Bridging gaps in clinical trial accessibility and reimbursement for large B-cell lymphoma therapies across Europe

Abstract

Large B-cell lymphoma (LBCL), including its most common subtype diffuse LBCL, is the most frequent aggressive lymphoma, accounting for 30%–40% of cases worldwide. It is a clinically heterogeneous disease, with outcomes influenced by molecular subtypes, comorbidities, and access to effective treatment. Although R-CHOP has long been the standard of care, approximately 30%–40% of patients relapse or are refractory to first-line therapy. Historically, salvage chemotherapy followed by autologous stem cell transplantation offered a potential cure, but only about half of patients are eligible, leaving a large unmet need for alternative therapies.¹

Since 2018, the therapeutic landscape has rapidly evolved with the approval of nine new treatments across 12 indications in Europe, including CAR-T therapies, bispecific antibodies, antibody–drug conjugates, and targeted immunotherapies such as tafasitamab–lenalidomide. These advances have broadened the treatment arsenal beyond chemotherapy, offering potentially curative options for chemotherapy-resistant patients and effective alternatives for those ineligible for intensive approaches. This shift toward more targeted and less toxic therapies represents a significant step forward in addressing prior treatment limitations.

However, access to these innovations remains uneven across Europe. Disparities stem from fragmented national reimbursement systems, inconsistent use of early access programs (EAPs), and geographic variations in clinical trial availability. While 29 out of 35 European countries have implemented EAPs,² differences in structure, funding, and transparency create unequal opportunities for early treatment access. Furthermore, health technology assessments (HTAs) and pricing negotiations often delay or restrict reimbursement, particularly in lower income or decentralized healthcare systems. The EU HTA Regulation (effective 2025) may harmonize clinical evaluations^3-6 but will not resolve national pricing autonomy.^{7, 8} To achieve equitable access, stronger coordination, pricing transparency, and integration of real-world patient outcomes into decision-making are urgently needed to ensure that innovation benefits all LBCL patients, regardless of geography or system structure.

While developing the European LBCL guidelines,⁹ the writing committee identified substantial variability in access to innovative therapies across Europe. To assess how these disparities could impact guideline implementation, the committee conducted an analysis of clinical trial activity and national reimbursement patterns. Data were obtained from EU CTIS, ClinicalTrials.gov, and direct consultations with industry stakeholders on the reimbursement status of EMA-approved therapies. The analysis focused on two areas: (I) the geographic distribution of active LBCL trials and (II) national reimbursement coverage. Findings highlight persistent inequities with significant implications for patient access and guideline applicability.

As of March 2025, the distribution of interventional LBCL trials actively recruiting across Europe demonstrates marked geographic heterogeneity. While countries such as France, Germany, Spain, and Italy lead in absolute trial numbers (Figure 1A), per capita analysis reveals more nuanced insights (Figure 1B). Spain and Italy exhibit both high trial volume and strong trial density relative to population size, indicating broad and decentralized clinical research activity. Germany, despite hosting a large number of trials overall, shows a lower trial-per-capita ratio, suggesting more limited access at the individual level. Interestingly, several smaller or less affluent countries—such as the Czech Republic, Croatia, and Hungary—rank among the top eight European nations for trial density, outperforming larger countries like Spain on a per capita basis. This suggests that trial access is driven not solely by economic strength but also by national strategies, research infrastructure, and site engagement.

Conversely, countries such as Iceland, Latvia, Lithuania, and Estonia report no active LBCL trials as of March 2025, pointing to significant gaps in clinical research availability, especially in parts of Northern and Eastern Europe. These findings underscore the importance of not only tracking total trial numbers but also assessing accessibility relative to population and geography.

Reimbursement patterns for EMA-approved LBCL therapies similarly reveal disparities. Using a standardized denominator of 12 EMA-approved indications (2018–2025), adjusted to 11 due to the absence of reimbursement for odronextamab as of March 2025, national differences in formal coverage become apparent (Figure 2). Germany and Austria lead with the highest number of fully reimbursed indications, reflecting healthcare systems that provide timely, structured access to innovative treatments. In contrast, France and Spain show moderate reimbursement levels, potentially influenced by rigorous HTA processes that require robust clinical benefit evidence before approval. The lag in reimbursement may also reflect prioritization processes or budgetary negotiations at the national level.

Many middle-income countries in Eastern and Southeastern Europe continue to face systemic barriers to reimbursement, including budget constraints, limited regulatory capacity, and fragmented healthcare infrastructures. These limitations restrict timely patient access to new therapies, exacerbating disparities already evident in clinical trial participation. Importantly, this reimbursement analysis excludes early access pathways—such as compassionate use, named patient programs, and transitional funding mechanisms—which, while helpful, vary widely in transparency, structure, and equity. For instance, countries like France and Spain may appear to have lower formal reimbursement levels than their actual early access activity would suggest.

In conclusion, smaller countries with strong research networks can achieve high trial density, whereas others with advanced health systems still face challenges in ensuring equitable trial or treatment access. These disparities—both in research participation and reimbursement—highlight the urgent need for harmonized strategies that align regulatory, financial, and infrastructural dimensions to achieve more equitable innovation delivery in hematologic malignancies.

This analysis underscores the persistent disparities in both clinical trial accessibility and national reimbursement for LBCL therapies across Europe, revealing how structural, regulatory, and policy-driven factors impact equitable access to innovation. While some countries, particularly Germany, France, Spain, and Italy, show high clinical trial volumes, per capita analysis provides a more nuanced view. Spain's streamlined regulatory processes and coordinated national research network have facilitated superior per capita trial access, surpassing Germany, where additional radiological approvals and bureaucratic delays hinder trial initiation. Interestingly, smaller or less affluent countries such as the Czech Republic, Croatia, and Hungary demonstrate high trial density relative to population, showing that efficient access is driven not solely by wealth but also by strategic policy and infrastructure.

However, significant gaps persist. Several Eastern and Baltic countries report no active LBCL trials, limiting research participation and access to innovation. While decentralized or hybrid trial models may address geographic barriers, trials remain selective and cannot replace equitable post-approval access. Moreover, Europe's complex, multilevel regulatory environment—further complicated by the recent implementation of the In Vitro Diagnostic Regulation (IVDR)¹⁰—has made early-phase research more challenging. These factors have contributed to a decline in Europe's share of global clinical trials,¹¹ particularly in oncology. In response, initiatives such as the EHA-led Coalition for Reducing Bureaucracy in Clinical Trials (https://bureaucracyincts.eu/) are advocating for streamlined, standardized, and faster clinical trial pathways across Europe.

Reimbursement patterns mirror these disparities. Germany and Austria lead in timely access to EMA-approved LBCL therapies, while countries like France and Spain face delays due to stringent HTA requirements, particularly when Phase III trials show progression free survival but not overall survival benefits.¹² In Eastern Europe, reimbursement is often constrained by budget limits and policy fragmentation. A striking example is the contrast between Croatia and Poland: despite similar healthcare expenditures, Poland's centralized model has enabled access to 9 of 11 EMA-approved LBCL therapies, including CAR-T, while Croatia reimburses only three. This illustrates that policy design—centralized structures and early access pathways—can overcome financial constraints.

Real-world evidence (RWE) and patient-reported outcomes (PROs) remain underutilized in both HTA and clinical trial design. While countries like Germany use RWE for reassessment, most systems lack standardized methods for integrating such data into access decisions. Aligning trial protocols, site selection, and reimbursement evaluations with real-world needs and capabilities is essential. Ultimately, improving access to innovation for LBCL across Europe will require harmonized regulatory processes, more inclusive clinical trial strategies, and policy frameworks that equitably translate therapeutic advances into patient benefit.

The EU HTA Regulation, in force since January 2025, introduces JCAs to harmonize evaluations of clinical effectiveness for innovative therapies, initially focusing on oncology. While JCAs aim to streamline access and reduce duplication, they are nonbinding, and many Member States continue to perform independent assessments based on economic and budgetary criteria. The JCA process itself remains complex and uneven, with challenges in aligning evidence generation and integrating RWE and PROs. Despite guidance from EMA and EU HTA bodies, disparities persist—especially in countries with limited trial infrastructure or cost-effectiveness-driven HTA models. These access inequities have serious consequences for patients with LBCL, where delayed reimbursement can mean preventable loss of life. Achieving equitable access will require stronger alignment between regulators, HTA bodies, and stakeholders, along with reforms to ensure affordability and inclusion in clinical research—testing Europe's commitment to patient-centered, sustainable innovation.

To ensure equitable access to innovative therapies in Europe, particularly for LBCL, coordinated reforms are urgently needed across regulatory, policy, clinical, and patient domains. The EU HTA Regulation's JCAs are a key step toward harmonizing clinical evaluations, but must be rigorously implemented and transparently integrated into national reimbursement decisions. This includes standardized use of RWE and PROs to reflect treatment impact beyond clinical trials.¹³

Regulators and HTA bodies should align reimbursement frameworks with JCA findings, transparently justify any divergences, and integrate RWE and PROs using existing EMA and EU HTA guidance.

Policymakers must incentivize broader clinical trial inclusion by mandating the listing of all recruiting trials in both ClinicalTrials.gov and EUCTIS and requiring representation of underrepresented countries in pivotal trials. Promoting decentralized and hybrid models can further expand patient access.

Patient organizations play a critical role in collecting structured patient experience data, contributing to trial design, and advocating for meaningful endpoints. Education on novel therapies and access pathways, particularly in underserved areas, can empower patients to engage in care decisions.

Industry must commit to equitable trial participation and pricing transparency. This includes supporting access programs in underfunded countries and ensuring synchronized trial listings. Long-term RWE collection should also be prioritized to inform post-marketing safety and reimbursement.

Achieving these reforms will require political will, collaborative governance, and sustained investment. Projects like ASCERTAIN¹⁴ and EHA-led guideline efforts are helping align stakeholders and standardize evaluation frameworks. Without harmonized HTA processes, synchronized trial registries, and fair pricing, Europe risks a fragmented system where therapeutic innovation does not reach all patients. Implementing these recommendations will help bridge the gap between innovation and access, positioning Europe as a leader in equitable, patient-centered precision medicine.

Florence Broussais: Conceptualization; data curation; writing—original draft; investigation. Elise Pennings: Writing—original draft. Natacha Bolanos: Writing—original draft. Lorna Warwick: Writing—review and editing. Robin Doeswijk: Writing—review and editing. Gauthier Quinonez: Data curation; writing—review and editing. Andrii Lebeda: Writing—review and editing. Maria Gomes Da Silva: Writing—review and editing. Sirpa Leppä: Writing—review and editing. Georg Lenz: Writing—review and editing. Anne-Ségolène Cottereau: Writing—review and editing. Christopher Fox: Writing—review and editing. Armando Lopez-Guillermo: Writing—review and editing. Timothy Illidge: Writing—review and editing. Wojciech Jurczak: Writing—review and editing. Hans Eich: Writing—review and editing. Igor Aurer: Writing—review and editing. Jean-Philippe Jais: Writing—review and editing. Marek Trneny: Writing—review and editing. Andy Andreas Rosenwald: Writing—review and editing. Andrew Davies: Writing—review and editing. Ben (Gerben) Zwezerijnen: Writing—review and editing. Martin Dreyling: Writing—review and editing. Umberto Vitolo: Writing—review and editing. Hervé Tilly: Writing—review and editing. Catherine Thieblemont: Supervision. Marie Jose Kersten: Supervision.

F.B., E.P., R.D., G.Q., A.L., A.-S.C., A.A.R., B.Z., and J.-P.J. have no conflict of interest to disclose.

N.B. and L.W. disclose an indirect financial relationship with Roche, Ipsen, Kite-Gilead, Janssen, Lilly, Novartis, Sobi, Takeda, and BMS, as the Lymphoma Coalition has received sponsorship from these companies to support specific activities such as educational, advocacy initiatives, CABs, Global Patient Surveys, and Global Summits. N.B. is a member of the Patient Global Advisory Board for Ipsen.

M.G.D.S. discloses financial and/or professional relationships with Janssen Cilag (direct and indirect), Roche (direct), Lilly (direct and indirect), AstraZeneca (indirect), Gilead (direct), BeiGene (indirect), AbbVie (direct and indirect), and Takeda (direct), and professional relationships with Sociedade Portuguesa de Hematologia.

S.L. discloses a direct financial relationship with AbbVie, Genmab, Incyte, Roche, and Sobi, and an indirect financial relationship with Bayer, BMS, Genmab, Hutchmed, Novartis, and Roche.

G.L. discloses a direct financial relationship with Roche/Genentech, Gilead, BMS, Novartis, AstraZeneca, AbbVie, Incyte, PentixaPharm, Sobi, Immogene/FLINDR, Hexal/Sandoz, Lilly, BeiGene, and MSD, and an indirect financial relationship with Roche/Genentech, Gilead, Bayer, Novartis, AstraZeneca, AbbVie, MSD, and Pierre Fabre.

A.L.-G. discloses a direct financial relationship with AbbVie, Atarabio, BMS, GenMab, Gilead/Kite, Incyte, Janssen, Lilly, Morphosys, Ono, Roche, SERB, SOBI, and Takeda, and an indirect financial relationship with BeiGene and AbbVie.

T.I. discloses a direct financial relationship with Takeda.

W.J. discloses a direct and indirect financial relationship with AbbVie, AstraZeneca, BeiGene, Janssen Cilag, Lilly, Regeneron, and Roche.

H.E. discloses a direct financial relationship (honoraria) with Kyowa Kirin and Takeda and serves as a Steering Committee Member of the International Lymphoma Radiation Oncology Group (ILROG).

I.A. discloses a direct financial relationship with Roche, Novartis/Sandoz, AbbVie, AstraZeneca, Genesis/Incyte, Sobi, and Takeda.

M.T. discloses a direct financial relationship with Roche, Gilead, AstraZeneca, Sobi, Takeda, Incyte, Lilly, BMS, Novartis, AbbVie, Janssen, Swixx, Carbou Sciences, and Autolus.

A.D. discloses a direct financial relationship with Roche (conference attendance, honorarium for talks, and advisory boards), AstraZeneca, Kite/Gilead, Sobi, AbbVie, Genmab, Celgene, MSD, Incyte, and Janssen (advisory boards), and an indirect financial relationship (research funding) with Roche, AstraZeneca, Kite/Gilead, Celgene, and MSD.

N.B. discloses an indirect financial relationship with Roche, Ipsen, Kite-Gilead, Janssen, Lilly, Novartis, Sobi, Takeda, and BMS, as the Lymphoma Coalition has received sponsorship from these companies to support specific activities such as educational, advocacy initiatives, CABs, Global Patient Surveys, and Global Summits. Additionally, N.B. is a member of the Patient Global Advisory Board for Ipsen.

M.D. discloses a financial relationship through speaker honoraria with AstraZeneca, BeiGene, Gilead/Kite, Janssen, Lilly, Novartis, and Roche, and a role on the scientific advisory board for AbbVie, AstraZeneca, BeiGene, BMS/Celgene, Gilead/Kite, Janssen, Lilly/Loxo, Novartis, and Roche.

U.V. discloses a direct financial relationship with AbbVie, Genmab, and Gilead (advisory board and lecture honoraria), as well as Incyte and MSD (lecture honoraria).

H.T. discloses a direct financial relationship with Roche and an indirect financial relationship with Roche, AstraZeneca, BMS, and AbbVie.

C.T. discloses a direct financial relationship (honoraria) with Janssen, Roche, AbbVie, Novartis, BMS, Incyte, and BeiGene.

M.J.K. discloses an indirect financial relationship with Bristol Myers Squibb, Kite/Gilead, Miltenyi Biotech, Novartis, Roche, Adicet Bio, AbbVie, BeiGene, Galapagos, Mustang Bio, and Janssen.

The article processing charges for this article has been covered by EHA as part of the EHA Guidelines initiative. This perspective paper received no external funding.