In July 2025, three high-profile cell and gene therapy programs were delayed or rejected by the US Food and Drug Administration (FDA).
Capricor’s CAP-1002, an allogeneic cell therapy for Duchenne muscular dystrophy, received a Complete Response Letter (CRL) due to incomplete clinical, CMC, and non-clinical data. Ultragenyx’s UX111, an AAV-based gene therapy for Sanfilippo Syndrome Type A, was issued a CRL citing manufacturing data gaps and facility readiness concerns. Rocket Pharmaceuticals' Kresladi, an ex vivo lentiviral gene therapy for leukocyte adhesion deficiency-I, was also delayed due to outstanding CMC questions.
Despite targeting different diseases and using distinct platforms, all three programs were stalled not by safety or efficacy concerns, but by shortcomings in manufacturing readiness. The message from regulators is clear: without a robust CMC strategy and validated processes, clinical innovation alone is no longer enough.
These rejections are not isolated events. Recent data show that 74% of CRLs issued by the FDA between 2020 and 2024 were driven by quality or manufacturing deficiencies. That includes gaps in process control, insufficient stability data, unvalidated analytical methods, or unresolved issues from Good Manufacturing Practices (GMP) inspections.
And it’s not just late-stage programs under scrutiny. According to Amy Gamber, Founder of BioMeridian Consulting, the FDA is also turning back early-stage submissions. “About 40% of investigational new drugs (INDs) are being stopped or not accepted due to CMC issues,” she noted. “These are often early-stage companies that have already poured months of effort and capital into getting ready. Then suddenly, they’re told their CMC package isn’t adequate. That means more delays, more costs, and more stress.”
FDA guidelines are getting tougher
This shift reflects a broader evolution in regulatory expectations. As Tony Hitchcock, a bioprocessing consultant with over 30 years’ experience in advanced biologics, explained, gene therapy has progressed beyond proof-of-concept and into more mainstream development. “Regulators now have a deeper understanding of the factors that influence safety and therapeutic functionality. In parallel, there have been significant advances in manufacturing processes and analytical tools for characterizing both production and final products. As a result, it’s no surprise that regulators now expect more comprehensive and higher-quality data in CMC submissions, particularly around process performance and product characterization. Expectations are also rising for process consistency, especially with regard to batch-to-batch variability, purity and potency.”
“It’s no surprise that regulators now expect more comprehensive and higher-quality data in CMC submissions, particularly around process performance and product characterization.”
– Tony Hitchcock.
These rising expectations place even greater pressure on early-stage development decisions. Nowhere is the phrase "the process is the product" more accurate than in gene and cell therapy. Early decisions about vector type, cell source, expansion method, or gene-editing approach have far-reaching consequences. These foundational choices shape not just the product’s performance, but its manufacturability, regulatory risk, and scalability.
“Early-stage design choices must be made through the lens of eventual commercial feasibility,” noted Arnaud Deladeriere, President and Principal Consultant at Cell & Gene Consulting. “That means selecting vector backbones and packaging systems compatible with scalable, well-characterized platforms; minimizing complex genetic elements that introduce variability or require bespoke analytics; and choosing host cell lines with documented performance in GMP settings. Too often, sponsors prioritize speed to IND and overlook critical factors like yield, stability, scalability, and regulatory history. By building cross-functional alignment early — across research, process development, regulatory, and quality — teams can avoid painting themselves into a corner later.”
Avoiding FDA rejections with smarter CMC
Historically, many biotechs have prioritized early clinical milestones over manufacturing maturity, deferring CMC planning until proof of concept was established. This approach, driven by cost constraints and investor focus on clinical outcomes, frequently pushed process development, facility planning, and regulatory alignment to later stages. But, as regulatory expectations around manufacturing increase, developers are now beginning to reconsider this approach: investing earlier in manufacturing infrastructure, building internal teams with deep technical expertise, or forging strategic Contract Development and Manufacturing Organization (CDMO) partnerships.
“The key is to view CDMO selection as a true partnership. Decisions should be based on capability, technical competence, and — critically — cultural alignment between organizations,” noted Tony Hitchcock. “For some early stage biotechs, working with a smaller, highly specialized CDMO may be more effective than partnering with a large multinational, especially if the goal is to divest assets during clinical development.”
Relying on cost as the primary decision driver often leads to problems. Companies that try to reduce expenses by developing processes internally and then handing them off to a CDMO without proper alignment can encounter delays, rework, and unexpected costs. “Fortunately, several CDMOs now offer well-established production platforms for cell and gene therapies, and while upfront costs may be higher, the value of their experience and infrastructure can be substantial,” said Tony.
This kind of deep, early alignment is critical as therapies advance toward late-stage development. Regulatory agencies now expect sponsors to demonstrate that manufacturing changes, such as tech transfers, scale-up activities, or switching facilities, will not compromise product quality, safety, or efficacy. Without comprehensive comparability data, validated control strategies, and clear documentation, even minor process deviations can result in a CRL. For companies relying on external manufacturing partners, the strength of the CDMO relationship often determines how smoothly these transitions are managed and whether a product ultimately reaches approval.
New tools alongside new expectations
While the regulatory bar is rising, the landscape isn’t all caution and constraint. Advances in manufacturing platforms, analytics, and process standardization are helping developers to navigate CMC complexity with greater confidence.
“These include suspension-based HEK293 (Human embryonic kidney 293) systems with standardized plasmid workflows, which are better suited for large-scale manufacturing. Modular, closed-system bioreactors and automated fill-finish technologies are also reducing contamination risks and improving reproducibility,” Arnaud said. “On the analytics side, digital platforms that integrate real-time process data with quality readouts are enabling more proactive control strategies. Finally, there’s a growing push toward standardized viral vector platforms — with common backbones, release methods, and analytics — which regulators are increasingly receptive to. These platforms reduce uncertainty, enable better comparability, and shorten development timelines.”
At the same time, these technological advances are raising regulatory expectations. “Weak CMC can compromise both your trial approval and your ability to secure marketing authorization,” noted Amy Gamber. “We’re seeing greater clarity, but also more specificity, in recent EMA and FDA guidelines. Potency assays are now expected in first-in-human trials. There’s also increased scrutiny on non-viral delivery tools, validation, comparability, and safety testing. A few years ago, we were navigating these areas with limited guidance. Today, regulators are far more prescriptive about what they want to see.”
Smart sponsors are taking note. The regulatory bar isn’t just higher — it’s moving. Those who anticipate where it’s heading and build with that in mind will be better positioned to advance through development and bring products to patients faster.
Frequently asked questions (FAQ):
What are the main reasons the FDA rejects cell and gene therapy applications?
FDA rejections often cite CMC issues, such as insufficient manufacturing data, lack of validated assays, facility readiness problems, and gaps in stability or comparability studies.
How do FDA guidelines for cell and gene therapy affect development?
Recent FDA guidelines require earlier inclusion of potency assays, validated analytical methods, and comparability data. They also demand greater consistency in manufacturing processes and product characterization.
What is CMC in cell and gene therapy?
CMC stands for Chemistry, Manufacturing, and Controls, the regulatory framework covering how a therapy is produced, tested, and controlled for quality. In cell and gene therapy, CMC defines whether a product can move through trials and gain approval.
How can companies avoid FDA rejections in cell and gene therapy?
By investing early in robust CMC strategy, selecting scalable platforms, partnering with experienced CDMOs, and aligning development decisions with FDA guidelines from the outset, companies can reduce regulatory risks.
