FDA’s newly released A New Framework for Rare Disease Review raises an important question: What evidence is reasonably attainable in rare disease drug development, and what can that evidence reliably support?

With FDA’s October 28 public meeting approaching, I’ve been considering the implications for clinical research planning and regulatory decision-making.

Small patient populations, heterogeneous disease progression, limited natural history information, and uncertain endpoints can complicate study design and evidence generation.

The evidence that would best answer a scientific question may not always be feasible to obtain. But feasibility alone does not establish what that evidence can support.

Consider longitudinal natural history information.

Evidence may be limited because observations were never collected, existing records cannot reasonably be accessed, or available data lack the quality or detail needed for a particular research question. These limitations can also overlap.

The distinction matters. Additional data collection may address missing information, while data-sharing arrangements may help overcome access barriers. Neither approach automatically establishes that the resulting evidence is suitable for its intended regulatory use.

For research teams, these considerations affect feasibility assessments, data requirements, alternative approaches, and how uncertainty is communicated throughout development.

FDA’s March 2026 RISE workshop examined barriers to rare disease data sharing and considerations for high-quality data. In a recent public comment, I asked how those findings will inform the proposed framework when relevant natural history evidence exists but is not reasonably accessible.

Evidence-generation decisions also affect patients. Additional data collection and study participation can impose burdens on patients and families, making patient priorities and the scientific value of proposed evidence important considerations. FDA’s framework recognizes patient needs and calls for earlier integration of patient perspectives.

Evidence may be reasonably attainable without being suitable for a particular regulatory purpose. And evidence suitable for one purpose may not be sufficient for another.

The central consideration is distinguishing what evidence can reasonably be obtained from what it can reliably support, while accounting for scientific uncertainty and patient needs without compromising regulatory standards. References: FDA white paper: https://lnkd.in/eBZFPdmf