A running FDA review of Replimune Group’s melanoma therapy RP1 continued to churn as regulators reiterated concerns about the evidence base. FDA briefing materials challenged whether the single-arm phase 2 Ignyte design can establish efficacy in the intended patient context after PD-1 exposure, and whether systemic benefit can be supported when RP1 is delivered locally. Replimune countered that randomization on top of continued PD-1 therapy is not feasible or ethical in a setting where PD-1 monotherapy has no proven continuing clinical benefit. The disagreement feeds into the question of how regulators should weigh endpoint selection and statistical inference when trials depart from randomized controls. Market impact has already been visible in the company’s share price volatility around each new briefing document. For the sector, the case highlights how FDA’s scrutiny is increasingly focused on trial design limitations, endpoint interpretability, and SAP alignment rather than just topline response rates.