Advanced therapy medicinal products (ATMPs) – including gene and cell therapies and tissue-engineered products – play a prominent role in pharmaceutical pipelines all around the world, representing the most advanced approaches available for the treatment of a range of pathologies. ATMPs are also key to personalised medicines: innovation in oncology, for example, represents a particularly cutting-edge frontier in the application of these new therapeutics, based on the stratification of patients according to their biomolecular profile and the likelihood of achieving positive outcomes by administering a specific ATMP for the selected target. The importance of advanced therapies is also reflected in the increasing number of clinical studies designed to assess their safety and efficacy, and often providing access for patients to innovative therapies.
The recent publication of the new EMA “Guideline on quality, non-clinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials” (EMA/CAT/22473/2025) provides guidance on the structure and data requirements for designing exploratory and confirmatory studies with ATMP investigational products. We summarise the main features of the guideline, which will come into force on 1 July 2025.
Its seven chapters cover in detail all the different aspects of the development, from R&D to manufacturing and quality control. It also discusses the preparation of both non-clinical (e.g. pharmacology, pharmacokinetic and toxicology studies) and clinical documentation (e.g. exploratory clinical trials, confirmatory or pivotal studies and long-term efficacy and safety follow-up). The last chapter provides some guidance on how to deal with ATMP-device combinations.
The importance of the definitions
ATMPs cover a wide range of different products, regulated under the (EC) 1394/2007 regulation. Their complexity requires special attention in the generation of data to be used to assess and validate their clinical efficacy and safety. The new EMA guideline refers to the definitions of the different ATMPs provided in the Reflection paper on classification of advanced therapy medicinal products (EMA/CAT/600280/2010 rev.1).
In particular, cell-based therapies can use cells of both human (allogenic or autologous) or animal origin. These may be genetically modified to obtain a new genotype or phenotype, in which case the ATMP is more correctly classified as a gene therapy. Cellular therapies can also be distinguished according to their intended therapeutic effect, i.e. somatic cell medicinal products or tissue engineered products.
Gene therapy medicinal products use specific vectors or delivery formulations/systems to achieve in vivo (or ex vivo) genetic regulation or modification of somatic cells in order to repair, regulate, replace or delete a specific gene involved in the pathogenesis of the disease. The guideline specifies that special attention should be given to clinical studies involving genome-editing techniques, due to their potential for off targeting events that may lead to specific safety concerns.
A development based on risk evaluation
The guideline also states that the development of ATMPs should follow the same general principles as other medicinal products, including the provisions of regulation(EU) 536/2014 on clinical development. However, it should be noted that the different steps in the course of clinical studies (i.e phases I, II, III and IV) may not be as clear-cut as for other types of medicines, the guideline says. As a result, a distinction is made between exploratory and confirmatory studies, the latter aimed at generating pivotal data to support a marketing authorisation application (MAA). In all cases, the responsibility for assessing the adequacy of the available data to support the MAA application rests with the developer.
The strategy used to demonstrate the biological activity of a given ATMP should always be explained and justified, including the method used to define the relevant potency assay. The use of surrogate potency markers should also be justified. The guideline recommends that in vivo potency tests should be avoided; if unavoidable, they must be justified according to the 3R principles.
The distinctive features of ATMPs should be addressed using a risk-based approach comprehensive of subsequent steps. For example, in the initial phase the risk analysis should be based on the available knowledge of the type of the investigational ATMP and its intended use. This initial picture should then be regularly updated as new data become available throughout the entire product life cycle.
In any case, the safety of the enrolled patients should always represent the first priority. The principles underlying the First-in-Human Clinical Trials with Investigational Medicinal Products guideline (EMEA/CHMP/SWP/294648/2007) can also be used to support the design of first-in-human (FIH) trials with investigational ATMPs.
With regard to the quality of gene therapies, the document indicates that the risk-based approach can usefully be applied to justify alternative approaches to the quality requirements, according to the relevant monographs of the European Pharmacopoeia. It is also important to note that the proposed risk-based approach does not replace the provision of suitable quality and safety data on the product and appropriate communication with the regulatory authorities, although it may facilitate compliance with GCP requirements. When submitting the clinical trial application, sponsors should pay a particular attention to demonstrating the availability of a robust quality system and the maturity achieved in the quality development of the investigational ATMP.
Key indications on the quality documentation
Chapter 4 of the guideline deals with the quality documentation for investigational ATMPs, which should comply with the relevant GMPs (EudraLex Volume 4, Part IV). The structure of the Investigational Medicinal Product Dossier (IMPD) should reflect that of the Common Technical Document (CTD) and cover both the active substance and the finished product. Where the manufacturing process is continuous, without distinction between active substance and finished product, the applicant may choose where to provide the necessary information, with a preference for the AS sections. Depending on the nature of the active substance, additional evidence should be provided even if it has been already authorised in a finished product within the EU.
Quality data for exploratory studies should at least include preliminary information on process parameters, in-process controls and release specifications, as well as the criteria used to establish them. Only methods suitable for the intended use should be included in the dossier.
Confirmatory studies should be based on investigational ATMPs at a mature stage of development, as substantial changes during pivotal studies may result in a lack of comparability as referred to in the MAA. The guideline indicates that changes in the manufacturing process should be evaluated using orthogonal methods, considering the impact on the whole product rather than on a single parameter.
We do not go further in detail on the different sections of the submission dossier and corresponding requirements for investigational advanced therapies, due to the limited space available. It is worth mentioning the possible differences in the regulatory classification of medical devices, which are often part of a product combination with investigational ATPMs. In the case of an integral combination (i.e. the device is considered to be an integral part of the active substance), it is classified as a starting material. In other cases, it may be considered as part of the finished product formulation or container closure, or may be required independently to enable administration to the patient.
