PRIME-ROSE - Project

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.

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.

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 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.