... Incorporating Biomarkers into Research and Clinical Practice...

... Key Messages from Individual Speakers and Participants...

... Biomarker results depend on the protein isoform and assay platform, and the specified reference and cutoff ranges These are critical elements for comparing and interpreting results from different tests (“GFAP is not GFAP”) (Gill, Lazarus, ...

... The current classification scheme of mild, moderate, and severe TBI does a disservice to patients on both ends of the severity spectrum. More precise language that incorporates additional clinical and ... information is needed to inform treatment and improve outcomes (Manley, Okonkwo)....

... NOTE: This list is the rapporteurs’ summary of points made by the individual speakers identified, and the statements have not been endorsed or verified by the National Academies of Sciences, Engineering, and Medicine. They are not intended to reflect ...

... testing of drug therapies for TBI and envisioning a future in which decision-making by care providers is informed in real time by having access to expanded biomarker information. Speakers and participants then shared suggestions for further advancing the use of biomarkers in TBI care, including their ...

... Using biomarkers as part of drug screening has the potential to save time and money in translating research to clinical therapies for TBI. Patrick Kochanek, University of Pittsburgh, discussed efforts conducted through the ... Operation Brain Trauma Therapy (OBTT) to identify blood-based biomarkers able to function as pharmacodynamic response biomarkers for evaluating drug candidates in several small animal injury models....

... He began by sharing an example of an early study by his group that measured biomarker levels and compared results at different time points and across several types of pediatric brain injuries seen in neurocritical care (in this case, head trauma after child abuse, accidental TBI, and hypoxic ...

... be needed for different TBI phenotypes (represented by different models of injury), and how well blood-based proteins would perform as biomarkers to assess drug performance....

... OBTT measured serum biomarkers, including glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1), among others, and compared levels at 4 hours and 24 hours to evaluate whether a drug was working. Biomarker levels measured after administration of the two most ... drug candidates identified through this screening (levetiracetam and glibenclamide) were compared with conventional outcome measures (Mondello et al., 2011, 2016). The consortium found that GFAP, but not UCH-L1, is a ... useful pharmacodynamic response biomarker in rat models of TBI. Serum GFAP level significantly increased at 4 hours and/or 24 hours after injury across all the tested TBI models, while the increase in UCH-L1 level in rats, unlike in humans, was too fast and transient ... versus penetrating injury) revealed some illuminating differences. Kochanek posited that blood-based biomarkers will be useful in helping understand different laboratory and clinical TBI endophenotypes. Measured GFAP levels also performed consistently across test parameters and sites, showing that ... are useful in comparing TBI models and monitoring model stability....

... GFAP levels measured at 24 hours correlated with outcomes at 21 days after injury, based on histologic measures of lesion volume and hemispheric tissue loss. Serum GFAP at 24 hours was able to predict which of the tested drugs would show a benefit in improved motor outcomes over ... initial 5 days and histology measured at 21 days, and which drugs in which injury models would fail to improve 21-day outcomes, demonstrating GFAP’s utility as a response biomarker. Generally, Kochanek ... , biomarker data in OBTT was better at predicting histology and motor function than cognitive or behavioral outcomes. While studies in the screening consortium were not powered optimally, these findings are very ...

... In conclusion, Kochanek shared the design of a “living translational model” for TBI drug screening and selection (Kochanek et al., 2020; see Figure 4-1). In this approach, initial identification of drug candidates (bottom of the pyramid) is followed by ... in small animal models, using serum pharmacodynamic response biomarkers to save money and time. Drugs that are successful in early testing would be further evaluated through more definitive preclinical testing and, ultimately, in clinical ... . Kochanek also advocated for the value of preclinical consortia to undertake rigorous biomarker evaluation and drug testing, in addition to discovery efforts within individual labs. There is a need for further assessment, he...

... NOTE: GFAP = glial fibrillary acidic protein; pNF-H = phosphorylated neurofilament heavy; TBI = traumatic brain injury....

... concluded, testing more biomarkers in this kind of environment to determine their temporal profiles across injury models and after various treatments and to optimize biomarker screening for both acute and chronic therapies....

... IMPROVING DIAGNOSIS AND ENVISIONING THE FUTURE OF TBI CARE2...

... future of TBI care, David Okonkwo, University of Pittsburgh, recalled the progress that has been achieved in TBI management over the past decades, and said the field is poised to move forward. A landmark paper in 1977 defined the modern management of TBI, and emphasized early diagnosis, surgical ...

... increased intracranial pressure, and aggressive medical therapy (Becker et al., 1977). Okonkwo highlighted six patterns of computed tomography (CT) scans used as a biomarker and how the ... the needle is moving, the field is ready to move it much faster. The first blood biomarker test for concussion detection was cleared by the Food and Drug Administration (FDA) in 2018, using GFAP and UCH-L1.3 Then in 2021, a rapid test developed by Abbott in collaboration with DoD was cleared by ... , also measuring biomarker proteins GFAP and UCH-L1 in plasma.4 Work is currently under way to develop a whole blood test that can more easily be used at the point of care, and Okonkwo noted ...

... field, noting the discovery of prostate-specific antigen (PSA) as a diagnostic marker for prostate cancer. Tests for PSA were quickly incorporated, and the mortality rate for prostate cancer has dropped by 50 percent since its adoption as a biomarker, he said. The changes from having effective ... , 2.8 million people are diagnosed with a TBI. As part of a pivot in this direction within the TBI field, he noted, the Biomedical Advanced Research and Development Authority (BARDA) in the Department of Health and Human Services (HHS) Office of the Assistant Secretary for Preparedness and Response is ... partnering with the pharmaceutical company Abbott to undertake “aid in diagnosis” studies in adults and children that could broaden applications for Abbott’s current TBI assay and aid providers in diagnosing and understanding the severity of brain ... . He also advocated for continuing to expand TBI biomarker uses in different clinical contexts and for additional indications....

... the need for additional systematic vetting. Research is also elucidating the relationship between biomarker levels measured shortly after injury and long-term outcomes. Combining large datasets from consortia in Europe and North America and using cluster analyses, researchers are beginning to ... CT patterns and care practices for three types of TBI patients. The first is for addressing isolated epidural hematoma, which has...

... 4 https://abbott.mediaroom.com/2021-01-11-Abbott-Receives-FDA-510-k-Clearance-for-the-First-Rapid-Handheld-Blood-Test-for-Concussions (accessed December 20, 2022)....

... a well-established treatment (to surgically drain the blood and remove the hematoma). Because there are no clear strategies to improve outcomes in that population beyond the current standard of hematoma removal, ... patients should not be put in clinical trials investigating alternative interventions. The second two patterns are for subdural hematoma/contusion and intraventricular hemorrhage, and clinical trials will need to focus on the differential implications of each....

... Okonkwo argued that using imaging and blood-based biomarkers enables providers to be much more precise in their communication with and about TBI patients than the terms “mild, moderate, and severe.” Reflecting on the use of blood tests for troponin, described by Wu, such tests ... emergency cardiac response, guiding actions and facilitating the provision of interventions only for those who need them. Similarly in oncology, a patient who presents with metastatic breast cancer ... venipuncture, but ideally will reach the point of needing only a finger prick of blood. If the test is negative, the person can return to work and daily living. If biomarker levels are abnormal, providers will need to consider the next course of action and a CT scan may need to be ordered. While ...

... accurate picture of the patient’s state. Based on the patient’s results, he said, it may be possible for the helicopter to bypass the trauma bay and go straight to an operating room equipped with an interoperative CT scanner. While the University of Pittsburgh has tested such a system for research ...

... future effects of biomarkers on clinical trials for new TBI therapies, using combinations of biomarkers, testing multiple drugs simultaneously, and gauging the effects of these treatments over the weeks afterward. Having the ability to understand and monitor treatment effects using biomarkers, he ... , would radically change the game for TBI clinical drug trials, as well for TBI patient evaluation and diagnosis. He closed with a call for recruiting everyone to use the available biomarkers, so that over the next 5 years the indications and contexts ...

... Actionable and rigorously evaluated information provided by preclinical consortia is needed as the field is looking for drugs to enter adaptive clinical trials, ... that additional preclinical research infrastructure might arise given that OBTT has ended. Kochanek added that an area ripe for further preclinical and clinical development is the use of blood biomarker measurements to confirm drug target engagement and as part of metabolomics analyses. Hoffman ... is now being carried on though the Pre-Clinical Interagency Research Resource-TBI (PRECISE-TBI) initiative,5 funded by VA in collaboration with DoD and the National Institutes of Health....

... to insufficient clarity coming out of the preclinical space. Many phase 2 trials have been insufficient to identify which drugs to push forward and how, he added, and the field needs to get trial design right. A participant added that in approaching clinical trials for TBI drugs, especially in ... stages of phase 1 and phase 2, researchers should be open to updating trials in response to the latest information and to more quickly ditching things that are not working. It is not necessary to finish the entire study before deciding it is not working, he added....

... The discussion turned to cultural changes that will be needed in clinical and research communities to embrace TBI biomarker advances. Okonkwo replied that TBI has long been referred to as a silent epidemic but is getting closer ... the point where the “silent” modifier can be dropped. TBI is becoming a signature injury of modern warfare and national dialogue around sports concussions has resulted in TBI becoming a larger part of public conversations over the last 15 years. Although ... of the scope of the problem has grown, he said, there is still an underappreciation for what the injury does to people and education continues to be vital. To see transformative effects will require being able to provide clinicians and patients with greater clarity about ...

... Frederick Korley, University of Michigan, introduced the panel and highlighted opportunities and challenges for implementing TBI biomarkers into routine clinical use, particularly how biomarkers could form part of an improved system for ... TBI. In their remarks and discussion, he encouraged panelists to consider the range of biomarker types and to focus on markers having sufficient levels of evidence that they are likely to be ready for use within the next 5 years or so. Context matters, he ... , and he also encouraged the panelists to couch their comments within identified contexts of use and to be clear about whether the biomarker is being used as a diagnostic, predictive, prognostic, or monitoring biomarker. Panelists each made brief ...

... Martin Schreiber, Oregon Health and Science University, focused on the use of biomarkers in TBI screening. Level 1 trauma centers have been operating at very high occupancy in the last ... years, and the ability to use biomarkers as a screening tool would be hugely beneficial to their workflow, he noted. The use of TBI screening tests would also ... other environment in which he works, forward military bases, Schreiber explained that TBI screening biomarkers will also be valuable tools for understanding who needs to be transported to higher levels of care or taken off duty, because such bases do not always have CT scanners....

... Beth McQuiston, Abbott Laboratories, commended DoD for the decade of research on assessing brain injury using blood biomarkers such as GFAP or UCH-L1 and noted that DoD research on these markers underpins Abbott’s biomarker detection device, which is now an FDA-cleared, commercially available ... for certain uses. She emphasized the importance of understanding the details of which platform, version, assay methodology, and molecular form of a protein are being referenced when discussing the results of blood biomarker tests, because these factors affect the reference ... and results....

... on the FDA clearance process for biomarkers. There are currently no FDA cleared biomarkers, she explained. Rather, the FDA Center for Devices and Radiological Health...

... 6 This section is based on a panel discussion among Frederick Korley, University of Michigan; Martin Schreiber, Oregon Health and Science University; Beth McQuiston, Abbott Laboratories; Allison Kumar, Arina Consulting; Carol Taylor-Burds, National Institute of Neurological ... and Stroke; Travis Polk, Combat Casualty Care Research Program, DoD; and Narayan Iyer, Biomedical Advanced Research and Development Authority, HHS....

... clears assays and devices that measure biomarker levels for clinical use. As McQuiston noted, such tests may use different underlying technologies and methodologies. FDA could implement a standardized way of collecting information for validating a particular biomarker to help in diagnosing a ... TBI patient population. This validation is where some of the key hurdles in translational research are encountered, she noted, because it is costly and difficult to conduct clinical studies that yield significant results on the highly heterogeneous TBI population. She added that it is not only TBI ... who need to be recruited to clinical studies, but also similar patients who are negative for a TBI, so that standards for biomarker sensitivity and specificity can be optimized....

... Carol Taylor-Burds, National Institute of Neurological Disorders and Stroke at the National Institutes of Health, said that she was struck by the progress that has been made in TBI biomarkers but also by the number of ... still out there for better understanding the underlying pathophysiology of TBI, incorporating biomarkers into the system of classifying TBI, and identifying additional therapeutic targets. She saw opportunities for imaging and novel networks to inform the next areas of therapeutics development....

..., he said, could be useless in a particular clinical environment. While there is an immediate need for biomarkers to triage who has a mild TBI and who does not, better understanding of the anticipated trajectory of recovery for more severe TBIs and what interventions are beneficial is also ... , Polk referenced work being done by the Defense Advanced Research Projects Agency (DARPA) through the Cornerstone Project to study the physiological and biochemical changes that occur immediately after a TBI to identify potential targets for countermeasures to prevent injury.7...

... mission of developing medical countermeasures to threats against the civilian population. Any mass casualty event typically includes TBIs, he said, and BARDA is investing in tools and products that can be of use in both worst-case scenarios and day-to-day applications. BARDA recently announced ... to advance the use of TBI biomarkers as an aid-in-diagnosis and thus facilitate...

...-world delivery of care for the civilian population. Ideally, progress in this area will help transform how biomarkers can be used beyond diagnosis and classification, including in therapeutic care and prognostication....

... Korley emphasized the need to draw on the information provided by the spectrum of biomarker classes, their contexts of use, and the diversity of populations experiencing TBI. One of the first challenges is how to incorporate biomarkers into a novel and more precise TBI ... system. Manley commented that the common classification terms mild, moderate, and severe have been hurting patients and there is an absolute need for more precise language. Studies have shown that 50 percent of people labeled as having “mild” TBI were not back to ... by 2 weeks, and 17 percent were unemployed 1 year later (Gaudette et al., 2022). On the other hand, patients with severe TBI are often able to recover improved function. These blunt classification terms are hurting patients on both ends of the ... spectrum, he argued, and while a classification change will not happen overnight, incorporation of additional information from available biomarkers can change the way ...

... Schreiber highlighted the gap between patients who have a positive CT scan and those who have a negative CT scan and are discharged without a TBI diagnosis but continue to suffer symptoms weeks or months later. Something to help patients who fall into this category ... needed, and biomarkers have the potential to enable more sensitive screening for brain injuries not easily detectable by CT. Polk added that biomarkers may also ... useful in better understanding and characterizing preinjury risk. Certain populations, including athletes and military servicemembers, are also at risk for repetitive concussive events. In thinking about TBI classification, he said, quantitative indicators or ... that can measure change from baseline would be useful in these populations. Public–private partnerships among industry, academia, clinicians, and federal agencies such as FDA, BARDA, and DoD will be important in developing and implementing these biomarker tools and approaches, added McQuiston....

... Understanding the reference ranges for TBI biomarkers and enabling calibration across different biomarker measurement platforms is important, said Ramon Diaz-Arrastia, University of Pennsylvania. When ... cholesterol level as a biomarker, for example, normal and elevated ranges are the same regardless of platform used, and at some point, cross-calibration for TBI assays will be needed. It is not feasible for clinicians to keep track of all the different reference ranges ...

..., because every platform provides a different range. But which assay is used by a hospital is often determined by the hospital’s laboratory systems, and that will be difficult to standardize. This is an area in which clinicians, health systems, and industry need to collaborate, noted McQuiston. When ... results are pulled up on a patient’s electronic health record, reference ranges for different manufacturers and platforms could be built into the back end of the system, so that the clinical user sees whether the result is flagged as being normal or out of ... a readout in whichever format is most valuable to them, she said. Lastly, there may be different reference ranges for different clinical indications and intended uses, McQuiston added. For example, a goal of maximizing sensitivity versus specificity will result in setting cutoff levels differently. ... added that cutoff levels will also become apparent for different ages. Pediatrics has been an understudied population in this area, and ranges correlating to different severities of pediatric injuries may be different than ranges for adults....

... Bruce Evans, fire chief at Upper Pine River Fire Protection District and member of the National Association of Emergency Medical Technicians, highlighted the economics of getting biomarkers deployed in the field, ... settings. He asked whether assays will be affected by issues such as extreme heat or cold, depending on where an ambulance might be stationed, and their potential for false positive or false negative readings. McQuiston replied that the testing Abbott conducted with DoD on its assay included ... from which to build a product. A biomarker that measures inflammation needs to be able to distinguish between a patient with a brain injury and one with inflammation from another cause. Another participant added that overtriage can occur in military settings, with more people evacuated to ... CT scans than necessary, and that incorporation of blood-based biomarker tests as part of diagnosis is reducing unnecessary evacuations for mild TBI. Evans added that from a ... economics standpoint, extrapolating these findings into the civilian market could have a significant return on investment....

... Iyer added that BARDA measures the anticipated economic impact of its investments, considering the value of the care delivered and how cost changes affect care. Evans added that special consideration is needed for the prehospital space, because ambulances are reimbursed ...

... be made from a high volume of use, given the millions of people assessed for TBI each year, but the price point for the tests cannot be set above what is reimbursable. Diaz-Arrastia said that prehospital research ...

... Corinne Peek-Asa, University of California, San Diego, noted the discussions during the workshop on acute prehospital triage, and asked about the best ways to use biomarkers at later stages of the continuum of care, after someone has received a TBI diagnosis. Kumar replied that ... next phase of biomarker research should extend “aid in diagnosis” results to understand the interpretation of available data for use in prognostication. Schreiber added that blood biomarker screening tests can now start to fulfill ... . Further along the continuum, it would be helpful to have biomarkers that correlate with outcomes, enabling more informed decisions with the patient and family about how aggressive to be in treatment and about the person’s anticipated trajectory toward recovery....