Disciplined CGT Will Win On 2026 Regulatory Flexibility

By Erin Harris, Editor-In-Chief, Cell & Gene
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Wilson Bryan, M.D., former director of FDA’s Office of Tissues and Advanced Therapies (OTAT), and Daniela Drago, Ph.D., RAC, Partner at NDA Partners, a ProPharma Group, joined me for our first Cell & Gene Live of 2026 to unpack what a more mature era of regulatory oversight means for sponsors. Their central message was that flexibility is still available, but only for programs built on disciplined planning, robust CMC, and scientifically rigorous clinical strategies.

From Early Firsts to Disciplined Flexibility

We started the hour by level-setting the conversation about the regulatory landscape. Dr. Bryan described how FDA’s approach to cell and gene therapies evolved across his tenure as OTAT director, which included landmark approvals, such as Kymriah, Yescarta, Luxturna, and Zolgensma. He characterized this evolution as a gradual increase in risk tolerance, both clinically and on the CMC side. And, he shared that a single death no longer halts an entire field, and long-term follow-up expectations have adjusted. For example, five years of follow-up may be sufficient for certain AAV vectors rather than a default 15-year requirement. At the same time, recent actions such as removing REMS for CAR-Ts sit alongside a consistently high bar for clinical evidence to support marketing approval, signaling that tolerance for risk does not equate to weaker standards.

Dr. Drago framed the current regulatory posture as “disciplined flexibility.” Nearly 50 CGTs have been approved in under a decade, and regulators have shifted from enabling scientific firsts to tightening expectations in a more methodical, sustainable way. She explained that flexibility around CMC, clinical design, and accelerated pathways depends on strong control strategies and a well-understood benefit–risk profile. The programs that succeed are those that build flexibility into a solid foundation rather than expecting flexibility to compensate for gaps in fundamentals.

Inside FDA’s Shifting Structure and Expectations

Our conversation turned to how leadership and staffing changes at FDA, especially within the Office of Therapeutic Products (OTP) and related groups, are influencing reviews and sponsor interactions. Dr. Bryan noted that CMC leadership and staffing in OTP have remained relatively stable, which helps maintain continuity in expectations. However, many CGTs are combination products, and significant staffing decreases at the Center for Devices and Radiological Health (CDRH) may complicate communication on device components and potentially delay approvals.

In nonclinical and clinical review groups, the picture is more mixed. Dr. Bryan explained that pharmacology/toxicology reviewers, who were at one point discouraged from sharing their views, are now expected to play a more active role again, something that could translate into more clinical holds driven by pharm/tox concerns. Clinically, substantial loss of leadership and experience, combined with high workload, means that while meetings are still granted and PDUFA timelines are being met, sponsor communications may feel more cursory, reflecting either limited bandwidth or less-experienced staff. The implication for CGT developers is to assume less room for late-stage rescue and more need for proactive clarity, documentation, and planning.

Lock In CMC Framework Early

CMC remains the most common source of friction for CGT programs, and Dr. Drago underscored that regulators distinguish credible strategies from risky ones based on whether sponsors can demonstrate true understanding and control of their product over time. When the story is coherent from early development through scale-up and commercialization, it builds confidence; when it isn’t, regulators see red flags. Most regulatory friction, in the U.S. and Europe, stems not from marginal efficacy but from manufacturing variability, incomplete characterization, or unrealistic scale-up plans. The best programs treat CMC as integral to overall development strategy, not a downstream technical detail.

Dr. Drago advised sponsors to lock a CMC framework early, especially for programs pursuing RMAT or Breakthrough Therapy designation, while preserving room for targeted optimization. Accelerated designations create more touchpoints and potentially faster timelines, but they do not lower the CMC bar; if anything, they invite more detailed questions given the higher stakes. The FDA will accept phase-appropriate validation and permissive release criteria during development, but those concessions must be anchored in sound process understanding, thoughtful risk assessments, and a plan for tightening controls toward licensure. By the time a program is pursuing RMAT/Breakthrough, its commercial process, control strategy, and comparability plan should be sufficiently mature to execute within compressed timelines.

Comparability is another recurring pain point. Common mistakes include planning too late, relying on weak analytics, and if platform arguments will bridge all gaps. While the FDA’s flexible approach to CMC allows some changes toward licensure without overly stringent data when comparability is well supported, programs often face requests for additional data when sponsors cannot clearly link pre- and post-change quality attributes to clinical outcomes. To stay ahead, Drago urged teams to invest in high-quality analytics, predefine CQAs and CPPs with realistic ranges, map likely process changes early, and align with regulators on comparability expectations before making high-impact moves.

One Piece of Advice for 2026

As we ended the hour, I asked Drs. Bryan and Drago to share one piece of advice to CGT developers navigating this increasingly rigorous environment, Dr. Bryan urged teams to run the most scientifically rigorous trial that is feasible, build a viable commercialization plan, and focus on products that can deliver transformative, ideally curative, benefit. If cell and gene therapies offer only marginal improvements and cannot be manufactured reliably at scale, enthusiasm and investment will inevitably wane.

Dr. Drago’s parting message was to treat regulators as development partners and prepare accordingly. Strong, early engagement can be especially powerful in rare diseases, but staff turnover and fewer advisory meetings mean there is less room for last-minute course correction. The programs most likely to withstand the pressures of 2026 are those grounded in disciplined planning, early and honest dialogue with FDA, and a sustained focus on outcomes that matter to patients.

This article offers a high-level summary of our Cell & Gene Live discussion that covered a wide range of critical topics with nuance and deep insight; to capture every detail and example the panel shared, be sure to watch the on-demand version of the full event.