Taylor-Bell Chief Division of Immunology and Hematology Devices OHT7: Office of In Vitro Diagnostics and Radiological Health 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)
Device Name T-TAS 01 System with PL chip
Indications for Use (Describe)
The T-TAS 01 Instrument is intended for use with T-TAS reagent chips in the clinical laboratory.
The T-TAS 01 PL chip is intended for use in the clinical laboratory for the platelet thrombus formation process (primary hemostatic function) in patients age 21 and older with a history of conditions associated with impaired primary hemostatic function or use of antiplatelet therapy. The test uses BAPA-anticoagulated whole blood specimens to measure platelet adhesion to a thrombogenic collagen-coated surface and aggregation, which causes an increase in flow pressure inside the PL chip. The test measures primary hemostatic function as the area under the pressure-time curve (AUC), with AUC < 260 suggesting abnormal primary hemostatic function. Additional testing may be necessary to identify the cause(s) of abnormal primary hemostatic function. The test has been evaluated in patients taking antiplatelet therapy, in patients with von Willebrand disease, and in patients with Glanzmann's thrombasthenia. Other primary hemostasis disorders have not been evaluated.
The BAPA tube for T-TAS 01 is intended to be used for the collection, transport, and storage of blood specimens for use with the T-TAS 01 system.
| 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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510(k) Summary [as required by 21 CFR 807.92(c)]
Submitter information:
| Company Name: | Fujimori Kogyo Co., Ltd. (ZACROS) |
|---|---|
| Company Address: | Shinjuku First West Building1-23-7 Nishi-shinjuku, Shinjuku-ku, Tokyo 160-0023JAPAN |
| Company Phone: | +81-3-6381-2573 |
| Company Fax: | +81-3-5909-5779 |
| Contact Name: | Jeffrey Dahlen, Ph.D. |
| Contact Email: | jeff-dahlen@zacros.co.jp |
| Date Summary was Prepared: | 2020-02-14 |
| Product information: | |
| 510(k) Number | K191364 |
| Trade/Proprietary Name(s): | Total Thrombus-formation Analysis (T-TAS) 01 System, which consists of: |
| T-TAS 01 Instrument (Catalog #18001) PL chip for T-TAS 01 (Catalog #18002) PL chip Reservoir Set for T-TAS 01 (Catalog #18003) BAPA tube for T-TAS 01 (Catalog #18004) | |
| Common/Usual Name(s): | Automated Platelet Aggregation System |
| Product Code: | JOZ |
| Regulation: | 21 CFR 864.5700 |
| Regulatory Classification: | Class II |
| Panel: | Hematology |
Predicate Method:
| Product Name: | Dade Behring (now Siemens) PFA-100 |
|---|---|
| 510(k) Document Number: | K060489 |
Device Description:
The T-TAS 01 system is an in vitro diagnostic device that is comprised of tabletop instrument controlled by a dedicated PC and a disposable, single-use flow chamber. The PL Chip for T-TAS 01 is designed to specifically measure platelet thrombus formation (PTF) under physiological conditions on a collagen-coated analytical path consisting of 26 microcapillary channels. Platelet thrombus formation is a direct indicator of the patient's primary hemostatic function. The assay is performed under arterial flow conditions using benzylsulfonyl-D-Arg-Pro-4-amidinobenzylamide (BAPA)-anticoagulated whole blood samples. BAPA is an anticoagulant that inhibits thrombin and factor Xa, blocking the coagulation cascade and allowing the PL assay to specifically measure only the platelet thrombus formation process (primary hemostasis). During the assay, the blood sample is exposed to arterial shear stresses at 1,500 s 4 in the presence of a collagencoated surface, which causes platelet attachment to collagen mediated by von Willebrand factor (vWF), and platelet activation. Platelet activation causes the release of endogenous factors contained within the platelets that recruit and activate other platelets and cause aggregation, and platelet thrombus formation. The growing platelet thrombus causes occlusion of the microcapillary channels, which increases the flow pressure within the assay chip. The process of platelet thrombus formation in the flow chamber is continuously monitored by a pressure sensor that tracks pressure changes in the flow path. Results are
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calculated automatically within 10 minutes or when the pressure a reading reaches 60 kPa above the baseline pressure, whichever occurs first. Results are displayed as AUC, which is the flow pressure curve over 10 minutes.
AUC results less than 260 are associated with abnormal primary hemostatic function.
Intended Use/Indications for Use:
The T-TAS 01 Instrument is intended for use with T-TAS reagent chips in the clinical laboratory.
The T-TAS 01 PL chip is intended for use in the clinical laboratory for the analysis of the platelet thrombus formation process (primary hemostatic function) in patients age 21 and older with a history of conditions associated with impaired primary hemostatic function or use of antiplatelet therapy. The test uses BAPAanticoagulated whole blood specimens to measure platelet adhesion to a thrombogenic collagen-coated surface and aggregation, which causes an increase in flow pressure inside the PL chip. The test measures primary hemostatic function as the area under the pressure-time curve (AUC), with AUC < 260 suggesting abnormal primary hemostatic function. Additional testing may be necessary to identify the cause(s) of abnormal primary hemostatic function. The test has been evaluated in patients taking antiplatelet therapy, in patients with von Willebrand disease, and in patients with Glanzmann's thrombasthenia. Other primary hemostasis disorders have not been evaluated.
The BAPA tube for T-TAS 01 is intended to be used for the collection, transport, and storage of blood specimens for use with the T-TAS 01 system
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Comparison with Predicate:
| Parameter | PFA-100 CEPI cartridge(Predicate Device) | T-TAS 01 System with PL-chip(Subject Device) |
|---|---|---|
| Intended Use | The Dade® PFA-100® PlateletFunction Analyzer and Dade® PFA-100® Reagents are in vitro diagnosticdevices intended to aid in thedetection of platelet dysfunction incitrated human whole blood.(Note: the PFA-100 was originallymarketed by Dade and is nowmarketed by Siemens Healthineers) | The T-TAS 01 Instrument is intended for usewith T-TAS reagent chips in the clinicallaboratory.The T-TAS 01 PL chip is intended for use in theclinical laboratory for the analysis of theplatelet thrombus formation process (primaryhemostatic function) in patients age 21 andolder with a history of conditions associatedwith impaired primary hemostatic function oruse of antiplatelet therapy. The test uses BAPA-anticoagulated whole blood specimens tomeasure platelet adhesion to a thrombogeniccollagen-coated surface and aggregation, whichcauses an increase in flow pressure inside thePL chip. The test measures primary hemostaticfunction as the area under the pressure-timecurve (AUC), with AUC < 260 suggestingabnormal primary hemostatic function.Additional testing may be necessary to identifythe cause(s) of abnormal primary hemostaticfunction. The test has been evaluated inpatients taking antiplatelet therapy, in patientswith von Willebrand disease, and in patientswith Glanzmann's thrombasthenia. Otherprimary hemostasis disorders have not beenevaluated.The BAPA tube for T-TAS 01 is intended to beused for the collection, transport, and storageof blood specimens for use with the T-TAS 01system |
| Location ofIntended Use | Clinical laboratory | Same |
| Intended UsePopulation | • Normal population• Patients taking aspirin• Patients with vWD• Patients with Glanzmann'sthrombasthenia• Adult & pediatric populations | • Patients taking antiplatelet therapy• Patients with vWD• Patients with Glanzmann's thrombasthenia• Adult population |
| Pre-analytic Considerations | ||
| Specimen Type | Buffered sodium citrate-anticoagulated whole blood | BAPA-anticoagulated whole blood |
| SamplePreparation | None | Same |
| ReagentPreparation | None | Same |
| PFA-100 CEPI cartridge(Predicate Device) | T-TAS 01 System with PL-chip(Subject Device) | |
| Parameter | ||
| Other ReagentsNecessary forAssay | Trigger solution | Mineral oil(for instrument micropump) |
| Assay Calibration | None required by user; all calibration performed at factory. | Same |
| Introduction ofBlood Sample | Manual transfer of sample fromblood collection tube to assaycartridge by pipette. | Same |
| Blood SampleVolumeRequired | 800 µL | 300-330 µL (320 µL recommended) |
| SampleIncubation TimePrior to Assay | 15 minutes at room temperature | 30 minutes |
| Chip/CartridgeWarm-up Timein InstrumentPrior to Assay | < 2.5 minutes | Same |
| MaximumAllowableSample StabilityTime Prior toAssay (ambienttemperature) | 4 hours | 6 hours |
| AssayTemperature | 37.9 ± 1 °C | 36 °C |
| RecommendedOperatingTemperature | 64 °F to 90 °F(18 °C to 29 °C) | 68 °F to 86 °F(20 °C to 30 °C) |
| RecommendedOperatingRelativeHumidity | 20-90% | 20-80% |
| Altitude(maximum) | 2,000 m (6,500 ft) | Same |
| Assay CartridgeStorageConditions | 2-25 °C, allow cold cartridge to warmto room temperature for 15 minutesprior to testing. | 2-8 °C, allow cold cartridge to warm to roomtemperature for 15 minutes prior to testing. |
| Open PouchStability | 4 hours at ambient temperature | 8 hours at ambient temperature |
| Quality Control Considerations | ||
| Internal QualityControl | Yes, self-test performed at leastonce per shift at the start of eachshift. | Same |
| External QualityControl | Yes, external quality control using | Same |
| PFA-100 CEPI cartridge(Predicate Device) | T-TAS 01 System with PL-chip(Subject Device) | |
| Parameter | ||
| Analytic Considerations | ||
| DetectionPrinciple | Measures time required for plateletsto adhere and aggregate, resulting inocclusion of an aperture under highshear flow conditions. | Measures integrated area under the curve ofpressure over time as platelets adhere to athrombogenic surface under high shear flowconditions. |
| Principal AssayComponentsInvolved inGeneratingResult | Platelets, collagen, exogenousepinephrine, endogenous plasmaand platelet components, aperture. | Platelets, collagen, endogenous plasma andplatelet components, capillary channels. |
| Mechanism ofPlateletActivation | Soluble exogenous agonist + vWF-mediated binding to collagen at highshear rate | vWF-mediated binding to collagen at high shearrate |
| Solution-phaseExogenousPlatelet Agonist | Epinephrine | None |
| PlateletAdhesion Matrix | Collagen | Same |
| Shear RateDuring Assay | $5,000 s^{-1}$ | $1,500 s^{-1}$ |
| Post-analytic Considerations | ||
| Time to Result | 4-8 minutes | ≤ 10 minutes |
| Units | Closure time (seconds) | AUC |
| Reference Range | 94-193 seconds | AUC 270.0-447.7 |
| RecommendedCutoff | > 170 seconds | AUC < 260 |
| Interpretation ofResult | Prolonged closure times (above thecutoff) are considered abnormal,and indicative of plateletdysfunction. | AUC ≥ 260 indicates that that primaryhemostatic defects are not identified.AUC < 260 is considered abnormal and indicatesimpaired primary hemostatic function (reducedplatelet thrombus formation). |
| Instrument Technical Considerations | ||
| Supports Use ofOperator IDs | No | Same |
| Supports Use ofPatient IDs | Yes | Same |
| Method forControllingInstrument | LCD screen and keypad | External computer with touchscreen |
| Number ofResults Stored inMemory | 20 Patient Results50 Control Results | Thousands (limited by PC memory) |
| InstrumentDimensions(LxWxH) | 15.1" x 9" x 14.2"(38 x 23 x 36 cm) | 14.2" x 12.6" x 9.7"(36 x 32 x 24.7 cm) |
| InstrumentWeight | 24 lbs (10.9 kg) | 13.2 lbs (6.0 kg) |
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Summary of Non-clinical Data:
Precision:
Assay precision was evaluated using three operators, three T-TAS 01 instruments, and three PL chip lots. BAPA-anticoagulated whole blood specimens collected from one control donor and two donors taking aspirin were tested. The blood specimens had AUC results representing specimens with normal primary hemostatic ability (High), abnormal primary hemostatic ability (Low), and hemostatic ability near the assay cutoff (Middle). The results were within the specification of CV ≤ 15% or SD ≤ 39 and are summarized below.
| Sample | N | Mean | RepeatabilityWithin-Run(SD, %CV) | Between-Operator(SD, %CV) | Between-Lot(SD, %CV) | Between-Instrument(SD, %CV) | Total(SD, %CV) |
|---|---|---|---|---|---|---|---|
| High | 36 | 428.1 | 10.7, 2.5 | 2.0, 0.5 | 4.7, 1.1 | 1.6, 0.4 | 11.9, 2.8 |
| Middle | 36 | 237.3 | 31.7, 13.4 | 6.4, 2.7 | 10.5, 4.4 | 0.0, 0.0 | 34.0, 14.3 |
| Low | 36 | 130.7 | 18.4, 14.1 | 11.8, 9.0 | 13.5, 10.3 | 0.0, 0.0 | 25.7, 19.6 |
Between-site reproducibility was also studied by performing 5 replicate PL assay measurements per day over 5 days at each of three different locations using BAPA-anticoagulated whole blood samples from four donors. The donors included a healthy control donor and three donors taking aspirin therapy that had high, middle, and low AUC results similar to the precision study. All results within each day of tested were within the specification of CV ≤ 15% or SD ≤ 39.
Assay Interference:
The following substances were tested for their ability to interfere with the PL assay AUC result and did not significantly affect the AUC results when present at the plasma concentrations indicated.
| Compound | Concentration | Compound | Concentration |
|---|---|---|---|
| Acetaminophen | 7.8 mg/dL | Heparin | 525 U/mL |
| Bilirubin | 40 mg/dL | L-Thyroxine | 0.0858 mg/dL |
| Caffeine | 21.6 mg/dL | Metformin | 2.4 mg/dL |
| Captopril | 0.528 mg/dL | Omeprazole | 1.68 mg/dL |
| Catechin | 5 mg/dL | Pravastatin | 0.414 mg/dL |
| Cilostazol | 1.25 mg/dL | Propranolol | 0.202 mg/dL |
| Dabigatran | 0.047 mg/dL | Rivaroxaban | 0.044 mg/dL |
| Dextran 40 | 2400 mg/dL | Streptokinase | 50,000 U/dL |
| Diltiazem | 0.18 mg/dL | Theophylline | 6 mg/dL |
| Dipyridamole | 0.25 mg/dL | Tirofiban | N/A |
| Fish Oil | 25.6 mg/dL | Triglycerides | 750 mg/dL |
| Ibuprofen | 0.438 mg/dL | Warfarin | 7.5 mg/dL |
Cilostazol, dipyridamole, ibuprofen, and tirofiban are all known to reduce platelet activity, and cause a dose-dependent reduction in AUC result. The maximum tirofiban concentration without interference was not determined.
Hemodilution up to 20% and under-filling of the BAPA collection tube up to 50% did not significantly affect PL assay AUC results.
Stability Studies:
Stability of the T-TAS 01 PL assay chip and stability of BAPA-anticoagulated blood samples were evaluated using fresh blood samples collected from healthy control donors taking aspirin. PL assay chip stability was evaluated using an isochronous design. Stability of the BAPA tube was determined by measuring the fill volume over time according to CLSI standard GP39-A6.
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Closed pouch PL chip stability: 12 months from the date of manufacture @ 2-8 °C Open pouch PL chip stability: 8 hours @ ambient temperature (20-25 °C) BAPA tube stability: 10 months from the date of manufacture @ ambient temperature (15-30 °C) BAPA-anticoagulated blood sample stability: 6 hours @ ambient temperature (20-25 °C)
Summary of Clinical Data:
Reference Interval:
The AUC reference interval for the T-TAS 01 PL assay is 270.0 - 447.7.
The reference interval was determined from the 5th to 95th percentile (central 90%) of AUC results obtained from PL assay measurements at three clinical sites using a population of 142 individuals (96 females, 46 males, age 38.0 ± 11.3 years) without a history of inherited or acquired platelet dysfunction, and without laboratory evidence of von Willebrand disease. PL assay AUC results were not influenced by age, gender, ethnicity, or race.
Clinical Performance:
Sensitivity and negative agreement of the PL assay for detecting conditions associated with abnormal primary hemostatic function were calculated from a total of 274 subjects enrolled at a total of 6 investigational sites. Negative agreement was calculated using PL assay results from healthy donors confirmed to have normal primary hemostatic function because they did not have laboratory evidence or prior diagnosis of disorders affecting primary hemostatic function, nor were they taking medications that affect primary hemostatic function. Sensitivity was calculated using PL assy results from the following patient groups with conditions associated with impaired primary hemostatic function: subjects taking antiplatelet therapy (81 mg aspirin monotherapy and dual antiplatelet therapy), subjects diagnosed with von Willebrand disease, and subjects diagnosed with Glanzmann's thrombasthenia. Within the vWD patient group, 12 patients had vWD type 1, 10 patients had vWD type 2, and 3 patients had vWD type 3.
| Group | N | Mean | SD | Median | Range |
|---|---|---|---|---|---|
| Healthy Donors | 142 | 381.5 | 55.5 | 390.9 | 142.5 - 467.7 |
| Aspirin Monotherapy | 57 | 218.4 | 114.4 | 205.7 | 2.7 - 410.9 |
| Clopidogrel + ASA | 18 | 46.2 | 47.3 | 21.7 | 3.6 - 159.8 |
| Prasugrel + ASA | 15 | 31.1 | 26.7 | 27.1 | 3.6 - 100.2 |
| Ticagrelor + ASA | 14 | 23.1 | 25.1 | 13.6 | 3.2 - 86.6 |
| von Willebrand Disease | 25 | 149.3 | 152.7 | 64.1 | 7.2 - 422.3 |
| Glanzmann's Thrombasthenia | 3 | 7.1 | 10.7 | 1.6 | 0.3 - 19.5 |
A summary of T-TAS 01 PL assay AUC results for the various subject groups is provided below.
The distribution of AUC results from healthy controls and subjects taking antiplatelet therapy is shown below.
{10}------------------------------------------------
Image /page/10/Figure/0 description: This image is a boxplot comparing the AUC values of different subject groups. The subject groups include Control, ASA, Clopidogrel + ASA, Prasugrel + ASA, and Ticagrelor + ASA. The AUC values for the control group are the highest, followed by ASA, and then the other three groups. The AUC values for Prasugrel + ASA and Ticagrelor + ASA are the lowest.
A summary of negative agreement and sensitivity of the AUC < 260 cutoff for aspirin monotherapy (ASA), dual antiplatelet therapy (DAPT, separated by DAPT type), von Willebrand disease (vWD), and Glanzmann's thrombasthenia (GT) is provided in the table below.
| Parameter | N | Value | 95% CI |
|---|---|---|---|
| Negative Agreement | 142 | 95.8% | 91.1-98.0% |
| Sensitivity (ASA) | 57 | 68.4% | 55.5-79.0% |
| Sensitivity (clopidogrel + ASA DAPT) | 18 | 100.0% | 81.5-100.0% |
| Sensitivity (prasugrel + ASA DAPT) | 15 | 100.0% | 78.2-100.0% |
| Sensitivity (ticagrelor + ASA DAPT) | 14 | 100.0% | 76.8-100.0% |
| Sensitivity (vWD) | 25 | 72.0% | 50.6-87.9% |
| Sensitivity (GT) | 3 | 100.0% | 43.9-100.0% |
Von Willebrand disease severity can be highly variable, particularly in Type 1 vWD, and patients with mild vWD may not present with clinically significant bleeding. Within the vWD patient group, abnormal PFA-100 Col/EPI and Col/ADP demonstrated sensitivity that was similar to the PL assay (80%, [95% Cl 61-90%]) and there was excellent overall agreement between the PL assay and PFA-100 assay (overall 88% [69-97%], percent positive agreement 72% [51-88%], percent negative agreement 100% [40-100%]). All 7 of the vWD patients with AUC results above 260 had either normal PFA-100 results or vWF activity, and FVIII:C results that were all higher than levels considered to be strongly associated with vWD (30%).
Conclusions:
The data and information provided in this submission demonstrate that the T-TAS 01 System with PL chip is at least as safe and as effective as the legally marketed predicate device, therefore supporting a substantial equivalence determination.
§ 864.5700 Automated platelet aggregation system.
(a)
Identification. An automated platelet aggregation system is a device used to determine changes in platelet shape and platelet aggregation following the addition of an aggregating reagent to a platelet-rich plasma.(b)
Classification. Class II (performance standards).