Genetic landscape of 6089 inherited retinal dystrophies affected cases in Spain and their therapeutic and extended epidemiological implications

Inherited retinal diseases (IRDs), defined by dysfunction or progressive loss of photoreceptors, are disorders characterized by elevated heterogeneity, both at the clinical and genetic levels. Our main goal was to address the genetic landscape of IRD in the largest cohort of Spanish patients reported to date. A retrospective hospital-based cross-sectional study was carried out on 6089 IRD affected individuals (from 4403 unrelated families), referred for genetic testing from all the Spanish autonomous communities. Clinical, demographic and familiar data were collected from each patient, including family pedigree, age of appearance of visual symptoms, presence of any systemic findings and geographical origin. Genetic studies were performed to the 3951 families with available DNA using different molecular techniques. Overall, 53.2% (2100/3951) of the studied families were genetically characterized, and 1549 different likely causative variants in 142 genes were identified. The most common phenotype encountered is retinitis pigmentosa (RP) (55.6% of families, 2447/4403). The most recurrently mutated genes were PRPH2, ABCA4 and RS1 in autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL) NON-RP cases, respectively; RHO, USH2A and RPGR in AD, AR and XL for non-syndromic RP; and USH2A and MYO7A in syndromic IRD. Pathogenic variants c.3386G > T (p.Arg1129Leu) in ABCA4 and c.2276G > T (p.Cys759Phe) in USH2A were the most frequent variants identified. Our study provides the general landscape for IRD in Spain, reporting the largest cohort ever presented. Our results have important implications for genetic diagnosis, counselling and new therapeutic strategies to both the Spanish population and other related populations.This work was supported by the Instituto de Salud Carlos III (ISCIII) of the Spanish Ministry of Health (FIS; PI16/00425 and PI19/00321), Centro de Investigación Biomédica en Red Enfermedades Raras (CIBERER, 06/07/0036), IIS-FJD BioBank (PT13/0010/0012), Comunidad de Madrid (CAM, RAREGenomics Project, B2017/BMD-3721), European Regional Development Fund (FEDER), the Organización Nacional de Ciegos Españoles (ONCE), Fundación Ramón Areces, Fundación Conchita Rábago and the University Chair UAM-IIS-FJD of Genomic Medicine. Irene Perea-Romero is supported by a PhD fellowship from the predoctoral Program from ISCIII (FI17/00192). Ionut F. Iancu is supported by a grant from the Comunidad de Madrid (CAM, PEJ-2017-AI/BMD7256). Marta del Pozo-Valero is supported by a PhD grant from the Fundación Conchita Rábago. Berta Almoguera is supported by a Juan Rodes program from ISCIII (JR17/00020). Pablo Minguez is supported by a Miguel Servet program from ISCIII (CP16/00116). Marta Corton is supported by a Miguel Servet program from ISCIII (CPII17/00006). The funders played no role in study design, data collection, data analysis, manuscript preparation and/or publication decisions

Biosimilars in Oncology – Part II: Considerations about the clinical use of oncology biosimilars

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Biosimilars in oncology - Part I: The principles of biosimilars

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Evaluating the benefits of TNF-alfa inhibitor biosimilar competition on off-patent and on-patent drug markets: A Southern European analysis

Background: The level of competition achieved following biosimilars market availability varies by country, care setting and molecule. Hence, biosimilars contribution to attaining price reductions and extended access to treatments can also vary. Objective: The aim of this study is to capture market dynamics for tumor necrosis factor (TNF)-alpha inhibitors and competing molecules in Southern European markets (2011–2020), and to evaluate the benefits of the competition generated by the availability of biosimilars. Methods: This study is based on a literature review examining market characteristics for TNF-alfa inhibitors and competing immunomodulator molecules, and on the quantitative analysis of market data for these molecules in Italy, Portugal and Spain. Results: Following biosimilars availability in Italian, Portuguese and Spanish markets, there has been an expansion in the overall access to TNF-alfa inhibitor pharmaceuticals. Further, savings have been generated within the TNF-alfa inhibitors class even after the increased use of these molecules. However, the potential of infliximab, etanercept and adalimumab biosimilars to generate price competition outside of their own drug class appeared limited in the studied markets. Considering this limitation and that shifts towards on-patent and higher-cost therapies have occurred after TNF-alfa inhibitor biosimilars availability, the importance of investing in biosimilars development for still on-patent immunology biologics is emphasized. Conclusion: This study highlights the need for policies that do not only seek higher utilization of biosimilars, but that also support a sustainable market for these products. This is expected to foster the future development of biosimilar medicines

An exploration of biosimilar TNF-alpha inhibitors uptake determinants in hospital environments in Italy, Portugal, and Spain

Background : The availability of biosimilar medicines in Southern European markets has allowed purchasing biologics at a lower cost for healthcare systems. However, the capacity to seize this cost-reduction opportunity in the long run depends on fostering a sustainable competitive environment for all the market players involved. Diverse policies and information campaigns have been launched in Italy, Portugal and Spain to support uptake of “best-value” biologics (BVB). Despite these measures, the utilization of lower-cost biologics in certain regions is low, especially when it comes to the treatment of chronic conditions. Objective : We aim to identify biosimilar uptake determinants in hospital environments in Italy, Portugal and Spain, using the class of TNF-alpha inhibitors as an example. Methods : This is a mixed-methods study based on (1) the quantitative analysis of regional uptake data for TNF-alpha inhibitor biosimilars and (2) the qualitative processing of semi-structured interviews capturing experts’ views on uptake determinants for biosimilars. Results : The organization of multi-stakeholder information campaigns supporting TNF-alpha inhibitor biosimilars use in Italy, Portugal and Spain has resulted in an increased familiarity of healthcare professionals and patients with the prescription/use of these products. However, barriers persist that impede high biosimilars uptake, especially in chronic patient populations eligible for a switch. These are: (1) the late publication of position statements on biosimilars interchangeability by regulatory health authorities; (2) the vague positioning of (national/regional) health authorities on best switching practices (including multiple biosimilar-to-biosimilar switches); (3) the existence of policy frameworks that do not necessarily support the initiation of switching protocols; (4) the establishment of sometimes inefficient purchasing procedures that limit biosimilars potential to compete for market shares. Diverse approaches taken regionally to address these barriers have contributed to heterogeneous TNF-alpha inhibitor biosimilars uptake across Southern Europe. Conclusion : Our research signaled the limited reach of biosimilar policies implemented locally, if not supported by a national policy framework. This study highlights the need for the coordinated implementation of policy measures fostering biosimilars use at the regional and national level in Italy, Portugal and Spain. These measures should account for the particularities of off-patent biologic and biosimilar markets and should jointly address supply- and demand-side challenges

Can Endangered Biosimilar Markets be Rescued?:The Need to Bridge Competing Interests for Long-Term Gain

Market signals such as: (1) the limited number of biosimilars in the development pipeline, (2) the focus of biosimilar development on high-profit therapeutic areas only, and (3) the increase in the number of biosimilar discontinuations and withdrawals, are indicative of sustainability threats facing biosimilar markets in Europe. Two prominent factors that undermine sustainability are: competing interests between the various stakeholders and a preferential focus on short-term gains, disregarding future sustainability threats, hence the need for effective policies that create sustainable competition in biologic markets. Thus far, measures implemented to foster biosimilar adoption have not been necessarily complied with and have had mixed success. Further, these policies have not consistently led to improving access to affordable biologics. In this commentary, we aim to raise awareness of vulnerabilities of biosimilar markets and of difficulties relating to reaching an agreement on policy solutions with a long-term vision. We propose to build on knowledge from collective action theory to advance in reconciling stakeholder interests. This first-of-its-kind approach can inform long-term solutions for biosimilar markets.</p

Can Endangered Biosimilar Markets be Rescued?:The Need to Bridge Competing Interests for Long-Term Gain

Market signals such as: (1) the limited number of biosimilars in the development pipeline, (2) the focus of biosimilar development on high-profit therapeutic areas only, and (3) the increase in the number of biosimilar discontinuations and withdrawals, are indicative of sustainability threats facing biosimilar markets in Europe. Two prominent factors that undermine sustainability are: competing interests between the various stakeholders and a preferential focus on short-term gains, disregarding future sustainability threats, hence the need for effective policies that create sustainable competition in biologic markets. Thus far, measures implemented to foster biosimilar adoption have not been necessarily complied with and have had mixed success. Further, these policies have not consistently led to improving access to affordable biologics. In this commentary, we aim to raise awareness of vulnerabilities of biosimilar markets and of difficulties relating to reaching an agreement on policy solutions with a long-term vision. We propose to build on knowledge from collective action theory to advance in reconciling stakeholder interests. This first-of-its-kind approach can inform long-term solutions for biosimilar markets.</p

Qualitative Analysis of the Design and Implementation of Benefit-Sharing Programs for Biologics Across Europe

Background: To encourage the rational prescribing of biologics, payers across Europe have experimented with the implementation of benefit-sharing programs. Benefit-sharing programs are incentive programs that promote the use of ‘best-value’ off-patent biologics and biosimilars by driving changes in prescribing practices. The aim of these programs is to generate savings that can be shared among stakeholders involved (e.g. health authorities/payers, health care professionals, hospital managers/administration) and are generally used to improve the quality of health care and to increase patients’ access to innovative services and medicines. However, the scarcity of information concerning the design, implementation and outcomes of benefit-sharing programs limits the transfer of knowledge to institutions aiming to adopt these types of incentive schemes in the future. Objective: The aim of our study was to map benefit-sharing experiences across Europe, to compare their design and implementation characteristics and to assess the impact of the different benefit-sharing strategies on the use of ‘best-value’ biologics. Method: Our approach was based on a literature review and on semi-structured interviews with payers/insurers, regulators, health care professionals and industry representatives. Results: Our analysis revealed variable design characteristics for benefit-sharing programs, depending on the organization of the health care system, the specific timeframe, the care setting and the policy environment. All these aspects can influence the robustness of benefit-sharing initiatives and their potential to stay in effect over time. We also noted a generalized lack of transparency regarding the distribution of savings and how they are reinvested. This lack of transparency has raised questions on how to optimally implement benefit-sharing in the future. Conclusions: To realize the full potential of benefit-sharing programs, we identify the importance of (i) setting up and timely monitoring success indicators for these programs; (ii) including quality of care and access to care parameters as success indicators; (iii) establishing clear pathways for the transparent redistribution/reinvestment of savings and (iv) transparently communicating with patients about the outcomes of benefit-sharing programs

Assessment of Nutrient Levels Provided by General Hospital Patient Menus: A Cross-Sectional Study Carried Out in the Region of Murcia (Spain)

Disease-related malnutrition remains a health problem with a high prevalence that increases the risk of poor patient outcomes, in addition to an elevation of healthcare costs. The aim of this study was to evaluate the nutritional quality of the menus at Ribera Molina Hospital, including their adequacy regarding recommended daily nutrient intakes and the agreement with the theoretical nutrition information provided by catering. The mean levels of energy, macronutrients, vitamins, and minerals provided by the basal, diabetic, and soft diets were calculated through the weighing of plated food served throughout the first 14 days of February 2020. A nutritional overestimation was seen in the nutrition information provided by the catering compared to the values derived from weighing foods (p < 0.01). Despite this, the nutritional content calculated by weighing satisfied the energy and protein requirements of 203 hospitalized patients previously studied in the internal medicine area of the hospital. The mean age of these patients was 62 years, and the main causes of admission were lung, cardiovascular, renal, and digestive diseases. There seems to be an insufficient amount of vitamins E and D, as well as magnesium, on all the menus. A possible insufficient amount of calcium, potassium, zinc, and copper was observed in some of the menus studied. It is necessary to update the hospital prescription manual so the nutritional contents of the diets are accurate and based on the weighted and calculated values to improve the adequacy of diets prescribed to patients

A Systematic Literature Review of Gaps and Challenges in Value Assessment of Biosimilars:An ISPOR Special Interest Group Report

OBJECTIVES: This study aims to provide an overview of the gaps and challenges in the value assessment of biosimilars and to identify potential approaches to address them.METHODS: A multidisciplinary, international team of biosimilar experts identified gaps and challenges. A systematic review was conducted of the peer-reviewed literature in PubMed, EMBASE, Web of Science Core Collection, EBSCOhost Business Source Complete; and of the gray literature. Preliminary results were presented at ISPOR conferences and this article benefited from 2 review rounds among ISPOR Biosimilar Special Interest Group members.RESULTS: Given that a biosimilar is highly similar to its reference biologic, health technology assessment agencies should accept the comparability exercise approved by regulatory authorities and, thus, conduct a price comparison when biosimilar reimbursement is requested for the same indication as the reference biologic. If the reference biologic is not reimbursed or is not the standard of care, a full economic evaluation of the biosimilar versus a relevant comparator needs to be conducted. To date, little consideration has been given to specific challenges, such as how biosimilar value assessment can account for the nocebo effect, potential differences between biologic-naive and biologic-experienced patients, the availability of intravenous and subcutaneous administration forms or different administration devices for the same active compound, value-added services, and the contribution of biosimilars for generating health gain at the population level.CONCLUSIONS: There is a need to gather further insights in the methodology of value assessment for biosimilars, and health technology assessment agencies need to develop more elaborate guidance on biosimilar value assessment in specific circumstances.</p