(90 days)
The VIDAS® TBI (GFAP, UCH-L1) test is composed of two automated assays - VIDAS® TBI (GFAP) and VIDAS® TBI (UCH-L1) - to be used on the VIDAS® 3 instrument for the quantitative measurement of Glial Fibrillary Acidic Protein (GFAP) and Ubiquitin C-terminal Hydrolase (UCH-L1) in human serum using the ELFA (Enzyme Linked Fluorescent Assay) technique. The results of both assays are requred to obtain an overall qualitative test interpretation.
The overall qualitative VIDAS® TBI (GFAP, UCH-L1) test result is used, in conjunction with clinical information, to aid in the evaluation of patients (18 years of age or older), presenting within 12 hours of suspected mild traumatic brain injury (Glasgow Coma Scale score 13-15), to assist in determining the need for a Computed Tomography (CT) scan of the head. A negative interpretation of VIDAS® TBI (GFAP, UCH-L1) test is associated with the absence of acute intracranial lesions visualized on a head CT scan.
The VIDAS® TBI (GFAP, UCH-L1) test is composed of two automated assays – VIDAS® TBI (GFAP) and VIDAS® TBI (UCH-L1) – to be used on the VIDAS® 3 instrument. Similar to other VIDAS assays, VIDAS TBI (GFAP) and VIDAS TBI (UCH-L1) test kits (specific to each biomarker) contain the solid phase receptacles (SPRs®), the reagent strips, Product Calibrator S1 and Product Control C1. These test kits will also contain the master lot entry (MLE) data i.e., a barcode printed on the outer label of the packaging, as well as the reference number of the package insert to download from the bioMérieux website.
Whether it be for the GFAP or UCH-L1 quantification, the test combines a three-step enzyme immunoassay sandwich method with a final fluorescent detection step, also known as enzyme-linked fluorescent assay (ELFA).
The Solid Phase Receptacle (SPR) serves as the solid phase as well as the pipetting device. The inner surface of the SPR is coated with antibodies aqainst the substance of interest i.e., anti-GFAP or anti-UCH-L1 antibodies. The reagent strip consists of 10 wells covered with a labeled foil seal. Well 1 is designated for the sample. Eight of the wells contain sample diluent, wash buffer, conjugate, and tracer. The last well contains the fluorescent substrate. All of the assay steps are performed automatically by the instrument.
The intensity of the fluorescence is proportional to the concentration of the analyte the sample. At the end of the assay, the biomarker concentration is automatically calculated by the instrument in relation to the calibration curve and stored in the Master Lot Entry (MLE) data.
VIDAS TBI (GFAP) and VIDAS TBI (UCH-L1) results are reported separately: the VIDAS 3 reports the calculated concentration and the qualitative interpretation for each. The final result i.e., the patient's status in relation to suspected mild traumatic brain injury, must be interpreted by the user according to the decision tree presented in the package insert.
This document describes the validation of the VIDAS® TBI (GFAP, UCH-L1) test, an automated assay for diagnosing mild traumatic brain injury. The submission compares the device to a predicate device, the BANYAN BTI™, and summarizes non-clinical and clinical testing results. The following points address the requested information based on the provided text:
1. A table of acceptance criteria and the reported device performance
The document does not explicitly state "acceptance criteria" for each performance metric in a table format. However, it presents the results of various assays and often implies that the results "demonstrate" or "confirm" the required performance, indicating these are the achieved results compared to an internal standard or regulatory expectation. Below is a table summarizing various performance metrics and their reported results. Specific acceptance criteria values are not provided in this public summary.
| Performance Metric | Reported Device Performance |
|---|---|
| Analytical Measuring Interval | |
| VIDAS TBI (GFAP) | 10.0 - 320.0 pg/mL |
| VIDAS TBI (UCH-L1) | 80.0 - 2560.0 pg/mL |
| Linearity | |
| VIDAS TBI (GFAP) | Demonstrated on the range 6.7 - 354.5 pg/mL |
| VIDAS TBI (UCH-L1) | Demonstrated on the range 58.9 - 2769.1 pg/mL |
| Detection Limits | |
| Limit of Blank (LoB) - GFAP | 4.4 pg/mL |
| Limit of Detection (LoD) - GFAP | 5.4 pg/mL |
| Limit of Quantitation (LoQ) - GFAP | 5.4 pg/mL |
| Limit of Blank (LoB) - UCH-L1 | 41.8 pg/mL |
| Limit of Detection (LoD) - UCH-L1 | 48.1 pg/mL |
| Limit of Quantitation (LoQ) - UCH-L1 | 48.1 pg/mL |
| Hook Effect | |
| VIDAS TBI (GFAP) | No hook effect up to 200,000.0 pg/mL |
| VIDAS TBI (UCH-L1) | No hook effect up to 400,000.0 pg/mL |
| Calibration Frequency | Verified for 56 days |
| Sample Stability | Verified for specified storage conditions and freeze/thaw cycles |
| Diagnostic Accuracy | |
| Diagnostic Sensitivity | 96.7% |
| Diagnostic Specificity | 41.2% |
| Positive Likelihood Ratio | 1.6 |
| Negative Likelihood Ratio | 0.1 |
| Positive Predictive Value | 9.9% |
| Negative Predictive Value | 99.5% |
2. Sample size used for the test set and the data provenance (e.g., country of origin of the data, retrospective or prospective)
- Test set sample size: For the diagnostic accuracy study, the sample size is not explicitly stated but refers to the "ALERT cohort." For the reference interval study, 513 apparently healthy US adult subjects were used.
- Data provenance: The diagnostic accuracy study was performed using the "ALERT cohort." The reference interval study was conducted at three sites (one internal European site and two external US sites). It is not specified whether these studies were retrospective or prospective, though "ALERT cohort" could suggest a pre-existing dataset.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g., radiologist with 10 years of experience)
This information is not provided in the document. The diagnostic accuracy study compares the device's results to the presence/absence of acute intracranial lesions visualized on a head CT scan, but the number or qualifications of experts interpreting these CT scans to establish ground truth are not mentioned.
4. Adjudication method (e.g., 2+1, 3+1, none) for the test set
This information is not provided in the document.
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
A multi-reader multi-case (MRMC) comparative effectiveness study was not performed. This device is an in vitro diagnostic test for quantitative measurement of biomarkers, not an AI-assisted imaging device that impacts human reader performance.
6. If a standalone (i.e., algorithm only without human-in-the-loop performance) was done
Yes, the diagnostic accuracy study presents the standalone performance of the VIDAS® TBI (GFAP, UCH-L1) assay. The results (sensitivity, specificity, etc.) are based on the device's output compared to the ground truth (CT scan findings). The device is used "in conjunction with clinical information," but the reported diagnostic accuracy figures are for the test itself.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc)
The ground truth for the diagnostic accuracy study was "absence of acute intracranial lesions visualized on a head CT scan." This indicates that CT scan results were used as the reference standard for traumatic brain injury assessment.
8. The sample size for the training set
This document describes a diagnostic device and its validation. It does not explicitly mention a "training set" in the context of machine learning or AI models with distinct training and test phases. The "test set" for diagnostic accuracy is referred to as the "ALERT cohort." The reference interval was established using 513 apparently healthy subjects.
9. How the ground truth for the training set was established
As there is no explicitly defined "training set" for an AI model in this submission, the method for establishing ground truth for a training set is not applicable or described. The clinical performance data presented (Diagnostic Accuracy and Reference interval) seems to represent the evaluation of the final device.
§ 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.”