Clinical trials in small populations, particularly those with progressive or degenerative rare diseases, face scientific and ethical hurdles that challenge traditional trial frameworks. High phenotypic variability, irreversible progression, and limited patient pools make randomized control trials (RCTs) often unfeasible or even inappropriate. Yet these trials are critical to accelerating treatments where time, function, and access are at stake. This session brings together trial designers, regulators, and rare-disease sponsors to explore strategies that improve the scientific rigor and regulatory viability of trials in these constrained settings. Panelists will discuss advanced trial designs, use of early functional biomarkers, and statistical models that embrace heterogeneity rather than eliminate it. Attendees will learn how to align study endpoints with disease trajectories, structure data collection to capture meaningful change, and design for power even when the patient population is small.