Summary1

Biological markers, or biomarkers, are quantitative measurements that provide information about biological processes, a disease state, or about response to treatment, providing much-needed insight into preclinical and clinical data.2 Biomarkers hold the potential of a better understanding of the etiology and pathogenesis of a given disorder, providing researchers and clinicians with valuable insight into diagnosis, treatment, and prognosis for many debilitating disorders and diseases. The burden of the maladies described in the workshop affect every population; thus, the commitment to finding additional biomarkers is a major aim in neuroscience medical research.

While many advances have been made in the development of biomarkers for disorders other than those of the nervous system, e.g., cancer biology, advances in establishing biomarkers for disorders of the nervous system have been disappointing, given escalating research investment. This is a result of a combination of many factors, including, but not limited to, complexity of the nervous system, access to tissue and the blood brain barrier, and incentives for industry and academia, causing development to fall between the cracks of academic, government, and industry research programs. The public health burden of nervous system disorders is great—well over 1,000 different disorders, according to the

1

The planning committee’s role was limited to planning the workshop, and the workshop summary has been prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop.

2

This definition of a biomarker was used throughout the workshop and is based on a definition developed by the FDA’s Biomarkers Definitions Working Group; however, there are other definitions of biomarkers and biosignatures that capture other roles and applications that were not included in the scope of this workshop.



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Summary1 Biological markers, or biomarkers, are quantitative measurements that provide information about biological processes, a disease state, or about response to treatment, providing much-needed insight into preclinical and clinical data.2 Biomarkers hold the potential of a better understanding of the etiology and pathogenesis of a given disorder, providing researchers and clinicians with valuable insight into diagnosis, treatment, and prognosis for many debilitating disorders and diseases. The burden of the maladies described in the workshop affect every population; thus, the commitment to finding additional biomarkers is a major aim in neuroscience medical research. While many advances have been made in the development of biomarkers for disorders other than those of the nervous system, e.g., cancer biology, advances in establishing biomarkers for disorders of the nervous system have been disappointing, given escalating research investment. This is a result of a combination of many factors, including, but not limited to, complexity of the nervous system, access to tissue and the blood brain barrier, and incentives for industry and academia, causing development to fall between the cracks of academic, government, and industry research programs. The public health burden of nervous system disorders is great—well over 1,000 different disorders, according to the 1 The planning committee’s role was limited to planning the workshop, and the workshop summary has been prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop. 2 This definition of a biomarker was used throughout the workshop and is based on a definition developed by the FDA’s Biomarkers Definitions Working Group; however, there are other definitions of biomarkers and biosignatures that capture other roles and applications that were not included in the scope of this workshop. 1

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2 NEUROSCIENCE BIOMARKERS AND BIOSIGNATURES Society for Neuroscience—and yet only a handful of biomarkers are available. Focused attention is needed in neuroscience biomarker research and development, yet it is often difficult to categorize which areas are the most ripe for investment and should be further pursued. Given the promising potential and high need for neuroscience biomarkers, the Institute of Medicine Forum on Neuroscience and Nervous System Disorders convened a workshop in Washington, DC, on February 26 and 27, 2007. The workshop brought together experts in various areas to discuss the most promising and practical arenas in neuroscience in which novel biomarkers will have the greatest near-term impact on the rate at which new treatments are brought forward for psychiatric and neurological disorders. Several themes, including the following needs and opportunities, were highlighted by workshop participants:3 • a better understanding of the Food and Drug Administration (FDA) evaluation and qualification process to help promote and increase neuroscience biomarker submission; • opportunities for public-private partnerships in a precompetitive space (i.e., the ability of organizations, including companies, sponsors, and developers, to work together on research and development without jeopardizing their intellectual property); • combined tools and technologies in arenas such as proteomics, genomics, and imaging to refine specificity within findings; • deconstruction of certain aspects of current characterizations and diagnostic criteria (e.g., Diagnostic and Statistical Manual [DSM] categorizations); • standardization and pooling of resources and data, especially from current and completed clinical trials, including reporting of negative results; and • development that draws upon successful models and lessons learned from outside fields. 3 Opinions and statements included in this workshop summary are solely those of the individual persons or participants at the workshop and are not necessarily adopted, endorsed, or verified as accurate by the National Academies.

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3 SUMMARY Workshop Goals and Objectives A major objective of the workshop was to identify and discuss biomarker targets that are not currently being aggressively pursued but could be developed to practicality within the next 5 years by public- private partnerships. The biomarker could be useful in either diagnostic or therapeutic settings but, regardless, should have the potential for substantial clinical impact. Essentially, the key words used to define the parameters are “near term” and “high impact.” One potential mechanism discussed by participants was the new collaborative effort, the Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium. The Consortium promotes public-private partnerships by facilitating collaborative research among the National Institutes of Health (NIH), academia, industry, and other foundations and patient advocacy groups to accelerate discovery, development, and qualification of biomarkers. The planning committee for this workshop chose to discuss certain areas of biomarker research for nervous system disorders that may be ripe for development. The workshop and this summary are not meant to be a comprehensive review of all possible neuroscience biomarkers that may be ripe for development in the near term or in the future. Further, workshop participants were charged to highlight the opportunities and needs for biomarker research and discovery, not necessarily the application of a given biomarker. Regulatory Considerations The evolution of biomarker application and the regulatory system is rapidly changing, incorporating new science and opportunities. The role of the FDA is to encourage qualification and use of new biomarkers while providing regulatory guidance on the design of qualification trials. Due, in part, to scientific, economic, and regulatory factors, biomarker development has lagged significantly behind therapeutic development. Some feel the biomarker qualification process by the FDA may present a hurdle for the submission of a biomarker. The FDA recently changed its definitions and requirements to include broader categories and to encourage submission of proposals. For instance, biomarkers may now fall under three categories: “possible,” “probable,” and “known.”

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4 NEUROSCIENCE BIOMARKERS AND BIOSIGNATURES Another concern is the lack of clear understanding about how the FDA defines and qualifies different types of biomarkers, including surrogate endpoints. Thus, there are now clearer definitions of biomarkers, surrogate endpoints, and the “qualification process.” With increased transparency of the application process, the FDA hopes to encourage proposal submissions, qualifications, partnerships, and consortia geared toward increasing biomarker innovation and discovery. Public-Private Partnership One successful partnership that was already under way before the creation of the FNIH but that is now funded through FNIH is the Alzheimer’s Disease Neuroimaging Initiative (ADNI). This public- private partnership has been extremely useful due to mechanisms set in place that allow for full data sharing in real time. Furthermore, ongoing results are published freely via the Internet. One of the greatest benefits of this partnership comes from the contributions of the special advisory committee members who have created both imaging and cerebrospinal fluid (CSF) protocols to help standardize collection. A major, if not the largest, accomplishment of the advisory committee came about through the push for higher rates of CSF sample collection from the public partners. The result was an increase in collection from 20 percent to 60 percent. However, this creates a new challenge and opportunity to expand ADNI to begin analyzing and categorizing collected biological samples. The success of the ADNI project is that it lies within the precompetitive space, allowing for broad applicability in future clinical trials and, in addition, fostering communication within otherwise proprietary realms in this area of research. Although ADNI is one example of a successful public-private partnership, there are many others that have been established that are also demonstrating similar successes; however, these were not discussed in detail at the workshop. POTENTIAL TOOLS Genomics and Proteomics Partly as an outgrowth of the Human Genome Project and the International HapMap Project, there has been an increased interest in

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5 SUMMARY genomics over the past several years. Genome-wide scanning in the search for a single nucleotide polymorphism that is associated with a disease is a relatively new tool that researchers have been using and developing in the hopes of identifying potential target loci for disease biomarkers. This technology has already been successfully utilized in Alzheimer’s disease and shows promise for use in individuals with schizophrenia. Although the technology is not yet available for whole-proteome scanning, proteomics is still a useful tool in helping to identify different patterns of expression of multiple protein biomarkers from CSF using, for example, liquid chromatography and mass spectrometry. Some researchers have found success in using samples obtained from CSF due to the greater concentration of potentially useful biomarkers it contains; for example, biomarkers found in the spinal cord have potential not only as a diagnostic test, but also as a measure of response to treatment. The capacity to report on the physiological state of the organism, which may not be reflected in genetic strategies, also make proteomics a valuable source of biomarkers, for example post-translational modifications and levels of protein activity that may not correlate to levels of gene transcription. A need expressed during the workshop was for a larger number of samples to be collected and analyzed. Traditionally, analysis of CSF has been limited due to a perceived negative opinion among the public toward lumbar puncture. The ADNI project addressed this challenge by pointing out that attitude toward lumbar puncture was suggested to be improved as a result of subjects viewing an educational video that profiled the low risks associated with lumbar punctures. Imaging Technologies Imaging tools are being used to discover surrogate biomarkers, guide therapeutic development, and detect and track disease progression; there is further hope in new, increasingly sophisticated technologies. Although the imaging field has many tools at hand, there is still no widely accepted surrogate biomarker for nervous system disorders using imaging tools. In addition, there are challenges to expansion that include validation of images, standardization of imaging protocols, and sophisticated informatics that would allow integration of various data. Another major challenge identified by workshop participants is the lack of radiotracers

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6 NEUROSCIENCE BIOMARKERS AND BIOSIGNATURES for molecular defects. One effort under way is the establishment of a clearinghouse for radiotracers that would allow interested parties to share tracers. This concept is still under development; however, it is showing progress. Combining structural and functional imaging biomarkers (e.g., computed tomography and magnetic resonance imaging [MRI] with positron emission tomography [PET]) offers exciting opportunities for advancement in the future as well. FUTURE DIRECTIONS Several future directions and next steps for biomarker development were identified by various workshop participants: • Biomarker development should follow a process similar to drug development, with the same scientific rigor applied to analyzing and qualifying biomarkers. This suggests creating standardization in reporting and analysis, patient selection, and specimen and assay characterization. • Clinical trials, ongoing and completed, offer a wealth of information and opportunities that can be utilized for biomarker development. First, clinical trials usually provide large amounts of stored tissues and other specimen that other researchers could potentially use. Second, data gleaned from clinical trials can be reanalyzed in light of new hypotheses. Third, incorporating potentially new biomarkers into clinical trials may shed light on future analysis, including identification of surrogate markers. Finally, reanalysis of data in light of a failed clinical trial is often encouraged by NIH and industry. • Reporting negative results ascertained from various studies and experiments can save invaluable time and resources. The field should create a register of successful and failed scientific study findings for other researchers to reference (note: legislation being considered by Congress may serve to address this gap). • More attention is needed in research that delves into the underlying pathophysiology and mechanisms of various neurological, psychiatric, and addiction disorders to help inform future opportunities in diagnostics and therapeutics. Animal models can be an important tool for elucidating these underlying mechanisms; however, better use and characterization is needed to advance this area of research. Thus, biomarkers that provide information on functional states and patterns of

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7 SUMMARY neurocircuitry—using several approaches that combine brain imaging, animal models, and genotyping in conjunction with genetics, familial histories, and DSM categories—would help to refine diagnosis and treatment. Specific attention was focused on the current challenges and future opportunities for nervous system disorders in the areas of psychiatric and drug addiction disorders and neurological and eye diseases. Based on workshop presentations and discussions, participants identified a number of promising areas where a novel biomarker is nearterm (Box S-1). BOX S-1 Challenges and Opportunities for Nervous System Disorders Psychiatric and Drug Addiction Disorders Depression: Three genes have recently been identified as biomarkers for treatment of depression, signaling major advances in biomarker research. The serotonin 2A receptor may serve as an important biomarker for yielding information about antidepressant treatment outcome. In addition, two other genes are currently being researched and developed as a biomarker that may signal full remission. More research is needed, but the genotypic findings suggest a possible new direction that may take hold for treatment of depression. One interesting proposal includes using whole-genome scanning technologies for possible predictors of response and side effects for treatment of depression. Schizophrenia: A few promising biomarkers utilize electrophysiology technologies to help detect cognitive dysfunction and working memory in the brain and have led to a few small clinical trials. The value of electrophysiology as a pathway to biomarker development for schizophrenia encompasses many opportunities that include a greater understanding of the neurocircuitry, including imaging, of psychiatric disorders and increased specificity for cognitive and behavioral tests. Addiction: A biosignature, rather than a single biomarker, is used to track addiction. Brain imaging with PET is helping to identify biomarkers of vulnerability by allowing injected agents to be tracked in vivo. The search for additional biomarkers of addiction should involve genetic and animal model studies, given the success the field has seen in utilizing these paths. For example, studies outside the addiction field on genetic risks for impulsivity are shedding light on the likelihood of drug experimentation.

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8 NEUROSCIENCE BIOMARKERS AND BIOSIGNATURES Neurological and Eye Diseases Multiple Sclerosis (MS): The current rating instruments for assessing the clinical course of MS are a major challenge to the field. Although there are other useful biomarkers to monitor the disease, there is no biomarker for the secondary, progressive stage of MS. Like those working in addiction, workers in the MS field have turned outside their field to cancer studies to glean valuable models that have proved successful. Most important, the cancer field was especially successful in setting up networks in the United States and Europe to foster growth in the design and conduct of, and report development for, cancer biomarker studies. The incorporation of potentially new biomarkers into clinical trials has the potential to be used in future analysis, including the possibility of identifying a surrogate marker. Stroke: A promising biomarker for acute ischemic stroke, using MRI technology, may hold the key to applications for stroke clinical trials. The field of stroke research needs a formal way to share clinical trial and observational studies data, specifically during Phase II trials, which would help to standardize and optimize MRI data and patient selection and outcomes. Currently, a promising proposal for a multistage approach to standardize, optimize, and establish the use of MRI biomarkers in stroke drug development is being examined. Spinal Muscular Atrophy (SMA): SMA is ripe for biomarker development, given the identification of a single defective gene over 10 years ago. It has been hypothesized that therapeutics that could increase the expression of this deleted gene may improve motor performance and muscular strength. However, this requires further delineation given that the detection of the SMA biomarker is only correlated with a certain subset of patients. Retinal Degeneration: Major advances have been made, and are under way, for identifying biomarkers for retinal degeneration and even several neuro- degenerative diseases such as MS. Advanced technologies such as optical coherence tomography and adaptive optics, in addition to metabolic biomarker candidates, are lending to further advancement in this area. However, despite the plethora of therapeutic targets, there is a need for increased understanding of the pathophysiology of the disorders.