Advanced therapy medicinal product (ATMP) classification – a case study on spinal cord injury

Abstract

Background

The classification of Advanced Therapy Medicinal Products (ATMPs) within the European regulatory framework poses significant challenges, particularly when biomaterials are combined with viable cells, as in spinal cord injury (SCI) therapies. Despite promising preclinical advances, many such therapies struggle to reach clinical application due to uncertainty surrounding product classification, especially in academic-led developments.

Main body

This review examines the regulatory criteria and procedures for ATMP classification in the European Union, with a focus on tissue-engineered products (TEPs). It addresses common difficulties in determining the principal mode of action, degree of manipulation, and intended function—key factors that guide classification. To illustrate these regulatory considerations in practice, we present the case of 1394UA, a hydrogel derived from human amniotic membrane extracellular matrix and integrated with induced neural stem cells, developed for SCI repair under the European Neurostimspinal project. The case highlights how early classification decisions can influence quality control strategies, non-clinical study design, and clinical development pathways.

Conclusion

Early regulatory classification is critical to reduce development uncertainty, especially for academic groups working on complex biomaterial–cell combinations. By clarifying regulatory expectations and aligning product features with appropriate ATMP designations, developers can better plan translational pathways. This review provides practical guidance to support the integration of regulatory science into early-stage ATMP development for SCI and similar applications.

Background

Spinal cord injury (SCI) remains a major unmet clinical challenge, with no approved regenerative therapies available in European Union. In recent years, a growing number of preclinical and early-stage clinical studies have explored the use of advanced therapy medicinal products (ATMPs) combining biomaterials and viable cells for neural repair. However, the regulatory classification of such complex products, particularly in academic-led development, often lacks clarity, which can hinder progression toward clinical translation.

This review aims to address the regulatory challenges surrounding ATMP classification in the context of SCI therapies, providing researchers and developers with practical insights into early classification pathways, particularly for tissue-engineered products (TEPs). To support this objective, we conducted a comprehensive literature search across PubMed/MEDLINE, Embase, and the Cochrane Library, covering publications from January 2010 to December 2025. The search strategy included terms such as spinal cord injury, hydrogel, extracellular matrix, amniotic membrane, neural stem cells, advanced therapy medicinal product, classification, EMA, regulatory, and quality. We also reviewed ongoing and completed clinical trials on ClinicalTrials.gov and performed targeted hand search of the European Medicines Agency (EMA) website for relevant regulatory documents.

We included peer-reviewed original articles, clinical trials, systematic reviews, consensus and guideline papers, and EU regulatory documents with clear translational relevance. Non–peer-reviewed materials and studies lacking relevance to either SCI or ATMP classification were excluded. The final selection emphasized literature that highlights regulatory frameworks and practical considerations for ATMP development.

Introduction

Academic institutions play a crucial role in advancing research and development of novel therapeutic products, especially for indications with an unmet medical need, across the European Union (EU) [1]. However, despite their significant contributions, a notable gap in regulatory science knowledge persists within academia. While a significant part of research in biomedical engineering is typically directed towards addressing unmet clinical needs, many studies are conducted without extensive consideration of quality and clinical requirements, market dynamics, and risk assessment [2]. Many promising research outcomes fail to progress toward market authorization (MA) due to limited understanding of regulatory pathways and commercialization challenges. Although Principal Investigators may understand the regulatory principles and pathways conceptually, the practical execution of ATMP‑specific requirements, such as preparing classification dossiers, designing compliant nonclinical development plans, preparing scientific advice packages, and managing iterative interactions with regulatory authorities, typically falls outside the skill set and available bandwidth of most academic teams. These activities require specialized regulatory expertise, operational experience, and familiarity with EMA procedural expectations. Consequently, effective translation often depends on engaging dedicated regulatory affairs professionals or external consultancy, who can convert high‑level regulatory understanding into actionable development steps and ensure that academic innovations progress efficiently and compliantly toward clinical translation. Addressing this gap is essential to ensure that innovative therapies can successfully transition from research to patient access. Therefore, enhancing regulatory expertise in academic settings is critical [3].

Among the innovations that fail to reach the market are numerous research findings in the past 10 years related to spinal cord injury (SCI) [4], a disorder that affects the nervous, vascular, and immune systems of over 15 million people worldwide [5]. There are currently no approved treatments in the EU for SCI, although the European Medicines Agency (EMA) issued a significant number of positive opinions on orphan medicinal product designations for such conditions [6]. There is, therefore, a critical clinical need for advancements in SCI treatments.

This review article aims to help bridge the gap in regulatory knowledge and reinforces the importance of integrating regulatory science within academic and translational research efforts. We propose a classification for a biomaterial (hydrogel) combined with cells for SCI repair, as this constitutes a critical regulatory step that should be undertaken as early as possible in the development lifecycle. Although still in the early stages of development, early consideration of the regulatory pathway is critical to ensure a smoother transition from preclinical research to clinical application, should the results prove successful. To this end, we aim to align with the regulatory strategy outlined in this article, incorporating compliance measures throughout the development of the biomaterial to facilitate eventual future market entry.

SCI therapeutic landscape: biomaterials, cell‑based strategies, and current preclinical approaches

SCI remains a debilitating condition, often leading to irreversible neurological deficits that severely impact motor, sensory, and autonomic functions. The persistent lack of effective regenerative treatments underscores the urgency of developing innovative therapeutic strategies aimed at restoring function and enhancing patients’ quality of life [4].

Several therapeutic modalities with unique mechanisms of action (MoA) have been explored in preclinical research, including the use of electrical stimulation, small molecules, exosomes, biomaterials and stem cells, and all aimed at addressing the multifaceted nature of SCI [7]. Among the most promising candidates to promote neural repair and functional recovery are biomaterials and cell-based therapies. Although many biomaterials are being investigated for SCI at the preclinical stage, only a few have progressed to Clinical Trials (CTs) [8–10]. Among cell types used as a treatment for SCI are mesenchymal stem cells (MSC), neural stem cells (NSCs), Schwann Cells and induced pluripotent stem cells (iPSC), each offering distinct MoAs. A much greater experience exists with stem cells in CTs for SCI, extensively reviewed in Sugai et al. (2025) [11]. A summary of main clinical findings with each cell type is provided in Table 1. A list of clinical studies for SCI involving biomaterials (with and without stem cells) are listed in Table 2.

Table 1.

Principal cell types used as cell-based therapies in SCI CTs

Stem Cell Type	CT phase	Key Findings	Clinical Relevance	Reference
Autologous MSCs	I-II-III	Improved motor power and daily living activities; no complications reported.	Potential for safe long-term application in humans.	[12]
NSCs	I-II	Significant improvements in motor function and neurological assessments in CTs	Demonstrates efficacy in promoting recovery post-SCI.	[11, 13]
Schwann cells	I	Improvements in motor and sensory function in a subset of patients	More clinical evidence needed	[11]
iPSC-derived NSCs	I-II	Promising results in animal models; ability to differentiate into NSCs observed.	Results of clinical studies currently being analysed	[13, 14]

Table 2.

Overview of SCI CTs with biomaterials

Product Name	Duration	Sponsor	Biomaterial	Cells	CT id	CT design	MAIN findings	Reference
Neuro-spinal scaffold™	2014–2023	In vivo Therapeutics	PLGAa) and poly-L-lysine	NA	NCT02138110	Prospective, open-label, single-arm, multicenter study	No treatment-related adverse effects. Improvement of impairment scale (AIS) (43.8%), exceeding historical controls	[15]
Neuroregen scaffold™	2015–2021	Chinese Academy of Sciences	LOCS b)	BMMCs or MSCs	NCT02352077	Phase I. Open-label, single-arm, multicenter study	No treatment-related adverse effects. Percentage of sensation level expansion was significantly higher in patients treated with MSC/NeuroRegen implantation than BMMNC/ NeuroRegen (57.14% vs. 10.71%, P < 0.05)	[16]
	2015–2021			BMMCs c) or MSCs	NCT02510365	Phase I. Open-label, single-arm, multicenter study	No treatment-related adverse effects. Significant improvement of the sensory and motor function in the two acute complete SCI patients treated with MSCs	[17]
	2016–2021			MSCs or NSCs	NCT02688049	Phase I/II. Randomized, double-blind, single center, two Arm (MSCs vs. NSCs)	Ongoing (No results published)	NA
	2019–2021			NA	NCT03966794	Phase I/II. Open-label, single-center, two arm (EESd) vs. scaffold & EES)	Ongoing (No results published)	NA
	2016–2021			BMMCs	NCT02688062	Phase I/II. Randomized, double-blind, single center, two Arm (scaffold with BMMCs vs. surgical intradural decompression and adhesiolysis)	Ongoing (No results published)	NA

^a)PLGA: poly (lactic-co-glycolic acid); ^b)LOCS: Linear ordered collagen scaffolds; ^c) BMMCs: Bone marrow mononuclear cells; ^d)EES: Epidural electrical stimulation

Cell-based therapies have shown promise in preclinical studies for their ability to differentiate into multiple cell types, promote cellular regeneration, and support recovery through mechanisms such as neuroprotection and immunomodulation. However, CTs to date have yielded mixed results, with many not progressing beyond early phases. This is often attributed to variability in patient responses, limited efficacy data, heterogeneous study designs, and challenges in meeting regulatory requirements for approval [18, 16].

Biomaterials are being developed to replace or repair damaged SCI. These materials may be used alone to provide structural support and modulate the local environment, or in combination with cellular components to enhance regeneration and promote long-term functional recovery through synergistic mechanisms [18]. A comprehensive strategy that integrates both approaches may offer the most effective therapeutic outcome for SCI. While biomaterials alone provide a supportive framework, their combination with cell-based therapies has the potential to improve the regeneration efficacy, although this remains predominantly in the experimental stage [14, 19–21]. Future investigations should aim to refine protocols that harness the advantages of each approach while simultaneously addressing their individual shortcomings [22].

Among the various types of biomaterials, hydrogels have been thoroughly investigated for their potential in SCI repair, due to their distinctive capacity to replicate the extracellular matrix (ECM) and create an environment that supports cell survival, proliferation, and differentiation [9]. Their highly hydrated and tunable structure allows for mechanical compatibility with spinal cord tissue and their use as carriers for stem cells, growth factors, or pharmaceuticals [8, 23].

Hydrogels can be employed in SCI repair through two principal strategies. One approach involves the use of preformed 3D hydrogel scaffolds, designed as solid constructs and surgically implanted at the injury site to provide structural support and promote axonal regeneration [24]. These scaffolds act as physical bridges, facilitating the reconnection of damaged spinal cord segments and supporting tissue repair. While this method has shown promise, it requires an invasive surgical procedure that may entail risks such as tissue damage, inflammation, or immune rejection [25]. Alternatively, injectable hydrogels offer a minimally invasive option. Unlike preformed scaffolds, they are delivered in liquid form and undergo in situ gelation upon injection at the injury location [26]. This approach provides several advantages, including adaptability to irregular lesion geometries, the possibility of repeated application without major surgery, and the capacity to establish a supportive microenvironment for neural regeneration [23, 27]. Promising results with ECM-based hydrogels in preclinical animal models further highlight their translational potential in regenerative medicine [25, 28].

In SCI research, preclinical studies commonly use standardized injury models, which differ from the heterogeneity seen in human clinical cases. This discrepancy reduces the translational relevance of preclinical findings and complicates the design of reliable, predictive non-clinical studies for regulatory purposes. To tackle this challenge, it may be advantageous to assess therapeutic strategies across a broader spectrum of injury types. Additionally, there is an urgent need to standardize assessment criteria for evaluating therapeutic efficacy in animal behavior tests, ensuring consistency with neurological assessments used in human CTs [25]. Reviews on suitable animal models for SCI emphasizes key steps to improve clinical translation and better link experimental and clinical research: (1) conduct comparative studies encompassing different injury types, more cervical models, multiple species, and both sexes to address inter-model variability; (2) strengthen data sharing to foster international collaboration and promote the use of clinically relevant animal models before testing biomaterial interventions; and (3) refine reporting standards by implementing randomization, blinding, sample size calculations, and transparent documentation on animal welfare and survival [29, 30].

Product classification and borderline products

The initial step towards identification of the appropriate regulatory pathway for successful development of any therapeutic product involves the correct product’s classification. In some cases, and especially when biomaterials are involved, the classification may not be straightforward, as the product may have characteristics of both Medical Devices (MDs) and Medicinal Products (MPs). MDs achieve their intended medical purpose almost exclusively through physical means and are governed in the EU by the Medical Device Regulation (2017/745) [31], while MPs achieve their intended medical purpose by pharmacological, immunological or metabolic means and are governed in the EU by the Medicinal Product Directive (2001/83/EC) [32]. In cases where both definitions apply, the principal MoA of the product will determine the correct classification [31–33]. When a product presents characteristics of both a MD and a MP, it may fall under the category of a combined or combination product. In these cases, classification depends on the primary mode of action, and both the Medical Device Regulation (EU) 2017/745 and the Medicinal Products Directive 2001/83/EC may apply to specific parts of the product. However, the route to commercialization and the organisms leading the revision process along the entire product development phase, will be defined by the specific product classification (MP or MD), based on the principal mode of action.

Biomaterials are often classified as MDs, as providing volume and scaffolder considered to be their primary function. However, they may also exert a secondary pharmacological function or incorporate, as an integral part, an ancillary medicinal substance. Even if the ancillary medicinal substance would be considered as a MP if used separately, as long as the primary function of the product is structural, they are still considered MD, specifically, class III (High risk) MD [31, 32].

Decellularized organ-derived ECMs are a particular type of biomaterials which can be presented in the form of a hydrogel. These ECM-based hydrogels retain ECM properties, supporting cell attachment, growth and differentiation. Translation of this type of products into clinical applications is particularly challenging due to the lack of specific regulations and quality guidelines. As with other biomaterials, decellularized ECM hydrogels have been primarily classified as MD. Under EU law, ATMP classification can be considered in two layers. Layer 1: identify the base ATMP category—gene therapy medicinal product (GTMP), somatic cell therapy medicinal product (CTMP), or tissue‑engineered product (TEP). Layer 2: determine whether the ATMP is also a combined ATMP, i.e., whether it contains a medical device as an integral part in addition to the cell/tissue component (Regulation (EC) No 1394/2007, Article 2(1)(d)). This attribute is not mutually exclusive with the base category. In this framework, a product consisting of a decellularized ECM scaffold combined with viable cells may fall under the ATMP scope when the cells/tissues are “engineered”—that is, they have undergone substantial manipulation or are intended for a non‑homologous function (Regulation (EC) No 1394/2007; Commission Directive 2009/120/EC). Conversely, simple seeding of minimally manipulated cells for homologous use does not automatically constitute an ATMP and may fall under the EU tissues and cells legislation [33, 34].

ATMPs are medicinal products based on genes, tissues, or cells with unique manufacturing methods and distinct MoA, offering new therapeutic options for a wide variety of diseases [33]. They are novel and complex products, where the still developing regulation needs to be continuously adapted to allow for the flexibility and case-by-case evaluation that these products require. Thus, transitioning from early research to clinical application may not be a well-defined path [35, 36]. Nonetheless, ongoing advancements and applications of ATMPs in regenerative medicine emphasize their potential to overcome these challenges and revolutionize treatment paradigms, with some products showing unprecedented efficacy rates [2, 3, 17, 18].

Case study: product classification

Product description

The product under development, designated 1394UA, is a novel biomaterial platform intended for SCI repair. Its foundation lies in the use of decellularized extracellular matrix (dECM) derived from the human amniotic membrane (AM). The design of 1394UA originates from engineering a biomimetic scaffold that structurally and biochemically mimics the native SCI microenvironment [37]. In the context of SCI, fibrotic scar formation, the presence of inhibitory molecules, and the absence of supportive tissue architecture critically hinder spontaneous neural regeneration [8, 22]. Effective tissue repair thus requires scaffolds that not only replicate the aligned, anisotropic structure of white matter tracts, but also support axon guidance, cell migration, and vascular integration [9]. The AM-derived dECM provides a rich composition of collagen, fibronectin, growth factors, and cytokines, and exhibits intrinsic anti-inflammatory, anti-fibrotic, and immune-privileged properties, making it a suitable material for neural applications [37–39]. To improve both the processability and functional performance, the AM-derived dECM is chemically modified with methacryloyl groups, yielding photo-crosslinkable methacryloyl Amniotic Membrane Materials (AMMA). This modification allows the formation of hydrogels and bioinks with improved mechanical stability and tunable degradation profiles, both critical for in vivo applications [40]. AMMA hydrogels can be structured into multichannel architectures that promote directed axonal growth and support the development of functional neural networks, as demonstrated in recent studies. However, a significant limitation of acellular scaffolds lies in the early infiltration of host immune and inflammatory cells post-implantation. Although this cellular influx is part of the regenerative process, it may also impede axonal outgrowth or contribute to glial scar formation [38]. To overcome this challenge, the concept of cell-laden scaffolds has emerged as a promising strategy. In this approach, the scaffold is pre-populated with therapeutically relevant cells prior to implantation, providing control over the local cellular environment and enhancing axonal bridging across lesion gaps [11, 12].

Accordingly, 1394UA integrates induced NSCs reprogrammed from human fibroblasts, into its AMMA scaffold. This combination is designed to provide not only the topographical and biochemical cues of the dECM, but also pre-differentiated neural progenitors capable of integrating with host tissue [38]. The incorporation of NSCs addresses key challenges in SCI therapy, such as limited endogenous regeneration and poor survival of transplanted cells, by providing a pre-formed neural network within the hydrogel framework. This dual-component strategy, merging a biologically active dECM-derived scaffold with therapeutically relevant NCS, offers a clinically translatable and modular platform for effective SCI repair [37–39].

Therapeutic indications

1394UA is the designated name of the AM-based biomaterial currently under development for SCI repair in this study. It is intended for allogenic use in the treatment of acute, sub-acute and chronic SCI in humans, within a defined, but yet to be determined, therapeutic window following injury. The proposed therapeutic strategy involves the application of a hydrogel specifically formulated to repair neural damage, stimulate axonal regeneration, and alleviate neuropathic pain associated with SCI lesions. Collectively, these effects aim to promote tissue regeneration and restore functional outcomes [38]. Administration of 1394UA must be carried out by a surgeon who is specifically trained and certified in its use.

Mechanism of action (MoA)

Understanding the MoA is critical for the appropriate classification and development of biomedical products [35]. In the case of 1394UA, the biomaterial has demonstrated the capacity to support long-term cell culture while exhibiting enhanced compressive strength, a key property for maintaining scaffold integrity in vivo. Moreover, the use of patterned hydrogel constructs allowed control over cellular alignment and elongation mimicking aspects of the native spinal cord microarchitecture [38, 39].

1394UA was comprehensively characterized through multiple analytical techniques, including X-ray microtomography, scanning electron microscopy, and mass spectrometry, which confirmed the structural and compositional features of the AMMA scaffold. Mechanical testing and in vitro assays further revealed that the hydrogel formulation provided a supportive environment for NSC culture, facilitating not only the adhesion and proliferation but also differentiation towards neural lineages [37–39]. These results suggest that 1394UA offers both structural and biochemical cues conductive to neural tissue regeneration, aligning well with its intended application in SCI repair. Given the promising results obtained, a regulatory classification exercise is now being considered to guide the product’s continued development.

Product classification example

Classifying a borderline product can be a complex task, and in certain instances, often require careful evaluation to precisely define its category. Establishing the correct classification early in the process is crucial, as it sets the regulatory framework that will guide the product’s development pathway [35]. To facilitate this process, the EMA has established an optional scientific recommendation procedure for ATMPs classification [41]. Early regulatory interactions play different roles depending on the type of advice. Classification advice helps developers correctly position the product within the appropriate regulatory framework, reducing development uncertainty but without a demonstrated impact on later marketing authorization outcomes. In contrast, formal Scientific Advice and early-support mechanisms such as PRIME have been associated with higher approval success rates, as they directly address clinical, quality, and non-clinical development expectations [35].

As part of this discussion, we present an exercise illustrating the classification process of 1394UA. The classification presented below reflects the author’s regulatory assessment only and has not been confirmed through the EMA/CAT ATMP classification procedure. The initial step involves two questions: (i) determining whether the product is intended for medicinal purpose, such as treating, preventing, or diagnosing a disease. Since this product is specfically developed for SCI repair, it is classified as having a medicinal purpose; and (ii) to understanding its principal MoA, and weather its therapeutic effect is exerted primarly through a physical mode or through a pharmacological, immunological or metabolic action. The answer to this question is decisive whether the product should be classified as a MD or a MP. In this case, the dECM in the form of an hydrogel provides primarly a supportive structure. However, the principal MoA is exerted by the NSC, which regulate the local cellular environment and facilitate axonal bridging across lesion gaps. Since the product contains living cells, once classified as MP, it falls under the category of an ATMP. Within the ATMP framework, several subcategories are recognized, such as cell therapy medicinal product (CTMP), tissue-engineered product (TEP) or combined ATMP may apply. An exercise for the ATMP classification of 1394UA is shown in Fig. 1. The first step concerns its composition, particularly whether it consists predominantly of biological materials. In this case, 1394UA is composed of a decellularized and solubilized AM, which is classified as a biological material, along with added neuronal cells (alive cells). The second step involves an assessment of the MoA, focusing on whether the product is intended to replace or modify the structure or function of body tissues or cells. Given its clear role in tissue repair, the answer is affirmative. A further evaluation of the product’s specific characteristics as outlined in Fig. 1, leads to its final classification as an ATMP-TEP, and not a combined ATMP. This outcome is consistent with the four ATMPs classification previously issued by EMA for products intended for SCI repair, all of which were all classified as TEPs [42].

Fig. 1.

Classification flowchart. Adapted from [34]

The classification of 1394UA as an ATMP must consider both its biomaterial composition and its functional role in promoting tissue regeneration. As per Article 3 of [31], 1394UA is composed of tissue which means all constituent parts of the human body formed by cells; and is intended for allogeneic use which means tissues removed from one person and applied to another; it is also intended for ‘human application’ which means the use of tissues on or in a human recipient and extracorporeal applications.

According to Article 1 of [33], 1394UA qualifies as a TEP on the basis of two criteria:

1. it contains or consists of tissues and is presented as having properties for, or is intended to be used in, human beings with the aim of regenerating, repairing or replacing human tissue. Specifically, 1394UA contains non-viable human-derived tissues, as the cells no longer have a functional cytoplasmic membrane due to chemical modification. This modification is nevertheless essential, as it enables the fine-tuning of the chemical and physical properties of decellularized matrices [38, 40].

2. the tissues have been undergone substantial manipulation, in order to achieve biological characteristics, physiological functions, or structural properties relevant for the intended regeneration, repair or replacement. EMA defines substantial manipulation as any alteration that would affect the biological characteristics and physiological functions of the tissues. EMA also states that manipulation results in changes that lead to significant alterations in tissue functionality [34]. In the case of 1394UA, the material is subject to enzymatic digestion, as tissue samples were digested with pepsin in a solution of HCl under constant stirring for 72 h [40].

As per art. 2(4) of Regulation (EC) Nº. 1394/2007 [33], 1394UA cannot be classified as a cell therapy medicinal product. An important aspect of the classification process concerns the mode of administration, which must be clearly defined before regulatory process is concluded. According to the EMA, for instance, if a product is administered via a bioresorbable scaffold that serves as a supportive framework, it may fall under the category of a combined ATMP and, in such cases, must also comply with additional criteria as per the Medical Devices Regulation (MDR) [31].

ATMP classification in the EU follows a two‑layer structure: first, the base ATMP category is identified (GTMP, CTMP or TEP); second, determining independently whether the product also qualifies as a combined ATMP due to the presence of an integral medical device. These designations are not mutually exclusive. Under Regulation (EC) No 1394/2007, a combined ATMP is a product that contains one or more medical devices as an integral part and includes viable cells/tissues, or if non‑viable, the cells/tissues have an effect on the human body that is not ancillary to that of the device (Article 2(1)(d)). Whether a product is a combined ATMP therefore relies on the presence of a medical device component that is integral to the product, in addition to the cell/tissue component. For 1394UA, the first layer clearly places the product within the definition of a tissue‑engineered product because it contains NSCs intended to regenerate neural tissue. The second layer requires determining whether, in addition to being a TEP, the product incorporates an integral, identifiable medical device component. In 1394UA, the structural matrix is a biological scaffold derived from human amniotic membrane and chemically modified to form a photo‑crosslinkable hydrogel that is injected in situ together with NSCs. The functional properties of the matrix are ultimately determined by the seeded cells, which remodel and integrate with the substrate to create a pre-formed neural network. This scaffold does not retain the characteristics of a standalone medical device within the final formulation; rather, it functions as an integral formulation component within a single medicinal product whose principal mode of action is mediated by the viable cells for tissue regeneration. Because the scaffold does not function as, nor can it be regulated as, a discrete device integral to the final product, the combined ATMP criteria are not met. Thus, while 1394UA satisfies the first layer as a TEP, it does not satisfy the second layer for a combined ATMP and is therefore classified only as TEP. This conclusion may be refined upon full physicochemical and functional characterization of the modified matrix. In conclusion, 1394UA is an ATMP based on tissue engineering for human use. This outcome is supported by the classification assessment presented in Fig. 1 and the final conclusions highlighted in red [33, 34]. Importantly, ATMP classification represents a regulatory starting point rather than a final determination, as it establishes the applicable framework while not substituting the subsequent quality, non-clinical, and clinical development requirements.

Applying for ATMP classification at EMA

The requirements for submitting a classification request may vary depending on the development stage of the product. If the product is still in its early stages of development, the available information may not be sufficient to be conclusive. In such cases, it may be considered acceptable to present the target product profile along with a general description of the intended product [41].

In cases where the product has reached a more advanced stage of development, the submission should include a detailed description of the pharmaceutical form and the characteristics of the finished product intended for clinical use, together with its qualitative and quantitative composition. It should be also present the key elements of manufacturing and quality aspects, including description and level of manipulations on cells and tissues. Such manipulation may involve procedures such as cutting, grinding, shaping, centrifugation, soaking in antibiotic or antimicrobial solutions, sterilization, irradiation, cell separation, concentration or purification, filtering, lyophilization, freezing, cryopreservation or vitrification. In addition, an outline of the planned non-clinical and clinical development must be provided [41].

Submitting a classification request as soon as there is a clear understanding of the MoA and of the intended product characteristics is highly recommended. The discussions with EMA and the outcome regarding classification might have a critical impact during the development stages and go-to-market strategy [36, 41].

Advanced therapy medicinal product

EU regulatory landscape of ATMP development and commercialization

Since 2009, several regulatory initiatives have been established in EU to facilitate the development of ATMPs aimed at addressing unmet medical needs. These pathways often allow for more flexible requirements, such as smaller datasets, to accelerate the translation process. However, this flexibility is balanced by a need for more rigorous post-market surveillance to ensure long-term safety and efficacy. As the field of ATMPs continues to develop, it is crucial that legislation adapts to promote a regulatory environment that supports innovative therapies to reach the market [36, 43].

Given that ATMPs aim to address significant unmet medical needs, assessing their potential benefits is often more straightforward than determining associated risks. Risk assessment based on preclinical testing is particularly challenging for ATMPs, as standard safety tests, typically performed by Clinical Research Organization (CROs) under Good Laboratory Practices (GLP) conditions, are not always appropriate for ATMPs. On one hand, ATMPs may exert their MoA through human-specific proteins/interactions, which cannot be adequately assessed in animal models. On the other hand, cell-based ATMPs are likely to be rejected in such models due to host vs. graft immune responses, limiting the predictive value of preclinical studies. Several guidelines outline the key parameters to be evaluated during the preclinical development of ATMPs (as discussed in Sect.  5.3). However, the heterogeneity among ATMP products, still requires a case-by-case assessment, which is usually defined during interactions with EMA in the form of scientific advice or meetings in the very early steps of development (i.e. meeting with Innovation Task Force). Therefore, coordinated efforts among all stakeholders during the development phase are essential to develop adequate testing strategies [43–45].

An outline of the regulatory framework for ATMPs in the EU, primarily established by Regulation (EC) No 1394/2007 [33], is presented in the next section. This includes the structure of the application dossier required for MA, together with specific considerations pertaining to the quality, non-clinical and clinical sections of the dossier.

EMA has made significant progress in shaping the regulatory landscape for ATMPs, with a total of 45 approvals between 2009 and 2024, 28 positive draft opinions issued, and 10 applications withdrawn during evaluation. Furthermore, in the same period, EMA provided scientific guidance for 682 ATMPs, reflecting the increasing emphasis on innovative therapies and the critical role of regulatory support in their development [46]. These statistics highlight both the complexity of the ATMPs regulatory pathway, and the challenges associated with obtaining regulatory approval. Given this complexity, early engagement with regulatory authorities, particularly through scientific advice, is highly recommended. Such engagement facilitates compliance with evolving requirements and fosters collaboration among stakeholders, ultimately improving the accessibility and development of these therapies [36, 43].

An increasing number of ATMP CTs are being conducted in the EU, reflecting their potential for curative and long-lasting therapeutic effects. TEPs represent a relatively small portion of these trials, accounting for approximately 6% of all ATMP CTs. Of the 90 TEP trials identified, 25 were Phase I/II trials, 35 were Phase II, 28 were Phase III, and two were Phase IV trials. Their development is geographically concentrated in specific EU member states, including Germany, Spain, Belgium, and Poland, each hosting more than 18 CTs sites [47].

Table 3 presents a comprehensive list of the EU legislation relevant for ATMPs. Of particular importance is the Regulation (EC) No 1394/2007, which establishes a unified legal framework for safety, efficacy, and support for innovation in the development and authorization of ATMPs [33]. Regulations are further supported by a collection of guidelines available on the EMA’s website [48]. Identification of applicable guidelines is key for early determination of the appropriate non-clinical, quality and clinical strategy, to generate the relevant data according to each phase within the product’s development, that will be expected by authorities at the time of submission of a Clinical trial application (CTA) or Marketing authorization application (MAA).

Table 3.

Overview of the ATMP relevant EU legislation sorted by relevance

EU legislation	Purpose
Directive 2001/83/EC	Establishes a harmonized framework for the authorization, production, and distribution of medicinal products for human use within the EU, ensuring their safety, efficacy, and quality.
Regulation (EC) No. 1394/2007	Establishes a specific regulatory framework for ATMPs, including gene therapies, somatic cell therapies, and tissue-engineered products. Amends Directive 2001/83/EC and Regulation (EC) No. 726/2004.
Regulation (EC) No. 726/2004	Provides a centralized procedure for the authorization and oversight of medicinal products across the EU, ensuring consistent safety, efficacy, and quality standards.
Regulation (EU) No. 536/2014	Harmonizes the regulation of CTs across the EU, ensuring high standards of safety and ethics while enhancing the efficiency of the approval process.
Regulation (EC) No. 668/2009	Addresses the importation of non-EU investigational medicinal products for CTs.
Directive 2009/120/EC	Revises the definitions and established detailed scientific and technical requirements for gene-therapy medicinal products, somatic cell-therapy medicinal products, tissue-engineered products, as well as ATMPs containing devices and combined ATMPs.
Directive 2001/20/EC	Addresses the implementation of good clinical practice in the conduct of CTs on medicines for human use.
Directive 2005/28/EC	Establishes rules for the Good Clinical Practices (GCP) of conducting CTs on medicinal products for human use, ensuring the protection of trial participants and the integrity of trial data within the EU.
Directive 2003/94/EC	Defines the principles for Good Manufacturing Practices (GMP) of medicinal products for human use and investigational medicinal products in the EU, ensuring their quality and safety.
Directive 2004/23/EC	Sets standards for quality and safety for the donation, procurement, testing, processing, preservation, storage, and distribution of human tissues and cells. It has the following technical implementing directives: Directive 2006/17/EC, Directive 2006/86/EC, Directive 2015/565, and Directive 2015/566.
Directive 2002/98/EC	Defines standards of quality and safety for the collection, testing, processing, storage and distribution of human blood and blood components.
Regulation (EC) No. 141/2000 & No. 847/2000	Facilitates the development and marketing of orphan medicinal products for the treatment of rare diseases by providing incentives such as market exclusivity and financial support to encourage research and investment in these areas.
Regulation (EC) No. 1901/2006 & No. 1902/2006	Ensures that medicines for pediatric use are developed and authorized in a manner that is appropriate for the specific needs of pediatric patients.
Directive2001/18/EC	Assessment of environmental and health risks of genetically modified organisms.
Regulation (EC) No. 507/2006	Establishes a special procedure for granting MA for orphan drugs in the EU, thereby facilitating their availability to patients in need.

Detailed information related to product’s quality, non-clinical and clinical development of the product are presented to regulatory agencies for evaluation in the form of Investigational Medicine Product Dossier (IMPD), for products under clinical development, or in the form of electronic Common Technical Document (CTD), for Marketing Authorization Approval (MAA). It is important to mention that, while CTs are under the remit of National Competent Authorities (NCA), MA for ATMPs requires a centralized approval, which is under the scope of EMA.

While IMPD and eCTD are structured differently, the content is highly similar. However, the expected available data increases as the product advances through clinical development, up to the expectations required for MAA. Specific data required depending on product stage is described in the applicable guidelines and it is summarized within the quality, non-clinical and clinical section below.

Figure 2 provides a general overview of the common structure of the application dossier, taking into account the international agreements on the CTD, which were established in November 2000 under the framework of the International Conference on Harmonisation (ICH). This dossier must be submitted to initiate the MA procedure and follow a standardized structure divided into five modules. Module 1 includes all relevant administrative information necessary to ensure compliance with regional regulations governing ATMPs. Module 2 provides a comprehensive overview of the product by outlining the dossier’s organization, goals, and scope. It also summarizes the quality data and evaluates the non-clinical and clinical evidence, complemented by tabulated summaries of key findings. Module 3 gathers extensive quality data, including product specifications and additional characterization, raw and starting materials, manufacturing process and in-process controls, product stability studies and packaging of the ATMP. Module 4 includes all available non-clinical data, providing insights into efficacy and MoA, toxicity, biodistribution, and overall safety assessments. Finally, Module 5 contains essential information derived from Clinical Study Reports (CSRs). It includes data clinical data available for the evaluation of efficacy and safety of these therapies, which often involve innovative study methods and non-standard outcome measures. In standard circumstances, ATMP applicants must submit comprehensive CT data similar to traditional medicines.

Fig. 2.

Requirements for MA. Adapted from ICH [49]

Quality

Quality section of IMPD or eCTD is usually divided into “Drug substance” and Drug product”. “Drug substance” refers to the manufacturing of the active ingredient, while the “Drug product” refers to the manufacturing of the pharmaceutical product, from the “Drug substance” in its final form and with appropriate excipients and packaging. Although typically, different specifications and manufacturing systems are used for “Drug substance” and “Drug product”, for some ATMPs, the manufacturing process is considered to be continuous, and if properly justified, it is possible to include the necessary information only in one of the quality sections (Drug substance or Drug product) of the dossier. In general, information about starting and raw materials used and their control, manufacture process development and validation, control or manufacture process through in-process controls, product specifications and additional characterization, description of analytical methods and their validation, justification of specifications and product stability studies are expected.

The manufacturing of ATMPs requires strict adherence to GMPs to ensure product quality and safety at all stages of development and production. Critical parameters within the process must be established to ensure the reproducibility, safety, and consistency of the final product, employing a “quality by design” approach as described in Part IV of EudraLex - Volume 4 - Good Manufacturing Practice (GMP) guidelines [50].

In line with EMA recommendations [51], the following considerations are of particular interest for ATMP development:

1. Manufacture process modifications: Manufacture process may suffer modifications and improvements through the product’s clinical development phase. Such modifications should be extensively documented within the “Manufacture process development” of the dossier. Before introduction of changes within the manufacture process, a comparability exercise, may be required to assess any impact on the product’s safety and/or efficacy. Design of the comparability exercise should be based on risk-assessment. For significant modifications to the manufacturing process introduced later in the development process, quality comparability assessments alone may be insufficient to guarantee the continuity of the product’s critical quality attributes. In such cases, EMA may request additional bridging non-clinical and/or clinical studies to support the safety and efficacy of the modified products. For complex comparability exercises, especially the ones performed at late stages in product development, discussion of the comparability exercise plan with EMA (or relevant competent authority) is recommended.

   Additionally, if the product is manufactured in more than one facility (i.e. Point-of-care manufacture systems), a comparability exercise demonstrating equivalency of batches produced at different facilities is essential.

   Thus, introduction of potential changes in manufacturing processes, including scale-up activities, should be planned in advance, since completing regulatory requirements before implementation of a particular change can be time-consuming, and can significantly impact the progress of product development.

• b.Process validation: Manufacturing process validation is not expected to be completed while the product is in clinical development stages, but it will be required at the time of MAA [51].
• c.Analytical methods: Analytical methods described in EU Pharmacopeia monographs should be used, when applicable. For specific analytical methods, not covered by EU Pharmacopeia, an in house method should be developed and qualified or validated, according to the stage of product development [51].

For each analytical method, especially those assessing product’s specifications, the Sponsor is required to provide qualification data, or at least demonstrate the method is suitable for the intended purpose, during clinical development phases. At the time of MAA, a full validation or verification (whichever applies) of the analytical method is expected.

1. Particular attention needs to be paid to the measurement of product’s potency [52]. While qualitative potency assays may be valid during clinical development, a quantitative potency test that assesses product’s biological activity related to its MoA should be ready before pivotal CTs and validated, with justified acceptance criteria, by the time of MAA [53].

2. Commercial reference standards may be used, if available, for determination of analytical method accuracy and to establish quantitative parameters in manufactured batches relative to a known reference. For ATMPs, however, it is common that commercial reference standards are not available. In these cases, a particular manufactured batch, thoroughly characterized and representative of the manufactured batches, may be established as a reference material for the assessment of critical quality attributes of the product, such as potency, which may be expressed as a percentage of the reference material. Establishment and characterization of appropriate reference materials should be completed by the time of MA.

• d.Stability studies: Stability studies assessing long-term storage and in-use stability of the product should be planned and conducted according to the time-points and parameters described in ICH Q5C. Stability testing of biotechnological/biological product. Besides stability testing of “Drug substance” or “Drug product”, stability studies may also be required for any starting material used [51, 54].
• e.Identity: Verification of the biological origin and specific markers characteristic of the cell or tissue type, using flow cytometry, immunophenotyping, or molecular methods. Proper identification confirms the product’s intended biological identity [51].
• f.Strength/Potency: Quantitative assessment of biological activity related to the intended MoA, such as specific enzyme activity, gene expression levels, or cell viability. Validated potency assays should be developed early and maintained throughout development to demonstrate consistency and support clinical efficacy. Establishing acceptable ranges and justified criteria for potency is critical [51, 53].
• g.Purity: Evaluation of residual host cell proteins, DNA, plasmid DNA (for gene therapies), and other contaminants. Analyzes should meet strict acceptance criteria to minimize safety risks, including adventitious agents [51, 53].
• h.Safety: Testing for microbial contamination, endotoxin levels, and other contaminants such as mycoplasma. The product must be manufactured under sterile conditions, and validated sterility and endotoxin tests must be performed at appropriate stages [51, 55].
• i.Physico-chemical properties: Parameters such as particle size, pH, osmolality, viscosity, and stability of the final product should be assessed as applicable. These attributes impact product handling, delivery, and stability, and should be optimized according to the product type [51].

The fulfillment of regulatory requirements at different stages of the manufacturing process with special focus on validation, which is critical to meet those requirements, makes the approach described in this article very interesting, and it should serve as inspiration for manufacturers that must ensure GMP compliance for cell therapy products [56].

Nonclinical development

The primary objective of non-clinical studies is to provide evidence on the pharmacological, pharmacokinetic and toxicological effects anticipated in humans following administration of the ATMP. These studies also support the determination of safe and therapeutically relevant dose range for First in Human (FIH) CTs, as well as provide insights to support the preferred administration route for the medicinal product. Moreover, non-clinical studies play a critical role in identifying target organs susceptible of toxicity, delineating parameters that should be monitored in patients, and determining at-risk patient populations for experiencing adverse events. Collectively, this information is essential for addressing key safety and efficacy concerns associated with ATMP development [56, 57]. In general, limitations in non-clinical development include the complexity of ATMP manufacturing processes and their intrinsic variability, and quality control standardization [21].

Unlike with other more traditional medicines, for ATMP products, most non-clinical studies are to be completed before FIH studies, with only very specific studies required at later stages of product development. Additionally, as per EMA’s recommendations [48, 51], the following considerations are of particular interest:

1. Pharmacology studies: In silico, in vitro and in vivo studies to characterize the product’s MoA and other pharmacological effects, together with a proof-of-concept study to demonstrate the efficacy of the ATMP, is usually considered sufficient. With the exception of safety pharmacology studies (if applicable), primary and secondary pharmacology studies are usually not conducted in GLP.

2. Pharmacokinetic (PK) studies: PK studies of ATMPs are typically designed to characterize the product’s biodistribution upon administration using the same route as intended in humans. Biodistribution studies should include analysis of ATMP persistence, mobilization and shedding. For cell-based ATMPs, host vs. graft effects may limit the feasibility of these studies to immunodeficient animals. GLP compliance of PK studies is not required.

3. Toxicology studies: In the case of ATMPs, conducting toxicology studies in a single animal species may suffice, if only one relevant animal species exist. However, addition of a second species, including both sexes, might be necessary in some cases, to address all safety aspects. Toxicology studies are usually conducted using healthy animals. However, for cell-based ATMPs, testing in immunocompetent animal species may be hampered by immune responses against the product. In such cases, use of immunodeficient animal models to assess toxicological endpoints may be required. Use of the same animal model for PK and toxicology studies may be beneficial to correlate PK biodistribution with toxicity signals. General toxicity studies are required to estimate safe starting doses and dosing regimens. Dosing schedules and administration route should mimic clinical use, and doses used in toxicity studies must cover the intended dose for clinical studies (human-equivalent dose) with appropriate safety margins. Finally, traditional genotoxicity and carcinogenicity studies are not required for ATMP. However, evaluation of risk of tumor formation prior to human exposure, using relevant in vitro/in vivo assays may be required to determine oncogenic potential of GTMP. Generally, toxicity studies are expected to be conducted under GLP, however, for ATMP, this is not always feasible, as discussed below.

GLP consists of a set of principles designed to ensure the consistent and reliable conduct of non-clinical safety studies. Due to the unique and complex nature of ATMPs, adaptations to standard GLP procedures are often required. While pivotal safety studies are generally expected to comply with GLP standards, there may be situations where full compliance is not feasible. In such cases, a scientific justification must be provided, clearly outlining the reasons for non-compliance, its potential impact on data reliability, and comprehensive documentation of how the study was conducted. For any preclinical study not conducted under GLP, following a set of GLP-principles is highly recommended: [51, 58]

1. Studies should be identified by a unique study code. Coding system does not have to follow any requisites, but it should be logical and consistent across studies. This helps authorities track studies and data across different sections of the dossier or across several documents.

2. Studies should adhere to a prospectively designed study protocol. Writing study reports, with the documentation of the study and results, together with a description of any deviations from the protocol, is highly recommended.

3. Data archiving with appropriate identification and traceability is essential.

SCI displays wide heterogeneity in lesion type, level, and severity, which limits the predictive value of any single animal model. Regulators and the field increasingly expect use of multiple injury models (e.g., contusion and transection) and, where feasible, inclusion of both thoracic and cervical segments to better reflect clinical variability. Standardization of behavioral assessments is critical; aligning commonly used preclinical scales (e.g., BBB, ladder‑rung) with clinical scales improves translational relevance [30].

Clinical development

Exploratory studies involving investigational ATMPs are frequently structured as phase I/II trials, integrating elements from both phase I and phase II designs. These studies aim to fulfill a broader range of objectives beyond merely evaluating safety and tolerability. In addition to establishing the initial safety profile, exploratory trials are often intended to evaluate the overall treatment strategy and the clinical application of the ATMP, while also assessing the feasibility of patient recruitment. They play a critical role in identifying and characterizing potential manufacturing and administration challenges that may impact product development. Furthermore, such trials allow for the characterization of pharmacokinetics and assessing biodistribution in humans, as well as the examination of pharmacodynamics and obtaining preliminary measurements of therapeutic efficacy. Another critical objective is the selection of appropriate dosages and establishing the recommended dose for subsequent CTs [13, 59].

Because SCI affects multiple domains of daily life, multidimensional endpoints are encouraged, such as upper‑extremity function (GRASSP) and global independence, which have established measurement properties and practical use in trials. Recent systematic reviews on current ATMP-based treatments for SCI underscore the need for these preliminary findings to be validated through multicenter, large-scale, randomized controlled trials conducted in clinical practice. Clinical development in SCI presents distinctive challenges that shape regulatory expectations for ATMPs. Heterogeneity in neurological level, completeness (AIS grade), and baseline function strongly influences outcomes and therefore trials should stratify by AIS grade and injury level to enable interpretable effect estimates. Trial feasibility is further constrained by therapeutic windows (acute, subacute, chronic) and specialized neurosurgical delivery requirements that must be planned into clinical operations and risk management for ATMPs [7, 11, 13]. Finally, consistent with ATMP pharmacovigilance principles, long‑term clinical follow‑up is typically required to monitor delayed risks and durability of effect in cell‑ and tissue‑based products [51].

Conclusion

This article contributes to better understanding the classification framework for ATMPs within the EU regulatory landscape, exemplified by the case of 1394UA. Our detailed analysis highlights that the classification of such products depends not only on their biomaterial composition but also on their functional role in tissue regeneration, which directly influences their regulatory pathway. For instance, 1394UA is classified as a TEP based on specific criteria, including its substantial manipulation and intended regenerative purpose. Early classification is crucial for aligning product development with regulatory expectations and ensuring a clear pathway toward clinical translation.

Furthermore, the process of applying for ATMP classification at EMA requires documentation of substances description, manufacturing processes, manipulation procedures, and intended MoA. Our discussion emphasizes that early engagement with regulatory authorities, coupled with detailed and transparent submission of product data, can significantly streamline the pathway from research to market.

As future work, we will focus on delineating additional requirements to achieve MA as outlined in Directive 2001/83/EC, Annex I [32], including the exploration of non-clinical and clinical evidence necessary for successful applications. We further encourage close collaboration between researchers and regulatory agencies to accelerate the development of these transformative therapies, which hold the potential to revolutionize the treatment landscape for SCI.

Abbreviations

AM

Amniotic Membrane

AMMA

Methacryloyl Amniotic Membrane Materials

ATMP

Advanced Therapy Medicinal Product

CTA

Clinical Trial Application

CT

Clinical Trial

CTD

Common Technical Document

CTMP

Cell Therapy Medicinal Product

dECM

Decellularized Extracellular Matrix

ECM

Extracellular Matrix

EMA

European Medicines Agency

FIH

First in Human

GCP

Good Clinical Practice

GLP

Good Laboratory Practice

GMP

Good Manufacturing Practice

ICH

International Council for Harmonisation

IMPD

Investigational Medicinal Product Dossier

MA

Marketing Authorization

MAA

Marketing Authorization Application

MD

Medical Device

MoA

Mechanism of Action

MSC

Mesenchymal Stem Cell

MP

Medicinal Product

NSC

Neural Stem Cell

PK

Pharmacokinetics

SCI

Spinal Cord Injury

TEP

Tissue-Engineered Product

Author contributions

LD created the article concept, coordinated the literature search, and drafted the manuscript. MC contributed to the regulatory analysis, ATMP classification framework, and critical revision of the case study section. PAAPM provided supervision, contributed to the biomaterials and hydrogel methodology content, and critically revised the manuscript for technical accuracy. BG contributed to multiple sections, refined the discussion and conclusions, and reviewed the manuscript for clarity. All authors approved the final manuscript and agree to be accountable for all aspects of the work.

Funding

This work is supported by national funds through FCT - Fundação para a Ciência e a Tecnologia, I.P., under the project UID 00481 - Centre for Mechanical Technology and Automation and the project UID 4501 - Institute of Biomedicine - Aveiro. Also, by FEDER - Fundo Europeu de Desenvolvimento Regional, through the project 3DNeuroStim COMPETE2030-FEDER-00744900.

Data availability

The data supporting the conclusions of this article are available from the corresponding author on reasonable request. All regulatory documents and guidelines referenced in this review are publicly accessible through the European Medicines Agency and official EU legislation portals, as cited in the manuscript. Certain ISO standards referenced may require purchase from official standards organizations.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Use of AI tools

The authors used GenAI (e.g., ChatGPT) to assist with literature synthesis and filtering, GitHub Copilot to identify and retrieve specific data sources, and Google searches to summarize large research studies. All content was reviewed and approved by the authors.

Competing interests

The authors declare no competing interests related to this work.