(89 days)
The i-STAT TBI test is a panel of in vitro diagnostic immunoassays for the quantitative measurements of glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) in whole blood and a semi-quantitative interpretation of test results derived from these measurements, using the i-STAT Alinity instrument. The interpretation of test results is used, in conjunction with other clinical information, to aid in the evaluation of patients, 18 years of age or older, presenting with suspected mild traumatic brain injury (Glasgow Coma Scale score 13-15), which may include one of the following four clinical criteria: 1) any period of loss of consciousness, 2) any loss of memory for events immediately before and after the accident, 3) any alteration in mental state at the time of accident, and/or 4) focal neurological deficits, within 24 hours of injury, to assist in determining the need for a CT (computed tomography) scan of the head. A 'Not Elevated' test interpretation is associated with the absence of acute traumatic intracranial lesions visualized on a head CT scan.
The test is to be used with venous whole blood collected with EDTA anticoagulant in point of care or clinical laboratory settings by a healthcare professional.
The i-STAT TBI cartridge is a multiplex immunoassay that contains assays for both ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein (GFAP). The assays test for the presence of these biomarkers in a whole blood sample and vield a semi-quantitative test interpretation based on measurements of both UCH-L1 and GFAP in approximately 15 minutes. The i-STAT TBI cartridge is designed to be run only on the i-STAT Alinity instrument.
The i-STAT Alinity instrument is a handheld, in vitro diagnostic device. The instrument is the main user interface of the i-STAT Alinity System and functions as the electro-mechanical interface to the test cartridge. The instrument executes the test cycle, acquires and processes the electrical sensor signals converting the signals into quantitative results. These functions are controlled by a microprocessor.
The i-STAT Alinity System is comprised of the i-STAT Alinity instrument, the i-STAT test cartridges and accessories (i-STAT Alinity Base Station, Electronic Simulator and Printer).
Assaved quality control materials are also available for use with the i-STAT TBI cartridge and include i-STAT TBI Control Level 1, i-STAT TBI Control Level 2, and the i-STAT TBI Calibration Verification Levels 1-3.
The i-STAT TBI Controls are available to monitor the performance of glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) assays on the i-STAT Alinity instrument.
The i-STAT TBI Calibration Verification Materials are available to verify the calibration of glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) assays throughout the reportable range on the i-STAT Alinity instrument.
The provided text describes the analytical and clinical performance of the i-STAT TBI cartridge with the i-STAT Alinity System, which measures GFAP and UCH-L1 to aid in the evaluation of patients with suspected mild traumatic brain injury (TBI). The information is presented to support a 510(k) premarket notification for substantial equivalence to a predicate device.
Here's an analysis of the acceptance criteria and the study proving the device meets them, based on the provided document:
1. A Table of Acceptance Criteria (Implied) and Reported Device Performance
The document does not explicitly present a "table of acceptance criteria" with predefined thresholds. Instead, it describes performance characteristics that are presumably deemed acceptable for demonstrating substantial equivalence. The core clinical performance criterion for this device, a TBI assessment test, is its ability to correctly identify patients not needing a head CT scan, which translates to high sensitivity and negative predictive value (NPV) for the absence of acute intracranial lesions.
Here's a summary of the reported core performance:
| Performance Metric | Reported Device Performance (i-STAT TBI cartridge with i-STAT Alinity System) |
|---|---|
| Clinical Sensitivity (for acute traumatic intracranial lesions) | 96.5% (273/283) [95% CI: 93.6%, 98.1%] |
| Clinical Specificity (for absence of acute traumatic intracranial lesions) | 40.3% (277/687) [95% CI: 36.7%, 44.0%] |
| Negative Predictive Value (NPV) | 96.5% (277/287) [95% CI: 93.7%, 98.1%] |
| Adjusted NPV at 6% prevalence | 99.4% [95% CI: 99.0%, 99.7%] |
| Positive Predictive Value (PPV) | 40.0% (273/683) [95% CI: 38.4%, 41.5%] |
| False Negative Rate | 3.5% (10/283) |
Key Implied Acceptance Criteria based on Regulatory Context:
- High Clinical Sensitivity: The device must reliably identify patients with acute intracranial lesions, minimizing false negatives to ensure patient safety and avoid missing critical injuries. A 96.5% sensitivity is presented as acceptable.
- High Negative Predictive Value (NPV): Crucially, the device's main utility is to aid in determining the need for a CT scan. A high NPV means that a "Not Elevated" result reliably indicates the absence of acute traumatic intracranial lesions. The 96.5% NPV (and higher adjusted NPV) supports this.
- Acceptable False Negative Rate: The reported 3.5% false negative rate, with the additional detail that "None of these ten (10) subjects with false negative results required surgical intervention related to their head injury as no neurosurgical lesions were identified by CT scan in these subjects," addresses a critical safety aspect.
- Analytical Performance: The document provides extensive data on analytical precision (semi-quantitative and qualitative, 20-day and multi-site), linearity, hook effect, traceability, reference interval, detection limit, analytical specificity (interference, cross-reactivity, cross-talk), and hematocrit sensitivity. These are all standard analytical performance characteristics that would need to meet predefined criteria (often internal to the manufacturer or based on regulatory guidance) to ensure the assay's reliability and robustness. While specific numerical acceptance criteria for each are not stated (e.g., "CV must be
§ 866.5830 Brain trauma assessment test.
(a)
Identification. A brain trauma assessment test is a device that consists of reagents used to detect and measure brain injury biomarkers in human specimens. The measurements aid in the evaluation of patients with suspected mild traumatic brain injury in conjunction with other clinical information to assist in determining the need for head imaging per current standard of care.(b)
Classification. Class II (special controls). The special controls for this device are:(1) The 21 CFR 809.10(b) compliant labeling must include detailed descriptions of and results from performance testing conducted to evaluate precision, accuracy, linearity, analytical sensitivity, interference, and cross-reactivity. This information must include the following:
(i) Performance testing of device precision must, at minimum, use one unmodified clinical specimen from the intended use population with concentration of the brain injury biomarker(s) near the medical decision point. Contrived specimens that have been generated from pooling of multiple samples or spiking of purified analyte to cover the measuring range may be used, but the contrived samples must be prepared to mimic clinical specimens as closely as possible. This testing must evaluate repeatability and reproducibility using a protocol from an FDA-recognized standard.
(ii) Device performance data must be demonstrated through a clinical study and must include the following:
(A) Data demonstrating clinical validity including the clinical sensitivity and specificity, and positive and negative predictive value of the test in the intended use population of patients with suspected mild traumatic brain injury (
i.e., Glasgow Coma Score (GCS) of 13-15), or equivalent standard of care for determination of severity of traumatic brain injury (TBI).(B) Study must be performed using the operators and in settings that are representative of the types of operators and settings for which the device is intended to be used.
(C) All eligible subjects must meet the well-defined study inclusion and exclusion criteria that define the intended use population. The prevalence of diseased or injured subjects in the study population must reflect the prevalence of the device's intended use population, or alternatively, statistical measures must be used to account for any bias due to enrichment of subpopulations of the intended use population.
(D) All eligible subjects must have undergone a head computerized tomography (CT) scan or other appropriate clinical diagnostic standard used to determine the presence of an intracranial lesion as part of standard of care and must also be evaluated by the subject device. All clinical diagnostic standards used in the clinical study must follow standard clinical practice in the United States.
(E) Relevant demographic variables and baseline characteristics including medical history and neurological history. In addition, head injury characteristics, neurological assessments, and physical evidence of trauma must be provided for each subject. This information includes but is not limited to the following: Time since head injury, time from head injury to CT scan, time from head injury to blood draw, GCS score or equivalent, experience of loss of consciousness, presence of confusion, episodes of vomiting, post-traumatic amnesia characteristics, presence of post-traumatic seizures, drug or alcohol intoxication, mechanism of injury, acute intracranial lesion type, neurosurgical lesion, and cranial fracture.
(F) Each CT scan or other imaging result must be independently evaluated in a blinded manner by at least two board-certified radiologists to determine whether it is positive or negative as defined by the presence or absence of acute intracranial lesions. This independent review must be conducted without access to test results of the device. Prior to conducting the review, the criteria and procedures to be followed for scoring the images must be established, including the mechanism for determining consensus.
(G) All the clinical samples must be tested with the subject device blinded to the TBI status and the neurological-lesion-status of the subject.
(H) Details on how missing values in data are handled must be provided.
(I) For banked clinical samples, details on storage conditions and storage period must be provided. In addition, a specimen stability study must be conducted for the duration of storage to demonstrate integrity of archived clinical samples. The samples evaluated in the assay test development must not be used to establish the clinical validity of the assays.
(iii) Performance testing of device analytical specificity must include the most commonly reported concomitant medications present in specimens from the intended use population. Additionally, potential cross-reacting endogenous analytes must be evaluated at the highest concentration reported in specimens from the intended use population.
(iv) Expected/reference values generated by testing a statistically appropriate number of samples from apparently healthy normal individuals.
(2) The 21 CFR 809.10(a) and (b) compliant labeling must include the following limitations:
(i) A limiting statement that this device is not intended to be used a stand-alone device but as an adjunct to other clinical information to aid in the evaluation of patients who are being considered for standard of care neuroimaging.
(ii) A limiting statement that reads “A negative result is generally associated with the absence of acute intracranial lesions. An appropriate neuroimaging method is required for diagnosis of acute intracranial lesions.”
(iii) As applicable, a limiting statement that reads “This device is for use by laboratory professionals in a clinical laboratory setting.”