Innovations In Clinical Neuroscience

ISCTM Supplement 2015

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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[ V O L U M E 1 2 , N U M B E R 3 ā€“ 4 , S U P P L E M E N T A , M A R C H ā€“ A P R I L 2 0 1 5 ] Innovations in CLINICAL NEUROSCIENCE 11S ABSTRACT Once a molecule has been characterized as engaging an identified target at the appropriate location (affinity and potency), the next step involves designing experiments that will determine its pharmacodynamic activities both for efficacy (on target) and safety-tolerability (on/off target). Two expert presentations focused on looking back at completed programs and two concentrated on looking forward at ongoing programs. Specific discussions pertain to assessment of pharmacologic agonists (mGluR2/3, k- opiate, peroxisome proliferator- activated receptor gamma) and antagonists (orexin and cannabinoid) in disorders of cognition, mood, and anxiety. Advanced experimental study designs using genetics to guide a treatment trial in Alzheimer's disease and neural target-based approaches as the primary outcome measure in the National Institute of Mental Health- sponsored Fast-Fail Trials (FAST)- Mood and Anxiety Spectrum Disorders (MAS) initiative for depression showcases novel methodological approaches. Of interest, some of these initiatives were successful, while others were not, and two are currently ongoing. In conclusion, methodologies that were utilized and are currently employed to reach a successful clinical drug trial outcome are appreciated, and in case of failure, approaches to reviewing programs to enable learning that would be helpful to future programs are brought forth. This article is based on proceedings from the "Designing the Right Series of Experiments" session, which was held during the International Society for Clinical Trials Meeting (ISCTM) in Philadelphia, Pennsylvania, September 30 to October 2, 2013. INTRODUCTION Methodological shortcomings have likely contributed to failed drug development in psychiatry, and intense scrutiny in feasibility of continuing these efforts is currently ongoing. The ability to design the right series of experiments is as important as formulating the correct question to be answered. Controlling for as many variables as possible in experimental design is a mainstay often thought to lead to less variance and success. However, in clinical trials using Lessons Learned and Potentials for Improvement in CNS Drug Development: ISCTM Section on Designing the Right Series of Experiments by STEVEN T. SZABO, MD, PhD; BRUCE J. KINON, MD; STEPHEN K. BRANNAN, MD; ANDREW K. KRYSTAL, MD, MSc; JOOP M A VAN GERVEN, MD, PhD; ATUL MAHABLESHWARKAR, MD; and GARY S. SACHS, MD Dr. Szabo is with Duke University Medical Center, Durham, North Carolina, and Veterans Administration Medical Center, Durham, North Carolina; Dr. Kinon is with Lundbeck LLC, Deerfield, Illinois (Dr. Kinon was with Eli Lilly and Company, Indianapolis, Indiana, when this material was presented); Dr. Brannan is with Takeda Global Research & Development Center, Inc., Deerfield, Illinois; Dr. Krystal is with Duke University Medical Center, Durham, North Carolina; Dr. van Gerven is with Centre for Human Drug Research, Leiden, The Netherlands; Dr. Mahableshwarkar is with Takeda Global Research & Development Center, Inc., Deerfield, Illinois; Dr. Sachs is with Massachusetts General Hospital, Boston, Massachusetts. Innov Clin Neurosci 2015;12(3ā€“4 Suppl A):11Sā€“25S FUNDING: No funding was provided for this article. FINANCIAL DISCLOSURES: Dr. Szabo is a consultant for Otsuka Pharmaceutical. Dr. Kinon was an employee of Eli Lilly and Company when this material was presented). Dr. Brannan and Dr. Mahableshwarkar are employees of Takeda Pharmaceuticals. Dr. Krystal has received grant support from Astellas Pharma Inc., Janssen Pharmaceuticals, Inc., Novartis Corporation, Sunovion Pharmaceuticals Inc., and Teva Pharmaceuticals USA and serves as a consultant to AstraZeneca, Eisai Inc., Jazz Pharmaceuticals, Inc, Johnson and Johnson, Merck & Co, Roche, Somnus Therapeutics Inc, Teva Pharmaceuticals USA, and Vantia Ltd. Dr. Sachs owns stock, stock options, or bonds in Concordant Rater Systems, LLC; has received grant support from GlaxoSmithKline, AstraZeneca, Wyeth, Eli Lilly, Sanofi, and Abbott Laboratories; and has served as advisor or consultant for GlaxoSmithKline, Pfizer, AstraZeneca, Wyeth, Eli Lilly, Sanofi, and Abbott Laboratories. ADDRESS CORRESPONDENCE TO: Steven T. Szabo, MD, PhD; Email: steven.szabo@duke.edu KEY WORDS: Clinical trials, experimental design, methodology, genetic, research domain criteria, RDoC, proof-of-concept P R O C E E D I N G S

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