Inclusion of functional measures and frailty in the development and evaluation of medicines for older adults.

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E7, the guidance for the conduct of clinical trials in people older than age 65 years, dates from 1994. Since then, the inclusion of older people in clinical trials has hardly improved, particularly for the oldest old age group (individuals older than age 75 years), which is the fastest growing demographic bracket in the EU. Even though most medications are taken by this group, relevant endpoints and safety outcomes for this cohort are rarely included and reported, both in clinical trials and regulatory approval documents. To improve the critical appraisal and the regulatory review of medicines taken by frail older adults, eight recommendations are presented and discussed in this Health Policy. These recommendations are brought together from different perspectives and experience of the treatment of older patients. On one side, the perspective of medical practitioners from various clinical disciplines, with their direct experience of clinical decision making; on the other, the perspective of regulators assessing the data submitted in medicine registration dossiers, their relevance to the risk-benefit balance for older patients, and the communication of the findings in the product information. Efforts to improve the participation of older people in clinical trials have been in place for more than a decade, with little success. The recommendations presented here are relevant for stakeholders, authorities, pharmaceutical companies, and researchers alike, as the implementation of these measures is not under the capacity of a single entity. Improving the inclusion of frail older adults requires awareness, focus, and action on the part of those who can effect a much needed change.

Analysis of the characteristics and the degree of pragmatism exhibited by pragmatic-labelled trials of antineoplastic treatments.

BACKGROUND: Pragmatic clinical trials (PCTs) are designed to reflect how an investigational treatment would be applied in clinical practice. As such, unlike their explanatory counterparts, they measure therapeutic effectiveness and are capable of generating high-quality real-world evidence. However, the conduct of PCTs remains extremely rare. The scarcity of such studies has contributed to the emergence of the efficacy-effectiveness gap and has led to calls for launching more of them, including in the field of oncology. This analysis aimed to identify self-labelled pragmatic trials of antineoplastic interventions and to evaluate whether their use of this label was justified. METHODS: We searched PubMed® and Embase® for publications corresponding with studies that investigated antitumor therapies and that were tagged as pragmatic in their titles, abstracts and/or index terms. Subsequently, we consulted all available source documents for the included trials and extracted relevant information from them. The data collected were then used to appraise the degree of pragmatism displayed by the PCTs with the help of the validated PRECIS-2 tool. RESULTS: The literature search returned 803 unique records, of which 46 were retained upon conclusion of the screening process. This ultimately resulted in the identification of 42 distinct trials that carried the 'pragmatic' label. These studies examined eight different categories of neoplasms and were mostly randomized, open-label, multicentric, single-country trials sponsored by non-commercial parties. On a scale of one (very explanatory) to five (very pragmatic), the median PCT had a PRECIS-2 score per domain of 3.13 (interquartile range: 2.57-3.53). The most and least pragmatic studies in the sample had a score of 4.44 and 1.57, respectively. Only a minority of trials were described in sufficient detail to allow them to be graded across all domains of the PRECIS-2 instrument. Many of the studies examined also had features that arguably precluded them from being pragmatic altogether, such as being monocentric or placebo-controlled in nature. CONCLUSION: PCTs of antineoplastic treatments are generally no more pragmatic than they are explanatory.

Defining the role of real-world data in cancer clinical research: The position of the European Organisation for Research and Treatment of Cancer.

The emergence of the precision medicine paradigm in oncology has led to increasing interest in the integration of real-world data (RWD) into cancer clinical research. As sources of real-world evidence (RWE), such data could potentially help address the uncertainties that surround the adoption of novel anticancer therapies into the clinic following their investigation in clinical trials. At present, RWE-generating studies which investigate antitumour interventions seem to primarily focus on collecting and analysing observational RWD, typically forgoing the use of randomisation despite its methodological benefits. This is appropriate in situations where randomised controlled trials (RCTs) are not feasible and non-randomised RWD analyses can offer valuable insights. Nevertheless, depending on how they are designed, RCTs have the potential to produce strong and actionable RWE themselves. The choice of which methodology to employ for RWD studies should be guided by the nature of the research question they are intended to answer. Here, we attempt to define some of the questions that do not necessarily require the conduct of RCTs. Moreover, we outline the strategy of the European Organisation for Research and Treatment of Cancer (EORTC) to contribute to the generation of robust and high-quality RWE by prioritising the execution of pragmatic trials and studies set up according to the trials-within-cohorts approach. If treatment allocation cannot be left up to random chance due to practical or ethical concerns, the EORTC will consider undertaking observational RWD research based on the target trial principle. New EORTC-sponsored RCTs may also feature concurrent prospective cohorts composed of off-trial patients.

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.

QUARTET: A SIOP Europe project for quality and excellence in radiotherapy and imaging for children and adolescents with cancer.

The European Society for Paediatric Oncology (SIOPE) Radiation Oncology Working Group presents the QUARTET Project: a centralised quality assurance programme designed to standardise care and improve the quality of radiotherapy and imaging for international clinical trials recruiting children and adolescents with cancer throughout Europe. QUARTET combines the paediatric radiation oncology expertise of SIOPE with the infrastructure and experience of the European Organisation for Research and Treatment of Cancer to deliver radiotherapy quality assurance programmes for large, prospective, international clinical trials. QUARTET-affiliated trials include children and adolescents with brain tumours, neuroblastoma, sarcomas including rhabdomyosarcoma, and renal tumours including Wilms' tumour. With nine prospective clinical trials and two retrospective studies within the active portfolio in March 2022, QUARTET will collect one of the largest repositories of paediatric radiotherapy and imaging data, support the clinical assessment of radiotherapy, and evaluate the role and benefit of radiotherapy quality assurance for this cohort of patients within the context of clinical trials.

Joint Final Report of EORTC 26951 and RTOG 9402: Phase III Trials With Procarbazine, Lomustine, and Vincristine Chemotherapy for Anaplastic Oligodendroglial Tumors.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the basis of the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Anaplastic oligodendroglial tumors (AOTs) are chemotherapy-sensitive brain tumors. We report the final very long-term survival results from European Organization for the Research and Treatment of Cancer 26951 and Radiation Therapy Oncology Group 9402 phase III trials initiated in 1990s, which both studied radiotherapy with/without neo/adjuvant procarbazine, lomustine, and vincristine (PCV) for newly diagnosed anaplastic oligodendroglial tumors. The median follow-up duration in both was 18-19 years. For European Organization for the Research and Treatment of Cancer 26951, median, 14-year, and probable 20-year overall survival rates without versus with PCV were 2.6 years, 13.4%, and 10.1% versus 3.5 years, 25.1%, and 16.8% (N = 368 overall; hazard ratio [HR] 0.78; 95% CI, 0.63 to 0.98; P = .033), with 1p19q codeletion 9.3 years, 26.2%, and 13.6% versus 14.2 years, 51.0%, and 37.1% (n = 80; HR 0.60; 95% CI, 0.35 to 1.03; P = .063), respectively. For Radiation Therapy Oncology Group 9402, analogous results were 4.8 years, 16.5%, and 11.2% versus 4.8 years, 29.1%, and 24.6% (N = 289 overall; HR 0.79; 95% CI, 0.61 to 1.03; P = .08), with codeletion 7.3 years, 25.0%, and 14.9% versus 13.2 years, 46.1%, and 37% (n = 125; HR 0.61; 95% CI, 0.40 to 0.94; P = .02), respectively. With that, the studies show similar long-term survival even without tumor recurrence in a significant proportion of patients after first-line treatment with radiotherapy/PCV.

The Porto European Cancer Research Summit 2021.

Key stakeholders from the cancer research continuum met in May 2021 at the European Cancer Research Summit in Porto to discuss priorities and specific action points required for the successful implementation of the European Cancer Mission and Europe's Beating Cancer Plan (EBCP). Speakers presented a unified view about the need to establish high-quality, networked infrastructures to decrease cancer incidence, increase the cure rate, improve patient's survival and quality of life, and deal with research and care inequalities across the European Union (EU). These infrastructures, featuring Comprehensive Cancer Centres (CCCs) as key components, will integrate care, prevention and research across the entire cancer continuum to support the development of personalized/precision cancer medicine in Europe. The three pillars of the recommended European infrastructures - namely translational research, clinical/prevention trials and outcomes research - were pondered at length. Speakers addressing the future needs of translational research focused on the prospects of multiomics assisted preclinical research, progress in Molecular and Digital Pathology, immunotherapy, liquid biopsy and science data. The clinical/prevention trial session presented the requirements for next-generation, multicentric trials entailing unified strategies for patient stratification, imaging, and biospecimen acquisition and storage. The third session highlighted the need for establishing outcomes research infrastructures to cover primary prevention, early detection, clinical effectiveness of innovations, health-related quality-of-life assessment, survivorship research and health economics. An important outcome of the Summit was the presentation of the Porto Declaration, which called for a collective and committed action throughout Europe to develop the cancer research infrastructures indispensable for fostering innovation and decreasing inequalities within and between member states. Moreover, the Summit guidelines will assist decision making in the context of a unique EU-wide cancer initiative that, if expertly implemented, will decrease the cancer death toll and improve the quality of life of those confronted with cancer, and this is carried out at an affordable cost.

Design, organisation and impact of treatment optimisation studies in breast, lung and colorectal cancer: The experience of the European Organisation for Research and Treatment of Cancer.

BACKGROUND: Treatment optimisation studies (TOSs) are clinical trials which aim to tackle research questions that are often left unaddressed within the current drug development paradigm due to a lack of financial and regulatory incentives to undertake them. Examples include comparative effectiveness, therapeutic sequencing and dose de-escalation studies. Trials of this nature have historically been primarily carried out by academic institutions and not-for-profit organisations such as the European Organisation for Research and Treatment of Cancer (EORTC). OBJECTIVES: Our objective was to conduct an in-depth analysis of the breast, lung and colorectal cancer TOSs that have been performed by the EORTC in the past four decades. METHODS: We searched the EORTC clinical trials database for relevant studies and subsequently analysed them based on a number of predefined criteria relating to their design, organisation and scientific impact. RESULTS: The 113 EORTC TOSs examined in this analysis were mainly standard-sized, international, multicentre phase III trials using a relatively simple, randomised, open-label design and comparing pharmacological combination regimens against standard-of-care treatments in terms of their potential to improve overall survival of patients with cancer. Although they were typically financially and/or materially supported by the industry, their legal sponsor was nearly always an independent party that did not benefit monetarily from their outcomes. If meaningful findings were obtained, their results, regardless of whether positive or negative, were published in high-impact journals, and the corresponding articles usually received a considerable number of citations. CONCLUSIONS: Our analysis provides an empirical framework for setting up future TOSs based on the EORTC experience in oncology.

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.

Cross-Border Access to Clinical Trials in the EU: Exploratory Study on Needs and Reality.

Objectives: To analyze the current situation of cross-border access to clinical trials in the EU with an overview of stakeholders' real-life experience, and to identify the needs, challenges, and potential for facilitation of cross-border access. Methods: We employed a mixed methods design. Semi-structured interviews and an online survey were conducted with a wide range of stakeholders: patient representatives, investigators/physicians, policy and regulatory experts, academic and commercial sponsor representatives, ethics committee members. Interviews underwent a framework analysis. The survey was analyzed descriptively. Results: Three hundred ninety six individuals responded to the survey. The majority were investigators/physicians (46%) and patient representatives (33%). Thirty eight individuals were interviewed. The majority were investigators/physicians (29%) and patient representatives (29%). All European regions were represented in the study. The highest response rate was received from residents of Western European countries (38% of survey respondents, 45% of interviewees), the lowest from Eastern Europe (9% of survey respondents, 5% of interviewees). The study suggested that cross-border participation in clinical trials occurs in practice, however very rarely. Ninety two percentage of survey respondents and the majority of interviewees perceived as needed the possibility to access clinical trials abroad. However, most interviewees also opined that patients ideally should not have to travel in order to access experimental treatment. The lack of access to treatment in the home country of the patient was described as the main motivation to participate in a clinical trial in another country. The logistical and financial burden for patients was perceived as the biggest challenge. Different stakeholders expressed diverging opinions regarding the allocation of financial and organizational responsibility for enabling cross-border access to clinical trials. Participants provided a number of proposals for improving the current system, which were carefully evaluated by the research team and informed future recommendations. Conclusions: Participation in clinical trials abroad is happening rarely but should be facilitated. There was a consensus on the need for reliable and accessible information regarding practical aspects, as well as multi-stakeholder, multi-national recommendations on existing options and best practice on cross-border access to clinical trials. Broader interdisciplinary research is recommended before discussing options in the EU legislative framework to enable clearly defined conditions for cross-border access to clinical trials.

Towards a cancer mission in Horizon Europe: recommendations.

A comprehensive translational cancer research approach focused on personalized and precision medicine, and covering the entire cancer research-care-prevention continuum has the potential to achieve in 2030 a 10-year cancer-specific survival for 75% of patients diagnosed in European Union (EU) member states with a well-developed healthcare system. Concerted actions across this continuum that spans from basic and preclinical research through clinical and prevention research to outcomes research, along with the establishment of interconnected high-quality infrastructures for translational research, clinical and prevention trials and outcomes research, will ensure that science-driven and social innovations benefit patients and individuals at risk across the EU. European infrastructures involving comprehensive cancer centres (CCCs) and CCC-like entities will provide researchers with access to the required critical mass of patients, biological materials and technological resources and can bridge research with healthcare systems. Here, we prioritize research areas to ensure a balanced research portfolio and provide recommendations for achieving key targets. Meeting these targets will require harmonization of EU and national priorities and policies, improved research coordination at the national, regional and EU level and increasingly efficient and flexible funding mechanisms. Long-term support by the EU and commitment of Member States to specialized schemes are also needed for the establishment and sustainability of trans-border infrastructures and networks. In addition to effectively engaging policymakers, all relevant stakeholders within the entire continuum should consensually inform policy through evidence-based advice.

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.

The European Organisation for Research and Treatment of Cancer, State of Science in radiation oncology and priorities for clinical trials meeting report.

BACKGROUND: New technologies and techniques in radiation oncology and imaging offer opportunities to enhance the benefit of loco-regional treatments, expand treatment to new patient populations such as those with oligometastatic disease and decrease normal tissue toxicity. Furthermore, novel agents have become available which may be combined with radiation therapy, and identification of radiation-related biomarkers can be studied to refine treatment prescriptions. Finally, the use of artificial intelligence (AI) capabilities may also improve treatment quality assurance or the ease with which radiation dosing is prescribed. All of these potential advances present both opportunities and challenges for academic clinical researchers. METHODS: Recently, the European Organisation for Research and Treatment of Cancer addressed these topics in a meeting of multiple stakeholders from Europe and North America. The following five themes radiobiology-based biomarkers, new technologies - particularly proton beam therapy, combination systemic and radiation therapy, management of oligometastatic disease and AI opportunities in radiation oncology were discussed in a State of Science format to define key controversies, unanswered questions and propose clinical trial priorities for development. CONCLUSIONS: Priorities for clinical trials implementing new science and technologies have been defined. Solutions to integrate the multidimensional complexity of data have been explored. New types of platforms and partnerships can support innovative approaches for clinical research in radiation oncology.

Sharing of Clinical Trial Data and Samples: The Cancer Patient Perspective.

Introduction: Today, many initiatives and papers are devoted to clinical trial data (and to a lesser extent sample) sharing. Journal editors, pharmaceutical companies, funding agencies, governmental organizations, regulators, and clinical investigators have been debating the legal, ethical, and social implications of clinical data and sample sharing for several years. However, only little research has been conducted to unveil the patient perspective. Aim: To substantiate the current debate, we aimed to explore the attitudes of patients toward the re-use of clinical trial samples and data and to determine how they would prefer to be involved in this process. Materials and Methods: Sixteen in-depth interviews were conducted with cancer patients currently participating in a clinical trial. Results: This study indicates a general willingness of cancer patients participating in a clinical trial to allow re-use of their clinical trial data and/or samples by the original research team, and a generally open approach to share data and/or samples with other research teams, but some would like to be informed in this case. Despite divergent opinions about how patients prefer to be engaged, ranging from passive donors up to those explicitly wanting more control, participants expressed positive opinions toward technical solutions that allow indicating their preferences. Conclusion: Patients were open to sharing and re-use of data and samples to advance medical research but opinions varied on the level of patient involvement and the need for re-consent. A stratified approach for consent that allows individualization of data and sample sharing preferences may be useful, yet the implementation of such an approach warrants further research.

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.

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.