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P219: Identifying Novel Endpoints in Rare Disease Studies Using Real-World Evidence: A Regulatory Science Perspective

Poster Presenter

Christina Mack

Chief Scientific Officer, Real-World Solutions
IQVIA
United States

Objectives

To describe the opportunities and challenges associated with real-world data (RWD) in novel endpoint development in rare disease, including providing detailed relevant case examples, with emphasis on considerations for regulatory strategy and interaction.

Method

Examples of rare disease New Drug Applications and Biologics License Applications using real-world evidence to identify novel endpoints were identified in a targeted review of publicly available information on submissions to EMA and FDA from Jan 2016-Jan 2024 [Co-authors: J Heidt, R D’Amico]

Results

Over 5 case examples in rare disease were identified from both FDA and EMA. Relevant submissions (e.g., voretigene neparvovec-rzyl, a gene therapy approved by FDA in 2017 for treatment of inherited retinal disease; obeticholic acid, a farnesoid X receptor agonist approved by EMA and FDA in 2016 for treatment of primary biliary cholangitis) 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. Natural history studies using RWD were often conducted due to requests from regulators for additional data to demonstrate the relationship between the proposed trial endpoint (e.g., a known biomarker) and clinical outcomes. 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. Consistency across multiple studies and independent datasets was viewed positively by regulators. Despite the utility of RWD in this context, regulators still highlighted key limitations, such as ability to capture certain prognostic variables (e.g., concomitant medication use). In a majority of cases, endpoints required or benefited from 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 pose to regulators during early engagement.

Conclusion

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 using RWD can be used to develop or validate biomarkers and to establish the most relevant trial endpoints for accelerated and/or full traditional approval, including surrogate endpoint(s), the optimal 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 or experience to navigate. The case studies identified in this review underscore the importance of selecting fit-for-purpose RWD sources, collecting and incorporating patient preference into endpoint development, and discussing the impact of disease specific considerations (e.g., gene mutation heterogeneity) on study design and interpretation. Particularly in rare disease, there is not a well-defined roadmap for novel endpoint development as each indication and patient population will present unique and varied challenges. As such, 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.