Global Hematology Trials Ensure Research Stays Applicable, Flexible, Patient-Centered

The hematology landscape is growing increasingly complex with the innovation of new therapy regimens and fragmented by molecular subclassification, and as such, the field’s reliance on multinational clinical trials has never been greater. A session at the European Hematology Association (EHA) 2026 Congress brought together voices from regulatory agencies, academic cooperative groups, the pharmaceutical industry, and patient advocacy to examine how global trials are designed, evaluated, and improved.

Session moderator Tarec El-Galaly, MD, DMSc, of Aarhus University in Denmark, opened with an assessment of Europe’s shifting position in global drug development. Research activity is increasingly concentrated outside the US and Europe, he noted, driven by globalization, regulatory complexity, and varying postmarketing access policies. Conducting a single-country trial is now virtually unheard of in Europe.

For Europe to remain an attractive site for phase 3 research, he argued, regulatory predictability is paramount. El-Galaly pointed to the EU Clinical Trial Regulation, with its streamlined application and assessment workflows and mandated timelines, as a significant step forward, and highlighted EHA’s recent work to advocate for better regulation.

Patient Advocacy: Representation Is Not Just Geography

Angelo Loris Brunetta, founder of the Thalassemia International Federation and vice chair of the EHA Patient Advocacy Committee, challenged the room to rethink the meaning of global. Patients with the same diagnosis carry vastly different experiences depending on cultural context, socioeconomic status, and regional disease burden, but the majority of clinical trials are conducted in a narrow band of high-income countries.

“If trials are not run in countries with higher disease burden, does the innovation become the privilege of the few rather than a right for everybody?” Brunetta asked.

He also raised a methodological concern: Outcomes that matter to patients, such as cognitive function in leukemia, are rarely the ones measured. “I dream that one day the primary clinical end point is the patient’s quality of life,” he said during the panel discussion.

The Academic Perspective: The Funding Gap

Michael Fuchs, MD, of the German Hodgkin Study Group in Cologne, provided an account of the operational and financial barriers facing academic cooperative groups attempting to conduct multinational studies. The German Hodgkin Study Group, founded in 1978, has enrolled more than 25,000 patients across its trials, including the recently completed HD21 study with Australian and New Zealand partners, which led to a label expansion. But sustaining that kind of international scope requires navigating a patchwork of funding sources—encompassing governmental programs, charitable donors, pharmaceutical partners, and EU grants—each with its own restrictions on trial duration, patient caps, and cross-border money transfers.

“Dealing with questions no one else could ask” is the mission, Fuchs said, but the structural support doesn’t always match this work. The German government’s maximum funding rate for clinical trial participation is 400 to 600 euros per patient. His wish for the field is sufficient and flexible funding, including coverage of investigational medicinal products, which can consume up to 40% of a trial’s budget.

Regulatory Science: When Regions Diverge

Filip Josephson, MD, PhD, of the Swedish Medicines Agency, offered a framework for how regulators approach regional variation in trial outcomes. Drawing on ICH E5 guidance, he distinguished intrinsic factors (eg, disease biology, pharmacokinetics, drug-target expression) from extrinsic ones, including local treatment practices, concomitant therapies, symptom reporting norms, and willingness to remain on treatment despite toxicity. For drugs with an established mechanism of action, regulatory suspicion of foreign data is relatively low; novel mechanisms tend to require closer examination.

When subgroup analyses reveal regional differences in outcomes, Josephson said, regulators tend to look to external factors, “assuming that if the same person takes a pill in Paris or in Singapore, the same effect would ensue.”

An FDA Case Study: The STARGLO Trial

Margret Merino, MD, clinical team leader for lymphoma at the FDA, walked through a recent example of regional heterogeneity shaping a regulatory outcome. The STARGLO trial (NCT04408638) evaluated glofitamab plus gemcitabine-oxaliplatin (GemOx) vs rituximab-GemOx in relapsed/refractory diffuse large B-cell lymphoma and was meant to support glofitamab’s accelerated approval in the US.

The trial met its primary end point of overall survival (OS), but the Kaplan-Meier curves told a tale of 2 regions: Patients treated in Asian countries showed an OS HR of 0.37 favoring glofitamab, whereas patients treated in non-Asian regions had an HR of 1.3 trending against the experimental arm. Only 9% of patients were enrolled from the US; nearly half came from Asian countries.

Subsequent analysis identified differences in patient age, transplant uptake, disease subtype, and postprogression therapy availability between the 2 regional cohorts. The application was reviewed at an FDA Oncologic Drugs Advisory Committee meeting in May 2025; the committee voted 8 to 1 that the trial population and results were not applicable to the proposed US population,¹ and the FDA issued a complete response letter requiring additional trial data.

“The STARGLO example demonstrates how, despite positive overall survival results, low US enrollment and differences in efficacy outcomes between regional subgroups resulted in uncertainty regarding the applicability of the results to the US patient population,” Merino said.

FDA Design Guidance: Enrollment, Control Arms, and Collaboration

Kelly Norsworthy, MD, director of the Division of Hematologic Malignancies at FDA, outlined the design considerations laid out in FDA’s 2024 draft guidance on multiregional clinical development programs in oncology.² For cancers common in the US, the guidance recommends equal allocation of participants across geographic regions, including North America; for less common cancers, allocation proportional to disease prevalence is acceptable.

Control arm selection was a recurring point of discussion in the session. According to Norsworthy, unavailability of a standard-of-care comparator in the US is not an acceptable justification for an inadequate control arm, particularly when a new therapy with substantially improved outcomes exists in the US.

She called for continuing international collaboration, emphasizing that FDA, EMA, academic groups, and industry all have something to learn from one another in designing these trials.

“I would love to see academic trans-Atlantic and other global collaborations forged, particularly for rare diseases, where international collaboration can be significantly impactful,” she said.

Industry Experience: The ADMIRAL Study

Markus Vallaster, MD, PhD, of Astellas, described the development of gilteritinib in FLT3-mutated acute myeloid leukemia as a case study in how a single global pivotal trial can support multiregional registration, even with different evidentiary thresholds in each jurisdiction. The ADMIRAL study (NCT02421939) enrolled patients in 14 countries across the US, Europe, and Asia, with investigator choice of salvage chemotherapy in the control arm to accommodate regional standard-of-care variation. Approval in Japan and the initial FDA approval were granted on the basis of complete remission end points, whereas the European Medicines Agency required OS data; the FDA then issued a label update once mature OS data were available.

The lesson, Vallaster said, is less about any single end point than about the architecture of regulatory engagement. “The burden of agency alignment is really critical to go through for these more complex multiregional studies to create evidence that is meaningful but also avoid unnecessary assessments that add to patient burden,” he noted.

What’s on the Wish List?

The panel discussion included an aspirational question from audience member Martin Dreyling, MD, of the University of Munich: If the speakers were granted a single wish to improve multinational studies, what would it be?

Some answered with ideas to accelerate the patient enrollment process, and others with a plea for sufficient funding, but the idea of solid trial design with applicable control arms appeared across several answers, with the goal of ensuring not just approval but also reimbursement and uptake.

“The payers and the HTAs [health technology assessment bodies] are extremely interested in the selection of the control arm,” Josephson noted.

“Even if the drug is approved, if you have a suboptimal control arm, physicians probably aren’t going to prescribe it directly, because they don’t think it’s as good as others that have better control arms,” Norsworthy added. “It’s something to think about: it’s not just the regulators, it’s also the patients and the providers.”

References

1. Conroy R. FDA ODAC votes 8-to-1 against applicability of glofitamab DLBCL data. Cancer Network. May 20, 2025. Accessed June 13, 2026. https://www.cancernetwork.com/view/fda-odac-votes-8-to-1-against-applicability-of-glofitamab-dlbcl-data

2. Considerations for generating clinical evidence from oncology multiregional clinical development programs. FDA. September 2024. Accessed June 13, 2026. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/considerations-generating-clinical-evidence-oncology-multiregional-clinical-development-programs