Lessons Learned and Potentials for Improvement in CNS Drug Development: ISCTM Section on Designing the Right Series of Experiments.

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.