(192 days)
No
The document describes a device that measures biomarkers and provides a semi-quantitative interpretation based on fixed cutoff values determined through statistical analysis of a training set. There is no mention of adaptive algorithms, learning from data during operation, or other characteristics typically associated with AI/ML. The interpretation is based on pre-defined thresholds, not a dynamic model.
No
The device is an in vitro diagnostic immunoassay that measures biomarkers to aid in the evaluation of patients with suspected traumatic brain injury, assisting in determining the need for a CT scan. It is used for diagnosis, not treatment.
Yes
The "Intended Use / Indications for Use" section explicitly states "The i-STAT TBI Plasma test is a panel of in vitro diagnostic immunoassays..." and "The i-STAT Alinity instrument is a handheld, in vitro diagnostic device...". The test aims to "aid in the evaluation of patients...to assist in determining the need for a CT (computed tomography) scan of the head," which is a diagnostic purpose.
No
The device description clearly states that the system is comprised of the i-STAT Alinity instrument, i-STAT test cartridges, and accessories, which are hardware components. While software is involved in processing signals, it is integral to a hardware system that performs in vitro diagnostic testing.
Yes, this device is an IVD (In Vitro Diagnostic).
The "Intended Use / Indications for Use" section explicitly states: "The i-STAT TBI Plasma test is a panel of in vitro diagnostic immunoassays..."
This statement clearly identifies the device as an in vitro diagnostic product.
N/A
Intended Use / Indications for Use
The i-STAT TBI Plasma 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 plasma and a semiquantitative 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) within 12 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 plasma prepared from EDTA anticoagulated specimens in clinical laboratory settings by a healthcare professional. The i-STAT TBI Plasma test is not intended to be used in point of care settings.
Product codes
QAT
Device Description
The i-STAT TBI Plasma 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 plasma sample and yield a semi-quantitative test interpretation based on measurements of both UCH-L1 and GFAP in approximately 15 minutes. The i-STAT TBI Plasma 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 designed to run only i-STAT test cartridges. The instrument is the main user interface of the i-STAT 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).
Mentions image processing
Not Found
Mentions AI, DNN, or ML
Not Found
Input Imaging Modality
Not Found
Anatomical Site
Not Found
Indicated Patient Age Range
18 years of age or older
Intended User / Care Setting
Clinical laboratory settings by a healthcare professional.
Description of the training set, sample size, data source, and annotation protocol
The assay cutoffs were determined by analyzing a training set with GFAP and UCH-L1 results from a total of 420 (274 males and 146 females) with suspected mild traumatic brain injury (TBI; Glasgow Coma Scale score of 13-15). Subjects who had blood drawn within 12 hours of injury and a head CT scan determination, were included in the analysis. Using a 10-fold cross validation and bootstrapping method, the cutoff values of 30 pg/mL (GFAP assay) and 360 pg/mL (UCH-L1 assay) were selected for the i-STAT TBI Plasma Cartridge using the selection criteria with an adjusted NPV (prevalence 6%)>=98.5% and sensitivity >=98%.
Description of the test set, sample size, data source, and annotation protocol
Not Found
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
Clinical Sensitivity and Specificity: Pivotal Study
- Study type: Prospective, multi-center clinical study collected and archived (frozen) plasma specimens.
- Sample size: Specimens from 1901 subjects were included in the analysis.
- Data source: Emergency departments (ED) in the United States, Germany, and Hungary. Patients presented with suspected traumatic brain injury with initial Glasgow Coma Scale (GCS) scores of 13-15 and had a computed tomography (CT) scan performed.
- Annotation protocol: CT scans were interpreted by at least two neuroradiologists masked to other clinical/laboratory data, with a third neuroradiologist for adjudication if necessary. Acute intracranial lesion was defined as any trauma-induced or related finding visualized on head CT scan.
- Key results:
- 120 specimens associated with positive CT scan results. 115 had an 'elevated' i-STAT TBI Plasma test interpretation (Clinical Sensitivity = 95.8%).
- 5 specimens associated with CT positive results had a 'not elevated' interpretation (FN rate = 4.2%).
- 5 subjects with lesions requiring surgical intervention; none had FN results.
- 1781 specimens associated with negative CT scan results. 720 had a 'not elevated' interpretation (Clinical Specificity = 40.4%).
- FP rate = 59.6% (1061/1781).
- Overall 725 specimens with 'not elevated' interpretation. 720 were associated with negative CT scans.
Clinical Sensitivity and Specificity: Supplemental Fresh Specimen Study
- Study type: Supplemental study using freshly collected plasma specimens.
- Sample size: A total of 88 subjects enrolled.
- Data source: Level 1 trauma center emergency departments (ED) in the United States (4 clinical sites of the TRACK-TBI study). Patients presented with suspected traumatic brain injury, with initial GCS scores of 13-15, and had a computed tomography (CT) scan of the head performed.
- Annotation protocol: Similar to the pivotal study, CT scans were interpreted by at least two neuroradiologists masked to other clinical/laboratory data, with a third neuroradiologist for adjudication if necessary. Acute intracranial lesion was defined as any trauma-induced or related finding visualized on head CT scan.
- Key results:
- 29 subjects associated with positive head CT scan results. 29 had an 'elevated' i-STAT TBI Plasma test interpretation (Clinical Sensitivity = 100.0%).
- FN rate = 0% (0/29).
- 59 subjects associated with negative CT scan results. 14 had a 'not elevated' interpretation (Clinical Specificity = 23.7%).
- FP rate = 76.2% (45/59).
- Overall 14 specimens with 'not elevated' interpretation. All 14 were associated with negative head CT scan results.
Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)
Pivotal Study (N=1901)
- Clinical Sensitivity: 95.8% (95% CI: 90.6%, 98.2%)
- Clinical Specificity: 40.4% (95% CI: 38.2%, 42.7%)
- Negative Predictive Value (NPV): 99.3% (95% CI: 98.5%, 99.7%)
- Positive Predictive Value (PPV): 9.8% (95% CI: 9.2%, 10.2%)
- Likelihood Ratio Negative (LRN): 0.10 (95% CI: 0.04, 0.23)
- Likelihood Ratio Positive (LRP): 1.61 (95% CI: 1.51, 1.69)
Supplemental Fresh Specimen Study (N=88)
- Clinical Sensitivity: 100.0% (95% CI: 88.3%, 100.0%)
- Clinical Specificity: 23.7% (95% CI: 14.7%, 36.0%)
- Negative Predictive Value (NPV)*: 100.0% (95% CI: 80.2%, 100.0%)
- Positive Predictive Value (PPV)*: 39.2% (95% CI: 35.9%, 43.4%)
- Likelihood Ratio Negative (LRN): 0.00 (95% CI: 0.00, 0.50)
- Likelihood Ratio Positive (LRP): 1.31 (95% CI: 1.14, 1.56)
*NPV and PPV estimated at 33.0% prevalence of CT scan positive rate for suspected mild TBI subjects. Adjusted NPV and PPV at 6% prevalence (to be comparable to the pivotal study) are 100.0% (95% Cl: 96.9%, 100.0%) and 7.7% (95% CI: 6.8%, 9.1%), respectively.
Predicate Device(s)
Reference Device(s)
Not Found
Predetermined Change Control Plan (PCCP) - All Relevant Information
Not Found
§ 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.”
0
Image /page/0/Picture/0 description: The image contains the logo of the U.S. Food and Drug Administration (FDA). On the left is the Department of Health & Human Services logo. To the right of that is the FDA logo, which is a blue square with the letters "FDA" in white. To the right of the square is the text "U.S. FOOD & DRUG ADMINISTRATION" in blue.
May 24, 2022
Abbott Laboratories Brian Ma Sr. Regulatory Affairs Specialist 400 College Road East Princeton, New Jersey 08540
Re: K201778
Trade/Device Name: i-STAT TBI Plasma cartridge with the i-STAT Alinity System Regulation Number: 21 CFR 866.5830 Regulation Name: Brain trauma assessment test Regulatory Class: Class II Product Code: QAT
Dear Brian Ma:
The Food and Drug Administration (FDA) is sending this letter to notify you of an administrative change related to your previous substantial equivalence (SE) determination letter for your device cleared on January 8, 2021. Specifically, FDA is updating this SE Letter due to a typographical error in the clearance date, which was incorrectly dated January 8, 2020.
Please note that the 510(k) submission was not re-reviewed. For questions regarding this letter please contact Ying (Katelin) Mao, OHT7: Office of In Vitro Diagnostics and Radiological Health, 301-796-6635, ying.mao(@)fda.hhs.gov .
Sincerely,
Ying Mao-S
Ying (Katelin) Mao, Ph.D. Chief Division of Immunology and Hematology Devices OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Quality Center for Devices and Radiological Health
1
Image /page/1/Picture/0 description: The image contains two logos. The logo on the left is the Department of Health & Human Services - USA logo. The logo on the right is the FDA U.S. Food & Drug Administration logo. The FDA logo has a blue square with the letters FDA in white, followed by the words "U.S. FOOD & DRUG ADMINISTRATION" in blue.
January 8, 2020
Abbott Laboratories Brian Ma Sr. Regulatory Affairs Specialist 400 College Road East Princeton, New Jersey 08540
Re: K201778
Trade/Device Name: i-STAT TBI Plasma cartridge with the i-STAT Alinity System Regulation Number: 21 CFR 866.5830 Regulation Name: Brain Trauma Assessment Test Regulatory Class: Class II Product Code: OAT Dated: December 4, 2020 Received: December 7, 2020
Dear Brian Ma:
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal
2
statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely,
Leonthena R. Carrington -S
Lea Carrington Director Division of Immunology and Hematology Devices OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Ouality Center for Devices and Radiological Health
Enclosure
3
Indications for Use
510(k) Number (if known) K201778
Device Name
i-STAT TBI Plasma cartridge with the i-STAT Alinity System
Indications for Use (Describe)
The i-STAT TBI Plasma 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 plasma and a semiquantitative 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) within 12 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 plasma prepared from EDTA anticoagulated specimens in clinical laboratory settings by a healthcare professional. The i-STAT TBI Plasma test is not intended to be used in point of care settings.
| Type of Use (Select one or both, as applicable) |
|---|
| ------------------------------------------------- |
X Prescription Use (Part 21 CFR 801 Subpart D)
| Over-The-Counter Use (21 CFR 801 Subpart C)
CONTINUE ON A SEPARATE PAGE IF NEEDED.
This section applies only to requirements of the Paperwork Reduction Act of 1995.
DO NOT SEND YOUR COMPLETED FORM TO THE PRA STAFF EMAIL ADDRESS BELOW.
The burden time for this collection of information is estimated to average 79 hours per response, including the time to review instructions, search existing data sources, gather and maintain the data needed and complete and review the collection of information. Send comments regarding this burden estimate or any other aspect of this information collection, including suggestions for reducing this burden, to:
Department of Health and Human Services Food and Drug Administration Office of Chief Information Officer Paperwork Reduction Act (PRA) Staff PRAStaff(@fda.hhs.gov
"An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB number."
4
510(k) Summary
The information in this 510(k) summary is being submitted in accordance with the requirements of 21 CFR 807.92.
| 1. | Submitter Information | ||
|---|---|---|---|
| Owner | Abbott Point of Care Inc. | ||
| 400 College Road East | |||
| Princeton, NJ 08540 | |||
| Contact | Primary: Brian Ma, PhD | ||
| Senior Specialist Regulatory Affairs | |||
| Phone: 613-688-5949 | |||
| Secondary: Susan Tibedo | |||
| Director Regulatory Affairs | |||
| Phone: 609-213-8514 |
Date Prepared
January 6, 2021
2. Device Information
Proprietary Name i-STAT TBI Plasma Cartridge with the i-STAT Alinity System Glial fibrillary acidic protein (GFAP) Common Name Ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1)
| Product
code | Device Classification
name | Regulation
Number | Class | Panel |
|-----------------|---------------------------------|----------------------|--------------------------|------------|
| QAT | Brain trauma assessment
test | 866.5830 | II (Special
controls) | Immunology |
5
3. Predicate Device
Proprietary Name Banyan Brain Trauma Indicator (BTI)
510(k) Number DEN170045
| Product
code | Device Classification
name | Regulation
Number | Class | Panel |
|-----------------|---------------------------------|----------------------|-----------------------------|--------------------|
| QAT | Brain trauma
assessment test | 866.5830 | II
(Special
controls) | Immunology
(82) |
4. Device Description
The i-STAT TBI Plasma 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 plasma sample and yield a semi-quantitative test interpretation based on measurements of both UCH-L1 and GFAP in approximately 15 minutes. The i-STAT TBI Plasma 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 designed to run only i-STAT test cartridges. The instrument is the main user interface of the i-STAT 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).
6
5. Intended Use Statement
The i-STAT TBI Plasma 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 plasma and a semiquantitative 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) within 12 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 plasma prepared from EDTA anticoagulated specimens in clinical laboratory settings by a healthcare professional. The i-STAT TBI Plasma test is not intended to be used in point of care settings.
7
| Similarities and Differences: System (Test and Instrument) | ||
|---|---|---|
| Feature or | ||
| Characteristic | i-STAT TBI Plasma Cartridge | |
| (Candidate) | Banyan BTI (DEN170045) | |
| (Predicate) | ||
| Intended Use / | ||
| Indications for Use | The i-STAT TBI Plasma 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 plasma 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) within 12 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 plasma | ||
| prepared from EDTA anticoagulated | ||
| specimens in clinical laboratory | ||
| settings by a healthcare professional. | The Banyan BTI is an in vitro diagnostic | |
| chemiluminescent enzyme-linked | ||
| immunosorbent assay (ELISA). The assay | ||
| provides a semi-quantitative measurement | ||
| of the concentrations of ubiquitin | ||
| C-terminal hydrolase-L1 (UCH-L1) and | ||
| glial fibrillary acidic protein (GFAP) in | ||
| human serum and is used with the | ||
| Synergy 2 Multi-mode Reader. | ||
| The assay results obtained from serum | ||
| collected within 12 hours of suspected | ||
| head injury are used, along with other | ||
| available clinical information, to aid in the | ||
| evaluation of patients 18 years of age and | ||
| older with suspected traumatic brain injury | ||
| (Glasgow Coma Scale score 13-15). A | ||
| negative assay result is associated with | ||
| the absence of acute intracranial lesions | ||
| visualized on a head CT (computed | ||
| tomography) scan. | ||
| Intended User | Clinical Laboratory | Clinical Laboratory |
| Measurands | GFAP and UCH-L1 | GFAP and UCH-L1 |
| Assay Technology | Enzyme-linked immunosorbent assay | Enzyme-linked immunosorbent assay |
| Assay Format | Single use multiplex cartridge (both | |
| assays (GFAP and UCH-L1) in one | ||
| cartridge) | Two test kits on separate 96-well microtiter | |
| plates - one for GFAP and one for UCH- | ||
| L1 | ||
| Detection | ||
| Technology | Electrochemical | Chemiluminescence |
| Specimen Type | Plasma | Serum |
| Sample Volume | 20 µL | GFAP kit: 150 µL |
| UCH-L1 kit: 100 µL | ||
| Similarities and Differences: System (Test and Instrument) | ||
| Feature or | ||
| Characteristic | i-STAT TBI Plasma Cartridge | |
| (Candidate) | Banyan BTI (DEN170045) | |
| (Predicate) | ||
| Preparation | Ready to Use | Manual preparation of reagents and plate. |
| Automation | Test and wash cycles are fully | |
| automated after sample loading step | Manual sample loading, reagent mixing, as | |
| well as transfer from incubation and | ||
| washing to read steps | ||
| Analytical | ||
| Measuring Interval | GFAP: 30 – 10,000 pg/mL | |
| UCH-L1: 200 – 3,200 pg/mL | GFAP: 10 – 320 pg/mL | |
| UCH-L1: 80 – 2,560 pg/mL | ||
| Time to Result | ~ 15 minutes | ~ 4 hours |
| Reportable Result | Quantitative results for GFAP and | |
| UCH-L1 and semi-quantitative | ||
| interpretation | Quantitative results for GFAP and UCH-L1 | |
| and semi-quantitative interpretation | ||
| Instrument Platform | i-STAT Alinity | Synergy 2 Multi-Mode Microplate Reader |
| (BioTek Instruments, Inc.) | ||
| Controls | GFAP and UCH-L1 combined: 2 | |
| levels (Control 1, Control 2) | GFAP: 2 levels (Control 1, Control 2) | |
| UCH-L1: 2 levels (Control 1, Control 2) | ||
| Calibration | No calibration needed by the end | |
| user, calibration is pre-set during | ||
| manufacture of the cartridge | Calibration curve generated by end user | |
| for each run using six standards |
6. Summary Comparison of Technological Characteristics
8
7. Performance Characteristics
1. Analytical Performance
a. Precision/Reproducibility
Semi-quantitative precision: The precision of the GFAP and UCH-L1 assays in the i-STAT TBI plasma cartridge with the i-STAT Alinity System was evaluated using plasma samples representing nine (9) levels of GFAP and seven (7) levels of UCH-L1 spanning the reportable range as well as the i-STAT TBI Controls (L1 and L2). This single-site study was based on CLSI document EP05-A3: Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline-Third Edition. Each sample was tested for at least 20 days with two (2) runs per day and two (2) results per run for a total of 80 measurements per sample per cartridge lot. Runs were separated by a minimum of 2 hours. The plasma samples were made of pooled plasma from healthy normal donors spiked with recombinant GFAP and UCH-L1 antigens or spiked with
9
native antigens from pooled TBI patient plasma as shown in the tables below. The components of variability were estimated for GFAP and UCH-L1 and the precision results are shown in Table 1, Table 2, and Table 3.
| Table 1: Estimate of GFAP Assay Precision | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Sample | N | Mean | ||||||||||
| (pg/mL) | Repeatability | Between-Run | Between-Day | Between-Lot | Within- | |||||||
| Laboratory | ||||||||||||
| SD | ||||||||||||
| (pg/mL) | CV | |||||||||||
| (%) | SD | |||||||||||
| (pg/mL) | CV | |||||||||||
| (%) | SD | |||||||||||
| (pg/mL) | CV | |||||||||||
| (%) | SD | |||||||||||
| (pg/mL) | CV | |||||||||||
| (%) | SD | |||||||||||
| (pg/mL) | CV | |||||||||||
| (%) | ||||||||||||
| 1 | 238‡ | 17.0 | 1.76 | 10.4% | 0.91 | 5.4% | 0.61 | 3.6% | 1.31 | 7.7% | 2.46 | 14.5% |
| 2 | 238‡ | 30.8 | 2.49 | 8.1% | 0.00 | 0.0% | 0.00 | 0.0% | 0.52 | 1.7% | 2.55 | 8.3% |
| 3 | 238‡ | 65.6 | 3.21 | 4.9% | 0.87 | 1.3% | 1.03 | 1.6% | 0.62 | 0.9% | 3.54 | 5.4% |
| 4 | 238*§ | 104.9 | 3.37 | 3.2% | 2.08 | 2.0% | 0.00 | 0.0% | 1.50 | 1.4% | 4.24 | 4.0% |
| 5 | 238‡ | 962.9 | 22.42 | 2.3% | 13.61 | 1.4% | 17.33 | 1.8% | 21.17 | 2.2% | 37.90 | 3.9% |
| 6 | 160 | 2029.5 | 39.18 | 1.9% | 26.30 | 1.3% | 19.10 | 0.9% | 94.89 | 4.7% | 107.69 | 5.3% |
| 7 | 240 | 3139.5 | 75.98 | 2.4% | 35.92 | 1.1% | 49.34 | 1.6% | 97.09 | 3.1% | 137.57 | 4.4% |
| 8 | 160*† | 5713.3 | 143.96 | 2.5% | 42.68 | 0.7% | 65.72 | 1.2% | 170.29 | 3.0% | 236.36 | 4.1% |
| 9 | 159† | 7537.2 | 129.57 | 1.7% | 133.30 | 1.8% | 35.89 | 0.5% | 187.57 | 2.5% | 266.51 | 3.5% |
Table 1: Estimate of GFAP Assay Precision
*Additional GFAP result(s) was obtained due to cartridge re-run due to a UCH-L1 star-out
†one (1) outlier removed from analysis
キtwo (2) outliers removed from analysis
Sthree (3) outliers removed from analysis
| Table 2: Estimate of UCH-L1 Assay Precision | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Repeatability | Between-Run | Between-Day | Between-Lot | Within- | ||||||||
| Laboratory | ||||||||||||
| Sample | N | Mean | ||||||||||
| (pg/mL) | SD | |||||||||||
| (pg/mL) | CV | |||||||||||
| (%) | SD | |||||||||||
| (pg/mL) | CV | |||||||||||
| (%) | SD | |||||||||||
| (pg/mL) | CV | |||||||||||
| (%) | SD | |||||||||||
| (pg/mL) | CV | |||||||||||
| (%) | SD | |||||||||||
| (pg/mL) | CV | |||||||||||
| (%) | ||||||||||||
| 1 | 238‡ | 72.5 | 4.88 | 6.7% | 1.73 | 2.4% | 0.00 | 0.0% | 3.93 | 5.4% | 6.50 | 9.0% |
| 2 | 239† | 300.1 | 15.12 | 5.0% | 5.94 | 2.0% | 0.00 | 0.0% | 15.54 | 5.2% | 22.48 | 7.5% |
| 3 | 240 | 519.9 | 29.56 | 5.7% | 1.54 | 0.3% | 13.38 | 2.6% | 8.21 | 1.6% | 33.51 | 6.4% |
| 4 | 238‡ | 1058.9 | 56.88 | 5.4% | 22.59 | 2.1% | 15.13 | 1.4% | 33.6 | 3.2% | 71.44 | 6.7% |
| 5 | 159* | 1639.6 | 91.57 | 5.6% | 8.72 | 0.5% | 15.74 | 1.0% | 28.46 | 1.7% | 97.56 | 6.0% |
| 6 | 240 | 2067.4 | 111.09 | 5.4% | 54.99 | 2.7% | 46.01 | 2.2% | 15.00 | 0.7% | 133.06 | 6.4% |
| 7 | 239† | 2849.7 | 145.4 | 5.1% | 100.56 | 3.5% | 0.00 | 0.0% | 15.16 | 0.5% | 177.44 | 6.2% |
*one (1) result was unavailable due to star-out
*one (1) outlier removed from analysis
‡two (2) outliers removed from analysis
10
| Table 3: Estimate of GFAP and UCH-L1 Assay Precision with i-STAT TBI Controls | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Sample | N | Mean | ||||||||||
| (pg/mL) | Repeatability | Between-Run | Between-Day | Between-Lot** | Within- | |||||||
| Laboratory | ||||||||||||
| SD | ||||||||||||
| (pg/mL) | CV | |||||||||||
| (%) | SD | |||||||||||
| (pg/mL) | CV | |||||||||||
| (%) | SD | |||||||||||
| (pg/mL) | CV | |||||||||||
| (%) | SD | |||||||||||
| (pg/mL) | CV | |||||||||||
| (%) | SD | |||||||||||
| (pg/mL) | CV | |||||||||||
| (%) | ||||||||||||
| GFAP Assay | ||||||||||||
| L1 | 238*§ | 196.7 | 9.94 | 5.1% | 2.69 | 1.4% | 2.25 | 1.1% | 5.70 | 2.9% | 11.98 | 6.1% |
| L2 | 242* | 5153.8 | 236.89 | 4.6% | 94.93 | 1.8% | 28.10 | 0.5% | 183.00 | 3.6% | 315.29 | 6.1% |
| UCH-L1 Assay | ||||||||||||
| L1 | 239† | 562.6 | 29.79 | 5.3% | 9.57 | 1.7% | 11.92 | 2.1% | 13.21 | 2.3% | 36.00 | 6.4% |
| L2 | 240 | 1624.7 | 90.14 | 5.5% | 53.68 | 3.3% | 0.00 | 0.0% | 32.25 | 2.0% | 109.76 | 6.8% |
- Additional GFAP result was obtained due to cartridge re-run due to a UCH-L1 star-out
*one (1) outlier removed from analysis
‡two (2) outliers removed from analysis
§three (3) outliers removed from analysis
**This refers to precision estimates calculated between cartridge lots. A single lot of i-STAT TBI controls was used for this study.
Qualitative precision: The qualitative agreement of cartridge results relative to the expected sample result (mean) was evaluated for the 80 measurements per sample per cartridge lot for each assay from the semi-quantitative analysis above. The mean, total number of replicates, total number of elevated results, and % correct call for each sample level are presented in Table 4 for GFAP and Table 5 for UCH-L1.
| Table 4: GFAP assay results for qualitative precision analysis | |||||
|---|---|---|---|---|---|
| Plasma | |||||
| Sample | Lot | Mean | |||
| (pg/mL) | Total Number | ||||
| of Replicates | Total Number of | ||||
| Results at or | |||||
| above the cut-off | % Correct | ||||
| Call | |||||
| 1A | A | 18.5 | 80 | 0 | 100% |
| B | 15.6 | 80 | 0 | 100% | |
| C | 17.1 | 80 | 0 | 100% | |
| 2B | D | 30.9 | 80 | 59 | 74% |
| E | 30.5 | 80 | 50 | 63% | |
| F | 31.5 | 80 | 69 | 86% | |
| 3C | D | 65.7 | 80 | 80 | 100% |
| E | 64.8 | 80 | 80 | 100% | |
| F | 66.0 | 80 | 80 | 100% | |
| 4C | A | 106.3 | 80 | 80 | 100% |
| B | 102.7 | 80 | 80 | 100% | |
| C | 105.1 | 81 | 81 | 100% | |
| 5C | A | 939.3 | 80 | 80 | 100% |
| B | 979.6 | 80 | 80 | 100% | |
| C | 973.8 | 80 | 80 | 100% | |
| 6C | G | 2096.8 | 80 | 80 | 100% |
| H | 1962.2 | 80 | 80 | 100% | |
| 7C | A | 3050.2 | 80 | 80 | 100% |
11
| Table 4: GFAP assay results for qualitative precision analysis | |||||
|---|---|---|---|---|---|
| Plasma | |||||
| Sample | Lot | Mean | |||
| (pg/mL) | Total Number | ||||
| of Replicates | Total Number of | ||||
| Results at or | |||||
| above the cut-off | % Correct | ||||
| Call | |||||
| B | 3244.7 | 80 | 80 | 100% | |
| C | 3123.6 | 80 | 80 | 100% | |
| 8C | G | 5579.9 | 80 | 80 | 100% |
| H | 5832.8 | 83 | 83 | 100% | |
| 9c | G | 7404.2 | 80 | 80 | 100% |
| H | 7685.7 | 80 | 80 | 100% | |
| i-STAT TBI Controls | |||||
| A | 203.4 | 81 | 81 | 100% | |
| L1C | B | 193.3 | 80 | 80 | 100% |
| C | 195.1 | 80 | 80 | 100% | |
| L2C | A | 5162.0 | 82 | 82 | 100% |
| B | 5335.2 | 80 | 80 | 100% | |
| C | 4964.2 | 80 | 80 | 100% |
A Below cut-off
^ Below cut-off
B Near cut-off (mean ± 25%)
© Above cut-off
^c Above cut-off
| Table 5: UCH-L1 assay results for qualitative precision analysis | |||||
|---|---|---|---|---|---|
| Plasma | |||||
| Sample | Lot | Mean | |||
| (pg/mL) | Total Number | ||||
| of Replicates | Total Number of | ||||
| Results at or | |||||
| above the cut-off | % Correct | ||||
| Call | |||||
| 1A | D | 70.7 | 80 | 0 | 100% |
| E | 73.5 | 80 | 0 | 100% | |
| F | 77.1 | 80 | 0 | 100% | |
| 2B | D | 295.6 | 80 | 0 | 100% |
| E | 289.0 | 80 | 1 | 99% | |
| F | 317.5 | 80 | 0 | 100% | |
| 3C | A | 525.1 | 80 | 80 | 100% |
| B | 509.1 | 80 | 80 | 100% | |
| C | 525.6 | 80 | 80 | 100% | |
| 4C | A | 1039.8 | 80 | 80 | 100% |
| B | 1039.0 | 80 | 80 | 100% | |
| C | 1098.8 | 80 | 80 | 100% | |
| 5C | G | 1617.9 | 79 | 79 | 100% |
| H | 1661.0 | 80 | 80 | 100% | |
| 6C | A | 2078.7 | 80 | 80 | 100% |
| B | 2040.2 | 80 | 80 | 100% | |
| C | 2083.2 | 80 | 80 | 100% | |
| 7C | A | 2865.0 | 80 | 80 | 100% |
| B | 2819.5 | 80 | 80 | 100% | |
| C | 2855.7 | 80 | 80 | 100% | |
| i-STAT TBI Controls | |||||
| L1C | A | 556.8 | 80 | 80 | 100% |
| B | 575.2 | 80 | 80 | 100% | |
| C | 552.6 | 80 | 80 | 100% | |
| L2C | A | 1601.2 | 80 | 80 | 100% |
| B | 1664.7 | 80 | 80 | 100% |
12
| Table 5: UCH-L1 assay results for qualitative precision analysis | |||||
|---|---|---|---|---|---|
| Plasma | |||||
| Sample | Lot | Mean | |||
| (pg/mL) | Total Number | ||||
| of Replicates | Total Number of | ||||
| Results at or | |||||
| above the cut-off | % Correct | ||||
| Call | |||||
| C | 1608.1 | 80 | 80 | 100% |
A Below cut-off
B Near cut-off (mean ± 25%)
C Above cut-off
Semi-quantitative multi-site precision: The precision performance of the GFAP and UCH-L1 assays in the i-STAT TBI Plasma cartridge on the i-STAT Alinity System was evaluated using seven (7) test materials representing six (6) levels of GFAP and five (5) levels of UCH-L1 at three (3) external clinical sites. At each site, each test material was tested once per day for five (5) days by two (2) different operators, with each operator using three (3) i-STAT Alinity Instruments. The plasma samples were made of pooled plasma from healthy normal donors spiked with recombinant GFAP and UCH-L1 antigens or spiked with native antigens from pooled TBI patient plasma as shown in the tables below. Thirty (30) replicates were obtained for the applicable assay analyzed for each test material at each of the three (3) sites for a total of 90 replicates for each test material. The estimates of GFAP and UCH-L1 precision are shown in Table 6 and Table 7.
13
| ble 6: i-STAT TBI Plasma Multi-site Precision - GFAP (pg/mL) - 2 Test - - - - - - - - Moan | nL) - All Sites | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| etween-Operato | Vithin-Site (Total | Between-Site | Overal | |||||||||||
| Test Material | N | 95% Cl | %CV | SD 95% CI) | %CV | 95% Cli | %CV | 95% Ci | %CV | 95% Cl | %CV | əsində aid bitki növü. İstinadlar SED | %CV | |
| ಕ್ಕಾ | 90 | 19.4 7, 26 | 2.60 14, 3.37 | |||||||||||
| ਟ | 13.4% | 0.00 0.00, 0.00) | 0.0% | 0.00 (0.00, 0.00 | 0.0% | 2.60 32, 2.97 | 13.4% | 2.88 66, 12.71 | 14.9% | 3.88 | 20.0% | |||
| б | 90 | 30.8 23, 36 | 1.76, 2.77 , | |||||||||||
| 2.15 | 7.0% | 0.55 (0.41, 0.83) | 1.8% | 0.20 (0.13, 0.59) | 0.7% | 2.22 97, 2.53` | 7.2% | 2.51 45, 11.07 | 8.1% | 3.35 | 10.9% | |||
| 10B | 90 | 66.2 54, 77 | 2.97 (2.44, 3.84 | 4.5% | 1.3% | 0.00 (0.00, 0.00 | 0.0% | 3.09 76, 3.54, | ||||||
| ਟ | 4.7% | 4.00 (2.31, 17.64 | 6.0% | 5.05 | 7.6% | |||||||||
| 8 | 90 | 150.1 37, 168 | 4.48 (3.73, 5.64 | 3.0% | 1.4% | 1.41 88, 4.13) | 0.9% | 4.98 (4.38, 5.78) | 3.3% | 4.09 (2.37, 18.08) | 2.7% | 6.45 | 4.3% | |
| દિવેલી કરવામાં આવેલું એક ગામના લોકોનો મુખ્ય વ્યવસાય ખેતી, ખેતમજૂરી તેમ જ પશુપાલન છે. આ ગામમાં મુખ્યત્વે ખેત-ઉત | 06 | 4504.7 4257, 4813 | 88.75 72.82, 114.75 | 2.0% | 62.32 39.53, 79.29) 139.53, 79.29) 142.89, 18.2.14 142.89, 286.6 | 1.2% | 0.00 0.00, 0.00, | 0.0% | 103.03 0.40, 120.20 | 2.3% | 74.34 [42.95, 328.25 | 1.7% | 127.05 | 2.8% |
| 7A | 90 | 9196.8 [8575, 10099 | 193.85 161.79, 243.68 | 2.1% | 2.1% | 63.22 (39.17, 184.60 | 0.7% | 270.84 229.00, 33.56 | 2.9% | 167.65 (96.86, 740.24 | 1.8% | 318.53 | 3.5% | |
| pooled normal donor plasma spiked with recombinant GFAP | and UCH-L1 antiger |
| e
| samp |
|---|
| patient |
| TB |
| led |
| pool |
| 3 |
| on. |
| 100 |
| antigens |
| S |
| ll |
WITH |
| spiked
: |
| ma
plasma |
| Controllers (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1
Ol
C
do |
| al
414
no. |
| oled
าดเ
0
S
t
D |
| |
| Test
Material | N | Mean
(Min, Max) | Within-Day | | Between-Day | | Between-Operator | | Within-Site (Total) | | Between-Site | | Overall | |
|------------------|----|-------------------------|----------------------------|-------|---------------------------|------|----------------------------|------|----------------------------|-------|-----------------------------|------|----------------|-------|
| | | | SD
(95% CI) | %CV | SD
(95% CI) | %CV | SD
(95% CI) | %CV | SD
(95% CI) | %CV | SD
(95% CI) | %CV | SD
(95% CI) | %CV |
| 5a | 90 | 60.5
(44, 83) | 6.03
(5.10, 7.44) | 10.0% | 1.57
(1.19, 2.38) | 2.6% | 2.69
(1.67, 7.85) | 4.4% | 6.23
(5.52, 7.18) | 10.3% | 0.00
(0.00, 0.00) | 0.0% | 6.23 | 10.3% |
| 11c | 90 | 297.9
(257, 348) | 16.53
(13.68, 21.08) | 5.6% | 5.01
(3.79, 7.59) | 1.7% | 3.71
(2.30, 10.84) | 1.2% | 17.28
(15.36, 19.79) | 5.8% | 9.22
(5.33, 40.71) | 3.1% | 19.58 | 6.6% |
| 8a | 90 | 538.0
(467, 613) | 28.88
(24.66, 35.04) | 5.4% | 9.52
(7.19, 14.43) | 1.8% | 17.19
(10.65, 50.19) | 3.2% | 30.41
(26.63, 35.57) | 5.7% | 3.25
(1.88, 14.36) | 0.6% | 30.58 | 5.7% |
| 6a | 90 | 5143.2
(4417, 6539) | 311.62
(263.93, 382.79) | 6.1% | 58.76
(44.39, 89.03) | 1.1% | 148.37
(91.93, 433.25) | 2.9% | 317.11
(280.91, 365.15) | 6.2% | 137.41
(79.39, 606.70) | 2.7% | 345.60 | 6.7% |
| 7a | 90 | 9538.7
(7946, 11016) | 516.39
(436.60, 636.06) | 5.4% | 107.70
(81.36, 163.20) | 1.1% | 236.10
(146.28, 689.40) | 2.5% | 527.50
(467.50, 607.02) | 5.5% | 351.68
(203.19, 1552.81) | 3.7% | 633.99 | 6.6% |
pooled normal don't plasma spiked with room
pooled TBI patient and normal donor plasma
14
Qualitative multi-site precision: The qualitative agreement of cartridge results relative to the expected sample result (mean) was evaluated for the 90 measurements per test material for each assay from the semi-quantitative analysis above. The mean, total number of replicates, total number of elevated results, and % correct call for each test material are presented in Table 8 for GFAP and Table 9 for UCH-L1.
| Table 8: Qualitative Precision Analysis - GFAP Assay - All Sites | ||||
|---|---|---|---|---|
| Test | ||||
| Material | Mean | |||
| (pg/mL) | Total Number | |||
| of Replicates | Total Number of | |||
| GFAP Results at or | ||||
| above the cut-off | % Correct Call | |||
| 5 A | 19.4 | 90 | 0 | 100% |
| 9 B | 30.8 | 90 | 60 | 67%* |
| 10 C | 66.2 | 90 | 90 | 100% |
| 8 C | 150.1 | 90 | 90 | 100% |
| 6 C | 4504.7 | 90 | 90 | 100% |
| 7 C | 9196.8 | 90 | 90 | 100% |
A Below cut-off: B Near cut-off (overall mean +/- 25%): ^ Above cut-off
*Test Material range includes cut-off. % Correct call based on test material overall mean for all sites.
| Table 9: Qualitative Precision Analysis - UCH-L1 Assay - All Sites | ||||
|---|---|---|---|---|
| Test | ||||
| Material | Mean | |||
| (pg/mL) | Total Number | |||
| of Replicates | Total Number of UCH- | |||
| L1 Results at or | ||||
| above the cut-off | % Correct | |||
| Call | ||||
| 5 A | 60.5 | 90 | 0 | 100% |
| 11 B | 297.9 | 90 | 0 | 100%* |
| 8 C | 538.0 | 90 | 90 | 100% |
| 6 C | 5143.2 | 90 | 90 | 100% |
| 7 C | 9538.7 | 90 | 90 | 100% |
A Below cut-off; B Near cut-off (overall mean +/- 25%); ^ Above cut-off
*Test Material range includes cut-off. % Correct call based on test material overall mean for all sites.
b. Linearity/assay reportable range
Linearity: The linearity of the GFAP and UCH-L1 assays in the i-STAT TBI Plasma cartridge with the i-STAT Alinity System was established by testing plasma samples of varying antigen levels that range from below the lower limit of the reportable range to above the upper reportable range for both GFAP and UCH-L1. The study was designed based on CLSI EP06-A: Evaluation of the Linearity of Quantitative Measurement Procedures. The study was conducted using plasma samples spiked with either native antigens from a TBI patient sample exhibiting high levels of both GFAP and UCH-L1 or with recombinant GFAP and UCH-L1 antigens. Plasma samples of varying GFAP and UCH-L1 levels were prepared through proportional mixing of low and high antigen concentration samples.
The regression equation for the linear range of the GFAP assay is y=1.02x-6.7. The regression equation for the linear range of the UCH-L1 assay is y=1.04x-17.7. Regression summary of the results obtained for each assay in the i-STAT TBI Plasma cartridge (y-
15
| Table 10: Linearity Across Reportable Range | |||||
|---|---|---|---|---|---|
| Assay | Reportable | ||||
| Range | |||||
| (pg/mL) | Slope | Intercept | r2 | ||
| GFAP | 30 - 10000 | 1.02 | -6.7 | 0.9985 | |
| UCH-L1 | 200 – 3200 | 1.04 | -17.7 | 0.9869 |
axis) versus the expected values (x-axis) is provided in Table 10.
Recovery: The recovery evaluation was performed using data collected as part of the linearity studies. The % recovery was calculated using the means of the GFAP and UCH-L1 assay results and the expected values of the plasma samples as determined by the i-STAT Alinity instruments. The % recovery is presented in Table 11 for the GFAP assay and Table 12 for the UCH-L1 assay.
| Table 11: GFAP Assay % Recovery | ||||
|---|---|---|---|---|
| Antigen | ||||
| Source | N | Mean GFAP | ||
| (pg/mL) | GFAP Expected | |||
| (pg/mL) | % Recovery | |||
| Native Plasma | 6 | 3245.5 | 3245.5 | 100.0% |
| 6 | 2607.8 | 2599.6 | 100.3% | |
| 6 | 1990.3 | 1953.6 | 101.9% | |
| 5 | 1353.2 | 1307.7 | 103.5% | |
| 6 | 634.8 | 661.7 | 95.9% | |
| 6 | 346.7 | 338.7 | 102.4% | |
| 6 | 169.5 | 177.3 | 95.6% | |
| 6 | 98.9 | 96.5 | 102.5% | |
| 6 | 49.4 | 56.1 | 88.1% | |
| 6 | 15.8 | 15.8 | 100.0% | |
| Recombinant | ||||
| Plasma | 5 | 10686.5 | 10686.5 | 100.0% |
| 6 | 9612.2 | 9618.9 | 99.9% | |
| 6 | 8581.2 | 8551.3 | 100.3% | |
| 6 | 7630.5 | 7483.8 | 102.0% | |
| 6 | 6117.7 | 6416.1 | 95.3% | |
| 6 | 5653.3 | 5348.6 | 105.7% | |
| 6 | 4539.1 | 4281.0 | 106.0% | |
| 6 | 3595.3 | 3213.4 | 111.9% | |
| 6 | 2355.7 | 2145.8 | 109.8% | |
| 6 | 1206.6 | 1078.3 | 111.9% | |
| 6 | 571.8 | 608.6 | 94.0% | |
| 6 | 294.5 | 309.6 | 95.1% | |
| 5 | 153.6 | 160.2 | 95.9% | |
| 5 | 81.5 | 85.4 | 95.4% | |
| 6 | 39.4 | 47.7 | 82.6% | |
| 6 | 23.5 | 29.2 | 80.5% | |
| 6 | 16.4 | 19.9 | 82.4% |
16
| Table 12: UCH-L1 Assay % Recovery | ||||
|---|---|---|---|---|
| Antigen | ||||
| Source | N | Mean UCH-L1 | ||
| (pg/mL) | UCH-L1 Expected | |||
| (pg/mL) | % Recovery | |||
| Native Plasma | 6 | 2286.6 | 2286.6 | 100.0% |
| 6 | 1945.6 | 1844.1 | 105.5% | |
| 6 | 1408.6 | 1401.6 | 100.5% | |
| 5 | 1012.6 | 959.2 | 105.6% | |
| 6 | 453.2 | 516.7 | 87.7% | |
| 6 | 296.4 | 295.4 | 100.3% | |
| 6 | 183.1 | 184.8 | 99.1% | |
| Recombinant | ||||
| Plasma | 6 | 4950.8 | 4298.9 | 115.2% |
| 6 | 3598.3 | 3245.7 | 110.9% | |
| 6 | 2492.8 | 2192.4 | 113.7% | |
| 6 | 1216.9 | 1139.1 | 106.8% | |
| 5 | 592.1 | 651.4 | 90.9% | |
| 6 | 345.1 | 368.6 | 93.6% | |
| 5 | 213.1 | 227.2 | 93.8% | |
| 5 | 154.4 | 156.5 | 98.7% |
Hook Effect: The GFAP and UCH-L1 assays in the i-STAT TBI Plasma cartridge on the i-STAT Alinity System were evaluated for high dose hook effect. The testing was conducted using plasma samples spiked to a high antigen level for each assay (>100,000 pg/mL). Each sample was tested to verify that the measured current response (nA)' is greater than that of a nominal GFAP target of 10,000 pg/mL and a nominal UCH-L1 target of 4,000 pg/mL. Hook effect was not observed for the GFAP and UCH-L1 assays as the current responses of high dose samples were significantly greater than 10,000 pg/mL for the GFAP assay and 4,000 pg/mL for the UCH-L1 assay.
Traceability, Calibration, and Reference Interval C.
Traceability and Calibration: The i-STAT System test for glial fibrillary acidic protein (GFAP) or ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) measures GFAP and UCH-L1 amount-of-substance concentration in plasma (units of measure: pg/mL) for in vitro diagnostic use.
There are no internationally recognized standard reference materials available for either glial fibrillary acidic protein (GFAP) or ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1). GFAP and UCH-L1 values assigned to i-STAT controls and calibration verification materials are traceable to Abbott Point of Care's working calibrators prepared using recombinant GFAP and UCH-L1 (expressed and purified from E. coli). The working calibrators are traceable to an in-house Reference Standard prepared from recombinant GFAP and UCH-L1 (expressed and purified from E. coli).
1 The i-STAT TBI Plasma cartridge measures assay current response in nanoamps (nA).
17
i-STAT System controls and calibration verification materials are validated for use only with the i-STAT System and assigned values may not be commutable with other methods.
Reference Interval: A reference interval study was conducted with a US-based general population. Plasma specimens from 225 self-declared healthy subjects between the ages of 18 and 79 years reporting no history of neurological disease within 1 year were tested with the i-STAT TBI Plasma cartridge with the i-STAT Alinity system to determine GFAP and UCH-L1 levels. Based on the test results, a 95% reference interval of an apparently healthy population of each biomarker was determined to be as follows:
| Table 13: Reference Interval | |||||
|---|---|---|---|---|---|
| Biomarker | N | Mean | |||
| (pg/mL) | SD | ||||
| (pg/mL) | Median | ||||
| (pg/mL) | Reference Interval | ||||
| (2.5th to 97.5th | |||||
| Percentile) (pg/mL) | |||||
| GFAP | 225 | 19 | 16.2 | 15 | 2 – 51 |
| UCH-L1 | 225 | 81 | 42.4 | 71 | 21 – 204 |
d. Detection Limit
Limit of Quantitation (LoQ): The LoQ was determined for the GFAP and UCH-L1 assays in the i-STAT TBI Plasma cartridge in a study based on CLSI EP17-A2: Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline-Second Edition. The testing was conducted on five (5) days using four (4) lots of i-STAT TBI cartridges with plasma from normal donors containing six (6) low levels of GFAP and UCH-L1. The LoQ for the GFAP and UCH-L1 assays in the i-STAT TBI Plasma cartridge tested on i-STAT Alinity instruments was determined to be below the lower limit of the reportable range for each assay as shown in Table 14.
| Table 14: LoQ Results for the GFAP and UCH-L1 Assays | ||
|---|---|---|
| Assay | Lower limit of the | |
| reportable range | ||
| (pg/mL) | LoQ | |
| (pg/mL) | ||
| GFAP | 30 | 23 |
| UCH-L1 | 200 | 70 |
e. Analytical Specificity
Endogenous and Exogenous Interferences: The interference performance of the GFAP and UCH-L1 assays in the i-STAT TBI Plasma cartridge on the i-STAT Alinity System was evaluated using plasma samples in a study based on CLSI EP07 ED3: Interference Testing in Clinical Chemistry, Third Edition. The effect of each substance was evaluated by comparing the performance of a control sample, spiked with blank solvent solution, with the test results from a sample spiked with the potentially interfering substance at the
18
toxic/pathological concentration based on CLSI EP37 ED1: Supplemental Tables for Interference Testing in Clinical Chemistry, First Edition, as applicable. A substance was identified as an interferent if the difference between the control and test samples was outside of a pre-determined acceptable range for each assay. Table 15 contains the list of potentially interfering substances tested for the GFAP and UCH-L1 assays and the interference results.
| Test Concentration | Interference | Interference | |||
|---|---|---|---|---|---|
| Substance | μmol/L | mg/dL | Assay | (Yes/No) | Results |
| Albumin | 150 g/L | 15 g/dL | GFAP | ||
| UCH-L1 | No | ||||
| Bilirubin | 684 | 40 | GFAP | ||
| UCH-L1 | No | ||||
| Bilirubin (conjugated) | 475 | 40 | GFAP | ||
| UCH-L1 | No | ||||
| Hemoglobin | 10 g/L | 1000 | GFAP | ||
| UCH-L1 | |||||
| GFAP | No | ||||
| Human anti-mouse antibody (HAMA) a | > 160x b | N/A | UCH-L1 | Yes | Highest concentration tested where no interference observed: 40x |
| Testing above this level showed decreased resultsc | |||||
| Intralipid (Intralipid 20%) | N/A | 4747 | GFAP | ||
| UCH-L1 | |||||
| GFAP | No | ||||
| Rheumatoid Factor (RF) a | 1000 IU/mL | N/A | UCH-L1 | Yes | Highest concentration tested where no interference observed: 500 IU/mL |
| Testing above this level showed decreased resultsc | |||||
| Triglycerides a | 33.88 mmol/L | 3000 | GFAP | ||
| UCH-L1 | No | ||||
| Acetaminophen a | 1.324 mmol/L | 15.6 | GFAP | ||
| UCH-L1 | No | ||||
| Sodium Ascorbate | 298 | 5.25 | GFAP | ||
| UCH-L1 | No | ||||
| Caffeine | 556 | 10.8 | GFAP | ||
| UCH-L1 | No | ||||
| Clopidogrel a | 21.4 | 9 μg/mL | GFAP | ||
| UCH-L1 | No | ||||
| Dopamine | 4.06 | 0.114 | GFAP | ||
| UCH-L1 | No | ||||
| Ethanol | 130 mmol/L | 600 | GFAP | ||
| UCH-L1 | Yes | Highest concentration | |||
| Table 15: Interfering Substance Testing | Test Concentration | Assay | Interference (Yes/No) | Interference Results | |
| Substance | μmol/L | mg/dL | tested where no interference observed: 65 mmol/L d Testing above this level showed decreased results | ||
| Erythromycin | 188 | 0.720 | GFAP | ||
| UCH-L1 | No | ||||
| No | |||||
| Nicotine | 5.97 | 0.00240 | GFAP | ||
| UCH-L1 | No | ||||
| No | |||||
| Metoprolol Tartrate a | 18.7 | 128.06 | GFAP | ||
| UCH-L1 | No | ||||
| No | |||||
| Acetylsalicylic acid a | 3.62 mmol/L | 6521.79 | GFAP | ||
| UCH-L1 | No | ||||
| No | |||||
| Chloramphenicol | 241 | 7.80 | GFAP | ||
| UCH-L1 | No | ||||
| No | |||||
| Diclofenac | 81 | 2.40 | GFAP | ||
| UCH-L1 | No | ||||
| No | |||||
| Ibuprofen a | 2.425 mmol/L | 50.0 | GFAP | ||
| UCH-L1 | No | ||||
| No | |||||
| Phenytoin | 238 | 6 | GFAP | ||
| UCH-L1 | No | ||||
| No | |||||
| Amphetamine | 2.44 | 0.033 | GFAP | ||
| UCH-L1 | No | ||||
| No | |||||
| Benzoylecgonine a | 8.64 | 2.5 μg/mL | GFAP | ||
| UCH-L1 | No | ||||
| No | |||||
| Nicardipine hydrochloride | 0.97 | 0.0465 | GFAP | ||
| UCH-L1 | No | ||||
| No | |||||
| EDDP† perchlorate a | 0.3308 | 125 ng/mL | GFAP | ||
| UCH-L1 | No | ||||
| No | |||||
| Methadone | 10.3 | 0.318 | GFAP | ||
| UCH-L1 | No | ||||
| No | |||||
| Methaqualone a | 32.36 | 8.1 μg/mL | GFAP | ||
| UCH-L1 | No | ||||
| No | |||||
| d-Methamphetamine a | 1.865 | 278.4 ng/mL | GFAP | ||
| UCH-L1 | No | ||||
| No | |||||
| Morphine | 27.3 | 0.78 | GFAP | ||
| UCH-L1 | No | ||||
| No | |||||
| Oxazepam | 15.1 | 0.432 | GFAP | ||
| UCH-L1 | No | ||||
| No | |||||
| Phencyclidine a | 0.0357 | 8.7 ng/mL | GFAP | ||
| UCH-L1 | No | ||||
| No | |||||
| Secobarbital | 66.8 | 159.17 | GFAP | ||
| UCH-L1 | No | ||||
| No | |||||
| Cocaine a | 11.406 | 3.46 μg/mL | GFAP | ||
| UCH-L1 | No | ||||
| No | |||||
| Propoxyphene a | 9.46 | 32.11 | GFAP | ||
| UCH-L1 | No | ||||
| No | |||||
| Warfarin | 243 | 7.5 | GFAP | ||
| UCH-L1 | No | ||||
| No | |||||
| Table 15: Interfering Substance Testing | |||||
| Substance | Test Concentration | Interference | |||
| (Yes/No) | Interference | ||||
| Results | |||||
| μmol/L | mg/dL | Assay | |||
| UCH-L1 | No | ||||
| Diazepam | 105 | 0.330 | GFAP | No | |
| UCH-L1 | No |
19
20
- 2-Ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine
a The test concentration used for this substance is not from CLSI guideline EP37 1* edition
b The 'x' factor listed indicates the number of times more activity than a known negative sample, for its ability to crosslink antibodies in a mouse system assay.
C One out of the five samples enriched for the presence of HAMA and two out of the five samples enriched for presence of RF exhibited an interference effect. See note regarding HAMA or other heterophile antibodies in Limitations of the Procedure section above.
d Note that the ethanol level is well above the CLSI highest therapeutic level of 43.4 mmol/L (200 mg/dL)
Cross-reactivity: The i-STAT TBI Plasma cartridge is specific to the measurement of GFAP and UCH-L1. The following proteins in Table 16 with significant homology to GFAP or UCH-L1 were tested at highest known physiological levels and none were found to have significant cross-reactive effects on measured the GFAP or UCH-L1 levels.
| Table 16: Interfering Substance Testing | |||
|---|---|---|---|
| Substance | Test | ||
| Concentration | |||
| pg/mL | Assay | Cross- | |
| reactivity | |||
| (Yes/No) | |||
| Keratin type II | 10 000 | GFAP | No |
| Internexin | 77 000 | GFAP | No |
| Neurofilament medium | 8600 | GFAP | No |
| Neurofilament heavy | 77 000 | GFAP | No |
| Neurofilament light | 68 | GFAP | No |
| Peripherin | 5000 | GFAP | No |
| Desmin | 127 000 | GFAP | No |
| Vimentin | 354 000 | GFAP | No |
| Ubiquitin Carboxyl-Terminal | |||
| Hydrolase L3 (UCH-L1) | 354 000 | UCH-L1 | No |
Cross-talk: The GFAP and UCH-L1 assays in the i-STAT TBI Plasma cartridge were evaluated for potential cross-talk to determine if high levels of the antigen (GFAP or UCH-L1) of one assay have potential to the impact the result of the other assay. Plasma samples spiked to low and high GFAP and UCH-L1 levels were evaluated in the presence of a single high level of the other antigen being evaluated for potential cross-talk. No cross-talk effect was observed as the results demonstrated that the GFAP result is not affected when UCH-L1 is present in a sample, and that the UCH-L1 result is not affected when GFAP is present in a sample.
21
| Table 17: Interfering Substance Testing | |||
|---|---|---|---|
| Substance | Test | ||
| Concentration | |||
| pg/mL | Assay | Cross-talk | |
| (Yes/No) | |||
| UCH-L1 | 100 000 | GFAP | No |
| GFAP | 100 000 | UCH-L1 | No |
f. Assay cutoff
Cutoff: The assay cutoffs were determined by analyzing a training set with GFAP and UCH-L1 results from a total of 420 (274 males and 146 females) with suspected mild traumatic brain injury (TBI; Glasgow Coma Scale score of 13-15). Subjects who had blood drawn within 12 hours of injury and a head CT scan determination, were included in the analysis. Using a 10-fold cross validation and bootstrapping method, the cutoff values of 30 pg/mL (GFAP assay) and 360 pg/mL (UCH-L1 assay) were selected for the i-STAT TBI Plasma Cartridge using the selection criteria with an adjusted NPV (prevalence 6%)≥98.5% and sensitivity ≥98%.
2. Clinical Study
Clinical Sensitivity and Specificity: A pivotal study using prospectively collected and archived (frozen) plasma specimens was conducted to establish the clinical performance of the i-STAT TBI Plasma test. The testing of the archived plasma specimens was conducted at three clinical sites in the United States.
The specimens were originally collected in a prospective, multi-center clinical study that enrolled consenting men and women 18 years of age or older who presented to emergency departments (ED) with suspected traumatic brain injury with initial Glasgow Coma Scale (GCS) scores of 13-15 and who had a computed tomography (CT) scan performed per the clinical site's standard of care. Subjects were enrolled at 22 clinical sites in three countries: United States, Germany and Hungary.
CT scans were performed in accordance with the clinical site's standard of care. Images were transmitted to a central neuroimaging processing center. Images were interpreted by at least two neuroradiologists who were masked to other clinical and laboratory data; procedures for scoring images were established before conducting image review. The clinical outcome was based on the consensus interpretation between two neuroradiologists with adjudication by a third neuroradiologist if necessary. Outcomes were positive or negative as defined by the presence or absence of acute traumatic intracranial lesions, respectively. Acute intracranial lesion was defined as any trauma induced or related finding visualized upon head CT scan.
Whole blood was collected into K2EDTA blood collection tubes from each subject using venipuncture and centrifuged to obtain plasma. Specimens were collected within 12 hours of head injury. The plasma specimens were divided into aliquots and frozen in cryovials before being provided to testing sites.
22
Of the 1994 subjects with GCS scores of 13 to 15 enrolled in the original study, specimens from 93 subjects were not included in the performance analysis due to subject discontinuation, lack of consent for specimen archiving for future testing, inconclusive or unreadable CT scan results, and/or unknown time from injury to blood collection. Specimens from 1901 subjects were included in the analysis.
The demographic characteristics of the subjects represented in the performance analysis are summarized in Table 18 below.
23
| Characteristic | Head CT Scan Result | Total | |
|---|---|---|---|
| Positive | Negative | ||
| N | 120 | 1781 | 1901 |
| Age1 (Years) | |||
| Mean | 58.8 | 48.5 | 49.1 |
| Median | 58.5 | 48.0 | 49.0 |
| Standard Deviation | 18.29 | 21.01 | 20.99 |
| Range | (20, 95) | (18, 98) | (18, 98) |
| Gender, N (%) | |||
| Male | 70 | ||
| (58.3%) | 1005 | ||
| (56.4%) | 1075 | ||
| (56.6%) | |||
| Female | 50 | ||
| (41.7%) | 776 | ||
| (43.6%) | 826 | ||
| (43.5%) | |||
| Race2, N (%) | |||
| White | 98 | ||
| (81.7%) | 1245 | ||
| (69.9%) | 1343 | ||
| (70.6%) | |||
| Black or African American | 16 | ||
| (13.3%) | 483 | ||
| (27.1%) | 499 | ||
| (26.2%) | |||
| Asian | 5 (4.2%) | 24 (1.3%) | 29 (1.5%) |
| Native Hawaiian/Pacific Islander | 1 (0.8%) | 2 (0.1%) | 3 (0.2%) |
| American Indian or Alaska Native | 1 (0.8%) | 9 (0.5%) | 10 (0.5%) |
| Unknown | 1 (0.8%) | 27 (1.5%) | 28 (1.5%) |
| Ethnicity, N (%) | |||
| Hispanic or Latino | 1 (0.8%) | 89 (5.0%) | 90 (4.7%) |
| Not Hispanic or Latino | 118 | ||
| (98.3%) | 1691 | ||
| (94.9%) | 1809 | ||
| (95.2%) | |||
| Not Reported | 1 (0.8%) | 1 (0.1%) | 2 (0.1%) |
Table 18: Demographic Characteristics
1 Age was calculated relative to the date of informed consent.
² Subjects could have indicated more than one race.
The head injury characteristics of the subjects represented by the 1901 specimens included in the performance analysis were tabulated. Information regarding time from head injury to exam, head injury to CT scan, and head injury to blood draw, as well as GCS, neurological assessment and physical evidence of trauma, categorized by head CT scan results, are shown in Table 19.
24
| Table 19: Head Injury Characteristics | ||||
|---|---|---|---|---|
| -- | -- | -- | -- | --------------------------------------- |
| Head CT Scan Result | |||
|---|---|---|---|
| Characteristic | Positive | Negative | Total |
| N | 120 | 1781 | 1901 |
| Time from head injury to exam (hours)1 | |||
| Mean | 1.9 | 1.6 | 1.6 |
| Median | 1.2 | 1.0 | 1.1 |
| Standard Deviation | 1.73 | 1.71 | 1.71 |
| Range | (0.3, 7.8) | (0.1, 10.7) | (0.1, 10.7) |
| Time from head injury to CT scan (hours)1 | |||
| Mean | 2.8 | 2.7 | 2.7 |
| Median | 2.1 | 2.2 | 2.1 |
| Standard Deviation | 1.95 | 1.93 | 1.93 |
| Range | (0.5, 8.9) | (0.2, 13.3) | (0.2, 13.3) |
| Time from head injury to blood draw (hours)1 | |||
| Mean | 3.8 | 3.5 | 3.5 |
| Median | 3.3 | 3.1 | 3.2 |
| Standard Deviation | 1.91 | 1.88 | 1.89 |
| Range | (0.3, 9.3) | (0.3, 11.9) | (0.3, 11.9) |
| Glasgow Coma Score - N (%) | |||
| 13 | 7 (5.8%) | 15 (0.8%) | 22 (1.2%) |
| 14 | 19 (15.8%) | 71 (4.0%) | 90 (4.7%) |
| 15 | 94 (78.3%) | 1695 (95.2%) | 1789 (94.1%) |
| Neurological assessment - N (%) of subjects experiencing: | |||
| Loss of Consciousness (LOC) | 82 (68.3%) | 721 (40.5%) | 803 (42.2%) |
| Alteration of Consciousness (AOC) | 92 (76.7%) | 978 (54.9%) | 1070 (56.3%) |
| Confusion | 44 (36.7%) | 313 (17.6%) | 357 (18.8%) |
| Vomiting | 14 (11.7%) | 128 (7.2%) | 142 (7.5%) |
| Post Traumatic Amnesia (PTA) | 81 (67.5%) | 546 (30.7%) | 627 (33.0%) |
| Post Traumatic Seizures | 2 (1.7%) | 11 (0.6%) | 13 (0.7%) |
| Subjects With Drug or Alcohol | |||
| Intoxication at the Time of | |||
| Presentation to Facility | 33 (27.5%) | 369 (20.7%) | 402 (21.1%) |
| Dangerous Mechanism of Injury2 | 27 (22.5%) | 369 (20.7%) | 396 (20.8%) |
| Physical Evidence3 | |||
| Visible Trauma Above the Clavicle | 101 (84.2%) | 1102 (61.9%) | 1203 (63.3%) |
| Suspected Open or Depressed Skull | |||
| Fracture | 14 (11.7%) | 46 (2.6%) | 60 (3.2%) |
1 Based on time subject was initially examined at the medical facility
2 Dangerous mechanism of injury was pedestrian struck by a motor vehicle, an occupant ejected from a motor vehicle, or a fall from an elevation of 3 or more feet or 5 stairs
3 Prior to head CT
The i-STAT TBI Plasma test clinical performance estimates are shown in Table 20. Of the 1901 specimens, 120 were associated with positive CT scan results. Of these 120 specimens, 115 had an 'elevated' i STAT TBI Plasma test interpretation (115/120, clinical sensitivity = 95.8%). Five specimens associated with CT scan positive results had an i-STAT TBI Plasma test interpretation that was 'not elevated'. The rate of false
25
negative (FN) results was 4.2% (5/120). Five subjects in the study were identified with lesion requiring surgical intervention; none of these five subjects had a FN result, suggesting that the i-STAT TBI Plasma test correctly classified all these five CTpositive subjects with a test interpretation of 'elevated.' Of the 1781 specimens associated with negative CT scan results, 720 had an i-STAT TBI Plasma test interpretation that was 'not elevated' (720/1781, clinical specificity = 40.4%). The rate of False Positive (FP) results was 59.6% (1061/1781).
Overall, there were 725 specimens with i-STAT TBI Plasma test interpretations of 'not elevated'. Of these. 720 specimens were associated with negative CT scan results. The Negative Predictive Value (NPV) of the assay was 99.3% (720/725).
| Table 20: Clinical Performance | |||
|---|---|---|---|
| i-STAT TBI Plasma | |||
| Test Interpretation | Adjudicated CT Scan Result | ||
| Positive | Adjudicated CT Scan Result | ||
| Negative | Total | ||
| Elevated | 115 | 1061 | 1176 |
| Not Elevated | 5 | 720 | 725 |
| Total | 120 | 1781 | 1901 |
| Clinical Performance Parameters | N=1901 | 95% Confidence Interval | |
| Clinical Sensitivity | 95.8% | 90.6%, 98.2% | |
| Clinical Specificity | 40.4% | 38.2%, 42.7% | |
| Negative Predictive Value (NPV) | 99.3% | 98.5%, 99.7% | |
| Positive Predictive Value (PPV) | 9.8% | 9.2%, 10.2% | |
| Likelihood Ratio Negative (LRN) | 0.10 | 0.04, 0.23 | |
| Likelihood Ratio Positive (LRP) | 1.61 | 1.51, 1.69 |
To supplement the results of the pivotal study (N=1901) described above, a study was conducted using freshly collected plasma specimens from consenting men and women 18 years of age or older who presented to Level 1 trauma center emergency departments (ED) with suspected traumatic brain injury, with initial Glasgow Coma Scale(GCS) scores of 13-15, and who had a computed tomography (CT) scan of the head performed per the clinical site's standard of care. A total of 88 subjects were enrolled across 4 clinical sites of the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study in the United States.
Similar to the pivotal study. CT scans were performed in accordance with the clinical site's standard of care. Images were interpreted by at least two neuroradiologists who were masked to other clinical and laboratory data; procedures for scoring images were established before conducting image review. The clinical outcome was based on the consensus interpretation between two neuroradiologists, with adjudication by a third neuroradiologist if necessary. Outcomes were positive or negative as defined by the presence or absence of acute traumatic intracranial lesions, respectively. Acute intracranial lesion was defined as any trauma induced or related finding visualized upon head CT scan.
Whole blood was collected into K3EDTA blood collection tubes from each subject
26
using venipuncture and centrifuged to obtain plasma. Specimens were collected within 12 hours of head injury. The demographic characteristics of the subjects represented in the performance analysis are summarized in Table 21 below:
| Table 21: Demographic Characteristics - Supplemental Fresh Specimen
| Study | |||
|---|---|---|---|
| Characteristic | Head CT Scan Result | Total | |
| Positive | Negative | ||
| N | 29 | 59 | 88 |
| Age (Years) | |||
| Mean | 49.2 | 39.3 | 42.5 |
| Median | 47 | 36 | 41 |
| Standard Deviation | 16.92 | 15.43 | 16.52 |
| Range | (24, 85) | (18, 76) | (18, 85) |
| Gender | |||
| Male | 23 | 40 | 63 |
| Female | 6 | 19 | 25 |
The head injury characteristics of the subjects in the supplemental plasma fresh specimen study including information regarding time from head injury to exam, head injury to CT scan, and head injury to blood draw, as well as GCS, neurological assessment and physical evidence of trauma, categorized by head CT scan results, are shown in Table 22.
| Table 22: Head Injury Characteristics – Supplemental Fresh Specimen Study | |||
|---|---|---|---|
| Characteristic | Head CT Scan Result | Total | |
| Positive | Negative | ||
| N | 29 | 59 | 88 |
| Time from head injury to CT scan (hours) | |||
| Mean | 2.5 | 2.2 | 2.3 |
| Median | 2.0 | 1.9 | 1.9 |
| Standard Deviation | 1.76 | 1.39 | 1.51 |
| Range | (0.7, 8.7) | (0.7, 7.5) | (0.7, 8.7) |
| Time from head injury to blood draw (hours) | |||
| Mean | 6.6 | 4.4 | 5.1 |
| Median | 6.0 | 3.9 | 4.3 |
| Standard Deviation | 2.93 | 1.96 | 2.54 |
| Range | (2.3, 11.8) | (2.0, 9.9) | (2.0, 11.8) |
| Glasgow Coma Score – N (%)1 |
27
| Table 22: Head Injury Characteristics - Supplemental Fresh Specimen Study | |||
|---|---|---|---|
| Characteristic | Head CT Scan Result | ||
| Positive | Negative | Total | |
| 13 | 1 (1.1%) | 0 (0.0%) | 1 (1.1%) |
| 14 | 6 (6.8%) | 9 (10.2%) | 15 (17.0%) |
| 15 | 22 (25.0%) | 50 (56.8%) | 72 (81.8%) |
| Neurological assessment - N (%) of subjects experiencing: | |||
| Loss of Consciousness (LOC) | 23 (79.3%) | 37 (62.7%) | 60 (68.2%) |
| Presence of Confusion | 19 (65.5%) | 40 (67.8%) | 59 (67.0%) |
| Vomiting2 | - | - | - |
| Post-traumatic Amnesia (PTA) | 22 (75.9%) | 38 (64.4%) | 60 (68.2%) |
| Post-traumatic Seizures | 0 (0%) | 0 (0%) | 0 (0%) |
| Subjects with Drug Intoxication at | |||
| the Time of Presentation to Site | 3 (10.3%) | 2 (3.4%) | 5 (5.7%) |
| Subjects with Alcohol Intoxication | |||
| at the Time of Presentation to Site | 6 (20.7%) | 4 (6.8%) | 10 (11.4%) |
| Physical Evidence - N (%) | |||
| Signs of Skull Fracture | 9 (31.0%) | 1 (1.7%) | 10 (11.4%) |
| Mechanism of Injury - N (%) | |||
| Acceleration/ Deceleration | 24 (82.8%) | 41 (69.5%) | 65 (73.9%) |
| Blow to Head | 4 (13.8%) | 8 (13.6%) | 12 (13.6%) |
| Head Against Object | 24 (82.8%) | 42 (71.2%) | 66 (75.0%) |
| Fall | 19 (65.5%) | 21 (35.6%) | 40 (45.5%) |
1 Percent based on total subjects
2 Information not collected
The i-STAT TBI Plasma test clinical performance estimates from the supplemental fresh plasma specimen study are shown in Table 23. Of the 88 subjects tested, 29 were associated with positive head CT scan results. Of these 29 subjects, 29 had an 'elevated' i-STAT TBI Plasma test interpretation (29/29, clinical sensitivity = 100.0%). The rate of False Negatives (FN) was 0% (0/29). Of the 59 subjects associated with negative CT scan results, 14 had an i-STAT TBI Plasma test interpretation that was 'not elevated' (14/59, clinical specificity = 23.7%). The rate of False Positive (FP) results was 76.2% (45/59).
Overall, there were 14 specimens with i-STAT TBI Plasma test interpretations of 'not elevated'. All 14 specimens were associated with negative head CT scan results. The Negative Predictive Value (NPV) of the assay was 100% (14/14).
| Table 23: Clinical Performance – Supplemental Fresh Specimen Study | ||
|---|---|---|
| i-STAT TBI Plasma | Adjudicated CT Scan Result | Total |
28
| Test Interpretation | Positive | Negative | |
|---|---|---|---|
| Elevated | 29 | 45 | 74 |
| Not Elevated | 0 | 14 | 14 |
| Total | 29 | 59 | 88 |
| Clinical Performance Parameters | N=88 | 95% Confidence Interval |
|---|---|---|
| Clinical Sensitivity | 100.0% | 88.3%, 100.0% |
| Clinical Specificity | 23.7% | 14.7%, 36.0% |
| Negative Predictive Value (NPV)* | 100.0% | 80.2%, 100.0% |
| Positive Predictive Value (PPV)* | 39.2% | 35.9%, 43.4% |
| Likelihood Ratio Negative (LRN) | 0.00 | 0.00, 0.50 |
| Likelihood Ratio Positive (LRP) | 1.31 | 1.14, 1.56 |
*NPV and PPV estimated at 33.0% prevalence of CT scan positive rate for suspected mild TBI subjects. Adjusted NPV and PPV at 6% prevalence (to be comparable to the pivotal study) are 100.0% (95% Cl: 96.9%, 100.0%) and 7.7% (95% CI: 6.8%, 9.1%), respectively.
8. Conclusion
Per special controls requirements of 21 CFR 866.5830, clinical studies were performed to support substantial equivalence. A pivotal study (N=1901) using archived plasma specimens from the same cohort of subjects that was used to demonstrate clinical performance of the predicate device showed similar clinical specificity and specificity with a similar number of false negative results. None of the false negative results were of subjects identified with a lesion requiring surgical intervention. The i-STAT TBI Plasma test showed high clinical sensitivity when validated in a supplemental fresh plasma specimen study (N=88). The clinical data demonstrates that the i-STAT TBI Plasma cartridge with the i-STAT Alinity System performs comparably to the predicate Banyan BTI device. In addition, a benefit-risk assessment was performed to help determine substantial equivalence for the device. Although similar clinical specificity to the predicate device was observed in the pivotal study, this was not as high in the supplemental fresh plasma study. However, the device shows potential for some reduction in the number of unnecessary CT scans. The i-STAT TBI Plasma cartridge offers significant benefit over the predicate device by establishing clinical workflow efficiencies through ease of use and a reduce test time. The assessment concludes that the benefits outweighs the risks. Overall, the results of analytical and clinical studies demonstrate that performance of the GFAP and UCH-L1 assays in the i-STAT TBI Plasma cartridge with the i-STAT Alinity System are substantially equivalent to the comparative method.