FDA review divisions apply inconsistent standards for surrogate endpoints in rare disease trials, causing identical biomarkers to be accepted by one division and rejected by another

Sponsors developing drugs for rare diseases (affecting fewer than 200,000 U.S. patients) face unpredictable and inconsistent FDA decisions on whether proposed surrogate endpoints -- biomarkers used as stand-ins for clinical outcomes -- are acceptable for accelerated approval. Different FDA review divisions apply different standards for the same surrogate endpoint in the same disease, creating regulatory uncertainty that chills investment in rare disease drug development. Why it matters: sponsors cannot predict whether their chosen endpoint will be accepted until late in development (after spending $50-100M+ on clinical trials), so rare disease programs carry regulatory risk that is independent of scientific merit, so investors discount rare disease companies due to this unpredictability, so fewer programs advance to clinical trials for diseases where patient populations are too small for traditional outcome-based trials, so the 95% of rare diseases that still lack any FDA-approved treatment remain untreated partly because of regulatory ambiguity rather than scientific impossibility. The structural root cause is that the FDA lacks disease-specific guidance documents for surrogate endpoints in most rare diseases, the Translational Science Team created by CDER in 2023 had only worked with nine rare disease programs by May 2024, and individual review divisions retain broad discretion to accept or reject surrogates without a centralized consistency framework -- a problem explicitly cited by the GAO in its 2025 report on FDA rare disease drug activities.