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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 As a result, many large pharmaceutical companies have decreased investment, or withdrawn entirely from their neuroscience research programs.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
1:00 p.m. | Opening Remarks and Review of Previous Neuroscience Forum Workshops |
STEVEN HYMAN, Workshop Chair
Director, Stanley Center for Psychiatric Research Broad Institute of Massachusetts Institute of Technology and Harvard University Distinguished Service Professor Professor of Stem Cell Biology and Regenerative Biology Harvard University |
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1:15 p.m. |
Where Are We Now?: The Utility and Translation of Animal Models for Nervous System Disorders and Novel Advancements in the Field
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DAVID MICHELSON
Vice President of Neuroscience and Ophthalmology Clinical Research Merck & Co., Inc. |
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?
1:30 p.m. | Overview and Session Objectives |
STEVIN ZORN, Session Moderator
President and CEO of MindImmune Therapeutics, Inc. Ryan Research Professor of Neuroscience, George and Anne Ryan Institute for Neuroscience, University of Rhode Island President, SH Zorn Consulting, LLC |
Case Studies
1:40 p.m. | Parkinson’s Disease (LRRK2) |
TODD SHERER Chief Executive Officer The Michael J. Fox Foundation for Parkinson’s Research |
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JAN EGEBJERG Vice President of Neurodegeneration and Biologics H. Lundbeck A/S |
2:15 p.m. | Schizophrenia |
STEVEN MCCARROLL (via WebEx)
Associate Professor, Department of Genetics, Harvard Medical School Director of Genetics, Broad Institute’s Stanley Center for Psychiatric Research |
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NIELS PLATH
Head of Department on Synaptic Transmission H. Lundbeck A/S |
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2:50 p.m. | Discussion Among Speakers and Workshop Participants |
3:30 p.m. | BREAK |
3:45 p.m. | Stem Cells and Organoids |
LEE RUBIN
Professor, Department of Stem Cell and Regenerative Biology Harvard University Director of Translational Medicine, Harvard Stem Cell Institute |
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STEVE FINKBEINER
Associate Director and Senior Investigator Gladstone Institute of Neurological Disease |
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4:20 p.m. | Engineered Primate Models |
GUOPING FENG
Poitras Professor of Neuroscience, Department of Brain and Cognitive Sciences McGovern Institute for Brain Research Massachusetts Institute of Technology |
4:40 p.m. |
Computational Quantitative Systems Pharmacology
Modeling of Brain Circuits |
HUGO GEERTS
Chief Scientist In Silico Biosciences |
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5:00 p.m. | Discussion Among Speakers and Workshop Participants |
5:50 p.m. | Day One Wrap-Up |
STEVEN HYMAN, Workshop Chair | |
6:00 p.m. | Adjourn Day One |
Day Two: September 13, 2016
8:30 a.m. | Day Two Opening Remarks |
STEVEN HYMAN, Workshop Chair |
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.
8:45 a.m. | Overview and Session Objectives |
RITA BALICE-GORDON, Session Moderator
Head, Neuroscience Research Sanofi |
Perspectives from the Private Sector
8:55 a.m. | Pharmaceutical Company |
KIM ANDERSEN
Senior Vice President and Head of Research H. Lundbeck A/S |
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9:10 a.m. | Biotechnology Company |
BILL MARTIN
Head of Research and Development BlackThorn Therapeutics, Inc. |
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9:25 a.m. | Venture Capital |
DOUG COLE
Managing Partner Flagship Ventures |
Public−Private Partnerships
9:40 a.m. | Understanding the Role of Public−Private Partnerships to De-Risk the Development Process and to Facilitate Data Sharing |
JOHN MICHAEL SAUER
Executive Director of the Predictive Safety Testing Consortium Critical Path Institute Adjunct Research Professor, Department of Pharmacology University of Arizona College of Medicine |
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9:55 a.m. | Discussion Among Speakers and Workshop Participants |
FRANK YOCCA, Discussant
Senior Vice President of CNS Research and Development BioXcel Corporation |
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10:30 a.m. | BREAK |
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.
10:45 a.m. | Overview and Session Objectives |
NITA FARAHANY, Session Co-Moderator
Professor of Law and Philosophy and Director of Duke Science and Society Duke University School of Law |
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LINDA BRADY, Session Co-Moderator
Director, Division of Neuroscience and Basic Behavioral Science National Institute of Mental Health |
Ethical Considerations
10:55 a.m. | Incorporating Safeguards into Preclinical Research and the Ethics of First-in-Human Trials |
JONATHAN KIMMELMAN
Associate Professor, Biomedical Ethics Unit/Social Studies of Medicine McGill University |
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11:10 a.m. | Considerations for Conducting Trials in Vulnerable Populations |
REBECCA DRESSER
Daniel Noyes Kirby Professor of Law Professor of Ethics in Medicine Washington University |
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11:25 a.m. | Discussion Among Speakers and Workshop Participants |
LUCIE BRUIJN, Discussant
Chief Scientist The ALS Association |
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12:15 p.m. | LUNCH |
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.
1:15 p.m. | Perspectives from the Food and Drug Administration |
ROBERT TEMPLE
Deputy Director for Clinical Science Center for Drug Evaluation and Research Food and Drug Administration |
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1:30 p.m. | Perspectives from the European Medicines Agency |
MARIA ISAAC (via WebEx)
Senior Scientific Officer European Medicines Agency |
1:45 p.m. | New Approaches to Establishing Safety and Conducting Toxicology Studies |
THOMAS HARTUNG
Professor and Chair for Evidence-Based Toxicology Johns Hopkins Bloomberg School of Public Health |
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2:00 p.m. | Discussion Among Speakers and Workshop Participants |
2:45 p.m. | BREAK |
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.
3:00 p.m. | Overview and Session Objectives |
STEVEN HYMAN, Workshop Chair | |
3:05 p.m. | Session Synopsis and Potential Next Steps |
Session Moderators | |
3:45 p.m. | Discussion Among Speakers and Workshop Participants |
4:25 p.m. | Final Comments |
STEVEN HYMAN, Workshop Chair | |
4:30 p.m. | ADJOURN |