Identifying Novel Endpoints in Rare Disease Studies Using Real-World Evidence: A Regulatory Science Perspective

Background: A major challenge in early drug development for rare disease is defining clinical endpoints. In diseases with no approved therapies, trial design may be impeded by the absence of well-validated biomarkers, endpoints, or outcome measures. Natural history studies (NHS) using real-world data (RWD) can be used to develop or validate biomarkers and to establish the most relevant trial endpoints, including surrogate endpoint(s), the timeline for endpoint estimation, and overall study duration. In recent years, regulatory agencies have created initiatives to support novel endpoint development in rare disease (e.g., the US FDA Rare Disease Endpoint Advancement Pilot Program); however, there are complexities in establishing regulatory acceptability of an endpoint that sponsors may not have the tools to navigate.

Objectives: To describe the opportunities and challenges associated with RWD in novel endpoint development, including providing detailed relevant case examples, with emphasis on considerations for regulatory strategy and interaction.

Methods: A targeted review of publicly available information on submissions to EMA and FDA from Jan 2017-Jan 2024 identified examples of New Drug Applications (NDAs) and Biologics License Applications (BLAs) which used real-world evidence (RWE) to identify novel endpoints as part of rare disease drug development. Relevant submissions (e.g., Luxturna, a gene therapy approved by FDA in 2017) were reviewed to understand trends in timing of regulatory engagement, mechanisms for obtaining regulator feedback, and regulatory requirements for establishing endpoints that effectively demonstrate clinical benefit.

Results: Over 5 case examples in rare disease were identified from both FDA and EMA. The most common feedback was related to the appropriateness of simple vs multi-component or composite endpoints, often due to concerns surrounding heterogeneity within a disease. In a majority of cases, endpoints required early and on-going interaction with regulators regarding endpoint interpretation and validation throughout development. Interpreting FDA and EMA feedback on relevant case studies in the context of regulatory guidance illustrates potential opportunities (e.g., identifying new biomarkers) and challenges (e.g., lack of regulatory precedent) in using RWD to develop novel endpoints. These findings give insight into mitigation strategies, including useful regulatory pathways and questions to ask during early engagement.

Conclusions: Understanding the landscape of prior successes and failures informs how regulatory guidance can be effectively operationalized by sponsors intending to identify novel, clinically meaningful endpoints in rare disease.