Multimodal Biomarkers for Central Nervous System Disorders: Development, Validation, and Clinical Integration: Proceedings of a Workshop (2023)
Chapter: 1 Introduction and Background
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Introduction and Background1
Central nervous system (CNS) disorders, including neurodegenerative diseases (e.g., Alzheimer’s disease [AD]) and psychiatric disorders (e.g., major depressive disorder and autism spectrum disorder) are widely prevalent and represent a substantial health burden worldwide (GBD, 2022). A key step toward reducing the burden of CNS disorders is the identification of disease-specific biomarkers that can help predict and monitor disease and guide development of effective treatments. Multimodal biomarkers in particular offer the potential for improved diagnosis and more accurate disease assessments. However, there remain challenges in current data collection, standardization, and validation practices that impede the development of multimodal biomarkers.
Biomarkers, as defined by the Food and Drug Administration (FDA)National Institutes of Health (NIH) Biomarker Working Group, are “a defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or biological responses to an exposure or interventions” (FDA-NIH Biomarker Working Group, 2016). Although traditionally viewed as biosamples, in this workshop, indicators also included imaging, electroencephalogram (EEG), and digital readouts. Biomarkers can serve different purposes such as assessment of susceptibility or risk for
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1 The planning committee’s role was limited to planning the workshop, and the Proceedings of a Workshop was prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants; have not been endorsed or verified by the Health and Medicine Division of the National Academies of Sciences, Engineering, and Medicine; and should not be construed as reflecting any group consensus.
a disease, diagnosis, responsiveness to a treatment, or assessment of drug safety (Cagney et al., 2018). Once a biomarker is established, it needs to undergo validation and a formal regulatory pathway before being incorporated into drug pipelines and clinical practices.
With advances in technology, the number of identified potential biomarkers for CNS disorders across different modalities (e.g., imaging, blood-based, genetic, proteomic, EEG, behavioral assessments, and digital measures) has been steadily increasing and revolutionizing our understanding of these diseases (Lleó, 2021). The development of multimodal biomarkers (biomarkers that are comprised of more than a single element as proposed by the FDA), for CNS disorders has followed from these advances (Quatieri et al., 2017). For example, studies have shown that the use of multimodal biomarkers (e.g., biomarkers that combine magnetic resonance imaging [MRI], positron emission tomography [PET], biological samples, and/or clinical data) may more accurately diagnose and measure disease severity in mild cognitive impairment and AD (Martiñez-Torteya et al., 2015; Walhovd et al., 2010; Zhang et al., 2011a). However, there have only been eight biomarkers approved as qualified by the FDA to date, none of which are multimodal or are used for CNS disorders (FDA, 2021). Nevertheless, many biomarkers are developed as part of a company’s therapeutic development program. Some of these are multimodal in nature but are still in the early stages of study.
To explore the opportunities and challenges for multimodal biomarkers for CNS disorders and discuss potential paths forward, the National Academies of Sciences, Engineering, and Medicine’s Forum on Neuroscience and Nervous System Disorders hosted a workshop2 on March 13–14, 2023. Participants included experts in CNS disorders, clinical care, drug development, and regulatory oversight as well as individuals living with these disorders. In his opening remarks, John Krystal, Robert L. McNeil, Jr., Professor of Translational Research, and Chair of the Department of Psychiatry at the Yale University School of Medicine, as well as Chief of Psychiatry at Yale-New Haven, posed a key question to frame the workshop discussions: “How can we develop the biomarkers that enable us to stratify people with various disorders, develop predictive models, develop precision medicine, and develop more effective treatments to alleviate the terrible disability associated with these disorders?” Frances Jensen, Professor and Chair of the Department of Neurology at the Perelman School of
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2 To learn more about the workshop, held under the auspices of the Forum on Neuroscience and Nervous System Disorders of the National Academies of Sciences, Engineering, and Medicine see here: https://www.nationalacademies.org/event/03-13-2023/multimodal-biomarkers-for-central-nervous-system-disorders-development-integration-and-clinical-utility-a-workshop (accessed May 23, 2023).
Medicine and Co-Director of the Penn Translational Neuroscience Center at the University of Pennsylvania, emphasized that the field is rapidly expanding and is multi-dimensional in nature, with patients, industry, academia, philanthropic organizations, and government regulators all playing key roles in determining how multimodal biomarkers are developed and applied. The workshop was designed to ensure that these diverse perspectives were represented.
WORKSHOP OBJECTIVES
The goal of this workshop was to bring together experts and thought leaders to discuss the promise and challenges in developing multimodal biomarkers for CNS disorders that are consistent, reliable, and clinically relevant. Linda Brady, Director of the Division of Neuroscience and Basic Behavioral Science at the National Institute of Mental Health, shared that the workshop would focus on the current state of knowledge for multimodal biomarkers, best practices for data collection and standardization, and regulatory considerations (see Box 1-1). Vikas Sharma, Global Head of Medicine CNS, Retinopathies, & Emerging Areas at Boehringer Ingelheim, said that this workshop is not intended to generate any consensus on these topics, but instead to generate robust discussion among the assembled workshop participants and broader community. He also emphasized the importance of centering patients in these discussions and noted that each day of the workshop would begin with perspectives from individuals with lived experience.
ORGANIZATION OF PROCEEDINGS
Chapter 2 provides speaker perspectives on the need for multimodal biomarkers for CNS disorders, including from individuals living with these disorders and from the FDA. The state of the science on multimodal biomarkers and how they have been used for neurodegenerative disease is discussed in Chapter 3. Chapter 4 includes case studies for how multimodal biomarkers might be developed to enable precision medicine approaches for a wide range of CNS disorders, including neuropsychiatric and neurodevelopmental disorders. Standardization of multimodal biomarkers is a key challenge highlighted in Chapter 5, along with methodological considerations and successful approaches. Chapter 6 focuses on regulatory challenges for multimodal biomarkers for CNS disorders, including the challenge of developing biomarkers for transdiagnostic approaches. The final chapter synthesizes key discussions from the workshop and highlights areas for further engagement and collaboration. Appendix A lists references from this workshop and Appendix B provides the workshop agenda.
