RESUMO
OBJECTIVE: The International Society of CNS Clinical Trials Methodology (ISCTM) Working Group on Rare Disease/Orphan Drug Development is dedicated to improving and streamlining trials to best develop new treatments for rare diseases. The rarity of these disorders requires a drug development strategy that differs from those of nonrare conditions. Rare disease drug development programs are challenged with small sample sizes, heterogeneous clinical presentations, and few, if any, off-the-shelf endpoints. When disease-specific clinical endpoints exist, they might not be validated and are typically not well known or broadly used in clinical practice. This paper aims to provide an overview of the special issues surrounding endpoints in rare disease drug development, with guidance, practical applications, and discussion. DISCUSSION: The paper covers regulatory considerations in endpoint selection; identification of relevant measurement domains; methods of quantifying clinical meaningfulness; incorporation of patient- and clinician-reported outcomes; considerations for global clinician- and patient-rated clinical assessments; cognition assessment challenges in rare diseases; translation considerations; training, standardization, and calibration of assessors; and endpoint quality assurance. Additionally, it provides guidance and resources for those involved in drug development for rare diseases. CONCLUSION: In keeping with the mission of ISCTM and the rare disease/orphan drug development working group, this article is designed to encourage thoughtful consideration and provide insight and guidance to promote and further efforts in in central nervous system (CNS) rare disease drug development efforts.
