FDA clarifies brain injury device regs as researchers race to better detect concussions

Consternation over concussions is spreading across the globe. The Economist just declared that "children need protection from high-impact sports such as rugby and American football." And the list of sufferers from traumatic brain injury includes not just athletes, but also military members and civilians.

The FDA is joining the chorus of efforts to address TBI through increased outreach and clarification of its regulations via issuance of a guidance document. The agency has not formally accepted any neuroimaging biomarkers for use in clinical trials, but at a March 3 FDA hearing, researchers from academia and industry said they are making progress on developing metrics that could serve as a sign of the condition.

GE Healthcare program manager Luca Marinelli, described the company's TBI imaging research in collaboration with the NFL. Using a "simultaneous multi-slice acquisition sequence" the company has increased the temporal resolution of fMRI brain images by a factor of three and shortened the length of the scan conducted in diffusion-weighted MRI imaging.

The research has enabled significant changes to what is available commercially, he said.

Marinelli said the team has been able to detect correlations between the severity of TBI and decreased communication between brain networks, such as executive control and visual processing.

But the gap between the company's research and real-world application at hospitals, or even in formal clinical trials, is vast due to scientific, practical and regulatory constraints.

First, the images' lack of sensitivity could hinder their use as formal biomarkers in a clinical trial or treatment protocol. CT scans are the standard of care for TBI patients, but the FDA says it is not unusual for the images to be entirely normal, particularly in mild cases of the condition.

Marinelli said that in a study of 111 patients with mild TBI, less than 5 subjects showed brain abnormalities using MRI imaging techniques, even though it is generally more sensitive than CT scanning.

"It (the TBI) is not mild if we look at symptoms. It is not mild if we look at how long these subjects are affected by the disease. But it is mild in the sense that if we look at the conventional radiological findings, we don't see any," Marinelli said.

GE is planning a second trial of 300 patients at 6 sites around the nation that will collect additional data with a greater level of detail.

Meanwhile, Dr. Esther Yuh, professor of radiology and biomedical imaging at the University of California, San Francisco, said her research of CT and MRI images of TBI showed that they score high on "interrater reliability," meaning multiple radiologists make similar diagnoses when presented with the same scan.

Due to its widespread clinical usage, the FDA does accept the use of "CT positive" and "CT negative" as a biomarker in TBI clinical trials, though it may have limited utility due to its poor record of detecting actual structural brain injury. Technically, the biomarker has not been formally qualified by the FDA, even though its use is generally permitted.

In a bid to formally qualify more precise neuroimaging biomarkers, the agency just released a draft guidance on clinical consideration for granting Investigational Device Exemptions (IDEs) for neurological devices targeting disease progression and clinical outcomes.

"When biomarkers are chosen as a metric (for device evaluation), there should be well established evidence and agreement in the clinical community that the chosen biomarker test reflects a characteristic that is important to the underlying disease process and that it is associated with a clinically meaningful outcome measure," the guidance states.

During the hearing, Kathryn O'Callaghan, a health scientist at the FDA's device arm (CDRH), said the agency evaluates biomarkers based on analytical and clinical reliability. Any biomarker-based test must accurately measure the target of interest. And the biomarker being measured or detected must be a reliable indicator of some sort of clinical outcome, she said.

Imaging devices have broad indications of use, but they do not permit specific use for formal quantification of visual biomarkers. "As the intended use becomes more specific, the expectation for the level of evidence increases," CDRH health scientist Daniel Krainak said.

Agency officials also touted the Medical Device Development Tool program. Launched in 2013 via a draft guidance, the program is a way for the FDA to qualify tools, including biomarker tests, "that medical device sponsors can use in the development and evaluation of medical devices."

The hearing also featured a discussion of biofluid biomarkers, such as possible blood tests for the condition. Representatives from the FDA's drugs and biologics arms participated as well.

- here's more about the FDA hearing
- get the draft guidance (PDF)