Secretory diarrhea in HIV positive patients remains a serious unmet clinical need, even and especially in the age of highly active anti-retroviral therapy (HAART). In 2013 Crofelemer was approved by the FDA as a first-in-class anti-diarrheal agent indicated for the symptomatic relief of non-infectious diarrhea in adult HIV patients on anti-retroviral therapy (ART). The safety and efficacy of crofelemer were established through ADVENT, an innovative two-stage, seamless adaptive clinical trial with dose selection at the end of stage 1. In this talk we will highlight the clinical, statistical, regulatory and operational challenges of this adequate and well controlled trial. Its successful implementation reflects the high degree of precision with which the trial was planned and executed. To our knowledge this is the first example of an adaptive confirmatory trial with dose selection that has proceeded all the way to NDA submission and approval.