Accelerating cancer treatment optimisation: A multistakeholder roadmap from the Cancer Medicines Forum.

1
Introduction
The landscape of oncology drug development is predominantly shaped by clinical trials designed to support innovation through expedited development and regulatory approval, enabling the rapid introduction of new therapies into markets. These trials are typically designed to meet regulatory requirements, including demonstrating adequate efficacy and safety in well-defined patient populations and supporting the benefit-risk assessment for the proposed indications. Nevertheless, addressing the requirements for marketing approval does not necessarily address medicines’ optimal use within clinical practice and healthcare systems. While the data generated satisfy the requirements for market authorisation and support a positive benefit-risk assessment, important questions regarding the optimisation of newly approved medicines, including dosage, treatment duration, schedule of administration, sequence, combination of different treatments and comparative effectiveness, often remain unresolved at the time of approval. [1] Furthermore, registrational trials do not capture evolving knowledge about benefits and harms in subgroups that emerge beyond the originally submitted data. [1], [2], [3], [4], [5] As a result, there is an opportunity to further research treatment strategies that could improve the overall benefit-risk by reducing patient burden and enhancing safety profiles, while maintaining or enhancing clinical effectiveness. Leveraging the evidence generated for regulatory approval to provide comprehensive and up-to-date information for clinical decision-making, particularly in an era increasingly shaped by innovative treatments and personalised approaches, has thus become an increasing priority. [6], [7]
Alongside the rise in opportunities for optimisation, the global incidence and prevalence of cancer are increasing, as are the rising costs associated with novel treatments. The World Health Organization (WHO) forecasts a 50 % increase in global cancer incidence by 2040. [8] Furthermore, advancements in early detection and therapeutic interventions have led to a growing population of cancer survivors, resulting in more individuals living with cancer or long-term side effects of the disease or treatment. Simultaneously, the cost of cancer care, especially new systemic therapies, continues to escalate, placing substantial pressure on healthcare systems. [9], [10], [11], [12]
Treatment optimisation research has thus emerged as a key response to the above-mentioned challenges. By generating actionable evidence, it may support clinicians and patients in making informed, patient-centred decisions while simultaneously contributing to more efficient and sustainable use of healthcare resources. It may be defined as research aimed at determining the optimal use of therapeutic interventions, including the optimal dose, duration, and schedule of treatment; the optimal sequence of therapeutic interventions; the identification of subpopulations that derive the greatest benefit from treatment interventions (e.g. through biomarker discovery); and the optimal combination of different treatment modalities. Producing evidence on treatment optimisation – both pre- and post-marketing authorisation – necessitates robust, patient-centred clinical research and effective collaboration among key stakeholders, including regulatory agencies, Health Technology Assessment (HTA) organisations, healthcare providers, researchers, and patients. [13], [14], [15]
Recognising the need for a systematic approach to treatment optimisation in oncology, the Cancer Medicines Forum (CMF) was established to explore how the European Medicines Agency (EMA) may support academia in driving concerted actions in this field. Founded in 2022, the CMF is co-chaired by the European Organisation for Research and Treatment of Cancer (EORTC) and the EMA. The initiative brings together key member organisations, including EMA, EORTC, the European Society for Medical Oncology (ESMO), the European Haematology Association (EHA), and the International Society of Geriatric Oncology (SIOG), as well as observers such as HTA representatives, patient organisations, the European Society for Paediatric Oncology (SIOPe), pharmaceutical industry representatives, the Organisation for Economic Co-operation and Development (OECD), the International Association of Mutual Benefit Societies (AIM), and the European Social Insurance Platform (ESIP). [16] Through fostering collaboration, the CMF aims to encourage a dialogue among different stakeholders to support treatment optimisation research.
A multidisciplinary workshop, organised on 5 April 2024 as part of the CMF initiatives, convened a diverse range of participants and stakeholders, including experts from regulatory agencies, academia, learned societies, health technology assessment organisations, industry, governmental bodies, patient organisations, public health organisations, clinicians and investigators. [17] The workshop aimed to examine existing barriers and explore potential strategies to integrate treatment optimisation into the current cancer clinical research framework. The initial workshop session presented the rationale for treatment optimisation in cancer care and provided an overview of the barriers identified through previously conducted multistakeholder group discussions [18] and analysis of existing studies. With this foundation, subsequent workshop sessions focused on identifying potential facilitators and solutions for systematically embedding treatment optimisation in oncology research.
The aim of this paper is to summarize the key recommendations expressed by participants during the workshop, reflecting the collective insights shared, ensuring a comprehensive portrayal of the workshop's discussions and outcomes. Strategic and overarching approaches proposed by various stakeholders for systematically integrating treatment optimization into the current clinical cancer research paradigm have been organized into a roadmap, which was refined and finalized through a three-round review process conducted by the authors.

2
Setting the scene and the need for a paradigm shift: key challenges in conducting treatment optimisation research
Since its inception, the CMF has fostered multistakeholder group discussions to identify the critical challenges (i.e. barriers) impeding the advancement of treatment optimisation research. [18] Additionally, and to provide a nuanced understanding of the practical difficulties associated with conducting treatment optimisation studies, three trials were presented as case studies during the workshop. The presentation of these studies aimed to both illustrate the discussion with concrete, real-world examples and to promote structured, collaborative analysis among stakeholders. These were carefully selected to represent treatment optimisation trials and to ensure diversity in development stage (one in regulatory activation, one recruiting, and one closed for recruitment with primary results published), setting (two national and one multinational) and investigational therapeutic classes (immunotherapy, endocrine treatment, and targeted therapy) (Table 1 provides a structured overview of these trials). The challenges identified by the stakeholder discussions and the detailed analysis of these studies were categorised into five key domains: lack of incentives, funding constraints, regulatory and legal barriers, recruitment difficulties, and challenges in implementing findings into clinical practice. Below, we further reflect on the identified barriers.
2.1
Lack of incentives: the unsuitability of the current frameworks
The current framework for clinical research and drug development lacks a structured approach to promote and prioritise treatment optimisation research. In the pre-authorisation setting, existing pathways are primarily focused on initial regulatory approval and assessment of benefit-risk profiles, rather than to refine treatment parameters. As a result, while early access to patients with high unmet medical needs is being prioritised, there is limited incentive for trial sponsors and drug developers to prioritise optimisation aspects. Consequently, new anticancer therapies often reach the market with many questions unresolved, adding complexity to clinical and healthcare allocation decisions.
The challenges associated with conducting optimisation research in the post-authorisation setting are also quite evident from the perspective of the stakeholders. While academia is well-placed to identify and address uncertainties in clinical decision-making, the absence of a dedicated international framework, including incentives, and structured approaches for academia-industry collaboration, to support treatment optimisation research presents significant barriers. Furthermore, the lack of structured processes to foster international collaboration and facilitate multistakeholder engagement further hinders progress in this field.

2.2
Funding constraints: limited opportunities to study sponsors
Treatment optimisation research often requires substantial financial investment, primarily due to the necessity of large sample sizes and prolonged follow-up periods. However, funding opportunities for such trials remain limited, posing a significant challenge for academic investigators and study sponsors. Comparative effectiveness research, particularly in the post-authorisation setting, usually struggles to attract significant financial support from the pharmaceutical industry, or philanthropic or public funders, especially when addressing clinically relevant questions such as treatment de-escalation. Consequently, securing adequate funding for these studies remains a persistent barrier.
In the European Union, despite recent funding initiatives introduced under the Cancer Mission for pragmatic clinical trials, which are relevant for optimization studies that integrate significant pragmatic elements into their design, [19] a comprehensive funding framework to systematically support public-health oriented research led by academia in oncology is still lacking. [20], [21], [22] Establishing a sustainable portfolio of public funding sources has been identified as a critical prerequisite for facilitating the conduct of such studies.

2.3
European legal barriers: lack of adaptative processes
Conducting treatment optimisation clinical trials, particularly those involving medicinal products, must be done within the existing legal frameworks of the European Union. Academic investigators have often debated whether the requirements for new investigational medicinal products should also apply to trials investigating modifications of the use of approved drugs, generally believed to pose minimal additional risk to participants, particularly those investigating dose optimisation, treatment schedules, combinations of different treatment modalities, or de-escalation. However, they are often subject to the same requirements as traditional interventional studies. [22], [23] Arguably, optimisation research would allow less stringent safeguards in view of its lower risk due to close alignment with standard clinical practice regarding interventions, comparators, procedures, and monitoring.
While the introduction of the “low-intervention clinical trials” category under the EU Clinical Trials Regulation 536/2014 [24] was intended to facilitate the conduct of trials involving authorised medicinal products, many treatment optimisation studies modify aspects of how the products are used (e.g. reduced treatment intensity, such as reduced dose, schedule and treatment duration) and therefore do not qualify for this designation. Furthermore, some argued that the practical benefits of this categorisation remain limited, often offering limited procedural simplifications, such as informed consent processes, labelling, and traceability of investigational medicinal products. Notably, the conduct of these trials may be hindered by administrative burdens, complex and unharmonized regulatory requirements, as well as suboptimal trial processes. Moreover, essential regulatory efficiencies, such as simplified submission dossiers and expedited assessment timelines, often remain inaccessible to these trials, thereby limiting the intended benefits of the designation. [25], [26]
In addition, it has been argued that the use of specialised diagnostic tests, which are often essential for patient stratification and for identifying individuals who may benefit from treatment intensification or de-escalation, remains inadequately integrated into current frameworks in Europe, thereby complicating the execution of such trials.

2.4
Recruitment difficulties and ethical concerns
Trials involving conventional treatments often face challenges in engaging both investigators and participants, as they may be perceived as less appealing compared to studies evaluating novel interventions. Consequently, recruitment tends to be more difficult than initially anticipated, especially when existing therapies are well-established in clinical practice and when the investigational medicine is accessible outside the trial setting, such as in the context of an early access program or following a reimbursement decision. [27], [28] Moreover, the absence of structured mechanisms to facilitate international collaboration often results in such trials being conducted at a national level rather than internationally. This limitation may reduce recruitment potential, diminish research efficiency, and complicate the applicability of study results.
Ethical considerations are also central to the implementation of treatment optimisation trials, particularly in de-escalation studies. The primary objective of reducing treatment intensity is to minimise toxicity and enhance quality of life while maintaining efficacy. This approach may raise concerns regarding the potential risk of under-treatment especially in life-threatening diseases.

2.5
Implementation in clinical practice: a challenge for treatment optimisation
The integration of treatment optimisation study findings into routine clinical practice often presents significant challenges, particularly in post-authorisation and real-world settings. The results of such studies are frequently not submitted for regulatory assessment, as submissions intended for label updates are at the discretion of the holder of the marketing authorisation rather than academic sponsors. Healthcare providers may have prior experience with the approved and labelled use of a given therapy and, as a result, may exhibit reluctance to systematically adopting optimised treatment regimens. The approved indication and label of a medicine play a critical role in health technology assessments, pricing, and reimbursement decisions. Consequently, findings from academic optimisation studies, particularly those suggesting modifications to established treatment regimens, may be difficult to incorporate into standard clinical practice, especially when their implementation could be considered off-label use. Several stakeholders have identified reimbursement complexity as a substantial barrier to the broader adoption of treatment optimisation study outcomes.

3
Potential solutions and pathways for the systematic integration of treatment optimisation research in oncology.
Building on the challenges outlined, stakeholders have contributed to identifying potential solutions, focusing mostly on policy as well as on strategic and overarching recommendations. These solutions, generated and discussed during the workshop, provide concrete and actionable steps to strengthen policy frameworks, regulatory processes, funding mechanisms, and societal engagement. Additionally, they underscore the importance of patient-centric approaches in ensuring the successful design and implementation of treatment optimisation studies, ultimately contributing to the personalisation and optimisation of therapies. The solutions were systematised into a roadmap (Table 2), presenting a possible way forward from the view of the stakeholders for the systematic implementation of treatment optimisation research in oncology. Below, we further reflect on proposed solutions.
The announced revision of the EMA’s anticancer guideline version 7 and the ongoing revision of the EU pharmaceutical legislation represent opportunities to support optimisation. [32] These developments, in conjunction with the aforementioned facilitators, create a valuable and timely opportunity to explicitly integrate treatment optimisation research within regulatory frameworks. Integrating optimisation trials into drug development programmes could facilitate the timely adoption of improved regimens, minimise unnecessary patient exposure to toxicities, help address funding challenges, ultimately enhancing the efficiency of clinical research. More concretely, regulatory and HTA agencies could systematically incorporate treatment optimisation considerations into established processes, such as scientific advice, protocol assistance, and joint scientific consultations. [33], [34] Internationally, and to foster this discussion, the U.S. Food and Drug Administration (FDA) has launched Project Optimus aimed at reforming the dose optimisation and selection paradigm in early oncology drug development, to emphasize dose selection that maximizes efficacy, safety and tolerability. [35], [36]
While stakeholders acknowledge that the pre-authorisation phase represents the most appropriate juncture to address treatment optimisation, especially for aspects related to treatment dose, schedule and duration, not all optimisation aspects may be adequately resolved within this setting, such as those concerning treatment sequencing and combination strategies, which inherently depend on the evolving understanding of disease contexts and the utilisation of available therapeutic modalities. Therefore, in the post-authorisation setting, there is an opportunity to develop a dedicated framework to systematically address treatment optimisation research questions that are not necessarily incorporated into drug development programmes. [37] Such an EU framework should foster international cooperation and multi-stakeholder collaboration, not only in identifying the most pressing treatment optimisation research priorities but also in ensuring the effective execution of these studies. Initiatives such as Project 5 in 5 offers a noteworthy example, encouraging the development of pragmatic clinical trials that address clinically relevant questions using approved oncology therapies. This US FDA crowdsourcing program fosters stakeholder collaboration and aims to identify five key research questions related to new technologies to be addressed over the next five years. [38] Existing mechanisms, such as the World Health Organization’s (WHO) Global Clinical Trials Forum, may serve as models for designing and implementing trials across diverse healthcare settings, fostering international partnerships to address common challenges. [39]
A well-structured framework may also allow to incorporate designated financial resources and funding mechanisms to support academic-led clinical trials. Public funding for advancing treatment optimisation research, as well as collaborations involving HTA agencies and insurers, could be further explored as funding models. [22] Various EU Member States, including Belgium and the Netherlands, have implemented national funding mechanisms for practice-oriented, academic-led clinical trials that focus on evaluating the effectiveness of interventions. These initiatives allocate public funds to address critical evidence gaps and high-priority societal issues, thereby generating actionable evidence for decision-making and contributing to the long-term financial sustainability of healthcare systems. [40], [41] Establishing a diversified portfolio of public funding sources is essential to sustaining and expanding these efforts. [42] By fostering a robust international network for conducting treatment optimisation trials supported by a range of non-commercial funding sources, independent clinical research may generate high-quality evidence that objectively informs treatment decisions, ultimately addressing the needs of both patients and society. [43]
The implementation of adaptive pathways to facilitate the conduct of treatment optimisation studies was identified as a key enabler. Streamlined processes are essential for efficiently addressing these research questions while maintaining rigorous oversight. While there are notable developments in this field, such as the harmonised guideline for Good Clinical Practice E6 (R3), the regulatory guidance on decentralised elements, eligibility criteria, and the deployment of trials in routine care settings, as well as the initiative Accelerating Clinical Trials in the EU (ACT EU), [23], [44], [45], [46], [47], [48] there are still opportunities to further streamline practical implementation. Alignment of expectations between sponsors and clinical trial authorisation competent authorities on adequate risk-based approaches for optimisation trials may further enhance the feasibility of these trials. This is particularly important given the apparent variability in the interpretation and application of EU regulations across Member States. Although the EU Clinical Trials Regulation was designed to harmonise trial governance, inconsistencies in implementation are still reported as a challenge. [25] Additionally, the coordinated implementation of multiple regulatory frameworks affecting treatment optimisation research, namely the EU Clinical Trials Regulation, the In Vitro Diagnostic Medical Devices Regulation, the revised EU Pharmaceutical Legislation, and the EU Health Technology Assessment Regulation, was emphasised as an urgent priority. Ensuring alignment across these frameworks will be essential to reducing administrative burden and facilitating cross-border collaboration. [24], [32], [49], [50]
The involvement of patients and patient organisations ensures that cancer research aligns with patients’ needs, with patient preference studies serving as a valuable tool to inform drug development. [51], [52] Identifying and actively participating in international collaborative networks could empower both healthcare professionals and patients and enhance collaboration among their organisations. [53]

4
Key recommendations and ways forward for integrating optimisation research
The optimisation of cancer treatment is an underdeveloped area of clinical research, yet it holds significant potential to enhance patient outcomes and support the sustainability of healthcare systems. To bridge this gap, the CMF has convened diverse stakeholders to propose structured solutions. Key strategic and overarching recommendations include integrating optimisation studies within both pre- and post-authorisation regulatory pathways, recognising the pre-authorisation phase as the most appropriate timing to address optimisation aspects that may be anticipated, while ensuring dedicated mechanisms, and fostering international collaboration among regulatory bodies, HTA agencies, and academia for questions arising post-authorisation.
Equally crucial is the involvement of patients in shaping research priorities, promoting patient-centred study designs, and developing research that addresses real-world needs, truly supporting the advancement of personalised medicine. The active engagement of patients is required for ensuring that the outcomes measured reflect what matters most to patients – symptom relief, quality of life and functional outcomes – beyond traditional endpoints. When possible, introduction of pragmatic elements in clinical trials, including an optimally representative of the ultimate patient population to be treated in the healthcare setting, and conducted as closely as possible to standard practice, should be implemented. Meaningful patient engagement not only supports the design and conduct of trials but also strengthens recruitment, retention, and relevance of the findings.
Clinical trial approaches should prioritise activities of meaningful clinical value and avoid unnecessary burdens. Therefore, it will be critical that these studies adhere to the principles of proportionality alongside adaptive and risk-based approaches. The CMF will continue to foster dialogue among stakeholders to ensure mutual understanding of requirements and alignment of expectations around optimisation research. By systematically integrating optimisation research into existing regulatory, clinical, and funding structures, stakeholders may generate high-quality evidence that informs clinical practice, enhances patient safety, and promotes the efficient allocation of healthcare resources. Implementing these strategies will not only address existing knowledge gaps but also support a paradigm shift toward a more sustainable and effective approach to cancer care.

5
Conclusion
Cancer drug development remains a complex endeavour driven by diverse stakeholder objectives and priorities, ranging from the rapid introduction of innovative therapies to address high unmet medical needs, to the comprehensive understanding and optimisation of existing treatments to enhance benefits and reduce harms. Within this landscape, optimisation trials are likely to become a pivotal mechanism for generating robust evidence that informs further refined clinical practice and nuancing health policy decisions. Nevertheless, the execution of such trials faces numerous challenges. Overcoming these hurdles necessitates a strong multistakeholder commitment, a mutual understanding of stakeholder perspectives and requirements, and the development of collaborative solutions, as appropriate. Initiatives such as the EMA's Cancer Medicines Forum exemplify how stakeholder engagement and aligning efforts may support these objectives, fostering a conducive environment for evidence generation and facilitating the successful integration of treatment optimization into clinical and regulatory pathways.

Funding
The public workshop and CMF-related activities did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. All authors contributed on a voluntary basis to the workshop, CMF-related activities and the manuscript.

CRediT authorship contribution statement
Gwenaelle Gravis: Writing – review & editing, Investigation. Martin Kaiser: Writing – review & editing, Investigation. Iphigenie Korakis: Writing – review & editing, Investigation. Denis Lacombe: Writing – review & editing, Writing – original draft, Visualization, Conceptualization. Momir Radulovic: Writing – review & editing, Investigation. Fábio Cardoso Borges: Writing – review & editing, Writing – original draft, Visualization, Conceptualization. Michael Zaiac: Writing – review & editing, Investigation. Raffaella Casolino: Writing – review & editing, Investigation. Caroline Voltz-Girolt: Writing – review & editing, Writing – original draft, Visualization, Conceptualization. Pierre Demolis: Writing – review & editing, Investigation. Francesco Pignatti: Writing – review & editing, Writing – original draft, Visualization, Supervision, Conceptualization. Rosa Giuliani: Writing – review & editing, Investigation. Daniel A Goldstein: Writing – review & editing, Investigation. Bertrand Tombal: Writing – review & editing, Investigation. Beate Wieseler: Writing – review & editing, Investigation. Guy Brusselle: Writing – review & editing, Investigation. Richard Sullivan: Writing – review & editing, Investigation. Ana E. Amariutei: Writing – review & editing, Investigation. Christopher M. Booth: Writing – review & editing, Investigation.

Declaration of Competing Interest
The views expressed in this article are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the agencies or organizations with which the authors are affiliated. FCB has received a fellowship grant from the European Organisation for Research and Treatment of Cancer Cancer Research Fund. GB has received honoraria and travel support from Ghent University Hospital. DAG has received consulting fees and holds stocks from Vivio Health; has received funding grants from Janssen Pharmaceuticals, Bristol Myers Squibb, and Merck & Co. GG has received speaking and lecture fees from Novartis, Amgen, AstraZeneca, Bristol Myers Squibb, Bayer, Johnson & Johnson, MSD, and Ipsen; has received travel support from Novartis, Amgen, AstraZeneca, Bristol Myers Squibb, Bayer, MSD, and Ipsen; has received consulting fees from AstraZeneca. MK has received consulting fees from AbbVie Inc., Bristol Myers Squibb, GlaxoSmithKline, Janssen Pharmaceuticals Inc., Karyopharm Therapeutics, Pfizer Inc., Regeneron Pharmaceuticals, Roche, Sanofi, Takeda Oncology, and Adaptive Biotechnologies Corporation; has received funding grants from Bristol Myers Squibb and Janssen Pharmaceuticals Inc.; has received speaking and lecturing fees from Janssen Pharmaceuticals Inc. RAJESHE 06-JAN-2026 06:59 IK has received travel support from Roche; has received speaking and lecture fees from Roche; has received funding to the institution for the conduct of clinical research as Principal Investigator from AbbVie, Astellas, Anaveon, Daiichi Sankyo, Immunocore, Dragonfly, Sotio, Amgen, Fore Therapeutics, C4 Therapeutics, Gilead, and ImCheck Therapeutics. MR has received honoraria from the Agency for Medicinal Products and Medical Devices of the Republic of Slovenia. RS has received honoraria from King's College London. MZ has received honoraria and holds stocks from Daiichi Sankyo Europe GmbH. All other authors declare no competing interests.