Methodological Challenges in Alzheimer Clinical Development
Despite great effort the development of drugs for Alzheimer-related disorders has not been successful. Parsimonious explanations are: (1) the tested drugs are not effective; and (2) we do not know the targets well enough to develop effective drugs. Many argue, however, that effectiveness is not recognized because imperfect development programs reduce the likelihood for detecting small clinical effects or effects in subgroups or particular phenotypes.As Alzheimer-related disorders are pleomorphic, multi-determined, and drugs in development may have small effects, incremental efforts are made to advance methods and improve efficiency by focusing on putative subgroups hypothesized to show enhanced responses.Sponsors and academics alter inclusion criteria, treatments, outcomes, and sample sizes, and use biomarkers for ‘enrichment’ and surrogate outcomes.Unanticipated consequences from these changes will be described, including failures in phase 2, vibration of effects, poor reproducibility, reliability, yield, and waste. Discuss are potential solutions, what is needed for better clinical development, efficiency, progress, and including incentives to advance quality clinical trials research.