The FDA released a user guide, the Learning and Education to Advance and Empower Rare Disease Drug Developers (LEADER 3D) based on case studies highlighting key concepts and regulatory considerations crucial for successful rare disease drug development programs. The case studies present successful approaches used by sponsors in designing and conducting their rare disease drug development programs.
Developing drugs for a rare disease requires careful planning and extensive interactions with the FDA. The used guide is based on two case studies. Each case study includes an introduction to the drug and disease, a drug mechanism of action, and at least one regulatory topic with excerpts from relevant FDA guidance documents, along with figures, graphics, FDA guidance documents, and additional resources.
The guide emphasizes the importance of working with the FDA early and throughout the drug development process. It underscores that rare disease drug development is not one-size-fits-all, and the quantity and type of data required vary depending on the unique considerations of each program. Key concepts and regulatory considerations are detailed, including safety evaluation and demonstrating substantial evidence. The guide explains the importance of demonstrating substantial evidence through adequate and well-controlled clinical investigations, or one adequate investigation with confirmatory evidence. It discusses the factors considered when determining whether a single clinical trial with confirmatory evidence meets the substantial evidence standard.
The document also covers clinical trial design features, including the use of randomized, double-blinded, concurrently controlled trials, as well as other designs that may be appropriate for rare diseases. Endpoint selection is emphasized, with the necessity of selecting meaningful and reliable endpoints relevant to the disease’s manifestations and impact on patients. The use of natural history studies for planning drug development and understanding the disease’s progression is discussed, along with dose selection and its considerations in rare disease trials. The importance of collaboration with the FDA is stressed throughout, recommending meetings at various stages of development to resolve questions and address challenges. The guide concludes by listing programs and resources relevant to rare disease drug development. These include meetings, such as Critical Path Innovation Meetings (CPIM) and the Initial Targeted Engagement for Regulatory Advice on CBER/CDER Products (INTERACT). Various FDA guidance documents are also listed, providing valuable references for further exploration of relevant topics.
A companion public report goes into further detail about the challenges in rare disease drug development (RDDD) and their resolution. The report highlights several key challenges across six core RDDD topics: nonclinical development, dose-finding, natural history studies and registries, novel endpoint and biomarker development, clinical trial design and analysis, and regulatory considerations.
