The FDA’s Manufacturing Flexibilities for Cell and Gene Therapies Guidance – Another Cog in the Nebulous Machine
In January 2026 the FDA announced an initiative1 to increase the flexibility in its oversight of chemistry, manufacturing and control (CMC) requirements for cell and gene therapies, thus hypothetically fueling the streamlined development of these innovative drug products. The reaction was likely one of restrained optimism. On one hand, anything that potentially facilitates development on the critical path towards a Biologics License Application should be viewed positively, especially as CGT drug products are often targeting rare disease and molecularly targeted indications where no current treatments exist. However, as had been the case with other announcements under Dr. Marty Makary’s FDA, this took more of a “press release vibe” with little in the way of nuance, inviting skepticism in advance of the finished work product.
The FDA subsequently followed up last month with the Guidance Document entitled Chemistry, Manufacturing, and Controls Flexibilities for Developing Human Cellular and Gene Therapy Products for a Biologics License Application (May 2026)2. Interestingly this was not released in draft form for public commentary as is typical, but rather was deemed to be for immediate implementation. A quick read of the text may help explain why.
Given its brevity with only eight pages of direct guidance, the inclusion of 36 footnotes throughout the document represents a stark juxtaposition. Of these 36 footnotes, 30 (83%) directly reference previously promulgated regulation and guidance. Instead of proposing new mechanisms and providing novel regulatory insights, the document more resembles something of a roadmap of where to look when considering CGT CMC complexities that have already been described before.
To be clear, there’s some utility in that. However, it nonetheless fails to support the FDA’s initially stated objective. Rather, it functions as a tacit, albeit pragmatic recognition of the complexities faced by developers of CGT drug products, with the underlying tone that where scientifically justified, bespoke approaches may be warranted.
On the other hand, and playing devil’s advocate, one can argue this type and other types of disciplinary flexibility didn’t exist until fairly recently. It wasn’t too long ago that, as an example, developers of AAV9-based investigational products may have sought to leverage the Zolgensma approval3 for a proposed investigational clinical dosing paradigm, only to be told that “it was a different gene therapy.” It was a reasonable point, given what we know about the effects of CMC-related items such as variable transgenes, promoter regions, and impurities arising during vector preparation. Nonetheless, it signified a regulatory rigidity amounting to something of a red line – especially when it came to advanced therapies, every drug product was its own drug product.
As such, having the current regulatory backdrop of CGT development (including CMC and other disciplines) be one of flexibility represents an overarching step forward. Continuing, recent guidance documents such as Considerations for the use of the Plausible Mechanism Framework to Develop Individualized Therapies that Target Specific Genetic Conditions with Known Biological Cause (February 2026)4, and the brand new Leveraging Prior Knowledge in the Development of Human Gene Therapy Products Incorporating Genome Editing (June 2026)5 further espouse the concepts of alternative means for generating substantial evidence of a drug product’s quality and effectiveness, as well as the value of “generally accepted scientific knowledge” as supportive of a drug product’s risk-benefit profile. While these guidance documents are geared towards genome edited products and are not specific to CMC considerations, both note that the tenets within may be applicable to other modalities, including more traditional CGTs. Taken in summation, artificial barriers (perceived or real) for CGT licensure appear to be undergoing a tangible deconstruction.
Of course, there remains the massive elephant in the room. These initiatives and related guidance had their inception and broad implementation under Makary’s leadership. With his departure, along with that of former CBER Director Dr. Vinay Prasad (and with no new permanent appointments made at the time of this writing), it’s fair to question the actionability of these recent regulatory paradigms. As noted within any FDA Guidance Document, they represent the Agency’s current thinking, but are otherwise considered nonbinding. Further, guidance documents may be withdrawn at any time at the FDA’s discretion. Regulatory affairs professionals will need to monitor this space carefully to see if a new Commissioner and his/her deputies possess a different line of thinking.
Ultimately though, and as has been the case with similar press releases over the past 1.5 years, even surface-level forward-thinking visions are a positive. The “Flexibilities” guidance document may not have been as impactful as forecasted, but it’s at least a conversation starter. As such, sponsors of CGT drug products should utilize it as the backdrop for program-specific CMC discussions with regulators to best navigate development.
1FDA Increases Flexibility on Requirements for Cell and Gene Therapies to Advance Innovation | FDA
Dr Eric Hardter
Director, Regulatory Affairs
Meet the author
Dr Eric Hardter is the Director of Regulatory Affairs at Boyds, with over 10 years of experience in regulatory affairs and a history in cell and gene therapy and rare disease spaces. His work at Boyds involves supporting both strategic and operational aspects of our clients’ work, including a focus on formal interaction with the FDA on their behalf. He is a core part of our work in building our US processes, procedures and best practices.