First in Vitro Diagnostic Blood Test for the evaluation of mTBI

Basic Information:

• On February 14, 2018, The U.S. Food and Drug Administration (US FDA) permitted marketing of the first blood test to evaluate mild traumatic brain injury (mTBI). 
• It is commonly known as concussion in adults. 
• Under Breakthrough Devices Program (Known as De Novo Program), The US FDA reviewed Banyan Brain Trauma Indicator in less than 6 months and authorized for marketing.

Current Practice:

• Most patients with a suspected head injury are examined using a neurological scale, called the 15-point Glasgow Coma Scale, followed by a computed tomography or CT scan of the head to detect brain tissue damage, or intracranial lesions, that may require treatment; however, a majority of patients evaluated for mTBI/concussion do not have detectable intracranial lesions after having a CT scan.

Unmet Need:

• Blood test for concussion will help health care professionals determine the need for a CT scan in patients suspected of having mTBI and help prevent unnecessary neuroimaging and associated radiation exposure to patients.

Demographic Facts:

• In 2013, there were approximately 2.8 million TBI-related emergency department visits, hospitalizations and deaths in the U.S. of these cases, TBI contributed to the deaths of nearly 50,000 people according to the U.S. Centers for Disease Control and Prevention. 
• Cause of TBI is a bump, blow or jolt to the head or a penetrating head injury that disrupts the brain’s normal functioning. Its severity may range from mild to severe, with 75 percent of TBIs that occur each year being assessed as mTBIs or concussions. 
• A majority of patients with concussion symptoms have a negative CT scan. 
• Potential effects of TBI can include impaired thinking or memory, movement, sensation or emotional functioning.

Mechanism of Action:

• The Brain Trauma Indicator works by measuring levels of proteins, known as UCH-L1 and GFAP, that are released from the brain into blood and measured within 12 hours of head injury.
• Levels of these blood proteins after mTBI/concussion can help predict which patients may have intracranial lesions visible by CT scan and which won’t. 
• Being able to predict if patients have a low probability of intracranial lesions can help health care professionals in their management of patients and the decision to perform a CT scan. 
• Test results can be available within 3 to 4 hours.

Submitted Clinical Study Overview:

• The FDA evaluated data from a multi-center, prospective clinical study of 1,947 individual blood samples from adults with suspected mTBI or concussion and reviewed the product’s performance by comparing mTBI or concussion blood tests results with CT scan results. 
• The Brain Trauma Indicator was able to predict the presence of intracranial lesions on a CT scan 97.5 percent of the time and those who did not have intracranial lesions on a CT scan 99.6 percent of the time. 
• These findings indicate that the test can reliably predict the absence of intracranial lesions and that health care professional can incorporate this tool into the standard of care for patients to rule out the need for a CT scan in at least one-third of patients who are suspected of having mTBI.

Forward looking statement of the US FDA's Commissioner Scott Gottlieb, M.D.:

• Helping to deliver innovative testing technologies that minimize health impacts to patients while still providing accurate and reliable results to inform appropriate evaluation and treatment is an FDA priority. 
• Today’s action supports the FDA’s Initiative to Reduce Unnecessary Radiation Exposure from Medical Imaging - an effort to ensure that each patient is getting the right imaging exam, at the right time, with the right radiation dose. 
• A blood-testing option for the evaluation of mTBI/concussion not only provides health care professionals with a new tool, but also sets the stage for a more modernized standard of care for testing of suspected cases. 
• In addition, availability of a blood test for mTBI/concussion will likely reduce the CT scans performed on patients with concussion each year, potentially saving our health care system the cost of often unnecessary neuroimaging tests.

Publication Summary of Studies:

1. ALERT-TBI Study:  Evaluate the utility of the Banyan UCH-L1/GFAP Detection Assay as an aid in the evaluation of suspected traumatic brain injury (Glasgow Coma Scale score 9-15) in conjunction with other clinical information within 12 hours of injury to assist in determining the need for a CT scan of the head.
2. Modeling the Kinetics of Serum Glial Fibrillary Acidic Protein, Ubiquitin Carboxyl Terminal Hydrolase-L1, and S100B Concentrations in Patients with Traumatic Brain Injury: GFAP concentrations increased 3.7% per hour among CT-positive patients whereas neither UCH-L1 nor S100B increased, compared with CT-negative patients. The kinetics and temporal profile of GFAP suggest it may be a more robust biomarker to detect patients with positive CT findings, particularly at later post-injury times.  
3. Prospective Assessment of Acute Blood Markers of Brain Injury in Sport-Related Concussion: GFAP levels did not differ between groups or in concussed athletes relative to pre-season. This study provides prospective evidence of significant increases in serum levels of UCH-L1 and S100B during the early acute period following sports related concussion, and lays the foundation for future studies examining the clinical potential for blood-based biomarkers in the early detection of concussion.
4. Neuronal Biomarker Ubiquitin C-Terminal Hydrolase Detects Traumatic Intracranial Lesions on Computed Tomography in Children and Youth with Mild Traumatic BrainInjury: UCH L1 showed good performance in infants and toddlers younger than 5 years and performed well in children and youth with a GCS score of 15.
5. Time Course and Diagnostic Accuracy of Glial and Neuronal Blood Biomarkers GFAP and UCH-L1 in a Large Cohort of Trauma Patients With and Without Mild Traumatic Brain Injury: GFAP and UCH-L1 were detectible within 1 hour of injury. GFAP peaked at 20 hours after injury and slowly declined over 72 hours. UCH-L1 rose rapidly and peaked at 8 hours after injury and declined rapidly over 48 hours.
6. Ability of Serum Glial Fibrillary Acidic Protein, Ubiquitin C-Terminal Hydrolase-L1, and S100B To Differentiate Normal and Abnormal Head Computed Tomography Findings in Patients with Suspected Mild or Moderate Traumatic Brain Injury: UCH-L1 out performed GFAP and S100B when the goal was to reduce CT use without sacrificing sensitivity. UCH-L1 values <40 pg/mL could potentially have aided in eliminating 83 of the 215 negative CT scans.
7. Acute Biomarkers of Traumatic Brain Injury: Relationship between Plasma Levels of Ubiquitin C-Terminal Hydrolase-L1 and Glial Fibrillary Acidic Protein (TRACK-TBI): The results demonstrate a role for multiple biomarker measurements in TBI research.
8. GFAP-BDP as an Acute Diagnostic Marker in Traumatic Brain Injury - Results from the Prospective Transforming Research and Clinical Knowledge in Traumatic Brain Injury Study (TRACK-TBI): The results demonstrate that measurement of serum GFAP-BDP may improve the ability of clinicians to identify TBI patients who may require further medical evaluation and management. Use of GFAP-BDP as a serum biomarker for TBI should lead to more accurate diagnosis and management of TBI.
9. Clinical utility of serum levels of ubiquitin c-terminal hydrolase as abiomarker for severe traumatic brain injury: Serum levels of UCH-L1 appear to have potential clinical utility in diagnosing TBI, including correlating to injury severity and survival outcome.
10. Brain injury biomarkers may improve the predictive power of the IMPACT Outcome Calculator: Results underline the importance of biomarkers in outcome prediction, and encourage further investigation to expand the predictive power of contemporary outcome calculators and prognostic models in TBI.
11. Elevated Levels of Serum Glial Fibrillary Acidic Protein Breakdown Products in Mild and Moderate Traumatic Brain Injury Are Associated With Intracranial Lesions and Neurosurgical Intervention: GFAP-BDP is detectable in serum within an hour of injury and is associated with measures of injury severity, including the GCS score, CT lesions, and neurosurgical intervention.
12. Serum levels of ubiquitin C-terminal hydrolase distinguish mild traumatic brain injury from trauma controls and are elevated in mild and moderate traumaticbrain injury patients with intracranial lesions and neurosurgical intervention: UCH-L1 is detectable in serum within an hour of injury and is associated with measures of injury severity including the GCS score, CT lesions, and NSI.
13. Neuronal and glial markers are differently associated with computed tomography findings and outcome in patients with severe traumatic brain injury - a case control study: Protein biomarker could provide better characterization of subjects at risk for specific types of cellular damage than that obtained with neuroimaging alone, as well as provide valuable information about injury severity and outcome after severe TBI.
14. Ubiquitin C-terminal hydrolase is a novel biomarker in humans for severe traumatic brain injury: UCH-L1 protein is present in human CSF and that its levels were significantly elevated after severe TBI using enzyme-linked immunosorbent assay (ELISA) analysis. UCH-L1 was detectable in CSF very early after injury and was associated with measures of injury severity and outcome.