US regulators and academics published a proposed “plausible mechanism” pathway to accelerate access to bespoke medicines for ultra-rare conditions. Vinay Prasad and Martin Makary (FDA authors) argue the framework would allow approvals based on mechanistic evidence when randomized trials are infeasible, citing the n-of-1 CRISPR case known as “KJ.” The proposal appears in The New England Journal of Medicine and has drawn both praise for addressing unmet needs and criticism from experts who say the paper is light on implementation details. Advocates include clinicians working on autologous and in‑vivo gene therapies; detractors warn about evidentiary standards and patient safety oversight. Clarification: “Bespoke medicines” refers to individualized or n-of-1 biologic therapies developed for single patients or extremely small cohorts where traditional randomized clinical trials are impractical. The shift could shorten time-to-clinic for personalized genetic and cell therapies while raising new regulatory and ethical trade-offs.