Why Single-Arm Trials Are Gaining Ground in Oncology Approvals

The pace of innovation in oncology, driven by personalized cancer treatment and highly targeted therapies, has created an urgent demand for more efficient and flexible regulatory pathways. In this rapidly evolving field, single-arm trials (SATs) are emerging as crucial tools, offering a viable route to bringing life-saving treatments to patients, especially when traditional randomized controlled trials (RCTs) are not feasible or ethically justifiable.

The European Medicines Agency (EMA) has demonstrated a pragmatic and increasingly successful approach to leveraging SATs in oncology. A compelling recent analysis revealed that nearly 90% of EMA oncology approvals based on SATs have been successful. This success story has gained even greater significance since the European Union’s (EU) implementation of joint EMA and Health Technology Assessment (HTA) evaluations.

Further solidifying its stance and providing crucial guidance, the EMA has published a reflection paper on establishing efficacy based on SATs submitted as pivotal evidence for marketing authorization. This paper acknowledges the growing reliance on SATs, particularly in areas of high unmet medical need and for rare diseases, while also addressing the inherent challenges, such as potential biases and confounding factors. It outlines considerations for robust study design, appropriate endpoints, and the necessary contextual evidence to support regulatory decision-making, signaling the EMA’s commitment to a clear, yet flexible, pathway for these innovative therapies.

In this article, we examine the nuances of the EMA’s acceptance of SATs, compare its approach with that of the U.S. Food and Drug Administration (FDA), and offer actionable strategies for biopharmaceutical companies seeking to optimize their success in this pivotal regulatory environment.

Key design features driving SAT approval success

Although SATs offer crucial flexibility in oncology drug development, their ultimate success in securing regulatory approval hinges on rigorous design and the generation of exceptionally robust data. The absence of a concurrent control arm requires an even greater focus on the intrinsic quality and interpretability of the trial’s findings. Design features of SATs that are important in this context include:

➔ Patient selection and the disease context

SATs are most compelling in areas of significant unmet medical need, particularly where no effective alternative treatments exist, or for diseases that are rapidly progressing and life-threatening. The EMA emphasizes well-defined patient populations, focusing on highly selective groups, often characterized by specific genetic mutations, biomarkers, or other precise diagnostic criteria. Such narrow patient cohorts are vital for reducing heterogeneity within the trial population, thereby strengthening the observed treatment effect and making it more attributable to the investigational therapy. SATs are uniquely suited for rare diseases and small populations, such as ultra-rare cancers, where the practical and ethical challenges of recruiting sufficient patients for an RCT are overwhelming.

➔ Endpoint selection and data robustness 

Given the inherent limitations of SATs, particularly in demonstrating long-term survival benefits without a comparator, there is a preference for objective, clinically meaningful primary endpoints in earlier phases of development. These often include objective response rate (ORR), duration of response (DoR), and progression-free survival (PFS). The magnitude of the observed effect is critical: the treatment’s benefit must be clinically significant and exceed what would be expected from natural disease progression or historical outcomes. This requires careful monitoring and the collection of high-quality data, including an independent review of imaging and response assessments, as well as robust statistical analysis to ensure the reliability and validity of the findings.

➔ Contextual evidence and external comparators 

While not direct comparators, well-curated historical controls or real-world evidence (RWE) can provide crucial context, helping to frame the observed treatment effect and strengthen the overall evidence base. Biomarker data is also critical, not only for precise patient selection but also for establishing the drug’s mechanism of action and providing biological plausibility for the observed clinical benefits. 

➔ Safety profile

A transparent and manageable safety profile is an indispensable component of a successful SAT submission, particularly in the absence of a direct comparator arm to contextualize adverse events.

EMA and FDA: Diverging paths in single-arm trial acceptance

When considering global oncology drug development, biopharma companies must navigate the distinct philosophies and practical approaches of the EMA and the FDA. While both agencies share the ultimate goal of ensuring safe and effective treatments reach patients, their pathways for accepting SATs exhibit notable divergences.

The EMA’s approach is often characterized by flexible pragmatism, particularly in areas of high unmet medical need. The agency has demonstrated openness to adaptive pathways and conditional marketing authorizations, which frequently use SAT data to expedite patient access to innovative therapies. A cornerstone of the EMA’s willingness to consider SATs is its strong focus on addressing significant unmet medical needs. If a therapy offers a substantial benefit in a disease area with limited or no existing treatments, the EMA is more inclined to accept robust SAT data, provided the trial design and evidence meet stringent quality criteria. Additionally, the EMA strongly emphasizes the importance of early and continuous dialogue through mechanisms such as scientific advice and the PRIME (PRIority MEdicines) scheme [4]. Engaging with the agency early allows companies to align on SAT design, endpoints, and the overall evidence package, significantly increasing the likelihood of a successful submission.

In contrast, the FDA generally maintains a preference for RCTs as the “gold standard” for demonstrating efficacy and safety. However, the FDA also offers an Accelerated Approval pathway, which, similar to EMA’s conditional approvals, allows for earlier approval of drugs for severe conditions based on surrogate endpoints that are reasonably likely to predict clinical benefit [5]. These approvals typically require confirmatory trials to verify the clinical benefit. For rare diseases or therapies granted breakthrough therapy designation, the FDA will also consider SATs, but often with more stringent post-marketing requirements and a clear understanding of the need for confirmatory evidence.

These differing approaches have significant implications for global development strategy. Companies must recognize that a “one-size-fits-all” trial design is unlikely to optimize success across both regulators. Instead, a tailored approach is often necessary, adapting trial designs and submission strategies to meet the specific expectations and flexibilities of each agency. This might involve strategic sequencing of regulatory submissions or designing trials with endpoints and data collection methods that can satisfy the requirements of both the EMA and the FDA, even if the primary submission strategy for one agency relies on a SAT. Understanding these diverging paths is crucial for efficient and effective global drug development.

How to navigate the EMA and HTA convergence with confidence

2025 marks a pivotal moment for pharmaceutical companies launching products in Europe, as the new EU HTA Regulation has come into full effect, mandating joint clinical assessments for specific products [2]. This convergence of regulatory approval and HTA evaluation means that evidence generation strategies must evolve beyond merely satisfying regulatory bodies to also addressing the value propositions required by HTA agencies.

Integrated evidence generation is no longer a future concept but an immediate necessity. Companies must now ensure that their clinical development programs, particularly those relying on SATs, generate data that satisfies both the EMA’s requirements for efficacy and safety, as well as the demands of HTA bodies for comparative effectiveness and patient value. This necessitates early HTA engagement, ideally in parallel with regulatory scientific advice. Proactive dialogue with HTA bodies (or their national representatives) from the outset can help shape trial designs to capture data relevant to their assessments. A critical shift involves focusing on patient-relevant outcomes — data that is not only clinically meaningful but also highly relevant to patients, caregivers, and healthcare systems, such as quality of life (QoL) measures, impact on daily activities, and resource utilization.

Anticipating HTA questions for SATs is crucial. A key challenge for SATs in the HTA context is addressing comparative effectiveness, as HTA bodies typically demand comparisons to existing standards of care or best supportive care. Companies must develop robust strategies to mitigate the inherent uncertainty associated with SATs, including comprehensive RWE generation plans, patient registries, and post-marketing studies. Furthermore, the economic value proposition must be considered early in development, even for therapies approved through SATs, as HTA bodies will rigorously assess cost-effectiveness and budget impact.

To navigate this new landscape with confidence, several actionable strategies for success are essential. Companies should actively seek integrated scientific advice from both EMA and HTA bodies where such mechanisms exist. Developing robust RWE plans is crucial to supplement SAT data and provide additional context on effectiveness and safety in real-world settings. The process of creating a value dossier should begin early, integrating clinical, humanistic, and economic evidence to build a compelling value story. Finally, fostering cross-functional collaboration between regulatory, clinical, market access, and HTA teams from the earliest stages of development is essential to ensure a cohesive and comprehensive approach to evidence generation and submission.

The future of oncology approvals

The EMA’s increasing acceptance of well-designed SATs, particularly in areas of high unmet medical need, presents a significant strategic opportunity for biopharma companies. While the EMA and FDA maintain distinct regulatory philosophies, understanding these differences is crucial for tailoring global development strategies. Most importantly, the impending convergence of EMA regulatory approvals with HTA evaluations in 2025 necessitates a proactive and integrated approach to evidence generation.

The strategic direction for biopharma companies is clear: using SATs effectively, especially for high-need oncology indications, is no longer just an option, but a critical necessity for efficient market access. Success in this new era will depend on a deep understanding of regulatory expectations, a commitment to generating robust and patient-relevant evidence, and a willingness to engage early and collaboratively with both regulatory and HTA bodies. By embracing proactive engagement, investing in comprehensive evidence generation, and adapting development strategies to the evolving European landscape, companies can navigate this complexity with confidence, ultimately bringing life-changing therapies to patients faster.

References

1. https://www.putassoc.com/insights/lessons-to-optimize-ema-regulatory-success-using-single-arm-trials-in-oncology/ 
2. https://health.ec.europa.eu/health-technology-assessment/implementation-regulation-health-technology-assessment/joint-clinical-assessments_en 
3. https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-establishing-efficacy-based-single-arm-trials-submitted-pivotal-evidence-marketing-authorisation-application_en.pdf 
4. https://www.ema.europa.eu/en/human-regulatory-overview/research-development/prime-priority-medicines 
5. https://www.fda.gov/about-fda/oncology-center-excellence/project-confirm 

--Issue 06--