Dear All (a wonkish guide to something you may have thought was obvious AND with thanks to Aaron Dane for co-authoring this newsletter),In a position paper recently released in the New England Journal of Medicine, we have notice of a shift in FDA  policy from a default expectation of two pivotal trials to a default of one pivotal trial + confirmatory evidence for approvals. Although two trials might still be needed for some approvals, the shift is in the starting default. To follow the plot, here are the links you need: [The new paper] Prasad V, Makary MA. One Pivotal Trial, the New Default Option for FDA Approval — Ending the Two-Trial Dogma. NEJM 2026;394(8):815–7. DOI: 10.1056/nejmsb2517623. [The serially updated one-trial guidance documents from FDA] "The 2023 Effectiveness Guidance": Demonstrating Substantial Evidence of Effectiveness With One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence. Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/demonstrating-substantial-evidence-effectiveness-one-adequate-and-well-controlled-clinical. "The 2019 Effectiveness Guidance": Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products (December 2019): https://www.fda.gov/media/133660/download. "The 1998 Effectiveness Guidance": Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products (May 1998): https://www.fda.gov/media/71655/download These 3 documents build on each other and are worth reading in their totality. [A review paper on use of...