The review, led by Ornella Gonzato with contributions from patient advocates Denise Reinke and Roger Wilson, oncologist Bernd Kasper and regulatory expert Maria Josefina Ruiz Alvarez, examines how two landmark frameworks can be operationalised in rare cancer research: the 2024 World Health Organization Guidance for best practices for clinical trials and the International Council for Harmonisation’s ICH E6(R3) Good Clinical Practice guideline. The WHO guidance articulates scientific validity, efficiency, ethical acceptability, social value, feasibility, equity and patient engagement as interdependent components of trial quality. ICH E6(R3) complements this by reframing Good Clinical Practice around quality by design and risk-proportionate oversight, emphasising critical-to-quality factors rather than box-ticking procedural compliance. Together, the authors argue, these documents shift trial governance toward principled flexibility.

The central problem is one of proportionality. When patient populations are intrinsically small and biologically fragmented, conventional fixed-sample randomised trials may impose disproportionate burdens on participants while offering only a slim probability of generating actionable knowledge. The WHO guidance explicitly ties ethical acceptability to proportionality between risk, burden and anticipated social value. Adaptive and Bayesian designs can improve efficiency while preserving methodological rigour, and the sarcoma field has become a proving ground for them. The biomarker-driven MULTISARC umbrella trial used centralised molecular profiling to allocate patients across treatment cohorts, showing how molecular stratification can enhance feasibility and interpretability even in highly fragmented populations. IMMUNOSARC employed a multicohort, single-arm design spanning multiple rare subtypes, illustrating how flexible, risk-proportionate approaches can support evidence generation when conventional randomisation is simply impractical.

But methodological innovation alone is not enough. The review emphasises that rare cancer research depends on collaborative infrastructure that often matters as much as the trial design itself. Cross-border networks such as the European Reference Network EURACAN and international sarcoma consortia enable accrual, harmonise standards and safeguard data quality. Multinational trials such as RAIN-3201, an international randomised phase III study, and rEECur, an international multi-arm seamless phase II/III trial in relapsed and refractory Ewing sarcoma, relied on coordinated governance, harmonised data collection and cross-border recruitment to maintain scientific validity while maximising the number of patients enrolled. In populations fragmented across dozens of subtypes, such infrastructures are frequently a prerequisite for adequately powered studies rather than a mere facilitator of research activity.

Equity emerges as a persistent tension throughout the analysis. Centralising expertise improves diagnostic accuracy and outcomes, but it can raise barriers to research participation. Travel burdens, financial costs and logistical complexity fall disproportionately on patients in rural regions, lower socioeconomic groups and older populations. Regulatory heterogeneity compounds the problem: in multinational rare cancer studies, variation in approval timelines, submission requirements and local governance procedures delays site activation and creates unequal opportunities for participation across countries. These asymmetries fall hardest on academic and investigator-initiated studies, which typically lack dedicated regulatory affairs departments. The authors point to ECRIN’s Regulatory and Ethical Database, which catalogues country-specific requirements across more than 750 searchable fields, as a practical tool for navigating this fragmentation, but they stress that differences in ethics committee composition, review timelines and national procedures persist alongside the EU’s Clinical Trials Information System harmonisation.

Decentralised and hybrid trial models offer a partial remedy. Remote informed consent, telemedicine visits, electronic patient-reported outcomes, local clinical assessments, remote monitoring and digital data capture can reduce the burden of participation for geographically dispersed patients, improving recruitment and retention. Registry-based initiatives such as RESAR, a prospective multicentre sarcoma registry, and ICONIC, a registry-based osteosarcoma platform with strong patient involvement, demonstrate how longitudinal real-world data collection can complement interventional studies, support external control arms when randomisation is infeasible and give researchers contextual evidence grounded in patient experience. The authors caution, however, that decentralisation should extend rather than replace specialist centres, and that digital-first approaches require infrastructure, regulatory alignment, data protection safeguards and explicit attention to digital inclusion so that efforts to improve accessibility do not unintentionally exclude under-resourced populations.

Patient-centredness, the review argues, is not merely an ethical nicety but a structural determinant of what the authors call operational validity—the ability of a trial to generate interpretable evidence under the real-world constraints of population size, feasibility and participation. In sarcomas, endpoints such as functional preservation and long-term toxicity may matter more to patients than short-term tumour response. The randomised multicentre surgical trial SarcoSIGHT shows that integrating functional and quality-of-life endpoints early in trial design is feasible while maintaining scientific rigour. Structured involvement of advocacy organisations such as the Sarcoma Patient Advocacy Global Network in protocol development, consent processes and dissemination enhances both feasibility and interpretability in very small populations, and patient-led initiatives like ICONIC demonstrate how engaged communities can shape research agendas and sustain engagement over time.

Digital and artificial intelligence-enabled tools extend this agenda further. Applications under active exploration include AI-assisted patient identification from electronic health records, wearable-based remote monitoring and digital twins as synthetic control alternatives—particularly relevant where randomising patients to a control arm is statistically or ethically constrained in ultra-rare populations. The WHO’s Global Action Plan for Clinical Trial Services calls for adopting such innovative designs and technologies to improve recruitment, data collection, analysis and oversight, while the Global Clinical Trials Forum provides the institutional architecture for aligning digital governance standards across jurisdictions. Yet the authors insist the governance risks demand equal attention: algorithmic bias can reproduce geographic and socioeconomic inequities in participant selection, unequal digital access can exclude vulnerable groups, and opaque AI-assisted decisions in eligibility or safety monitoring require audit trails and human oversight embedded by design.

The cross-cutting lessons are strikingly consistent. Methodological flexibility succeeds when linked to clear biological rationale, not innovation for its own sake. Feasibility and scientific validity are inseparable, because recruitment failure and attrition can render even a methodologically sound trial inconclusive. International collaborative infrastructure is an enabling condition, not a luxury. Patient-centred approaches improve operational performance, not just ethical acceptability. And despite all this progress, regulatory fragmentation remains the stubborn barrier that governance frameworks must address with greater specificity. The WHO Global Action Plan’s sixth action on streamlining regulatory and ethics review will need teeth if equitable, multinational rare cancer trials are to become routine rather than exceptional.

The implications reach well beyond sarcomas. As molecular stratification carves common cancers into progressively smaller and more dispersed subsets, the governance lessons forged in rare cancer research are increasingly relevant to precision oncology at large. The authors identify outstanding questions that will define the next decade: how to translate principles into proportionate governance across diverse regulatory systems, how to combine adaptive designs, registries, real-world data and decentralised models optimally, how to integrate patient involvement into regulatory decision-making, how to deploy digital tools equitably and transparently, and what sustainable funding models can maintain international research infrastructures. The review is candid about its limitations—it is a structured narrative synthesis, examples are illustrative rather than exhaustive, most evidence comes from high-income settings, and direct causal evidence linking patient engagement practices to trial outcomes remains limited. But its core message is clear: in rare cancers, operational validity depends on the interaction of methodological innovation, collaborative infrastructure, patient-centred governance and proportional regulation, and sarcoma research has shown the way.

Subject of Research: Patient-centred clinical trial design and governance for rare cancers, using sarcomas as a model for applying 2024 WHO guidance and ICH E6(R3)

Article Title: Patient-centred and fit-for-purpose clinical trials in rare cancers: lessons from sarcomas for operationalising 2024 WHO Guidance and ICH E6(R3)

Article References: Gonzato, O., Reinke, D., Wilson, R., Kasper, B., & Ruiz Alvarez, M. J. (2026). Patient-centred and fit-for-purpose clinical trials in rare cancers: lessons from sarcomas for operationalising 2024 WHO Guidance and ICH E6(R3). eClinicalMedicine, 100, Article 104192. https://doi.org/10.1016/j.eclinm.2026.104192

Image Credits: AI Generated

DOI: 10.1016/j.eclinm.2026.104192

Keywords: rare cancers, sarcoma, clinical trials, WHO guidance, ICH E6(R3), adaptive trial design, patient engagement, decentralised trials, real-world data, regulatory harmonisation, operational validity, precision oncology