Article

Q&A for innovators: Navigating the complex regulatory world of ATMPs/CGTs

Louis Cicchini, Ph.D.
Michael Day, Ph.D.
Joerg Schneider, Ph.D.

Navigating regulatory and definition differences between ATMPs in the EU and cell and gene therapies in the US

The past few years have seen a rapid rise in the number of cell and gene therapies being developed and brought to market. Known as advanced therapy medicinal products (ATMPs) in Europe and cell and gene therapies (CGTs) in the United States, these innovations often are developed by small biotech companies and academic medical centers. These organizations will likely have very little knowledge of the regulatory environment and will therefore struggle with the nuances between the major regulatory authorities.

To address some of the issues innovators from small biotech and academic centers face, we pose and answer questions on regulatory differences between the major markets and what these mean for the development of ATMPs or CGTs. The questions illustrate key principles for these complex products. However, each product is unique and therefore requires a tailored assessment.

How do the major regulatory authorities differ with how they define gene therapies?

While ATMPs are largely equivalent to CGTs, there are some notable differences. Although there is more overlap than difference between the health authorities, there are nuances that could potentially trip up a sponsor.

In the EU, ATMPs fall under four sub-types: gene therapy medicinal product (GTMP), somatic cell therapy medicinal product (sCTMP), tissue engineered product (TEP) and combined ATMP (cATMP).¹ Under current legislation, the EU is much more precise in its delineation of GTMPs than the U.S. However, the new EU legislation will bring some important changes.

In the US, cellular and gene therapies is the umbrella and nested under this are human gene therapies and somatic cell therapies. There is no separate category for TEPs.

What will the impact of the proposed European pharmaceutical legislation be on ATMPs?

In April 2023, the European Commission adopted a proposal for a new directive and regulation, revising the existing pharmaceutical legislation.²

One of the changes proposed under the new EU pharmaceutical legislation is to redefine the term GTMP to include genome editing techniques and synthetic nucleic acids, which were categorized as chemical medicinal products. Nevertheless, categorization based on mechanism of action continues to create differences that can be confusing for sponsors.³For example, the EU excludes what would otherwise be considered a GTMP if it is intended to be used in the treatment or prophylaxis of infectious disease. It is therefore advisable to seek advice from the health authorities to determine how your product will be classified before embarking on a clinical development program.

In June 2025, the Council of the EU agreed its position on the so-called “pharma package” designed to improve access to medicines. The package introduces article 56a, which enables member states to require a marketing authorization holder (MAH) to make a product available in sufficient quantities to cover the needs of patients in that country.⁴ This could be problematic for ATMPs for several reasons, but particularly due to the storage and logistics requirements for these products.

Another question is whether an MAH could meet the provision requirements at short notice. For instance, if a personalized therapy for rare disease must be manufactured close to the site of care and administered within hours of completion of manufacturing, this would require a manufacturing site in all member states that requires access. On a positive note, the pharma package does provide for longer periods of exclusivity, particularly for orphan drugs, which would receive 10 years of market exclusivity with the possibility of extending that to 12 years.

What do I do if I'm unsure about the classification of my ATMP?

Engaging with the regulators early on can help you to navigate uncertainty over product classification. Initial targeted engagement for regulatory advice (INTERACT) meetings with the FDA’s CBER can offer some very early-stage interactions and may be an opportunity to present your concept. However, pre-IND meetings are the best setting for sorting out your classification with the FDA and sponsors can submit a formal request for designation with the Office of Combination products.⁵

In the EU, the Committee for Advanced Therapies (CAT) provides recommendations for the classification and, in some cases, the national competent authorities do this.⁶However, it’s worth noting that, in the EU, if a product is a combination of a cell and gene therapy, such as CAR-T cells, it is always classified as a gene therapy.

In the US, companies can engage with the Office of Therapeutic Products (OTP) under CBER that regulates all CGTs, including many therapies where the classification line is blurred, such as genetically modified cells.⁷

What do you need to know before you speak with the regulators?

While the health authorities are eager to support innovators, they expect sponsors to have a clear justification and understanding of their drug and of regulatory guidance before seeking advice. It is therefore important to do your due diligence first. The FDA expects applicants to have specific questions and the agency lists examples, such as “Does the FDA agree with the stability testing of the drug substance and drug product?”⁸ The agency expects the sponsor to understand and state their process and provide their justification. Applicants in the United States submit a request for designation (RFD) through the Office of Combination Products (OCP), which will make a recommendation within 60 days.⁹ It is important, however, that applicants have a justification for their request.

In the EU, sponsors can submit a request for an ATMP classification directly to the Committee for Advanced Therapies (CAT) through a form, which the CAT will respond to within 60 days.¹⁰

What are FDA’s expectations for managing the CMC journey?

In the US, requirements for Phase 1 are that a facility is fit-for-purpose, which means you are not locked into commercial standards. The emphasis in Phase 1 is patient safety and sterility assurance. By Phase 2, process consistency is expected, and you should start refining your critical process parameters, and at this point you have to start tightening your specifications and show phase appropriate validation. The quality of materials must increase as you move along these phases, and then by the time you get to phase three, you have to have fully GMP compliant, validated processes and demonstrate you are ready for commercial supply.

CMC remains one of the biggest challenges facing developers of CGTs, with FDA signaling its intention to rigorously review CMC strategies and processes.

How do the major regulatory authorities differ on starting materials for gene therapies?

While the FDA does have some allowances for investigator-led INDs, the agency expects higher quality input materials than they would for early phase small molecules.¹¹ FDA does not allow research grade excipients or starting materials. Their concern is that, because of the nature of CGTs, if the starting materials are not fully qualified there could be a risk to the patient. This places a greater onus on CMC in CGTs than in traditional small molecules, and this can be a learning curve for small companies and innovators. Very often with investigator-initiated INDs, researchers have used starting materials that may have some level of certification, but which is not sufficient for a commercial IND.

For its part, EMA requires GMP grade manufacturing of investigational medical products for first-in-human studies. EMA has updated its guideline on quality, non-clinical and clinical requirements for ATMPs, emphasizing that ex vivo genome editing machinery be defined as starting materials.¹² While this has disappointed many developers who had requested a risk-based analysis and potential classification as a raw material that would allow for manufacturing outside of GMP principles, overall the new guideline does provide some harmonization around the development of ATMPs for clinical trials in Europe.

What are the considerations if you have a gene therapy medicinal product produced in the US and you want to import that into Europe?

Importation to Europe requires companies to have their EU GMP certification.¹³ The site has to be inspected or recognized under a mutual recognition agreement. So, while the US site might be FDA compliant, if you don't have EU GMP certification and qualified persons (QP) within the EU, you can't legally release that batch into Europe.¹⁴

A big consideration for US companies is timing. Even before you start planning for EU certification, you need to make sure you understand and can meet requirements or your import could be delayed by many months, and you may have to undergo rigorous facility inspections.

What will the EU SOHO legislation mean for my clinical trial and final product?

The EU legislation for substances of human origin (SoHOs), which was revised in 2024 to bring blood products, tissues and cells under one regulation, seeks to provide greater protection to patients and donors.¹⁵ The updated legislation extends activities covered to include donor registration, collection and testing, as well as storage, distribution, import, and export. This has a significant impact on the ATMP developers as all parties handling any of the SoHO activities, now known as SoHO entities, must comply with the new SoHO regulation.

Any SoHO entity has until 7 August 2027 to transition to the requirements. For ATMP developers, the emphasis needs to be on understanding the legislation and their own use of SoHOs.

How accepting are the regulators of alternative or complementary analytical and pre-clinical testing methodologies (e.g. orthogonal, digital twin, etc.)?

The FDA has demonstrated an openness to accepting alternative methods, where feasible and justifiable.¹⁶ EMA has also clarified its position on alternative methods, demonstrating an increased commitment to methods that may be more appropriate for ATMP evaluation. These include:

Orthogonal Methods

FDA generally encourages use of orthogonal assays (i.e., methods using different scientific principles to measure the same attribute) to build confidence in critical quality attributes (CQAs). For example, identity, potency, and purity assays in gene therapy programs often require at least two complementary methods (e.g., qPCR and next generation sequencing (NGS) for vector genome integrity, or infectivity assay in addition to copy number assessment). This expectation is consistent with both Phase 1 IND and later-phase submissions, and FDA reviewers will often ask how orthogonal methods were leveraged in assay qualification/validation.

Assay Requirements

FDA applies a “phase-appropriate” lens. For early-phase (IND), assays need to be qualified (not yet fully validated) but must be reliable, reproducible, and sensitive enough to support safety decisions. By Phase 3 and into pre-registration stage assets, full validation is required under ICH Q2(R2), including accuracy, precision, specificity, linearity, range, and robustness. Importantly, potency assays are often singled out as the most common CMC deficiency in CGT programs — FDA expects functional, biologically relevant assays.

EMA’s guidelines

EMA’s guidelines for investigational ATMPs (effective July 2025) specifically state that orthogonal methods should be considered for analytical testing to ensure the robustness and reliability of results related to product quality, particularly when reference standards, validated methods, or standardized assays are lacking. This guideline aligns with the broader move toward regulatory convergence with the FDA in analytical and comparability principles.

For clinical trial materials, validated analytical methods are encouraged but not strictly required for early phases; orthogonal testing bolsters confidence in the data when full validation isn’t feasible.

Alternative/NAMs Integration

The FDA Modernization Act opened the door for New Approach Methodologies (NAMs), such as in silico or organ-on-chip, to supplement or, in some cases, replace certain in vivo studies.¹⁷ However, FDA has been clear that acceptance is case-by-case, and sponsors must provide strong scientific justification and correlation to human biology. For example, organoid or chip-based models may be used to explore biodistribution or off-target effects, but FDA still may require some level of in vivo safety assessment until NAMs are further validated. As of April 2025, the ISTAND pilot lists only eight NAMs accepted into the program. Of these, just one has advanced to the Qualification Plan phase (the second stage of the process). Further, only one tissue chip technology is listed, and it still resides in the initial Letter of Intent phase. This slow progress highlights the immense challenge and urgent need for accelerated development and wider implementation.¹⁸

EMA

For the EMA, a prominent regulatory-accepted NAM is the in vitro micronucleus test (MNvit) for genotoxicity assessment, which has received a formal qualification opinion from EMA's CHMP for specific contexts of use as an alternative to certain in vivo genotoxicity assays.¹⁹ Developers can reference these qualification opinions published by EMA to guide their use of the test in regulatory submissions for safety assessment of medicinal products, including ATMPs.

Are there paths to early access for ATMP/CGT developers to consider and how can sponsors navigate these?

Health authorities offer a variety of pathways to assist developers of ATMPs or CGTs with expediting product development. In the United States, programs include Fast Track designation²⁰, Breakthrough Therapy designation²¹, and Regenerative Medicine Advanced Therapy (RMAT) designation²². In the EU, innovators can take advantage of the EMA’s priority medicines (PRIME) designation²³, while the UK Medicines and Healthcare products Regulatory Agency’s (MHRA) has the Innovative Licensing and Access Pathway (ILAP).²⁴

In September 2025, FDA released draft guidance on innovative designs for clinical trials of CGTs in small populations, providing recommendations on the planning, design, conduct and analysis of CGT trials to support assessment of the product’s effectiveness.²⁵

Conclusion

Given the complex and constantly evolving nature of CGTs/ATMPs, innovators need to remain vigilant and proactively engage with regulatory authorities. Understanding the nuanced differences in regulatory frameworks across regions is key to navigating the complexities of these exciting therapies.

Early interaction with health authorities not only aids in clarifying product classifications but also helps in aligning development strategies with regulatory expectations. By fostering open communication and seeking guidance from regulators and external subject matter experts, sponsors can better position themselves to overcome challenges and facilitate the successful development and commercialization of their innovative therapies.

*Sources continued below

About the authors:

Louis Cicchini, Ph.D., is Director of Scientific Affairs for Cell & Gene Therapy (CGT) at Cencora. He specializes in strategic planning for advanced therapies, focusing on the development and implementation of cross-functional commercialization strategies that enhance access to CGTs.

Michael Day, Ph.D., is Senior Director of Regulatory Strategy and CMC at Cencora. Mike brings more than 25 years of regulatory, CMC, and quality experience, including direct interactions with FDA on CRLs and BLA submissions in cell and gene therapies.

Joerg Schneider, Ph.D., is Director, Principal Consultant at Cencora. Joerg is a translational biopharmaceutical expert with more than 23 years of experience. His expertise covers a wide range of technologies and product classes, including CGTs, vaccine adjuvants, glycoconjugate vaccines, monoclonal antibodies, and non-antibody scaffold drugs.

Disclaimer:
The information provided in this article does not constitute legal advice. Cencora, Inc., strongly encourages readers to review available information related to the topics discussed and to rely on their own experience and expertise in making decisions related thereto.

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Sources

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