By Juliane Mills, Executive Director, Therapeutic Strategy Lead, Rare Disease
On November 20, 2025, the second meeting of the U.S. Food and Drug Administration’s Rare Disease Innovation, Science, and Exploration (RISE) workshop series convened at the National Press Club in Washington D.C. Co-led by the Duke-Margolis Institute for Health Policy and the Rare Disease Innovation Hub at the FDA, the workshop’s core purpose is to enhance understanding of regulatory considerations for individualized treatments and to inform future policy.
The day’s discussion brought together a diverse group of scientists, clinicians, regulators, policymakers, patient/caregivers, and advocates. The central call-to-action was clear: we need to develop an approval pathway for a process, rather than a medicine, to enable N of 1 (or N of few) treatments to scale from a single patient to hundreds or even thousands.
The Challenge: Shifting from Product to Process Approval
The groundbreaking potential of N of 1 therapies is undeniable, yet realizing this potential demands a fundamental shift in regulatory thinking. While the FDA has approval pathways in place for individualized medicine, they were designed for academic investigators without an eye to commercialization. The current path is inefficient to allow scaling of these critical treatments to the many therapeutic areas and many patients who need them. The urgent challenge lies in establishing a “process-centric” regulatory pathway that can efficiently evaluate and approve platforms for individualized therapies, rather than requiring full approval for each individual product derived from them.
Key Discussions and Insights from the RISE Meeting
The meeting explored various facets of this challenge, highlighting both the complexities and the potential solutions:
- The Evolving Regulatory Landscape: The FDA’s journey in this space isn’t new; they published guidance in 2021 for Individualized Antisense Oligonucleotides (ASOs). However, these initial guidelines were framed from the perspective of academic investigators, not foreseeing the commercial enterprise individualized ASOs would become. The FDA now anticipates that an approved process could operate similarly to how Master Protocols function today for umbrella trials, where a single disease is treated with multiple therapies. This necessitates a fundamental shift in mindset from product approval to process approval. Recommendations included leveraging established models like accredited medical centers and shared governance, with the FDA expressing amenability to a standard submission process built around a standardized protocol.
- Understanding the Current N of 1 IND Landscape: To provide context, the Center for Drug Evaluation and Research (CDER), responsible for reviewing Investigational New Drug (IND) applications for ASOs, shared data from 2015-2025:
- 49 N of 1 INDs reviewed for antisense oligonucleotides (ASOs)
- 88% were for neurological disease
- 6% were for inborn errors of metabolism
- 6% were for ‘other’ indications
- 30% of the programs included an adult with ALS.
- 53% were for pediatric patients
- 69% enrolled a single patient
- Critical Considerations for N of 1 Development:
- Risk of Disease vs. Risk of Therapy: The urgency for patients with rare diseases cannot be overstated. As soon as personalized therapy technology became feasible (e.g., with milasen in 2018), the desperate need to scale development became clear. Patients cannot afford to wait for us to reinvent the approval. Risk assessment, especially in diseases with fatal outcomes, is a deeply personal decision. We need to honor patient autonomy and balance it with treatment risk on a patient-by-patient and disease-by-disease basis.
- Non-clinical Considerations: Essential non-clinical data includes proof of concept for direct benefit, maximum tolerated dose (MTD) data (often missing), proof of feasibility for the route of administration (which must be consistent with the animal model), and comprehensive toxicity data. The most common reasons for holds or delayed starts were incomplete submission packages, inadequate support for proposed dosing, and a lack of non-clinical dose-ranging data.
- Clinical Development & Reimbursement: A critical question arises once a process is “approved” with the first N of 1 treatment developed on a platform: what data are needed for subsequent patients treated from the same platform? Are additional animal toxicology studies always necessary? When will cellular studies alone be sufficient for on-target and off-target assessment? Furthermore, what data will payers require to reimburse for this innovative development? The consensus from this meeting was a need for robust natural history data and assessments that can measure changes in function, quality of life, and caregiver burden.
- Evidence and Integrating Data: The discussion also touched upon the vital need for data sharing without compromising competitive advantage. Options like C-PATH and RareX were highlighted as potential avenues. There’s a clear need for centralizable, long-term data for patients receiving these therapies, ensuring quality while minimizing the burden on all stakeholders to create a sustainable solution.
This meeting underscored the immense potential of individualized therapies and the collective commitment to overcoming regulatory hurdles. By shifting our focus from individual product approval to a robust, approved process, we can accelerate access to life-changing treatments for patients who need them most.
