FDA reviewers reiterated concerns that Replimune’s melanoma therapy RP1 does not have adequate data to support approval in briefing documents ahead of a third FDA advisory committee push. Regulators said the single-arm approach may be insufficient to evaluate RP1’s efficacy separate from the effects of the PD-1 inhibitor nivolumab (Opdivo), and they challenged whether local intratumoral delivery provides systemic benefit. Replimune countered in its own briefing that placebo-controlled layering on top of PD-1 therapy in PD-1-refractory patients would be neither ethical nor feasible due to a lack of evidence for continued PD-1 monotherapy benefit. The dispute continues a longer pattern in which statistical analysis plan selection and endpoint interpretability have driven major outcomes for the program. For the broader cell and gene therapy space, the controversy reinforces that regulators are scrutinizing not only clinical endpoints but also the statistical structure used to interpret single-arm evidence in life-threatening settings.