The FDA pushed back on pivotal gene therapy submissions, citing trial design, control group and endpoint issues in public rejection letters and company disclosures. REGENXBIO received an FDA complete response highlighting heterogenous populations, weak external controls and insufficient surrogate endpoint validation for its Hunter syndrome therapy. Separately, UniQure disclosed agency demands for a sham‑surgery‑controlled trial for AMT‑130 in Huntington’s disease. Regulators’ renewed insistence on rigorous controls and clinically meaningful endpoints signals higher evidentiary expectations for rare‑disease gene therapies and could add years and substantial cost to development timelines. Companies and investors will need to weigh ethical, logistical and financial impacts of newly requested randomized or sham‑controlled designs.