EMA Guideline On Clinical-Stage ATMPs Comes Into Effect: On The Verge Of Convergence?

By Don Fink, Dark Horse Consulting

On July 1, 2025, the EMA’s Guideline on quality, non-clinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials¹ is slated to come into effect. First adopted by EMA’s Committee for Advanced Therapies (CAT) in December 2018 with initial public consultation instigated February 21, 2019, the current version of the guideline was adopted by EMA’s Committee for Medicinal Product for Human Use (CHMP) on January 20, 2025. Twice released for public consultation, the advanced therapy medicinal products (ATMP) guideline has been intentionally compiled as a primary-source multidisciplinary reference document. It provides guidance and recommendations pertaining to the structural organization and content expectations related to quality, non-clinical, and clinical data to be included in clinical trial applications involving investigational ATMPs. The clinical trial applications are for ATMPs under study in either early-phase exploratory or late-stage confirmatory clinical trials, with the latter intended to provide pivotal data for a marketing authorization application (MAA) that represents a perspective bias of the guidance. The drafting of this guideline embodies a credible, if not overly ambitious, effort to consolidate information drawn from over 40 separate guidelines and reflection papers, as well as question and answer documents that delve into quality, non-clinical, and clinical aspects of investigational ATMPs that collectively comprise gene therapy medicinal products, somatic cell therapy medicinal products, tissue engineered products, and combined ATMPs (i.e., combination products).

Over the course of the guideline’s six-year maturation and curation, the organizational structure and content has remained largely intact. First shared for public consultation in February 2019, the initial draft guideline was 53 pages in length. The current CHMP-adopted version clocks in at 60 pages, with the bulk of the difference attributable to fleshing out a glossary of abbreviations used in the guideline and a more extensive assemblage of references. The table of contents for both the original and final versions of the guideline are identical save for the addition of a one-half page section 7 in the current version that provides cursory coverage of ATMP-device combinations. Based on comments received from the most recent public consultation period (March 2024), various updates have been made and incorporated in the current guideline version.² These updates are largely cosmetic and include (1) reference to the International Council for Harmonisation (ICH) E11 guidance that addresses clinical investigation of ATMPs in pediatric populations, (2) a statement that the guideline will be updated to include further information pertaining to ongoing development of gene-editing products as additional experience is gained, (3) addition of a new reference in the introduction section of the guideline regarding device-drug combination ATMPs, (4) incorporation of new text in the introduction encouraging ATMP developers to seek early guidance at either the national member state or European level to inform development, (5) a recommendation that sponsors adopt a risk-based approach when evaluating quality, non-clinical, and clinical data generated for ATMPs, and (6) notification that immature quality development may compromise use of clinical trial data to support a marketing authorization. The inference from this final point is that a weak quality system could prevent authorization of a clinical trial if there are apparent deficiencies that pose risk to the safety of study participants and robustness of the clinical data generated.

Considering the extent of exposure afforded this guideline over the extended period of its development and the robust record of available written analysis and commentary accompanying milestones of public consultation, along with resulting interim draft document updates, this article will take a different approach with respect to highlighting key points. Rather than generating another summary of the updated version of the guideline, the question is posed as to what extent the content of EMA’s guideline on clinical-stage ATMPs evokes evidence of regulatory convergence between the unicameral U.S. FDA and the multi-cameral, multiple member-state EMA regulatory authorities with respect to the evaluation of cell and gene therapy products, i.e., ATMPs. Although the guideline is advertised as being multidisciplinary across quality, non-clinical, and clinical considerations, the preponderance of the content is centered on the discipline of chemistry, manufacturing, and controls (CMC). Accordingly, the section of the guideline addressing quality documentation will serve as the focus of exploration related to the progression of regulatory convergence.

Pursuit Of Global Regulatory Convergence

Developing innovative medical products categorized as ATMPs is currently a global endeavor. Monitoring the activities associated with medicinal product development is the responsibility of regulatory authorities charged with ensuring that investigational new therapies are of suitable quality, possess an acceptable safety profile in the context of risk-benefit assessment, and are demonstrated to be clinically effective with respect to treatment of a target disease or condition. Regarding specific requirements affiliated with various national regulatory authorities, where there is divergence and incompatibility, efficient development and timely accessibility of innovative products for patients can be jeopardized.³ In the words of former FDA Commissioner Margaret Hamburg: “…in our modern world, the mosaic of regulations that govern drug development and oversight nation by nation are creating unnecessary barriers.”⁴ The U.S. FDA’s CBER, which is responsible for regulation of cell and gene therapy products, identifies regulatory convergence as one strategy for dealing with a dense body of international regulatory requirements that can impede efficient product development.⁵ CBER defines regulatory convergence as the alignment, over time, of requirements across countries or regions that results in incremental adoption of “internationally recognized technical guidance documents, standards and scientific principles, common or similar practices and procedures, or adoption of regulatory mechanisms that might be specific to a local legal context but that align with shared principles to achieve a common public health goal.”

Admittedly, global regulatory convergence is perhaps not in the pantheon of hot topics most likely to pique interest. That said, it is a subject that is routinely making the agendas of international cell and gene-focused conferences developed by professional societies and advocacy organizations such as the International Society for Cell and Gene Therapy, American Society of Gene and Cell Therapy, and the Alliance for Regenerative Medicine. Since October of 2024, the following regulatory convergence topics have been discussed at various conferences hosted by these organizations:

• Regulatory convergence as an opportunity for global cell and gene product approval despite regional differences
• Balancing global regulatory convergence efficiencies against unique regional requirements
• Global convergence: CMC harmonization for advanced therapies
• Regulatory convergence for ATMPs: building global standards
• Opportunities for regulatory convergence in cell and gene therapy

Guideline Regulatory Convergence Status: Alignment Vs. Dischord

Section 4 of the EMA guideline on multidisciplinary requirements for use of ATMPs in clinical trials addresses quality documentation (i.e., CMC). This section of the guideline constitutes nearly 70% of the subject matter covered in the guideline and accordingly affords the greatest opportunity to evaluate the extent to which there is regulatory convergence between EMA’s regulation of ATMPs and FDA regulatory best practices for products that may be likened to the EMA’s categorical definition of ATMPs, cell and gene therapies.

From the vantage point of an ex-FDA cell therapy CMC reviewer, the overwhelming majority of content contained in the quality documentation section of the ATMP guideline is familiar and recognizable as information that is to be included in a clinical trial application for either an exploratory, early stage clinical study (i.e., U.S. FDA-IND) or a confirmatory clinical trial, with the latter intended to provide pivotal clinical safety and effectiveness data to support an MAA (i.e., U.S. FDA-biologics license application [BLA]). The content of the quality documentation section is captured in an organizational framing that mirrors common technical document (CTD) section headings for Module 3, thus serving as a road map for organizing CMC information to include in either an investigational or marketing application submitted to the respective regulatory authorities.⁶ This signals that over time, significant regulatory convergence has transpired within the review discipline of CMC; however, overall consensus alignment shouldn’t be misconstrued as being complete. For a nuanced example, consider the differences in terminology used. The EMA AMTP guideline refers to CTD sections 3.2.S and 3.2.P as “Active substance” and “Investigational medicinal product,” respectively, whereas in the CTD table of contents guidance these same section headers are referred to as “Drug substance” and “Drug product.” Further, in line with previous criticisms noted by stakeholders, the continued abrupt juxtaposition of information in this final guideline pertaining to gene therapy medicinal products (GTMPs) and cell-based medicinal products (CBMP), as well as stating that CMC requirements outlined are applicable to both early exploratory clinical trials and late-stage pivotal clinical studies intended to support marketing authorization, has caused stakeholder confusion with respect to guideline interpretation.⁷ A reading of the EMA guideline on clinical-stage ATMPS reveals continued differences between EMA and FDA approaches to the regulation of advanced therapies that will need to be managed by sponsors intending to engage both regulatory authorities during product development. These include but are not limited to testing of allogeneic cell and tissue donors, good manufacturing practice (GMP) compliance, and expectations for comparability and potency.

Allogeneic Donor Eligibility Determination

The importance of guarding against the inadvertent spread of communicable disease through the use of allogeneic sourced cells and tissues is acknowledged in the ATMP guideline; however, only limited general guidance is provided in the text and through reference citation regarding specific requirements regarding donor screening and testing for infectious disease. This includes considerations for the occurrence of emerging pathogens.^8,9 Rather than describing a unifying strategy, the guideline reminds readers that information provided in an investigational medicinal product dossier (IMPD) that pertains to testing of human cell-based starting materials must comply with relevant EU and member state-specific legal requirements. The guideline also references risks for communicable disease transmission to be considered when pooling of cells from different donors is deemed necessary.

In contrast, the FDA is more prescriptive in its requirements with respect to performing donor eligibility determination, including identification of relevant communicable disease agents and diseases to be screened and tested for, recommendations about what tests are to be used, stipulation as to the qualifications of laboratories where testing is to be performed, and restrictions regarding the pooling of human cells or tissue from two or more donors during manufacturing.^10,11,12 Nonconforming differences related to determining allogeneic donor eligibility can and have resulted in timeline delays and increased cost to cell therapy product developers. This can arise from the use of cellular starting materials obtained from donors screened and tested in compliance with requirements in one jurisdiction that are then used to pursue development in other jurisdictions under the oversight of different regulatory authorities.

Expectations For GMP Compliance

The guideline provides a number of references to GMP requirements as outlined in GMP guidelines that are specific to ATMPs¹³ and that serve as a prerequisite for conducting clinical trials, whether at the exploratory or pivotal stage. In the European Union, ensuring compliance with GMP requirements is achieved, in part, through mandatory self-inspections, with documented results and observations providing physical evidence that an effective quality system is in place.¹⁴

In lieu of verification, the U.S. approach to GMP is through reliance on attestation at the earliest stages of clinical development, with a graduated, step-wise, phase-appropriate increase in GMP compliance considered acceptable. Full compliance with GMP is verified during a pre-license inspection performed by FDA inspectors at the time of a license application (i.e., BLA) review. In light of the differing emphasis on GMP verification, sponsors outside of the EU developing ATMPs need to have remediation plans in place to address the level of GMP compliance expected when contemplating conducting clinical trials in EU member states.

Comparability And Potency — Nuanced Differences

The ATMP guideline generously references both comparability and potency. This is to be expected given the likelihood that manufacturing changes will be introduced during the product life cycle that will require demonstrating that pre-/post-change products are comparable, whether the changes occur during the investigational phase or post-product approval. Potency represents a product’s critical quality attribute that could be susceptible to the impact of a manufacturing change. These are key topics around which there is notable regulatory convergence.

Points of distinction include FDA statements that indicate when the pursuit of desired manufacturing process improvements results in pre- and post-change products that are not comparable due to a significant benefit in effectiveness and/or safety, this may be interpreted to mean noncomparable products are in fact different products. From a statistical perspective, FDA contends that to successfully establish comparability based solely on an analytical analysis, it is necessary to demonstrate equivalence between pre- and post-change product.¹⁵ This can be a significant challenge in the context of limited manufacturing experience.

With respect to potency, the EMA guideline states a “suitable potency assay should be in place when material for the first-in-human clinical trial is produced.” In contrast, FDA guidance offers the flexibility that if drug product release testing does not include an assay for potency when initiating early-phase clinical evaluation, then other aspects of the design control strategy may be relied on to provide adequate potency assurance.¹⁶

These differences in perspective between EMA and FDA with respect to comparability and potency considerations can pose challenges to efficient product development if their significance is not adequately appreciated by sponsors.

Recap

Six years after initial adoption, EMA’s guideline on quality, non-clinical, and clinical requirements for investigational ATMPs in clinical trials comes into effect July 1, 2025. This expansive primary-source guideline covers the waterfront with respect to recommendations and requirements related to clinical testing of cell-based and gene therapy medicinal products, as well as combined ATMPS, with the overall objective being eventual submission of a marketing authorization application. More than the whole of its substantive content, this guideline is a testament to the degree of convergence that has occurred between EMA and the U.S. FDA, particularly with respect to the review of CMC. To date, regulatory convergence does not equate to complete unanimity, as indicated by differences pertaining to donor eligibility determination, GMP compliance expectations, and comparability and potency, among others not touched on here. Mutual recognition, built on the foundation of a developed trust in the capabilities of regulatory reviewers within disparate global jurisdictions as it relates to competent review of ATMPs, could represent a strategy going forward for mitigating these differences.

References

1. European Medicines Agency. Guideline on quality, non-clinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials (January 25, 2025). [Available at https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-quality-non-clinical-clinical-requirements-investigational-advanced-therapy-medicinal-products-clinical-trials_en.pdf (accessed June 12, 2025)].
2. Eglovitch J. (February 7, 2025). EMA adopts guideline on requirements for clinical-stage ATMPs. RAPS Regulatory Focus. [Available at https://www.raps.org/news-and-articles/news-articles/2025/2/ema-adopts-guideline-on-requirements-for-clinical (accessed June 12, 2025)].
3. European Federation of Pharmaceutical Industries and Associations (February 2020). Convergence of Regulatory Requirements Benefits Patients and Society. [Available at https://www.efpia.eu/media/554422/convergence-of-regulatory-requirements-benefits-patients-and-society.pdf (accessed June 12, 2025)].
4. Zerhouni E and Hamburg M. The need for global regulatory harmonization: A public health imperative. Sci Transl Med. 2016, May 11; 8:388. [Available at https://www.science.org/doi/10.1126/scitranslmed.aaf1396?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed (accessed June 12, 2025)].
5. U.S. Food and Drug Administration (n.d.). Regulatory Harmonization and Convergence. [Available at https://www.fda.gov/vaccines-blood-biologics/international-activities/regulatory-harmonization-and-convergence (accessed June 12, 2025)].
6. U.S. Food and Drug Administration (n.d.). eCTD v4.0 Comprehensive Table of Contents Headings and Hierarchy. [Available at https://www.fda.gov/media/179699/download (accessed June 12, 2025)].
7. PharmaLex (July 1, 2024). EMA adopts collaborative approach with ATMP guideline. [Available at https://www.pharmalex.com/thought-leadership/blogs/ema-adopts-collaborative-approach-with-atmp-guideline-update/ (accessed June 12, 2025)].
8. European Union (March 31, 2004). Directive 2004/23/EC on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells. [Available at https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2004:102:0048:0058:en:PDF (accessed June 3, 2025)].
9. European Union (June 13, 2024). Regulation (EU) 2024/1938 2004/23/EC on standards of quality and safety for substances of human origin intended for human application. [Available at https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:02024R1938-20240717 (accessed June 12, 2025)].
10. U.S. Food and Drug Administration (January 2025). Recommendations for Determining Eligibility of Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) Draft Guidance for Industry. [Available at https://www.fda.gov/media/184904/download (accessed June 12, 2025)].
11. 21 CFR 1271: Subpart C – Donor Eligibility. [Available at https://www.ecfr.gov/current/title-21/chapter-I/subchapter-L/part-1271/subpart-C (accessed June 12, 2025)].
12. 21 CFR § 1271.220(b). [Available at https://www.ecfr.gov/current/title-21/chapter-I/subchapter-L/part-1271/subpart-D/section-1271.220 (accessed June 12, 2025)].
13. European Union (November 24, 2017). Guidelines on Good Manufacturing Practice for Advanced Therapy Medicinal Products. [Available at https://health.ec.europa.eu/document/download/e1786e5d-1587-42af-b8ff-6a810ccb6836_en?filename=pharm731_2ib_atmps_guidelines.pdf (accessed June 12, 2025)].
14. GMP Journal (April 3, 2024). Self-Inspections. [Available at https://www.gmp-journal.com/current-articles/details/self-inspections.html#:~:text=The%20checks%20during%20the%20self,an%20assessment%20of%20
    quality%20oversight (accessed June 12, 2025)].
15. U.S. Food and Drug Administration (July 2023). Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products – Draft Guidance for Industry. [Available at https://www.fda.gov/media/170198/download (accessed June 12, 2025)].
16. U.S. Food and Drug Administration (December 2023). Potency Assurance for Cellular and Gene Therapy Products – Draft Guidance for Industry. [Available at https://www.fda.gov/media/175132/download (accessed June 12, 2025)].

About The Author:

Don Fink, Ph.D., is a regulatory master practice expert with Dark Horse Consulting (DHC) providing strategic support across various service areas, including manufacturing, comparability, analytical development, quality systems, and regulatory that pertain to cell and gene therapies and tissue engineering products. Since joining DHC in 2021, Fink has engaged with over 100 clients in the regenerative medicine space, ranging from early-stage development (INTERACT and pre-IND meetings) through IND and eventual biologics license application (BLA). Prior to joining DHC in 2021, Fink was an expert chemistry, manufacturing, and control (CMC) reviewer in the current Office of Therapeutic Products (OTP), CBER, FDA, accumulating over 20 years of experience primarily in the cell therapy space. Fink has served as an invited panelist, given numerous presentations, and authored/co-authored several book chapters describing FDA’s CMC regulatory approach for regenerative medicine products, many composed of a stem cell component.