Modeling and simulation of the exposure-response and dropout pattern of guanfacine extended-release in pediatric patients with ADHD.

Guanfacine extended-release (GXR) is a selective α2A-adrenergic receptor agonist approved in the United States for once-daily administration for the treatment of attention-deficit hyperactivity disorder (ADHD) in children and adolescents ages 6-17 years old either as monotherapy or adjunctive to stimulant medications. This analysis integrates exposure-response, placebo, and dropout data from 10 clinical trials that used GXR in adolescents and children with ADHD. In these trials, the ADHD Rating Scale-IV (ADHD RS-IV) score was collected longitudinally within patients over the course of 6-13 weeks. Non-linear mixed effects models were developed and used to describe the exposure-response of the GXR and placebo time course. The OpenBUGS program was utilized to describe the dropout time course across the trials. Placebo time course was best described by an inverse Bateman function with a 3-group mixture model that allowed for the onset and offset of the placebo response. Dropout time modeling indicated a missing at random mechanism for dropouts which was best described by a Weibull distribution with an estimated percentage of non-dropout patients. A linear exposure-response model with an adolescent effect on maximum slope (SLPmax), and a time delay for reaching SLPmax, provided the best description of the GXR exposure-response time course. The GXR exposure-response model indicated that the typical (95 % confidence interval) decrease in ADHD RS-IV score from the placebo-response trajectory would be 37.1 % (32.2, 42.0 %) per 0.1 mg/kg of GXR exposure. There was little noticeable difference between the exposure-response in adolescents and children or across ADHD subtypes.

Coalition Against Major Diseases: Precompetitive Collaborations and Regulatory Paths to Accelerating Drug Development for Neurodegenerative Diseases.

Precompetitive collaborations have been successful in several disease areas and industries. Such collaborations are critical to address the gaps and challenges in therapeutic development for chronic neurodegenerative diseases. On November 5, 2012, members of the scientific community, advocates, regulators, industry, and government officials met at the US Food and Drug Administration to develop tools to expedite drug development and maximize the potential for success in future drug trials for Alzheimer disease and Parkinson disease. The meeting established that multiple collaborative approaches are essential for accelerating drug development. Such approaches include precompetitive data sharing, regulatory qualification of biomarkers and clinical outcome assessments, implementation of data standards, and development of quantitative drug disease trial models. While challenges to collaboration among industry partners are formidable, they are not insurmountable. The Coalition Against Major Diseases (CAMD) has several positive examples to highlight. This review represents proceedings from CAMD's annual conference and discusses the key themes that are being advanced by the Critical Path Institute.