(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.
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Image /page/0/Picture/0 description: The image shows the logo of the U.S. Food and Drug Administration (FDA). The logo consists of two parts: a symbol on the left and the FDA name and title on the right. The symbol on the left is a stylized representation of a human figure, while the text on the right reads "FDA U.S. FOOD & DRUG ADMINISTRATION" in blue letters.
May 1, 2024
Biomerieux Inc. Chris Goodpaster Senior Regulatory Affairs Specialist 595 Anglum Rd. Hazelwood, Missouri 63042
Re: K240279
Trade/Device Name: VIDAS TBI (GFAP, UCH-L1) Regulation Number: 21 CFR 866.5830 Regulation Name: Brain Trauma Assessment Test Regulatory Class: Class II Product Code: QAT Dated: January 31, 2024 Received: February 1, 2024
Dear Chris Goodpaster:
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 (the 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 available 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.
Additional information about changes that may require a new premarket notification are provided in the FDA guidance documents entitled "Deciding When to Submit a 510(k) for a Change to an Existing Device"
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(https://www.fda.gov/media/99812/download) and "Deciding When to Submit a 510(k) for a Software Change to an Existing Device" (https://www.fda.gov/media/99785/download).
Your device is also subject to, among other requirements, the Quality System (QS) regulation (21 CFR Part 820), which includes, but is not limited to, 21 CFR 820.30. Design controls; 21 CFR 820.90. Nonconforming product; and 21 CFR 820.100, Corrective and preventive action. Please note that regardless of whether a change requires premarket review. the OS regulation requires device manufacturers to review and approve changes to device design and production (21 CFR 820.30 and 21 CFR 820.70) and document changes and approvals in the device master record (21 CFR 820.181).
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 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 Part 803) for devices or postmarketing safety reporting (21 CFR Part 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safetyreporting-combination-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 Part 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR Parts 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 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 mediation-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.
Ying Mao -S
Ying Mao, Ph.D. Branch Chief Division of Immunology and Hematology Devices OHT7: Office of In Vitro Diagnostics Office of Product Evaluation and Quality Center for Devices and Radiological Health
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Indications for Use
510(k) Number (if known) K240279
Device Name VIDAS® TBI (GFAP, UCH-L1)
Indications for Use (Describe)
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.
| Type of Use (Select one or both, as applicable) | |
|---|---|
| 区 Prescription Use (Part 21 CFR 801 Subpart D) | Over-The-Counter Use (21 CFR 801 Subpart C) |
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510(k) SUMMARY
This 510(k) summary of safety and effectiveness information is being submitted in accordance with the requirement of Safe Medical Devices Act of 1990 and 21 CFR 807.92.
VIDAS® TBI (GFAP, UCH-L1)
A. Submitter Information
| Submitter's Name: | bioMérieux Inc |
|---|---|
| Address : | 595 Anglum Rd., Hazelwood, MO 63042 |
| Contact Person: | Chris Goodpaster |
| Phone Number: | 1 (314)-731-7303 |
| Fax Number: | 1 (314)-731-8689 |
| Date of Preparation: | 26 January 2024 |
B. Device Name
| Trade Name: | VIDAS® TBI (GFAP, UCH-L1) |
|---|---|
| Common Name: | VIDAS® TBI (GFAP, UCH-L1) |
| Classification Name: | Brain trauma assessment test (21 CFR 866.5830, Product Code QAT) - Class 2 in vitro Diagnostic device |
C. Predicate Device Name
Trade Name: BANYAN BTI™, Banyan, DEN170045
D. Device Description
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):
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- 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.
E. Intended Use
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 Cterminal Hydrolase (UCH-L1) in human serum using the ELFA (Enzyme Linked Fluorescent Assay) technique. The results of both assays are required 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.
F. Technological Characteristics Summary
A general comparison of the similarities and differences of the assays with the predicate is presented in table 1 below.
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| Item | VIDAS TBI (GFAP, UCH-L1) | Predicate Device:Banyan BTI™ DEN170045 |
|---|---|---|
| Intended Use | The VIDAS® TBI (GFAP, UCH-L1) test iscomposed of two automated assays -VIDAS® TBI (GFAP) and VIDAS® TBI(UCH-L1) - to be used on the VIDAS® 3instrument for the quantitativemeasurement of Glial Fibrillary AcidicProtein (GFAP) and Ubiquitin C-terminalHydrolase (UCH-L1) in human serumusing the ELFA (Enzyme LinkedFluorescent Assay) technique. The resultsof both assays are required to obtain anoverall qualitative test interpretation.The overall qualitative VIDAS® TBI (GFAP,UCH-L1) test result is used, in conjunctionwith clinical information, to aid in theevaluation of patients (18 years of age orolder), presenting within 12 hours ofsuspected mild traumatic brain injury(Glasgow Coma Scale score 13-15), toassist in determining the need for aComputed Tomography (CT) scan of thehead. A negative interpretation of VIDAS®TBI (GFAP, UCH-L1) test is associatedwith the absence of acute intracraniallesions visualized on a head CT scan. | The Banyan BTI™ is an in vitro diagnosticchemiluminescent enzyme-linkedimmunosorbent assay (ELISA). The assayprovides a semi-quantitative measurementof the concentrations of ubiquitin C-terminal hydrolase-L1 (UCH-L1) and glialfibrillary acidic protein (GFAP) in humanserum and is used with the Synergy 2Multi-mode Reader.The assay results obtained from serumcollected within 12 hours of suspectedhead injury are used, along with otheravailable clinical information, to aid in theevaluation of patients 18 years of age andolder with suspected traumatic brain injury(Glasgow Coma Scale score 13-15).A negative assay result is associated withthe absence of acute intracranial lesionsvisualized on a head CT ComputedTomography) scan.The Banyan BTI™ is for prescription useonly. |
| Specimen | Serum | Serum |
| Analyte | Ubiquitin C-terminal Hydrolase (UCH-L1)and Glial Fibrillary Acidic Protein (GFAP) | Ubiquitin C-terminal Hydrolase (UCH-L1)and Glial Fibrillary Acidic Protein (GFAP) |
| Automated | Yes | No |
| AssayTechnique | Labeled antibody sandwich method (threeimmunological steps) with a finalfluorescent detection step, also known asenzyme-linked fluorescent assay (ELFA). | Chemiluminescent enzyme-linkedimmunosorbent assay (ELISA) |
Table 1: VIDAS TBI (GFAP, UCH-L1) Comparison with Predicate
G. Nonclinical Testing
A summary of the performance results is presented below.
Sample stability
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The following storage conditions are tested and confirmed on serum samples:
- +18°C to +25°C for 3 hours after centrifugation or at +2°C to +8°C for 43 hours .
- -19°C to -31°C for 5 months, with one freeze/thaw cycle .
- -60°C or colder for 5 months, with one freeze/thaw cycle .
Calibration Frequency
The 56-day calibration frequency was verified for VIDAS TBI (GFAP, UCH-L1).
Tubes Type
Two studies were performed to evaluate the suitability of specific collection tube types with the VIDAS TBI (GFAP, UCH-L1) assay.
The first study was performed with a minimum of 30 samples collected both in serum tubes with separator gel (SST) and in serum tubes (CAT). A second study was performed with a minimum of 40 samples collected both in serum tubes with separator gel (SST) and in rapid serum tubes.
The following types of tubes were validated with the VIDAS TBI (GFAP, UCH-L1) assay:
- Plastic tube with coagulation activator .
- Plastic tube with rapid coaqulation activator .
- Plastic tubes with or without separation gel .
Metrological traceability, product Calibrator S1 and product Control C1
The metrological traceability of the VIDAS TBI (GFAP, UCH-L1) assay was established by standardizing the assay against internal reference calibrators as, for the GFAP and UCH-L1 analytes, there is no certified reference material (CRM), primary calibrators, reference measurement procedures (RMPs) or harmonization protocol available, and as such no traceability to the International System of Units (SI).
The metrological traceability was established in accordance with the ISO 17511:2020 standard.
The internal reference calibrators were assigned using the BANYAN BTI assay. The concentrations for the VIDAS TBI (GFAP, UCH-L1) assay were therefore assigned to agree with the BANYAN BTI assay.
Analytical Measuring Interval
The VIDAS TBI (GFAP, UCH-L1) analytical measuring intervals are defined as follows:
- · 10.0 320.0 pg/mL for VIDAS TBI (GFAP)
- · 80.0 2560.0 pg/mL for VIDAS TBI (UCH-L1)
Linearity
The study was performed as recommended by CLSI EP06-Ed2 "Evaluation of Linearity of Quantitative Measurement Procedures". The study was conducted on the VIDAS 3 instrument.
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Linearity of VIDAS TBI (GFAP) was demonstrated on the range 6.7 - 354.5 pg/mL. Linearity of VIDAS TBI (UCH-L1) was demonstrated on the range 58.9 - 2769.1 pg/mL.
Detection Limits
The study was performed as recommended by CLSI EP17-A2 "Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures".
The claimed Limit of Blank (LoB), Limit of Detection (LoD) and Limit of Quantitation (LoQ) for the VIDAS TBI (GFAP, UCH-L1) assay on the VIDAS 3 instrument were:
| VIDAS TBI (GFAP) | VIDAS TBI (UCH-L1) | |
|---|---|---|
| Limit of Blank (LoB) | 4.4 pg/mL | 41.8 pg/mL |
| Limit of Detection (LoD) | 5.4 pg/mL | 48.1 pg/mL |
| Limit of Quantitation (LoQ) | 5.4 pg/mL | 48.1 pg/mL |
Table 2: VIDAS TBI (GFAP, UCH-L1) Detection Limits
The accuracy goal associated to LoQ is defined as 15% total within-lot precision, which is satisfactory for the intended clinical use.
Hook Effect
For VIDAS TBI (GFAP), no hook effect was found up to 200,000.0 pg/mL. For VIDAS TBI (UCH-L1), no hook effect was found up to 400,000.0 pg/mL.
Precision
The study was performed as recommended by CLSI EP05-A3 "Evaluation of Precision of Quantitative Measurement Methods". The precision estimates are as follows:
| VIDASTBI(GFAP,UCH-L1) | Sample | N | Mean[pg/mL] | RepeatabilityWithin-runprecision | Within-lotwithin-instrument | Within-LaboratoryPrecisionBetween-lot within-instrument | |||
|---|---|---|---|---|---|---|---|---|---|
| StandardDeviation[pg/mL] | CV (%)* | StandardDeviation[pg/mL] | CV (%)* | StandardDeviation[pg/mL] | CV (%)* | ||||
| GFAP | Sample 1 | 75 | 15.63 | 0.93 | 5.9 | 0.93 | 5.9 | 1.11 | 7.1 |
| Sample 2 | 75 | 31.03 | 1.16 | 3.7 | 1.17 | 3.8 | 1.95 | 6.3 | |
| Sample 3 | 75 | 75.29 | 4.69 | 6.2 | 4.69 | 6.2 | 6.58 | 8.7 | |
| Sample 4 | 75 | 199.54 | 5.93 | 3.0 | 6.42 | 3.2 | 12.28 | 6.2 | |
| Sample 5 | 75 | 282.23 | 8.23 | 2.9 | 8.56 | 3.0 | 18.22 | 6.5 | |
| UCH-L1 | Sample 6 | 75 | 141.30 | 6.58 | 4.7 | 7.85 | 5.6 | 7.93 | 5.6 |
| Sample 7 | 75 | 274.52 | 10.72 | 3.9 | 11.03 | 4.0 | 11.55 | 4.2 | |
| Sample 8 | 75 | 388.91 | 14.54 | 3.7 | 14.54 | 3.7 | 16.47 | 4.2 | |
| Sample 9 | 75 | 837.10 | 30.20 | 3.6 | 30.20 | 3.6 | 34.54 | 4.1 | |
| Sample 10 | 75 | 2253.47 | 104.87 | 4.7 | 104.87 | 4.7 | 135.80 | 6.0 |
Table 3: VIDAS TBI (GFAP, UCH-L1) Precision
*CV (%): Coefficient of Variation (%)
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Interference
The study was performed as recommended by CLSI EP07-Ed3 "Interference Testing in Clinical Chemistry".
Study of drugs and other potentially interfering substances No significant interference was detected up to the maximum concentrations indicated below:
| Tested drug | VIDAS TBI (GFAP, UCH-L1)Concentration |
|---|---|
| Acetaminophen (Paracetamol) | 15.6 mg/dL |
| Acetylsalicylic acid (Aspirin) | 3.0 mg/dL |
| Benzoylecgonine tetrahydrate | 37.5 ng/mL |
| Cardene | 0.047 mg/dL |
| Coumadin (Warfarin) | 7.5 mg/dL |
| EDDP* | 125 ng/mL |
| Ethanol | 600.1 mg/dL |
| lbuprofen | 21.9 mg/dL |
| Lopressor (Metroprolol + tartrate salt) | 18.7 µmol/L |
| Methadone hydrochloride | 0.318 mg/dL |
| d-Methamphetamine | 125 ng/mL |
| Methaqualone Solution | 37.5 ng/mL |
| Metoclopramide | 0.225 mg/dL |
| Morphine monohydrate | 0.78 mg/dL |
| Ondansetron hydrochloride dihydrate | 0.96 mg/dL |
| Oxazepam | 0.435 mg/dL |
| Phencyclidine hydrochloride | 3.1 ng/mL |
| Plavix | 4.5 mg/dL |
| Propoxyphene | 0.321 mg/dL |
| Secobarbital | 1.59 mg/dL |
Table 4: Drugs Concentrations Found Not to Interfere
*2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine
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| Tested substance | VIDAS TBI (GFAP)Concentration | VIDAS TBI (UCH-L1)Concentration |
|---|---|---|
| Bilirubin (conjugated) | 0.4 g/L (475 [Mu]mol/L) | 0.4 g/L (475 [Mu]mol/L) |
| Bilirubin (unconjugated) | 0.4 g/L (684 [Mu]mol/L) | 0.4 g/L (684 [Mu]mol/L) |
| Biotin | 3.84 [Mu]g/mL | 3.51 [Mu]g/mL |
| Hemoglobin | 10 g/L (620 [Mu]mol/L) | 0.6 g/L (37.2 [Mu]mol/L)* |
| Human Albumin | 60 g/L | 60 g/L |
| Human Anti Mouse Antibodies (HAMA) | 2000 ng/mL | 2000 ng/mL |
| Lipids | 30 g/L | 30 g/L |
| Rheumatoid factor | 802 IU/mL | 175 IU/mL** |
| Total proteins | 120 g/L | 120 g/L |
Table 5: Other Substances Found Not to Interfere
- For VIDAS TBI (UCH-L1), no interference was observed for hemoglobin up to the concentration of 0.6 g/L. Above this concentration, the interference leads to an increase of the VIDAS TBI (UCH-L1) results.
** For VIDAS TBI (UCH-L1), no interference was observed for rheumatoid factors up to the concentration of 175 IU/mL. Above this concentration, the interference leads to an increase of the VIDAS TBI (UCH-L1) results.
Cross-reactivity of structurally related molecules:
Table 6: Cross-reactivity Results of VIDAS TBI (GFAP)
| Tested substance | VIDAS TBI (GFAP)Tested concentration (ng/mL) | Cross-reactivity (%) |
|---|---|---|
| Desmin | 127 | |
| Internexin | 77 | |
| Keratin type II | 10 | |
| Neurofilament light | 0.068 | No interference observed up tothe concentration tested. |
| Neurofilament medium | 8.6 | No interference observed up tothe concentration tested. |
| Neurofilament heavy | 77 | |
| Peripherin | 5 | |
| Vimentin | 354 |
Table 7: Cross-reactivity Results of VIDAS TBI (UCH-L1)
| Tested substance | VIDAS TBI (UCH-L1)Tested concentration (ng/mL) | Cross-reactivity (%) |
|---|---|---|
| UCH-L3 | 354 | No interference observed up tothe concentration tested. |
{10}------------------------------------------------
H. Clinical Testing
Reference interval
The study was performed as recommended by CLSI EP28-A3 "Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory, Approved Guideline – Third Edition".
Reference intervals were determined using two cohorts of apparently healthy US adult (≥ 18 years) subjects (N=513). Testing was conducted at three sites (one internal European site, and two external US sites) using the VIDAS 3 instrument. The reference intervals were defined by the central 95% distribution of GFAP and UCH-L1 concentration, i.e by the 2.5th and 97.5th percentiles. 91.0% of the reference value subjects had a negative overall assay interpretation for VIDAS® TBI (GFAP. UCH-L1). Among the 513 apparently healthy subjects included in this study, 43 individuals had a positive assay interpretation (8.4%) and 470 (91.6%) had a negative assay interpretation.
The overall reference interval for apparently healthy subjects was <10 to 31.63 for GFAP and <80 to 249.70 for UCH-L1.
Diagnostic Accuracy
The study was performed using the ALERT cohort and was performed as recommended by CLSI EP12-A2 guideline 'User Protocol for Evaluation of Qualitative Test Performance; Approved guideline - Second edition'. The clinical performance study was conducted on the VIDAS 3 instrument.
The diagnostic accuracy performance characteristics obtained for the VIDASTBI (GFAP. UCH-L1) assay at the cut-off values were the following:
- · The diagnostic sensitivity observed was 96.7%
- · The diagnostic specificity observed was 41.2%
- The positive likelihood ratio was 1.6
- The negative likelihood ratio was 0.1
- · The positive predictive value observed was 9.9%
- The negative predictive value observed was 99.5%
The clinical performance of the VIDAS TBI (GFAP, UCH-L1) assay demonstrates that the assay is safe and effective to yield results correlated with the presence of GFAP and UCH-L1 for patients with mild traumatic brain injury as per product intended purpose, using human serum samples.
l. Conclusion
The results from the non-clinical and clinical studies submitted in this premarket notification demonstrate that the VIDAS TBI (GFAP, UCH-L1) assay is substantially equivalent to the predicate device and meets special controls requirements of 21 CFR 866.5830.
§ 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.”