Blueprint for Breakthroughs is a LinkedIn newsletter published by Adrienne B. Mendoza, MHA, SVP BioBridge Global and Chief Operating Officer (COO), BBG Advanced Therapies
Originally published on LinkedIn on January 13, 2026
Where FDA Is Coming From
The Center for Biologics Evaluation and Research (CBER) has always had one of the hardest jobs in the agency: regulating blood, tissues, vaccines—and now cell and gene therapies—under the same statutory mandate to assure safety, purity, and potency, without choking off innovation. Over the past decade, FDA has approved nearly 50 CGTs, largely by applying a regulatory framework built for conventional biologics. That framework assumed large, repeatable lots and mature manufacturing systems. CGTs, by contrast, are often small-batch, patient-specific, and time-sensitive.
Historically, FDA tried to square this circle through risk-based judgment and case-by-case flexibility. Concepts like minimal manipulation, homologous use, and enforcement discretion allowed lower-risk products to move forward with lighter oversight, while higher-risk therapies underwent full premarket review. That approach worked—until CGTs stretched it to the breaking point.
The result was a gray zone. Some sponsors received flexibility on specifications, lot history, or trial design; others did not. Expectations lived more in reviewers’ experience than in written guidance. Feedback during the review process and interpretation of CFRs appeared subjective and inconsistent. Predictability suffered.
This January, the FDA made this flexibility explicit.
What FDA Just Said—Out Loud
On January 11, the FDA announced it is “sharing information about the agency’s flexible approach to overseeing CMC requirements for cell and gene therapies.” That phrasing matters. Several signals stand out:
- CBER acknowledged reality. Applying largely uniform CMC expectations to individualized, small-batch CGTs is not sustainable.
- Flexibility is now intentional. FDA explicitly calls this “regulatory flexibility tailored for cell and gene therapies”—common-sense adjustments to address CGT-specific challenges without compromising safety, purity, or potency
- Consistency is the goal. Flexibilities that used to be applied case by case are now being communicated broadly, so sponsors are not dependent on which review team they happen to draw
CMC is also being reinforced, not loosened, by what sits around it. The 2025 trio of draft guidances—on innovative trial designs for small populations, expanded use of expedited programs for regenerative medicines, earlier opportunities for FDA feedback on CMC and clinical plans, and post-approval methods to capture safety and efficacy—provide the clinical and post-market scaffolding for this shift.
In August 2025, FDA added PreCheck, a voluntary program to de‑risk and accelerate U.S. manufacturing by assessing facilities and CMC elements earlier and more predictably in the lifecycle, with an emphasis on onshoring and modernization. For CGT developers, PreCheck is about getting facility and CMC readiness right up front—streamlining inspections, clarifying expectations, and enabling platform-level efficiencies so there are not surprises.
This is not FDA “getting soft.” It is FDA aligning the rulebook with how CGTs actually behave in the real world, while keeping the core obligation to assure safety, purity, and potency firmly in place.
The Practical Moves: Where Flexibility Shows Up
1. CMC Expectations That Can Evolve
FDA now says clearly that for CGTs:
- Pre-approval expectations for lot history and specifications may be more flexible—particularly in rare diseases and small populations—provided sponsors have a credible plan to refine and tighten those specifications as manufacturing experience grows.
- CBER has identified regulatory flexibilities already available under existing regulations to accommodate CGT complexity and time constraints, while preserving control strategies that protect safety, purity, and potency.
- CMC is explicitly framed as lifecycle work, not a single gate before BLA.
2. Trial Designs That Fit Tiny Populations
The draft guidance on innovative designs for small populations is FDA’s clearest acknowledgment yet that traditional randomized trials often do not fit CGTs.
FDA now explicitly encourages:
- Adaptive designs and Bayesian or other advanced methods that extract more information from small N.
- Thoughtful use of external or natural-history controls when randomization is not feasible.
- Trial designs that transition cleanly into long-term postapproval follow-up, rather than stopping at first approval.
This marks a departure from the era when “gold standard” implicitly meant large, simple randomized trials—an approach many CGTs cannot realistically execute.
3. Expedited Pathways and Postapproval Data—Together
The updated expedited programs guidance for regenerative medicines, paired with the new postapproval methods guidance, makes FDA’s expectations unmistakable.
FDA is prepared to use RMAT and other expedited pathways for serious conditions—and expects sponsors to repay that flexibility with disciplined commitments for post-approval evidence generation.
That trade looks like:
- Greater latitude in early trial design and endpoints, including surrogate markers, functional outcomes, and staged benefit–risk assessments.
- Stronger expectations for registries, long-term follow-up, and real-world data systems purpose-built for CGTs.
- A direct link between how much FDA flexes pre-approval and how robust the postapproval evidence plan is.
Flexibility is not a shortcut. It is an exchange
What Hasn’t Changed—and Where FDA Will Not Bend
Despite the new openness, several lines remain firm:
- The obligation to demonstrate safety, purity, and potency is unchanged. FDA is explicit that flexibility will not “compromise or undermine” its ability to assure these attributes.
- For higher-risk products—particularly complex gene therapies or novel indications— FDA still expects strong mechanistic rationale, adequate preclinical support, and rigorous long-term safety monitoring.
- FDA’s posture toward unsanctioned stem cell clinics and unapproved products has not softened. Risk-based enforcement, including warning letters, seizures, and injunctions, remains very much in play.
The takeaway is straightforward: FDA is flexible on how you get to robust evidence—not on whether that evidence exists.
What This Means in Practice
For teams developing, supplying, or enabling CGTs/ATMPs, this guidance should directly inform strategy.
1. Treat CMC as a Living Program
- Build a lifecycle CMC plan that shows how specifications, assays, and processes will mature from early clinical phases through postapproval, instead of presenting everything as final at BLA.
- Design analytical methods—and partnerships with testing labs—that allow for method evolution and comparability, rather than locking the program into today’s assays indefinitely.
- Document your control strategy so reviewers can easily follow the logic of risk management over time.
2. Make Starting Materials Central to Your Regulatory Story
This is where starting-material strategy becomes a regulatory lever, rather than just an operational detail.
- Donor and patient material quality, including leukapheresis/apheresis, should be treated as CMC variables. Consistent, standardized collection supports tighter specifications as programs mature.
- If decentralized or mobile collection is part of the model to create tighter control of SOPs, data capture, and chain-of-identity/custody, then work with partners that are robust enough to demonstrate risk reduction—not added variability.
- Align starting-material strategy with access strategy. FDA flexibility does not solve geographic gaps; it simply gives sponsors more room to design around them.
3. Build Trials That Feed Long-Term Evidence Systems
- Use innovative and adaptive designs that respect small populations while generating data that can flow directly into registries and long-term follow-up.
- Plan postapproval evidence infrastructure from the outset—registries, PROs, and RWE pipelines are part of how sponsors “pay back” regulatory flexibility.
4. Choose Partners Who Can Operate in a Flexible World
- Choose Partners Who Can Operate in a Flexible World
- Prioritize apheresis, testing, and manufacturing partners who are comfortable with lifecycle evolution and design phase-appropriate controls—lean but safe in early development, then progressively more robust as you move toward and beyond BLA, instead of freezing an overbuilt Phase 1 process.
- Look for teams that understand the financial dimension: they should be technically strong and cost-effective, able to scale requirements and infrastructure with the program so you can conserve cash for trials, evidence generation, and market access work.
- Favor integrated partners who can help you tell one coherent, phase-appropriate story—from starting material and access, through CMC, into real-world performance and postapproval commitments—rather than isolated vendors that only see one slice of the lifecycle.
One Lens Worth Keeping
The cleanest way to interpret FDA’s message is this:
The agency is aligning expectations with how CGTs are actually made and used. Flexibility is real—but it belongs to teams that can demonstrate discipline across the full product lifecycle.
For those who have lived inside quality systems for cell therapy, this feels less like a revolution than a long-overdue catch-up. FDA is effectively saying: We’ll meet you where you are—if you can show us how you’ll protect patients as you scale.
That is where the next decade of CGT success will be written—not only in breakthrough data, but in the quieter, harder work of building systems, partnerships, and infrastructure that can thrive in a flexible, risk-based regulatory world.
A Final Note on Support
If you’re working to translate FDA’s new flexibility into real-world CMC, starting material, and postapproval decisions, you don’t have to do it alone. At BBG Advanced Therapies, the Quality & Regulatory team operates in this space every day—connecting leukapheresis and starting materials, manufacturing strategy, potency testing, safety studies, and long-term evidence generation into a single, coherent, inspection-ready story.
This article was informed by their practical experience. Leaders like Valery Freeman-Allen, Joe Higdon, and the broader BioBridge Global team work side by side with sponsors to turn FDA’s “we’ll flex if you get serious” message into disciplined, defensible lifecycle strategies for advanced therapies.
