Advancing Regulatory Science for Rare Diseases
We continue our analysis of the report on the Accelerating Rare Disease Cures (ARC) initiative, (https://www.fda.gov/media/189930/download) published by the U.S. Food and Drug Administration (FDA). A separate section of the report is devoted to scientific and regulatory innovations, demonstrating how the agency is developing an external methodological framework, internal statistical standards, and applied formats for early developer support.
This report presents two FDA-funded studies aimed at developing tools for orphan drug development.
The first study is being conducted by the University of Michigan and focuses on the methodology of clinical trials in small populations. It is developing approaches to:
• seamless designs,
• multicomponent clinical endpoints,
• interim analyses,
• Bayesian joint modeling.
These tools allow the ability to obtain interpretable results to be pre-designed into a protocol with a limited number of patients.
The second study is nosological in nature and is being implemented by Wake Forest School of Medicine in collaboration with the Critical Path Institute. It is dedicated to hereditary tubulointerstitial kidney disease (ADTKD). The project uses a registry database, models disease progression, and integrates retrospective and prospective biomarkers—including fluid-based and imaging—as a basis for planning clinical programs and interpreting treatment effects.
A separate section of the report is devoted to the FDA's internal procedures for improving evidence assessment in situations where standard statistical approaches are poorly applicable. To this end:
• Specialized guidelines are being developed for specialists conducting orphan drug evaluations;
• A constantly updated set of approaches to study design and analysis is being developed;
• A format for specialized case reviews of complex cases is being introduced, where protocols and active developments for rare diseases are discussed.
The goal of these reviews is to identify methodological risks before patient enrollment or in the early stages of review, rather than after the selected design can no longer be adjusted.
The START (Support for Clinical Trials Advancing Rare Disease Therapeutics) program is an applied tool that links methodology to specific developments. This is a pilot format for expanded FDA engagement with developers, aimed at aligning key elements of clinical strategy at early stages and building an evidence base suitable for subsequent registration dossier submission.
By 2024, 7 development programs were included in the START program. FDA oversight covers:
• clinical trial design,
• control group selection,
• target population refinement,
• use of preclinical data,
• product characteristics.
• product characteristics.
Operation is ongoing until a key development milestone is reached—for example, progression to a decisive study or the preparation of a registration dossier. Examples in the report include nomlabofusp (Friedreich's disease), ABBV-CLS-7262 (vanishing white matter disease), and DNL126 (mucopolysaccharidosis IIIA, Sanfilippo syndrome).
In the next post, we'll explore other key components of the ARC (Accelerating Rare Disease Cures) program and their importance for the development of orphan drugs.
The beginning of the series on the ARC program can be found at the link in the previous post (https://t.me/occ_cis/261)
