How do cancer clinicians perceive real-world data and the evidence derived therefrom? Findings from an international survey of the European Organisation for Research and Treatment of Cancer.

Background: The role of real-world evidence (RWE) in the development of anticancer therapies has been gradually growing over time. Regulators, payers and health technology assessment agencies, spurred by the rise of the precision medicine model, are increasingly incorporating RWE into their decision-making regarding the authorization and reimbursement of novel antineoplastic treatments. However, it remains unclear how this trend is viewed by clinicians in the field. This study aimed to investigate the opinions of these stakeholders with respect to RWE and its suitability for informing regulatory, reimbursement-related and clinical decisions in oncology. Methods: An online survey was disseminated to clinicians belonging to the network of the European Organisation for Research and Treatment of Cancer between May and July 2021. Results: In total, 557 clinicians across 30 different countries participated in the survey, representing 13 distinct cancer domains. Despite seeing the methodological challenges associated with its interpretation as difficult to overcome, the respondents mostly (75.0%) perceived RWE positively, and believed such evidence could be relatively strong, depending on the designs and data sources of the studies from which it is produced. Few (4.6%) saw a future expansion of its influence on decision-makers as a negative evolution. Furthermore, nearly all (94.0%) participants were open to the idea of sharing anonymized or pseudonymized electronic health data of their patients with external parties for research purposes. Nevertheless, most clinicians (77.0%) still considered randomized controlled trials (RCTs) to be the gold standard for generating clinical evidence in oncology, and a plurality (49.2%) thought that RWE cannot fully address the knowledge gaps that remain after a new antitumor intervention has entered the market. Moreover, a majority of respondents (50.7%) expressed that they relied more heavily on RCT-derived evidence than on RWE for their own decision-making. Conclusion: While cancer clinicians have positive opinions about RWE and want to contribute to its generation, they also continue to hold RCTs in high regard as sources of actionable evidence.

Past, Current, and Future Cancer Clinical Research Collaborations: The Case of the European Organisation for Research and Treatment of Cancer.

Although collaborations between academic institutions and industry have led to important scientific breakthroughs in the discovery stage of the pharmaceutical research and development process, the role of multistakeholder partnerships in the clinical development of anticancer medicines necessitates further clarification. The benefits associated with such cooperation could be undercut by the conflicting goals and motivations of the actors included. The aim of this review was to identify and characterize past, present, and future stakeholder partnership models in cancer clinical research through the lens of the European Organisation for Research and Treatment of Cancer (EORTC). Based on the analysis of several landmark EORTC trials performed across the span of three decades, four existing models of stakeholder cooperation were delineated and characterized. Additionally, a hypothetical fifth model representing a potential future collaborative framework for cancer clinical research was formulated. These models mainly differ in terms of the nature and responsibilities of the partners included and show that clinical research partnerships in oncology have evolved over time from small-scale academia-industry collaborations to complex interdisciplinary cooperation involving many different stakeholders.

The fourth edition of the European Network for Health Technology Assessment Forum: highlights and outcomes.

The European Network for Health Technology Assessment (EUnetHTA) organizes an annual Forum with stakeholders to receive feedback on its activities, processes, and outputs produced. The fourth edition of the EUnetHTA Forum brought together representatives of HTA bodies, patient organizations, healthcare professionals (HCPs), academia, payers, regulators, and industry. The aim of this paper is to provide an overview of the highlights presented at the 2019 EUnetHTA Forum, reporting the main items and themes discussed in the plenary panel and breakout sessions. The leading topic was the concept of unmet medical need seen from different stakeholders' perspectives. Breakout sessions covered the joint production of assessment reports and engagement with payers, patients, and HCPs. Synergies, pragmatism, and inclusiveness across Member States and stakeholders were emphasized as leading factors to put in place a collaboration that serves the interest of patients and public health in a truly European spirit.

Views of European Drug Development Stakeholders on Treatment Optimization and Its Potential for Use in Decision-Making.

BACKGROUND: The current drug development paradigm has been criticized for being too drug-centered and for not adequately focusing on the patients who will eventually be administered the therapeutic interventions it generates. The drug-driven nature of the present framework has led to the emergence of a research gap between the pre-approval development of anticancer medicines and their post-registration use in real-life clinical practice. This gap could potentially be bridged by transitioning toward a patient-centered paradigm that places a strong emphasis on treatment optimization, which strives to optimize the way health technologies are applied in a real-world environment. However, questions remain concerning the ideal features of treatment optimization studies and their acceptability among key stakeholders. OBJECTIVES: The aim of this study was to explore the views of key stakeholders in the drug development process regarding the concept of treatment optimization. METHODS: Semi-structured interviews were conducted between December 2018 and May 2019 with 26 participants across ten EU Member States and six different stakeholder groups, including academic clinicians as well as representatives of patient organizations, regulatory authorities, health technology assessment agencies, payers, and industry. RESULTS: Based on the input of the experts interviewed, clarification was obtained regarding the optimal features of treatment optimization studies in terms of their conduct, funding, timing, design, and setting. Moreover, a number of opportunities and challenges of undertaking such trials were identified. Inter-stakeholder discussion during their design was seen as desirable. There was also broad support among the participants for regulatory measures to facilitate treatment optimization, although there was no agreement on the optimal scale and nature of these initiatives. Furthermore, the interviewees believed that the evidence strength of well-designed treatment optimization studies performed according to rigorous quality standards is greater than or at least equal to that of classical clinical trials. In addition, there was a strong consensus that the results of treatment optimization studies should be taken into account during the decision-making of regulators, payers, and/or clinicians. CONCLUSIONS: Stakeholders involved in drug development consider treatment optimization studies to be valuable tools to address current evidence gaps and support their implementation into the existing research framework.

Current models, challenges and best practices for work conducted between European academic cooperative groups and industry.

BACKGROUND: The academia-industry interface is important, and, despite challenges that inevitably occur, bears the potential for positive synergies to emerge. Perceived barriers to wider collaboration in academia-industry oncology research in Europe need to be addressed, current academic cooperative group and industry models for collaboration need to be discussed, and a common terminology to facilitate understanding of both sectors' concerns needs to be established with an eye towards improving academia-industry partnerships on clinical trials for the benefit of patients with cancer. METHODOLOGY: CAREFOR (Clinical Academic Cancer Research Forum), a multi-stakeholder platform formed to improve the direction for academic clinical trials in the field of oncology in Europe, formed the CAREFOR-Industry Working Group comprised of experienced professionals from European academic cooperative groups joined by industry representatives selected based on their activities in the area of medical oncology. They jointly discussed academic cooperative groups, clinical trials conducted between academic cooperative groups and industry, examples of successful collaborative models, common legal negotiation points in clinical trial contracts, data access, and principles of interaction. RESULTS: Four principles of interaction between the academia and industry are proposed: (1) clarify the roles and responsibilities of all partners involved in the study, (2) involve legal teams from an early stage; (3) acknowledge that data is an important output of the study, (4) agree on the intent of the trial prior to its start. CONCLUSIONS: The CAREFOR-Industry Working Group describes current models, challenges, and effective strategies for academia-industry research in Europe with an eye towards improving academia-industry partnerships on clinical trials for patients with cancer. Current perceived challenges are explained, and future opportunities/recommendations for improvement are described for the areas of most significant impact. Challenges are addressed from both the academic and industry perspectives, and principles of interaction for the optimal alignment between academia and industry in selected areas are proposed.

Addressing the dichotomy between individual and societal approaches to personalised medicine in oncology.

Academic, industry, regulatory leaders and patient advocates in cancer clinical research met in November 2018 at the Innovation and Biomarkers in Cancer Drug Development meeting in Brussels to address the existing dichotomy between increasing calls for personalised oncology approaches based on individual molecular profiles and the need to make resource and regulatory decisions at the societal level in differing health-care delivery systems around the globe. Novel clinical trial designs, the utility and limitations of real-world evidence (RWE) and emerging technologies for profiling patient tumours and tumour-derived DNA in plasma were discussed. While randomised clinical trials remain the gold standard approach to defining clinical utility of local and systemic therapeutic interventions, the broader adoption of comprehensive tumour profiling and novel trial designs coupled with RWE may allow patient and physician autonomy to be appropriately balanced with broader assessments of safety and overall societal benefit.

Late translational research: putting forward a new model for developing new anti-cancer treatments that addresses the needs of patients and society.

Bringing therapeutic innovation and the latest science to routine patient care, while safeguarding principles of affordability and equality, is a challenging mission in the current complex multi-stakeholder environment. Precision oncology and new approaches to clinical trials (methods and clinical setting) have dramatically changed clinical research and the clinical development of new treatments. Improved understanding of molecular biology and immunology paves the way for innovative pharmacological approaches. However, we argue that the evidence generated during the clinical development of these new products for the purpose of obtaining marketing authorisations often does not address fundamental questions concerning the impact of these new interventions on the most relevant clinical outcomes: namely, quality of life and patient survival. Similarly, patient populations (for example defined by biomarkers), treatment duration, and sequence and combination of treatments within current treatment pathways are often poorly defined by clinical developments for regulatory purposes. Finally, the lack of integrated translational research within the pathway of development is a major limiting factor to delivering cost-effective and affordable, evidence-based care to clinical practice. This leaves many gaps in the knowledge on the efficacy and therapeutic use of medicines, which can impose a significant financial burden on healthcare systems, possibly to the detriment of more cost-effective interventions. We argue that policy changes are required to integrate clinical research and healthcare to inform clinical practice. New routes toward optimising the integration of drug development and care are being proposed to achieve this ultimate goal.

'Mind the gap' between the development of therapeutic innovations and the clinical practice in oncology: A proposal of the European Organisation for Research and Treatment of Cancer (EORTC) to optimise cancer clinical research.

In Europe, most of the cancer clinical research dedicated to therapeutic innovations aims primarily at regulatory approval. Once an anticancer drug enters the common market, each member state determines its real-world use based on its own criteria: pricing, reimbursement and clinical indications. Such an innovation-centred clinical research landscape might neglect patient-relevant issues in real-world setting, such as comparative effectiveness of distinct treatment options or long-term safety monitoring. The European Organisation for Research and Treatment of Cancer (EORTC) advocates reforming the current 'innovation-centred' system to a truly 'patient-centred' paradigm with systematically coordinated applied clinical research in conjunction with drug development, featuring the following strategy.

Societal challenges of precision medicine: Bringing order to chaos.

The increasing number of drugs targeting specific proteins implicated in tumourigenesis and the commercial promotion of relatively affordable genome-wide analyses has led to an increasing expectation among patients with cancer that they can now receive effective personalised treatment based on the often complex genomic signature of their tumour. For such approaches to work in routine practice, the development of correspondingly complex biomarker assays through an appropriate and rigorous regulatory framework will be required. It is becoming increasingly evident that a re-engineering of clinical research is necessary so that regulatory considerations and procedures facilitate the efficient translation of these required biomarker assays from the discovery setting through to clinical application. This article discusses the practical requirements and challenges of developing such new precision medicine strategies, based on leveraging complex genomic profiles, as discussed at the Innovation and Biomarkers in Cancer Drug Development meeting (8th-9th September 2016, Brussels, Belgium).

Imaging biomarker roadmap for cancer studies.

Imaging biomarkers (IBs) are integral to the routine management of patients with cancer. IBs used daily in oncology include clinical TNM stage, objective response and left ventricular ejection fraction. Other CT, MRI, PET and ultrasonography biomarkers are used extensively in cancer research and drug development. New IBs need to be established either as useful tools for testing research hypotheses in clinical trials and research studies, or as clinical decision-making tools for use in healthcare, by crossing 'translational gaps' through validation and qualification. Important differences exist between IBs and biospecimen-derived biomarkers and, therefore, the development of IBs requires a tailored 'roadmap'. Recognizing this need, Cancer Research UK (CRUK) and the European Organisation for Research and Treatment of Cancer (EORTC) assembled experts to review, debate and summarize the challenges of IB validation and qualification. This consensus group has produced 14 key recommendations for accelerating the clinical translation of IBs, which highlight the role of parallel (rather than sequential) tracks of technical (assay) validation, biological/clinical validation and assessment of cost-effectiveness; the need for IB standardization and accreditation systems; the need to continually revisit IB precision; an alternative framework for biological/clinical validation of IBs; and the essential requirements for multicentre studies to qualify IBs for clinical use.

Making Change Happen in Health.

Integrating personalised medicine into Europe's healthcare systems will undoubtedly need to draw upon diverse talents via a multi-stakeholder approach taking expertise from academia, industry, healthcare organisations, government, policymakers and, of course, patient groups. It will also need a long-term budget commitment geared towards stimulating research and innovation in order to succeed. The role of HTA also needs to be boosted, while EU engagement in health needs to increase, not decrease, and requires a long-term strategy to provide a structure, a framework, and a consensus. Health equals wealth and the authors argue here that investment in research and innovation, alongside laws and rules that are fit-for-purpose and reflect the swiftly changing world of medicine, are vital. Europe needs to grasp these points at every level for the benefit of the millions of potential patients spread across the soon-to-be 27 Member States.

Precision Medicine: From "Omics" to Economics towards Data-Driven Healthcare - Time for European Transformation.

There is room for improvement for optimally bringing the latest science to the patient while taking into account patient priorities such as quality of life. Too often, regulatory agencies, governments, and funding agencies do not stimulate the integration of research into care and vice versa. Re-engineering the drug development process is a priority, and healthcare systems are long due for transformation. On one hand, patients need efficient access to treatments, but despite precision oncology approaches, efficiently shared screening platforms for sorting patients based on the biology of their tumour for trial access are lacking and, on the other hand, the true value of cancer care is poorly addressed as central questions such as dose, scheduling, duration, and combination are not or sub-optimally addressed by registration trials. Solid evidence on those parameters could potentially lead to a rational and wiser use of anti-cancer treatments. Together, optimally targeting patient population and robust comparative effectiveness data could lead to more affordable and economically sound approaches. The drug development process and healthcare models need to be interconnected through redesigned systems taking into account the full math from drug development into affordable care.

Towards new methods for the determination of dose limiting toxicities and the assessment of the recommended dose for further studies of molecularly targeted agents--dose-Limiting Toxicity and Toxicity Assessment Recommendation Group for Early Trials of Targeted therapies, an European Organisation for Research and Treatment of Cancer-led study.

INTRODUCTION: Traditional dose-limiting toxicity (DLT) definition, which uses grade (G) 3-4 toxicity data from cycle 1 (C1) only, may not be appropriate for molecularly targeted agents (MTAs) of prolonged administration, for which late or lower grade toxicities also deserve attention. PATIENTS AND METHODS: In collaboration with pharmaceutical companies and academia, an European Organisation for Research and Treatment of Cancer (EORTC)-led initiative, Dose-Limiting Toxicity and Toxicity Assessment Recommendation Group for Early Trials of Targeted therapies (DLT-TARGETT), collected data from completed phase 1 trials evaluating MTAs as monotherapy. All toxicities at least possibly related to the study drugs that occurred during C1-6, their type, grade (CTCAEv3.0), and duration as well as patients' relative dose-intensity (RDI), were recorded. RESULTS: The 54 eligible trials enrolled 2084 evaluable adult patients with solid tumours between 1999 and 2013, and evaluated small molecules (40), antibodies (seven), recombinant peptides (five) and antisense oligodeoxynucleotides (two). A maximum tolerated dose was set in 43 trials. Fifteen percent of the patients received <75% of the intended RDI in C1, but only 9.1% of them presented protocol-defined DLTs. After C1, 16-19% of patients received <75% of the intended RDI. A similar proportion of G ⩾ 3 toxicities was recorded in C1 and after C1 (936 and 1087 toxicities, respectively), with the first G⩾3 toxicity occurring after C1 in 18.6% of patients. CONCLUSION: Although protocol-defined DLT period is traditionally limited to C1, almost 20% of patients present significant reductions in RDI at any time in phase 1 trials of MTAs. Recommended phase 2 dose assessment should incorporate all available information from any cycle (notably lower grade toxicities leading to such RDI decrease), and be based on achieving >75% RDI.

How can innovative forms of clinical research contribute to deliver affordable cancer care in an evolving health care environment?

As health care costs are constantly rising and governments are reforming their healthcare systems there is an urgent need to reshape the European clinical research landscape. To bridge the translational gap extensive research to understand the mechanism of the agents and of the disease has to be performed and the real benefit of drugs needs to be assessed independently. Furthermore, meaningful data for reimbursement strategies will be a major goal of future clinical trials as well. Therefore, a new integrated model of clinical cancer research is needed to optimise the R&D process. Strategies to ensure that we can gather robust and relevant data about the effectiveness of various healthcare interventions have to be developed to provide optimal patient care within the limits of a healthcare budget.

Improving cancer outcomes through international collaboration in academic cancer treatment trials.

PURPOSE: The need for international collaboration in cancer clinical trials has grown stronger as we have made progress both in cancer treatment and screening. We sought to identify those efforts already underway which facilitate such collaboration, as well as barriers to greater collaboration. METHODS: We reviewed the collective experiences of many cooperative groups, governmental organizations, nongovernmental organizations, and academic investigators in their work to build international collaboration in cancer clinical trials across multiple disease sites. RESULTS: More than a decade of work has led to effective global harmonization for many of the elements critical to cancer clinical trials. Many barriers remain, but effective international collaboration in academic cancer treatment trials should become the norm, rather than the exception. CONCLUSION: Our ability to strengthen international collaborations will result in maximization of our resources and patients, permitting us to change practice by establishing more effective therapeutic strategies. Regulatory, logistical, and financial hurdles, however, often hamper the conduct of joint trials. We must work together as a global community to overcome these barriers so that we may continue to improve cancer treatment for patients around the world.

Prognostic value of health-related quality-of-life data in predicting survival in patients with anaplastic oligodendrogliomas, from a phase III EORTC brain cancer group study.

PURPOSE: This is one of a few studies that have explored the value of baseline symptoms and health-related quality of life (HRQOL) in predicting survival in patients with brain cancer. PATIENTS AND METHODS: Baseline HRQOL scores (from the European Organisation for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire C30 and the EORTC Brain Cancer Module) were examined in 247 patients with anaplastic oligodendrogliomas to determine the relationship with overall survival by using Cox proportional hazards regression models. Refined techniques as the bootstrap resampling procedure and the computation of C indexes and R2 coefficients were used to explore the stability of the models as well as better assess the potential benefit of using HRQOL to predict survival in clinical practice and research. RESULTS: Classical analysis controlled for major clinical prognostic factors selected emotional functioning (P = .0016), communication deficit (P = .0261), future uncertainty (P = .0481), and weakness of legs (P = .0001) as statistically significant prognostic factors of survival. However, several issues question the validity of these findings and no single model was found to be preferable over all others. C indexes, which estimate the probability of a model to correctly predict which patient among a randomly chosen pair of patients will survive longer, and R2 coefficients, which measure the proportion of variability explained by the model, did not exhibit major improvement when adding selected or all HRQOL scores to clinical factors. CONCLUSION: While classical techniques lead to positive results, more refined analyses suggest that baseline HRQOL scores add relatively little to clinical factors to predict survival. These results may have implications for future use of HRQOL as a prognostic factor for patients with cancer.