(528 days)
The i-STAT PTP45 cartridge is intended for use in the in vitro quantitative measurement of the extrinsic coagulation pathway when activated by thromboplastin in non-anticoagulated whole blood (venous or capillary), using the i-STAT 1 System. Measurements of prothrombin time are used to aid in the monitoring of patients receiving anticoagulant therapy with coumarin derivatives. The i-STAT PT246 Prothrombin Time test result is reported in seconds and as an International Normalized Ratio (INR). The test is intended for point of care use and is for prescription use only.
The i-STAT 1 System consists of the i-STAT 1 analyzer and the i-STAT cartridges. Other components of the i-STAT 1 System are the Electronic Simulator, the i-STAT 1 Downloader/Recharger and the i-STAT Printer. The i-STAT 1 analyzer is a handheld, in vitro diagnostic analytical device designed to run only i-STAT test cartridges. The system is designed for use by trained medical professionals at the patient point of care or in the clinical laboratory and is for prescription use only.
The i-STAT PTPlus cartridge is a coagulation cartridge for determining the time required for complete activation of the extrinsic coagulation cascade. The cartridge contains electrochemical sensors and test reagents that must be mixed with the sample. The reagents include the reactive ingredient to activate the coagulation cascade as well as electrochemical markers that generate a sensor signal when the cascade is fully activated.
The analysis time of the i-STAT PT2405 cartridge is up to 300 seconds (5 minutes). The sample volume required for the i-STAT PT2105 cartridge is approximately 20 ul of whole blood (venous or capillary) without added anticoagulant. The i-STAT PTplus cartridge is a single-use disposable unit that is self-contained. The test reagents and sample fluids do not contact the instrument or user. All the test steps and fluid movements occur within the cartridge.
The i-STAT 1 System has an internal quality control (internal simulator) and an external quality control (Electronic Simulator). The internal and external simulators are used to check the instrument signal-reading function. In addition to the quality controls within the i-STAT 1 System, liquid quality controls are available as an optional quality control methodology to meet the regulatory compliance requirements applicable to the facility where they are to be used.
The liquid quality controls are the i-STAT PT2008 Control Levels 1 and 2 and can be used for the quality control of the i-STAT PT2005 cartridge. The coagulation controls consist of lyophilized citrated human plasma and calcium chloride fluid for reconstitution.
i-STAT PT2145 Control Level 1 has been formulated to produce a normal prothrombin time. Level 2 has been formulated to produce an extended prothrombin time.
Each level of control is packaged as a box of 5 vials containing 1 mL of lyophilized citrated human plasma and 5 vials of 1.5 mL of calcium chloride diluent.
The i-STAT PT2"45 controls are intended for use with the i-STAT PTP"46 cartridge on the i-STAT System, and values assigned to these controls may not be commutable with other commercial methods.
Here's an analysis of the provided FDA 510(k) summary for the i-STAT PTplus Cartridge with the i-STAT 1 System, structured to address your request about acceptance criteria and study proof.
Device: i-STAT PTplus Cartridge with the i-STAT 1 System
Device Name: Prothrombin Time Test
Regulation Number: 21 CFR 864.7750
Regulatory Class: Class II
This document is a 510(k) summary, which focuses on demonstrating substantial equivalence to a predicate device, rather than defining specific pre-defined acceptance criteria in the same way one might for a novel high-risk device or an AI/ML product where clinical endpoints are primary. For an IVD like a PT test, the "acceptance criteria" are generally established through analytical performance metrics that demonstrate equivalence or non-inferiority to a legally marketed predicate and established scientific principles for laboratory tests. The studies predominantly prove analytical performance.
1. Table of Acceptance Criteria and Reported Device Performance
Given this is a 510(k) for an In Vitro Diagnostic (IVD) device, the "acceptance criteria" aren't explicitly stated as pass/fail thresholds against specific performance numbers in the summary. Instead, they are implicitly defined by robust analytical performance demonstrating precision, linearity, traceability, and method comparison with a predicate and a reference method. The goal is to show the new device performs comparably and acceptably for its intended use.
Here, I've interpreted "acceptance criteria" as ranges or levels of performance that are considered acceptable for a prothrombin time test, and then listed the reported device performance.
| Performance Metric | Implicit Acceptance Criteria (General for IVD PT Test) | Reported Device Performance (i-STAT PTplus) |
|---|---|---|
| Reportable Range (INR) | Must cover clinically relevant range. Predicate range: 0.8-8.0 INR. New device should cover at least this and ideally extend. | 0.8 - 8.0 INR (matches predicate in lower-to-mid range, extends higher in seconds) |
| Reportable Range (seconds) | Must cover clinically relevant range. (Predicate only specifies INR). | 8.1 - 80.8 seconds (extends beyond the predicate's specified INR range when converted to seconds). |
| Precision/Reproducibility | Low coefficient of variation (CV%) and standard deviation (SD) across different levels (normal, therapeutic, high) and testing conditions (within-run, between-run, between-day). Comparable to predicate or established clinical standards. | Liquid Controls (Within-laboratory for INR): |
| L1 (1.03 INR): SD 0.031 (3.0% CV) (Lot A), SD 0.034 (3.3% CV) (Lot B), SD 0.029 (2.8% CV) (Lot C) | ||
| L2 (2.43 INR): SD 0.090 (3.7% CV) (Lot A), SD 0.090 (4.0% CV) (Lot B), SD 0.058 (2.5% CV) (Lot C) | ||
| L3 (5.34 INR): SD 0.366 (6.8% CV) (Lot A), SD 0.208 (4.2% CV) (Lot B), SD 0.090 (1.7% CV) (Lot C) | ||
| Whole Blood (Capillary INR): | ||
| Non-therapeutic (1.48 INR): SD 0.143 (9.7% CV) | ||
| Therapeutic (2.82 INR): SD 0.148 (5.2% CV) | ||
| Very High Therapeutic (5.02 INR): SD 0.201 (4.0% CV) | ||
| Whole Blood (Venous INR): | ||
| Non-therapeutic (1.45 INR): SD 0.109 (7.5% CV) | ||
| Therapeutic (2.85 INR): SD 0.069 (2.4% CV) | ||
| Very High Therapeutic (5.38 INR): SD 0.088 (1.6% CV) | ||
| Method Comparison (vs. Predicate) | High correlation (R value close to 1), slope close to 1, and intercept close to 0, indicating strong agreement with the predicate device. | Venous (INR): N=191, R=0.98, Slope=0.875, Intercept=0.113 |
| Capillary (INR): N=153, R=0.97, Slope=0.885, Intercept=0.104 | ||
| Method Comparison (vs. Reference) | High correlation (R value close to 1), slope close to 1, and intercept close to 0, indicating strong agreement with the reference method ( | Venous (INR): N=211, R=0.92, Slope=1.037, Intercept=0.004 |
| Capillary (INR): N=203, R=0.91, Slope=1.022, Intercept=0.047 | ||
| Interference | No clinically significant interference from common endogenous/exogenous substances at specified concentrations. | No interference found for most tested substances. |
| Interference identified for Chlorhexidine digluconate (≥ 9.58x10^-4 %), Daptomycin (≥ 0.22 mg/mL), and Oritavancin (≥ 104 mg/L). This "interference" is a finding and typically results in a warning or limitation in the labeling rather than a failure of acceptance criteria if the impact is characterized. | ||
| Factor Sensitivity (FII, FV, FVII, FX) | Device should show expected sensitivity to factor deficiencies. | FII - 39.5%; FV - 42.0%; FVII - 21.5%; FX - 22.0% (estimated sensitivity at which the device detects a change) |
| Fibrinogen Sensitivity | Insensitive to changes in fibrinogen within a specified range. | Insensitive across 63 – 702 mg/dL. |
| Platelet Sensitivity | Insensitive to changes in platelet count within a specified range. | Insensitive in the range of 70,000 - 670,000/mm². |
| Hematocrit Sensitivity | Insensitive to changes in hematocrit within a specified range. | Insensitive in the range of 24 to 54% PCV. |
| Heparin Sensitivity | Insensitive to unfractionated heparin up to a certain concentration. | Insensitive up to 1.0 IU/mL. |
| Lupus Anticoagulant Sensitivity | May or may not be sensitive; characterization is important for clinical context. | Sensitive to both low and high levels of lupus anticoagulant antibodies. |
| Reference Range | Established normal range for healthy individuals. | Capillary: 0.9 - 1.3 INR (Mean 1.1 INR), 9.0 - 13.8 seconds (Mean 10.6 seconds) |
| Venous: 0.9 - 1.3 INR (Mean 1.1 INR), 9.2 - 13.0 seconds (Mean 10.6 seconds) |
2. Sample Size Used for the Test Set and Data Provenance
- Precision/Reproducibility (Liquid Controls): N=104-120 per fluid level per cartridge lot (total of 9 measurements * ~115 samples = ~1035 data points). Data provenance implied as internal laboratory study.
- Precision (Whole Blood):
- Capillary: N=58 (non-therapeutic), N=119 (therapeutic), N=9 (very high therapeutic).
- Venous: N=65 (non-therapeutic), N=131 (therapeutic), N=13 (very high therapeutic).
- Data provenance: Samples collected from "three (3) point of care sites" for repeatability analysis. Implied retrospective or prospective collection based on CLSI guidelines.
- Method Comparison (vs. Predicate):
- Venous: N=191* (samples with outliers included)
- Capillary: N=153* (samples with outliers included)
- Data provenance: "prospectively collected from subjects undergoing anticoagulant therapy with coumarin derivates and from subjects who were not on anticoagulant therapy at three (3) clinical sites." (Prospective)
- Method Comparison (vs. Reference):
- Venous: N=211* (samples with outliers included)
- Capillary: N=203* (samples with outliers included)
- Data provenance: "prospectively collected from subjects undergoing anticoagulant therapy with coumarin derivates and from subjects who were not on anticoagulant therapy at three (3) clinical sites." (Prospective)
- Interference: Not explicitly stated N, but implied adequate for the substances tested.
- Factor Sensitivity: Not explicitly stated N.
- Fibrinogen, Platelet, Hematocrit, Heparin Sensitivity, Lupus Anticoagulant: Not explicitly stated N.
- Reference Range:
- Capillary: N=146
- Venous: N=154
- Data provenance: "apparently healthy adult subjects" from "three (3) clinical sites." (Likely Prospective)
Country of Origin: Not explicitly stated, but "CLSI guidelines" are US-based and "FDA" approval implies US studies or studies compliant with US standards. Assuming US/North American origin.
3. Number of Experts Used to Establish Ground Truth for the Test Set and Qualifications
This section is not applicable in the context of this device. This is an In Vitro Diagnostic (IVD) device for measuring a quantitative biomarker (prothrombin time). The "ground truth" for these studies is typically established by:
- Reference Methods: Such as the Sysmex CS-2500 instrument in this case, which is a laboratory instrument considered a more definitive measurement.
- Predicate Devices: The CoaguChek® XS Plus System, which is a legally marketed device used for comparison to demonstrate equivalence.
- Assigned Values for Controls/Calibrators: For analytical precision and linearity.
- Clinical Outcomes/Pathology: Not used directly for establishing "ground truth" for the PT measurement itself, but the PT values might be correlated with outcomes in broader clinical studies (which are not detailed here as part of the 510k).
There are no human "experts" rating images or making diagnoses that would require adjudication; the measurements are quantitative.
4. Adjudication Method for the Test Set
Not applicable. As a quantitative IVD, there is no subjective rating or interpretation by multiple readers that would require an adjudication method (like 2+1, 3+1 consensus for imaging studies). Measurements from instruments are taken as-is for statistical analysis.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
Not applicable. This is an In Vitro Diagnostic (IVD) device, not an AI/ML imaging device that assists human readers. Therefore, an MRMC study and analysis of human reader improvement with AI assistance are not relevant to this submission.
6. Standalone (Algorithm Only) Performance
The device itself (i-STAT PTplus Cartridge with the i-STAT 1 System) is the "standalone" diagnostic method. Its performance is measured directly by comparing its results to a predicate device and a laboratory reference instrument (Sysmex CS-2500). There isn't a separate "algorithm" that generates interpretations for human-in-the-loop use. The reported analytical performance (precision, correlation, etc.) reflects its standalone performance.
7. The Type of Ground Truth Used
The ground truth for evaluating the i-STAT PTplus cartridge performance was established primarily through:
- Validated Reference Method: The Sysmex CS-2500 (using Dade Innovin reagent) for venous plasma measurements, considered a reliable laboratory method for PT.
- Legally Marketed Predicate Device: The CoaguChek® XS Plus System, used for direct comparison to demonstrate substantial equivalence.
- Internal Control Fluids/Levels: For precision studies against known or assigned values.
- Clinical Samples: From patients on and not on anticoagulant therapy, characterized by their clinical status.
8. The Sample Size for the Training Set
Not applicable. This device does not use machine learning or AI that requires a "training set" in the traditional sense. It's a chemical and electrochemical analysis system. The development and internal validation of the cartridge's reagents and measurement principles would involve extensive R&D and analytical testing, but this isn't structured as a conventional ML training set.
9. How the Ground Truth for the Training Set Was Established
Not applicable. As stated above, there is no AI/ML training set for this device. The "ground truth" for development and validation would involve standard analytical chemistry and medical device engineering practices, using reference materials, spiked samples, and clinical samples analyzed by established laboratory methods.
§ 864.7750 Prothrombin time test.
(a)
Identification. A prothrombin time test is a device used as a general screening procedure for the detection of possible clotting factor deficiencies in the extrinsic coagulation pathway, which involves the reaction between coagulation factors III and VII, and to monitor patients receiving coumarin therapy (the administration of one of the coumarin anticoagulants in the treatment of venous thrombosis or pulmonary embolism).(b)
Classification. Class II (performance standards).