Closing the ATMP access gap? How Europe’s HTA frameworks and manufacturers are adapting
Europe's health technology assessment (HTA) frameworks were designed for medicines supported by robust comparative evidence, predictable clinical pathways and manageable budget impacts. Advanced therapy medicinal products (ATMPs) have challenged each of these assumptions by generating clinical and financial uncertainty that conventional HTA frameworks were never built to absorb.
Although HTA bodies are moving towards more flexible, lifecycle-based approaches to manage uncertainty, significant challenges remain for both healthcare systems and manufacturers.1,2 This article explores how healthcare systems and manufacturers can continue to evolve to improve access to ATMPs while supporting robust, sustainable decision-making.
Why ATMPs continue to challenge conventional HTA frameworks
The core challenge remains that most ATMPs do not fit neatly into either 1) traditional clinical evidence methodologies or 2) traditional financing models.
Clinical development programs for ATMPs are frequently based on small and high unmet need patient populations, with limited comparative data (often being single-arm trials) and immature long-term overall survival data. Long-term durability claims may depend on extrapolations extending many years beyond observed trial evidence. For payers and HTA bodies, this creates considerable uncertainty around comparative effectiveness and long-term value.3
At the same time, the financial impact and clinical value of one-time therapies with very high upfront costs is intrinsically complex to evaluate. Cost-effectiveness models must make strong assumptions about lifetime treatment benefits introducing significant uncertainty. Moreover, ATMPs are particularly difficult to reconcile with annual healthcare budgeting cycles due to their one-off high cost, which exacerbates as the size of the eligible populations or duration of treatment benefits remains uncertain.3,4
This combination of evidentiary and financial uncertainty increasingly exposes the limitations of traditional “one-off” HTA decision making.
The experience of therapies such as Zolgensma illustrates both the clinical promise and financial pressure associated with ATMPs. Its clinical results in infants with spinal muscular atrophy were truly transformative, but uncertainty around long-term effectiveness compounded by the significant budget impact created by its very high upfront cost led to reimbursement hurdles and delays while negotiations over its value continued.5
The HTA response so far: evolving toward a lifecycle approach
Many European HTA bodies have begun to adopt more flexible approaches to evidence generation and value assessment. Recognizing the uncertainty inherent in therapies for small patient populations, we have seen HTAs become more accepting of immature clinical data at launch while placing greater emphasis on long-term follow-up and real-world evidence.
Although HTA bodies across Europe are moving in the same general direction, the mechanisms they are adopting differ. Germany and England illustrate two distinct but complementary models of adaptation.
1. Germany: from rapid access to structured evidence generation
Germany illustrates the shift towards lifecycle evidence generation. While AMNOG historically enabled rapid post-approval access following EMA authorization, increasing numbers of high-cost ATMPs have been associated with more structured post-launch evidence requirements. Under the new 2019 GSAV reform, G-BA can require “application-accompanying data collection”, linking reimbursement to mandatory real-world evidence generation and scheduled reassessment6 – a route already used to gain access for several ATMPs including Hemgenix, Roctavian and Casgevy.7-9
This evolution towards conditional, evidence-generating access models also reflects growing concerns around affordability. Recent discussions publicly raised by Germany’s Federal Office for Social Security (Bundesamt für Soziale Sicherung) around high-cost risk pools and financial equalization mechanisms suggest that the debate is evolving beyond product-level negotiations toward broader system-level sustainability questions.10
2. England: integrating regulations, HTA and access planning
While post-launch evidence generation remains important, England has increasingly focused on integrating regulations, HTA and NHS implementation earlier in the development pathway.
NICE’s Highly Specialised Technologies pathway introduced greater flexibility for ultra-rare conditions, while mechanisms such as the Cancer Drugs Fund and Innovative Medicines Fund created structured managed access routes linked to further evidence generation, although practical utilization of the latter remains limited.11-13
More recently, the UK has also focused on earlier coordination between regulators, HTA bodies and the NHS. The Innovative Licensing and Access Pathway (ILAP), relaunched in 2025, aims to accelerate patient access through coordinated engagement involving the MHRA, NICE and NHS England.11-13 For ATMP manufacturers, this creates opportunities for earlier alignment around evidence generation, value demonstration and implementation planning.
Taken together, these reforms signal that England is increasingly attempting to compress the traditional separation between regulation, HTA and NHS adoption, particularly for therapies with significant evidence uncertainty at launch.
The JCA challenge– harmonized reviews at a demanding evidence bar
A key recent development is the introduction of the EU Joint Clinical Assessment (JCA), implemented from January 2025, with the first wave focusing on ATMPs and oncology products. This process aims to harmonize clinical evidence reviews across Europe, with 27 EU member states utilizing a single report to analyze relative clinical effectiveness, safety, and PICO-driven outcomes.14
For manufacturers, this creates both opportunity and complexity. On one hand, JCAs may reduce duplication and create greater alignment across member states. Yet for ATMPs specifically, the JCA raises as many questions as it answers. Early experience, most notably the first completed assessment of Ipsen's Ojemda (tovorafenib), as well as the two discontinued assessments for Tacquell (autologous melanoma-derived tumor infiltrating lymphocytes) and Focus V (catequentinib) due to missing or insufficient evidence, has highlighted a demanding evidence bar. Outcomes have fallen short of manufacturers expectations and exposed the tension between JCA evidence requirements and the clinical realities of ATMP development.15-17
Evidence packages built on small patient populations, single-arm trials, surrogate endpoints and immature long-term data do not sit easily within a rigid and highly comparative framework. Under the JCA, choices made during development will be scrutinized against a single, unforgiving standard, and will be significantly harder to course-correct once pivotal programs are underway.18
Importantly, the JCA does not necessarily eliminate fragmentation. Rather, it risks shifting fragmentation downstream, away from clinical assessment and toward interpretation, affordability and evidence follow-up at national level.
The focus for manufacturers: developing credible long-term evidence and affordability strategies
Although HTA frameworks are becoming more adaptive, the fundamental challenge remains the same: balancing timely patient access with evidence uncertainty, affordability and health system readiness. Increasingly, however, this challenge is being managed across the product lifecycle rather than at a single reimbursement decision.
For ATMP manufacturers, this means demonstrating a credible lifecycle strategy built around two priorities: earlier evidence generation and more flexible access models.
1. Moving towards earlier and integrated evidence generation strategies
Given the complexity of ATMP evidence packages and the high stakes of HTA evaluations, particularly under the JCA, manufacturers need to plan evidence generation with these requirements in mind. Success increasingly depends on anticipating multi-stakeholder evidence needs, including methodological expectations, early in development and addressing them in an integrated way. Integrated evidence planning (IEP) provides a structured approach by aligning clinical, regulatory, and payer requirements into a single, lifecycle-based strategy rather than addressing them sequentially.
A critical payer input to that planning process is early engagement with HTA bodies. Formal early advice processes, including Joint Scientific Consultations under the EU HTA framework, allow manufacturers to validate evidence needs and methodologies, including endpoints, comparators and follow-up strategies before pivotal trial designs are locked, reducing the risk of costly misalignment later in development.
Yet even the most robust pre-launch evidence package will rarely eliminate uncertainty entirely for ATMPs. This is why manufacturers are increasingly complementing upfront planning with iterative post-launch evidence generation, combining initial market access with structured data collection through registries, long-term follow-up studies and real-world evidence programs. Coverage-with-evidence-development (CED) arrangements are emerging as one practical mechanism for operationalizing this adaptive model. Under these approaches, reimbursement is conditional on participation in agreed evidence-generation activities, with reassessment scheduled once additional data become available. For ATMPs, CED frameworks provide a pragmatic way to reconcile early patient access with progressive reduction of uncertainty over time while maintaining alignment with formal HTA decision criteria.19
2. Exploring more flexible and outcome-oriented access models.
Companies are testing more flexible and outcomes-based models to address affordability and uncertainty. Managed entry agreements (MEA) are increasingly being designed to link payment to observed outcomes such as durability of response or survival, with outcomes-based agreements being increasingly utilised as managed access models in EU.
Beyond that, alternative payment structures are attracting growing attention as healthcare systems attempt to address the budget impact associated with one-time therapies. Multi-year payment models, annuity-based structures, staged payments and amortization approaches are all being explored as mechanisms to spread costs over time and reduce pressure on annual healthcare budgets.20 Internationally, variants of these models have already been applied to several ATMPs, including Luxturna and Zolgensma.21,22
At the same time, engagement is broadening beyond individual products, with manufacturers participating in discussions on system-level solutions. These include high-cost risk pools, reinsurance mechanisms for ultra-high-cost cases, and multi-year budget forecasting supported by scenario analysis and epidemiological modelling. These more innovative mechanisms are currently being discussed and need yet to be tested, but aim to be a response aiming to socialize risks of overly heavy and/or time-concentrated costs among all interested stakeholders, from healthcare systems and insurers to the broader pharma industry.23-25
For manufacturers, this means that pricing strategy alone is no longer sufficient. Companies increasingly need to demonstrate an understanding of how therapies can be operationally and financially integrated into healthcare systems over the long term.
Conclusion
ATMPs are accelerating the evolution of HTA from a one-time reimbursement decision to a continuous process of evidence generation, reassessment and access planning. As this transition continues, success will depend not only on how HTA evolves, but on how effectively manufacturers work with healthcare systems to reduce uncertainty and support sustainable access.
References
1. British Pharmacological Society. Expanding collaboration into new solutions for PPWR: a 13-year partnership journey. Pharmacology Matters. Published 2026. Accessed May 15, 2026. (https://www.bps.ac.uk/publications/pharmacology-matters/pharmacology-matters-article/?tx_news_pi1%5Baction%5D=detail&tx_news_pi1%5Bcontroller%5D=News&tx_news_pi1%5Bnews%5D=567&cHash=141245380e233a8312143600c9491f5c)
2. Vallano, A., Pontes, C., & Agustí, A. (2023). The challenges of access to innovative medicines with limited evidence in the European Union. Frontiers in pharmacology, 14, 1215431.
3. Iglesias-Lopez, C., Agustí, A., Vallano, A., & Obach, M. (2021). Current landscape of clinical development and approval of advanced therapies. Molecular Therapy Methods & Clinical Development, 23, 606-618.
4. Ektare V., Budget Impact Modeling of Cell and Gene Therapies, 2024, ISPOR EU Annual Conference, Barcelona
5. National Institute for Health and Care Excellence, NICE HTA Programme, NICE Methods Team. NICE Health Technology Evaluations: The Manual. NICE; updated 2025. Accessed May 14, 2026. NICE HTA manual
6. Global Legal Insights. Pricing & Reimbursement Laws and Regulations – Germany 2025 (2025).
7. G-BA, Application-related data collection and restriction of supply authorisation: Etranacogen dezaparvovec – haemophilia B (Anwendungsbegleitende Datenerhebung und Beschränkung der Versorgungsbefugnis: Etranacogen Dezaparvovec – Hämophilie B - Gemeinsamer Bundesausschuss)
8. G-BA, Application-related data collection and restriction of supply authorisation: Valoctocogen Roxaparvovec (Roctavian®) (Roctavian - Gemeinsamer Bundesausschuss)
9. G-BA, Application-related data collection and restriction of supply authorisation: Exagamglogen Autotemcel – Sichelzellkrankheit (Anwendungsbegleitende Datenerhebung und Beschränkung der Versorgungsbefugnis: Exagamglogen Autotemcel – Sichelzellkrankheit - Gemeinsamer Bundesausschuss)
10. BAS clarification on gene therapy reimbursement. Reported in Navlin Daily (2025). (https://www.navlindaily.com/article/27427/bas-confirms-insurers-cannot-deny-gene-therapy-coverage-for-rare-diseases-on-cost-grounds)
11. National Institute for Health and Care Excellence, NICE HTA Programme, NICE Methods Team. NICE Health Technology Evaluations: The Manual. NICE; updated 2025. Accessed May 14, 2026. NICE HTA manual
12. Pink Sheet Editorial Team, Citeline Market Access Group, Informa Pharma Intelligence. England’s Innovative Medicines Fund falls short on evidence, serves as stopgap. Accessed May 14, 2026. Pink Sheet IMF article
13. Medicines and Healthcare products Regulatory Agency, National Institute for Health and Care Excellence, NHS England. UK patients enabled access to transformative new medicines in shortest time possible via new integrated innovative licensing and access pathway. Published 2025. Accessed May 14, 2026. UK Government ILAP announcement
14. European Commission, Directorate-General for Health and Food Safety, European Union. Joint clinical assessments. European Commission. Accessed May 14, 2026. European Commission HTA JCA page
15. IQVIA Institute for Human Data Science, IQVIA Market Access Centre of Excellence, IQVIA HTA Team. Joint scientific consultations: getting the most from early scientific advice. Published November 2024. Accessed May 14, 2026. IQVIA JSC article
16. Joint Clinical Assessment report on tovorafenib (Ojemda), June 9th, 2026 (Joint Clinical Assessment report on tovorafenib (Ojemda) - Public Health)
17. Francesca Bruce. Two EU Joint Clinical Assessments Cancelled As EU Marketing Authorization Issues Raised. July 2026 (Insights Citeline)
18. Eberle K, Morgese P, Rochau U, et al. The PICO puzzle: can public data predict EU HTA outcomes? J Mark Access Health Policy. 2025;13(1):2286285.
19. Organisation for Economic Co-operation and Development. Performance-Based Managed Entry Agreements for New Medicines in OECD Countries and EU Member States. OECD Health Working Papers No. 115. Published 2019. Accessed May 15, 2026. OECD iLibrary
20. Van Dyck W, Michelsen S, Veredas D, Huys I, Luyten J, Simoens S. When do annuity-based payments help to address the affordability challenge of funding advanced therapies? Insights from a budget impact simulation. J Mark Access Health Policy. 2026;14(2):23. doi:10.3390/jmahp14020023
21. Liu A, Narasimhan V, Novartis Market Access Team. Novartis CEO Narasimhan preps Zolgensma launch with call for new drug payment model. Fierce Pharma. Accessed May 14, 2026. Fierce Pharma Zolgensma payment model article
22. Simoens D, Shravah V, Jones WK, Kaja S. Clinical and pharmacovigilance safety evaluation of LUXTURNA® (voretigene neparvovec-rzyl). Cutan Ocul Toxicol. 2025;44(4):361-373. doi:10.1080/15569527.2025.2573463
23. Milliman Research Team, Milliman Health Practice, Milliman Market Analytics Group. Rising tides, rising costs: diving into the ACA high-cost risk pool. Published January 15, 2025. Accessed May 14, 2026. Milliman high-cost risk pool article
24. Center for Biomedical System Design, NEWDIGS Initiative, Massachusetts Institute of Technology. Risk Pools. Paying for Cures Initiative. Massachusetts Institute of Technology; 2011. Accessed May 14, 2026. NEWDIGS risk pools resource
25. Blahous C, Capretta JC, Butler SM. Managing high-cost health care: risk pools, reinsurance, and catastrophic coverage. Niskanen Center. Published June 27, 2018. Accessed May 14, 2026. Niskanen Center risk pools article
