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Workshop Agenda

Therapeutic Development for Nervous System Disorders in the Absence of Predictive Animal Models of Disease: A Workshop

September 12–13, 2016

National Academy of Sciences Building
2101 Constitution Ave., NW | Room 120
Washington, DC 20418

Background: Although the prevalence and burden of nervous system disorders remain high, development of new therapeutics lags behind other disease areas. Current drug development from discovery to regulatory approval takes on average 12–15 years. Gaps in understanding of the underlying mechanisms of disease, a dearth of biomarkers, and limitations in the capacity of animal models to predict drug efficacy for human brain disorders have contributed to a high rate of late-stage failures in drug development. As a result, many large pharmaceutical companies have decreased investment, or withdrawn entirely from their neuroscience research programs.

In 2012, the Forum on Neuroscience and Nervous System Disorders hosted a public workshop on Improving the Utility and Translation of Animal Models for Nervous System Disorders to discuss potential opportunities for maximizing the translation of effective therapies from animal models to clinical practice. During the workshop, several participants emphasized the utility of animal models for investigating basic neural processes, but their limitations for fully recapitulating nervous system disorders, and predicting therapeutic efficacy in human clinical trials. Given these concerns, the Forum hosted a second public workshop

on Improving and Accelerating Therapeutic Development for Nervous System Disorders to explore opportunities and challenges in neuroscience research for accelerating entry of potential treatments into first-inhuman trials. Workshop participants explored the potential usefulness of supplementing animal models of basic mechanisms with new technologies ranging from use of human-induced pluripotent stem cells (iPSCs), to partially humanized animal models, to a greater emphasis on advancing human experimental biology. Much discussion was engendered about circumstances in which a therapeutic might be tested in patients (of different ages), in the absence of a predictive animal model as long as safety had been established. Among ethicists and regulators, there were particular concerns expressed about proceeding to clinical trials in children, and about potential use of biologics. A larger concern within industry was the challenge of making a financial commitment to clinical trials, absent a predictive animal model, especially for common polygenic brain disorders where patient selection remains challenging.

Building on the discussions from these two activities, the Forum will host a public workshop to more deeply explore ways to motivate and accelerate drug development for nervous system disorders. The workshop will 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. The workshop will bring together key stakeholders to discuss scientific, regulatory, and business challenges and to identify potential opportunities in this domain to motivate and accelerate therapeutic development to address unmet medical needs.

Meeting Objectives:

• Explore the utility of novel approaches to the process of target validation and biomarker development including human genetics, stem cell technologies, including use of iPS cells and human brain organoids, experimental human biology such as molecular imaging and neurophysiology, and computational modeling.
• Discuss future technological developments that would facilitate bringing compounds that appear to be safe into human dose finding and efficacy trials, even if an animal model of the human disease is not achievable.
• Discuss the regulatory landscape and what would be needed for regulatory agencies and Institutional Review Boards to consider these approaches.

• Explore the private-sector environment for proceeding with drug development approaches in situations that lack animal models to predict drug efficacy.
• Consider ethical issues, including for exploratory trials in pediatric populations.

Day One: September 12, 2016

SESSION I: NEUROSCIENCE DRUG DEVELOPMENT IN THE ABSENCE OF PREDICTIVE ANIMAL MODELS OF DISEASE

Session Objectives:

• Discuss opportunities to move into human trials when compounds appear to be safe based on dose finding and efficacy trials.
• Consider the evidence and technological developments needed to decrease the translational gap between animal and human trials.
  • Using case studies, explore the utility of novel approaches and technology for target identification and validation (e.g., establishing predictive validity in proof-of-concept studies), and to identify biomarkers.
• Discuss the role of bidirectional translational endpoints and the relationship between preclinical endophenotypes and clinical outcome measures.
  • What are the clinical questions that could drive preclinical research?

Case Studies

Day Two: September 13, 2016

SESSION II: PRIVATE-SECTOR THRESHOLDS FOR INVESTMENT IN NEUROSCIENCE CLINICAL TRIALS

Session Objectives:

• Discuss the decision-making process within the private sector for proceeding with drug development approaches in situations that lack predictive animal models of disease.
• Consider potential incentives that might encourage industry to reinvest or increase investments in central nervous system trials.

Perspectives from the Private Sector

Public−Private Partnerships

SESSION III: ETHICAL AND REGULATORY CONSIDERATIONS FOR HUMAN TRIALS

Session Objectives:

• Consider the ethical implications of bringing compounds that appear safe to human efficacy trials without preclinical data from animal models.
  • What are the risks and potential benefits to patients?
  • What do patients consider to be tolerable risks?
• Discuss the unique challenges for trials in vulnerable populations.
• Discuss the regulatory landscape and the evidence needed for regulatory agencies to consider trials in humans in the absence of predictive animal models of disease.
• Explore areas within the drug development pipeline where new and emerging tools, technologies, and techniques might be subject to regulatory processes.

Ethical Considerations

Regulatory Considerations

• What evidence is needed to conduct efficacy trials in humans? What constitutes a feasible outcome measure and what is the role of surrogates?
• Discuss how accelerating to human trials would alter the drug development pipeline. Consider potential challenges to such an approach.

SESSION IV: MOVING FORWARD

Session Objectives:

• Highlight workshop key themes.
• Identify opportunities and key stakeholders necessary for bringing compounds that appear to be safe into human efficacy trials for nervous system disorders.