On July 1, 2025, the EMA guideline -“Guideline on quality, non-clinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials” (EMA/CAT/22473/2025)- entered into force: which provides detailed guidance on the quality, non-clinical, and clinical, requirements necessary for the submission of Clinical Trial Applications (CTAs) for Advanced Therapy Medicinal Products (ATMPs) under development.
Definitions
The guideline is intended for developers of investigational Advanced Therapy Medicinal Products (ATMPs), as defined in Article 2(1)(a–d) of Regulation (EC) n. 1394/2007 , and classified into four categories: Gene therapy medicinal products, developed to deliver genetic material into patients’ cells with the aim of correcting genetic defects or inducing specific therapeutic effects; Somatic cell therapy medicinal products, which use substantially manipulated cells to restore or modify altered biological functions;
Tissue-engineered products, designed to regenerate, repair, or replace damaged tissues by combining cells and biomaterials into complex three-dimensional structures;
and combined ATMPs with integrated medical devices, where the biological component and the device component act in synergy to achieve the intended therapeutic effect.
The guideline provides a structured framework for the preparation of Clinical Trial Application (CTA) dossiers, with particular focus on the required standards for pharmaceutical quality, preclinical data, and clinical trial design.
Quality Requirements
Comprehensive information is required regarding the characterization of the active substance and the final product, the description of manufacturing and control processes (including release specifications), as well as the strategy for managing Critical Quality Attributes (CQAs) and Critical Process Parameters (CPPs).
Particular attention is given to compliance with Good Manufacturing Practice (GMP) during clinical manufacturing phases, with a focus on traceability, sterility, process validation, and quality risk management.
Non-Clinical Requirements
The guidance outlines the preclinical data required to support product safety, including studies on biodistribution, persistence, genomic insertion (for gene therapy products), tumorigenicity (for cell-based products), and immunogenicity assessments.
Preclinical programs must be designed using a risk-based approach, taking into account the biological characteristics of the product and its intended mechanism of action.
Clinical Requirements
Guidance is provided on the design of clinical trials in accordance with Good Clinical Practice (GCP), with particular attention to the definition of appropriate inclusion and exclusion criteria, the selection of clinically relevant endpoints, and the development of safety monitoring plans—including Data Monitoring Committees and serious adverse event (SAE) management strategies.
The importance of patient stratification and the integration of predictive biomarkers, when available, is also emphasized, as these elements can significantly enhance the effectiveness and robustness of the study design.
Risk Assessment
The development of Advanced Therapy Medicinal Products (ATMPs) presents a unique level of complexity, requiring a regulatory approach that is both flexible and rigorous. In this context, risk assessment emerges as a key strategic tool to guide decision-making throughout the entire product life cycle—from early concept through clinical development and beyond.
The EMA highlights that applying a risk-based approach allows for tailoring the extent and depth of quality, non-clinical, and clinical data according to the potential risks associated with the product and its intended use. This means that, from the earliest stages of development, the sponsor should conduct a systematic risk analysis, based on established knowledge about the product type, the origin of biological materials, manufacturing methods, and the therapeutic target.
Key elements to consider in this assessment include:
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the origin of the cells (autologous, allogeneic, or xenogeneic) and their level of manipulation;
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the nature and safety profile of the vectors used for genetic modification, where applicable;
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the characteristics of the manufacturing process, with particular attention to critical parameters and steps that may introduce variability or contamination;
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the use of non-cellular components and integrated medical devices.
A dynamic analysis
This analysis is not static: it must be periodically updated in light of new data collected during development, in order to support scientifically sound decisions regarding the management of critical issues. The primary objective remains the protection of the safety of subjects enrolled in clinical trials, along with ensuring that the data generated are robust and reliable.
From an operational standpoint, the risk-based approach allows for:
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optimizing the design of preclinical studies by selecting more relevant in vivo and in vitro models and reducing non-essential studies;
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modulating the quantity and quality of physico-chemical and biological characterization data, providing justification for any alternative approaches to the specifications outlined in the European Pharmacopoeia;
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planning clinical studies focused on risk management, by defining mitigation and safety monitoring strategies early on—especially in the initial stages (e.g., First-in-Human trials).
The rigorous application of this approach is crucial to avoid downstream regulatory issues. Inadequate risk management in the early phases can compromise the usability of clinical data in support of a future marketing authorization application—particularly if the investigational product has not been sufficiently characterized or manufactured under appropriate GMP conditions.
