ARTICLE IN BRIEF
The FDA-approved blood test predicted which patients with mild traumatic brain injury had intracranial lesions with 97.5 percent accuracy, and patients without lesions 99.6 percent of the time.
The US Food and Drug Administration (FDA) approved a blood test in February for two biomarkers associated with bleeding after traumatic brain injury (TBI); the test is intended to identify patients who do not need to undergo imaging for intracranial lesions.
If performed within 12 hours of injury, the test is almost 100 percent accurate, the FDA said in its February 14 announcement. The assay was approved in less than six months under the FDA Breakthrough Devices Program, in part to help prevent unnecessary radiation exposure.
The Brain Trauma Indicator was developed by Banyan Biomarkers, Inc., in partnership with the Department of Defense. It measures levels of two proteins — glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1(UCH-L1) — both of which are released into the bloodstream after head trauma.
Although exact numbers are unknown, it is estimated that about 75 percent of traumatic brain injuries are mild TBIs (mTBIs), and most patients with mTBI/concussive symptoms have a negative computed tomography (CT) scan, according to the FDA.
Approval was based on results from the prospective, multicenter ALERT-TBI clinical trial. The study enrolled patients at 24 clinical sites and compared the test's results to head CT scans. The FDA evaluated data on 1,947 individual blood samples from adults with suspected mTBI/concussion, comparing tests results with CT findings.
The test predicted patients with intracranial lesions (positive predictive evidence) with 97.5 percent accuracy, and patients without lesions (negative predictive evidence) 99.6 percent of the time. Test results were available within three to four hours.
“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,” said FDA Commissioner Scott Gottlieb, MD, in an announcement.
The Brain Trauma Indicator was reviewed under the FDA's De Novo premarket review pathway, an expedited review pathway for some novel low- to moderate-risk devices for which there is no prior legally marketed device.
Banyan Biomarkers was founded in 2002 by Ronald Hayes, PhD, former director of the University of Florida's Center for Traumatic Brain Injury Studies, at the McKnight Brain Institute, in Gainesville.
Details of the final data on which the FDA based its approval of the blood test were not available at press time, however FDA spokeswoman Deborah Kotz said they will be made available soon.
Earlier findings were reported November 2015 in the Journal of Neurotrauma. In another study, published in May 2016 in JAMA Neurology, some of the same investigators studied the time course of detectable levels of the biomarkers over a seven-day period and found that testing for both GFAP and UCH-L1 to be considerably more predictive of bleeding than either biomarker on its own.
The first study was a prospective multicenter observational study in 251 patients with mild to moderate TBI at US and European emergency departments. All underwent a CT scan as part of routine care and had blood drawn for biomarker analysis within six hours of injury.
Positive CT images were found for 36 patients, and UCH-L1 was 100 percent sensitive and 39 percent specific. The UCH-L1 biomarker could have eliminated the need for 83 of the 215 negative CT scans, the researchers reported in JAMA Neurology.
In the second study, the team evaluated the test in 1,831 blood samples collected from 584 patients enrolled within four hours of injury. They did repeat blood sampling at four-hour intervals up to 180 hours post-injury.
Both glial GFAP and UCH-L1 were detectable within one hour after injury, with GFAP peaking at 20 hours and slowly declining; UCH-L1 peaked at eight hours and declined over 48 hours after mild and moderate TBI. Mild-to moderate TBI was defined as blunt head trauma with loss of consciousness, amnesia, or disorientation and a Glasgow Coma Scale score of 9-15.
The researchers also analyzed another potential biomarker for TBI, S100B, but found it was not able to achieve the same performance as UCH-L1.
They concluded, when obtained within six hours of head injury, the combination of GFAP and UCH-L1 was very sensitive for a positive CT scan of bleeding among patients with mild to moderate TBI. GFAP performed consistently in detecting mTBI, CT lesions, and neurosurgical intervention across seven days. UCH-L1 performed best in the early post-injury period.
For detecting intracranial lesions on CT, the diagnostic ranges of areas under the curve were 0.80 (95 percent CI, 0.67-0.92) to 0.97 (95 percent CI, 0.93-1.00) for GFAP and 0.31 (95 percent CI, 0-0.63) to 0.77 (95 percent CI, 0.68-0.85) for UCH-L1.
“People have been given the wrong impression about this test, and I think it is important for the public to understand that this is not a test for concussions,” said Javier Cárdenas, MD, FAAN, director of the Barrow Concussion and Brain Injury Center at St. Joseph's Hospital, in Phoenix, AZ. “This test helps identify bleeding in the brain from a head injury in a broad spectrum of TBIs.”
He said that he believes the test will be embraced by the emergency medical community despite medicolegal concerns about missing an injury that would have been detected by CT.
“There has been a bit of a pendulum swing in attitudes toward using CT scans, especially of the head,” he told Neurology Today. “Today there is much more caution, and this test should reduce the number of CT scans, especially in kids. The brain radiation absorption rate for pediatric patients is several times greater than adults and remains that way into their 20s.”
The other advantage is having a means of differentiating more serious head injuries among in-field members of the armed forces, where access to a CT scan is often limited, he noted.
But Tad D. Seifert, MD, director of the sports neurology program at Norton Healthcare in Louisville, KY, had a different view of the test. He told Neurology Today that the test may have limited utility in emergency rooms or for head injuries in sports.
“The primary challenge with this test is the four-hour turnaround. In the setting of an emergency room, time is at a premium, and a four-hour wait is a lifetime.”
This also makes it impractical from a sports standpoint, he told Neurology Today.
“For evaluating concussion on the sidelines, the test has very limited utility. I think scientists in the laboratory have to figure out how to get a test that provides results much faster.”
He also emphasized that the two biomarkers do not identify whether or not a person has suffered a concussion, but whether CT imaging is likely to detect blood.
“The purpose is to predict blood on imaging, and from a clinical standpoint, that is a scenario that goes well beyond concussion,” he said.