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August 5, 2019

Autopsy Analyses in Neurological Drug Development—Opening the Black Box

Author Affiliations
  • 1KMB Consulting, San Diego, California
JAMA Neurol. 2019;76(9):1003-1004. doi:10.1001/jamaneurol.2019.2265

Therapeutic development for neurological diseases is challenging, evidenced by the high failure rate despite substantial investments by industry, government, academia, and nonprofit organizations. Challenges include a lack of knowledge about human disease biological mechanisms, using animal models that differ in brain architecture and neurological functioning compared with humans, phenotypic heterogeneity in human diseases, and, for some disorders, an overlap in conditions that appear symptomatically similar. An additional challenge is that the central nervous system (CNS) is somewhat of a “black box” in that CNS biological effects cannot be directly and easily monitored similar to cardiometabolic plasma analyses or oncology tumor imaging. Progress in CNS biomarkers (eg, imaging and cerebrospinal fluid analyses) has been made, but these are indirect measures and not widely validated. Autopsy analyses in clinical trials of experimental therapeutics for neurological diseases, particularly neurodegenerative disorders, would provide important information on the therapeutics and disease. However, autopsies are rarely incorporated in neurological drug development studies, despite greater public awareness that brain donations can illuminate the neurological condition (ie, chronic traumatic encephalopathy). This Viewpoint encourages incorporating autopsy analyses into neurology drug clinical trials, discussing their use, as well as barriers to implementation and potential solutions, based on personal experience leading neurotherapeutic programs for which autopsy analyses critically informed development.