A New Window Into FDA’s Approach to Bespoke Therapies: Signals, Open Questions, and Our Early Read 

Authors: Forge Regulatory Team

The New England Journal of Medicine recently published an FDA perspective outlining an early regulatory concept for individualized gene editing therapies. While not formal guidance, the article signals that the FDA is exploring a more structured way to evaluate bespoke, n-of-1 interventions, moving beyond the purely case-by-case approach used for treatments like milasen or Baby K.J.’s gene-editing therapy. 

The paper describes how evidence gathered across several individualized gene editing treatments could eventually support platform-level authorization, even though each therapy is unique. Although focused on ultra-rare pediatric conditions, the framework may ultimately apply to diseases with multiple genetic variants and, potentially, to other modalities that follow similar logic. 

This early vision raises important scientific and operational questions for developers and CDMOs, setting the stage for deeper discussion on what a scalable pathway for individualized therapies could look like. 

Four Key Areas Where Developers and Manufacturers May Seek Additional Clarity 

The FDA’s perspective offers an encouraging signal of openness toward tailored therapeutic approaches. However, for developers and manufacturing partners, several operational and scientific questions remain. These points highlight where additional discussion, clarity, or future guidance may be valuable for advancing such programs efficiently and responsibly. 

1.Entry Criteria and Feasibility

• An indication with a known causative genetic alteration.
• A well-characterized natural history of the disease.
• Confirmation of biological impact and clinical improvement that excludes regression to the mean.

Natural history data for ultra-rare (n=1) therapies may be impractical and alternative controls should be considered. Confirmatory evidence of target engagement and robust statistics to prohibit random variance can only be assessed after treatment has begun. Developers may seek clarification on several fronts: 

• How first-in-patient decisions will be evaluated. 
• Requirements for diseases lacking biopsy-accessible tissues and whether surrogate markers may be acceptable. 
• Considerations for additional n=1 therapies with limited biomarker data, limited natural history data, or inability to enroll clinical trials in ultra-rare populations.

2.Manufacturing and Technical Considerations
For CDMOs and developers, manufacturing requirements remain one of the most practical areas of uncertainty. The publication does not specify how traditional cGMP, comparability, and release expectations will apply to highly individualized or rapid-turnaround therapies. 

Developers and manufacturing partners may need further guidance on: 

• cGMP and phase appropriate manufacturing requirements for bespoke or n-of-1 products. 
• Platform comparability standards as individualized constructs evolve. 
• Timelines and expectations for rapid manufacturing and release to treat ultra-acute diseases. 
• How much process or assay variation is acceptable across individualized therapies within the same platform. 

These considerations are particularly relevant to CDMOs working with academic laboratories, emerging biotechs, and patient-led foundations striving to translate discoveries quickly into clinical reality.

3.Ecosystem Roles and Funding

Individualized therapy development requires an ecosystem that extends well beyond commercial sponsors. The publication does not yet describe how academic researchers, rare disease foundations, or clinical centers might participate, or how such efforts might be resourced within this emerging framework. 

Developers may seek further insight into how the pathway interacts with existing initiatives, including: 

• NIH or FNIH programs (e.g., The Bespoke Gene Therapy Consortium). 
• FDA’s existing infrastructure (e.g., Rare Disease Innovation Hub, Platform Designation, Accelerated Approval Pathway). 

Clarity on how these entities can collaborate within a unified structure could help streamline early discovery, natural history data collection, manufacturing readiness, and regulatory planning, ultimately accelerating access for patients.

4.Need for Formal Guidance

Finally, because the publication appears as a perspective article rather than official FDA guidance, developers may look for further documentation to understand regulatory expectations in practice. Areas where structured guidance would be most valuable include: 

• Review expectations. 
• Evidence thresholds. 
• Platform qualification approaches. 
• Post marketing commitments. 

Opportunities for public comment, similar to prior draft guidances for individualized antisense oligonucleotides (ASOs), would help the field align on consistent scientific and regulatory standards. 

Industry Perspective: The Role of a Gene Therapy CDMO 

As a gene therapy CDMO focused on scalable, high-quality manufacturing for both rare and more prevalent genetic diseases, we are closely following these discussions with our clients and partners. Translating individualized therapies from discovery to the clinic will require new ways of thinking, both scientifically and operationally. 

From a manufacturing and regulatory standpoint, several areas merit deeper exploration within this emerging framework: 

• Practical definitions of “platform data” in individualized gene therapy. 
• Manufacturing and Quality Control expectations across iterative therapy designs. 
• Pathway applicability to AAV, non-viral modalities, RNA therapeutics, and future genome editing technologies. 
• Integration with ongoing natural history study efforts, to align clinical data generation with product readiness. 
• Resource and infrastructure needs to responsibly expand individualized therapy development at scale. 

Each of these dimensions will shape how the field balances flexibility with rigor, ensuring therapies designed for one patient or small populations can be manufactured safely, reproducibly, and to consistent quality standards. 

This emerging pathway has the potential to reshape how individualized and ultra-rare therapies reach patients. Continued dialogue among regulators, developers, manufacturers, clinicians, and advocacy groups will be essential to ensure the approach is scientifically sound, operationally feasible, and centered on patient need.

Disclaimer: The perspectives shared here do not represent official FDA positions or commitments.