SUPPLEMENTARY INFORMATION:

I. Background

The RISE Workshop series, co-convened by the FDA Rare Disease Innovation Hub and the Duke Margolis Institute for Health Policy, brings together innovators in drug development, rare disease research, patient advocacy, and regulatory science to discuss challenges in the development of medical products for rare diseases that are common to multiple rare diseases or a class of diseases and for which evolving science offers innovative solutions. The workshops focus on cross-cutting or common issues and do not cover specific products under review by the Agency.

The September 29, 2026, RISE Workshop focuses on statistical considerations for rare disease clinical investigations. Statistical considerations affect numerous aspects of drug development, testing, and review, including clinical trial design and measurement of product effectiveness. Statistical review for rare disease products can be particularly complex, and it requires significant attention to the nuance of the disease state and specific product. Small patient populations constrain sample sizes, limit statistical power, and increase the risk of inconclusive results, yet the urgency of patient need makes timely, reliable evidence critically important. Every clinical investigation design decision involves trade-offs between efficiency and reliability, as well as feasibility and rigor. Meeting this challenge requires both scientific innovation and a shared commitment to transparency about those trade-offs.

II. Issues for Consideration and Request for Information

FDA is seeking feedback from the public—including rare disease medical product developers, disease advocates, and researchers—on the appropriate use of tailored approaches to statistical review of rare disease medical products. FDA has developed two pre-read documents that inform the September 29, 2026, RISE Workshop; one document discusses statistical considerations for clinical trials of rare disease drugs and biologics, and the other document covers statistical considerations for clinical studies of rare disease medical devices. FDA welcomes feedback on either or both of the pre-read documents, as well as feedback related to the content discussed in the RISE Workshop itself.

The pre-read documents are attached in their entirety, and FDA is specifically seeking information that addresses the following discussion questions from the pre-read documents:

For Drugs and Biologics

1. To what extent should we consider adjusting standard success criteria ( e.g., significance thresholds) in a rare disease trial and how should disease severity, feasibility constraints, and the availability of corroborating evidence factor into that decision?

2. What would make randomized designs more acceptable and feasible to patients and sponsors in rare disease settings and what role can enhanced medical care for participants in the control arm, patient engagement, and innovative design features play in addressing the concerns of patients and advocacy communities? Examples may include:

a. Ensuring that participants on the control arm always receive treatment and care that meets or exceeds the standard of care they would receive in clinical practice if they did not participate in the study.

b. Incorporating sequential analyses to ensure that the study stops as soon as possible if there is convincing evidence of efficacy or continues if results are promising but not yet sufficient to inform reliable conclusions.

3. Endpoint selection in rare diseases involves balancing what matters most to patients, what is statistically feasible, and what regulators can accept as evidence of benefit. Where does the rare disease and statistical community see the greatest unmet need in this space—and what would most help move the field toward endpoints that are both meaningful to patients and credible to regulators?

4. Which efficiency-enhancing strategies offer the most feasible and meaningful gains in rare disease studies—and what practical barriers currently stand in the way of their wider adoption?

For Medical Devices

1. For new Class III devices for small patient populations, what are important considerations for the premarket-postmarket data shift specific to products serving small populations? ( printed page 58458) What mechanisms ( e.g., registries, electronic health records, post-approval studies) would best support timely, reliable postmarket data collection? (Note: the pre-read document uses brain-computer interface (BCI) devices for amyotrophic lateral sclerosis (ALS) as a case example.)

2. Under what clinical situations and statistical conditions can a single-arm device study with a performance goal or external control provide acceptable evidence of reasonable assurance of safety and effectiveness for devices for small patient populations—and what pre-specifications are needed to ensure such designs provide reliable and acceptable evidence? (Note: the pre-read document uses BCI devices for ALS as a case example.)

3. What design features would make an external data source appropriate for future pivotal studies in small populations? What infrastructure should be built proactively and by whom? (Note: the pre-read document uses BCI devices for ALS as a case example.)

4. What sources of prior information—feasibility studies, natural history data, international experience, prior device generations—are most appropriate and credible in small patient populations, and can hierarchical borrowing and Bayesian adaptive designs meaningfully improve efficiency and accelerate reliable evidence generation in this space?

91 FR 58456