A senior FDA official defended the agency’s reviewers and insisted uniQure must conduct a randomized sham‑controlled trial for AMT‑130, rejecting the company’s claims that the requirement was inconsistent with prior guidance. The FDA said the proposed control would involve anesthesia and superficial scalp incisions for control-arm patients, not deeper burr-hole procedures, and argued the design is justified by invasiveness and heterogeneity in Huntington’s disease outcomes. uniQure had sought to rely on external control data from its Phase 1/2 program, which showed promising reductions in progression versus historical comparators; the FDA concluded those data are insufficient for a Biologics License Application without randomized internal controls. The agency’s public rebuttal escalates a contentious regulator–developer standoff and raises the likelihood of additional pivotal trials before approval can be considered. The exchange signals stricter evidentiary expectations for invasive CNS gene therapies and underscores the FDA’s insistence on randomized internal controls when effect sizes are hard to separate from bias and placebo effects. Companies developing intracranial or surgical biologics should expect renewed emphasis on randomized trial designs.