[Towards more informed consent: Making information understandable]. / Vers un consentement plus éclairé - Rendre l'information accessible.

In clinical research and care, information notices are too often reduced to complicated and hard-to-understand mandatory documents. However, every person has the right to transparent and truthful information. These considerations prompted the creation of a multidisciplinary working group in the fall of 2020, headed by the College des relecteurs de l'Inserm. This group associates the different actors involved in the development, evaluation and use of information notices: Health and research professionals, representatives of patient associations or research foundations, ethicists, jurists, scientific educators and communicators. This group has created a set of texts, pictograms and illustrations, adapted to the people concerned and accepted by all actors. These contents will be easily used by professionals through the app Noticeinfobox©. A pilot phase was conducted to generate the notices of the France Genomic Medicine Plan 2025, used for genetic examinations. This app Noticeinfobox© is a response to society's request to be an actor in its own healthcare and to adopt more ethical and responsible research.

Title: Vers un consentement plus éclairé - Rendre l'information accessible. Abstract: Trop souvent, les notices d'information proposées dans le cadre de recherches cliniques se réduisent à des documents réglementaires difficilement compréhensibles. Pourtant, les personnes concernées doivent avoir accès à une information transparente et loyale. Ces considérations ont motivé la création d'un groupe de travail pluridisciplinaire, piloté par le Collège des relecteurs de l'Inserm, associant les acteurs impliqués dans l'élaboration, l'évaluation et l'utilisation de ces notices d'information. Un ensemble de textes, pictogrammes et illustrations, adaptés aux personnes concernées, validés et facilement utilisables via une application a été créé. Une phase pilote, dans le cadre du plan France médecine génomique 2025, a permis de générer des notices simplifiées pour les examens génétiques. Dans cet article, nous présentons le travail réalisé par le groupe de travail « Notices d'information ¼ afin de répondre à la demande sociétale d'être acteur de son parcours de soin et de contribuer à une recherche plus éthique et responsable.

Precision cancer medicine: Concepts, current practice, and future developments.

Precision cancer medicine is a multidisciplinary team effort that requires involvement and commitment of many stakeholders including the society at large. Building on the success of significant advances in precision therapy for oncological patients over the last two decades, future developments will be significantly shaped by improvements in scalable molecular diagnostics in which increasingly complex multilayered datasets require transformation into clinically useful information guiding patient management at fast turnaround times. Adaptive profiling strategies involving tissue- and liquid-based testing that account for the immense plasticity of cancer during the patient's journey and also include early detection approaches are already finding their way into clinical routine and will become paramount. A second major driver is the development of smart clinical trials and trial concepts which, complemented by real-world evidence, rapidly broaden the spectrum of therapeutic options. Tight coordination with regulatory agencies and health technology assessment bodies is crucial in this context. Multicentric networks operating nationally and internationally are key in implementing precision oncology in clinical practice and support developing and improving the ecosystem and framework needed to turn invocation into benefits for patients. The review provides an overview of the diagnostic tools, innovative clinical studies, and collaborative efforts needed to realize precision cancer medicine.

Implementation of precision medicine in healthcare-A European perspective.

The technical development of high-throughput sequencing technologies and the parallel development of targeted therapies in the last decade have enabled a transition from traditional medicine to personalized treatment and care. In this way, by using comprehensive genomic testing, more effective treatments with fewer side effects are provided to each patient-that is, precision or personalized medicine (PM). In several European countries-such as in England, France, Denmark, and Spain-the governments have adopted national strategies and taken "top-down" decisions to invest in national infrastructure for PM. In other countries-such as Sweden, Germany, and Italy with regionally organized healthcare systems-the profession has instead taken "bottom-up" initiatives to build competence networks and infrastructure to enable equal access to PM. In this review, we summarize key learnings at the European level on the implementation process to establish sustainable governance and organization for PM at the regional, national, and EU/international levels. We also discuss critical ethical and legal aspects of implementing PM, and the importance of access to real-world data and performing clinical trials for evidence generation, as well as the need for improved reimbursement models, increased cross-disciplinary education and patient involvement. In summary, PM represents a paradigm shift, and modernization of healthcare and all relevant stakeholders-that is, healthcare, academia, policymakers, industry, and patients-must be involved in this system transformation to create a sustainable, non-siloed ecosystem for precision healthcare that benefits our patients and society at large.

Meeting the Need for a Discussion of Unmet Medical Need.

As Europe and the world continue to battle against COVID, the customary complacency of society over future threats is clearly on display. Just 30 months ago, such a massive disruption to global lives, livelihoods and quality of life seemed unimaginable. Some remedial European Union action is now emerging, and more is proposed, including in relation to tackling "unmet medical need" (UMN). This initiative-directing attention to the future of treating disease and contemplating incentives to stimulate research and development-is welcome in principle. But the current approach being considered by EU officials merits further discussion, because it may prove counter-productive, impeding rather than promoting innovation. This paper aims to feed into these ongoing policy discussions, and rather than presenting research in the classical sense, it discusses the key elements from a multistakeholder perspective. Its central concern is over the risk that the envisaged support will fail to generate valuable new treatments if the legislation is phrased in a rigidly linear manner that does not reflect the serpentine realities of the innovation process, or if the definition placed on unmet medical need is too restrictive. It cautions that such an approach presumes that "unmet need" can be precisely and comprehensively defined in advance on the basis of the past. It cautions that such an approach can reinforce the comfortable delusion that the future is totally predictable-the delusion that left the world as easy prey to COVID. Instead, the paper urges reflection on how the legislation that will shortly enter the pipeline can be phrased so as to allow for the flourishing of a culture capable of rapid adaptation to the unexpected.

Equal access to innovative therapies and precision cancer care.

Patients with cancers of differing histologies that express certain biomarkers are likely to benefit from treatment with targeted therapies. However, targets can be present in malignancies other than those indicated by a drug's label, and as a result, affected patients will have no access to those potentially useful drugs. To tackle this issue, the French National Cancer Institute developed the AcSé Programme in 2013. This programme is designed to make treatment decisions or recommendations on the basis of the presence of relevant biomarkers for malignancies with no targeted therapies available and also aims to improve safety, and evaluate the efficacy of targeted drugs used outside of their approved indications. Patients across France have access to molecular testing in 28 molecular genetics centres and to targeted therapies within phase II trials provided no other trials exist in which they could reasonably be included. Trials include patients below the age of 18 if safe dosing data are available. As of January 2016, 183 French clinical sites and over 7,000 patients are participating in AcSé led trials. Proof of concept is being demonstrated through trials designed to investigate the effectiveness of crizotinib and vemurafenib in a wide variety of cancers.

Three Rounds of External Quality Assessment in France to Evaluate the Performance of 28 Platforms for Multiparametric Molecular Testing in Metastatic Colorectal and Non-Small Cell Lung Cancer.

Personalized medicine has gained increasing importance in clinical oncology, and several clinically important biomarkers are implemented in routine practice. In an effort to guarantee high quality of molecular testing in France, three subsequent external quality assessment rounds were organized at the initiative of the National Cancer Institute between 2012 and 2014. The schemes included clinically relevant biomarkers for metastatic colorectal (KRAS, NRAS, BRAF, PIK3CA, microsatellite instability) and non-small cell lung cancer (EGFR, KRAS, BRAF, PIK3CA, ERBB2), and they represent the first multigene/multicancer studies throughout Europe. In total, 56 laboratories coordinated by 28 regional molecular centers participated in the schemes. Laboratories received formalin-fixed, paraffin-embedded samples and were asked to use routine methods for molecular testing to predict patient response to targeted therapies. They were encouraged to return results within 14 calendar days after sample receipt. Both genotyping and reporting were evaluated separately. During the three external quality assessment rounds, mean genotype scores were all above the preset standard of 90% for all biomarkers. Participants were mainly challenged in case of rare insertions or deletions. Assessment of the written reports showed substantial progress between the external quality assessment schemes on multiple criteria. Several essential elements such as the clinical interpretation of test results and the reason for testing still require improvement by continued external quality assessment education.

Real-Life Distribution of KRAS and NRAS Mutations in Metastatic Colorectal Carcinoma from French Routine Genotyping.

In metastatic colorectal cancer, KRAS and NRAS genotyping is mandatory before prescription of panitumumab or cetuximab. In order to perform such molecular tests, the French National Cancer Institute has set up a nationwide network of molecular centers. We report here the percentage of these mutations according to a prospective nonselected cohort of incident metastatic colorectal carcinoma patients. A total of 6,803 patients were tested between July 1, 2013, and December 31, 2013. Overall, 49.06% of patients harbored a mutation in either KRAS or NRAS. Mutations of NRAS exons 3 and 4 were very rare. No NRAS exon 3 at c.59 or exon 4 at c.117 mutations were retrieved, and only 1 NRAS exon 4 at c.146 mutation was detected. This present cohort is likely to represent most of the incident cases of metastatic colorectal adenocarcinomas arising in France over 6 months and is to our knowledge the largest population set genotyped for these genes in this condition. This is a unique opportunity to observe the frequency of RAS mutations regardless of most inclusion bias.

Improvement of the quality of BRAF testing in melanomas with nationwide external quality assessment, for the BRAF EQA group.

BACKGROUND: Knowledge about tumour gene mutation status is essential for the treatment of increasing numbers of cancer patients, and testing quality has a major impact on treatment response and cost. In 2012, 4,629 tests for BRAF p.V600 were performed in France, in patients with melanomas. METHODS: Two batches of unstained melanoma sections were sent, in May and November 2012, to the 46 laboratories supported by the French National Institute of Cancer (INCa). An external quality assessment (EQA) evaluated mutation status, response times and compliance with INCa recommendations. RESULTS: All the French laboratories involved in testing participated in the EQA. Fourteen different methods were used to detect BRAF mutations, most consisting of combinations of in-house techniques. False responses were noted in 25/520 cases (4.8%), 11 of which concerned confusion between p.V600E and p.V600K. Thus, 2.7% of responses would have led to inappropriate treatment. Within six months, mean response times decreased from 22 to 12 days (P<0.001), and the percentage of samples evaluated by a pathologist for tumour cell content increased, from 75.2% to 96.9% (P<0.001). CONCLUSION: Despite the use of non-certified methods, the false response rate was low. Nationwide EQA can improve the quality of molecular pathology tests on tumours.

Performance and cost efficiency of KRAS mutation testing for metastatic colorectal cancer in routine diagnosis: the MOKAECM study, a nationwide experience.

PURPOSE: Rapid advances in the understanding of cancer biology have transformed drug development thus leading to the approval of targeted therapies and to the development of molecular tests to select patients that will respond to treatments. KRAS status has emerged as a negative predictor of clinical benefit from anti-EGFR antibodies in colorectal cancer, and anti-EGFR antibodies use was limited to KRAS wild type tumors. In order to ensure wide access to tumor molecular profiling, the French National Cancer Institute (INCa) has set up a national network of 28 regional molecular genetics centers. Concurrently, a nationwide external quality assessment for KRAS testing (MOKAECM) was granted to analyze reproducibility and costs. METHODS: 96 cell-line DNAs and 24 DNA samples from paraffin embedded tumor tissues were sent to 40 French laboratories. A total of 5448 KRAS results were collected and analyzed and a micro-costing study was performed on sites for 5 common methods by an independent team of health economists. RESULTS: This work provided a baseline picture of the accuracy and reliability of KRAS analysis in routine testing conditions at a nationwide level. Inter-laboratory Kappa values were >0.8 for KRAS results despite differences detection methods and the use of in-house technologies. Specificity was excellent with only one false positive in 1128 FFPE data, and sensitivity was higher for targeted techniques as compared to Sanger sequencing based methods that were dependent upon local expertise. Estimated reagent costs per patient ranged from €5.5 to €19.0. CONCLUSION: The INCa has set-up a network of public laboratories dedicated to molecular oncology tests. Our results showed almost perfect agreements in KRAS testing at a nationwide level despite different testing methods ensuring a cost-effective equal access to personalized colorectal cancer treatment.

Europe does it better: molecular testing across a national health care system-the French example.

Drug approvals for molecularly stratified tumor subgroups make molecular testing mandatory and require that molecular diagnostics be performed nationwide. To this end, the French National Cancer Institute (INCa) and the French Ministry of Health have set up a national network of 28 regional molecular genetics centers. Selective molecular tests are performed in these facilities. They are free of charge for all patients in their region, irrespective of the type of establishment in which they are receiving treatment. A specific program has also been implemented to anticipate the launch of new targeted therapies and to accelerate the time-to-access to new drugs and experimental therapies. The initiative has been operational for 5 years and has been successful in meeting its initial aims of uniform nationwide test provision and fast implementation of molecular tests for new tumor biomarkers.

Tumour molecular profiling for deciding therapy-the French initiative.

The use of tumour molecular profiles for therapeutic decision making requires that molecular diagnostics be introduced into routine clinical practice. To this end, the French National Cancer Institute and French Ministry of Health have set up a national network of 28 regional molecular genetics centres. These facilities perform selected molecular tests, free of charge, for all patients in their region, regardless of the institution where they are treated. A specific programme has also been implemented to anticipate the launch of new targeted treatments and reduce time-to-access to new drugs and experimental therapies. In 2011, 55,000 patients with cancer in France benefited from molecular predictive tests. The French nationwide initiative for tumour molecular profiling is a tool to fight inequalities in access to molecular testing and targeted therapy, and demonstrates that molecular stratification of tumours for therapeutic decisions is a cost-effective strategy that can be successfully integrated into the health-care system.

Biomarker discovery, development, and implementation in France: a report from the French National Cancer Institute and cooperative groups.

Biomarkers are increasingly changing the medical practice in oncology. One of the major challenges in the field of personalized medicine or biologically adapted therapies is to ensure a rapid and extensive implementation of emerging biomarkers as soon as proof of their medical usefulness is obtained. A special program has been developed in France to facilitate the assessment and use of biomarkers. The French National Cancer Institute has set up a total of 28 laboratories in public hospitals to perform biomarker testing for clinical use. This program is enabling all patients who present with cancer to receive free testing for biomarkers, such as K-Ras, epidermal growth factor receptor, c-Kit, and Braf mutations. Funding for these laboratories comes from the French Ministry of Health. The future of these laboratories includes the development of DNA arrays and multiplex technologies for clinical use. Toward that end, the French National Cancer Institute is financing several large clinical trials that several large clinical trials are currently evaluating the feasibility and medical utility of DNA arrays and next-generation sequencing in the context of academic centers. The programs are being run by cooperative groups.