CGT’s unfinished business

Advanced therapy medicinal products (ATMPs) have introduced highly personalized therapeutic approaches to oncology, autoimmune diseases and genetic disorders. As the pipeline grows, regulatory compliance has become a key strategic consideration shaping operational and manufacturing decisions. Working with developers across multiple territories, we repeatedly see the same challenge: a program designed for one regulatory environment encounters friction when it must satisfy another. The issue is rarely a lack of guidance, but rather the difficulty of interpreting and applying it consistently across jurisdictions.

The U.S., EU and UK represent the most mature regulatory landscapes for ATMPs, each with established classification criteria, specialized committees and approval processes. There is genuine common ground. The FDA, EMA and MHRA have adopted risk-based approaches to quality, potency and safety, moving away from one-size-fits-all models. Expectations around data integrity and quality systems are broadly aligned. Each has also established accelerated pathways to support timely patient access, including FDA’s Regenerative Medicine Advanced Therapy (RMAT) designation, the EMA’s Priority Medicines (PRIME) program and the MHRA’s Innovative Licensing and Access Pathway (ILAP).

Yet several aspects still differ across jurisdictions.

Classification: In the EU and UK, ATMPs encompass three categories: gene therapy medicinal products, somatic cell therapy medicinal products and tissue-engineered products, with classification directly influencing the regulatory pathway. The FDA categorizes CGTs primarily by mechanism of action and manufacturing approach. This structural difference can create uncertainty in global development planning, particularly for products that sit at the boundary of categories in one jurisdiction but not another.

Chemistry, manufacturing and controls (CMC): GMP requirements are broadly aligned between the EU and UK. Under the updated EMA guideline on investigational ATMPs in clinical trials (EMA/CAT/22473/2025), investigational products must be manufactured to GMP standards from first clinical use.¹ The FDA’s position is more flexible at early development stages. In its January 2026 announcement, CBER confirmed that compliance with 21 CFR Part 211 is not required before phase 2 or 3 manufacturing, with additional flexibility at phase 1.2 Sponsors developing ATMPs outside the EU who plan clinical trials in Europe should have a GMP remediation plan in place, supported by a robust quality management system. Supply chain planning must also account for regional requirements, including the need for EU and UK Qualified Persons for batch certification and importation.

Comparability: The FDA’s January 2026 guidance confirmed that CBER will accept minor manufacturing changes during development without exstensive comparability data, provided evidence supports pre- and post-change comparability.² The EMA requires an ongoing comparability program throughout development, with flexibility decreasing as products approach pivotal trials.³ Because frequent manufacturing changes are common in CGT programs, comparability risks at marketing authorization should be considered early.

Long-term follow-up (LTFU): For gene therapies using integrating vectors or genome-editing, the FDA recommends observing subjects for delayed adverse events for up to 15 years following product exposure.⁴ Shorter periods may apply to lower-risk products based on risk assessment. The EMA similarly applies a risk-based approach considering product characteristics, disease context, and patient factors. These differences influence both trial design and post-marketing pharmacovigilance commitments.

Greater harmonization across these frameworks would reduce development costs, support earlier risk identification and facilitate global patient access to innovative therapies. In 2023, the WHO issued guidance specifically encouraging regulatory cooperation and reliance between authorities involved in the oversight of ATMPs.⁵ However, ATMPs remain excluded from Mutual Recognition Agreements covering GMP inspections between the EU and most major partners, and full alignment remains a longer-term goal.

In the current landscape, early and consistent communication with regulators remains critical. Proactive dialogue can clarify expectations, support trial design and identify issues before they affect timelines. Developers who build regulatory strategy into their manufacturing planning from the outset and design to the highest applicable cross-regional standard, will be better positioned to navigate complexity and deliver therapies to patients. 

References

1. EMA. (2025, July). Guideline on Quality, Non-Clinical and Clinical Requirements for Investigational Advanced Therapy Medicinal Products in Clinical Trials.
2. FDA, CBER. (2026, Jan. 11). Flexible Requirements for Cell and Gene Therapies to Advance Innovation.
3. EMA, Committee for Advanced Therapies. (2019, Dec). Questions and Answers on Comparability Considerations for ATMP.
4. FDA, CBER. (2020, Jan). Long Term Follow-Up After Administration of Human Gene Therapy Products. [Guidance for Industry]
5. WHO Expert Committee on Biological Standardization. (2023, Mar). Considerations in Developing a Regulatory Framework for Human Cells and Tissues and for Advanced Therapy Medicinal Products. WHO Technical Report Series 1048, Annex 3.