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B Workshop Agenda NEUROSCIENCE TRIALS OF THE FUTURE: A WORKSHOP March 3â4, 2016 Keck Center 500 Fifth Street, NW, Room 100 Washington, DC 20001 Background: Although major strides have been made over the past two decades in basic neurosciences, the pace of translation into more effective treatments has eluded the field. Among the many factors contributing to this reality are the standard clinical trial methods that have barely changed, perhaps with the exception of increased use of electronic data acquisition and analysis. Clinical trials in neuropsychiatric disorders continue to suffer from high failure rates even with biological targets that are well validated. Even in the hands of experienced investigators, the now commonplace problem of poor assay sensitivity, and attendant trial failure, have adversely affected pharmaceutical and device development. Signal detection in central nervous system trials is regularly beset by high placebo or non- specific response, intrasubject variability of endpoints, intersubject and intersite variability in multicenter trials, poor treatment adherence, and weak patient engagement and retention. The net effect of these challenges has been to simply increase the trial sample size in an attempt to control type II error. Yet, promising early clinical data often are not 79
80 NEUROSCIENCE TRIALS OF THE FUTURE replicated in larger registration trials, and Phase III failure rates in neuroscience randomized controlled trials remain among the highest in medicine. The apparent unsustainability of the current clinical development scenario has driven many large pharmaceutical companies entirely out of investment in neurosciences. Quite apart from the business perspective, the fact that many early-stage clinical trials misleadingly provide a signal (a type I error) raises the question of whether volunteering for these trials is in the best interest of trial subjects, in particular, and for the patients with that particular disorder in general. Better methods, from clinical study design through execution and evaluation, could help restore the integrity, feasibility, acceptability, efficiency, and economic viability of clinical neuropsychiatric development. However, in order to use innovative approaches to address these challenges, buy-in and acceptance from the regulatory community will be important. For example, adaptive trials could offer a more efficient means of addressing experimental questions involving multiple uncertainties, although they are often infrequently used. In addition, understanding the utility of wearable and patient monitoring devices (and the data generated) in neuroscience clinical trials is needed. Given the current challenges in neuroscience clinical trials, this public workshop will bring together key stakeholders to discuss opportunities to improve the integrity, efficiency, and validity of clinical trials for nervous system disorders (focusing specifically on Phase II and Phase III trials). Meeting Objectives: ⢠Examine assay sensitivity challenges in clinical trials for nervous system disorders, including causes of type I error in early trials and poor signal detection and type II error in later stage trials. ⢠Explore opportunities to improve clinical trial methodology for nervous system disorders, including strategies for: o Guiding the selection of patient populations, such as using endophenotyping to increase the yield of responders and using genomics, proteomics, and imaging biomarkers to âstageâ nervous system disorders. o Increasing patient engagement through all phases of the clinical trial (i.e., recruitment, screening, and posttrial) and improving adherence and retention.
APPENDIX B 81 o Using patient-centric technologies (e.g., wearables) and integrating such real-world, real-time data with traditional clinical data. o Improving monitoring during clinical trials. o Leveraging recent advances in diagnostics, biomarkers, and endpoints to develop more efficient clinical trials. o Using novel trial designs (e.g., adaptive, enrichment, and platform design studies) for nervous system disorders, including associated regulatory challenges and opportunities. March 3, 2016 8:30 a.m. Opening Remarks ATUL PANDE, workshop co-chair Chief Medical Officer and Executive Vice President Tal Medical RICHARD KEEFE, workshop co-chair Professor of Psychiatry and Behavioral Sciences Duke University School of Medicine Neuroscience Clinical Trials: Challenges and Opportunities 8:45 a.m. STEVEN ROMANO Senior Vice President and Chief Science Officer Mallinckrodt Pharmaceuticals 9:05 a.m. SHITIJ KAPUR Executive Dean and Head of School Institute of Psychiatry, Psychology & Neuroscience Kingâs College London 9:30 a.m. Discussion Among Speakers and Workshop Participants 9:45 a.m. BREAK
82 NEUROSCIENCE TRIALS OF THE FUTURE SESSION I: CLINICAL TRIAL DESIGN Session Objectives: Discuss current challenges to clinical trial design for nervous system disorders. Explore elements of clinical trial protocols that might be improved and lead to more efficient trials. Discuss how novel trial designs (e.g., adaptive, enrichment, and platform design studies) might be used for nervous system disorders. 10:00 a.m. Session Overview and Objectives STEPHEN BRANNAN, session moderator Vice President of Clinical Research and Medical Affairs Forum Pharmaceuticals Biomarkers 10:10 a.m. ANIL MALHOTRA Director, Psychiatry Research, Zucker Hillside Hospital Professor, Molecular Medicine and Psychiatry Hofstra Northwell School of Medicine at Hofstra University 10:25 a.m. ALICE CHEN-PLOTKIN Assistant Professor of Neurology Perelman School of Medicine, University of Pennsylvania Diagnosis and Patient Identification ⢠Discuss alternatives to the Diagnostic and Statistical Manual of Psychiatric Disorders (DSM). 10:40 a.m. SARAH MORRIS Acting Head, NIMH RDoC Unit Program Officer, Schizophrenia Spectrum Disorders Research Program National Institute of Mental Health
APPENDIX B 83 10:55 a.m. ROBERT BILDER Professor-in-Residence, Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles Editor-in-Chief, Diagnostics in Neuropsychiatry Statistical Approaches and Considerations 11:10 a.m. MICHAEL PENCINA Director of Biostatistics, Duke Clinical Research Institute Professor of Biostatistics and Bioinformatics Duke University Novel Clinical Trial Designs 11:25 a.m. ERIK SNOWBERG Professor of Economics and Political Science California Institute of Technology SYLVAIN CHASSANG Professor of Economics and Public Affairs Princeton University 11:45 a.m. JAIDEEP KAPUR Study Chair, Established Status Epilepticus Treatment Trial (ESETT) Eugene Meyer III Professor of Neuroscience, Neurology University of Virginia School of Medicine 12:00 p.m. Panel Remarks Additional Panelists: TIFFANY FARCHIONE Deputy Director, Division of Psychiatry Products Center for Drug Evaluation and Research Food and Drug Administration
84 NEUROSCIENCE TRIALS OF THE FUTURE CARLOS PEÃA Director, Division of Neurological and Physical Medicine Devices Office of Device Evaluation Center for Devices and Radiological Health Food and Drug Administration 12:30 p.m. Discussion Among Speakers and Workshop Participants 1:00 p.m. LUNCH SESSION II: CLINICAL TRIAL METHODOLOGY Session Objectives: Explore opportunities to improve clinical trial methodology for nervous system disorders, including strategies for patient selection, engagement, and retention. Examine the extent to which current diagnostic methods contribute to the inherent variability in study populations. Discuss the utility of patient-centric technologies (e.g., wearables) and how such real-world, real-time data might be integrated with traditional clinical data to improve the integrity and efficiency of trials. Consider lessons learned and best practices from other therapeutic areas that might be applied to neuroscience clinical trials. 1:45 p.m. Session Overview and Objectives AMIR KALALI, session moderator Head, Neuroscience Center of Excellence Quintiles 2:00 p.m. Transforming Clinical Trials with Technology (guided panel discussion) ⢠Discuss opportunities to improve patient engagement and retention. ⢠Discuss how to improve patient adherence to assigned treatment. ⢠Discuss opportunities to improve patient assessments.
APPENDIX B 85 ⢠Consider the potential applications of emerging technologies (e.g., wearables) for clinical trials. o What are common clinical applications of these technologies? o What are the known benefits and risks associated with use? What are the scientific controversies behind this evidence? CARLOS RODARTE Chief Executive Officer Health Rhythms JOHN REITES Head, Digital Health Acceleration Quintiles DREW SCHILLER Chief Technology Officer and Co-Founder Validic GLEN DE VRIES President and Co-Founder Medidata Solutions, Inc. KARL KIEBURTZ Robert J. Joynt Professor in Neurology Senior Associate Dean for Clinical Research Director of the Clinical & Translational Science Institute University of Rochester Medical Center 3:15 p.m. BREAK
86 NEUROSCIENCE TRIALS OF THE FUTURE Lessons Learned from Other Therapeutic Areas 3:30 p.m. Oncology PERRY NISEN Chief Executive Officer Sanford Burnham Prebys Medical Discovery Institute 3:45 p.m. Cardiology ADRIAN FELIPE HERNANDEZ Professor of Medicine Duke Clinical Research Institute Duke University School of Medicine 4:00 p.m. Discussion Among Speakers and Workshop Participants 4:45 p.m. Day One Wrap-Up Workshop Co-Chairs 5:00 p.m. ADJOURN DAY ONE March 4, 2016 8:30 a.m. Day Two Opening ATUL PANDE, workshop co-chair Chief Medical Officer and Executive Vice President Tal Medical RICHARD KEEFE, workshop co-chair Professor of Psychiatry and Behavioral Sciences Duke University School of Medicine
APPENDIX B 87 KEYNOTE SESSION III: INTERNATIONAL REGULATORY LANDSCAPE Session Objectives: Consider the regulatory landscape for neuroscience clinical trials. Explore differences in regulatory pathways among countries and consider the impact. 8:50 a.m. Session Overview and Objectives THOMAS LAUGHREN, session moderator Director Laughren Psychopharm Consulting, LLC Key Regulatory Opportunities for Neuroscience Clinical Trials 9:00 a.m. Regulatory Opportunities and Challenges in the United States ROBERT CALIFF Commissioner of Food and Drugs Food and Drug Administration 9:20 a.m. Regulatory Opportunities and Challenges in Europe LUCA PANI Director General Italian Medicines Agency (AIFA) 9:40 a.m. Discussion Among Speakers and Workshop Participants 10:45 a.m. BREAK SESSION IV: ETHICAL CONSIDERATIONS Session Objectives: Examine ethical, legal, and social questions about neuroscience clinical trials. Consider potential data protection and human subjectsâ issues that might arise as clinical trials continue to transform.
88 NEUROSCIENCE TRIALS OF THE FUTURE 11:00 a.m. Session Overview and Objectives PETRA KAUFMANN Director, Office of Rare Diseases Research and Division of Clinical Innovation National Center for Advancing Translational Sciences Data Protection 11:10 a.m. FRANK ROCKHOLD Senior Vice President, Global Clinical Safety and Pharmacovigilance GlaxoSmithKline Professor of Biostatistics and Bioinformatics (starting March 2016) Duke University School of Medicine Human Subjects Protection 11:25 a.m. GREG KOSKI President and Co-Founder Alliance for Clinical Research Excellence and Safety (ACRES) 11:40 a.m. EMIL CHIAUZZI Research Director PatientsLikeMe 12:00 p.m. Discussion Among Speakers and Workshop Participants 12:30 p.m. LUNCH SESSION V: REIMBURSEMENT Session Objectives: Consider how data collected by payers are used to inform reimbursement decisions and influence the long-term translation of products in the marketplace. Consider economic outcome measures used to determine payer practices. How will and should these measures be worked into future clinical trials?
APPENDIX B 89 1:15 p.m. Session Overview and Objectives DANIEL BURCH, session co-moderator Vice President and Global Therapeutic Area Head for Neuroscience Pharmaceutical Product Development (PPD) MICHAEL POLLOCK, session co-moderator Vice President, Real World Outcomes Pharmaceutical Product Development (PPD) Improving the Evidence Base for Reimbursement What evidence is needed from research to align with insurance policies and evidence criteria? 1:25 p.m. RHONDA ROBINSON BEALE via teleconference Senior Vice President and Medical Officer Blue Cross of Idaho Challenges of Generating the Required Evidence: An Industry Perspective 1:40 p.m. PAUL STANG Vice President, Global R&D Epidemiology Janssen Research and Development Pragmatic Trials: Challenges and Opportunities for Neuroscience Trials 1:55 p.m. MARK CZIRAKY Co-Founder and Vice President of Research HealthCore, Inc. 2:10 p.m. Discussion Among Speakers and Workshop Participants 2:45 p.m. BREAK
90 NEUROSCIENCE TRIALS OF THE FUTURE SESSION VI: MOVING FORWARD Session Objectives: A panel will synthesize and discuss key highlights from the workshop presentations and discussions, including identifying next steps and promising areas for future action and research. 3:00 p.m. Panel Discussion: Session Moderators ATUL PANDE, workshop co-chair RICHARD KEEFE, workshop co-chair STEPHEN BRANNAN, session I moderator AMIR KALALI, session II moderator THOMAS LAUGHREN, session III moderator PETRA KAUFMANN, session IV moderator DANIEL BURCH AND MICHAEL POLLOCK, session V moderators 3:45 p.m. Discussion Among Session Moderators and Workshop Participants 4:15 p.m. Closing Remarks from the Workshop Co-Chairs 4:30 p.m. ADJOURN WORKSHOP
