(344 days)
The Quantra QPlus System is intended for in vitro diagnostic use.
The system is intended to be used by trained professionals at the point-of-care and in clinical laboratories to evaluate the viscoelastic properties of whole blood by means of the following functional parameters: Clot Time (CT), Clot Time with Heparinase (CTH), Clot Stiffness (CS), Fibrinogen Contribution to Clot Stiffness (FCS), Platelet Contribution to Clot Stiffness (PCS), and Clot Time Ratio (CTR).
The Quantra QPlus System is indicated for the evaluation of blood coagulation in perioperative patients age 18 years and older to assess possible hypocoagulable and hypercoagulable conditions in cardiovascular or major orthopedic surgeries before, during, and following the procedure.
Results obtained with the Quantra QPlus System should not be the sole basis for patient diagnosis.
For prescription use only.
The Quantra OPlus System is an in vitro diagnostic device designed to assess a patient's coagulation status by measuring the shear modulus of a blood sample during clot formation in perioperative settings in the point of care (POC) or clinical laboratory settings. The system consists of the Quantra Hemostasis Analyzer (instrument), QPlus Cartridge (singleuse disposable cartridge), Quantra Controls Level 2 (external quality control materials), and the Quantra Cleaning Cartridge.
The Quantra Hemostasis Analyzer is a fully integrated and automated in vitro diagnostic device designed to assess a patient's coagulation status by measuring the viscoelastic properties of a blood sample during clot formation. The analyzer consists of a base instrument with a software component. The instrument and the software are a closed system, using only Quantra assay cartridges.
The QPlus Cartridge is a single-use four-channel plastic cartridge which has a sample port on one end to draw the blood sample into the cartridge without requiring any sample pipetting. Lyophilized reagents are embedded into the four channels within the cartridge. The four channels enable four independent reactions/tests to be run simultaneously.
The cartridge comes sealed in a foil pouch. After a OPlus Cartridge is removed from its primary packaging, it is inserted into the instrument dock. A venous whole blood sample, collected in a 3.2% sodium citrate anticoagulant blood collection tube (minimum volume 2.7 mL), is attached directly to the cartridge and the test is initiated using the touch screen interface on the Quantra Hemostasis Analyzer. The fluidic system within the instrument draws the sample into the cartridge where it is warmed to 37°C, aliquoted, introduced and mixed with the lyophilized reagents, and analyzed. When the test is complete, the cartridge is released from the dock to be disposed of in an appropriate biosafety sharps container.
The analyzer displays the test results in three different views: dial display screen, stiffness curves, and trend data. The dial display screen is the primary viewing screen and has a dial for each of the six output parameters. Each dial shows the reference range, assay measurement range, parameter abbreviation, and the numerical result for the corresponding parameter. The stiffness curves are a graphical display of shear modulus measurements over time that enable the user to view the development of clot stiffness over time. The trend data display provides numeric results of tests run during the past 48 hours for a specific patient. In the trend data view, multiple samples from the same patient are displayed.
The device outputs four directly measured parameters (Clot Time, Clot Time with Heparinase, Clot Stiffness, and Fibrinogen Contribution to Clot Stiffness) as well as two calculated parameters (Clot Time Ratio and Platelet Contribution to Clot Stiffness).
Acceptance Criteria and Device Performance for The Quantra QPlus System
The Quantra QPlus System's performance was evaluated through various studies to demonstrate its analytical and clinical capabilities. The acceptance criteria largely stemmed from the regulatory requirements outlined in 21 CFR §864.5430(b)(1).
1. Table of Acceptance Criteria and Reported Device Performance
The acceptance criteria are derived from the special controls specified in 21 CFR §864.5430(b)(1). The reported device performance is summarized from the analytical and clinical studies described in the document.
| Acceptance Criteria Category | Specific Criteria (from 21 CFR §864.5430(b)(1)) | Reported Device Performance |
|---|---|---|
| Precision | i. A study assessing precision... to cover the measurement range for each reported parameter (test output). Testing must include native specimens... (not to exceed 10-20% contrived specimens). This testing must evaluate repeatability and reproducibility and provide assessments of within-run, within-day, between-run, between-day, between-reagent lot, between-instrument, between-site, and between-operator precision, as applicable to the system. | Single-site Precision: Within-laboratory precision (total) of 3.6-6.1% for QQC Level 1 and 3.6-9.8% for QQC Level 2. Multi-site Precision: Total precision (reproducibility) %CVs ranged from 3.9-5.3% for QQC Level 1 and 3.6-8.3% for QQC Level 2 (pooled data). Whole Blood Repeatability: CVtot or SDtot for CT, CTH, CS, FCS, and PCS were generally within acceptable limits (e.g., CT and CTH below 12%, CS below 12%, FCS below 14% or 0.2 hPa). |
| Linearity/Reportable Range | ii. Studies that demonstrate the performance of each parameter (test output) throughout the claimed measurement range, to include linearity studies or dose-response studies, as applicable to the parameter (test output). | Dose-Response Studies: Heparin (CT, CTH), Dabigatran (CT, CTH), platelet count (PCS, CS), platelet activity (PCS, CS, FCS), and fibrinogen (FCS, CS) demonstrated appropriate functional responses across claimed ranges. Combined Support: Data from functional response studies, whole blood repeatability, and clinical samples supported the claimed reportable ranges for all parameters (CT, CTH, CTR, CS, FCS, PCS). |
| Analytical Specificity (Interference) | iii. Potential interferent study that includes evaluation of hemolyzed and lipemic samples as potential interferents; exogenous and endogenous interferents associated with each patient population intended for use with the device... must be evaluated; and potential interferents that are specific for... the device. Evaluation of all potential interferents must be performed using a protocol determined to be acceptable by the FDA (e.g., an FDA-recognized standard) and include both normal and abnormal specimens covering coagulation profiles representative of the intended use population. | Interference Study: Evaluated lipid (Intralipid), hemolysis, clopidogrel, tranexamic acid, aspirin, dabigatran, rivaroxaban, heparin, and protamine sulfate in normal and hypocoagulable blood. Detailed results of concentrations where no effect was observed and where effects were demonstrated are provided in the document. |
| Specimen Stability | iv. A study that evaluates specimen stability under the intended conditions for specimen collection, handling, and storage, using samples that cover the coagulation profiles representative of the intended use population, and using protocols determined to be acceptable by FDA. | Specimen Stability Study: Supported a 4-hour claim at room temperature for citrated whole blood specimens (normal and two types of hypocoagulable specimens). |
| Multi-site Clinical Study | v. A multi-site clinical study, determined to be acceptable by FDA, demonstrating performance, relative to clinically relevant and clinically validated laboratory test(s) for each parameter (test output). The study must be performed in the intended use population and include representation from all patient populations... conducted at a minimum of three external sites... Test samples must be collected at time intervals relevant to the device's use... Clinical specimens... must be evaluated at each of the three clinical sites... Analysis of the concordance of clinical interpretation of patient coagulation status made from individual test parameter (test output) results as compared to clinical interpretation of coagulation status from a clinically relevant laboratory test or tests (e.g., a comparative viscoelastic device or standard laboratory tests) must be conducted. | Clinical Performance Study: A multi-center, prospective observational study (NCT03152461) conducted at 4 sites. Concordance with SLTs: Overall agreement ranged from 0.72 (CT) to 0.98 (CTR) for various parameters against Composite Clinical Indices. Concordance with ROTEM: Correlation (R) ranged from 0.84 to 0.89 for Quantra parameters vs. comparable ROTEM assays. Overall agreement ranged from 0.85 (CT) to 0.95 (FCS) for various parameters vs. ROTEM. |
| Reference Values | F. Expected (reference) values for each parameter (test output) must be demonstrated by testing a statistically appropriate number of samples from apparently healthy normal individuals. | Reference Range Study: Established adult reference ranges for CT (104-166 sec), CTH (103-153 sec), CS (13.0-33.2 hPa), FCS (1.0-3.7 hPa), and PCS (11.9-29.8 hPa) from 129 healthy individuals. |
| User Interpretation Study | vi. For a device with a user interface that has information that needs to be interpreted by the user... a study evaluating the ability of device users to correctly interpret results. | Reader Study: 14 critical care professionals at 3 sites correctly interpreted results from Quantra dial display screens >95% of the time after training. |
2. Sample Sizes Used for the Test Set and Data Provenance
-
Clinical Performance Study:
- Total Subjects: 277 eligible subjects (initially 302 consented, 25 did not complete).
- Patient Categories:
- 264 patients undergoing cardiac, vascular, or orthopedic surgery
- 7 patients presented with acute bleeding or suspected hypercoagulation post-cardiac surgery
- 13 patients with abnormal coagulation profiles
- 18 normal individuals whose blood was artificially manipulated (contrived) to mimic abnormal coagulation profiles (used to supplement clinical data).
- Data Provenance: Multi-center, prospective observational study conducted in the United States at four clinical sites (University of Virginia School of Medicine, Duke University Medical Center, Medical University of South Carolina, and University of Maryland School of Medicine).
-
Reference Range Study:
- Total Subjects: 129 eligible subjects (initially 158 healthy male and female volunteers >= 18 years old were enrolled).
- Data Provenance: Multi-center, prospective, observational study across three external sites in the United States.
-
Precision Studies (Whole Blood Repeatability):
- Whole Blood Specimens: Included normal, abnormal, and contrived samples to cover reportable ranges. Specific 'n' values range from 3 to 20 for different parameters and ranges in the detailed tables.
- Data Provenance: Conducted at one internal site.
-
Interference Study:
- Whole Blood Samples: Spiked normal and hypocoagulable blood (heparin-treated, abciximab-treated, fibrinogen-depleted plasma).
- Data Provenance: Not explicitly stated, but typically conducted in a laboratory setting.
3. Number of Experts and Qualifications for Ground Truth
The document does not explicitly state the number of experts used to establish ground truth for the test set in the same way one might describe a panel of radiologists reviewing images. Instead, the ground truth for the clinical performance study relied on:
- Standard Laboratory Tests (SLTs): These are FDA-cleared and widely accepted methods (e.g., aPTT, ACT, INR, Clauss fibrinogen, platelet count).
- ROTEM delta Thromboelastometry System: An FDA-cleared viscoelastic device (K101533, K083842).
The "Clinical Composite Indices (CCIs)" were developed "based on in-depth review of the clinical literature, clinical guidelines and consideration from multiple physicians." While "multiple physicians" were involved in developing these indices, their specific number and qualifications (e.g., years of experience, specialty) are not detailed for establishing the ground truth of individual cases within the test set.
4. Adjudication Method
No explicit adjudication method (e.g., 2+1, 3+1) is described for resolving disagreements in ground truth for the clinical test set. The ground truth was established by:
- Clinically relevant and validated standard laboratory tests (SLTs): These tests inherently have established methodologies and result interpretations.
- The ROTEM delta Thromboelastometry System: Also an established device with its own interpretation criteria.
- Clinical Composite Indices (CCIs): Criteria for these indices were defined based on literature and physician input, providing objective classification categories ("Low," "Normal/Subclinical," "High").
The comparison was then made between the Quantra QPlus System's classification and the classification derived from these objective comparators. Therefore, rather than a subjective adjudication process, this relied on agreement with established, objective laboratory and device results.
5. Multi Reader Multi Case (MRMC) Comparative Effectiveness Study
No explicit MRMC comparative effectiveness study, evaluating how much human readers improve with AI vs. without AI assistance, was conducted or described in this document. The "Reader Study" (Section O) focused solely on the ability of potential Quantra users to correctly interpret results displayed on the Quantra Hemostasis Analyzer's dial display screen, rather than a comparison of diagnostic accuracy with and without AI assistance to human interpretation.
6. Standalone (Algorithm Only Without Human-in-the-Loop Performance)
Yes, the primary performance evaluation of the Quantra QPlus System (which includes the analyzer and its embedded software/algorithm) focused on its standalone performance. The analytical performance studies (precision, linearity, interference, stability) and the clinical concordance studies (against SLTs and ROTEM) all evaluated the device's ability to accurately measure and classify coagulation parameters directly, without human interpretation influencing the measurement itself. The "Reader Study" evaluated the user's ability to interpret the device's output, confirming appropriate human-device interaction, but the core measurement and classification performance is standalone.
7. Type of Ground Truth Used
The ground truth used for evaluating the clinical performance of the Quantra QPlus System was a combination of:
- Standard Laboratory Tests (SLTs): These included aPTT, ACT, INR, Clauss fibrinogen, and platelet count. These are widely accepted and routinely used in clinical practice.
- A Comparative Viscoelastic Device (ROTEM delta): This is an FDA-cleared device that provides similar viscoelastic measurements.
- Clinical Composite Indices (CCIs): These were derived from the SLT data and the status of heparin use, developed based on clinical literature, guidelines, and physician input. These effectively codified expert consensus into objective criteria for classifying coagulation states.
- Pathology/Outcomes Data: Not directly mentioned as primary ground truth, but the relevance of coagulation assessment for perioperative patients is linked to patient outcomes (e.g., blood product usage, bleeding/thrombosis risk).
8. Sample Size for the Training Set
The document does not specify a separate "training set" or its sample size. This is typical for a De Novo submission for a diagnostic device like the Quantra QPlus System, which is an in vitro diagnostic (IVD) device. The device's algorithms for calculating parameters (CT, CTH, CS, FCS, PCS, CTR) are based on the physics of SEER Sonorheometry and established coagulation principles, rather than being "trained" on a large dataset of clinical images or physiological waveforms in the way a deep learning AI model would be.
The "functional response studies" (e.g., heparin dose-response, platelet/fibrinogen levels) could be seen as part of the developmental work that informed the algorithm's design and parameter calculation methods, ensuring they reflect known biological responses. These studies involve spiking samples from a smaller number of donors (e.g., 5 normal donors for heparin, 4 donors for platelet count, etc.).
9. How the Ground Truth for the Training Set Was Established
As noted above, there isn't a traditional "training set" with ground truth established in the AI/machine learning sense. The device's underlying principles are based on the physics of mechanical properties of clots and their progression. The "ground truth" for developing and validating the functional calculations within the device would have involved:
- Known concentrations/manipulations: For instance, in dose-response studies, blood samples were spiked with known concentrations of heparin or platelet inhibitors, or adjusted to known platelet/fibrinogen levels. The expected outcome (e.g., linear increase in CT with heparin, decrease in CS/PCS with platelet inhibition) serves as the "ground truth" for the algorithm's ability to reflect these changes.
- Reference methods: Fibrinogen levels, for example, were confirmed using the Clauss fibrinogen assay, a standard reference method.
This approach ensures the device accurately measures the intended physical properties and reflects real-world physiological changes in a quantifiable manner.
§ 864.5430 Coagulation system for the measurement of whole blood viscoelastic properties in perioperative patients.
(a)
Identification. A coagulation system for the measurement of whole blood viscoelastic properties in perioperative patients is an in vitro diagnostic device used to evaluate blood coagulation, fibrinolysis, or both, in perioperative patients, as an aid in the assessment of coagulopathies when used in conjunction with clinical signs and symptoms and other clinical and laboratory findings.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Design verification and validation must include detailed documentation of, and results from, the following:
(i) A study assessing precision using protocols determined to be acceptable by FDA, to cover the measurement range for each reported parameter (test output). Testing must include native specimens with coagulation profiles representative of the intended use population. In order to cover the measuring range, testing may include a limited number of contrived specimens, not to exceed 10 to 20 percent, or as otherwise deemed appropriate by FDA. The contrived specimens must be prepared to resemble clinical specimens. This testing must evaluate repeatability and reproducibility and provide assessments of within-run, within-day, between-run, between-day, between-reagent lot, between-instrument, between-site, and between-operator precision, as applicable to the system;
(ii) Studies that demonstrate the performance of each parameter (test output) throughout the claimed measurement range, to include linearity studies or dose-response studies, as applicable to the parameter (test output);
(iii) Potential interferent study that includes evaluation of hemolyzed and lipemic samples as potential interferents; exogenous and endogenous interferents associated with each patient population intended for use with the device, and which might be expected to affect assay performance, must be evaluated; and potential interferents that are specific for, or related to, the technology or methodology of the device. Evaluation of all potential interferents must be performed using a protocol determined to be acceptable to the FDA (
e.g., an FDA-recognized standard) and include both normal and abnormal specimens covering coagulation profiles representative of the intended use population;(iv) A study that evaluates specimen stability under the intended conditions for specimen collection, handling, and storage, using samples that cover the coagulation profiles representative of the intended use population, and using protocols determined to be acceptable by FDA;
(v) A multisite clinical study, determined to be acceptable by FDA, demonstrating performance, relative to clinically relevant and clinically validated laboratory test(s) for each parameter (test output). Further, the study must meet all of the following criteria:
(A) The study must be performed in the intended use population and include representation from all patient populations for whom the device is intended to be used. Potential endogenous and exogenous interferents for each target patient population must be evaluated or known prior to the study;
(B) The study must be conducted at a minimum of three external sites representative of the intended use setting by the intended operators;
(C) Test samples must be collected at time intervals relevant to the device's use in the intended use population;
(D) Clinical specimens, which cover coagulation profiles representative of the intended use population, must be evaluated at each of the three clinical sites in the study;
(E) Analysis of the concordance of clinical interpretation of patient coagulation status made from individual test parameter (test output) results as compared to clinical interpretation of coagulation status from a clinically relevant laboratory test or tests (
e.g., a comparative viscoelastic device or standard laboratory tests) must be conducted; and(F) Expected (reference) values for each parameter (test output) must be demonstrated by testing a statistically appropriate number of samples from apparently healthy normal individuals;
(vi) For a device with a user interface that has information that needs to be interpreted by the user in correctly using the device to achieve the intended test results or a device that does not provide a final output that is a comprehensive interpretation of all parameter (test output) results, a study evaluating the ability of device users to correctly interpret results;
(vii) For any device indicated to guide blood product use, a clinical outcome study determined to be acceptable by FDA that specifically validates the device's indicated use in guiding blood product use; and
(viii) For any device indicated to guide use of medication, a clinical outcome study determined to be acceptable by FDA that specifically validates the device's indicated use in guiding use of medication.
(2) The labeling required under § 809.10(b) of this chapter must include the following:
(i) A summary of results from the study required by paragraph (b)(1)(i) of this section, including repeatability, reproducibility, and assessments of within-run, within-day, between-run, between-day, between-reagent lot, between-instrument, between-site, and between-operator precision, as applicable to the system.
(ii) The claimed measurement range of each parameter (test output), as supported by demonstrated performance of the parameter (test output) throughout the claimed measurement range, including studies required by paragraphs (b)(1)(i) through (iii) and (v) of this section, and, if applicable, paragraphs (b)(1)(vii) and (viii) of this section.
(iii) Identification of known interferents, including all endogenous, exogenous, technology-specific, and patient population-specific interferents, specific to each parameter (test output). The information must include the concentration(s) or level(s) at which interference was found to occur and the concentration range or levels at which interference was not found to occur.
(iv) Information regarding the multisite clinical study required by paragraph (b)(1)(v) of this section, including:
(A) Each patient population evaluated;
(B) Each intended use setting and the operators;
(C) A summary of the results, including the concordance analysis to clinically relevant laboratory test(s); and
(D) Demonstrated expected (reference) values for each parameter (test output).
(3) The labeling required under § 809.10 of this chapter must include the following:
(i) A limiting statement that the result(s) from the device is(are) not intended to be used as the sole basis for a patient diagnosis.
(ii) Unless appropriate clinical outcome studies are done in accordance with paragraph (b)(1)(vii) of this section that specifically validate an indication for the device's use in guiding blood product use, a limiting statement that the device has not been evaluated to guide blood product use.
(iii) Unless appropriate clinical outcome studies are done in accordance with paragraph (b)(1)(viii) of this section that specifically validate an indication for the device's use in guiding use of medication, a limiting statement that the device has not been evaluated to guide use of medication.