The FDA’s activity in 2025 reflected a mix of scientific progress and operational instability. Precision medicine programs benefitted from new draft guidance, renewed discussion of individualized approval pathways, and deeper engagement with small population trial design. At the same time, sponsors encountered late-stage reversals, shifting expectations, and constraints inside the agency. Together, these dynamics shaped how gene therapies and rare disease programs moved through development.
For teams planning 2026 regulatory or clinical strategy, these are the top five FDA regulatory signals that sponsors can act on now.
In September 2025, the FDA released draft guidance on innovative clinical trial designs for cell and gene therapy (CGT) developers. The guidance noted that single-arm trials, external controls, natural history comparators, and Bayesian or adaptive methods are acceptable, but only when supported by strong rationale.
The shift sponsors should act on is the higher level of precision required earlier in development. Several programs in 2025 faced setbacks because early agreements on external controls or endpoints lacked sufficient detail to withstand later FDA scrutiny.
Action: Build statistical justification early. Define trial parameters, comparator logic, feasibility constraints, and alternative designs up front.
The FDA’s draft guidance on post-approval evidence also clarified expectations for long-term safety, durability, and real-world data (RWD). Sponsors should now assume that long-term follow-up, structured registries, and real-world evidence collection will be required for CGTs and other precision medicine therapies, regardless of approval pathway.
Action: Incorporate lifecycle evidence, RWD infrastructure, and long-term monitoring plans into early development strategy.
In November 2025, senior FDA leadership outlined the Plausible Mechanism (PM) Pathway. The concept provides a potential regulatory path for ultra-rare or individualized therapies if the following applies:
This represents an important shift whereby mechanistic clarity may substitute for large clinical datasets when traditional trials are not feasible.
Action: For ultra-rare programs, invest early in target biology, natural history datasets, and biomarker frameworks.
One of the clearest signals from 2025 is that initial FDA alignment is not always durable. This was demonstrated through the following cases:
uniQure’s Huntington’s disease program received early feedback that its single-arm study with an external control could form the basis of a BLA. However, at the November 2025 pre-BLA meeting, the FDA reversed course and said the data was no longer adequate for filing.
Similarly, Sarepta Therapeutic's Elevidys program experienced changing expectations related to safety management and distribution decisions. This also included a reversal of the previous platform designation that the FDA had granted.
These episodes created uncertainty and demonstrated that programs built around negotiated evidence frameworks can still face late-stage reinterpretation.
Action: Build regulatory scenario planning into core strategy. Include contingency analyses, alternative comparators, and flexible evidence plans.
The Rare Pediatric PRV program expired in December 2024, disrupting a widely used incentive. Throughout 2025, voucher scarcity increased prices, and several were sold for more than $150M. In December 2025, the U.S. House unanimously passed the Give Kids A Chance Act to revive the program; next, the Senate will vote on this measure.
While reinstatement appears likely, its timing and structure remain uncertain. This affects early-stage financing and partnership strategy for companies in pediatric rare disease.
Action: Model multiple PRV scenarios and assess impacts on valuation, timing, and portfolio decisions.
FDA decisions in 2025 underscored scientific progress alongside shifting regulatory expectations in ways that introduced new uncertainty.
Sponsors who internalize these signals now will be better positioned to:
The shift toward natural history datasets, registries, and long-term follow up highlights a growing need for continuous evidence generation across the drug development lifecycle. Sano Genetics’ infrastructure for patient engagement allows sponsors to establish these data assets early, supporting both near-term development decisions and future regulatory pathways.
For a deeper analysis across FDA movements in 2025, download our full report, The FDA and precision medicine in 2025: Twists and turns.