US regulatory officials published a 'plausible mechanism pathway' framework in The New England Journal of Medicine proposing an expedited approval route for bespoke medicines for ultra-rare conditions unsuited to randomized trials. Authors include CBER director Vinay Prasad and Martin Makary; the article draws on the high-profile n-of-1 CRISPR case known as baby KJ. Thought leaders are divided: proponents argue the pathway could shorten timelines for life-threatening rare-disease therapies and autologous advanced therapies; critics warn the paper lacks operational detail and could lower evidentiary standards. The NEJM piece cites calls from clinicians and developers for streamlined routes for personalized in vivo and ex vivo genetic treatments. This proposed pathway centers on molecularly targeted, patient-specific interventions and raises immediate questions about post-approval evidence, safety monitoring and how regulators will balance access with uncertainty.