HIGHLIGHTS FROM THE 8TH ANNUAL NEW ENGLAND RARE DISEASE STATISTICS (NERDS) WORKSHOP 2025: TRANSFORMING RARE DISEASE DRUG DEVELOPMENT

Highlights from the Workshop

A recurring theme in trial design for rare diseases was the incorporation of external data to reduce the need for large control arms in randomized clinical trials (RCTs). Dr. Yuan Ji, Professor of Public Health Sciences at the University of Chicago, introduced pioneering research on Bayesian approaches for information borrowing, sample size estimation and adaptive designs. Utilizing Bayesian additive regression trees (BART) along with the Meta-Analytic Predictive (MAP) prior, their flexible non-parametric regression method can incorporate historical controls while maintaining similarity between the external data and the trial population as well as addressing unmeasured confounders. Moreover, adaptive design methodologies, such as platform trials and seamless Phase II/III designs, were discussed as mechanisms to improve efficiency and operational feasibility and address ethical concerns. These concepts strongly align with PROMETRIKA’s work in developing customized statistical design frameworks that can be tailored to address the unique trial design challenges, regulatory priorities, and development goals of individual sponsors.  

Clinical dose-escalation strategy for rare diseases is particularly critical because patient populations are small, disease progression can be heterogeneous, and safety data are often limited. Dr. Qi Zhang from Sanofi shared an FDA case study of Xenpozyme^Ò and showcased how a thoughtful dose-escalation strategy enabled safe and effective drug development for the rare disease acid sphingomyelinase deficiency (ASMD), a genetic disorder causing toxic buildup of sphingomyelin in organs. Using ASM knockout mouse models, researchers discovered that toxicity from high doses could be mitigated by gradually increasing doses. Through early single ascending dose and multiple ascending dose studies, the team identified the maximum tolerated dose and established a within-patient dose-escalation algorithm, later confirmed in the Phase II/III adult and Phase I/II pediatric trials. Overall, the Xenpozyme case illustrates how integrating nonclinical insights, adaptive trial design, and model-informed strategies can optimize dosing and accelerate rare disease drug development. Such strategies are closely aligned with PROMETRIKA’s work in advancing statistical design frameworks for rare disease trials.

Dr. Edward Neilan, the Chief Medical and Scientific Officer of the National Organization for Rare Diseases (NORD), provided a highlight of the importance of maintaining a focus on rare disease research and the collaboration of patients, industry partners, policy makers, researchers, and clinicians to promote progress. It has been estimated that 90% of rare diseases lack FDA-approved therapies. To address this predicament, a key regulatory update was the FDA’s new CDER/CBER Rare Disease Evidence Principles (RDEP) statement. This framework recognizes the challenges of conducting large trials in ultra-rare, genetically defined diseases and offers a more flexible approach to generating evidence. Under RDEP, a single well-controlled study may be sufficient when supported by strong confirmatory data such as biomarker evidence, natural history comparisons, or real-world data. The FDA also provides clear eligibility criteria and earlier alignment with sponsors, helping streamline development while maintaining high standards for safety and effectiveness. For PROMETRIKA and the broader rare disease community, this represents a significant step forward. RDEP has the potential to accelerate development timelines, reduce uncertainty for sponsors, and most importantly, bring much-needed therapies closer to patients who have waited far too long.