Confirmatory Evidence Used in Non-Oncologic Rare Disease New Molecular Entity Marketing Applications Approved by FDA, 2020-2023

Rare disease drug development is often challenging due to limited understanding of disease biology, heterogeneity, and small patient populations, among other reasons. For a new molecular entity to be approved for marketing under a new drug application or original biologics license application by the FDA's Center for Drug Evaluation and Research, the product should be shown to be both safe and effective. In some cases, one adequate and well-controlled clinical trial and confirmatory evidence are sufficient to establish substantial evidence of effectiveness. This important topic is the focus of a September 2023 draft guidance entitled Demonstrating Substantial Evidence of Effectiveness Based on One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence. Most non-oncologic rare disease marketing applications (67%) approved between 2020 and 2023 utilized a single adequate and well-controlled trial plus confirmatory evidence to demonstrate effectiveness. Though different types of confirmatory evidence were utilized in different applications, mechanistic or pharmacodynamic evidence was used to support 77.5% of recent rare disease marketing applications that were approved based on one adequate and well-controlled trial plus confirmatory evidence. The quantity of confirmatory evidence necessary to support effectiveness may vary across development programs. Early and frequent discussions with the Agency to align on the developmental plan will facilitate efficient drug development and regulatory assessment.