While Europe has established a comprehensive framework to standardize the development of “living drugs”, challenges ranging from scalable manufacturing to reimbursement uncertainty continue to emerge alongside these regulatory guidelines. Understanding the barriers and potential solutions is crucial for translating promising research into accessible life-changing therapies.
Regulatory hurdles associated with advanced therapy development cannot be evaluated in isolation, with the key aspects depicted above having an equal impact on treatment’s success and availability. © Green Elephant Biotech.
From exploratory laboratory research to clinical-grade manufacturing, the moment a therapy involves human cells, gene editing, or tissue engineering, it crosses a regulatory threshold. At this point, it is classified by the European Medicines Agency (EMA) as an Advanced Therapy Medicinal Product (ATMP). These highly specialized “living drugs” harness cells, tissues, or genetic material to repair, replace, or modify human functions and structures (1).
In Europe, the development of ATMPs is governed by Regulation (EC) No. 1394/2007, which seeks to harmonize standards for product quality (i.e., robustness and reproducibility), safety (i.e., absence of carcinogenicity and contamination), and efficacy (i.e., potency) across EU member states (2). While this framework was designed to streamline approval and ensure patient safety, experience over recent years has shown that it has also contributed to making ATMP development a highly regulated and operationally complex endeavor.
To date, only 59% of advanced therapies evaluated by the EMA have received a positive opinion, with many encountering additional commercial barriers even after approval. Scientific uncertainty, high pricing, manufacturing complexity, and fragmented national reimbursement policies together contribute to an ATMP withdrawal rate of 36% across Europe (1).
Although biological relevance and economic viability are understandably prioritized, there remain strategic levers that policymakers and manufacturers can use to improve patient access to advanced therapies. Below, we explore several frequently overlooked challenges that ATMP developers face along the path from innovation to patient delivery.
Clinical success of an advanced therapy is susceptible to commercial failure
Among the most widely discussed obstacles in ATMP development are pricing and reimbursement — issues that sit at the intersection of regulatory acceptance and manufacturing feasibility. Because many ATMPs target rare or ultra-rare genetic disorders, Health Technology Assessment (HTA) bodies often regard the available clinical evidence as insufficient to justify widespread reimbursement.
Clinical trials involving small patient populations and limited follow-up periods face a heightened risk of unfavorable HTA decisions. This risk is further amplified by the absence of robust natural history data or clearly-defined clinical endpoints, both of which complicate the assessment of long-term benefits, such as healthcare cost savings (1).
To manage this uncertainty, several EU member states have introduced mitigation mechanisms. Outcome-Based Agreements (OBAs), for example, link a manufacturer’s revenue to the real-world performance of an ATMP after market entry. Split-payment models address the challenge of high upfront costs by distributing payments over time and adjusting them if predefined outcomes or commercial milestones are not met (3).
A frequently cited example is Zolgensma (onasemnogene abeparvovec), a one-time gene therapy for spinal muscular atrophy (SMA). By delivering a functional copy of the SMN1 gene via a viral vector, the therapy prevents further motor neuron degeneration. Despite its list price of EUR 2.15 million, access was enabled in several EU countries through the use of OBAs and split-payment arrangements (3, 4).
Quality assurance – when acting in good faith creates one of the largest roadblocks
Advanced therapies are often administered to critically ill patients and frequently have irreversible effects, raising the regulatory bar well above that of conventional small-molecule drugs. Once classified as an ATMP, a product must comply with an extensive legal framework covering manufacturing processes, quality control, safety, and clinical use (5).
The challenge lies in the inherent variability of living systems. Cells and tissues can differ significantly in potency, stability, and functional performance, complicating quality assurance at both the clinical trial stage and during manufacturing. While cell quality verification may be manageable for a single batch, ensuring consistency at scale remains a substantial hurdle.
Differences in cell culture vessels, process control strategies, and scale-up approaches can introduce subtle but consequential sources of variability beyond biological, increasing the risk of unfavorable EMA assessments. In the documented cases of ATMP withdrawal, therapies supported by strong clinical data ultimately failed to demonstrate the level of reproducibility and process robustness required for regulatory confidence (1). Such manufacturing variability extends its impact onto long-term product quality, commercial sustainability, and ultimately, patient safety.
Although Regulation 1394/2007 clearly defines quality, safety, and efficacy requirements, adherence without sufficient regulatory guidance can be costly and discouraging. Evidence suggests that EU member states applying particularly strict interpretations of cell quality and clinical data requirements may inadvertently restrict patient access by limiting flexibility for unconventional or emerging therapies (4).
Looking ahead, artificial intelligence is expected to play an increasing role in addressing these challenges. Predictive models capable of forecasting process deviations could support product uniformity and enable automated corrective actions. Complementary strategies, such as cell banking and dynamic culturing, are also being explored to support greater digitization and control of ATMP manufacturing processes (6).
Regulation No. 1394/2007 was the right step towards regulating advanced therapies, but there is more to consider
The ATMP journey does not end with successful clinical trial outcomes. Commercialization depends heavily on the marketing authorization holder’s strategic decisions and operational capacity. While EMA approval theoretically enables EU-wide access, national healthcare systems retain the authority to decide whether and when a therapy is launched locally.
As a result, disparities in patient access persist across Europe. A 2023 investigation revealed that no ATMPs had ever been launched in Estonia or Latvia. By contrast, availability was highest in Germany at 89%, followed by France and Italy at 61% (7).
Germany’s leadership in access is largely attributed to policies that allow free price setting and streamlined reimbursement during the first six months following market entry. Smaller healthcare markets, particularly in the Baltic states, have historically faced delays in launching innovative medicines. Even in larger markets, such as Spain, limited long-term efficacy data and uncertainty around sustained benefit have constrained access to ATMPs despite sufficient market size.
Consequently, ATMP developers frequently identify country-specific reimbursement and regulatory requirements as one of the most significant challenges in Europe, alongside manufacturing complexity and clinical trial design (8). Additional layers of regulation, including legislation governing genetically modified organisms (GMOs), further compound this complexity.
ATMPs represent some of the most transformative advances in modern medicine. By leveraging living cells or genetic material, they offer the potential to address previously untreatable diseases and redefine therapeutic paradigms. This promise also means that every upstream decision — from culture conditions to labware selection — can directly influence the safety, efficacy, and consistency of the final therapy (5).
At the core of many challenges facing advanced therapies lies a common theme: the need for collaboration. Sustained dialogue among regulators, industry stakeholders, and funding bodies is widely expected to support GMP compliance, encourage investment, and ultimately improve patient access.
These considerations, however, should remain secondary to the primary objective of improving health outcomes and quality of life. At Green Elephant Biotech, we closely follow the evolving ATMP landscape and work to support developers and manufacturers who advocate for broader patient access to advanced therapies.
Thank you for reading and stay tuned!
As the year draws to a close, we would like to thank the readers of the Green Elephant Knowledge Hub for their continued curiosity and engagement with both our content and our products – CellScrew® and 96-well PLAtes. We are looking ahead with anticipation to the insights and updates that 2026 will bring for all of us!
References:
- Izeta, A, Cuende, N, Regulation of advanced therapies in Europe: Are we on the right track? (2023), Cell Stem Cell, 30, pp. 1013-16. doi: 10.1016/j.stem.2023.07.004.
- Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 (Text with EEA relevance). (2019). EUR-Lex. Available https://eur-lex.europa.eu/eli/reg/2007/1394/oj/eng (Accessed 22 December 2025).
- ATMP Pricing in Practice: Success & Cautionary Case Studies. (2025). Remap Consulting. Available https://remapconsulting.com/advanced-therapy-medicinal-products/atmp-pricing-reimbursement-europe-case-studies/ (Accessed 19 December 2025).
- Verbeken, G, Convents, L, Delmotte, N, Draye, JP, Jennes, S, Vanderkelen, A, Nijs, G, Lewalle, P, Baudoux, E, Cornu, O, Vanlaere, I, Pierlot, A, Rose, T, Pirnay, JP, Current State‐Of‐Play of the EU Advanced Therapy Medicinal Product (ATMP) Field, With an Emphasis on Belgian Human Cell and Tissue Products (2025), Wound Repair Regen, 33, pp. e70039. doi: 10.1111/wrr.70039.
- Galli, MC, Serabian, M, Regulatory aspects of gene therapy and cell therapy products, 1st edition (2015), Berlin: Springer Nature Switzerland.
- Kakroodi, FA, Khodadoust, E, Alizadeh, M, Tehrani, RSH, Sarabi, PA, Rahmanian, M, Vosough, M, Current challenges and future directions of ATMPs in regenerative medicine (2025), Regen Ther, 30, pp. 358-70. doi: 10.1016/j.reth.2025.06.017.
- Čechová, Z, Kubátová, J, Bártová, A, Jamárik, J, Samek, J, Beyond Reimbursement Status: Availability of Advanced Therapy Medicinal Products Across the European Union (2025), Ther Innov & Reg Sci, 59, pp. 728-36. doi: 10.1007/s43441-025-00769-z.
- Ham, RMT, Hoekman, J, Hövels, AM, Broekmans, AW, Leufkens, HGM, Klungel, OH, Challenges in Advanced Therapy Medicinal Product Development: A Survey among Companies in Europe (2018), Mol Ther Methods Clin Dev, 11. pp. 121-30. doi: 10.1016/j.omtm.2018.10.003.
