PRIME-ROSE was launched in July 2023 and will be running over 5 years (2023 – 2028). Oslo University Hospital (OUH) in Norway is leading the project with Kjetil Taskén as Coordinator. The consortium consists of altogether 24 partners, including nine beneficiaries and fifteen associated partners. In addition, PRIME-ROSE is part of the Cancer Mission cluster of projects on Diagnosis and Treatment.
Project Duration: 5 years (2023 – 2028)
European Countries: 18
Cancer is one of the leading causes of death and morbidity in the EU with 3.7 million new cases every year. PRIME-ROSE shares the ambition of the EU Mission on Cancer and endorses the need for sustainable and affordable access to new and innovative drugs for cancer patients in Europe. PRIME-ROSE further aligns with Flagship No. 6 of the EU Beating Cancer Plan, the “Cancer Diagnostic and Treatment for All” initiative to increase knowledge and access to innovative cancer diagnosis and treatments to improve quality of life and survival for cancer patients.
The PRIME-ROSE vision is access to affordable Precision Cancer Medicine (PCM) that prolongs life at the best quality possible for all cancer patients. PCM is an approach that depends on access to adequate molecular diagnostics and drugs to have impact and move towards implementation in the national healthcare systems. Today there is inequality in access to PCM between and within EU countries, and while the promise of PCM is clear, implementation remains a challenge. This in particular affects cancer patients with the poorest prognosis who have exhausted all lines of standard of care treatment, those with tumours carrying rare mutations and patients with carcinoma of unknown primary.
PRIME-ROSE builds on a bottom-up, clinician-initiated family of PCM clinical trials which have been particularly successful in bringing up inclusion rates to offer additional lines of treatment and in providing patient benefit. These trials share the pragmatic clinical trial design of the original Dutch DRUP trial, with broad inclusion criteria and a limited set of endpoints. However, the trials are still anchored into national context and are funded independently. The result is a distributed DRUP-like clinical trial network that addresses local priorities while collaborating internationally for scale and impact.
PRIME-ROSE will use these adaptive and pragmatic clinical trial platforms to answer key questions regarding clinical effectiveness, provide health-economic evaluations, and contribute to scientific progress across cancers. In particular, the cross-country collaboration provided by PRIME-ROSE will
build capacity as well as enable cross-trial data aggregation and analysis, initiate shared cohorts across borders and provide health-economic evaluations. To ensure successful implementation, the consortium will work together with regulators, policymakers, payers, healthcare providers and patient advocacy groups to implement evidence-based PCM in routine practice and address inequalities in access.
Altogether, the Europe-wide precision cancer medicine deployment will address key scientific and methodological questions to accelerate broad and equitable access to new and effective cancer treatments. PRIME-ROSE consists of eight closely aligned and fully integrated work packages. Among these, WP7 is responsible for the overall project coordination. The other work packages are described in more detail below.
Figure: PERT-chart describing the interconnectivity of the work packages.
DRUP-like clinical trials are unique in the way they enable international collaboration while allowing for national specificities and encourage independent exploration that then feed back to the community and inform the set-up of the next-generation of cohorts. The trials follow the same trial design and share a core set of patient-relevant endpoints.
The purpose of PRIME-ROSE is to exploit the shared core features by establishing a platform that allows the joint analysis of data generated in cohorts in different countries. Targetable mutations appear in variable frequencies. Currently, learning across the field progresses unevenly as cohorts with more frequent mutations recruit and deliver results more rapidly. International collaboration is essential to generate evidence on increasingly rarer genetic profiles, and the PRIME-ROSE platform is a concrete example for the European Health Data Space and in line with the European Strategy for Data to improve health care.
Work package 1 will build a data platform in accordance with GDPR regulations and FAIR principles and collect and aggregate data from each participating institution. This will constitute the foundation of evidence generation in the project, and the platform will feed the other work packages. In addition, WP1 will develop tools for analysis and visualization for up-to-date multi-centric clinical trial monitoring and continuous evidence generation.
Current health economic models used for Health Technology Assessment largely require data from control arms generated in Randomised Clinical Trials (RCTs). In the presence of an actionable mutation, randomisation to a non-targeted agent poses an ethical problem, in particular in a patient population that has already exhausted all available standard of care options. We therefore aim to generate multiple, synthetic control arms and randomise a fixed treatment arm to these, that will allow us to evaluate clinical efficacy and cost effectiveness by established methods.
DRUP-like clinical trials follow a pragmatic study design. Work package two will use different control cohorts, and three main study directions will be included:
Synthetic control cohorts with specific mutations: These cohorts will consist of patients who match regarding specific target mutations, but who have received standard treatment.
Synthetic control cohorts with expected penetrance of a speficic mutation: These cohorts will be based on extraction of larger patient control cohorts from registry data. For these cohorts, no information about the presence or absence of a specific target mutation will be available.
Synthetic control cohorts exploiting patients without a specific mutation: These cohorts will consist of patients who have been tested for a specific mutation, but who are not carriers.
Trials in work packages 1, 3 and 4 will be designed with randomised external control arms from multiple sources in order to build empirical evidence for or against the effectiveness of a new treatment in comparison to standard treatment. Furthermore, multiple, randomised control arms extracted and sampled from registry cohort data will be combined for meta-analysis to obtain further indication of efficiacy.
PRIME-ROSE clinical trials target refractory cancer patients who have an advanced malignancy and are progressing on standard treatment, but with sufficient quality of health to anticipate benefit from another line of treatment. The protocols contain few inclusion and exclusion criteria to ensure high patient participation and generation of data that reflects a real-world setting.
DRUP-like trials follow a combined umbrella and basket design with a Simon two-stage model (see figure) for expanding cohorts to investigate potentially effective targeted therapies on a specific tumour type with an identified biomarker. The patients are treated based on identification of a molecular target. If actionable targets are identified and a suitable drug is available in the trial, an indication / target / drug-specific cohort is opened.
If a positive signal is identified in stage I and II, an expansion cohort is designed, depending on support from the pharmaceutical industry and the healthcare system. For DRUP-like trials, this means that if five or more patients in a stage I or II cohort experience clinical benefit after 16 weeks of treatment, the combination of diagnostic subgroup, biomarker and drug treatment is considered a success, and a stage III expansion cohort is planned. This expansion cohort is designed to confirm the findings and provide additional evidence of clinical benefit and toxicity.
WP3 aims to initiate and run at least four expansion cohorts, and the design of these will be based on data from WP1. Moreover, biomarkers and endpoints will be refined in these cohorts to meet clinical needs and develop PCM treatment further. Finally, the team will finalize data analyses from the expansion cohorts.
Research Leader Oslo University Hospital Comprehensive Cancer Center and Head IMPRESS-Norway, Norway
Figure: The Simon two-stage model for cohort expansion used in the similarly organised DRUP-like trials
The European Medicines Agency (EMA) evaluates the results of clinical trials that are carried out by pharmaceutical companies to assess safety and efficacy and grant approvals. However, these approvals alone are not comprehensive enough to guide decisions in routine practice, which comprises of a diverse patient population with various types of tumours and a broad range of mutations.
Furthermore, the current methodologies, structures and reimbursement pathways created for large, untargeted therapeutic approaches are unsuitable to fulfil the evidentiary requirements of the multiple decision-makers in health when applied to precision cancer medicine (PCM).
Off-label use is common in clinical practice today, but the effectiveness data are often not collected, the practice is not harmonised or regulated, and potential disparities and inequalities in access have not yet been studied and addressed. PRIME-ROSE will address these challenges to stimulate repurposing medicines to offer safe, effective and affordable treatment options for cancer patients.
Work package four will address off-label use at different levels:
The well-established off-label use
Use of drugs for indications awaiting EMA approval
Off-label use with limited evidence
PRIME-ROSE will set up the basis for a European compendium for well-established off-label use of targeted therapies in oncology and provide recommendations for adaptations of the current regulatory framework.
Moreover, the project will run a pragmatic observational study to generate real-world evidence on licensed or unlicensed medicines awaiting EMA approval (DRUG Access Protocol) as well as pragmatic observational studies to generate data on off-label use with limited evidence to facilitate drug-repurposing (Off-label Study Protocol Norway and DRUG Access Protocol).
Finally, this work package will study disparity and inequality in access to off-label use, such as inequality based on region, gender or age, and provide recommendations.
Reimbursement of pharmaceuticals is often based on some form of cost-effectiveness analysis with country specific variations for evaluation requirements and reimbursement. Normally, a cost-effectiveness analysis compiles information from multiple sources, and efficacy data are typically received from clinical trials. These data are supplemented with for example epidemiological data and information on resource use, costs and patient benefits, ideally measured by QALY (quality adjusted life year-metric), and analysed in model-based frameworks.
There are several challenges within the current frameworks related to precision cancer medicine (PCM). Firstly, one-armed PCM trials do not provide a relevant comparator. However, work package two in our project will provide strategies for obtaining synthetic controls that reflect standard of care. This is an important step to support reimbursement decisions. Moreover, PCM implies small sample sizes. Whereas regulatory approval is centralized to the EMA in Europe, reimbursement systems are local in EU countries with varying requirements in terms of data and information. Local decision makers are struggling with evaluating small one-armed studies, and this results in longer time to market and a sub-optimal knowledge base for decision makers regarding implementation and reimbursement.
The overall aim of work package 5 is to provide additional necessary documentation for local decision makers to assess and implement new drugs based on our results from work packages 3 (expansion cohorts) and 4 (early access & drug repurposing). Experience with evaluation of data from the suggested PCM models will give valuable information on how to streamline the reimbursement process for local requirements.
In more detail, the team will map requirements of reimbursement systems in the countries participating in the project. Furthermore, the current standard of care and access to PCM in the participating countries will be identified. Next, a model for economic evaluation, including budget impact and cost-effectiveness analysis of PCM compared to standard of care will be designed and constructed. Finally, the project will prepare recommendations based on clinical evidence of effectiveness and safety as well as results from the cost-effectiveness and budget impact analyses.
Precision cancer medicine represents a paradigm shift for the healthcare sector, and implementation requires contributions and consideration from several fields of expertise, including health economics, efficacy analyses, and organizational sciences as well as from legal experts on EU and national legislation. The current consortium builds and cross-links existing national networks for the implementation of precision medicine.
PRIME-ROSE and the closely related project PCM4EU (Personalised Cancer Medicine for all EU Citizens) cross-link PCM initiatives of a growing number of countries, allowing for complex multi-stakeholder interactions and cross- disciplinary work reaching beyond the classical medical setting. The access to necessary competence at national and international levels and established trusted relationships helps to pragmatically address and overcome potential hurdles. Project partners with complementary expertise, notably on the implementation process, on communication and on broad stakeholder engagement, will ensure that the project realises its desired social impact.
This work package will underpin the work of the DRUP community with the necessary foundation based on theories of system change in complex systems and innovation in healthcare, ensure synergies with other cancer-related initiatives and identify critical success factors for implementation. PRIME-ROSE aims to strengthen interactions especially with three stakeholder communities: regulatory authorities, the cancer patient community and payers.
WP6 will interact directly with WP3 (expansion cohorts) and WP4 (early access & drug repurposing) to give input on patient-relevant endpoints in this specific clinical setting. Collaboration with the European Medicines Agency (EMA) and the cancer patient advocacy community on patient utilities of trial outcomes will further provide a better understanding of how certain outcomes impact patients. This ensures that long-term, clinical trials capture outcomes that not only prolong but also truly improve the lives of patients.
The project will build on already existing patient involvement to ensure patients are consistently and meaningfully involved and contribute to the development of novel pragmatic and personalised outcome-based risk sharing agreements. Furthermore, the patient involvement will help reduce inequality in cancer by enabling access to treatment options for all patients in Europe.
The consortium builds on national initiatives in each country consisting of academically initiated trials and a broad national ecosystem of stakeholders. The project is dependent on a strong coherence, coordination and mutual learning.
WP7 will manage the project and coordinate with national PCM initiatives to ensure that scientific progress rapidly benefits patients.
Core Coordinating Team:
The PRIME-ROSE consortium composition reflects the unique approach taken by the community that has assembled around the shared interest of providing cancer patients who have exhausted other treatment options with access to precision medicine diagnostics and treatments. DRUP-like clinical trials (DLCTs) are initiated and conducted by clinicians, who also act as neutral brokers between drug manufacturers and payers, and as the convening forces in an ever-growing ecosystem of parties who contribute with diverse expertise.
The consortium will develop a unified DRUP data environment, allowing the consortium to generate larger data sets than available to any singular participant. The project will identify and work with key stakeholders to ensure usability for precision medicine and health economics. Engagement of stakeholders will aim at understanding clinician and patient needs, usability, clinical ethical and legal requirements for the trials, inclusion into daily clinical practice, drug reimbursement system, fostering trust in the trials as well as improving system efficiency compared to the current standard.
This work package will focus on a stakeholder engagement strategy as well as disseminate project outputs in an effective, timely and targeted way. Project stakeholders include patients, patient organisations, clinicians, health care management, health policy makers, medical societies and professional organisations, public & private research organisations, HTA bodies and payers, regulators, investors and research funding organisations as well as, pharmaceutical and diagnostic companies and digital service providers.