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Introduction and Overview¹

Compared with other disease areas, central nervous system (CNS) disorders have had the highest failure rate for new compounds in advanced clinical trials (TCSDD, 2012). David Michelson, vice president of neuroscience and ophthalmology clinical research at Merck Research Laboratories, cited multiple reasons that may lead to these trial failures, including lack of safety and off-target activity. However, he said most CNS drugs fail because of efficacy. The core issue underlying these problems, he said, is a poor understanding of disease biology. Even when mechanistic pathways are clarified, moving the biology in the desired direction has been difficult.

Concern about the poor productivity in neuroscience drug development has gained intensity over the past decade, amplified by a retraction in investment from the pharmaceutical industry (Choi et al., 2014). This retreat by industry has been fueled by the high failure rate of compounds in advanced clinical trials for nervous system disorders, according to Steven Hyman, director of the Stanley Center for Psychiatric Research at the Broad Institute of Massachusetts Institute of Technology and Harvard University.

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¹ The planning committee’s role was limited to planning the workshop, and the Proceedings of a Workshop has been 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, and have not been endorsed or verified by the National Academies of Sciences, Engineering, and Medicine, and they should not be construed as reflecting any group consensus.

ORIGINS OF THE WORKSHOP

In response to the de-emphasis of CNS disorders in therapeutic development relative to other disease areas such as cancer, metabolism, and autoimmunity, the National Academies of Sciences, Engineering, and Medicine’s Forum on Neuroscience and Nervous System Disorders initiated a series of workshops in 2012 to address the challenges that have slowed drug development for nervous system disorders. The first of these workshops, Improving the Utility and Translation of Animal Models for Nervous System Disorders,² focused on strategies to maximize the translation of effective therapies for nervous system disorders from animal models to clinical practice (IOM, 2013). Several workshop participants noted that although animal models can provide critical insight on disease mechanisms and targets, they often fail to fully mimic the diseases they are meant to model, resulting in a mismatch between endpoints used in preclinical and clinical studies. Consequently, they may fail to predict efficacy and may even screen out potentially effective compounds.

In 2013, a second workshop was convened: Accelerating Therapeutic Development for Nervous System Disorders Toward First-in-Human Trials,³ where participants explored the potential usefulness of supplementing animal models of basic mechanisms with new technologies and approaches, including human induced pluripotent stem (iPS) cells, partially humanized animal models, computational neuroscience systems, and human experimental biology approaches (IOM, 2014). A key question addressed during these workshops concerned how to move forward in the absence of a predictive animal model of disease mechanisms that could reliably demonstrate efficacy in humans.

WORKSHOP OBJECTIVES

Motivated by the notion that advances in genetics and other new technologies are beginning to bring forth new molecular targets and identify new biomarkers, the Neuroscience Forum hosted the third workshop in this series on September 12–13, 2016, in Washington, DC. Among the topics Hyman identified as requiring further discussion were ethical and

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² For more information about this workshop go to http://nationalacademies.org/hmd/Activities/Research/NeuroForum/2012-MAR-28.aspx (accessed February 2, 2017).

³ For more information about this workshop go to http://nationalacademies.org/hmd/Activities/Research/NeuroForum/2013-APR-08.aspx (accessed February 2, 2017).

regulatory considerations and business issues: How do companies decide whether it is worth investing in expensive clinical programs if no predictive animal model is available?

Michelson described the challenge of moving forward in the absence of predictive efficacy models in terms of two levers that can be pulled to get more drugs to market: reducing the burden of failure and increasing the probability of success. The challenges addressed in this workshop related to the second lever: increasing the probability of success through new strategies for establishing the safety of potential therapeutics, better target selection, dose selection, and signal detection.

The workshop brought together key stakeholders to consider the evidence needed to bring compounds that appear to be safe into human efficacy trials, both from an ethical and regulatory point of view, and from a pragmatic and financial point of view in the absence of a predictive animal model of disease (see Box 1-1).

ORGANIZATION OF THE PROCEEDINGS

The following proceedings summarize the workshop presentations and discussions. Chapter 2 lays out the current limitations with existing animal models, the challenges to addressing obstacles, and the opportunities identified by individual workshop participants to move the field forward. Chapter 3 presents two case studies that showcase novel approaches being used in the field to develop treatments for Parkinson’s disease and schizophrenia. Innovative modeling approaches are the focus of Chapter 4, including cellular approaches that exploit emerging iPS cell technologies and discoveries that enable growing cells in three dimensions, genetically engineered primate models, and computational quantitative systems pharmacology modeling of brain circuits. Chapter 5 turns to the business side of drug development, including how decision making in the private sector might proceed in the absence of predictive animal models of disease and efforts to de-risk drug development through public‒private partnerships and other collaborations. Chapters 6 and 7 consider the ethical and regulatory implications of bringing compounds to market without preclinical data from animal models, as well as the unique challenges confronted when trials involve vulnerable populations.