Two high-profile gene therapy programs ran into fresh regulatory headwinds as the FDA pushed for more rigorous evidence. In a public complete response letter, the agency told Regenxbio that its Hunter syndrome submission lacked adequate controls and convincing surrogate‑to‑clinical benefit linkage, asking for normalization of biomarkers or new neurodevelopmental outcome data. Separately, UniQure disclosed FDA staff ‘strongly recommended’ a randomized, sham‑surgery controlled trial for its Huntington’s program. Both actions illustrate the FDA’s current stance: rare‑disease programs must now satisfy more traditional trial standards or provide persuasive biomarker validation. Companies that had built submissions around external controls or surrogate endpoints face extended timelines and costly trials to meet the agency’s expectations. Regulatory consultants warn that these decisions could ripple through the rare‑disease ecosystem, making accelerated pathways harder to predict and increasing the value of early, detailed FDA engagement on trial design and endpoints.