Drug development programs face unique challenges in demonstrating the safety and effectiveness of drugs for treating rare diseases. The FDA’s Accelerating Rare disease Cures (ARC) Program started the Learning and Education to Advance and Empower Rare Disease Drug Developers (LEADER 3D) initiative to better understand and address the challenges of bringing therapies for rare diseases to market, especially for diseases that have small patient populations.[1] On March 13, 2025, the FDA’s Center for Drug Evaluation and Research (CDER) published two case studies along with a user guide as part of the LEADER 3D initiative, which highlighted examples of successful approaches taken by sponsors of drug development programs for rare diseases.[2]
To be approved for marketing by CDER, a drug must be safe and effective for its intended use.[3] Furthermore, the drug’s effectiveness must be established by “substantial evidence.”[4] Establishing effectiveness typically requires at least two adequate and well-controlled clinical investigations as outlined by 21 CFR 314.126(b), each investigation independently convincing of the effectiveness of the drug.[5]
Although two investigations are typically required, Section 505(d) of the Federal Food, Drug, and Cosmetic Act permits the FDA to determine that data from one adequate and well-controlled clinical investigation together with confirmatory evidence demonstrates substantial evidence of effectiveness.[6] Factors include the persuasiveness of the single trial, the robustness of the confirmatory evidence, the seriousness of the disease, the unmet medical need, the size of the patient population, and the practicality and ethics of conducting more than one trial.[7]
The published case studies highlight examples of successful uses of clinical trial designs, endpoint selection, natural history studies, and dose selection for the development of rare disease drugs. One of the case studies examines, fosdenopterin (Nulibry®), which is used to treat a rare autosomal recessive disease, molybdenum cofactor deficiency (MoCD) Type A.[8] The fosdenopterin case study describes a successful a clinical trial design that utilized data from multiple clinical studies together with an external control group of genotype-matched untreated participants to overcome the limitations of an extremely small patient population.[9] The Applicant further submitted evidence from a relevant mouse model and mechanistic/pharmacodynamic evidence as confirmatory evidence to meet the substantial evidence of effectiveness requirement.[10] The other published case study, which was on olipudase alfa-rpcp (Xenpozyme®), emphasized the usefulness of first in-human dose escalation studies for addressing the unique issues of toxicity specific to the rare disease, acid sphingomyelinase deficiency.[11]
Together, the case studies and user guide provide a valuable resource for designing drug development programs to address unmet needs for rare diseases.
Editor: Brenden S. Gingrich, Ph.D.
[1] See FDA, March 13, 2025, https://www.fda.gov/about-fda/accelerating-rare-disease-cures-arc-program/learning-and-education-advance-and-empower-rare-disease-drug-developers-leader-3d#case-studies.
[2] Id.
[3] FDA, LEADER 3D Case Study User Guide, March 13, 2025, https://www.fda.gov/media/185425/download?attachment, at 2.
[4] Substantial evidence is defined by Section 505(d) of the Federal Food, Drug, and Cosmetic Act as “evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could be fairly and reasonably be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof.”
[5] FDA, LEADER 3D Case Study User Guide, March 13, 2025, https://www.fda.gov/media/185425/download?attachment, at 2.
[6] Id.
[7] Id. at 3.
[8]See FDA, Fosdenopterin (Nulibry) Use of a Single Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence to Demonstrate Substantial Evidence of Effectiveness for a Rare Disease, March 13, 2025, https://www.fda.gov/media/185752/download?attachment, at 1.
[9] Id. at 4-5.
[10] Id. at 5-6.
[11] See FDA, Olipudase alfa-rpcp (Xenppozyme) A Clinical Dose Escalation Strategy for a Rare Disease Drug Program, https://www.fda.gov/media/185753/download?attachment, at 4-5.
