Navigating the Maze: A Comparative Guide to EU National Competent Authorities for ATMP Oversight

Abstract

This article provides a comprehensive comparative analysis of the roles and processes of National Competent Authorities (NCAs) in the European Union for Advanced Therapy Medicinal Product (ATMP) oversight. Aimed at researchers, scientists, and drug development professionals, it explores the foundational EU regulatory framework, details the methodological application for approvals at the national level, offers troubleshooting strategies for common challenges like the Hospital Exemption and pricing, and validates approaches through a comparative analysis of national implementation. The goal is to equip stakeholders with the knowledge to efficiently navigate this complex landscape and accelerate patient access to transformative therapies.

Understanding the EU ATMP Landscape: The Centralized Framework and National Pillars

The Centralized Role of EMA and the Committee for Advanced Therapies (CAT)

Advanced Therapy Medicinal Products (ATMPs), encompassing gene therapies, somatic cell therapies, tissue-engineered products, and combined ATMPs, represent a groundbreaking class of medicines with the potential to address previously untreatable conditions [1]. Within the European Union, these innovative therapies are subject to a centralized authorization procedure overseen by the European Medicines Agency (EMA), distinguishing them from most conventional medicines that may be authorized at national levels [2]. This centralized model ensures that ATMPs undergo a single evaluation process resulting in authorization valid across all Member States, thereby streamlining market access while maintaining high standards of quality, safety, and efficacy [1].

The regulatory framework for ATMPs is established under Regulation (EC) No 1394/2007, which created the Committee for Advanced Therapies (CAT) as a dedicated scientific committee within the EMA [3] [4]. This regulation builds upon earlier legislation, including Directive 2001/83/EC and Regulation (EC) No 726/2004, to address the unique scientific and technical challenges posed by ATMPs [4]. The CAT operates as a multidisciplinary committee comprising some of Europe's foremost experts in advanced therapies, providing the specialized scientific expertise required to evaluate these complex products [3] [1]. This article examines the centralized regulatory pathway for ATMPs, with particular focus on the CAT's pivotal role in the evaluation, classification, and oversight of these transformative medicines.

The Committee for Advanced Therapies (CAT): Composition and Mandate

Institutional Position and Expertise

The Committee for Advanced Therapies (CAT) functions as a cornerstone of the EU's regulatory framework for innovative medicines. Established in accordance with Regulation (EC) No 1394/2007, the CAT operates as a multidisciplinary body within the EMA's scientific committee structure [3]. Its membership brings together independent experts across relevant scientific domains, ensuring comprehensive evaluation of ATMP applications [3]. The committee's specialized expertise encompasses the broad spectrum of advanced therapies, including cell biology, gene therapy, tissue engineering, and regenerative medicine, reflecting the complex nature of the products under its purview.

The CAT works in close collaboration with other EMA committees, particularly the Committee for Medicinal Products for Human Use (CHMP), which retains ultimate responsibility for adopting final opinions on marketing authorization applications [3] [1]. This collaborative model ensures that ATMP evaluation benefits from both specialized expertise and broader regulatory perspective. While the CAT prepares draft opinions on each ATMP application, the CHMP adopts the final opinion on which the European Commission bases its marketing authorization decision [1]. This dual-committee approach balances specialized assessment with integrated regulatory oversight.

Core Functions and Responsibilities

The CAT's responsibilities extend across multiple aspects of ATMP regulation, forming a comprehensive framework for oversight and support:

• Evaluation of ATMP Applications: The committee's primary responsibility involves preparing draft opinions on each ATMP application submitted to the EMA before the CHMP adopts a final opinion on marketing authorization [3]. This evaluation encompasses rigorous assessment of quality, safety, and efficacy data submitted by applicants [1].

• Classification and Certification: The CAT provides scientific recommendations on the classification of borderline products as ATMPs [3] [1]. It also participates in certifying quality and non-clinical data for small and medium-sized enterprises (SMEs) developing ATMPs, offering valuable support to smaller developers [3] [1].

• Scientific Advice and Guidance: The committee contributes to scientific advice in cooperation with the Scientific Advice Working Party (SAWP), helping developers design robust development programs [3]. It also assists in developing scientific guidelines related to ATMPs and provides expertise for EU initiatives on innovative medicines [3].

• Regulatory Support Activities: The CAT plays roles in pharmacovigilance and risk-management systems for ATMPs, advises the CHMP on products requiring ATMP expertise, and contributes to post-authorization monitoring [3] [1].

Table 1: Key Functions of the Committee for Advanced Therapies (CAT)

Function	Description	Legal Basis/Reference
ATMP Evaluation	Prepares draft opinions on quality, safety, and efficacy of ATMP applications for marketing authorization	Regulation (EC) No 1394/2007 [3]
ATMP Classification	Provides scientific recommendations on whether products qualify as ATMPs	EMA/CAT procedural advice [1]
ATMP Certification	Certifies quality and non-clinical data for SMEs developing ATMPs	SME Regulation [3]
Scientific Advice	Contributes to scientific advice for ATMP developers in cooperation with SAWP	CAT mandate [3] [5]
Guideline Development	Assists in developing scientific guidelines and regulatory requirements for ATMPs	Regulation (EC) No 1394/2007 [3]

The Centralized ATMP Authorization Pathway

Marketing Authorization Procedure

The centralized authorization procedure for ATMPs follows a structured pathway with clearly defined stages and timelines. All ATMPs must be authorized through the centralized procedure at the EMA, unlike conventional medicines that may utilize national authorization routes [1]. This requirement reflects the complex and innovative nature of ATMPs and ensures consistent evaluation standards across the EU.

The authorization process begins with submission of a Marketing Authorization Application (MAA) to the EMA, containing comprehensive data on the product's quality, non-clinical studies, and clinical efficacy and safety [4]. Upon receipt, the EMA initiates the evaluation procedure, with the CAT taking a central role in the scientific assessment. The CAT prepares a draft opinion on the application, which it transmits to the CHMP [1]. The CHMP then considers this opinion while forming its final recommendation to the European Commission, which issues the binding decision on marketing authorization [1]. This process typically occurs within defined timelines, with the entire procedure from application to decision taking up to 210 active days, excluding clock stops when additional information is requested from the applicant.

CAT Evaluation Criteria and Standards

The CAT evaluates ATMP applications against rigorous standards for quality, safety, and efficacy, adapted to the specific characteristics of advanced therapies. For gene therapy medicinal products (GTMPs), the evaluation includes assessment of vector design, transgene expression, and long-term safety monitoring, with particular attention to potential risks such as insertional mutagenesis and immune responses [1]. Somatic cell therapy medicinal products (sCTMPs) are evaluated based on criteria including cell characterization, potency assays, and tumorigenicity risk assessment [1]. Tissue-engineered products (TEPs) undergo evaluation focusing on scaffold materials, cell-scaffold interactions, and functional integration into host tissues [1].

The evaluation process also addresses product-specific considerations, such as the use of genetically modified organisms (GMOs) in some ATMPs, which requires additional assessment under relevant EU Directives [4]. Similarly, ATMPs containing medical devices as integral components (combined ATMPs) undergo evaluation of both the biological and device components, including their interactions [1]. Throughout this process, the CAT applies scientific guidelines specific to ATMPs, which provide detailed guidance on data requirements and evaluation standards.

Figure 1: Centralized Authorization Pathway for ATMPs in the European Union

Supporting Innovation: CAT's Role in ATMP Development

Classification Procedures

A critical function of the CAT involves providing scientific recommendations on the classification of borderline products as ATMPs [1]. Developers can submit a classification request to the CAT when uncertain whether their product qualifies as an ATMP [6]. The committee evaluates the product's characteristics against defined criteria in Regulation (EC) No 1394/2007 and provides a recommendation within 60 days [6]. This procedure offers developers regulatory certainty early in development, enabling appropriate planning of regulatory strategies.

The classification process examines whether products undergo substantial manipulation or are intended for use different from their original essential function [1]. For example, stem cell-based products typically qualify as ATMPs when the cells have been subjected to substantial manipulation exceeding minimal manipulation, or when used for purposes different from their normal functions in the body [1]. The CAT has established clear guidelines for classification, including specific criteria for combined ATMPs that incorporate medical devices as integral components [1]. This classification service provides valuable guidance to innovators navigating the complex regulatory landscape for advanced therapies.

Support Mechanisms for Developers

The CAT and EMA offer multiple support mechanisms to facilitate ATMP development, particularly addressing challenges faced by academic researchers and small companies:

• ATMP Certification: The CAT provides certification of quality and non-clinical data for SMEs, offering a voluntary procedure where SMEs can obtain EMA certification that their product's quality and non-clinical data comply with Part IV of Annex I to Directive 2001/83/EC [3]. This certification can enhance credibility with investors and support further development.

• Scientific Advice: The CAT contributes to scientific advice procedures in cooperation with the Scientific Advice Working Party (SAWP), allowing developers to obtain regulatory feedback on specific development challenges [3] [5]. This advice helps optimize development strategies and generate data meeting regulatory requirements.

• PRIME Scheme: While not exclusive to ATMPs, the PRIority MEdicines (PRIME) scheme provides enhanced support for medicines targeting unmet medical needs, with approximately half of PRIME-designated products being ATMPs [4] [5]. This scheme offers early and proactive regulatory guidance, potentially accelerating development.

• Innovation Task Force: The Innovation Task Force (ITF) provides a platform for early dialogue on innovative medicines, addressing scientific, regulatory, and technical issues [4] [5]. ITF briefing meetings facilitate informal exchanges before formal regulatory procedures.

Table 2: EMA and CAT Support Mechanisms for ATMP Developers

Support Mechanism	Target Audience	Key Benefits	Reference
ATMP Classification	All developers with borderline products	Regulatory certainty on product classification within 60 days	[1] [6]
ATMP Certification	Small and medium-sized enterprises (SMEs)	Certification of quality and non-clinical data for credibility with investors	[3] [1]
Scientific Advice	All ATMP developers	Regulatory feedback on development strategies and data requirements	[3] [5]
PRIME Scheme	Developers addressing unmet medical needs	Enhanced support and accelerated assessment for promising therapies	[4] [5]
ITF Briefing Meetings	Developers of innovative medicines	Early informal dialogue on scientific and regulatory challenges	[4] [5]

Comparative Analysis: EU vs. US Regulatory Frameworks

Institutional Structures and Terminology

The regulatory frameworks for advanced therapies in the EU and US display both convergence and divergence in institutional approaches and terminology. The EU employs the specific term Advanced Therapy Medicinal Products (ATMPs) with a precise legal definition established under Regulation (EC) No 1394/2007 [4] [1]. In contrast, the US FDA uses the broader terminology of "cell and gene therapies" without a distinct statutory category equivalent to ATMPs [4] [6]. This fundamental difference in classification reflects varying historical approaches to regulating these innovative products.

The institutional structures also differ significantly. The EU has established the Committee for Advanced Therapies (CAT) as a dedicated committee within EMA specifically for ATMP evaluation [3] [1]. The US framework centers on the Center for Biologics Evaluation and Research (CBER) within FDA, which regulates cell and gene therapies alongside other biologics [4] [6]. While both systems provide specialized review, the EU's dedicated committee structure offers a potentially more tailored approach to ATMP evaluation, whereas the US system integrates these products within broader biologics regulation.

Regulatory Pathways and Requirements

Both regions have developed specialized pathways accommodating the unique characteristics of advanced therapies, though with distinct requirements and processes:

• Marketing Authorization Pathways: The EU employs a mandatory centralized procedure for all ATMPs [1] [2], while the US utilizes the Biologics License Application (BLA) pathway for cell and gene therapies [4]. Both systems require demonstration of safety, purity, and potency, but specific data requirements may differ.

• Expedited Programs: Both regions offer expedited programs for promising therapies. The EU's PRIME scheme provides enhanced support [4] [5], while the US offers multiple programs including Fast Track, Breakthrough Therapy, and the Regenerative Medicine Advanced Therapy (RMAT) designation [4]. These programs aim to accelerate development and review of therapies addressing unmet needs.

• Clinical Trial Requirements: Both require authorization before initiating clinical trials—Clinical Trial Application (CTA) in the EU [4] and Investigational New Drug (IND) application in the US [4]. However, specific requirements for manufacturing standards, preclinical studies, and trial design may differ.

• Starting Material Standards: Recent EU guidelines require GMP-grade manufacturing of investigational ATMPs for first-in-human studies, while FDA expects higher quality input materials than for early-phase small molecules [6]. Both regulators emphasize phase-appropriate quality requirements.

Figure 2: Comparative Overview of EU and US Regulatory Systems for Advanced Therapies

Emerging Challenges and Regulatory Evolution

Addressing Complex Scientific and Regulatory Issues

The regulation of ATMPs continues to evolve in response to emerging scientific advances and regulatory challenges. Several key areas represent ongoing foci for regulatory development:

• Novel Technologies: The CAT and EMA face continuing challenges in regulating rapidly evolving technologies such as genome editing, synthetic biology, and personalized cell therapies [6]. The proposed revisions to EU pharmaceutical legislation aim to address some of these challenges by redefining GTMPs to include genome editing techniques and synthetic nucleic acids [6].

• Manufacturing Complexity: The complex manufacturing processes for ATMPs, particularly personalized therapies, present significant regulatory challenges [4] [6]. Regulators must balance flexibility for innovation with ensuring product consistency and quality. Recent guidelines address requirements for starting materials and phase-appropriate manufacturing standards [6].

• Combined Products: Combined ATMPs incorporating medical devices or scaffolds require integrated assessment of both biological and non-biological components [1]. The evolving regulatory framework for medical devices under the Medical Device Regulation (MDR) adds complexity to evaluating these integrated products [7].

• Analytical Methods: Both EMA and FDA have demonstrated increasing openness to alternative analytical methods appropriate for ATMP characterization, including orthogonal methods and new approach methodologies (NAMs) [6]. However, developers must provide robust scientific justification for these methods.

Recent and Upcoming Regulatory Developments

The regulatory landscape for ATMPs continues to evolve through several significant developments:

• Revised Pharmaceutical Legislation: The proposed EU pharmaceutical legislation includes important changes for ATMPs, including modified definitions and new provisions affecting market exclusivity and access requirements [6]. The legislation introduces 10+2 years of market exclusivity for orphan medicines, potentially benefiting many ATMPs [6].

• SoHO Regulation: The new Substances of Human Origin (SoHO) Regulation (effective 2024, with transition until 2027) establishes a unified framework for human-derived materials, affecting ATMPs using cells or tissues [4]. This regulation extends requirements to donor registration, collection, testing, and distribution activities [6].

• Updated Guidelines: EMA has updated its "Guideline on quality, non-clinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials" (effective 2025), providing clarified requirements for ATMP development [4] [6]. These updates aim to harmonize standards while addressing technology-specific considerations.

• HTA Harmonization: Implementation of Regulation (EU) 2021/2282 on Health Technology Assessment (HTA) aims to streamline joint clinical assessments across member states, particularly relevant for ATMPs facing complex reimbursement decisions [4].

The centralized regulatory framework for ATMPs in the European Union, with the Committee for Advanced Therapies (CAT) playing a pivotal role, represents a tailored approach to overseeing these innovative therapies. Through its multidisciplinary expertise and specialized evaluation processes, the CAT provides the scientific foundation for ATMP regulation, balancing innovation with patient safety. The mandatory centralized authorization pathway ensures consistent standards across member states, while various support mechanisms facilitate development of promising therapies.

The comparative analysis reveals both convergence and divergence between EU and US regulatory approaches, with each system evolving to address emerging scientific advances and regulatory challenges. Ongoing developments in EU pharmaceutical legislation, SoHO regulation, and updated scientific guidelines continue to shape the landscape for ATMP development and authorization. For researchers and developers navigating this complex field, early engagement with regulatory agencies through classification procedures, scientific advice, and support schemes remains crucial for successful development of these transformative medicines.

Within the complex framework of the European Union's medicinal product regulation, National Competent Authorities (NCAs) serve as the foundational regulatory bodies in individual member states [8]. These authorities work in conjunction with the European Medicines Agency (EMA), a decentralized EU agency, to form the European medicines regulatory network (EMRN) [9]. This collaborative model enables EU Member States to pool scientific expertise and coordinate regulatory activities efficiently and effectively [9]. For developers and researchers of Advanced Therapy Medicinal Products (ATMPs)—innovative treatments based on genes, tissues, or cells—understanding the distinct yet complementary roles of NCAs and the EMA is critical for successful product development and market access [1] [10].

The definition of an NCA is a "medicines regulatory authority in a European Union Member State" [8]. While the EMA manages the centralized authorization procedure for certain medicines, including all ATMPs intended for the broader market, the NCAs are primarily responsible for authorizing medicines that do not fall under this centralized procedure [11] [9]. Furthermore, NCAs are typically responsible for the authorization of clinical trials within their territories and play a vital role in the regulatory system by supplying thousands of European experts who serve on the EMA's scientific committees, including the Committee for Advanced Therapies (CAT) [11].

The EU Regulatory Network for ATMPs: A Framework of Collaboration

The regulation of ATMPs involves a tightly integrated system where the EMA and NCAs have distinct, well-defined responsibilities. The overall legal framework is established in Regulation (EC) No 1394/2007, the specific ATMP Regulation [12]. This regulation led to the creation of the Committee for Advanced Therapies (CAT), a multidisciplinary committee within the EMA responsible for the scientific assessment of ATMPs [1] [12]. The centralized marketing authorization procedure, mandatory for ATMPs, results in a single evaluation and authorization that is valid across all EU Member States and the European Economic Area (EEA) [1] [13].

However, the regulatory network provides flexibility for specific situations. ATMPs can be supplied legally in the EU through one of three pathways [14]:

• Centrally authorized via the EMA.
• Administered as part of a clinical trial authorized by an NCA.
• Used under a hospital exemption (HE), where a national authority grants special permission for the use of an unlicensed ATMP under specific conditions in a hospital [13] [14]. The implementation of the HE scheme varies between Member States, as it is further regulated at the national level [13].

The following diagram illustrates the logical relationships and workflows within this network, highlighting the roles of the different bodies in the lifecycle of an ATMP.

Comprehensive Directory of EU National Competent Authorities

For researchers and drug development professionals, direct interaction with the relevant NCA is often necessary. The table below provides the contact details for the primary NCAs in each EU Member State, as supplied by the EMA [11]. This list serves as an essential resource for initiating national procedures, including clinical trial applications and hospital exemption requests.

Table 1: National Competent Authorities (NCAs) in the European Union and EEA

Country	Name of Authority	Contact Details
Austria	Austrian Agency for Health and Food Safety	Spargelfeldstraße 191, 1220 Wien, AustriaTel. +43 5 0555-0www.ages.at
Belgium	Federal Agency for Medicines and Health Products (FAMHP)	Avenue Galilée 5/03, 1210 Brussels, BelgiumTel. +32 2 528 40 00E-mail: welcome@fagg-afmps.bewww.famhp.be
Bulgaria	Bulgarian Drug Agency	8 Damyan Gruev Str., Sofia 1303, BulgariaTel. +359 2 890 35 55www.bda.bg
Croatia	Agency for Medicinal Products and Medical Devices of Croatia	Ksaverska cesta 4, 10000 Zagreb, CroatiaTel. +385 1 4884 100www.halmed.hr
Cyprus	Ministry of Health - Pharmaceutical Services	Pharmaceutical Services, Ministry of Health, 1475 Nicosia, CyprusTel. +357 22608620www.moh.gov.cy/phs
Czechia	State Institute for Drug Control	Šrobárova 48, 100 41 Praha 10, CzechiaTel. +420 272 185 333www.sukl.cz
Denmark	Danish Medicines Agency	Axel Heides Gade 1, 2300 København S, DenmarkTel. +45 7222 7400www.laegemiddelstyrelsen.dk
Estonia	State Agency of Medicines	1 Nooruse Street, 50411 Tartu, EstoniaTel. +372 737 41 40www.ravimiamet.ee
Finland	Finnish Medicines Agency	P.O. Box 55, FI-00034 FIMEA, FinlandTel. +358 29 522 3341www.fimea.fi
France	National Agency for the Safety of Medicine and Health Products	143-147 bd Anatole France, 93285 Saint Denis cedex, FranceTel. +33 1 55 87 30 00www.ansm.sante.fr
Germany	Federal Institute for Drugs and Medical Devices (BfArM)Paul Ehrlich Institute (PEI)	Kurt-Georg-Kiesinger-Allee 3, 53175 Bonn, GermanyTel. +49 (0)228-207-30www.bfarm.dePaul-Ehrlich-Straße 51-59, 63225 Langen, GermanyTel. +49 6103 77 0www.pei.de
Greece	National Organization for Medicines	Messogion Avenue 284, 15562 Athens, GreeceTel. +30 213 2040 200www.eof.gr
Hungary	National Centre for Public Health and Pharmacy	Albert Flórián út 2-6, 1097 Budapest, HungaryTel. +36 1 476 1100www.nnk.gov.hu
Ireland	Health Products Regulatory Authority (HPRA)	Kevin O'Malley House, Earlsfort Centre, Earlsfort Terrace, Dublin 2, IrelandTel. +353 1 676 4971www.hpra.ie
Italy	Italian Medicines Agency	Via del Tritone, 181, 00187 Roma, ItalyTel. +39 06 5978401www.aifa.gov.it
Latvia	State Agency of Medicines	15 Jersikas Street, 1003 Riga, LatviaTel. +371 7078424www.zva.gov.lv
Lithuania	State Medicines Control Agency	Studentų str. 45A, 08107, Vilnius, LithuaniaTel. +370 5 263 9264www.vvkt.lt
Malta	Malta Medicines Authority (MMA)	Sir Temi Żammit Buildings, Malta Life Sciences Park, San Ġwann, SĠN 3000, MaltaTel. +356 23439000www.medicinesauthority.gov.mt
Netherlands	Medicines Evaluation Board (MEB)	Graadt van Roggenweg 500, 3531 AH Utrecht, The NetherlandsTel. +31 (0) 88 224 8000Contact: Submit your question via website
Norway	Norwegian Medical Products Agency	Postboks 240 Skøyen, 0213 Oslo, NorwayTel. +47 22 89 77 00www.dmp.no
Poland	Office for Registration of Medicinal Products, Medical Devices and Biocidal Products	Al. Jerozolimskie 181C, 02-222 Warsaw, PolandTel. +48 (22) 492 11 00www.urpl.gov.pl
Portugal	National Authority of Medicines and Health Products	Parque de Saúde de Lisboa - Avenida do Brasil, 53, 1749-004 Lisboa, PortugalTel. +351 217987100www.infarmed.pt
Romania	National Authority of Medicines and Medical Devices of Romania	Str. Aviator Sanatescu 48, 011478 Bucharest, RomaniaTel. +4021 317 11 00www.anm.ro
Slovakia	State Institute for Drug Control	Kvetná 11, 825 08 Bratislava 26, SlovakiaTel. +421 2 5070 1111www.sukl.sk
Slovenia	Agency for Medicinal Products and Medical Devices of the Republic of Slovenia	Slovenčeva ulica 22, 1000 Ljubljana, SloveniaTel. + 38 6 8 2000 500www.jazmp.si
Spain	Spanish Agency Of Medicines And Medical Devices	Parque Empresarial Las Mercedes Edificio 8C/. Campezo, 1, 28022 Madrid, Spainwww.aemps.gob.es
Sweden	Swedish Medical Products Agency	Dag Hammarskjölds väg 42 / Box 26, 751 03 Uppsala, SwedenTel. +46 18 17 46 00www.lakemedelsverket.se

Comparative Analysis of ATMP Regulatory Pathways and Outcomes

The interaction between the EMA and NCAs shapes the entire lifecycle of an ATMP, from research to patient access. A comparative analysis of the regulatory pathways reveals significant differences in outcomes, particularly between commercially developed ATMPs and those originating from academic hospitals.

Table 2: Comparison of Key EU Regulatory Pathways for ATMPs

Regulatory Aspect	Centralized Marketing Authorization (EMA-led)	Hospital Exemption (NCA-led)	Clinical Trial Authorization (NCA-led)
Governing Body	European Medicines Agency (EMA) and European Commission [1]	National Competent Authority (NCA) [13]	National Competent Authority (NCA) [11]
Geographical Scope	Valid in all EU Member States and EEA countries [13]	Restricted to the hospital and Member State where the product is manufactured [13]	Conducted in specific trial sites within the authorizing Member State(s)
Primary Objective	Widespread commercial availability	Non-routine, custom-made use for an individual patient [13]	Generate data on safety and efficacy for regulatory approval
Key Data Requirements	Comprehensive quality, non-clinical, and clinical data proving benefit-risk balance [10]	Requirements vary by Member State; some require scientific evidence, others do not [13]	Protocol-focused data on manufacturing, pre-clinical justification, and patient safety
Post-Authorization Monitoring	EU-wide pharmacovigilance and risk management [1]	National oversight; traceability and reporting as per national requirements	Safety reporting and protocol compliance monitoring by NCA and Ethics Committees
Outcome for Patient Access	Broad access, but subject to national reimbursement decisions [13]	Limited, local access for specific clinical needs	Access to potentially innovative therapy, but within a research protocol

The application of these pathways has led to a distinct market landscape. As of 2025, the EU has authorized 19 ATMPs via the centralized procedure, with gene therapies (GTMPs) dominating (16 out of 19), while therapies classified as somatic cell therapy (sCTMP) or tissue-engineered products (TEP) are far less common [13]. This disparity highlights the significant regulatory and commercial challenges, particularly for cell- and tissue-based products often developed in hospital settings.

A critical challenge post-authorization is navigating the "economic valley of death," where lengthy national pricing and reimbursement negotiations with individual NCAs can prevent patient access even after EMA approval [13]. For example, a 2023 report indicated that in Spain, only 5 out of 18 authorized ATMPs were reimbursed by the national public health system [13]. A 2025 Belgian report showed only 8 of 19 authorized ATMPs were marketed and reimbursed in the country [13]. This demonstrates that NCA-level reimbursement decisions are a major determinant of ultimate patient access to centrally authorized ATMPs.

Experimental Protocols and Research Tools for ATMP Development

For researchers navigating this regulatory landscape, engagement with the network is a critical component of the development process. Key experimental and procedural protocols involve direct interaction with both the EMA and NCAs.

Key Regulatory Interaction Protocols

• ATMP Classification Procedure: Early in development, developers can request a scientific recommendation on ATMP classification from the CAT [12]. This procedure determines whether a product falls under the ATMP regulation and its specific category (GTMP, sCTMP, TEP). The methodology involves submitting detailed data on the product's composition, manufacturing process (noting if it involves "substantial manipulation"), and intended mechanism of action. This classification is a critical first step that defines the regulatory path.
• Certification for SMEs: Micro-, small-, and medium-sized enterprises (SMEs) can apply for an certification of quality and non-clinical data [1] [12]. This voluntary procedure allows the CAT to evaluate these data modules before a clinical trial or marketing authorization application. A positive certification provides confidence in the quality and non-clinical development strategy, which is valuable for fundraising and further development planning.
• Scientific Advice Protocol: Developers can seek scientific advice from the EMA or national authorities to optimize their development plan [10]. The protocol involves submitting specific questions on quality, non-clinical, and clinical testing. The EMA's PRIME (Priority Medicines) scheme, which has supported multiple ATMPs, uses this tool to provide enhanced, early dialogue for promising therapies addressing high unmet medical need [10].

The Scientist's Toolkit: Essential Regulatory and Research Materials

Engaging successfully with the regulatory network requires a set of "tools" — key documents and materials that form the basis of any regulatory submission.

Table 3: Research Reagent Solutions and Key Materials for ATMP Development

Item or Document	Function in ATMP Development & Regulation
ATMP Classification Report	A formal CAT recommendation that legally defines the product type and applicable regulations, guiding the entire development strategy [12].
Investigator's Brochure (IB)	A comprehensive document compiling all pre-clinical and clinical data on the product, essential for submissions to NCAs for Clinical Trial Authorization [12].
Good Manufacturing Practice (GMP) Data	Documentation proving the product is manufactured under a certified quality management system, a mandatory requirement for all regulatory pathways [12].
Pharmacovigilance System Description	A detailed plan for monitoring patient safety and reporting adverse events, required for both clinical trials and marketing authorization [1] [12].
Hospital Exemption Dossier	The application submitted to an NCA for manufacturing and using a non-routine, custom-made ATMP. Its content requirements, particularly for non-clinical data, vary significantly between Member States [13].

The EU regulatory network for ATMPs is a sophisticated, multi-layered system where the European Medicines Agency (EMA) and National Competent Authorities (NCAs) perform distinct but interdependent functions. The EMA provides centralized authorization and scientific oversight, while NCAs are the cornerstone for clinical trial authorization, national supervision, and the implementation of flexible pathways like the hospital exemption. The current state-of-play reveals a system that has successfully authorized novel therapies, particularly in the gene therapy domain, but also faces significant challenges in ensuring equitable patient access and sustaining non-commercial, hospital-based production. For researchers and developers, a deep understanding of this network's structure, key contact points, and procedural protocols is not merely administrative—it is a fundamental component of successful ATMP development, from bench to bedside.

Advanced Therapy Medicinal Products (ATMPs)—encompassing gene therapies, somatic cell therapies, tissue-engineered products, and combined ATMPs—represent a groundbreaking class of biopharmaceuticals that offer new potential for treating previously untreatable diseases [15] [16]. The European Union established a dedicated regulatory framework through Regulation (EC) No 1394/2007 to harmonize the approval and supervision of these complex therapies across member states while ensuring the highest standards of public health protection [15]. This regulation, active since December 2008, created a centralized marketing authorization procedure for ATMPs managed through the European Medicines Agency (EMA) and its Committee for Advanced Therapies (CAT) [15] [16].

Despite this centralized EU-level framework, national competent authorities play crucial roles in implementing and enforcing these regulations within their jurisdictions, leading to variations in how certain aspects are applied. This guide provides a comparative analysis of how key European countries have transposed and implemented Regulation (EC) No 1394/2007, offering researchers and drug development professionals essential insights for navigating this complex regulatory landscape.

Core Principles of the EU ATMP Regulation

Regulation (EC) No 1394/2007 establishes several fundamental principles governing ATMPs in the European Union. The regulation applies to ATMPs that are intended for market placement and either prepared industrially or manufactured using industrial processes [15]. A critical exemption exists for ATMPs "prepared on a non-routine basis" and used within the same Member State in a hospital under the exclusive professional responsibility of a medical practitioner—the so-called "hospital exemption" [15]. This provision allows customized treatments for individual patients while maintaining appropriate quality and safety standards.

The regulation mandates a centralized marketing authorization procedure whereby all ATMPs undergo scientific evaluation by the EMA's Committee for Advanced Therapies (CAT) and Committee for Medicinal Products for Human Use (CHMP) [16]. This ensures consistent evaluation standards across the EU and facilitates market access for these innovative technologies. The CAT possesses multidisciplinary expertise spanning gene therapy, cell therapy, tissue engineering, medical devices, pharmacovigilance, and ethics [15].

Table 1: Key Components of Regulation (EC) No 1394/2007

Component	Description	Purpose
Centralized Authorization	Mandatory EMA evaluation for market approval	Ensure high-level, consistent scientific assessment across EU
Committee for Advanced Therapies (CAT)	Multidisciplinary expert committee within EMA	Provide specialized evaluation of ATMP quality, safety, and efficacy
Hospital Exemption	Exclusion for non-routine custom-made products	Facilitate personalized patient treatment while maintaining oversight
Combined ATMP Provisions	Specific rules for products incorporating medical devices	Address unique regulatory challenges of combination products
Technical Requirements	Adapted quality, non-clinical, and clinical requirements	Account for specific characteristics of ATMPs through flexible guidelines

Comparative Analysis of National Implementation

Germany: The Paul-Ehrlich-Institut Framework

Germany has implemented Regulation (EC) No 1394/2007 through its Medicines Act (Arzneimittelgesetz, AMG), with the Paul-Ehrlich-Institut (PEI) serving as the national competent authority for ATMPs [17]. The PEI employs a distinctive modular authorization system for non-routinely manufactured ATMPs under Section 4b AMG, which adapts the Common Technical Document (CTD) format into a streamlined, abbreviated application process specifically designed for hospital-based production [17].

The German framework establishes a fee structure ranging from €4,250 to €17,000, scaled according to the procedural scope [17]. Notably, the PEI allows applicants who are not yet holders of manufacturing authorization to initiate the application process, provided they subsequently obtain the necessary permits from competent state authorities [17]. This approach facilitates early engagement with regulatory requirements, particularly beneficial for academic researchers and hospital-based developers.

The German implementation also features flexible pharmacovigilance requirements that account for small patient populations. When only a few patients are treated annually, the PEI may waive the requirement for a comprehensive database for recording adverse reactions, instead accepting detailed descriptions of existing safety monitoring systems [17].

United Kingdom: Post-Brexit Regulatory Alignment and Innovation

Following its departure from the European Union, the United Kingdom has maintained substantial alignment with Regulation (EC) No 1394/2007 through the Medicines and Healthcare products Regulatory Agency (MHRA) and the Human Medicines Regulations 2012 [18]. The MHRA has introduced innovative regulatory approaches to address ATMP manufacturing challenges, particularly through its 2025 regulations on modular and point-of-care manufacturing [19].

The UK framework permits two pathways for unlicensed ATMPs: the hospital exemption pathway for non-routinely prepared products used in hospital settings under a prescription for a specific patient, and the "specials" scheme which applies more broadly to all medicinal products [18]. The MHRA has demonstrated notable regulatory innovation through its creation of two new manufacturing licenses: the "manufacturer's license (MM)" for modular manufacturing and "manufacturer's license (POC)" for point-of-care manufacturing [19]. This framework utilizes a Master File system where a central "control site" maintains responsibility for supervising satellite manufacturing locations, enabling product release at the main manufacturing facility rather than at the bedside [19].

Table 2: Comparison of National ATMP Implementation Frameworks

Country	Competent Authority	National Legislation	Fee Range	Unique Features
Germany	Paul-Ehrlich-Institut (PEI)	Section 4b AMG	€4,250 - €17,000	Modular application system; Flexible pharmacovigilance for small scale
United Kingdom	Medicines and Healthcare products Regulatory Agency (MHRA)	Human Medicines Regulations 2012	Not specified in sources	Modular & point-of-care manufacturing licenses; Master File system
Switzerland	Swissmedic (ATMP Division)	Therapeutic Products Act (TPA)	Not specified in sources	Broader ATMP definition; Conditional approval pathway; Pending harmonization with EU

Switzerland: Ongoing Harmonization Efforts

Though not an EU member state, Switzerland is undertaking significant efforts to align its regulatory framework with Regulation (EC) No 1394/2007 through the ongoing revision of its Therapeutic Products Act (TPA) [20]. Swissmedic, Switzerland's regulatory authority, has established a dedicated ATMP division to oversee these complex products, recognizing their potential for treating severe chronic and currently untreatable diseases [21].

The proposed Swiss framework introduces a broader ATMP definition than the EU's, explicitly including nucleic acids within its scope [20]. Stakeholders have expressed concerns about potential "Swiss finish" - the addition of unique national requirements that could create trade barriers and regulatory complications [20]. The proposed revisions include provisions for conditional marketing authorization to address situations where limited clinical data exists due to small patient populations, allowing post-approval data collection [20].

Switzerland is also considering implementing a hospital exemption pathway, which has received positive feedback from academia and industry as enabling clinical research and providing therapeutic alternatives when no approved drugs are available [20]. Stakeholders have emphasized that clear guidelines and oversight mechanisms must accompany any such exemption to ensure patient safety.

Methodologies for Regulatory Analysis

Comparative Legal Framework Assessment

The analysis of national transposition of Regulation (EC) No 1394/2007 employed a systematic comparative methodology. Researchers conducted a targeted review of official regulatory documents from national competent authorities, including legislation, guidelines, presentations, and reports [16]. The research methodology involved:

• Keyword-based searching using terms including "advanced therapy," "regenerative medicine," "cell therapy," "gene therapy," and "tissue engineering" across regulatory agency websites [16]
• Analysis of regulatory frameworks in each jurisdiction to identify classification criteria for ATMPs and their subcategories [16]
• Examination of implementation procedures including authorization pathways, fee structures, and oversight mechanisms [17] [18]
• Identification of divergent national approaches to hospital exemptions, manufacturing requirements, and pharmacovigilance systems [17] [20]

This methodological approach enabled the identification of both harmonized elements and national peculiarities in how Regulation (EC) No 1394/2007 has been implemented across different European jurisdictions.

Institutional Relationship Mapping

The complex interactions between EU and national regulatory bodies can be visualized through the following institutional relationship diagram:

Essential Research Reagent Solutions for ATMP Development

The development and regulatory approval of ATMPs requires specialized reagents and materials to ensure product quality, safety, and efficacy. The following table outlines key research reagent solutions essential for navigating the ATMP regulatory landscape:

Table 3: Essential Research Reagent Solutions for ATMP Development

Reagent Category	Specific Examples	Research Function	Regulatory Importance
Cell Separation Media	Ficoll density gradients, magnetic bead separation kits	Isolation of specific cell populations from source material	Demonstrates manufacturing consistency and product characterization required by regulators
Cell Culture Supplements	Serum-free media, growth factors, cytokines	Maintenance and expansion of cell populations	Provides evidence of controlled manufacturing process essential for quality assessment
Gene Delivery Vectors	Lentiviral, retroviral, AAV vectors	Introduction of genetic material into target cells	Critical component requiring comprehensive safety testing and characterization for regulatory approval
Characterization Antibodies	Flow cytometry antibodies, immunocytochemistry reagents	Phenotypic characterization of cell products	Supports product identity and purity assessments required in regulatory dossiers
Potency Assay Components	ELISA kits, qPCR reagents, functional assay materials	Measurement of biological activity	Provides quantitative evidence of product efficacy for benefit-risk assessment
Mycoplasma Detection Kits	PCR-based detection systems	Screening for microbial contamination	Ensures product safety and compliance with good manufacturing practices

Regulatory Pathway Workflows

The journey from ATMP development to market authorization follows distinct pathways across European jurisdictions. The following workflow diagram illustrates key decision points and regulatory milestones:

The implementation of Regulation (EC) No 1394/2007 across European countries demonstrates a shared commitment to fostering ATMP development while ensuring patient safety. Despite this common foundation, significant national variations exist in implementation approaches, fee structures, procedural requirements, and flexibility for hospital-based production.

Germany has established a streamlined modular system for non-routine ATMPs with proportional oversight [17]. The United Kingdom is pioneering innovative manufacturing frameworks for modular and point-of-care production [19]. Switzerland is actively working to harmonize its national framework with EU standards while addressing stakeholder concerns about over-regulation [20].

For researchers and drug development professionals, understanding these nuanced differences in national implementation is essential for strategic planning and successful regulatory navigation. As the ATMP field continues to evolve rapidly, regulatory frameworks must maintain flexibility to accommodate scientific advances while preserving their fundamental commitment to product quality, patient safety, and therapeutic efficacy.

Advanced Therapy Medicinal Products (ATMPs) represent a groundbreaking category of medications that utilize biological-based products to treat, diagnose, or prevent diseases by repairing, regenerating, or replacing damaged tissues and organs [22]. These innovative therapies offer potential solutions for complex and previously untreatable conditions, particularly in areas of high unmet medical need such as rare diseases, oncology, and regenerative medicine [4]. The European Medicines Agency (EMA) classifies ATMPs into three main categories, each with distinct mechanisms of action and therapeutic applications. Gene therapy medicines contain genes that lead to a therapeutic, prophylactic, or diagnostic effect; somatic-cell therapy medicines contain cells or tissues that have been manipulated to change their biological characteristics; and tissue-engineered medicines contain cells or tissues that have been modified to repair, regenerate, or replace human tissue [1]. Some ATMPs may also incorporate medical devices as integral components, classified as combined ATMPs [1].

The regulation of these complex biological products requires specialized frameworks to ensure their quality, safety, and efficacy while balancing innovation with patient safety. In the European Union, the Committee for Advanced Therapies (CAT) plays a central role in the scientific assessment of ATMPs, providing the expertise needed to evaluate these sophisticated therapies and offering recommendations on their classification [1]. Understanding the key classifications, regulatory pathways, and technical requirements for ATMPs is essential for researchers, scientists, and drug development professionals working to advance these transformative treatments from laboratory research to clinical application.

Comprehensive Comparison of ATMP Classifications

Detailed Classification Definitions and Characteristics

Table 1: Comparative Analysis of ATMP Categories in the EU Regulatory Framework

Classification	Definition	Key Examples	Technical Features	Primary Applications
Gene Therapy Medicinal Products (GTMPs)	Contains genes that lead to therapeutic, prophylactic, or diagnostic effect through recombinant genes	Libmeldy, Casgevy [4]	Incorporates human genome editing; uses viral or bacterial vectors for gene delivery [23]	Genetic disorders, cancer, long-term diseases [1]
Somatic Cell Therapy Medicinal Products (sCTMPs)	Contains cells or tissues manipulated to change biological characteristics or not intended for same essential functions	CAR-T cell therapies (e.g., Kymriah) [4]	Cells substantially manipulated; expanded under GMP conditions; allogeneic or autologous sourcing [23] [22]	Oncology, regenerative medicine, immunological disorders
Tissue-Engineered Products (TEPs)	Contains cells or tissues modified to repair, regenerate, or replace human tissue	Products with cells embedded in biodegradable matrices [1]	Combination with scaffolds or matrices; in vitro tissue construction [1]	Repair of damaged organs, cartilage repair, wound healing
Combined ATMPs	Incorporates one or more medical devices as integral part of the medicine	Cells embedded in biodegradable matrix or scaffold [1]	Device component requires separate certification; complex regulatory pathway [24]	Complex tissue regeneration, organ replacement

Regulatory Classification Frameworks: EU vs. US Terminology

The terminology and classification systems for advanced therapies differ significantly between major regulatory regions, creating important considerations for global development strategies. In the European Union, ATMPs are precisely categorized into the four subtypes detailed in Table 1, with the Committee for Advanced Therapies (CAT) providing recommendations on classification through a formal process that typically yields a response within 60 days [6] [1]. The EU maintains strict delineations between these categories, with specific provisions that products combining cell and gene therapy elements, such as CAR-T cells, are always classified as gene therapies [6].

In contrast, the United States regulatory framework does not formally use the term ATMP. Instead, the FDA's Center for Biologics Evaluation and Research (CBER) typically classifies these products under broader categories such as cell and gene therapies, or human cells, tissues, and cellular and tissue-based products (HCT/Ps) [4]. The FDA's Office of Therapeutic Products (OTP) within CBER regulates all cell and gene therapies, including many therapies where the classification line is blurred, such as genetically modified cells [6]. For developers uncertain about product classification, the FDA offers INTERACT meetings for very early-stage interactions and pre-IND meetings to resolve classification questions, while sponsors can also submit a formal Request for Designation to the Office of Combination Products [6].

Regulatory Pathways and Oversight Frameworks

Comparative Regulatory Pathways: EU vs. US Approaches

Table 2: Regulatory Pathway Comparison for ATMPs/CGTs in EU and US

Regulatory Aspect	European Union (EMA)	United States (FDA)
Governing Regulations	Regulation (EC) No 1394/2007; Directive 2009/120/EC; SoHO Regulation (2024) [4] [25]	Public Health Service Act; Federal Food, Drug, and Cosmetic Act; 21 CFR [4]
Classification Body	Committee for Advanced Therapies (CAT) [1]	Office of Therapeutic Products (OTP), CBER [6]
Clinical Trial Authorization	Clinical Trial Application (CTA) to national authorities [4]	Investigational New Drug (IND) submission [4]
Market Authorization	Marketing Authorization Application (MAA) through centralized procedure [4]	Biologics License Application (BLA) [4]
Expedited Pathways	PRIME scheme; accelerated assessment [4]	RMAT; Fast Track; Breakthrough Therapy [4] [26]
GMP Approach	Mandatory GMP compliance for clinical trials [24]	Phase-appropriate GMP with attestation; verified at BLA [24]
Donor Eligibility	Varies by member state; general guidance [24]	Prescriptive requirements; restrictions on pooling [24]

Emerging Regulatory Initiatives and Global Convergence

Recent regulatory developments reflect efforts to address the unique challenges of ATMP development while fostering global convergence. The EMA's new guideline on quality, non-clinical, and clinical requirements for investigational ATMPs in clinical trials, effective July 2025, represents a comprehensive multidisciplinary reference document that consolidates information from over 40 separate guidelines and reflection papers [24]. This extensive guideline provides recommendations for ATMPs under study in both early-phase exploratory and late-stage confirmatory clinical trials, with a particular emphasis on Chemistry, Manufacturing, and Controls (CMC) documentation that mirrors Common Technical Document (CTD) section headings for Module 3 [24].

Simultaneously, the FDA has demonstrated a proactive approach through the September 2025 release of three draft guidance documents focusing on expedited programs, postapproval monitoring, and innovative trial designs for small populations [26]. Perhaps most significantly, the FDA has launched the Gene Therapies Global Pilot Program (CoGenT), an initiative designed to explore concurrent, collaborative regulatory reviews of gene therapy applications with international partners like the EMA, modeled after the successful Project Orbis for oncology products [26]. This program aims to increase regulatory harmonization, improve review efficiency, and ultimately accelerate global patient access to gene therapies.

Regulatory agencies are also embracing technological advancements to manage the complexity of ATMP oversight. The FDA's January 2025 draft guidance on 'Considerations for the Use of Artificial Intelligence To Support Regulatory Decision-Making for Drug and Biological Products' outlines a risk-based credibility assessment framework to ensure AI models used in drug development are trustworthy and fit for purpose [26]. Companies are increasingly deploying augmented intelligence systems that use machine learning to process regulatory databases, with some systems capable of scanning up to 9,000 regulations per day with over 85% accuracy [26].

Figure 1: Comparative Regulatory Pathways for ATMPs in EU and US Frameworks

Experimental Protocols and Methodologies

Standardized Methodologies for ATMP Development and Testing

The development and manufacturing of ATMPs require specialized experimental protocols and methodologies to address their unique biological complexity and ensure product quality, safety, and efficacy. A critical challenge in ATMP translation involves successfully transitioning from non-clinical Good Laboratory Practice (GLP) studies to Good Manufacturing Practice (GMP)-compliant manufacturing processes that reliably meet quality specifications defined during product development [22]. This transition requires extensive testing and documentation to validate that the manufacturing process consistently achieves the product's critical quality attributes (CQAs), which are initially identified through GLP studies and further refined during chemistry, manufacturing, and control (CMC) development [22].

Safety testing represents another crucial methodological domain, with tumorigenicity risk assessment being particularly important for cell-based ATMPs. For pluripotent stem cell (PSC)-derived products, the in vivo teratoma formation assay remains a standard method to validate pluripotency of PSCs as starting materials and detect residual undifferentiated PSCs in the final drug products [22]. For somatic cell-based therapies, tumorigenicity is typically assessed using in vivo studies in immunocompromised models (e.g., NOG/NSG mice) rather than teratoma tests [22]. Regarding in vitro safety testing, conventional soft agar colony formation assays have limited sensitivity for detecting rare transformed cells in therapeutic products, leading to recommendations for more sensitive methods such as digital soft agar assays or cell proliferation characterization tests [22].

Figure 2: ATMP Development Workflow: Key Methodological Stages

The Scientist's Toolkit: Essential Research Reagents and Materials

Table 3: Essential Research Reagents and Materials for ATMP Development

Reagent/Material Category	Specific Examples	Function in ATMP Development	Quality Standards
Cell Culture Media & Supplements	Serum-free media, cytokines, growth factors	Supports cell expansion and maintenance while preserving phenotype	GMP-grade for manufacturing; research grade for early development [6]
Genetic Modification Tools	Viral vectors (lentiviral, retroviral), CRISPR-Cas9 components, mRNA	Enables genetic manipulation for gene therapies and genetically-modified cell therapies	GMP-grade for clinical use; defined as starting materials in EU [23] [6]
Cell Separation & Selection Reagents	Antibodies, magnetic beads, fluorescence-activated cell sorting (FACS) reagents	Isulates specific cell populations; removes unwanted cells	GMP-compliant with certificate of analysis [22]
Scaffolds & Matrices	Biodegradable polymers, hydrogels, decellularized tissues	Provides structural support for tissue-engineered products; critical for combined ATMPs	Biocompatibility testing; mechanical property characterization [1]
Analytical Assay Components	ELISA kits, flow cytometry antibodies, PCR reagents	Characterizes product quality, potency, identity, purity	Qualified/validated for intended use; orthogonal methods recommended [6]
Cryopreservation Solutions	DMSO, cryoprotectants, controlled-rate freezing containers	Maintains cell viability and function during storage and transport	Defined formulation; endotoxin testing [22]

Manufacturing Challenges and Innovative Solutions

Addressing Key Manufacturing Hurdles in ATMP Production

The manufacturing of ATMPs presents unique challenges that differentiate them from conventional pharmaceuticals and established biologics. These challenges stem from the biological nature of the products, their complexity, and the need for specialized processes. Manufacturing has been reported as one of the most significant challenges for ATMPs based on European surveys, with particular difficulties in maintaining aseptic conditions throughout production [22]. Traditional sterilization methods such as filtration, heat, or radiation are not feasible for cell-based products as they would compromise cellular viability, necessitating strict aseptic processing validated through simulation tests (media fills) [22].

Scalability and process comparability represent additional major hurdles in ATMP manufacturing. Scaling up the manufacturing of ATMPs is a multifaceted challenge involving technical, regulatory, and financial aspects, with the most critical concern being the demonstration of product comparability after manufacturing process changes [22]. Regulatory authorities in the US, EU, and Japan have issued tailored guidance to address these challenges, emphasizing risk-based comparability assessments, extended analytical characterization, and staged testing to ensure changes do not impact safety or efficacy [22]. However, harmonization remains limited, with regional differences in stability testing requirements and other technical standards creating complications for global development programs.

To address these manufacturing challenges, several innovative approaches are being implemented. Closed and automated systems are increasingly employed to reduce contamination risk and improve process consistency [22]. Modular, flexible facility and equipment designs that can be easily adapted to meet GMP requirements are being implemented to address the infrastructure challenges [22]. Comprehensive process validation protocols and quality management systems are being developed to ensure product consistency and reliability throughout the manufacturing lifecycle [22].

Emerging Technologies and Manufacturing Innovations

The field of ATMP manufacturing is rapidly evolving with the integration of novel technologies aimed at addressing persistent challenges in production consistency, scalability, and monitoring. Artificial intelligence (AI) and machine learning technologies are being deployed to address monitoring concerns, automation, and data management throughout the manufacturing process [22]. The FDA's January 2025 draft guidance on 'Considerations for the Use of Artificial Intelligence To Support Regulatory Decision-Making for Drug and Biological Products' establishes a framework for the responsible implementation of these technologies, outlining a risk-based credibility assessment approach to ensure AI models used in drug development are trustworthy and fit for purpose [26].

Organoid technology represents another promising innovation, holding significant potential in overcoming challenges associated with preclinical modeling of ATMPs by providing more accurate models for diseases, drug screening, and personalized medicine [22]. These advanced cell culture systems offer more physiologically relevant models for assessing product efficacy and safety during development. Similarly, advancements in biobanking technologies are helping researchers overcome storage and stability concerns through improved cryopreservation methods and storage monitoring systems [22].

The regulatory landscape for these innovative manufacturing approaches is also evolving, with agencies demonstrating openness to alternative methods where feasible and justifiable [6]. The FDA generally encourages the use of orthogonal assays (methods using different scientific principles to measure the same attribute) to build confidence in critical quality attributes, particularly for identity, potency, and purity assessments in gene therapy programs [6]. This approach is consistent with both Phase 1 IND and later-phase submissions, with regulators often asking how orthogonal methods were leveraged in assay qualification and validation.

The landscape of Advanced Therapy Medicinal Products continues to evolve rapidly, with distinct regulatory frameworks governing gene therapies, somatic cell therapies, and tissue-engineered products in the European Union. The precise classification system employed by the EMA, overseen by the Committee for Advanced Therapies, provides a structured pathway for developers while ensuring appropriate oversight of these complex biological products. As reflected throughout this comparison guide, understanding the specific requirements, manufacturing challenges, and regulatory expectations for each ATMP category is essential for successful product development.

The ongoing efforts toward global regulatory convergence, exemplified by initiatives like the CoGenT pilot program, signal a promising trend toward harmonized standards that may accelerate the development and availability of these transformative therapies. However, significant differences remain in classification approaches, technical requirements, and regulatory processes between major regions like the EU and US. For researchers, scientists, and drug development professionals working in this innovative field, navigating this complex landscape requires careful planning, early regulatory engagement, and robust scientific approaches to address the unique challenges presented by each ATMP category.

Navigating National Pathways: A Step-by-Step Guide to NCA Applications

Advanced Therapy Medicinal Products (ATMPs) represent a groundbreaking category of biological medicines for human use based on genes, cells, or tissue engineering [27]. The European regulatory framework categorizes ATMPs into four distinct classes: gene therapy medicinal products (GTMPs), which contain recombinant genes for therapeutic, prophylactic, or diagnostic effects; somatic-cell therapy medicines (sCTMPs), which contain manipulated cells or tissues; tissue-engineered medicines (TEPs), containing cells or tissues modified to repair, regenerate, or replace human tissue; and combined ATMPs, which incorporate one or more medical devices as an integral part of the medicine [1] [28]. This classification is not merely administrative but determines the entire developmental pathway, regulatory requirements, and evidence standards that researchers must follow.

The European Medicines Agency (EMA) oversees a centralized authorization procedure for all ATMPs, ensuring a single evaluation and authorization valid across the European Union and European Economic Area [1] [28]. At the heart of this system lies the Committee for Advanced Therapies (CAT), the specialized EMA committee responsible for assessing ATMP quality, safety, and efficacy, providing classification recommendations, and following scientific progress in this rapidly evolving field [1] [27]. For developers, determining whether a product qualifies as an ATMP—and which specific category it falls into—is a critical first step that shapes all subsequent development strategies. The ATMP Classification Procedure, established under Article 17 of Regulation (EC) No 1394/2007, provides a formal mechanism for obtaining regulatory clarity on this fundamental question early in the development process [29] [27].

The ATMP Classification Procedure: A Step-by-Step Analysis

Procedural Framework and Timeline

The ATMP classification procedure is a voluntary, free-of-charge service provided by the EMA through its Committee for Advanced Therapies [27]. This optional procedure allows developers to obtain a formal scientific recommendation on whether their product meets the criteria for classification as an ATMP within a structured 60-day timeline [29] [27]. The process begins when developers submit a formal request to the EMA, after which the CAT consults with the European Commission and delivers its scientific recommendation within the mandated two-month timeframe [27].

The EMA has established a detailed calendar of submission deadlines and corresponding CAT discussion dates for the classification procedure throughout 2025 and 2026 [29]. For example, a submission filed by January 9, 2025, would begin procedural review on January 24, 2025, with CAT discussion on February 21, 2025, and final adoption on March 21, 2025 [29]. This predictable scheduling system allows developers to plan their regulatory activities with precision and integrate them seamlessly with their scientific development timelines.

Table: ATMP Classification Procedure Timeline for Selected 2025 Submission Dates

Submission Deadline	Procedure Start	CAT Discussion	Final Adoption
9 January 2025	24 January 2025	21 February 2025	21 March 2025
6 March 2025	21 March 2025	16 April 2025	16 May 2025
30 April 2025	19 May 2025	13 June 2025	18 July 2025
30 July 2025	14 August 2025	12 September 2025	10 October 2025

Application Methodology and Requirements

To initiate the classification procedure, developers must complete and submit two key forms: one providing administrative information and another containing the classification request and briefing information [27]. These documents must be submitted via email to the EMA on specific submission dates published on the agency's dedicated webpage [27]. The application requires detailed information about the product's composition, manufacturing process, intended use, and scientific rationale supporting the proposed classification.

The CAT evaluates each submission against established regulatory criteria, particularly focusing on whether human cells or tissues have undergone "substantial manipulation" or are intended for use different from their "essential function" in the body [1] [13]. The committee draws upon several key guidance documents during its assessment, including the "Reflection paper on classification of advanced therapy medicinal products" (EMA/CAT/600280/2010 rev.1) and "Procedural advice on the provision of scientific recommendation on classification of ATMPs" (EMA/CAT/99623/2009 Rev.2) [27]. Upon conclusion of the procedure, the EMA publishes a summary report of the classification outcome, with appropriate redactions to protect commercially confidential information [29] [27].

ATMP Classification Procedure Workflow

Comparative Analysis of Regulatory Pathways

Centralized vs. National Procedures

The European regulatory system for ATMPs establishes a clear distinction between centrally authorized products intended for broad commercial distribution and non-routine preparations falling under national oversight frameworks. While the EMA's centralized authorization procedure is mandatory for all ATMPs seeking market approval across the EU, the regulation also provides for a Hospital Exemption (HE) clause that allows member states to permit the use of non-routine ATMPs manufactured and used within a single hospital setting under national oversight [13]. This dual-track system creates important strategic considerations for developers regarding the appropriate regulatory pathway for their specific product and development objectives.

The Hospital Exemption pathway is designed to accommodate custom-made ATMPs prepared on a non-routine basis according to specific quality standards for individual patients within the same member state [13]. However, implementation of this clause varies significantly across member states, with substantial differences in evidentiary requirements, regulatory standards, and procedural frameworks [13]. Some countries require comprehensive scientific and clinical evidence for HE approvals, while others have less demanding requirements, creating a fragmented regulatory landscape for hospital-exempted ATMPs across the EU [13].

Outcomes and Strategic Implications

Since the implementation of the ATMP Regulation in 2008, the classification and authorization process has yielded 19 authorized ATMPs in the EU as of 2025, with a pronounced distribution across product categories [13]. Gene therapy medicines dominate the authorized product landscape, comprising 16 of the 19 authorizations (84.2%), while tissue-engineered products and somatic cell therapy medicines represent only 3 authorized products combined (15.8%) [13]. This disparity reflects both the scientific maturity and commercial investment patterns across different ATMP categories.

Table: Authorized ATMPs in the EU by Product Category (2008-2025)

ATMP Category	Number Authorized	Percentage	Examples
Gene Therapy Medicines (GTMP)	16	84.2%	Treatments for immunodeficiencies, spinal muscular atrophy
Somatic Cell Therapy Medicines (sCTMP)	1	5.3%	Ebvallo (allogeneic T-cell immunotherapy)
Tissue-Engineered Products (TEP)	2	10.5%	Holoclar (limbal stem cells), Spherox (cartilage repair)
Total	19	100%

A critical challenge in the ATMP ecosystem involves the transition from marketing authorization to patient accessibility. Even after successful centralized approval, ATMPs must navigate complex pricing and reimbursement negotiations with individual member states, creating what has been termed an "economic valley of death" that can impede patient access [13]. The high costs associated with many ATMPs, particularly gene therapies, have strained public health insurance systems and led to situations where only a subset of authorized ATMPs receive reimbursement in specific countries [13]. For instance, in 2023, Spain reimbursed only 5 of the 18 then-approved ATMPs (28%) through its national public health system, while Belgium currently reimburses just 8 of the 19 authorized ATMPs [13].

Essential Regulatory Toolkit for ATMP Developers

Successful navigation of the ATMP classification and development process requires leveraging specialized regulatory tools and resources designed to support product developers. The ATMP pilot program for academia and non-profit organizations, launched by the EMA in September 2022, provides dedicated regulatory support for developers targeting unmet medical needs, including guidance throughout the regulatory process and potential fee reductions or waivers [1]. This initiative aims to assess the level of regulatory support needed to increase the number of ATMPs reaching patients in the EU.

Additional valuable resources include the EMA's online training modules, available through the TransMed Academy, which cover essential topics such as ATMP classification applications, environmental risk assessments, scientific advice procedures, ATMP certification, and quality considerations in clinical development [1]. The EMA also maintains a comprehensive database of published classification recommendations that offers valuable insights into regulatory precedents and decision patterns, helping developers understand how similar products have been classified [27].

Table: Essential Research and Regulatory Tools for ATMP Development

Tool/Resource	Function	Access Point
CAT Scientific Recommendation on Classification	Determines regulatory status as ATMP and specific category	EMA formal procedure
ATMP Pilot for Academia/Non-profits	Enhanced regulatory support with fee reductions	EMA targeted program
Training Modules	Education on regulatory requirements and procedures	TransMed Academy
Published Classification Summaries	Precedent research for similar products	EMA website
Reflection Paper on Classification	Guidance on interpretation of legal criteria	EMA/CAT/600280/2010 rev.1

Stakeholder Interactions and Relationships

The ATMP classification process involves multiple stakeholders with distinct roles and responsibilities. The Committee for Advanced Therapies serves as the primary scientific evaluator, providing recommendations that are generally followed by National Competent Authorities, though these recommendations remain non-binding if product characteristics change during development [27]. National Competent Authorities implement the classification outcomes at the member state level, particularly regarding the Hospital Exemption pathway [13] [27].

ATMP Regulatory Stakeholder Relationships

Future Evolution of ATMP Classification

The regulatory framework for ATMP classification continues to evolve in response to scientific advancements and practical implementation experience. The European Commission has proposed a full reform of EU pharmaceutical legislation that would potentially transform the CAT from a permanent scientific committee to a working party and replace the dedicated ATMP classification procedure with a broader scientific recommendation on regulatory status covering all medicine types [27]. However, this reform remains in the proposal stage and would undergo a multi-year legislative process before potential implementation [27].

The strategic importance of the classification procedure is evidenced by its frequent use within the developer community. As of October 2024, the CAT had adopted 675 recommendations out of 682 submitted requests, making it the most frequently used procedure among the committee's activities [27]. This high utilization rate reflects both the complexity of ATMP classification and the value that developers place on obtaining regulatory clarity early in the development process. As the field of advanced therapies continues to advance rapidly, with emerging areas such as artificial intelligence integration in therapy development and increasingly sophisticated combination products, the classification framework will likely continue to adapt to accommodate these scientific innovations while maintaining its fundamental purpose of ensuring product quality, safety, and efficacy [30].

The clinical trial application (CTA) process for Advanced Therapy Medicinal Products (ATMPs) represents a specialized and evolving landscape within the European Union (EU). ATMPs—encompassing gene therapies, somatic-cell therapies, tissue-engineered products, and combined therapies—are subject to a complex regulatory framework designed to manage their unique scientific and manufacturing complexities [31]. The recent full implementation of the Clinical Trials Regulation (CTR) 536/2014 has fundamentally transformed this process, moving from a directive that was implemented differently across member states to a regulation that applies directly and consistently across the EU [32] [33]. This guide examines the current CTA process for ATMPs within the context of this new regulatory environment, providing drug development professionals with a clear comparison of procedures, timelines, and strategic considerations for securing national approvals.

The regulation of ATMPs involves multiple overlapping frameworks. While the Advanced Therapy Medicinal Products Regulation (EC) 1394/2007 provides the core legal foundation [31], the recently applicable Clinical Trials Regulation establishes the procedural pathway for all clinical trials [32]. Furthermore, the upcoming Substances of Human Origin (SoHO) Regulation, applicable from 2027, will update standards for quality and safety of human tissues and cells used as starting materials for ATMPs [31]. Understanding the interplay between these regulations is crucial for successful CTA submission and approval.

The Centralized CTIS Platform: A Single Entry Point

Transition from Directive to Regulation

The Clinical Trials Regulation (CTR) has replaced the previous Clinical Trials Directive (CTD), creating a harmonized application process across all EU Member States [33]. The transition period concluded on January 30, 2025, meaning all clinical trials in the EU, including ongoing trials previously approved under the CTD, are now governed by the CTR [32]. This shift marks a significant step toward creating a more favorable environment for conducting clinical trials in the EU while maintaining the highest safety standards for participants [33].

Key changes introduced by the CTR include:

• Streamlined Application Procedure: A single entry point for application submission via the Clinical Trials Information System (CTIS) [32] [33]
• Harmonized Assessment: Consistent rules for authorizing and conducting clinical trials throughout the EU [33]
• Increased Transparency: Public availability of information on trial authorization, conduct, and results [33]
• Silent Agreement Principle: Extension to the entire authorization process, providing greater legal certainty for sponsors [33]

Clinical Trials Information System (CTIS) Workflow

The CTIS serves as the single-entry point for sponsors and regulators for the submission and assessment of clinical trial applications in the EU [32]. Run by the European Medicines Agency (EMA), this system stores and processes applications without parallel processes, eliminating the previous requirement for separate submissions to each national competent authority and ethics committee [33].

The following diagram illustrates the streamlined CTA submission and assessment workflow under the CTR via CTIS:

For each clinical trial submitted through CTIS, one Reporting Member State (RMS) is designated to lead the assessment of common elements (Part I), while each concerned Member State assesses elements specific to their territory (Part II) [33]. This coordinated approach maintains strict timelines for assessment and response, with opportunities for sponsors to address objections through a structured process [33].

Comparative Analysis of Regulatory Requirements

Key Regulatory Tools and Their Impact on Timelines

The development and approval of ATMPs can be significantly accelerated through strategic use of available regulatory tools. Recent research examining 27 EMA-approved ATMPs reveals that participation in expedited programs substantially reduces time to marketing authorization [34].

Table 1: Impact of Regulatory Tools on ATMP Approval Timelines

Regulatory Tool	Designation Rate Among Approved ATMPs	Median Time Reduction	Key Features
PRIME Scheme	52%	42.7% faster approval (376 vs. 669 days) [34]	Enhanced scientific advice, early rapporteur appointment, eligibility for accelerated assessment [34]
Orphan Designation	74%	32.8% reduction in approval time [34]	Market exclusivity, protocol assistance, fee reductions [34]
Conditional Approval	41%	405 days median approval time [34]	Approval based on less comprehensive data when benefit-risk balance is positive [34]

PRIME-designated products demonstrated more efficient regulatory processes with fewer and shorter clock stops and more frequent scientific advice interactions [34]. This underscores the value of early and frequent engagement with regulatory authorities throughout ATMP development.

Country-Specific Considerations and Additional Authorizations

Despite the harmonized framework under CTR, sponsors must still account for certain national requirements and potential additional authorizations:

• United Kingdom: Following Brexit, the UK maintains a separate national application process through the Medicines and Healthcare products Regulatory Agency (MHRA) and relevant Ethics Committee [35]
• Genetically Modified Organisms (GMOs): Trials involving GMOs require additional approvals beyond the standard CTA, including environmental risk assessments and biosafety regulations that vary across Member States [35]
• Combined Studies: ATMPs incorporating medical devices or in vitro diagnostics must navigate distinct regulatory pathways under both CTR and relevant device regulations (MDR/IVDR) [35]
• National Language Requirements: Member States may have specific requirements regarding the language of submission documents and patient-facing materials [35]

Essential Documentation and Regulatory Strategy

Core CTA Dossier Components

A well-prepared CTA dossier is fundamental to successful application. Under CTR, sponsors must submit comprehensive documentation through CTIS, with particular attention to ATMP-specific requirements:

• Investigator's Brochure (IB): Comprehensive document containing all known preclinical and clinical data on the ATMP
• Investigational Medicinal Product Dossier (IMPD): Detailed quality, manufacturing, and control data specific to ATMPs [35]
• Clinical Trial Protocol: Scientific and ethical rationale, methodology, and statistical considerations
• Informed Consent Forms: Participant information documents meeting national requirements
• GMP and Manufacturing Documentation: Comprehensive data on quality control, validation, and production processes [24]

The EMA's Guideline on quality, non-clinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials, effective July 1, 2025, provides specific guidance on documentation expectations for ATMPs [24]. This multidisciplinary document consolidates information from over 40 separate guidelines and reflection papers, serving as a primary reference for ATMP CTA preparation [24].

Table 2: Key Regulatory Resources for ATMP Development

Resource Category	Specific Examples	Function & Purpose
Core Regulatory Guidelines	EMA Guideline on Clinical-Stage ATMPs (effective July 2025) [24]	Primary-source multidisciplinary reference for quality, non-clinical, and clinical data expectations in CTAs
Expedited Pathways	PRIME Scheme, Orphan Designation, Conditional Marketing Authorization [34]	Accelerate development and review of promising therapies addressing unmet medical needs
Scientific Advice Mechanisms	EMA Scientific Advice, National Competent Authority Consultations [35]	Early regulatory guidance on development plans to prevent delays and optimize trial designs
International Standards	ICH Guidelines, Good Manufacturing Practice (GMP) Standards [24] [31]	Harmonized technical requirements for pharmaceutical development and manufacturing quality
Transparency Platforms	CTIS Public Database, Clinical Trial Registries [32] [33]	Access to information on authorized trials, supporting study design and site selection

Strategic Approaches for Successful ATMP CTA Submissions

Managing the Assessment Process and Responding to Queries

Once a CTA is submitted through CTIS, sponsors must be prepared to manage Requests for Information (RFIs) from regulatory authorities. Under CTR, missing response deadlines can result in application rejection, requiring a new submission process [35]. Effective RFI management includes:

• Establishing Clear Response Procedures: Designate specialized team members with authority to respond quickly to queries
• Anticipating Common Concerns: Based on therapeutic area trends and previous trial experience [35]
• Maintaining Cross-Functional Collaboration: Ensure coordination between sponsors, regulatory teams, and contract research organizations (CROs) [35]

Lifecycle Management and Post-Approval Compliance

After trial authorization, sponsors must maintain ongoing regulatory compliance through:

• Substantial Modifications: Submitting amendments to trial protocols, patient information, or investigational product specifications for regulatory review [35]
• Annual Safety Reporting: Continuous pharmacovigilance and reporting of adverse events [35]
• End-of-Trial Notifications: Submitting final reports detailing patient outcomes and trial findings [35]

The ACT EU initiative, a collaboration between EMA, the European Commission, and member state agencies, seeks to further transform how clinical trials are initiated, designed, and run, with focus areas forming the basis for the 2025-2026 workplan [32].

The CTA process for ATMPs in the EU has undergone significant transformation with the full implementation of the Clinical Trials Regulation. The centralized CTIS platform provides a harmonized application process, while maintaining specific national considerations for ethics and local implementation. For ATMP developers, understanding this framework and strategically employing available regulatory tools—including PRIME designation, orphan status, and early scientific advice—can significantly accelerate approval timelines and enhance the efficiency of clinical development.

As the regulatory landscape continues to evolve through initiatives like ACT EU and the upcoming implementation of the SoHO Regulation, sponsors who maintain current regulatory intelligence and engage early with competent authorities will be best positioned to successfully navigate the CTA process and advance innovative ATMPs to patients in need.

The Hospital Exemption (HE) is a specific regulatory pathway established under the European Union's Advanced Therapy Medicinal Product (ATMP) Regulation (Article 28 of Regulation (EC) No 1394/2007) [36] [25]. It creates an exception from the standard, centralized marketing authorization procedure mandatory for most ATMPs within the EU [36] [37]. The HE is designed for ATMPs that are "prepared on a non-routine basis according to specific quality standards, and used within the same Member State in a hospital under the exclusive professional responsibility of a medical practitioner, in order to comply with an individual medical prescription for a custom-made product for an individual patient" [36]. This pathway is particularly relevant for academic researchers, hospitals, and small developers who are preparing patient-specific therapies for unmet medical needs, often before the start of formal clinical trials or when industrial-scale development is not feasible [36] [25].

While the HE is defined at the EU level, its implementation and oversight are delegated to National Competent Authorities in each Member State [36] [37]. This decentralization has resulted in a highly heterogeneous regulatory landscape across the EU, with significant differences in how the core concepts of the HE are interpreted and applied [36] [25] [37]. For researchers and developers, understanding these national variations is crucial for effectively leveraging the HE pathway. The European Commission has recognized the challenges posed by this fragmentation and has proposed reforms to the general pharmaceutical legislation, which include new provisions aimed at harmonizing the HE pathway while maintaining its essential character [36] [37].

Comparative Analysis of National HE Implementation

The following tables summarize the key areas of variation in how different EU Member States have implemented the Hospital Exemption pathway, based on available literature and official reports.

Table 1: Interpretation of Core HE Criteria Across Member States

HE Criterion	EU-Level Definition	Examples of National Interpretation
"Non-routine basis"	Not expressly defined in binding EU law; generally means not "prepared industrially or manufactured by a method involving an industrial process" [36].	Some Member States set an upper patient number limit; others require treatment one patient at a time (e.g., France); some base it on scale or frequency of preparation [36].
"Custom-made product"	Not expressly defined in binding EU law [36].	Varies from a literal interpretation of "specially designed for a particular patient" to more flexible approaches linked to the non-routine nature [36].
Eligible Approval Holders	The manufacturing must be authorized by the national competent authority [36].	Some states limit holders to public hospitals; others allow private entities; the type of eligible entities varies [36].
Intended Purpose	Framework allows for treatment under an individual medical prescription [36].	Used for early ATMP development, compassionate use, treating unmet medical needs, or as an alternative to marketing authorization [36].

Table 2: Regulatory and Administrative Heterogeneity in HE Pathways

Aspect	Status in EU Law	National Variations and Examples
Specific Quality Standards	Must be equivalent to those for centrally authorized ATMPs [36].	Heterogeneous interpretation and implementation of "equivalent standards" across Member States [36].
Clinical Evidence Requirements	No specific EU-level requirement detailed in HE clause.	Divergence in the level of non-clinical and clinical evidence required for approval [25] [13].
Approval Duration & Validity	No EU legislative provision on duration [36].	Approval periods vary from one year to several years, or with no specified end date [36].
Coexistence with Authorized ATMPs	No explicit EU rule on use when a similar authorized product exists [37].	Spain: HE products may be authorized for indications overlapping with centrally approved ATMPs [37]. Other Proposals: European Parliament suggests restricting HE if an authorized ATMP or clinical trial is available [37].
Pricing & Reimbursement	Outside the scope of EU pharmaceutical legislation [37].	Spain: HE products receive a technical data sheet and price/reimbursement approval, making them resemble authorized medicines [37]. Italy: Access supported by a dedicated national fund for innovative drugs [31].

National Implementation Models

• The Spanish Model: Spain has developed a distinctive approach where ATMPs under the HE are treated in a manner similar to authorized products [37]. The Spanish Agency for Medicines and Health Products (AEMPS) approves a "technical data sheet" for these therapies, analogous to the Summary of Product Characteristics for a licensed medicine, and grants them price and reimbursement status [37]. This model blurs the line between HE and centrally authorized ATMPs, as seen with products like ARI-0001 (for leukemia) and ARI-0002H (for multiple myeloma), which can sometimes be used in treatment lines that compete with industrially manufactured ATMPs [37].
• The Belgian Context: In contrast to Spain, Belgium has implemented stringent regulatory policies that have made utilizing the HE pathway virtually impossible for some public health institutions, leading to the discontinuation of certain human cell and tissue products (HCTPs) that were previously available to patients and surgeons [13]. This demonstrates how restrictive national interpretations can limit the HE's objective of maintaining patient access to non-industrial ATMPs [13].

Methodologies for Evidence Generation under HE

Generating robust data on the quality, safety, and efficacy of an ATMP intended for the HE pathway requires carefully designed experimental protocols. The methodologies below align with regulatory expectations and scientific best practices.

Protocol for Quality and Manufacturing Data Generation

Objective: To establish and document that the ATMP is manufactured consistently to predefined quality standards, ensuring patient safety [36] [24].

• Process Validation: Develop a master production process flow diagram. For each manufacturing step (e.g., cell isolation, activation, genetic modification, formulation), define and validate Critical Process Parameters (CPPs). The validation approach should be phase-appropriate, becoming more rigorous as experience with the product grows [24].
• Analytical Method Qualification: Employ orthogonal analytical methods (methods based on different scientific principles) to measure the same Critical Quality Attribute (CQA) [6]. For example, for a genetically modified cell therapy, combine flow cytometry with quantitative PCR to assess identity and purity. The EMA guideline emphasizes the use of orthogonal methods to ensure robustness, especially when standardized assays are lacking [6].
• Potency Assay Development: Establish a biologically relevant functional potency assay that is linked to the proposed mechanism of action. This is a common challenge in CMC (Chemistry, Manufacturing, and Controls) for ATMPs. The assay must be justified and qualified to demonstrate its ability to reliably measure the product's biological activity [6] [24].
• Starting Material Control: Qualify all starting materials, including cells, tissues, and vectors. For ex vivo genome editing, the editing machinery is considered a starting material, not a raw material, and must be manufactured under GMP principles [6]. Adhere to the EU Substances of Human Origin (SoHO) Regulation for donor screening, testing, and informed consent [6] [31].

Protocol for Clinical Data Collection and Outcomes Analysis

Objective: To systematically collect clinical data on safety and efficacy to support the HE application and contribute to broader knowledge [25] [37].

• Study Design: Implement a prospective, single-arm cohort study design. Due to the custom-made and non-routine nature of HE products, randomized controlled trials are often not feasible. The study should target a well-defined patient population with a clear unmet medical need [25].
• Endpoint Definition: Define primary and secondary endpoints that are clinically meaningful. For early-phase studies, these may include safety/tolerability (e.g., incidence of adverse events, cytokine release syndrome), feasibility (e.g., success rate of product manufacturing), and preliminary efficacy (e.g., overall response rate, biomarker change) [25].
• Pharmacovigilance and Traceability: Establish a comprehensive pharmacovigilance plan equivalent to that required for authorized ATMPs [36] [37]. This includes systems for the unique identification of the product and traceability from the donor/starting material to the individual patient, and vice-versa, for a minimum of 30 years [36].
• Long-Term Follow-Up: Institute a long-term follow-up protocol to monitor for delayed adverse events, particularly for genetically modified products (e.g., insertional mutagenesis) or products with persistent biological activity. The proposed EU legislation mandates annual reporting of use, safety, and efficacy data to the national authority [36] [37].

Visualizing the HE Pathway and Key Workflows

The following diagrams illustrate the logical flow of the HE pathway and a typical experimental workflow for an ATMP developed under this framework.

Diagram 1: The Hospital Exemption (HE) Journey from Development to Clinical Use

Diagram 2: Key Experimental and Production Workflow for an HE ATMP

The Scientist's Toolkit: Essential Reagents and Materials

The development and testing of an ATMP under the Hospital Exemption require a suite of specialized reagents and materials. The table below details key solutions and their functions in the experimental and quality control process.

Table 3: Key Research Reagent Solutions for ATMP Development

Research Reagent / Material	Primary Function in ATMP Development
Cell Separation Kits	Isolation of specific cell populations (e.g., T-cells, stem cells) from a heterogeneous starting material (e.g., apheresis product, biopsy) using markers like CD3, CD34. Essential for ensuring a defined and consistent cell source.
Cell Culture Media & Supplements	Ex vivo expansion and maintenance of cells. Formulations often include cytokines (e.g., IL-2 for T-cells) and growth factors to promote cell growth and viability while maintaining functional properties.
Gene Delivery Vectors	Introduction of genetic material into cells for gene therapies or genetically-modified cell therapies (e.g., CAR-T). Includes viral vectors (Lentivirus, Retrovirus) and non-viral methods (electroporation, transfection).
Flow Cytometry Antibodies	Characterization of cell product identity, purity, and potency. Used to quantify specific cell surface and intracellular markers (e.g., CD19 CAR expression, memory T-cell subsets).
qPCR/dPCR Reagents	Quantitative analysis for vector copy number (for genetically modified products), detection of residual impurities, and measurement of specific transgene expression. An orthogonal method to flow cytometry.
Functional Assay Kits	Measurement of biological activity (potency). Examples include cytokine release assays (e.g., IFN-γ ELISA/MSD), cytotoxicity assays (e.g., against tumor cell lines), and differentiation assays.
Mycoplasma Detection Kits	Critical safety test to ensure the final cell product and potential reagents used during manufacturing are free from mycoplasma contamination.
Endotoxin Detection Kits	Critical safety test to quantify bacterial endotoxins in the final product, ensuring it is within safe limits for human administration.

The Hospital Exemption remains a vital, though complex, pathway for providing patient access to innovative ATMPs developed in non-industrial settings. The primary challenge for researchers and developers lies in navigating the significant heterogeneity in national requirements and interpretations of the EU framework [36] [37]. Success depends on a proactive strategy: engaging with the National Competent Authority early, generating robust and comprehensive evidence tailored to national expectations, and implementing rigorous pharmacovigilance and data collection systems [6] [37].

The future of the HE pathway is evolving. The ongoing revision of the EU's general pharmaceutical legislation aims to address the current fragmentation by introducing harmonized data collection and reporting obligations [36] [37]. These proposed changes include mandatory annual reporting on the use, safety, and efficacy of HE products to national authorities, who would then transfer this data to the EMA for inclusion in a central repository [36]. Furthermore, there is active discussion about creating an adapted framework for certain less complex ATMPs developed under the HE, which could streamline their pathway to patients [36] [25]. For the research community, these changes underscore the importance of systematic data generation, not only for national approval but also to inform future EU policy and potentially support broader marketing authorization applications [36].

Advanced Therapy Medicinal Products (ATMPs), which include gene therapies, somatic-cell therapies, and tissue-engineered products, represent a groundbreaking class of treatments in the European Union (EU) [1]. The regulatory framework governing these therapies is established principally in Directive 2001/83/EC and further refined through the ATMP-specific Regulation (EC) No 1394/2007 [10]. This legislation ensures that all ATMPs meet stringent standards for quality, safety, and efficacy before receiving marketing authorization from the European Commission, based on scientific assessments conducted by the European Medicines Agency (EMA) and its Committee for Advanced Therapies (CAT) [1] [10].

While the EMA provides centralized authorization valid across all EU Member States, the post-authorization phase introduces a complex division of responsibilities between European and national institutions [38]. The national competent authorities (NCAs) of individual member states assume critical roles in three crucial domains: determining pricing and reimbursement schemes, overseeing the implementation of pharmacovigilance activities, and managing additional post-authorization measures (PAMs) [38] [39]. This decentralized approach, particularly for pricing and reimbursement, leads to significant variations in patient access to authorized ATMPs across the EU [40]. Understanding this intricate interplay between centralized authorization and national-level implementation is essential for researchers, scientists, and drug development professionals navigating the European regulatory environment for ATMPs.

Table 1: ATMP Classification and Definitions

ATMP Category	Definition	Examples
Gene Therapy Medicines	Contain genes that lead to a therapeutic, prophylactic or diagnostic effect by inserting recombinant DNA [1].	Luxturna (retinal disease), Zalmoxis (HSCT adjunct) [10].
Somatic-Cell Therapy Medicines	Contain cells or tissues that have been manipulated to change their biological characteristics [1].	Alofisel (rectal fistula), ChondroCelect (cartilage disease) [10].
Tissue-Engineered Medicines	Contain cells or tissues that have been modified to repair, regenerate or replace human tissue [1].	Spherox (cartilage diseases), Holoclar (corneal diseases) [10].
Combined ATMPs	Contain one or more medical devices as an integral part of the medicine [1].	Cells embedded in a biodegradable matrix or scaffold [1].

The Evolving Role of NCAs in Pharmacovigilance and Post-Authorization Monitoring

Following the granting of a centralized marketing authorization, NCAs work in conjunction with the EMA to monitor the safety of ATMPs within their respective territories. The Pharmacovigilance Risk Assessment Committee (PRAC) is primarily responsible for assessing and monitoring the safety of medicines for human use at the EU level [38]. However, NCAs are integral components of this system, performing routine monitoring activities that range from assessing how risks will be managed to continuously monitoring suspected side effects reported by patients and healthcare professionals within their countries [38].

A critical development in the regulatory landscape has been the increased emphasis on Post-Authorization Measures (PAMs). These are regulatory measures that marketing authorization holders must complete to provide additional data after a medicine has been authorized [41]. Recent research covering ATMPs approved between 2013 and 2024 identified 118 PAMs, with 41.5% involving the use of real-world data (RWD) [39]. This highlights the instrumental role of RWD in addressing the uncertainties that often remain at the time of ATMP approval, particularly concerning long-term efficacy and safety [39]. NCAs play a vital role in overseeing the implementation of these PAMs at the national level, ensuring that marketing authorization holders comply with their obligations.

Table 2: Categories of Post-Authorization Measures (PAMs) in the EU

PAM Category	Legal Basis	Purpose and Characteristics	NCA Involvement
Specific Obligations (SOB)	Conditional marketing authorization or approval under exceptional circumstances [41].	Binding conditions for annual re-assessment/renewal; crucial for addressing residual uncertainties [41].	Monitor compliance within national territory; may participate in annual reassessment.
Annex II Conditions (ANX)	Imposed by the European Commission when granting the marketing authorisation [41].	Key to the benefit/risk balance of the product; can consist of safety or efficacy studies [41].	Oversee national implementation; may require reporting at national level.
Additional Pharmacovigilance Activities (MEA)	Listed in the risk-management plan (RMP) [41].	Required to investigate a safety concern or assess risk-minimisation effectiveness [41].	Direct reporting of adverse events; implementation of risk minimization measures nationally.

The methodology for evidence generation in the post-authorization phase is evolving. A 2025 study analyzing PAMs for ATMPs found that registries were the main source of RWD, mentioned in 53.1% of RWD-PAMs [39]. Furthermore, the study revealed that 32.5% of these RWD-PAMs incorporated patient-reported outcomes, emphasizing the growing importance of patient-centric data in the regulatory decision-making process [39]. This shift toward robust post-authorization evidence generation reflects the unique characteristics of ATMPs, including their complexity, frequent targeting of rare diseases, and reliance on smaller clinical trials for initial approval [39].

Comparative Analysis of NCA Roles in Pricing and Reimbursement

One of the most significant divisions of responsibility in the EU regulatory framework concerns pricing and reimbursement. While the EMA grants centralized marketing authorization valid across all member states, decisions about pricing and reimbursement take place at the national level [38]. This means that even after an ATMP receives EU-wide regulatory approval, it must undergo separate assessments in each country to determine whether and how it will be funded by the national healthcare system [38] [40]. This decentralized approach results in striking disparities in patient access to authorized ATMPs across Europe.

Empirical research from 2023 revealed that access to ATMPs is highly uneven across European countries [40]. A survey of 20 countries showed that 6 countries (30% of respondents) reimbursed no ATMPs at all, while the number of reimbursed ATMPs in other countries varied significantly [40]. This disparity arises from multiple factors, including regulatory differences, commercial decisions by marketing authorization holders, and the divergent assessment processes and criteria applied by national payers [40]. The challenge is particularly acute for ATMPs targeting rare diseases, which often have limited clinical trial data at the time of authorization and face difficulties demonstrating cost-effectiveness to national health technology assessment (HTA) bodies [40].

To manage the financial risks and evidentiary uncertainties associated with ATMPs, NCAs and payers are increasingly implementing special pricing mechanisms and managed entry agreements (MEAs) [40]. These arrangements may include outcomes-based schemes (pay-for-performance), coverage with evidence development, discounts, or rebates [40]. The primary purposes of these schemes are to control expenditure, share risk, generate additional evidence, and limit the patient population to those most likely to benefit [40]. This reflects a pragmatic approach by NCAs to balance early patient access with the need for financial sustainability and further evidence generation.

Table 3: National-Level Decision-Making Factors for ATMP Pricing and Reimbursement

Decision Factor	Description	Impact on ATMP Access
Health Technology Assessment (HTA)	National HTA bodies assess the relative effectiveness and often the cost-effectiveness of new medicines [38].	Divergent HTA methodologies and evidentiary requirements across countries contribute to unequal access [40].
Budget Impact Analysis	Evaluation of the therapy's impact on national or regional healthcare budgets [38].	High-cost ATMPs may be restricted or rejected due to budget constraints, even with positive HTA [40].
Managed Entry Agreements (MEAs)	Special arrangements to manage uncertainty and financial risk, such as outcomes-based agreements [40].	Can enable initial access while generating additional evidence; implementation varies by country [40].
Orphan Drug & Rare Disease Policies	National frameworks for orphan drugs, which many ATMPs are designated as [40].	Some countries have specific pathways for rare disease therapies; others apply standard assessment criteria [40].

Research Methodologies for Studying NCA Variations

For researchers and drug development professionals investigating the comparative landscape of NCA oversight for ATMPs, several methodological approaches can be employed. The complex interplay between centralized authorization and national implementation requires mixed-methods research designs that combine quantitative analysis of regulatory outcomes with qualitative assessment of policy frameworks and decision-making processes.

A primary methodology involves the systematic extraction of regulatory documents from publicly available sources. This approach was demonstrated in a 2025 study that analyzed all PAMs from EMA regulatory documents for ATMPs approved between 2013 and 2024 [39]. Researchers can extend this methodology by incorporating cross-national comparative analysis of how different NCAs implement EU-wide PAMs, examining variations in timelines, evidence requirements, and monitoring intensity. This requires consulting not only EMA sources but also national regulatory databases and HTA agency publications.

Another essential methodology is the structured survey of NCAs and payers, as implemented in a 2023 international review of regulatory and P&R decisions for all ATMPs with European marketing authorization [40]. Such surveys should be designed to capture both quantitative data (e.g., number of reimbursed ATMPs, price levels, time to reimbursement) and qualitative information (e.g., assessment criteria, special arrangements, reasons for non-reimbursement). Pre-filling survey responses with information from literature reviews and previous enquiries enhances response accuracy and facilitates validation [40].

The Scientist's Toolkit: Research Reagents for Regulatory Analysis

Table 4: Essential Methodological Resources for Comparative NCA Research

Research Resource	Function and Application	Source Examples
EMA Regulatory Documents	Provide complete record of authorization requirements, including imposed PAMs and specific obligations [39].	European Public Assessment Reports (EPARs), Risk Management Plans (RMPs) [39] [41].
HMA-EMA Catalogues	Identify and characterize real-world data studies and sources used for post-authorization monitoring [39].	Catalogue of RWD studies, Catalogue of RWD sources [39].
National HTA Reports	Reveal country-specific assessment methodologies, decision rationales, and evidence requirements [40].	Institute for Quality and Efficiency in Health Care (IQWiG) - Germany, National Institute for Health and Care Excellence (NICE) - UK [40].
Clinical Trials Registries	Track ongoing post-authorization studies and their design parameters across jurisdictions [39].	ClinicalTrials.gov, EU Clinical Trials Register [39].
International Policy Databases	Enable comparative analysis of pharmaceutical policies and reimbursement frameworks across countries [40].	Pharmaceutical Pricing and Reimbursement Information (PPRI) Network, OECD Health Statistics [40].

The oversight of Advanced Therapy Medicinal Products in the post-authorization phase represents a complex collaboration between centralized EU regulatory bodies and National Competent Authorities. While the EMA's Committee for Advanced Therapies (CAT) provides the specialized expertise required for evaluating ATMPs and recommends authorization, NCAs assume critical responsibilities in implementing pharmacovigilance activities, overseeing post-authorization measures, and making determinative decisions on pricing and reimbursement within their respective healthcare systems [1] [38]. This division of labor creates a regulatory environment where EU-wide authorization does not guarantee uniform patient access, with significant variations emerging at the national level [40].

Future developments in ATMP regulation will likely focus on enhancing the use of real-world data to address the evidence gaps that persist at the time of authorization [39]. The finding that 41.5% of post-authorization measures for ATMPs already involve RWD indicates a shift toward more pragmatic evidence generation frameworks [39]. Additionally, greater cooperation between countries and stakeholders will be essential for addressing the current inequalities in ATMP access [40]. Initiatives such as the WHO Regional Office for Europe's Access to Novel Medicines Platform represent promising approaches to this challenge [40].

For researchers and drug development professionals, understanding the nuanced roles of NCAs in the three key areas of pricing, reimbursement, and pharmacovigilance is essential for navigating the European ATMP landscape. The continuing evolution of regulatory frameworks, including the implementation of the PRIority MEdicines (PRIME) scheme and adaptive pathways, will require ongoing methodological innovation in comparative regulatory research [10] [39]. By systematically analyzing the implementation of post-authorization measures and pricing/reimbursement decisions across member states, stakeholders can contribute to more efficient development pathways and more equitable patient access to these transformative therapies.

Overcoming Hurdles: Solutions for Common NCA Challenges in ATMP Development

Addressing Variability in Hospital Exemption Implementation Across Member States

The Hospital Exemption (HE) is a specific pathway established by the European Advanced Therapy Medicinal Products (ATMP) Regulation (EC) No 1394/2007 [36]. It allows ATMPs—which include gene therapies, somatic cell therapies, and tissue-engineered products—to be prepared and used within a single European Union Member State without obtaining a centralized marketing authorization from the European Medicines Agency (EMA) [36]. This exemption applies to ATMPs that are "prepared on a non-routine basis according to specific quality standards, and used within the same Member State in a hospital under the exclusive professional responsibility of a medical practitioner, in order to comply with an individual medical prescription for a custom-made product for an individual patient" [36] [37].

While the HE pathway provides vital access to innovative therapies, particularly for rare diseases and unmet medical needs, its implementation across EU Member States is characterized by significant heterogeneity [36]. National Competent Authorities (NCAs) have interpreted and transposed the EU-level provisions differently, creating a fragmented regulatory landscape with implications for patient access, innovation, and market dynamics [25]. This guide objectively compares the implementation of the HE pathway across key Member States, providing researchers and drug development professionals with critical insights for strategic planning.

Comparative Analysis of National HE Frameworks

Implementation Status and Key Jurisdictions

The adoption of HE frameworks across the EU is inconsistent. As of 2025, only 19 of the 27 EU Member States have actively adopted and implemented HE frameworks [42]. Key implementing countries include Germany, Spain, Italy, and the Netherlands [42]. Conversely, countries like Cyprus, the Czech Republic, and Malta have established HE legislation but have not yet approved any HE products for use [42]. Estonia and Sweden are currently in the process of revising their national frameworks [42]. This disparity means that patient access to HE ATMPs is heavily dependent on geography.

Table 1: Hospital Exemption Implementation Status Across Select EU Member States

Member State	HE Framework Status	Number of Approved HE ATMPs	Notable Characteristics
Germany	Implemented	Data not specified	HE products can serve as a bridge to EMA approval (e.g., NOVOCART Inject) [42].
Spain	Implemented ("Spanish Model")	Multiple (e.g., ARI-0001, ARI0002H)	Issues "technical data sheets" similar to SmPCs; provides price & reimbursement approval [37].
Italy	Implemented	Multiple (e.g., GD2-CART01)	HE used for pediatric indications (e.g., Bambino Gesù Hospital) [42].
Netherlands	Implemented	Multiple (e.g., TIL therapy)	HE products transitioning to central authorization (e.g., TIL therapy EMA review) [42].
Belgium	Implemented	Data not specified	Requires extensive data for NCA approval [42].
Denmark	Implemented	Data not specified	Fastest approval time among reported states (14 days) [42].
Poland	Implemented	Data not specified	Minimal clinical/preclinical data requirements for approval [42].

Quantitative Analysis of Approved HE ATMPs

Between 2008 and 2025, a total of 110 HE ATMPs have been approved across the EU, with 62 products remaining available on the market as of 2025 [42]. These products address 28 different therapeutic indications, demonstrating the pathway's role in addressing diverse medical needs, including rare diseases [42].

The distribution of these therapies by product type is summarized in the table below.

Table 2: Breakdown of Approved HE ATMPs by Product Type (2008-2025)

Product Type	Number of Approved HE ATMPs
Somatic Cell Therapy Products	37
Tissue-Engineered Products	21
Gene Therapy Products	4
Total Available (2025)	62

Divergence in Regulatory Requirements and Processes

Substantial national variability exists in the core regulatory elements of the HE pathway, creating a complex environment for developers.

Table 3: Comparative Analysis of HE Regulatory Requirements and Processes

Regulatory Aspect	Examples of National Variability
Interpretation of "Non-routine"	Some states set an upper patient limit; others require preparation "one patient at a time" (e.g., France) [36].
Data Requirements for Approval	Ranges from extensive preclinical/clinical data (Belgium, Spain, Germany) to minimal requirements (Poland) [42].
Approval Timeline	Highly variable; from 14 days (Denmark) to 210 days (Spain) [42].
Eligible Approval Holders	Some states limit to public hospitals; others allow private entities [36].
Intended Purpose of HE	Early R&D, compassionate use, treatment for unmet needs, or alternative to marketing authorization [36].
Coexistence with Authorized ATMPs	Not all states restrict HE use when a centrally authorized ATMP is available, leading to potential market overlap [37].

Methodologies for Analyzing HE Variability and Outcomes

Regulatory Mapping and Data Collection

Objective: To systematically identify, catalog, and compare the specific legal provisions, guidelines, and administrative procedures governing the HE pathway in each Member State.

Experimental Protocol:

• Primary Source Identification: Access and retrieve the national laws, decrees, and implementing regulations that transpose the EU ATMP Regulation. Key sources include official state gazettes and health ministry websites.
• Guideline Collection: Collate all supplementary guidance documents, application forms, and informational materials published by National Competent Authorities (NCAs).
• Data Extraction: Use a standardized data extraction template to capture information on:
  • Legal basis and responsible NCA.
  • Definitions of key terms ("non-routine", "custom-made").
  • Application content requirements (quality, non-clinical, clinical data).
  • Approval process timelines and fees.
  • Pharmacovigilance and traceability rules.
  • Pricing and reimbursement mechanisms, if applicable.
• Stakeholder Interviews: Conduct structured interviews with regulatory affairs professionals from industry and academia, as well as with NCA representatives, to validate findings and gather insights on practical implementation challenges.

This methodology underpins studies such as the European Commission's HE study (2023-2025) and academic assessments like the one published in Cytotherapy (2020) [36].

Longitudinal Product Tracking and Outcome Studies

Objective: To monitor the development trajectory of HE products and assess their clinical and commercial outcomes, including their potential to transition to centralized marketing authorization.

Experimental Protocol:

• Product Registry Analysis: Utilize public data from NCAs, the EMA, and clinical trial registries (e.g., EU Clinical Trials Register) to track individual HE products.
• Data Point Tracking: For each product, record:
  • Approval date and indication from the NCA.
  • Clinical trial affiliations and phases.
  • Real-world evidence (RWE) publications.
  • Applications for regulatory designations (e.g., PRIME, Orphan Drug).
  • Submission and outcome of a centralized Marketing Authorisation Application (MAA) to the EMA.
• Case Study Compilation: Perform in-depth analysis of successful transition cases, such as Spain's ARI-0001 (CAR-T for acute lymphoblastic leukemia) and Germany's NOVOCART Inject, to identify critical success factors [42]. Factors include the role of academic sponsors, regulatory strategy, and data collection frameworks.

The Scientist's Toolkit: Key Reagents and Materials

The development and analysis of ATMPs under the HE pathway rely on a standardized set of biological, analytical, and data management tools.

Table 4: Essential Research Reagent Solutions for ATMP Development and Analysis

Research Reagent / Material	Function in HE ATMP Analysis
Starting Materials (SoHO)	Blood, tissues, or cells serving as the raw material for ATMP manufacturing; require stringent quality and safety standards [25].
Cell Lineage-Specific Markers	Antibodies and flow cytometry panels for characterizing cell identity, purity, and potency of the final ATMP product.
Vector Systems	Viral (e.g., lentiviral, retroviral) or non-viral vectors for genetic modification in gene therapy and CAR-T products.
Sterility and Mycoplasma Testing Kits	Critical quality control assays to ensure the final ATMP product is free from microbial contamination.
Cytokine and Metabolite Assays	ELISA, MSD, or other immunoassays to monitor patient immune responses and product activity in vitro and in vivo.
Data Standardization Platforms	Secure, GDPR-compliant databases for collecting and analyzing real-world evidence on safety and efficacy [36].

Visualization of the HE Regulatory Ecosystem and Pressures

The HE pathway exists within a dynamic ecosystem of competing interests and regulatory pressures, which directly influences its variable implementation across Member States.

The implementation of the Hospital Exemption pathway across EU Member States is markedly heterogeneous, creating a complex and fragmented landscape for developers of advanced therapies. Key variations exist in the interpretation of "non-routine" basis, data requirements for approval, approval timelines, and the conditions for use relative to centrally authorized ATMPs [36]. This variability presents both challenges, such as regulatory uncertainty and uneven patient access, and opportunities, including the role of HE as a critical bridge to centralized marketing authorization for academic and non-profit developers [42].

The future regulatory environment is poised for change. The European Commission's proposed revision of the general pharmaceutical legislation aims to address this fragmentation by introducing more harmonized reporting obligations and a central registry managed by the EMA [36]. Furthermore, the ongoing European Commission study on HE (2023-2025) is expected to provide a comprehensive mapping and recommendations for best practices [36]. For researchers and drug development professionals, a deep understanding of these national differences is not merely academic—it is a strategic necessity for navigating the European ATMP landscape, optimizing development pathways, and ultimately ensuring that innovative therapies can reach the patients who need them.

Strategies for Navigating Divergent National GMO Regulations for Gene Therapies

For developers of Advanced Therapy Medicinal Products (ATMPs), navigating the genetically modified organism (GMO) regulatory landscape across European member states presents a significant challenge. While the Clinical Trial Regulation (EU) No 536/2014 has streamlined clinical trial applications through the centralized Clinical Trial Information System (CTIS), GMO applications remain a separate, country-specific process that cannot be submitted via CTIS [43]. This regulatory fragmentation can delay trial commencement by up to 12 months due to duplicative processes and varying national requirements [44]. The core challenge stems from the dual regulatory framework consisting of the Contained Use Directive (2009/41/EC) and the Deliberate Release Directive (2001/18/EC), which member states implement differently based on their assessment of potential GMO risks to humans and the environment [43] [44]. This guide systematically compares national approaches to provide researchers, scientists, and drug development professionals with actionable strategies for efficient multinational trial planning.

Comparative Analysis of National GMO Requirements

Key Regulatory Variations Across Member States

The table below summarizes the divergent GMO regulatory requirements across major European countries hosting gene therapy clinical trials, illustrating the significant administrative burden facing sponsors.

Table 1: Comparative GMO Application Requirements for Gene Therapy Trials in Select European Countries

European Country	GMO Directive Application	Core Documentation Requirements	Submission Method	Language Requirements	SNIF Required
Germany	Deliberate Release (DR)	Cover letter, CAF for AAV with German-specific information, proof of SNIF submission, product administration manual [43]	Common European Submission Portal (CESP) to Paul Ehrlich Institute [43]	German or English [43]	Yes [43]
France	Contained Use (CU)	CAF for AAV including site plans, list of facilities [43]	"Simplified procedures" platform to ANSM [43]	French or English [43]	No [43]
Italy	Contained Use (CU)	Cover letter, CAF for AAV, proof of payment [43]	Via certified email account (PEC) [43]	Italian [43]	No [43]
Spain	Deliberate Release (DR)	Cover letter, clinical trial request form (Spanish), CAF for AAV (Spanish), SNIF (English and Spanish), proof of payment [43]	Email and regular post to Ministry of Agriculture or electronically via "sede electronica del MAPA" [43]	Spanish (except cover letter and SNIF for ESFC platform) [43]	Yes [43]
Netherlands	Deliberate Release (DR)	Cover letter, CAF for AAV, personal data (confidential) [43]	Regular post to Loketgentherapie or electronically via "berennenbox" [43]	Dutch or English [43]	Yes [43]

Experimental Protocol: GMO Application Process

The methodology for navigating divergent national GMO regulations involves a systematic approach to application preparation and submission:

• Step 1: Product Classification - Determine whether your investigational medicinal product consisting of or containing AAV vectors will be regulated under contained use or deliberate release directives in each target member state [43]. This varies by country, with some applying contained use (e.g., France, Italy), others deliberate release (e.g., Germany, Spain, Netherlands), and some making case-by-case determinations [43] [45].

• Step 2: Common Application Form (CAF) Preparation - Complete the product-specific CAF for AAV vectors where endorsed by the member state [43]. Note that several countries including Bulgaria, Malta, Poland, Slovakia, Cyprus, Greece, and Sweden do not endorse the CAF and require national documentation instead [43].

• Step 3: Environmental Risk Assessment (ERA) - For products meeting predefined criteria (no replication competent AAV and non-harmful transgene), simply cross-reference the pre-defined ERA in the CAF. Otherwise, develop a comprehensive ERA in accordance with Annex II of Directive 2001/18/EC [43].

• Step 4: SNIF Preparation - For countries requiring deliberate release applications (Germany, Greece, Spain, Hungary, Ireland, Latvia, Netherlands, Sweden, Slovenia, Slovakia, Romania), prepare a Summary Notification Information Format form for submission through the ESFC platform [43].

• Step 5: Country-Specific Documentation - Adapt application packages to include country-specific requirements such as site plans (France), product administration manuals (Germany), proof of payment (Italy, Spain), and confidential personal data (Netherlands) [43].

• Step 6: Submission Through Appropriate Channels - Utilize the specified submission methods for each country, which may include portals (CESP for Germany), platforms ("Simplified procedures" for France), certified email (Italy), or combined electronic and physical submissions (Spain) [43].

Figure 1: GMO Application Workflow - This diagram illustrates the sequential process for preparing and submitting GMO applications across European member states, highlighting key decision points and documentation requirements.

Strategic Framework for Multi-Country Submissions

Regulatory Pathway Selection Algorithm

Choosing the appropriate regulatory pathway requires careful analysis of both product characteristics and national regulatory frameworks. The decision matrix below provides a systematic approach to this selection process.

Table 2: Regulatory Pathway Decision Matrix for Gene Therapy GMO Applications

Product Characteristics	Recommended Directive	Key Member States	Time Advantage	Documentation Complexity
Administered to patients in controlled healthcare settings	Contained Use [43]	France, Italy, Austria, Denmark, Poland [43]	Shorter (no SNIF requirement) [43]	Moderate (CAF + national requirements) [43]
Potential environmental exposure risk	Deliberate Release [43]	Germany, Spain, Netherlands, Portugal [43]	Longer (SNIF + public consultation) [43]	High (CAF + SNIF + national requirements) [43]
AAV vectors without replication competence & non-harmful transgene	CAF with predefined ERA [43]	All CAF-endorsing countries [43]	Significant time savings	Low (cross-reference predefined ERA) [43]
Novel vectors or harmful transgenes	Custom ERA required [43]	All member states	Extended timeline for custom ERA	High (develop comprehensive ERA) [43]

The Scientist's Toolkit: Essential Research Reagent Solutions

Table 3: Key Research Reagents and Materials for GMO Compliance Documentation

Research Reagent/Material	Function in GMO Applications	Regulatory Standard	Application Context
AAV Vector Lots	Critical starting material for gene therapy products [6]	GMP-grade required for commercial INDs [6]	Quality documentation for CAF and national applications
Orthogonal Assay Systems	Complementary methods to measure critical quality attributes (identity, potency, purity) [6]	Phase-appropriate qualification (early) to full validation (Phase 3) [6]	Building confidence in product characterization for ERA
Replication Competent Virus (RCV) Testing	Essential safety testing for viral vector-based products [46]	British Pharmacopoeia guidance on best practices [46]	Environmental risk assessment and product safety documentation
GMP-Grade Starting Materials	Raw materials for ATMP manufacturing [47]	EU GMP compliance for commercial products [6]	Manufacturing process description in CAF and national applications
Environmental Risk Assessment (ERA) Templates	Structured assessment of potential environmental impacts [43]	Annex II of Directive 2001/18/EC [43]	Core component for deliberate release applications

Navigating divergent national GMO regulations requires a strategic approach that acknowledges both the commonalities and distinct requirements across European member states. The implementation of the Common Application Forms (CAFs) represents progress toward harmonization, though limited adoption across all member states remains a challenge [43]. As the regulatory landscape evolves, developers should monitor several key trends: potential GMO exemption schemes similar to those temporarily adopted for COVID-19 treatments [47], ongoing revisions to the EU pharmaceutical legislation [6], and increasing regulatory acceptance of alternative assessment methodologies [6]. By leveraging the comparative frameworks and strategic tools presented in this guide, researchers and drug development professionals can optimize their regulatory navigation strategies, potentially reducing submission timelines and accelerating patient access to innovative gene therapies.

For developers of Advanced Therapy Medicinal Products (ATMPs), navigating the requirements of National Competent Authorities (NCAs) is a critical step in the journey from lab to patient. Effective preparation for scientific advice and inspections can significantly streamline development and enhance the likelihood of regulatory success. This guide provides a structured comparison of these processes and offers practical protocols for engagement.

Understanding and Accessing Scientific Advice

Scientific advice is a prospective, non-binding guidance mechanism that helps developers design robust, agreed-upon development plans. Complying with this advice, while not a guarantee of marketing authorization, increases the chances of a successful application by preventing major objections during evaluation [48].

When to Seek Scientific Advice

Scientific advice is particularly valuable in specific scenarios common to ATMP development [48]:

• Innovative Products: When developing an innovative medicine where EU guidelines are absent or insufficient.
• Deviating from Guidelines: When choosing to deviate from established scientific guidelines.
• Limited Regulatory Experience: For developers with limited regulatory knowledge, such as academic groups or small-to-medium-sized enterprises (SMEs).
• Orphan Medicines: A special form of scientific advice, called "protocol assistance," is available for designated orphan medicines and addresses criteria like demonstrating "significant benefit" [48].

Questions can cover quality (manufacturing, testing), non-clinical (toxicology), clinical (study design, endpoints), and methodological aspects [48]. However, questions on topics like compassionate use, ATMP classification, or the adequacy of existing data for an application are generally out of scope [48].

The Scientific Advice Procedure

The process for seeking scientific advice from the EMA is highly structured. For ATMPs, the Committee for Advanced Therapies (CAT) is always consulted [24]. The following diagram outlines the key stages a developer will go through.

The process for seeking scientific advice from the EMA is highly structured [48]. For ATMPs, the Committee for Advanced Therapies (CAT) is always consulted [24]. The key stages are:

• Registration: The developer must register with the EMA if not already done [48].
• Formal Request: A briefing document with specific questions is submitted via the IRIS platform for validation [48].
• Appointment of Coordinators: The Scientific Advice Working Party (SAWP) appoints two coordinators [48].
• Assessment: Assessment teams prepare reports and may request clarifications [48].
• Meeting: A meeting with the developer may be organized, especially if the SAWP disagrees with the proposed plan [48].
• Consultation: The SAWP consults other EMA committees (like the CAT for ATMPs), working parties, and patients [48].
• Final Response: The SAWP consolidates a response, which is adopted by the CHMP and sent to the developer [48].

Preparing for Good Manufacturing Practice (GMP) Inspections

For ATMPs, demonstrating control over a complex and often personalized manufacturing process is paramount. GMP ensures that medicines are of consistent high quality and appropriate for their intended use [49].

Key GMP Requirements for ATMPs

The EU's GMP framework applies to all manufacturers, regardless of their global location [49]. Key obligations include:

• Manufacturing/Import Authorization: Manufacturers and importers in the EEA must hold a national authorization [49].
• Active Substance Registration: Manufacturers of active substances intended for the EU market must register with an NCA [49].
• GMP Compliance: Compliance with EU GMP guidelines is mandatory, verified through inspections [49].
• Electronic Databases: Manufacturing authorizations, GMP certificates, and non-compliance statements are recorded in the publicly accessible EudraGMDP database [49].

The GMP Inspection Process

Inspections for sites within the EU are conducted by the local NCA. For sites outside the EU, the NCA of the importing Member State is responsible, unless a Mutual Recognition Agreement (MRA) is in place [49]. The general workflow for GMP oversight and inspection is shown below.

Comparative Analysis of NCA Interactions

Engaging with NCAs for scientific advice and GMP compliance, while based on common EU regulations, can involve nuanced differences in focus and procedure. The table below contrasts these two critical types of interactions.

Table 1: Comparison of NCA Interactions for Scientific Advice vs. GMP Inspections

Aspect	Scientific Advice	GMP Inspections
Purpose & Nature	Prospective, non-binding guidance on development strategy [48]	Retrospective/proactive verification of compliance with quality standards [49]
Key Focus Areas	Study design, endpoints, manufacturing plans, overall development strategy [48]	Facility, equipment, processes, quality control, documentation, personnel [49]
Typical Interlocutor	EMA's SAWP/CAT, with possible national NCA involvement [48]	National CA of the manufacturing site or importing Member State [49]
Outcome	Written advice on specific questions, increasing likelihood of MAA success [48]	GMP certificate (compliance) or non-compliance statement, entered in EudraGMDP [49]
Compliance Value	Not legally binding, but strong de facto weight for MAA assessment [48]	Legally mandatory for manufacturing authorization and market supply [49]

Essential Toolkit for ATMP Developers

Navigating the regulatory landscape requires a set of essential tools and documents. The following table details key resources for preparing for scientific advice and inspections.

Table 2: Research Reagent Solutions: The ATMP Developer's Regulatory Toolkit

Tool/Resource	Function & Purpose	Relevant Context
IRIS Platform	The mandatory portal for submitting scientific advice requests and supporting documentation to EMA [48].	Scientific Advice
EudraGMDP Database	Publicly accessible database to check GMP certificates and compliance status of manufacturing sites [49].	GMP Inspection
Briefing Document	A comprehensive document outlining the development plan and specific questions for regulatory advice [48].	Scientific Advice
Pharmacovigilance System Master File (PSMF)	A detailed document describing the pharmacovigilance system for an authorized product [50].	Post-Authorization
Risk Management Plan (RMP)	A plan to identify, characterize, and minimize a product's safety risks after authorization [51].	Post-Authorization
ATMP Guideline	The primary multidisciplinary guideline on quality, non-clinical, and clinical requirements for clinical-stage ATMPs [24].	Scientific Advice

Experimental Protocols for Regulatory Preparedness

Protocol for Drafting a Scientific Advice Briefing Document

A well-prepared briefing document is critical for a successful scientific advice procedure [48].

• Methodology:
  • Executive Summary: Begin with a concise overview of the product, its mode of action, and the intended indication.
  • Development Plan Summary: Present the proposed non-clinical and clinical development strategy, including study designs and endpoints.
  • Specific Questions: Formulate clear, focused, and non-overlapping questions. For each question, present the developer's proposal and justification.
  • Background Data: Include summaries of existing quality, non-clinical, and clinical data that inform the questions asked.
• Expected Outcome: A structured document that enables the SAWP and its consulted committees (like the CAT) to provide precise, actionable advice on the proposed development path. This prevents questions that are purely regulatory or ask for a pre-evaluation of data [48].

Protocol for a Mock GMP Audit

A mock audit is a proactive simulation of an NCA inspection to identify and rectify compliance gaps.

• Methodology:
  • Planning: Define the audit scope based on the manufacturing process and EU GMP guidelines, particularly those specific to ATMPs [24].
  • Document Review: Examine the Quality Management System (QMS) documentation, including SOPs, batch records, validation reports, and supplier qualifications.
  • Facility Walkthrough: Observe operations, facility and equipment cleanliness, material and personnel flows, and in-process controls.
  • Staff Interviews: Interview key personnel from manufacturing, quality control, and quality assurance to assess training and understanding of GMP.
• Expected Outcome: A detailed report identifying major and minor deficiencies, observations, and strengths. This allows for corrective actions to be implemented before the official NCA inspection, thereby reducing the risk of a non-compliance statement.

Engaging early and strategically with NCAs through scientific advice and preparing rigorously for GMP inspections are indispensable practices for ATMP developers. By understanding the distinct landscapes of these interactions and employing a disciplined, tool-based approach, developers can navigate regulatory complexities more effectively, accelerating the delivery of advanced therapies to patients.

The rapid advancement of Advanced Therapy Medicinal Products (ATMPs), including cell and gene therapies, has created new treatment possibilities for previously untreatable diseases. However, this promising field faces a significant challenge: the proliferation of unregulated and illegally supplied products that pose serious risks to patient safety. These products are often marketed directly to vulnerable patients through online channels and social media, bypassing the rigorous scientific evaluation and regulatory oversight required for approved therapies [1].

The European Medicines Agency (EMA) and national competent authorities (NCAs) have recognized this growing threat. In March 2025, the EMA's Committee for Advanced Therapies (CAT) and the Heads of Medicines Agencies (HMA) issued a joint statement specifically addressing the risks of unregulated advanced therapies, highlighting reports of providers offering unregulated dendritic cell therapies for cancer treatments within the EU [1]. This guide provides researchers, scientists, and drug development professionals with a comprehensive framework for identifying, evaluating, and reporting suspicious ATMPs to the appropriate NCAs, thereby supporting the integrity of the regulatory ecosystem and protecting patient safety.

Understanding the Regulatory Context for ATMPs

The Legal Framework for ATMP Authorization

In the European Union, ATMPs are strictly regulated and must receive centralized marketing authorization from the European Commission based on scientific assessment by the EMA [1]. The regulatory framework is established under Regulation (EC) No 1394/2007, which sets forth rigorous requirements for quality, safety, and efficacy [4]. The Committee for Advanced Therapies (CAT), a specialized committee within the EMA, plays a pivotal role in the scientific assessment of ATMPs, providing the necessary expertise to evaluate these complex products [1].

ATMPs are classified into three main categories, each with distinct characteristics and regulatory considerations:

• Gene Therapy Medicinal Products (GTMPs): Contain genes that lead to therapeutic, prophylactic, or diagnostic effects by inserting 'recombinant' genes into the body [1].
• Somatic-Cell Therapy Medicinal Products (sCTMPs): Contain cells or tissues that have been manipulated to change their biological characteristics or are not intended for the same essential functions in the body [1].
• Tissue-Engineered Products (TEPs): Contain cells or tissues that have been modified to repair, regenerate, or replace human tissue [1].

Additionally, some ATMPs may contain one or more medical devices as integral components, classified as combined ATMPs (cATMPs) [1].

Recent Regulatory Developments

The regulatory landscape for ATMPs continues to evolve with several significant developments:

• The Medical Research Act (Medizinforschungsgesetz, MFG) in Germany, effective since October 2024, aims to improve the legal framework for clinical trials and simplify bureaucratic processes [52]. The Act establishes a Specialised Ethics Committee for particularly complex procedures, including those for ATMPs [52] [53].
• The UK's Medicines and Healthcare products Regulatory Agency (MHRA) has introduced new regulations on modular and point-of-care manufacturing of ATMPs, creating specific licenses for these innovative approaches that will become effective in July 2025 [19].
• The EU has adopted the Substances of Human Origin (SoHO) Regulation in 2024, which establishes a unified framework for the quality and safety of substances of human origin. SoHO entities have until August 2027 to transition to the new requirements [4] [6].

Table 1: Regulatory Framework Overview for ATMPs in Key Jurisdictions

Jurisdiction	Regulatory Body	Key Legislation/Guidance	Special Programs
European Union	European Medicines Agency (EMA)	Regulation (EC) No 1394/2007 [4]	Priority Medicines (PRIME) scheme [4]
United Kingdom	Medicines and Healthcare products Regulatory Agency (MHRA)	Human Medicines Regulations 2012 [18]	Hospital Exemption, "Specials" scheme [18]
Germany	Paul-Ehrlich-Institut (PEI) & BfArM [52]	Medical Research Act (MFG) [52]	Central coordination office for advice [52]
France	French National Agency for Medicines and Health Products Safety (ANSM)	French Public Health Code [54]	Prior authorisation (Visa) for advertising [54]

Identifying Unregulated ATMPs: Key Warning Signs

Characteristics of Unregulated Products

Identifying unregulated ATMPs requires vigilance and understanding of common red flags. The EMA and HMA have highlighted several warning signs that indicate an advanced therapy may be unregulated and illegally supplied [1]:

• Providers market the product as "experimental" but use it outside an authorized clinical trial: Legitimate clinical trials must receive approval from national competent authorities and ethics committees, with detailed information on product quality, non-clinical, and clinical controls [4] [1].
• Providers cannot confirm that the product has been approved by the EMA or an NCA: All legitimate ATMPs will have received marketing authorization from the European Commission based on EMA assessment, or approval from the relevant NCA in non-EU countries [1].
• Claims of benefits exceed those of approved treatments without supporting medical literature: Unregulated products often make exaggerated claims that are not supported by robust clinical evidence or published in peer-reviewed literature [1].

Additional indicators include direct-to-consumer marketing through websites or social media channels, presentation as a "last hope" treatment for desperate patients, and lack of transparency about manufacturing standards and quality controls [1].

Regulatory Classification Challenges

The complex classification of ATMPs can sometimes create confusion. For instance, in the EU, if a product is a combination of cell and gene therapy, such as CAR-T cells, it is always classified as a gene therapy [6]. The proposed new EU pharmaceutical legislation seeks to redefine GTMPs to include genome editing techniques and synthetic nucleic acids, which further complicates the landscape [6].

When uncertainty exists about a product's classification, developers can submit a request for ATMP classification directly to the CAT, which typically responds within 60 days [6]. This formal process helps clarify the regulatory status of borderline products and ensures appropriate oversight.

Experimental Protocols for Detecting Unregulated ATMPs

Regulatory Verification Workflow

Researchers and healthcare professionals can implement a systematic approach to verify the regulatory status of ATMPs. The following workflow provides a methodology for identifying potential unregulated products:

Diagram 1: ATMP Regulatory Verification Workflow

This verification protocol involves multiple experimental and documentary assessment steps that researchers should systematically apply:

• Marketing Authorization Verification: Contact the relevant NCA to confirm whether the product has received marketing authorization. In the EU, authorized ATMPs are listed in the European public assessment report (EPAR) database [1].
• Clinical Trial Approval Confirmation: For investigational products, verify that appropriate Clinical Trial Authorization (CTA) has been obtained from the national competent authority and that the trial has received approval from an ethics committee [4] [18].
• Evidence-Based Claim Assessment: Conduct a comprehensive literature review to evaluate whether efficacy and safety claims are supported by peer-reviewed publications or robust clinical data.
• Manufacturing Standards Evaluation: Assess whether the product is manufactured in compliance with Good Manufacturing Practice (GMP) standards, which is required for all ATMPs in clinical trials and commercial distribution [6].

Analytical Testing Methodologies

For suspected unregulated ATMPs that can be physically obtained (e.g., by regulatory authorities during inspections), specific analytical methodologies can help identify substandard or falsified products:

Table 2: Analytical Methods for ATMP Quality Assessment

Method Category	Specific Techniques	Parameters Assessed	Regulatory Acceptance
Orthogonal Methods	qPCR, Next Generation Sequencing (NGS), infectivity assays [6]	Vector genome integrity, identity, potency, purity [6]	Encouraged by FDA and EMA to build confidence in critical quality attributes [6]
Potency Assays	Functional, biologically relevant assays [6]	Biological activity, mechanism of action [6]	Required for marketing authorization; most common CMC deficiency in CGT programs [6]
Characterization Methods	Identity testing, viability assays, purity assessments [6]	Product composition, impurity profiles [6]	Phase-appropriate requirements from early development to commercial [6]
New Approach Methodologies (NAMs)	In silico models, organ-on-chip, organoid models [6]	Biodistribution, off-target effects [6]	Case-by-case acceptance with strong scientific justification [6]

The FDA applies a "phase-appropriate" approach to analytical requirements, with increasing rigor throughout development. For early-phase investigations, assays need to be qualified but must be reliable, reproducible, and sensitive enough to support safety decisions. By Phase 3 and registration, full validation is required under ICH Q2(R2) guidelines [6].

EMA's guidelines for investigational ATMPs specifically state that orthogonal methods should be considered for analytical testing to ensure the robustness and reliability of results, particularly when reference standards or validated methods are lacking [6].

Reporting Mechanisms to National Competent Authorities

Authority-Specific Reporting Channels

Each EU Member State has established specific procedures for reporting suspected unregulated ATMPs. The following table summarizes the reporting mechanisms for selected NCAs:

Table 3: Reporting Mechanisms to National Competent Authorities

Country	Competent Authority	Reporting Contact	Specialized Office
United Kingdom	Medicines and Healthcare products Regulatory Agency (MHRA) [18]	Innovation Office [18]	Pharmacovigilance team for safety concerns [18]
Germany	Paul-Ehrlich-Institut (PEI) & Federal Institute for Drugs and Medical Devices (BfArM) [52]	Joint objection portal [52]	Central coordination office [52] [53]
France	French National Agency for Medicines and Health Products Safety (ANSM) [54]	Not specified in search results	Advertising compliance for promotional violations [54]
EU-Wide	European Medicines Agency (EMA) [1]	National Competent Authorities [1]	Committee for Advanced Therapies (CAT) [1]

When reporting suspected unregulated ATMPs, provide comprehensive information including product details, manufacturer or provider information, distribution channels, promotional materials, and any available evidence of potential harm or misleading claims.

Cross-Border Collaboration and Information Sharing

The regulatory framework for ATMPs facilitates cross-border collaboration between NCAs. The EMA serves as a coordination point for EU-wide regulatory activities, with the CAT playing a central role in evaluating ATMPs and providing scientific expertise [1]. Recent initiatives like the Medical Research Act in Germany have established structures such as central coordination offices to harmonize processes between different regulatory authorities [52] [53].

The International Coalition of Medicines Regulatory Authorities (ICMRA) provides a platform for global collaboration, as evidenced by the MHRA's consultation with 16 different regulatory bodies when developing its new framework for modular and point-of-care manufacturing [19].

Regulatory Assessment Tools

Researchers and developers working with ATMPs should familiarize themselves with key regulatory tools and resources:

• ATMP Classification Procedure: Formal process for determining whether a product qualifies as an ATMP and its specific category [1] [6].
• Scientific Advice Procedures: Opportunities for early dialogue with regulators about innovative development approaches [4] [52].
• Pharmacovigilance Systems: Processes for monitoring and reporting adverse events for authorized ATMPs [1].
• Hospital Exemption Provisions: Pathways for using non-authorized ATMPs in hospital settings under specific conditions [18].

The following toolkit assists researchers in maintaining compliance and proper documentation:

Diagram 2: Essential ATMP Documentation Toolkit

The identification and reporting of unregulated ATMPs represents a critical shared responsibility for researchers, developers, and healthcare professionals. By understanding the regulatory frameworks, recognizing warning signs, implementing systematic verification protocols, and utilizing appropriate reporting channels, the scientific community can significantly contribute to patient safety and ecosystem integrity.

Recent regulatory developments, including the EU's SoHO Regulation, Germany's Medical Research Act, and the UK's point-of-care manufacturing framework, demonstrate ongoing efforts to adapt regulatory systems to the unique challenges of advanced therapies [4] [52] [19]. However, these systems depend on vigilant reporting of non-compliant products to function effectively.

As the CAT and HMA emphasized in their March 2025 joint statement, patients and caregivers should be encouraged to seek second opinions before proceeding with treatments promoted online and to contact their national competent authority to verify product approval [1]. Through collaborative vigilance and proper reporting mechanisms, the scientific community can help ensure that patients benefit from genuine advances in advanced therapies while being protected from unregulated and potentially harmful products.

National Approaches in Practice: A Comparative Analysis of Key EU Member States

Advanced Therapy Medicinal Products represent a groundbreaking class of therapies with the potential to treat previously incurable conditions. Within the European Union, these therapies face a complex regulatory and reimbursement landscape that varies significantly between Member States. This case study provides a focused analysis of Belgium's specific approach to the Hospital Exemption pathway and ATMP reimbursement frameworks. Belgium's experience offers a compelling case of a Member State grappling with the tension between fostering innovation and ensuring sustainable patient access. The country has recently initiated significant regulatory reforms while confronting persistent challenges in reimbursement implementation and HE utilization, providing valuable insights for the broader comparison of EU national competent authorities for ATMP oversight.

The Hospital Exemption Landscape in Belgium

Regulatory Framework and Implementation Challenges

The Hospital Exemption is a crucial pathway under the EU ATMP Regulation that allows unlicensed ATMPs to be manufactured and used within a specific hospital setting under the professional responsibility of a physician [13]. This pathway is intended for products prepared on a non-routine basis according to specific quality standards and used for an individual patient [13]. Unlike regular marketing authorization, the HE is regulated at the Member State level, leading to significant variation in implementation across the EU.

In Belgium, the HE application process requires extensive quality data and documentation of non-clinical pharmacological, pharmacokinetic, and toxicological properties [13]. However, the decision-making process lacks transparency, with no public assessment reports available and only the final outcome communicated to applicants [13]. This opacity creates significant uncertainty for developers and healthcare institutions seeking to utilize this pathway.

Comparative HE Utilization in the EU

Table 1: Hospital Exemption Implementation Across Selected EU Member States

Member State	HE Application Requirements	Decision Transparency	Reported Utilization Level
Belgium	Stringent quality and non-clinical data requirements	Low - no public assessment reports	Virtually impossible due to regulatory barriers
Italy	Scientific and/or clinical evidence requirements	Moderate	More accessible than in Belgium
Other EU States	Variable requirements between states	Varies significantly	Generally underutilized across EU

Belgium represents one of the most restrictive implementations of the HE pathway among EU Member States. While the HE scheme was theoretically enacted to protect academic and hospital-based HCTPs not intended for commercial exploitation, "stringent regulatory policies made it virtually impossible in Belgium, resulting in meaningful HCTPs no longer being available to surgeons and their patients" [13]. The limited financial resources available to public actors further hampered HE utilization, creating a situation where non-industry developed therapies face nearly insurmountable barriers to reaching patients [13].

ATMP Reimbursement Framework in Belgium

Institutional Structure and Process

Belgium has established a comprehensive social security system that includes compulsory health insurance managed by the National Institute for Health and Disability Insurance (NIHDI) [55]. The country operates a positive reimbursement list system, meaning the health insurance only covers medicinal products included on the official list of reimbursable pharmaceutical specialties [55].

The reimbursement process for ATMPs involves parallel pricing and reimbursement applications [55]. Pharmaceutical companies must submit simultaneous applications to the Minister of Economic Affairs (for pricing) and to the Commission for Reimbursement of Medicinal Products within NIHDI (for reimbursement) [55]. The final reimbursement decision is made by the Minister of Social Affairs and Public Health based on the CRM's advice [55].

Reimbursement Challenges for ATMPs

The Belgian reimbursement system faces particular challenges with ATMPs due to their unique characteristics. A significant issue identified in recent research is the "disconnection between an ATMP, which is reimbursed, and the necessary associated medical acts, which still are currently not always reimbursed" [56]. This creates financial and operational burdens for hospitals, particularly for cell therapies, which face inadequate nomenclature for clinical procedures, while gene therapies struggle with care coordination and data management challenges [56].

Additional barriers include insufficient collaboration between referring and specialized centers, hospital resource constraints, and fragmented budgeting systems that separate product reimbursement from related medical acts [56]. Furthermore, the collection of real-world evidence for cell and gene therapies requires significant hospital resources that are currently not funded, creating additional implementation challenges [56].

Table 2: ATMP Reimbursement Challenges and Impacts in Belgium

Challenge Category	Specific Issues	Impact on Patient Access
Reimbursement Structure	Disconnection between product reimbursement and associated medical acts	Creates financial burdens for hospitals administering ATMPs
Care Pathway Financing	Unfunded patient selection, preparation, administration, and follow-up activities	Limits hospital capacity to deliver ATMP treatments
Data Collection Requirements	Unfunded real-world evidence collection and registry management	Hinders post-authorization evidence generation and monitoring
Referral System	Insufficient incentives and awareness of available ATMPs among providers	Results in missed or delayed referrals to specialized centers

Quantitative Analysis of ATMP Authorization and Availability

EU-Wide Authorization Trends

As of 2025, the ATMP Regulation has produced 19 authorized ATMPs in the European Union, with a distinct predominance of gene therapy products [13]. The distribution shows that 16 (84.2%) belong to the gene therapy medicinal product class, while only 3 (15.8%) are human cell and tissue products - specifically 2 tissue-engineered products and 1 somatic cell therapy medicinal product [13]. This imbalance highlights the significant barriers facing non-gene therapy ATMPs in navigating the regulatory pathway.

The success rate for marketing authorization applications is considerably lower for ATMPs compared to all drug applications combined (59% versus 76%), suggesting the "specificities of developing products based on small batches of living cells with complex manufacturing processes, which are difficult to scale at low cost" create particular regulatory hurdles [13].

ATMP Availability in Belgium vs. Other EU Markets

Table 3: ATMP Availability Across Selected EU Member States

Member State	ATMP Availability Ratio	Leading Products Available	Notable Gaps
Germany	89%	Multiple CAR-T therapies, gene therapies	Few significant gaps reported
France	61%	CAR-T therapies, selected gene therapies	Several authorized ATMPs not launched
Italy	61%	CAR-T therapies, selected gene therapies	Several authorized ATMPs not launched
Belgium	~42% (8 of 19 authorized)	Selected CAR-T and gene therapies	Significant number of authorized ATMPs not marketed
Spain	28% (2023 data)	Very limited ATMP portfolio	Majority of authorized ATMPs not reimbursed
Estonia/Latvia	0%	No ATMPs launched	Complete absence of ATMP availability

Recent data indicates significant disparities in ATMP availability across EU Member States [57]. Germany leads with 89% availability of authorized ATMPs, followed by France and Italy at 61% [57]. Belgium has 8 of the 19 authorized ATMPs currently marketed and reimbursed, representing approximately 42% availability [13] [57]. This places Belgium in the middle tier of EU countries for ATMP access, ahead of Spain (28% in 2023) and Estonia and Latvia where no ATMPs have been launched, but significantly behind the leading countries [13] [57].

The commercial availability of an ATMP in Belgium does not guarantee patient access, as additional barriers exist at the institutional and care pathway levels. The "concentration of accredited treatment centers, limitations in hospital budgets for associated medical acts, and geographical inequities" further complicate the access landscape [58] [56].

Recent Regulatory Initiatives and Future Directions

Belgium's ATMP Readiness Plan

Recognizing the challenges in the current landscape, Belgium has launched a comprehensive initiative to improve its ATMP regulatory environment. In 2025, the Federal Agency for Medicines and Health Products launched a dedicated ATMP spearhead domain to support end-to-end development of these therapies [59]. This initiative aims to provide "regulatory flexibility and early interactions between developers and regulators," addressing one of the key bottlenecks in ATMP development [59].

Belgium has set specific 2028 targets for ATMP readiness, including building regulatory expertise through internal training, recruiting new assessors, and establishing coordination mechanisms [59]. The FAMHP's first steps include "the expansion of our regulatory capacity and expertise... a coordinator has been nominated," signaling a structured approach to enhancing regulatory support [59].

Clinical Trial Acceleration

Complementing the ATMP spearhead domain, the Belgian FAMHP has announced accelerated evaluation timelines for clinical trial applications effective January 2026 [60]. The new framework establishes significantly shorter review timelines:

• Phase I, I/II, and II trials: evaluation within 20 days after submission
• Phase II/III, III, III/IV, and IV trials: evaluation within 35 days
• For ATMPs and certain biotechnological medicines, a possible extension of 10 days applies [60]

These deadlines represent roughly a 50% reduction from current timelines and demonstrate Belgium's commitment to "speeding up access to innovative treatments for patients and further strengthening Belgium's leadership in clinical research within the EU" [60].

Multi-Stakeholder Engagement

A crucial component of Belgium's strategy involves creating a multi-stakeholder platform to facilitate interactions between industry, academia, healthcare professionals, and patients [59]. This recognizes that "academic institutions have a central role in the research and early development of ATMPs," while acknowledging that "the later stages of development, including scaling and commercialisation, are usually conducted by industry" [59].

However, significant barriers remain for academic translation, including challenges in funding, GMP access, and regulatory navigation [59]. Most academic trials remain in early phases, and the Hospital Exemption route continues to be underused due to "legal uncertainty and reimbursement hurdles" [59].

Methodological Framework for ATMP Landscape Analysis

Research Protocols for Policy Analysis

Analyzing the HE landscape and ATMP reimbursement requires specific methodological approaches. The research underlying this case study employed multiple complementary methods:

Documentary Analysis Protocol: Systematic review of official documents including competent authority reports, scientific literature, trade publications, and regulatory guidelines. Each document was coded for key themes including regulatory requirements, reimbursement criteria, implementation challenges, and access outcomes [13].

Stakeholder Survey Methodology: Structured surveys were administered to Belgian academic and hospital HCTP producers to assess the practical impact of regulatory frameworks on product sustainability and patient access. Survey questions focused on experiences with regulatory pathways, reimbursement outcomes, and operational challenges [13].

Data Verification Framework: For availability analysis, researchers collected data through open governmental sources, databases, and direct communication with national competent authorities. Spearman's correlation coefficients were calculated to examine relationships between ATMP availability and product characteristics including time since authorization, target population size, and cost [57].

Visualizing the ATMP Regulatory Pathway

The following diagram illustrates the complex regulatory decision pathway for ATMPs in Belgium, highlighting the critical junction between the standard marketing authorization route and the Hospital Exemption pathway:

ATMP Regulatory Pathway in Belgium

Essential Research Reagents for ATMP Policy Analysis

Table 4: Key Methodological Tools for ATMP Policy Research

Research Tool	Specific Application	Function in Analysis
Competent Authority Databases	Tracking MA and HE applications and outcomes	Provides quantitative data on regulatory decision patterns and timelines
HTA Agency Assessment Reports	Analyzing reimbursement recommendations and conditions	Reveals criteria for positive reimbursement decisions and evidence requirements
National Reimbursement Lists	Determining final market availability status	Identifies gap between regulatory approval and commercial availability
Stakeholder Interview Protocols	Gathering perspectives from industry, academia, and hospitals	Captures qualitative insights on practical implementation challenges
EU Regulatory Documents (EMA/CAT)	Understanding centralized procedure requirements	Establishes baseline EU framework against which national implementation is assessed
Pricing and Reimbursement Legal Frameworks	Mapping institutional structures and decision processes	Identifies key actors, timelines, and procedural requirements in national systems

Belgium presents a complex case study in ATMP regulation and reimbursement, characterized by recent regulatory modernization efforts alongside persistent implementation challenges. The country's restrictive approach to the Hospital Exemption pathway has significantly limited non-commercial ATMP development, while reimbursement mechanisms struggle with structural gaps in funding associated medical acts. Belgium's middling position in EU ATMP availability rankings reflects these systemic challenges, despite its strong clinical research infrastructure and recent regulatory initiatives.

The Belgian experience offers valuable insights for the broader comparison of EU national competent authorities, particularly regarding the critical importance of aligning regulatory pathways with reimbursement mechanisms. As Belgium works toward its 2028 ATMP readiness targets through the FAMHP's spearhead domain and accelerated clinical trial pathways, its progress in addressing these alignment challenges will be instructive for other Member States facing similar tensions between innovation promotion and sustainable access. The success of these initiatives will ultimately determine whether Belgium can leverage its significant scientific and clinical capabilities to improve patient access to these transformative therapies.

Advanced Therapy Medicinal Products (ATMPs), which include gene therapies, somatic cell therapies, and tissue-engineered products, represent a groundbreaking shift in treating conditions with limited therapeutic options, such as rare genetic disorders and certain cancers [31]. As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. The European Union has established a centralized authorization procedure for these therapies, yet their actual market availability differs significantly across Member States due to varying national pricing, reimbursement policies, and implementation capacities [61] [31]. Within this complex landscape, Italy has emerged as a leading European market for patient access to ATMPs, ranking alongside France with 61% availability of authorized ATMPs, second only to Germany (89%) among EU Member States [61]. This case study examines Italy's multifaceted approach to sustaining ATMP development and patient access through strategic public investment, regulatory adaptation, and specialized funding mechanisms, offering a compelling model for other national competent authorities.

Table: ATMP Availability in Select EU Member States

Country	ATMP Availability (%)	Notable Initiatives
Germany	89%	Extensive specialized treatment centers
Italy	61%	Dedicated innovation fund, outcome-based payment mechanisms
France	61%	Established reimbursement pathways
Estonia	0%	No ATMPs launched yet
Latvia	0%	No ATMPs launched yet

Italy's Regulatory Framework and Public Investment Strategy

Regulatory Foundations and Institutional Oversight

Italy's regulatory framework for ATMPs integrates European legislation with national adaptations designed to facilitate patient access. The framework is built upon Regulation (EC) 1394/2007 on advanced therapy medicinal products, which defines the various ATMP categories and establishes specific rules for authorization, supervision, and pharmacovigilance [31]. At the national level, Legislative Decree No. 219/2006 and the implementing decrees of Directive 2004/23/EC concerning human tissues provide the foundational legal structure [31]. The Italian Medicines Agency (AIFA) serves as the national competent authority with primary responsibility for ATMP oversight, evaluation, and reimbursement decisions. To address unique challenges associated with human tissue importation for ATMP manufacturing, the Italian Ministry of Health issued clarifying guidelines in December 2022, specifying that applications for clearance can be filed directly with the Border Office of the Ministry of Health (USMAF) or the manufacturer site itself, streamlining previously ambiguous procedures [31].

Strategic Public Investment Mechanisms

Italy has established targeted financial mechanisms to support innovative therapies, recognizing their transformative potential despite high upfront costs. The cornerstone of this approach is a dedicated fund for innovative drugs, which for 2025 has an allocation of €900 million [31]. This fund specifically bridges the gap between cutting-edge drug development and patient accessibility by supporting the reimbursement of drugs that demonstrate substantial therapeutic advancements, particularly those addressing unmet medical needs typical of ATMPs [31].

A significant development in Italy's pull incentive strategy occurred in July 2025 with the publication of Determina Pres/966/2025, which formally activated a national pull incentive with a budget of €100 million per year for innovative antibiotics, demonstrating Italy's commitment to strategic therapeutic areas [62]. Although specifically targeting antimicrobials, this mechanism represents the same strategic approach to addressing market failures for innovative therapies that could be applied to ATMPs. Qualifying therapies are reimbursed under the Fondo Farmaci Innovativi and are exempt from Italy's pharmaceutical payback mechanisms, estimated to increase annual revenues by approximately 15% [62].

Diagram: Italy's Integrated Regulatory and Investment Approach for ATMPs

Comparative Performance Analysis: Italy Versus EU Peers

Quantitative Assessment of ATMP Access and Expenditure

Italy's strategic approach has yielded measurable outcomes in patient access to advanced therapies. According to a 2024 analysis of real-world data, of the 18 ATMPs currently authorized in Europe, 9 are reimbursed by the Italian National Health System (INHS), with 6 actually utilized in clinical practice, generating cumulative expenditure of approximately €300 million from 2016 to 2023, largely driven by CAR-T therapies [63]. The timeline from European Commission decision to first patient treatment in Italy reaches an average of 340.6 days from the publication of the reimbursement decision in the official Gazette to the first patient treatment, following an even longer evaluation period by regulatory agencies [63]. This places Italy in the leading cohort of EU nations for ATMP access, though significant disparities persist across the Union, with Estonia and Latvia confirming that no ATMPs have been launched on their markets yet [61].

Table: Italy's ATMP Utilization and Expenditure (2016-2023)

Metric	Value	Reference Period
EU-Authorized ATMPs	18	By end of 2023
INHS-Reimbursed ATMPs	9	2016-2023
Actually Utilized ATMPs	6	2016-2023
Cumulative Expenditure	~€300 million	2016-2023
Primary Expenditure Driver	CAR-T therapies	2016-2023
Average Time to Patient Access	340.6 days	From reimbursement decision to treatment

Infrastructure and Implementation Capabilities

Italy has developed substantial infrastructure to support ATMP administration nationwide. The country has authorized 107 health facilities for ATMP administration, with almost all Italian regions having at least one specialized treatment center that performed at least one ATMP treatment in 2023 [63]. This decentralized yet coordinated network ensures broader geographic access for patients across the country. To manage the inherent uncertainties of ATMPs regarding long-term efficacy and safety, Italy has been one of the first European countries to implement outcome-based payment mechanisms, creating a chronological alignment between costs and benefits that characterizes these transformative treatments [63]. The country also utilizes AIFA registries to verify prescriptive appropriateness after reimbursement decisions, enabling continuous monitoring of real-world outcomes [63].

Experimental Protocols and Methodologies for ATMP Assessment

Methodological Framework for Analyzing ATMP Availability and Access

To evaluate Italy's performance in ATMP access, researchers have developed systematic assessment methodologies. A 2025 study on ATMP availability across the EU employed a rigorous protocol beginning with data extraction from the Committee for Advanced Therapies meeting reports to identify all authorized ATMPs, followed by collection of availability data from 23 EU Member States through open governmental sources, databases, and direct communication with national competent authorities [61]. Market availability was defined as actual product launch in each Member State, with verification conducted through email communication with NCAs for 20 of 27 EU MS (74%) to ensure data reliability [61]. Correlation analysis using Spearman's correlation coefficients examined relationships between ATMP availability and product characteristics including time since marketing authorization, target patient population size, and cost, with data on the latter two parameters retrieved from German Federal Joint Committee (G-BA) benefit assessments based on their completeness [61].

Protocol for Tracking ATMP Utilization and Expenditure

A separate methodological approach analyzed Italy's actual ATMP usage patterns and financial impact through real-world data collection from the Italian National Health System expenditure data flow between January 2016 and December 2023 [63]. This analysis developed six specific indicators to measure temporal milestones: (1) clinical development time; (2) EMA assessment time; (3) lag time between European Commission decision and Pricing & Reimbursement dossier submission; (4) AIFA assessment time; (5) time to first purchase of an ATMP by a public healthcare facility (used as a proxy for patient treatment); and (6) overall regulatory time as the sum of indicators ii-iv [63]. Expenditure was evaluated using the 'drug traceability' flow, representing actual annual expenditure plus value added tax without accounting for managed entry agreements, with compound annual growth rate calculated to evaluate spending growth [63].

Diagram: Methodological Framework for EU ATMP Availability Assessment

Research Reagent Solutions for ATMP Development and Analysis

The development, manufacturing, and quality control of ATMPs requires specialized reagents and analytical services. The global ATMP service providers market, valued at $16.68 billion in 2024 and projected to reach $42.57 billion by 2034, reflects the growing infrastructure supporting this sector [64]. These services encompass critical reagent solutions and analytical capabilities essential for ATMP development and characterization.

Table: Essential Research Reagent Solutions for ATMP Development

Reagent Category	Specific Applications	Function in ATMP Development
PCR Assays	Vector copy number analysis, Mycoplasma testing	Quantification of genetic material, safety testing
Flow Cytometry Reagents	Cell phenotype characterization, purity assessment	Verification of cell identity, potency, and composition
ELISA Kits	Cytokine detection, protein expression analysis	Monitoring immune responses, transgene expression
Endotoxin Testing	Sterility testing, safety assessment	Detection of bacterial endotoxins in final product
Microbiological Media	Sterility testing, adventitious agent detection	Ensuring product sterility and absence of contaminants
Cell Culture Reagents	MSC manufacture, pluripotent stem cell expansion	Ex vivo cell growth and maintenance

Discussion: Challenges and Future Perspectives

Persistent Challenges in ATMP Implementation

Despite Italy's relative success in ATMP access, significant challenges remain. The high per-treatment cost of ATMPs continues to strain healthcare budgets, though Italian authorities have managed this through negotiated pricing and outcome-based agreements [63] [31]. Manufacturing complexity presents another substantial barrier, with ATMPs requiring highly specialized equipment, facilities, and expertise throughout the production process [65]. The transition from centralized to decentralized manufacturing models introduces additional challenges in maintaining batch-to-batch reproducibility while scaling up production [65]. Furthermore, the initial focus on rare diseases with small patient populations, while clinically meaningful, creates commercial sustainability challenges that have led several MAHs to withdraw ATMPs from the European market for commercial reasons, including the first ever authorized ATMP, Glybera, and two therapies from Bluebird Bio, one of which had reached advanced negotiation stages with AIFA prior to withdrawal [63].

Future Directions and Strategic Opportunities

Looking ahead, Italy is positioned to build upon its current framework to further enhance ATMP sustainability and access. The European Commission's Horizon Europe program has allocated €40 million for a 2025 call focused on "Optimising the manufacturing of Advanced Therapy Medicinal Products (ATMPs)," which presents opportunities for Italian research institutions and companies to collaborate on addressing manufacturing challenges [65]. The forthcoming implementation of the Substances of Human Origin (SoHO) Regulation in 2027 will replace existing tissue and cell directives, potentially streamlining cross-border circulation of starting materials and enhancing cooperation among public health authorities [31]. Additionally, Italy's ongoing revision of AIFA's innovation criteria, which will now encompass production technology, mechanism of action, administration method, clinical efficacy, and healthcare service implications, promises a more nuanced approach to evaluating and rewarding true therapeutic innovation [31].

Italy's multifaceted approach to sustaining ATMPs through strategic public investment, regulatory adaptation, and specialized funding mechanisms offers valuable insights for other national competent authorities. By establishing a €900 million annual innovation fund, implementing outcome-based payment models, developing nationwide treatment infrastructure, and creating targeted pull incentives, Italy has achieved one of the highest ATMP availability rates in the European Union while maintaining contained expenditure growth. The Italian model demonstrates that strategic public investment in innovative therapies requires not only financial resources but also integrated regulatory frameworks, monitoring systems for real-world outcomes, and flexible payment mechanisms that align with the transformative potential of these treatments. As the ATMP landscape continues to evolve with an expanding pipeline and technological advancements, Italy's experience provides a constructive template for balancing therapeutic innovation with fiscal sustainability in public healthcare systems.

The regulation of Advanced Therapy Medicinal Products (ATMPs) represents one of the most dynamic and challenging frontiers in pharmaceutical development. For researchers, scientists, and drug development professionals navigating this complex landscape, understanding the performance of National Competent Authorities (NCAs) is critical for strategic planning and successful product development. The European Medicines Agency (EMA) and its network of NCAs operate within a framework that must balance rigorous safety standards with the need to foster innovation in cell and gene therapies, tissue-engineered products, and combined ATMPs.

The European regulatory environment for ATMPs is characterized by a rapidly evolving guidance landscape. A comprehensive analysis identified 126 guidance documents applicable to ATMPs from 1990 to 2023, with the majority originating from the EMA and International Council for Harmonisation [66]. This proliferation of guidance reflects the scientific complexity of ATMPs and the need for specific regulatory frameworks. The recent implementation of the EMA's Guideline on clinical-stage ATMPs in July 2025 represents a significant consolidation effort, combining quality, non-clinical, and clinical requirements into a single multidisciplinary reference document [24]. This guideline, which replaces over 40 separate documents, aims to provide clearer direction for sponsors while maintaining flexibility in a rapidly advancing field.

Strategic Direction and Regulatory Science Initiatives

EMA's Regulatory Science Strategy to 2025

The EMA has proactively developed a comprehensive Regulatory Science Strategy (RSS) to address emerging challenges in ATMP development and regulation. This strategy was formulated through an extensive stakeholder consultation process involving 154 responses from industry, academia, healthcare professionals, patients, and consumer organizations [67]. The development methodology included:

• Baseline literature review and horizon scanning across 60 areas of science, technology, and health
• 70 interviews with European Medicines Regulatory Network (EMRN) stakeholders
• Public consultation spanning six months using structured surveys with Likert scales and qualitative feedback
• Follow-up workshops to review preliminary analysis and implementation planning

Table 1: Key Focus Areas in EMA's Regulatory Science Strategy to 2025

Strategic Focus Area	Key Objectives	Stakeholder Priority Rating
Advanced Therapy Development	Enhance scientific advice, develop ATMP-specific guidelines, address manufacturing challenges	High (4.2/5.0)
Patient-Centric Development	Incorporate patient preferences in benefit-risk assessment, use real-world evidence	High (4.5/5.0)
Innovative Clinical Trials	Promote complex innovative trial designs, develop efficacy endpoints	Medium-High (4.0/5.0)
Manufacturing Innovation	Address quality challenges, develop platform manufacturing approaches	Medium (3.8/5.0)
Health Threat Preparedness	Advance antimicrobial resistance strategies, medicine repurposing	Medium-High (4.1/5.0)

The stakeholder consultation revealed strong emphasis on regulatory convergence with other jurisdictions, particularly regarding chemistry, manufacturing, and controls (CMC) requirements [24]. This alignment is seen as crucial for efficient global development of ATMPs, though significant differences remain in areas such as allogeneic donor eligibility determination and Good Manufacturing Practice (GMP) compliance expectations.

Scientific Support and Protocol Assistance

The EMA and NCAs provide various scientific support mechanisms to assist ATMP developers, particularly for small and medium-sized enterprises and academic researchers. These initiatives include:

• Early-stage scientific advice at both national (NCA) and European (EMA) levels
• Protocol assistance for orphan designated medicines
• ITF (Innovation Task Force) briefing meetings for emerging therapies
• Priority Medicines (PRIME) scheme for promising therapies addressing unmet needs

The recently implemented ATMP guideline encourages sponsors to seek early guidance at either the national member state or European level to inform development strategy [24]. This emphasis on early interaction reflects recognition of the unique developmental challenges presented by ATMPs, including complex manufacturing requirements and novel clinical trial designs.

Methodologies for Benchmarking NCA Performance

Assessment Framework for Regulatory Performance

Benchmarking NCA performance requires a multidimensional approach that captures both quantitative metrics and qualitative aspects of regulatory oversight. Based on analysis of available data and regulatory frameworks, the following key performance indicators emerge as critical for comprehensive assessment:

Table 2: NCA Performance Benchmarking Framework

Performance Dimension	Key Metrics	Data Sources
Timeliness	Median/mean review times for clinical trial applications, scientific advice requests, marketing authorization applications	EMA annual reports, national authority reports
Transparency	Publication of assessment reports, meeting minutes, decision rationales, public consultation processes	Institutional websites, policy documents
Stakeholder Engagement	Diversity of consultation participants, incorporation of feedback, patient engagement initiatives	Stakeholder analysis, consultation documentation
Regulatory Convergence	Alignment with international standards, mutual recognition agreements, harmonized requirements	Comparative guideline analysis, international agreements
Support Initiatives	Early advice programs, fee reductions, SME support offices, scientific advice quality	Program documentation, user satisfaction surveys

The methodology for data collection should combine systematic documentation analysis with stakeholder perception assessment. For the EMA's Regulatory Science Strategy development, this involved quantitative preference elicitation through 5-point Likert scales combined with qualitative thematic analysis using the framework method [67]. This mixed-methods approach enables both prioritization of initiatives and understanding of underlying rationale.

Experimental Protocols for Regulatory Analysis

Researchers conducting comparative analyses of NCA performance should implement structured protocols to ensure consistency and objectivity:

Protocol 1: Guidance Document Mapping

• Identify all applicable guidance documents from official NCA websites
• Categorize by therapeutic area, document type (guideline, reflection paper, Q&A), and implementation date
• Analyze revision history to determine update frequency and responsiveness to emerging technologies
• Map cross-references to identify interconnected guidance networks

Protocol 2: Timeline Analysis

• Collect data on published procedural timelines for key regulatory milestones
• Track actual performance against stated timelines through annual reports
• Compare same-product submissions across different regions where possible
• Analyze variability in review times based on product complexity and applicant type

Protocol 3: Stakeholder Perception Assessment

• Develop structured surveys with quantitative scoring and qualitative feedback opportunities
• Ensure representative sampling across stakeholder groups (industry, academia, patients)
• Conduct semi-structured interviews to explore specific themes in depth
• Perform comparative analysis of perceptions across different NCAs

Comparative Analysis of Regulatory Approaches

EMA-FDA Convergence and Divergence in ATMP Regulation

Analysis of the EMA's new clinical-stage ATMP guideline reveals significant progress in regulatory convergence with the U.S. Food and Drug Administration (FDA), particularly in CMC requirements [24]. The organizational structure of the quality documentation section mirrors Common Technical Document (CTD) headings, facilitating preparation of submissions for both regions. However, important differences remain that impact development strategies:

• Donor Eligibility Determination: EMA references general EU and member state requirements, while FDA maintains more prescriptive requirements for screening and testing of allogeneic donors [24]
• GMP Compliance: EMA mandates compliance from early clinical stages, while FDA employs a phased, risk-based approach with full verification at pre-license inspection [24]
• Potency Assays: Differing expectations for demonstration of product potency throughout development
• Comparability Protocols: Varying requirements for managing manufacturing changes

The regulatory convergence initiative is actively discussed at international conferences hosted by professional societies, focusing on opportunities for global approval despite regional differences and balancing convergence efficiencies against unique regional requirements [24].

Transparency Initiatives and Stakeholder Engagement

Transparency represents a critical dimension of NCA performance, with significant variability in practices across the European regulatory network. The EMA has established robust transparency measures including:

• Publication of assessment reports for authorized medicines
• Public access to clinical trial data
• Publication of meeting minutes from scientific committees
• Public consultations on guidelines and regulatory science strategies

The development of the Regulatory Science Strategy exemplified best practices in stakeholder engagement, utilizing a partially blind analysis approach where respondent information was separated from responses to ensure neutral weighting of feedback [67]. The qualitative analysis employed the framework method, enabling multiple researchers to independently analyze large datasets through five iterative stages: familiarization, identifying a thematic framework, coding, summarizing, and mapping and interpretation.

The stakeholder distribution for the RSS consultation comprised healthcare professionals (20 responses), academia and research organizations (23 responses), industry associations (36 responses), and individual companies (32 responses), providing comprehensive perspective representation [67].

Research Toolkit for NCA Performance Assessment

Table 3: Essential Research Reagents for Regulatory Science Analysis

Research Reagent	Function/Significance	Application in NCA Benchmarking
Regulatory Guidance Database	Comprehensive collection of guidelines, reflection papers, and Q&A documents	Tracking evolution of regulatory requirements and convergence
Stakeholder Survey Framework	Structured instrument with Likert scales and qualitative feedback	Assessing perceptions of NCA performance across stakeholder groups
Timeline Tracking System	Database of regulatory milestones and decision points	Quantifying review performance and identifying bottlenecks
Comparative Analysis Matrix	Framework for side-by-side comparison of regulatory requirements	Identifying divergence and convergence across regions
Transparency Assessment Tool	Scoring system for publication practices and data accessibility	Evaluating openness of regulatory decision-making

Benchmarking NCA performance for ATMP oversight requires a multifaceted approach that captures both quantitative metrics and qualitative aspects of regulatory processes. The analysis reveals significant efforts toward regulatory convergence, particularly between EMA and FDA, though important differences remain in areas such as donor eligibility and GMP implementation. The EMA's proactive development of a Regulatory Science Strategy through comprehensive stakeholder consultation demonstrates commitment to evolving regulatory science capabilities in line with technological advances.

For researchers and drug development professionals, understanding these regulatory landscapes is essential for strategic planning. The methodologies and toolkits presented provide practical approaches for ongoing assessment of NCA performance, enabling evidence-based evaluation of regulatory systems. As ATMP technologies continue to evolve, with emerging areas such as gene editing products specifically flagged for future guideline development [24], continuous monitoring of NCA performance will remain critical for efficient advancement of innovative therapies to patients.

Future developments in NCA performance will likely focus on enhanced regulatory agility to accommodate rapid technological advances, greater harmonization of international requirements to facilitate global development, and increased transparency in regulatory decision-making processes. The implementation of the new clinical-stage ATMP guideline in July 2025 provides an important opportunity to assess the impact of consolidated guidance on regulatory performance and development efficiency [24].

The Impact of the New Substances of Human Origin (SoHO) Regulation on National Processes

The European Union's new Substances of Human Origin (SoHO) Regulation (adopted in June 2024 and applicable from 7 August 2027) establishes a unified framework for human cells, tissues, and blood, repealing the previous Blood Directive and Tissues and Cells Directive [68]. This regulatory shift coincides with the evolving landscape for Advanced Therapy Medicinal Products (ATMPs), creating a complex interface that national competent authorities (NCAs) and drug development professionals must navigate. For researchers and scientists, understanding this interaction is crucial, as the collection of human biomaterials (SoHO) is a necessary first step in developing most ATMPs [68]. This guide objectively compares the evolving regulatory performance and provides a structured analysis of its impact on national processes for ATMP oversight.

Comparative Analysis of the EU Regulatory Framework for SoHO and ATMPs

The regulatory frameworks for SoHO and ATMPs, while governing interconnected fields, have historically involved different stakeholder communities. Recent research analyzing public consultations found a very low overlap in organisations contributing to both SoHO and ATMP regulations, indicating significant institutional fragmentation between entities collecting biomaterials and those developing ATMPs for the market [68].

Table 1: Key Legislative Transitions and Timelines

Legislative Instrument	Previous Directive/Regulation	New/Updated Regulation	Date of Application/Key Milestone
Substances of Human Origin (SoHO)	Blood Directive (2002/98/EC) & Tissues and Cells Directive (2004/23/EC) [68] [4]	SoHO Regulation (2024) [68]	7 August 2027 [68] [6]
Advanced Therapy Medicinal Products (ATMP)	Directive 2001/83/EC & Regulation (EC) No 1394/2007 [4]	Revised Pharmaceutical Legislation (Proposed) [6]	Ongoing revision; CAT classification required [6]
GMP for ATMPs	Part IV of EU GMP Guidelines (2017 version) [69]	Revised GMP Guidelines (Proposed) [69]	Public consultation open until 8 July 2025 [69]

The diagram below illustrates the new regulatory workflow for an ATMP derived from SoHO, highlighting the interconnected roles of different regulatory bodies and the expanded scope of the new SoHO Regulation.

Figure 1. The Integrated SoHO and ATMP Regulatory Workflow. This diagram outlines the pathway from the donation of human biological materials to the authorization of a finished ATMP, demonstrating the points of oversight by national and European authorities under the new regulatory framework.

Experimental Analysis of Regulatory Implementation

Methodology for Assessing National Implementation Landscapes

To evaluate the impact of the SoHO Regulation on national ATMP processes, a systematic analysis of regulatory documentation and stakeholder engagement is required. The following protocol outlines a robust methodology for researchers.

Experimental Protocol 1: Mapping the Transition of National Regulatory Requirements

• Objective: To identify and quantify changes in national regulatory requirements for ATMP developers resulting from the implementation of the SoHO Regulation.
• Data Sources:
  • National transposition measures of the SoHO Regulation from official government gazettes.
  • Guidance documents published by NCAs (e.g., PEI in Germany, MHRA in the UK).
  • Public consultation submissions from industry and academic stakeholders [68].
• Procedure:
  • Document Retrieval: Systematically collect all national-level regulatory documents related to SoHO and ATMPs published before and after June 2024.
  • Content Analysis: Code the documents for specific requirements (e.g., donor screening, traceability, quality controls) using a predefined taxonomy.
  • Gap Analysis: Compare pre- and post-SoHO Regulation requirements to identify new obligations, removed clauses, and modified standards.
• Key Metrics: Number of new procedural steps, changes in documentation burden, updates to quality and safety specification standards.

Quantitative Data on Regulatory Shifts

Implementation of the new framework introduces specific, measurable changes for ATMP developers and NCAs. The following table summarizes the core quantitative changes in regulatory requirements.

Table 2: Key Regulatory Changes for ATMP Developers Using SoHO

Aspect	Previous Framework	New SoHO Regulation (from Aug 2027)	Impact on ATMP Development
Regulatory Scope	Separate Directives for Blood, and for Tissues and Cells [68] [4].	Unified regulation covering blood, tissues, cells, and new substances like breast milk and intestinal microbiota [68].	Broader scope requires due diligence on a wider range of potential starting materials.
Oversight of Activities	-	Explicitly covers donor registration, collection, testing, storage, distribution, import, and export [6].	Any party handling these activities, now defined as "SoHO entities," must comply, increasing the chain of control [6].
GMP for Starting Materials	Guidelines based on older GMP principles.	Updated EU GMP Part IV for ATMPs, aligning with revised Annex 1 and integrating ICH Q9/Q10 [69].	Stricter controls for sterile products and a mandated Contamination Control Strategy (CCS).
Supply Chain Logistics	Primarily centralized manufacturing models.	Explicit pathways for Point-of-Care (POC) and Modular Manufacture (MM) as seen in UK's MHRA framework [70] [19].	Enables decentralized manufacturing for short shelf-life products; requires new Master File submissions for POC/MM sites [19].

The Scientist's Toolkit: Essential Research Reagents and Materials for SoHO-Compliant ATMP Development

Navigating the SoHO-ATMP interface requires specific tools and materials to ensure compliance and maintain quality. The following table details key solutions for the featured experimental protocols and general development work.

Table 3: Key Research Reagent Solutions for SoHO-Compliant ATMP Development

Research Reagent / Material	Function in Experimental Protocol	Critical Quality Attributes (CQAs) for SoHO/ATMP Compliance
Qualified Starting Materials	Serves as the initial SoHO input (e.g., donor cells) for the ATMP manufacturing process.	Must be sourced from a registered "SoHO entity"; requires full donor screening and testing data per SoHO Regulation [6] [4].
Orthogonal Assay Kits	Used to measure Critical Quality Attributes (CQAs) like identity, potency, and purity using different scientific principles [6].	Essential for building confidence in results, especially when reference standards are lacking. EMA guidelines encourage their use [6].
GMP-Grade Culture Media/Excipients	Supports the ex vivo manipulation and expansion of cells during the ATMP development protocol.	FDA does not allow research-grade materials; EMA requires GMP-grade manufacturing for investigational products [6].
Closed Single-Use Bioprocess Systems	Provides a sterile, single-use environment for cell culture and other manufacturing steps, minimizing contamination risk.	Recognized in the proposed revised GMP guidelines as a key technology to protect product quality [69].
Rapid Microbiological Testing Methods	Enables quick sterility testing and microbial monitoring, critical for products with short shelf-lives.	Acknowledged in the updated GMP guidelines as an advancement for ATMP manufacturing control [69].

The new SoHO Regulation significantly reshapes the initial, critical stages of the ATMP development pipeline. For researchers, scientists, and national authorities, the key outcomes are greater regulatory harmonization and an expanded scope of controlled activities. The successful development and authorization of ATMPs will now depend on demonstrating seamless compliance across two interconnected regulatory regimes: the SoHO Regulation governing the starting materials and the ATMP Regulation governing the final medicinal product. Building robust bridges between the historically fragmented communities of biomaterial collection and ATMP development is not just a regulatory necessity but a fundamental prerequisite for fostering 'homegrown' innovation in advanced therapies in Europe [68].

Conclusion

The oversight of ATMPs in the EU is a complex, two-tiered system where a strong centralized framework from the EMA is implemented with significant variation at the national level by NCAs. Success hinges on understanding these national nuances, particularly in areas like the Hospital Exemption, GMO approvals, and pricing negotiations. While challenges of divergence and access persist, future directions point toward greater harmonization through initiatives like the new SoHO Regulation and ongoing EU-level collaborations. For researchers and developers, proactive, early engagement with target NCAs is not just advisable—it is a critical determinant of efficiency and ultimately, in delivering these breakthrough therapies to patients across Europe.

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