Les enjeux économiques de la médecine stratifiée/personnalisée en oncologie et hématologie

Stratified/personalized medicine is based on the use of innovative technologies such as Next generation sequencing (NGS) and gene therapy. It is in oncology and in rare diseases (βeta-Thalassemia) that innovative technologies are more promising for patients. By favoring an individualized treatment or a better knowledge of patients’ profiling and adapted treatment, they offer the possibility to improve patients’ care, optimize and rationalize care pathways and healthcare expenditure. These innovative technologies are supposed to bring a more relevant use of care and more efficiency. In order to support the development of innovations that could impact patients ’care, French healthcare authorities have created several tools: Temporary Authorisation for Use (ATU), Economic Program Research (PRME), Référentiel des actes Innovants Hors Nomenclatures (RIHN) for innovative biological acts and, more recently, article 51 for new funding models. We are using data and analyses obtained and performed in three different projects. The first project is a cost-efficacy study of gene therapy in βeta-thalassemia (financed by Assistance Publique Hôpitaux de Paris). This monocentric study is based on data from Necker’s hospital “Étude Nationale de Coûts à méthodologie Commune” (ENCC), a French common cost methodology and on medicalized information system program (Programme de Médicalisation des Systèmes d'Information, PMSI). A second project is a study of impact of NGS analyses use in solid tumors (financed by French National Institute of Cancer – INCa). Data were collected and obtained from seven platforms of biomolecular biology. The third project concerns NGS use in maligns hemopathies and was financed by “Direction Générale de l’Offre de Soins” (French Ministry of Health) under a “Programme de Recherche Médico-Economique” (PRME, an economic and medical research program). Real-world data were collected from 27 biomolecular platforms in an eCRF (electronic Care Report Form). We have studied how patients are stratified, clinical utility/outcomes of these innovative technologies. For both projects using NGS analyses, we have studied the impact of genomic use for patients, the impact of obtained information on clinical decision, according to identified alterations. To define the value of the information obtained through NGS analyses, we have used cost data and measures of uncertainty. However, during these projects, we have observed an important heterogeneity on French national territory: differences in type of panel of genes used, turnaround time to deliver NGS results or type and available data. Patients’ care pathways are different among the involved biomolecular platforms. Organization of care pathways have an impact on proposed treatments and access to experimental treatments as part of clinical trials. We have studied problems encountered by these innovative technologies such as: cost, tariff, number of patients treated/analyzed, evaluation, reimbursement, patient access (consent, equity in the access to health care selection), nationwide deployment and financing. In the end, we have handled modifications induced by these innovative technologies and responses addressed by the by French healthcare system (France genomic plan, article 51). We have developed in particular the example of gene therapy that will help to understand challenges linked to disruptive innovations.Innovantes telles que le séquençage haut débit (SHD ou en anglais Next Generation Sequencing, NGS) et la thérapie génique. En permettant une meilleure connaissance du profil biologique et génétique des patients, ces innovations permettent d’individualiser ou d’adapter les traitements. Elles sont pour cela porteuses de promesses pour les patients, pour améliorer leur prise en charge, pour rationaliser et pour optimiser les parcours de soins et les dépenses de santé. C’est en particulier dans le domaine du cancer et des maladies rares (βeta-thalassémie) que l’utilisation de ces technologies innovantes est la plus importante. Une innovation en santé est une innovation répondant à un besoin médical : un nouveau médicament, un nouveau produit ou une nouvelle technologie qui a des applications pratiques pour le patient, le parcours de soins ou le système de santé, une valeur économique/un développement commercial et une diffusion possible. Ces technologies innovantes doivent permettre une meilleure pertinence des soins et une meilleure efficience. Afin d’encourager et de soutenir le développement des innovations susceptibles d’influer sur la prise en charge des patients, les autorités de santé françaises ont mis en place différents dispositifs : Autorisation Temporaire d’Utilisation/Recommandation Temporaire d’Utilisation (ATU/RTU, pour les médicaments), forfait innovation (pour les dispositifs médicaux, les actes innovants), Référentiel des actes Innovants Hors Nomenclatures (RIHN, pour les actes innovants en biologie) et, plus récemment, l’article 51 (nouveaux modes de financement). Néanmoins certains de ces dispositifs sont peu utilisés ou nécessitent de pouvoir être évalués. Nous nous appuyons sur les données et analyses effectuées dans trois projets. Le premier projet est une étude coût-efficacité de la thérapie génique dans la βeta-thalassémie financée par l’Assistance Publique Hôpitaux de Paris (APHP). Cette étude monocentrique utilise les données de l’Étude Nationale de Coûts à méthodologie Commune (ENCC) de l’hôpital Necker et du Programme de Médicalisation des Systèmes d'Information (PMSI). Le deuxième projet est une étude d’impact de l’utilisation du NGS dans les tumeurs solides et a été financé par l’Institut National du Cancer (INCa). Les données ont été collectées auprès de sept plateformes de biologie moléculaire. Un troisième projet portant sur l’utilisation du NGS dans les hémopathies malignes a été financé par la Direction Générale de l’Offre de Soins (DGOS) dans le cadre d’un Programme de Recherche Médico-Economique (PRME). Les données ont été collectées en vie réelle, dans questionnaire électronique (eCRF, electronic Care Report Form), auprès de 27 plateformes de biologie moléculaire. Nous avons étudié la façon dont les patients sont stratifiés ainsi que l’utilité clinique/les résultats de ces innovations technologiques. Pour les deux projets utilisant le NGS nous avons analysé l’impact de la génétique pour les patients, selon les mutations identifiées, l’information obtenue et la décision de traitement prise par le clinicien. Pour définir la valeur de l’information obtenue par les analyses NGS, nous avons intégré des données de coût et des mesures de l’incertitude. Néanmoins ces projets ont fait apparaître une forte hétérogénéité sur le terrain, que ce soit en termes de panels de gènes utilisés, de délais de rendu des résultats, ou de données. L’organisation des parcours de soins des patients est également très différente selon les plateformes de biologie moléculaire participantes. Cette organisation agit également sur les traitements proposés et l’accès à des traitements expérimentaux proposés dans le cadre d’essais cliniques [...

Impact of Next Generation Sequencing on Clinical Practice in Oncology in France: Better Genetic Profiles for Patients Improve Access to Experimental Treatments

International audienceObjectives: We evaluated how next generation sequencing (NGS) can modify care pathways in an observational impact study in France.Methods: All patients with lung cancer, colorectal cancer, or melanoma who had NGS analyses of somatic genomic alterations done in 1 of 7 biomolecular platforms certified by the French National Cancer Institute (INCa) between 2013 and 2016 were eligible. We compared patients' pathways before and after their NGS results. Endpoints consisted of the turnaround time in obtaining results, the number of patients with at least 1 genomic alteration identified, the number of actionable alterations, the impact of the genomic multidisciplinary tumor board on care pathways, the number of changes in the treatment plan, and the survival outcome up to 1 year after NGS analyses.Results: 1213 patients with a request for NGS analysis were included. NGS was performed for 1155 patients, identified at least 1 genomic alteration for 867 (75%), and provided an actionable alteration for 614 (53%). Turnaround time between analyses and results was on average 8 days (Min: 0; Max: 95) for all cancer types. Before NGS analysis, 33 of 614 patients (5%) were prescribed a targeted therapy compared with 54 of 614 patients (8%) after NGS analysis. Proposition of inclusion in clinical trials with experimental treatments increased from 5% (n = 31 of 614) before to 28% (n = 178 of 614) after NGS analysis. Patients who benefited from a genotype matched treatment after NGS analysis tended to have a better survival outcome at 1 year than patients with nonmatched treatment: 258 days (±107) compared with 234 days (±106), (P = .41).Conclusions: NGS analyses resulted in a change in patients' care pathways for 20% of patients (n = 232 of 1155)

Targeted High-throughput Sequencing for Hematological Malignancies: A GBMHM Survey of Practice and Cost Evaluation in France

The objective of this study was to assess the clinical impact and financial costs of next-generation sequencing (NGS) in 5 categories of pediatric and adult hematological cancers. NGS prescriptions were prospectively collected from 26 laboratories, with varied technical and reporting practice (all or only significant targets). Impact was defined by the identification of (1) an actionable mutation, (2) a mutation with prognostic and/or theranostic value, and/or (3) a mutation allowing nosological refinement, reported by local investigators. A microcosting study was undertaken in 4 laboratories, identifying the types and volumes of resources required for each procedural step. Individual index prescriptions for 3961 patients were available for impact analysis on the management of myeloid disorders (two thirds) and, mainly mature B, lymphoid disorders (one third). NGS results were considered to impact the management for 73.4% of prescriptions: useful for evaluation of prognostic risk in 34.9% and necessary for treatment adaptation (actionable) in 19.6%, but having no immediate individual therapeutic impact in 18.9%. The average overall cost per sample was 191 € for the restricted mature lymphoid amplicon panel. Capture panel costs varied from 369 € to 513 €. Unit costs varied from 0.5 € to 5.7 € per kb sequenced, from 3.6 € to 11.3 € per target gene/hot-spot sequenced and from 4.3 € to 73.8 € per target gene/hot-spot reported. Comparable costs for the Amplicon panels were 5–8 € per kb and 10.5–14.7 € per target gene/hot-spot sequenced and reported, demonstrating comparable costs with greater informativity/flexibility for capture strategies. Sustainable funding of precision medicine requires a transparent discussion of its impact on care pathways and its financial aspects

COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases treated with rituximab: a cohort study

International audienceBackground: Various observations have suggested that the course of COVID-19 might be less favourable in patients with inflammatory rheumatic and musculoskeletal diseases receiving rituximab compared with those not receiving rituximab. We aimed to investigate whether treatment with rituximab is associated with severe COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases.Methods: In this cohort study, we analysed data from the French RMD COVID-19 cohort, which included patients aged 18 years or older with inflammatory rheumatic and musculoskeletal diseases and highly suspected or confirmed COVID-19. The primary endpoint was the severity of COVID-19 in patients treated with rituximab (rituximab group) compared with patients who did not receive rituximab (no rituximab group). Severe disease was defined as that requiring admission to an intensive care unit or leading to death. Secondary objectives were to analyse deaths and duration of hospital stay. The inverse probability of treatment weighting propensity score method was used to adjust for potential confounding factors (age, sex, arterial hypertension, diabetes, smoking status, body-mass index, interstitial lung disease, cardiovascular diseases, cancer, corticosteroid use, chronic renal failure, and the underlying disease [rheumatoid arthritis vs others]). Odds ratios and hazard ratios and their 95% CIs were calculated as effect size, by dividing the two population mean differences by their SD. This study is registered with ClinicalTrials.gov, NCT04353609.Findings: Between April 15, 2020, and Nov 20, 2020, data were collected for 1090 patients (mean age 55·2 years [SD 16·4]); 734 (67%) were female and 356 (33%) were male. Of the 1090 patients, 137 (13%) developed severe COVID-19 and 89 (8%) died. After adjusting for potential confounding factors, severe disease was observed more frequently (effect size 3·26, 95% CI 1·66-6·40, p=0·0006) and the duration of hospital stay was markedly longer (0·62, 0·46-0·85, p=0·0024) in the 63 patients in the rituximab group than in the 1027 patients in the no rituximab group. 13 (21%) of 63 patients in the rituximab group died compared with 76 (7%) of 1027 patients in the no rituximab group, but the adjusted risk of death was not significantly increased in the rituximab group (effect size 1·32, 95% CI 0·55-3·19, p=0·53).Interpretation: Rituximab therapy is associated with more severe COVID-19. Rituximab will have to be prescribed with particular caution in patients with inflammatory rheumatic and musculoskeletal diseases