Rare and ultra-rare disease settings present numerous challenges for clinical R&D and regulatory review due to small heterogeneous populations, recruitment difficulties, geographical barriers, scarcity of natural history studies to inform endpoint selection and clinical trial duration, and ethical challenges related to randomization of patients to placebo arms, to name a few. This panel will discuss various approaches to clinical trial design, including digitalization, shared single placebo arm, incorporating external control and longitudinal measures, AI implementation, as well as understanding regulatory and policy environment, incentives to payers, value to patients and their caregivers, and successful execution of novel clinical design programs (CDPs) and analytical approaches.