Ethical considerations in the conduct of rare disease neuroscience clinical trials

Abstract Approximately 7,000 rare diseases collectively affect an estimated 300 million people worldwide, yet fewer than 5 percent of these conditions have an approved therapy. Drug development for rare neurological and neurodevelopmental disorders presents unique ethical challenges that distinguish it from clinical research in more prevalent conditions. The rarity and heterogeneity of these disorders necessitate trial designs that depart from conventional randomized controlled trial paradigms, raising important questions about equipoise, placebo use, informed consent, data sharing, and equitable access. In this position paper of the International Society of CNS Clinical Trials and Methodology (ISCTM), the Orphan Diseases Working Group examines key ethical considerations specific to rare disease neuroscience clinical trials. We address the challenges of maintaining clinical equipoise in small, often heterogenous populations; the justification and limitations of placebo-controlled designs; the ethical complexities introduced by gene therapies and other biologics, including consent, assent, and participation of vulnerable populations; the imperative for responsible data sharing and transparent communication with patient advocacy organizations; and best practices for compassionate use programs. Drawing on existing regulatory frameworks, published literature, and the collective experience of the working group, we offer recommendations intended to guide sponsors, investigators, regulators, and ethics committees in the ethical design and conduct of these critical trials.