Written by:
Núria Nieto, Specialist in Advanced Therapies at Klinea Biotech & Pharma Engineering
Jordi Gibert, Head of the Biotechnology Unit at Klinea Biotech & Pharma Engineering
Andrea Romero, Quality Assurance and Regulatory Affairs at ATMP, Konexio Biotech.
Advanced therapy medicinal products (ATMPs) are treatments for humans based on genes, cells or tissues [1]. ATMPs represent one of the most significant innovations in contemporary regenerative medicine, as they are radically transforming the approach to a wide range of diseases that are difficult to cure using conventional methods. Unlike traditional drug treatments, which focus primarily on symptom relief, these therapies address the underlying cause of the disease by harnessing biological mechanisms to repair, replace or regenerate damaged tissues, organs or cells. This is a revolution in the field of medicine and pharmaceutical manufacturing, redefining current therapeutic possibilities.
The term ATMP encompasses four distinct types of therapeutic products. On the one hand, we have gene therapy, which involves the insertion, modification or removal of genetic material with the aim of treating or preventing diseases. On the other hand, there is cell therapy, which uses human cells that have undergone substantial manipulation, modifying their biological, physiological or structural properties for therapeutic, diagnostic or preventive purposes. Thirdly, there is tissue engineering, in which manipulated cells and/or tissues are used to regenerate, restore or replace damaged biological structures, when they are intended to perform the same functions as in the donor. Finally, combined ATMPs integrate one or more medical devices, with or without any type of activity, together with cells or tissues (viable or non-viable), which act synergistically to fulfil a therapeutic function [1].
Despite their enormous potential, the development, authorisation and marketing of these medicines pose significant regulatory and scientific challenges. It is a rapidly expanding field, highly heterogeneous in terms of the type of medicinal product and disease to be treated, and with considerable technical, clinical and regulatory complexity. It is therefore essential to understand how its regulation is structured and what mechanisms exist to ensure its safety, efficacy and quality, the three fundamental pillars on which the evaluation of any medicinal product for human use in Europe is based.
In this context, the regulation of ATMPs in the European Union has evolved to offer specific routes to market access, both through standard procedures and exceptional mechanisms. This article provides an overview of the main authorisation models existing in Europe, including centralised marketing authorisation, compassionate use, hospital exemption, as well as the differences between the authorisation procedures applicable to these products. Understanding this regulatory framework is key to facilitating the development, access and availability of these types of therapies, which may represent the only option for patients.
Marketing authorisation: The centralised route for ATMPs in the EU
Marketing Authorisation (MA) is the standard process required for an ATMP to be marketed in the European Union. This procedure is carried out exclusively through the centralised procedure, managed by the European Medicines Agency (EMA). Once authorisation has been obtained, the product is made available in the 27 EU Member States, Iceland, Liechtenstein and Norway (which are part of the European Economic Area, EEA), ensuring unified access to the European market with a single application [2].
The primary objective of the clinical development phase of the ATMP is precisely to obtain this authorisation. During this period, the applicant collects and submits evidence demonstrating the efficacy, safety and quality of the ATMP, integrated into a rigorous technical dossier. The EMA evaluates this data to issue a decision based on the benefit-risk balance, a fundamental requirement enshrined in European legislation [3,4].
The inherent complexity of ATMPs has prompted the EMA to develop a multifaceted authorisation system. This model recognises that generating comprehensive evidence of efficacy and safety for highly innovative products poses unique challenges, especially in rare or high-mortality diseases. Thus, the regulatory framework establishes more categories for authorisation, each adapted to different levels of scientific robustness and disease type [5].
Standard Authorisation represents the highest level of requirement, applicable when the developer submits conclusive preclinical and clinical data that unequivocally demonstrate the product’s benefit-risk profile. This type of authorisation, which becomes valid indefinitely after renewal at five years, is characteristic of ATMPs with robust clinical trials [6].
In the face of unmet medical needs where rapid access can be crucial, the EMA has Conditional Authorisation [7,8]. This mechanism accepts preliminary data suggesting a positive benefit-risk balance, provided that the applicant commits to completing post-marketing studies. The validity, initially annual, allows pioneering treatments such as CAR-T therapies for refractory leukaemias and lymphomas to reach patients years earlier than under Standard Authorisation [9]. The transition to Standard Authorisation occurs only when the promised results are verified, thus ensuring that flexibility does not compromise safety [10].
At the extreme end of the regulatory spectrum is Authorisation in Exceptional Circumstances, reserved for situations where the collection of complete evidence is scientifically unfeasible or ethically questionable. This scenario is common in very rare diseases with minimal patient cohorts, where traditional controlled trials are impossible. The authorisation, which remains valid indefinitely but under enhanced supervision, requires rigorous methodological justification and an active pharmacovigilance plan [11,12].
It is essential to emphasise that these categories (Table 1) never compromise the quality of the ATMP product, but rather correspond to pragmatic adaptations to diverse scientific realities [13,14].
Decentralised authorisation process in the EU
In addition to the centralised procedure, there are decentralised and national procedures that allow medicines to be authorised in one or more Member States (Table 2). The decentralised procedure is used to authorise medicines in more than one Member State of the European Union in parallel. It can be used for medicines that do not need to be authorised through the centralised procedure and have not been previously authorised in any Member State [22].
Exceptional decentralised access: Therapeutic bridges for critical situations
When development timelines clash with clinical urgency, the EU has established exceptional access routes. Compassionate Use allows unauthorised ATMPs to be administered to patients with serious or rare diseases for whom no alternatives are available, provided that they are unable to participate in clinical trials [23,24]. This mechanism, coordinated and implemented at national level under European guidelines, varies significantly between Member States. Although not all Member States have well-defined legislation and processes regarding compassionate use, most do [25]. The three European countries that best represent this type of authorisation in terms of European and national regulation are Germany, Italy and Spain, in addition to the United Kingdom, whose Compassionate Use programmes are supervised by their respective national medicines agencies. In the United Kingdom, the Early Access to Medicines Scheme operates, requiring advanced phase III data; in Germany, it is regulated by the German Medicinal Product Act, requiring strict hospital supervision; while Italy contemplates it in its 2017 Ministerial Decree for serious or rare diseases. In Spain, it is regulated by Royal Decree 1015 of 2009 [26] and access is supervised by the Spanish Agency for Medicines and Health Products (AEMPS). Although the EMA does not administer the programmes, it issues scientific opinions on protocols for use to ensure consistency in safety between countries [25].
In addition, the Hospital Exemption [27] authorises the manufacture and use of ATMPs without marketing authorisation in specific hospital settings. This provision, which is crucial for autologous or personalised therapies, is governed by four pillars:
- These must be non-routine preparations manufactured under GMP standards: industrial production or standardised processes are excluded. However, the lack of an EU definition of ‘non-routine’ has led to divergent national interpretations.
- Administered exclusively within the same institution: restricts administration to the manufacturing hospital, limiting scalability and creating geographical inequalities.
- Under direct medical responsibility: the doctor prescribes and supervises treatment on an individual basis.
- Intended for individual patients: ambiguity in ‘custom-made’ leads to disparities in its application. For example, while Spain requires nominative prescriptions, Finland accepts small batches for similar pathologies.
In Spain, the AEMPS requires evaluation of preclinical data, accreditation of facilities, and traceability systems equivalent to those required for commercial products[28].
However, the Hospital Exemption route faces substantial challenges due to regulatory fragmentation. The criteria for implementing the exemption vary significantly between Member States, creating inequalities in access. While France limits its application to rare diseases without authorised treatment, other countries allow broader uses, such as Italy, where there is no numerical limit on patients [29]. This disparity has prompted harmonisation initiatives in the new European pharmaceutical code (currently in progress), which will standardise quality and supervision requirements for the Hospital Exemption without compromising its flexibility. The proposal includes having a centralised EU register for ATMPs under hospital exemption, unified criteria for the definition of ‘non-routine preparations’ and mandatory safety reports. These measures, derived from Regulation (EC) 1394/2007 [30], will address the current fragmentation while maintaining the flexibility necessary to preserve access to personalised therapies, standardising quality and supervision requirements.
Conclusion: Dynamic balance between innovation and guarantees
The European regulatory ecosystem for ATMPs reflects a constant evolution towards models that reconcile medical urgency with scientific rigour. Flexible authorisation pathways, development support programmes and early access mechanisms are adaptive responses to the unique characteristics of these transformative therapies. Spain, through the AEMPS, has efficiently implemented these frameworks, although challenges remain in harmonising national criteria, especially in hospital exemption and compassionate use. The near future will likely see greater international convergence, driven by the exponential growth of technological platforms such as gene editing and iPSC cells, which will require agile frameworks without compromising the safety standards that characterise the European model. Continued collaboration between regulators, developers, and clinicians will remain essential to turning scientific potential into accessible therapeutic realities.