Meet Ajay Duggal at Digestive Disease Week 2026 in Chicago on May 1–4

Seventy-seven percent of drugs for rare diseases with pivotal efficacy data have orphan designations, and most are approved with Phase III randomized controlled trials (Domike et al, 2024). This creates a regulatory paradox: FDA rules permit Phase II approval with post-marketing commitment data, yet sponsors conduct resource-intensive Phase III trials anyway. 

The estimands framework is not optional sophistication. It's becoming mandatory intellectual honesty about what research questions a trial will actually address. Organizations that treat estimands as a regulatory checkbox rather than a fundamental design element put themselves at risk of producing trials whose analyses are defensible, but whose results may be ambiguous (Stanworth et al., 2024). 

FDA is quietly preparing one of the most disruptive shifts in global early phase regulation: an optional clinical trial notification pathway that trades some traditional animal toxicology for validated nonanimal methods, aiming to cut time and cost to first-in-human (FiH) dosing while keeping centralized federal control.