PS26: Challenges and Novel Approaches in Rare Disease Trials from Industry and Regulatory Perspectives

Drug development for the rare diseases, which are numbered at more than 7000 per NIH reporting, presents formidable challenges stemming from small and, at times, exceptionally limited populations. The natural history of many rare diseases remains poorly understood, compounded by constraints on available tools and outcome measures, resulting in a scarcity of well-established study designs and statistical methodologies in clinical trials. Nevertheless, the current landscape of rare disease drug development is marked by an era of excitement and innovation. Scientific progress and newfound opportunities are steering advancements in rare disease drug development, with a focus on pioneering novel endpoints, surrogate biomarkers, historical control/real-world data (RWD), and the integration of Artificial Intelligence (AI) to revolutionize trial design and approval processes. The Food and Drug Administration (FDA) actively supports these endeavors through initiatives such as the Accelerating Rare Diseases Cures (ARC) program and the Rare Disease Endpoint Advancement (RDEA) Pilot Program, providing crucial resources to propel product development. Recent breakthroughs in pharmaceutical and biotech endeavors highlight significant strides worthy of statistical scrutiny. Her are a few examples: • The approval of tofersen marked a milestone in treating SOD1-ALS, an ultra-rare genetic form affecting approximately 330 individuals in the US. A proposed causal inference model demonstrated empirical evidence correlating the reduction in plasma NfL with improvements in clinical outcomes, offering a promising avenue for further exploration. • An accelerated approval was granted to Sarepta's gene therapy, delandistrogene moxeparvovec for Duchenne muscular dystrophy (DMD) based on early and mid-phase trials. While muscle biopsies exhibited a notable increase in microdystrophin levels, a 48-week assessment revealed no significant difference in ambulatory function between treatment and placebo groups. This regulatory pathway is intended to provide earlier access to therapies that have an effect on surrogate endpoints that might predict clinical benefit. • Sickle cell disease (SCD), a painful and rare genetic blood disorder predominantly affecting people of color, poses unique challenges in recruitment and retention. A novel approach in SCD trial design involves utilizing patient-level external control data and propensity score matching to construct an innovative ePRO VOC endpoint, facilitating nuanced analysis and informed decision-making for effective treatments. This conference session seeks to illuminate the unique challenges and novel approaches in conducting rare disease trials, and offers a comprehensive exploration from both industry and regulatory perspectives. The session will feature presentations by thought leaders from industry and regulatory agencies who are at the forefront of rare disease research. This will be followed by a panel discussion, encouraging interactive dialogue on the interplay between innovation and regulation, and strategies to align both sectors towards the common goal of advancing rare disease therapeutics. Through this session, attendees will gain a nuanced understanding of the current state of rare disease trials, and the strategies being employed to overcome their unique challenges. The objective is to foster collaboration and knowledge sharing to ultimately drive progress in this critical area of research.