(28 days)
The TBI test is a panel of in vitro diagnostic chemiluminescent microparticle immunoassays (CMIA) used for the quantitative measurements of glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) in human plasma and serum and provides a semi-quantitative interpretation of test results derived from these measurements using the ARCHITECT i1000SR System.
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) within 12 hours of injury, to assist in determining the need for a CT (computed tomography) scan of the head. A negative test result is associated with the absence of acute intracranial lesions visualized on a head CT scan.
The TBI test is intended for use in clinical laboratory settings by healthcare professionals.
The TBI test is a panel of in vitro diagnostic quantitative measurements of GFAP and UCH-L1 and provides a semi-quantitative interpretation of GFAP and UCH-L1 in human plasma and serum.
GFAP: This assay is an automated, two-step immunoassay for the quantitative measurement of GFAP in human plasma and serum using chemiluminescent microparticle immunoassay (CMIA) technology.
UCH-L1: This assay is an automated, two-step immunoassay for the quantitative measurement of UCH-L1 in human plasma and serum using CMIA technology.
Interpretation of Results: The assay cutoffs were established to be 35.0 pg/mL (35.0 ng/L) for GFAP and 400.0 pg/mL (400.0 ng/L) for UCH-L1. The GFAP and UCH-L1 results are reported separately and the software provides a TBI interpretation relative to the respective cutoff values.
The provided text describes the TBI (Traumatic Brain Injury) test, an in vitro diagnostic device, and its performance evaluation for the ARCHITECT i1000SR system. The submission is a 510(k) for substantial equivalence to a predicate device (TBI on the Alinity i system).
Here's an analysis of the acceptance criteria and study as per your request, based on the provided text:
Acceptance Criteria and Reported Device Performance
The document does not explicitly present a "table of acceptance criteria" in the format of specific thresholds for the performance metrics. Instead, it states that the device "met the pre-defined product requirements for all characteristics evaluated in the verification studies." The performance metrics reported are for precision (20-Day and Reproducibility), Limits of Blank (LoB), Detection (LoD), Quantitation (LoQ), and Linearity, along with a comparison summary using Passing-Bablok regression against the predicate device.
Table of Reported Device Performance (Implied Acceptance through Meeting Requirements):
| Performance Metric | Reported Device Performance (TBI on ARCHITECT i1000SR) |
|---|---|
| GFAP 20-Day Precision | 2.2 to 6.2 %CV for samples with GFAP concentrations from 20.4 to 37,098.8 pg/mL |
| UCH-L1 20-Day Precision | 2.2 to 4.5 %CV for samples with UCH-L1 concentrations from 187.6 to 19,645.0 pg/mL |
| GFAP Reproducibility | 2.7 to 6.0 %CV for samples with GFAP concentrations from 23.6 to 34,087.5 pg/mL; 1.30 pg/mL SD for sample with GFAP concentration 19.1 pg/mL |
| UCH-L1 Reproducibility | 2.4 to 3.9 %CV for samples with UCH-L1 concentrations from 193.0 to 20,363.2 pg/mL |
| GFAP LoB | 2.0 pg/mL |
| GFAP LoD | 3.2 pg/mL |
| GFAP LoQ | 6.1 pg/mL |
| UCH-L1 LoB | 9.2 pg/mL |
| UCH-L1 LoD | 18.3 pg/mL |
| UCH-L1 LoQ | 26.3 pg/mL |
| GFAP Linearity | 6.1 to 42,000.0 pg/mL |
| UCH-L1 Linearity | 26.3 to 25,000.0 pg/mL |
| Sample Onboard Stability | 2 hours |
| Reagent Onboard/Calibration Curve Storage Stability | 30 days |
| Comparison to Predicate (GFAP) | N=123, R=1.00 (95% CI: 1.00, 1.00), Intercept: -0.6 (95% CI: -1.1, -0.3), Slope: 1.03 (95% CI: 1.02, 1.05) |
| Comparison to Predicate (UCH-L1) | N=123, R=1.00 (95% CI: 1.00, 1.00), Intercept: -6.0 (95% CI: -7.9, -4.0), Slope: 1.06 (95% CI: 1.05, 1.07) |
Study Details:
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Sample sizes used for the test set and the data provenance:
- Test Set (Method Comparison): N=123 for both GFAP and UCH-L1 assays in the comparison study against the predicate device.
- Data Provenance: The document does not specify the country of origin of the data or whether the data was retrospective or prospective. It refers to "verification studies" and "studies were performed based on guidance from CLSI EP09c, 3rd ed." These are typically laboratory-based analytical performance studies. The clinical utility of the test (used to aid in evaluation of patients with suspected mild TBI to determine need for CT scan) suggests that patient samples were likely used for the comparison study, but details about their collection (retrospective/prospective, patient demographics, clinical context) are not provided in this summary.
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Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- This information is not applicable and not provided in the document. The TBI test is an in vitro diagnostic (IVD) quantitative measurement of biomarkers (GFAP and UCH-L1). The "ground truth" for its performance is established by comparison to a legally marketed predicate device (K223602, TBI for Alinity i) and internal analytical performance studies using known concentrations or reference methods. The "interpretation of test results" for the TBI test (positive/negative) is based on established cutoff values for GFAP and UCH-L1, which are compared to CT scan results (absence of acute intracranial lesions). There is no mention of human experts directly establishing "ground truth" for the device's output itself in this context.
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Adjudication method (e.g., 2+1, 3+1, none) for the test set:
- Not applicable. This is an IVD device measuring biomarkers. Adjudication methods like 2+1 or 3+1 are typically used in image-based diagnostic studies where human readers interpret images, and consensus is sometimes needed to establish ground truth or resolve discrepancies.
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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:
- No. This is an in vitro diagnostic (IVD) test, not an AI-assisted imaging device that impacts human reader performance. Therefore, an MRMC study and effect size on human readers are not applicable.
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If a standalone (i.e., algorithm only without human-in-the-loop performance) was done:
- Yes, in a sense. The TBI test is a standalone device (a panel of immunoassays interpreted by defined cutoffs). Its performance is evaluated analytically (precision, linearity, LoD/LoQ) and by direct comparison of its measurements to those of a predicate device, which is also a standalone IVD. The interpretation of the test results (positive/negative) is an automated process based on the measured biomarker levels and predefined cutoffs. While the "interpretation of test results is used, in conjunction with other clinical information, to aid in the evaluation of patients... to assist in determining the need for a CT (computed tomography) scan," the device itself provides the result as an algorithm-driven interpretation (based on raw measurement data).
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The type of ground truth used (expert consensus, pathology, outcomes data, etc.):
- For the quantitative measurements (GFAP, UCH-L1), the "ground truth" in the comparative study is the performance of the legally marketed predicate device (TBI on Alinity i system, K223602). Analytical performance metrics (LoB, LoD, LoQ, linearity, precision) are established using reference materials or samples with known or characterized concentrations.
- For the clinical context of determining the "need for a CT scan of the head," the ground truth stated for a negative test result is its association with "the absence of acute intracranial lesions visualized on a head CT scan." This implies that CT scan findings serve as the clinical ground truth for evaluating the negative predictive value of the test, though this specific performance characteristic is not detailed in the provided summary. For the positive result, the test aids in determining the need for a CT scan, but the summary doesn't explicitly state the ground truth for a positive result (e.g., presence of lesions, clinical outcome).
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The sample size for the training set:
- No information about a "training set" is provided. This is an IVD device based on established immunoassay technology and predefined cutoffs, not a machine learning or AI algorithm that typically requires a distinct training phase with labeled data. The cutoffs (35.0 pg/mL for GFAP and 400.0 pg/mL for UCH-L1) are stated as "established," but the method and data used for their establishment are not described in this summary.
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How the ground truth for the training set was established:
- Not applicable as no "training set" is mentioned in the context of this 510(k) summary.
§ 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.”