Search

Introduction: Biosimilars have improved access to biologic medicines; however, historical thinking may jeopardize the viability of future markets., Areas Covered: An expert panel of eight diverse European stakeholders provided insights about rethinking biosimilars and cost-savings, reducing patient access inequalities, increasing inter-market equity, and improving education. The insights reported here (Part 2) follow a study that provides perspectives on leveraging the holistic benefits of biosimilars for market sustainability based on independent survey results and telephone interviews of stakeholders from diverse biosimilar markets (Part 1). Directional recommendations are provided for payers., Expert Opinion: The panel's market maturity framework for biosimilars has three stages: 'Invest,' 'Expand' and 'Harvest.' Across market stages, re-thinking the benefits of biosimilars beyond cost-savings, considering earlier or expanded access/new indications, product innovations, and re-investment of biosimilar-generated cost-savings should be communicated to stakeholders to promote further engagement. During 'Expand' and 'Harvest' stages, development of efficient, forward-looking procurement systems and mechanisms that drive uptake and stabilize competition between manufacturers are key. Future biosimilars will target various therapy areas beyond those targeted by existing biosimilars. To ensure a healthy, accessible future market, stakeholders must align their objectives, communicate, collaborate, and coordinate via education, incentivization, and procurement, to maximize the totality of benefits.

Introduction: Approved biosimilars exhibit comparable efficacy, safety, and immunogenicity to reference products. This report provides perspectives on the societal value of biosimilars within Europe and potential factors that have influenced market dynamics., Methods: An independent, self-administered survey or one-on-one in-depth interview was used to collect viewpoints about the impact of biosimilar medicines within European markets. Key insights were also sought from an expert panel of European stakeholders., Results: Survey respondents were clinicians, pharmacists, and payers from Europe ( N  = 103). Perceived benefits of biosimilars included increased access to innovative medicines (73% of respondents) or biologic treatments (66%). Biosimilar competition was thought to expand access to biologics (~50% of respondents) or drug combinations (~36%) and reduce biologic access time (34%). Key drivers of biologic access after biosimilar competition included increased biologic awareness (51%) and changes to prescribing guidelines (37%) and/or treatment paradigms (28%). The expert panel developed a market maturity framework of biosimilar adoption/opportunities comprising three stages: 'Invest,' 'Expand,' and 'Harvest.' Findings were supported by published literature., Conclusions: In Europe, the perceptions of well-informed survey/interview respondents are that biosimilars have improved patient outcomes via increased access to biologics and innovative biologic products, contributing to earlier and longer treatment of a broader population.

Pompe disease is a lysosomal storage disorder caused by deficiency of acid alpha-glucosidase (GAA), resulting in glycogen accumulation with profound pathology in skeletal muscle. We recently developed an optimized form of lentiviral gene therapy for Pompe disease in which a codon-optimized version of the GAA transgene (LV-GAAco) was fused to an insulin-like growth factor 2 (IGF2) peptide (LV-IGF2.GAAco), to promote cellular uptake via the cation-independent mannose-6-phosphate/IGF2 receptor. Lentiviral gene therapy with LV-IGF2.GAAco showed superior efficacy in heart, skeletal muscle, and brain of Gaa -/- mice compared to gene therapy with untagged LV-GAAco. Here, we used quantitative mass spectrometry using TMT labeling to analyze the muscle proteome and the response to gene therapy in Gaa -/- mice. We found that muscle of Gaa -/- mice displayed altered levels of proteins including those with functions in the CLEAR signaling pathway, autophagy, cytoplasmic glycogen metabolism, calcium homeostasis, redox signaling, mitochondrial function, fatty acid transport, muscle contraction, cytoskeletal organization, phagosome maturation, and inflammation. Gene therapy with LV-GAAco resulted in partial correction of the muscle proteome, while gene therapy with LV-IGF2.GAAco resulted in a near-complete restoration to wild type levels without inducing extra proteomic changes, supporting clinical development of lentiviral gene therapy for Pompe disease. SIGNIFICANCE: Lysosomal glycogen accumulation is the primary cause of Pompe disease, and leads to a cascade of pathological events in cardiac and skeletal muscle and in the central nervous system. In this study, we identified the proteomic changes that are caused by Pompe disease in skeletal muscle of a mouse model. We showed that lentiviral gene therapy with LV-IGF2.GAAco nearly completely corrects disease-associated proteomic changes. This study supports the future clinical development of lentiviral gene therapy with LV-IGF2.GAAco as a new treatment option for Pompe disease., Competing Interests: Declaration of Competing Interest A.T. van der Ploeg received funding for research, clinical trials and as advisor from Sanofi-Genzyme, Amicus Therapeutics, Biomarin, Ultragenix, Sarepta, Audentes and Spark Therapeutics on enzyme replacement therapy or next-generation therapies in the field of Pompe disease, and other lysosomal storage diseases or neuromuscular disorders, under agreements with Erasmus MC University Medical Center. N. van Til has been employee of and advisor to Avrobio. W.W.M. Pim Pijnappel and A.T. van der Ploeg are advisors of LentiCure B.V. W.W.M.Pijnappel, E. Vlaar, and A.T. van der Ploeg are inventors on patents in the field of gene therapy., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The Belgian government has taken several measures to increase the uptake of biosimilars in past years. However, no formal evaluation of the impact of these measures has been made yet. This study aimed to investigate the impact of the implemented measures on biosimilar uptake., Methods: An interrupted time series analysis was performed using an autoregressive integrated moving average (ARIMA) model with the Box-Jenkins method. All data were expressed as defined daily doses (DDD) per month/quarter and obtained from the Belgian National Institute for Health and Disability Insurance (NIHDI). Three molecules were included in the analysis: etanercept (ambulatory), filgrastim (hospital), and epoetin (hospital). A significance level of 5% was used for all analyses., Results: In the ambulatory care, the effect of a financial prescriber incentive of 2019 was investigated. After this intervention, 44.504 (95% CI -61.61 to -14.812; P < 0.001) fewer etanercept biosimilar DDDs were dispensed monthly than expected in the absence of the intervention. Two interventions were modelled for biosimilars in the hospital setting. The first intervention of 2016 includes prescription targets for biosimilars and monitoring of hospitals on adequate tendering. The second intervention involves an information campaign on biosimilars. After the first intervention, a small decrease in quarterly epoetin biosimilar uptake of 449.820 DDD (95% CI -880.113 to -19.527; P = 0.05) was observed. The second intervention led to a larger increase in quarterly epoetin biosimilar uptake of 2733.692 DDD (95% CI 1648.648-3818.736; P < 0.001). For filgrastim, 1809.833 DDD (95% CI 1354.797-2264.869; P < 0.001) more biosimilars were dispensed immediately after the first intervention and 151.639 DDD (95% CI -203.128 to -100.150; P < 0.001) fewer biosimilars each quarter after the first intervention. An immediate and sustained increase of 700.932 DDD (95% CI 180.536-1221.328; P = 0.016) in quarterly biosimilar volume was observed after the second intervention. All other parameter estimates were not statistically significant., Conclusions: The results of this study suggest that the impact of past policy interventions to increase the uptake of biosimilars has been variable and limited. A holistic policy framework is required to develop a competitive and sustainable off-patent biologicals market in Belgium., (© 2023. The Author(s).)

Background: Factors like the number of biosimilar competitors and competitive pricing strategies from originator companies may influence price competition and biosimilar uptake. Objective: The aim of this study was to analyze multiple facets of biosimilar competition of TNF-alpha inhibitors in Europe by exploring the existence of a biosimilar first-mover advantage, pricing strategies of originator companies, and the evolution in patient access. Methods: Sales and volume data on biosimilar and originator infliximab, etanercept, and adalimumab between 2008 and 2020 were provided by IQVIA. Countries included 24 European Union Member States, Norway, Switzerland, United Kingdom, Serbia, and Bosnia and Herzegovina. Sales value was expressed as ex-manufacturer price per defined daily dose (DDD), and volume data were transformed into the number of DDDs per 1,000 inhabitants per day. Descriptive analyses were conducted based on the evolution in price per DDD, trends in biosimilar and originator market shares and utilization trends. Results: Market entry of the first biosimilars of infliximab and adalimumab resulted in a decrease of the volume-weighted average price (VWAP) per DDD by 13.6% and 0.9% on average, whilst the second biosimilars resulted in a decrease by 26.4% and 27.3%, respectively. The first and second etanercept biosimilars generated a similar decrease in the VWAP per DDD by 9.3% and 9.1% on average, respectively. Average market share captured by the first biosimilars was at least twice as large as the second biosimilars for all molecules. In addition, sharp reductions in price per DDD of Humira ® in most countries indicated a pricing strategy resulting in low uptake of adalimumab biosimilars. Lastly, utilization of infliximab, etanercept, and adalimumab following biosimilar entry increased by an average of 88.9%, 14.6%, and 22.4%, respectively. However, introduction of (multiple) biosimilar competitors did not necessarily translate into increase in treatment access for all three molecules across some European countries indicating a shift in utilization from one molecule towards the other(s). Conclusion: Overall, this study revealed that biosimilar entry results in increased utilization and price reduction, although at a heterogenous rate among TNF-alpha inhibitors. Observed trends in market shares indicate a biosimilar first-mover advantage whereas pricing strategies considered to be anti-competitive can limit market uptake., Competing Interests: SS, IH and AV founded the KU Leuven Fund on Market Analysis of Biologics and Biosimilars following Loss of Exclusivity (MABEL Fund). AV is involved in consulting, advisory work and speaking engagements for a few companies, i.e., Accord, Amgen, Biogen, Effik, Medicines for Europe, Pfizer/Hospira, Mundipharma, Roche, Novartis, Sandoz. SS was involved in a stakeholder roundtable on biologics and biosimilars sponsored by Amgen, Pfizer and MSD, and he has participated in advisory board meetings for Amgen, Pfizer, Organon, and Sandoz. He has contributed to studies on biologics and biosimilars for Hospira, Celltrion, Mundipharma, and Pfizer; and he has had speaking engagements for Amgen, Celltrion, Organon, and Sandoz. EC declares that the research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest., (Copyright © 2023 Car, Vulto, Houdenhoven, Huys and Simoens.)

Objectives: To develop evidence-based points to consider for cost-effective use of biological and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in the treatment of inflammatory rheumatic diseases, specifically rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis., Methods: Following EULAR procedures, an international task force was formed, consisting of 13 experts in rheumatology, epidemiology and pharmacology from seven European countries. Twelve strategies for cost-effective use of b/tsDMARDs were identified through individual and group discussion. For each strategy, PubMed and Embase were systematically searched for relevant English-language systematic reviews and, for six strategies, additionally for randomised controlled trials (RCTs). Thirty systematic reviews and 21 RCTs were included. Based on the evidence, a set of overarching principles and points to consider was formulated by the task force using a Delphi procedure. Level of evidence (1a-5) and grade (A-D) were determined for each point to consider. Individual voting on the level of agreement (LoA; between 0 (completely disagree) and 10 (completely agree)) was performed anonymously., Results: The task force agreed on five overarching principles. For 10 of 12 strategies, the evidence was sufficient to formulate one or more points to consider, leading to 20 in total, regarding response prediction, drug formulary use, biosimilars, loading doses, low-dose initial therapy, concomitant conventional synthetic DMARD use, route of administration, medication adherence, disease activity-guided dose optimisation and non-medical drug switching. Ten points to consider (50%) were supported by level 1 or 2 evidence. The mean LoA (SD) varied between 7.9 (1.2) and 9.8 (0.4)., Conclusion: These points to consider can be used in rheumatology practices and complement inflammatory rheumatic disease treatment guidelines to incorporate cost-effectiveness in b/tsDMARD treatment., Competing Interests: Competing interests: BvdB: speakers bureau for UCB, Pfizer, Sanofi-Aventis, Galapagos, Amgen and Eli Lilly. DA: speakers bureau for Abbvie, Amgen, Lilly, Janssen, Merck, Novartis, Pfizer, Roche and Sandoz; consultant of Abbvie, Amgen, Lilly, Janssen, Merck, Novartis, Pfizer, Roche and Sandoz; research support from: Abbvie, Amgen, Lilly, Novartis, Roche, SoBi and Sanofi. RA: speakers bureau for Abbvie, BMS, Celltrion, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfize and Roche; paid instructor for Abbvie, BMS, Celltrion, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer and Roche; consultant of Abbvie, BMS, Celltrion, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer and Roche; research support from Abbvie, BMS, Celltrion, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer and Roche. KC: consultant of Eli Lilly, AbbVie and Pfizer. JI: speakers bureau for AbbVie, Gilead, Roche and UCB; research support from GSK, Janssen and Pfizer. DM: invitation to attend congress: Celltrion Healthcare and GSK. PV: speakers bureau for Eli Lilly, MSD, Galapagos and Roularta; consultant of Galapagos, Gilead, Pfizer, Sidekick Health, Eli Lilly, Nordic Pharma, Abbvie, Celltrion, BMS and UCB; research support from Pfizer. AGV: speakers bureau for Amgen, Biogen Idec, Bristol Meyers Squibb, Effik Benelux, F. Hoffmann-La Roche, Eli Lilly, Febelgen/Medaxes, Medicines for Europe AISBL, Mundipharma, Pfizer/Hospira and Hexal/Sandoz; paid instructor for Effik Benelux, Fresenius/Kabi, Amgen and Sandoz/Novartis; consultant of Biogen Idec, Effik Benelux, Fresenius/Kabi, Pfizer/Hospira, Sandoz/Novartis and Samsung Bioepis. AAdB: research support from Abbvie, Galapagos, Pfizer, Novartis, Lilly, Sanofi and Gilead. CJTvdT, JG, PMJW and LV have no competing interests to declare., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Competing Interests: SS, IH, and AV are founders of the KU Leuven MABEL Fund. SS was involved in a stakeholder roundtable on biologics and biosimilars sponsored by Amgen, Pfizer, and MSD, and he has participated in advisory board meetings for Amgen, Pfizer, and Sandoz. He has contributed to studies on biologics and biosimilars for Hospira, Celltrion, Mundipharma, and Pfizer; and he has had speaking engagements for Amgen, Celltrion, and Sandoz. AV is involved in consulting, educational work, and speaking engagements for a number of companies, i.e., AbbVie, Accord, Amgen, Biogen, Effik, EGA, Pfizer/Hospira, Fresenius-Kabi, Mundipharma, Roche, Novartis, Sandoz, and Boehringer Ingelheim. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Barcina Lacosta, Vulto, Huys and Simoens.)

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., Competing Interests: SS, IH, and AGV are founders of the KU Leuven MABEL Fund. SS was involved in a stakeholder roundtable on biologics and biosimilars sponsored by Amgen, Pfizer and MSD, and he has participated in advisory board meetings for Amgen, Pfizer, and Sandoz. He has contributed to studies on biologics and biosimilars for Hospira, Celltrion, Mundipharma and Pfizer; and he has had speaking engagements for Amgen, Celltrion and Sandoz. AG is involved in consulting, educational work and speaking engagements for a number of companies, i.e., AbbVie, Accord, Amgen, Biogen, Effik, EGA, Pfizer/Hospira, Fresenius-Kabi, Mundipharma, Roche, Novartis, Sandoz, Boehringer Ingelheim. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Barcina Lacosta, Vulto, Huys and Simoens.)

Purpose: With the growing availability of biosimilars on the global market, clinicians and pharmacists have multiple off-patent biological products to choose from. Besides the competitiveness of the product's price, other criteria should be considered when selecting a best-value biological. This article aims to provide a model to facilitate transparent best-value biological selection in the off-patent biological medicines segment., Summary: The presented model was developed on the basis of established multicriteria decision analysis tools for rational and transparent medicine selection, ie, the System of Objectified Judgement Analysis and InforMatrix. Criteria for the model were informed by earlier research, a literature search, and evaluation by the authors. The developed model includes up-to-date guidance on criteria that can be considered in selection and provides background on the allocation of weights that may aid hospital pharmacists and clinicians with decision-making in practice. Three main categories of criteria besides price were identified and included in the model: (1) product-driven criteria, (2) service-driven criteria, and (3) patient-driven criteria. Product-driven criteria include technical product features and licensed therapeutic indications. Service-driven criteria consist of supply conditions, value-added services, and environment and sustainability criteria. Patient-driven criteria contain product administration elements such as ease of use and service elements such as patient support programs. Relative weighting of the criteria is largely context dependent and should in a given setting be determined at the beginning of the process., Conclusion: The practical model described here may support hospital pharmacists and clinicians with transparent and evidence-based best-value biological selection in clinical practice., (© American Society of Health-System Pharmacists 2022.)

Background: A competitive market for off-patent biologicals leads to more affordable and high-quality healthcare. In recent years, Belgium has been characterized by its low use of biosimilars and by its shifts from off-patent biologicals toward new alternative therapies. Yet, the prescribing decisions involved in these observations are poorly understood. This study aims to better understand prescribing choices among Belgian physicians in the ambulatory care setting., Methods: This study consisted of two phases. First, a scoping literature review to identify determinants of prescribing choices was conducted. Scientific databases (Embase and PubMed) were searched until 4 November 2021. Second, the nominal group technique (NGT) was employed during focus group discussions with Belgian physicians to consider and validate these determinants for off-patent biologicals in the Belgian context. The qualitative data resulting from the literature review and focus group discussions were analyzed using the thematic framework method., Results: Fifty-three scientific articles that discussed elements that determine prescribing choices were identified. Out of these, 17 determinants of prescribing choices were found. These were divided into five categories: (1) product-related, (2) physicians' personal, (3) healthcare system-related, (4) patient-related, and (5) determinants related to the pharmaceutical company or brand. Nineteen Belgian physicians from different therapeutic areas that regularly prescribe biologicals then participated in focus group discussions. Using the NGT, the group discussions revealed that prescribing choices for off-patent biologicals are determined by a complex set of elements. Clinical data, geographical region, working environment, pharmaceutical marketing, patient profile, clinical guidelines, and preference of key opinion leaders (KOL) were considered most influential. Physicians indicated that the importance of these determinants differs depending on product classes or therapeutic domain., Conclusions: Multiple elements determine the choice of an off-patent biological or biosimilar product. The importance of each of these determinants varies depending on the context in which the prescribing choice is made. To increase the prescription of best-value biologicals in the Belgian ambulatory care, a set of synergistic measures is required including information for healthcare providers (HCP) and patients, prescribing feedback, prescribing targets, tangible incentives, KOL involvement, guidelines regarding pharmaceutical promotion, and regular revision of reimbursement modalities., (© 2022. The Author(s).)

Pompe disease is caused by deficiency of acid α-glucosidase (GAA), resulting in glycogen accumulation in various tissues, including cardiac and skeletal muscles and the central nervous system (CNS). Enzyme replacement therapy (ERT) improves cardiac, motor, and respiratory functions but is limited by poor cellular uptake and its inability to cross the blood-brain barrier. Previously, we showed that hematopoietic stem cell (HSPC)-mediated lentiviral gene therapy (LVGT) with codon-optimized GAA (LV- GAAco ) caused glycogen reduction in heart, skeletal muscles, and partially in the brain at high vector copy number (VCN). Here, we fused insulin-like growth factor 2 ( IGF2 ) to a codon-optimized version of GAA (LV- IGF2.GAAco ) to improve cellular uptake by the cation-independent mannose 6-phosphate/IGF2 (CI-M6P/IGF2) receptor. In contrast to LV- GAAco , LV- IGF2.GAAco was able to completely normalize glycogen levels, pathology, and impaired autophagy at a clinically relevant VCN of 3 in heart and skeletal muscles. LV- IGF2.GAAco was particularly effective in treating the CNS, as normalization of glycogen levels and neuroinflammation was achieved at a VCN between 0.5 and 3, doses at which LV- GAAco was largely ineffective. These results identify IGF2.GAA as a candidate transgene for future clinical development of HSPC-LVGT for Pompe disease., Competing Interests: A.v.d.P. has received consulting fees from Sanofi Genzyme and has provided consulting services, participated in advisory board meetings, and received grants for premarketing studies and research from industries via agreements between Erasmus MC and the industry. N.v.T. is currently an employee of AVROBIO, Inc., Cambridge, MA, United States. M.S. is currently an employee of ProPharma Group, Leiden, the Netherlands. Contributions from N.v.T. and M.S. were made during their employment at Erasmus MC and were made independent of their current affiliations., (© 2022 The Author(s).)

Background: By improving the affordability and accessibility of biologicals, biosimilar competition provides important benefits to healthcare systems and patients. In Belgium, biosimilar uptake and competition is limited compared to other European markets. Whereas other countries have initiated structured biosimilar introduction or switching plans, no such framework or guiding principles are yet available in Belgium. Objective: This study aims to develop recommendations that can inform policy action in Belgium on biosimilar use, especially in the context of switch decision-making, and this by drawing from the perspectives of healthcare professionals involved in procuring, prescribing, switching and dispensing biologicals including biosimilars. Methods: This study made use of the consensus-building Nominal Group Technique, consisting of a three-step process 1) individual grading, 2) three structured Focus Group Discussions, 3) final individual grading involving an expert group of Belgian healthcare professionals (physician specialists and hospital pharmacists). Results: Participants ( n = 13) voiced challenges with the use of biosimilars and switching in practice, and a lack of incentives to use them. Six concrete areas for policy development to support stakeholders with biosimilar use and switch decision-making were identified: 1) address stakeholder hesitations regarding (multiple) switching, 2) provide meaningful incentives, 3) guide healthcare professionals with product decision-making, 4), align practical product modalities when possible, 5) involve healthcare professionals in policy making, and 6) provide practical switch support and patient information material, particularly in the ambulatory care setting. For each area, specific consensus-based recommendations were developed. Furthermore, a set of switch management and patient communication principles was derived, including amongst others, generating buy-in from involved stakeholders prior to switching and communicating with a one-voice message. Conclusion: Without cohesive actions to reduce hurdles and without tangible benefits or steering mechanisms, changes in biosimilar use are unlikely in Belgium. To overcome this and stimulate market competitiveness, this study advances a set of concrete policy recommendations. At large, policy makers should develop an integrated policy framework, with a pro-active, best-value biological implementation roadmap that provides guidance and compelling measures to incentivize healthcare professionals to use biosimilars. Particular consideration should go to the ambulatory care setting, since drivers for biosimilar use are quasi absent in this context., Competing Interests: IH, SS, PD and AGV founded the KU Leuven Fund on Market Analysis of Biologics and Biosimilars following Loss of Exclusivity (MABEL Fund). AGV is involved in consulting, advisory work and speaking engagements for a number of companies, i.e., Accord, Amgen, Biogen, Effik, Medicines for Europe, Pfizer/Hospira, Mundipharma, Roche, Novartis, Sandoz. SS was involved in a stakeholder roundtable on biologics and biosimilars sponsored by Amgen, Pfizer and MSD, and he has participated in advisory board meetings for Amgen, Pfizer and Sandoz. He has contributed to studies on biologics and biosimilars for Hospira, Celltrion, Mundipharma and Pfizer; and he has had speaking engagements for Amgen, Celltrion and Sandoz. LB has participated in advisory board meetings and had speaking engagements for Amgen and Biogen. PD participated at advisory board meetings for AbbVie, Amgen, Hospira, and Samsung Bioepis and is on the Speakers’ Bureau of AbbVie, Celltrion, Hospira, Merck Serono, and Roche., (Copyright © 2022 Barbier, Simoens, Declerck, Vulto and Huys.)

Enzyme replacement therapy (ERT) is the current standard treatment for Pompe disease, a lysosomal storage disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). ERT has shown to be lifesaving in patients with classic infantile Pompe disease. However, a major drawback is the development of neutralizing antibodies against ERT. Hematopoietic stem and progenitor cell-mediated lentiviral gene therapy (HSPC-LVGT) provides a novel, potential lifelong therapy with a single intervention and may induce immune tolerance. Here, we investigated whether ERT can be safely applied as additional or alternative therapy following HSPC-LVGT in a murine model of Pompe disease. We found that lentiviral expression at subtherapeutic dose was sufficient to induce tolerance to the transgene product, as well as to subsequently administered ERT. Immune tolerance was established within 4-6 weeks after gene therapy. The mice tolerated ERT doses up to 100 mg/kg, allowing ERT to eliminate glycogen accumulation in cardiac and skeletal muscle and normalizing locomotor function. The presence of HSPC-derived cells expressing GAA in the thymus suggested the establishment of central immune tolerance. These findings demonstrate that lentiviral gene therapy in murine Pompe disease induced robust and long-term immune tolerance to GAA either expressed by a transgene or supplied as ERT., Competing Interests: A.T.v.d.P. has received consulting fees from Sanofi Genzyme and has provided consulting services, participated in advisory board meetings, and received grants for premarketing studies and research from industries via agreements between Erasmus MC and the industry. N.P.v.T. is an employee of AVROBIO (Cambridge, MA)., (© 2022 The Author(s).)

Background: Beyond evaluation and approval, European and national regulators have a key role in providing reliable information on biosimilars and the science underpinning their development, approval, and use., Objectives: This study aims to (i) review biosimilar information and guidance provided by EMA and national medicines agencies and (ii) explore stakeholder perspectives on the role of regulators in enabling acceptance and use of biosimilars., Methods: This study consists of (i) a comparative review of regulatory information and position statements across medicine agencies ( n = 32) and (ii) qualitative interviews with stakeholders in Europe ( n = 14)., Results: The comparative analysis showed that regulatory information and guidance about biosimilars offered by national medicines agencies in Europe varies, and is limited or absent in multiple instances. Approximately 40% (13/31) of the national medicines agencies' websites did not offer any information regarding biosimilars, and for about half (15/31) no educational materials were provided. Only less than half of national medicines agencies provided guidance on biosimilar interchangeability and switching (8/31 and 12/31, respectively). Among the national medicines agencies that did offer guidance, the extent (e.g., elaborate position vs. brief statement) and content (e.g., full endorsement vs. more cautious) of the guidance differed substantially. Countries that have a strong involvement in EU level biosimilar regulatory activities generally had more elaborate information nationally. Interviewees underwrote the need for (national) regulators to intensify biosimilar stakeholder guidance, especially in terms of providing clear positions regarding biosimilar interchangeability and switching, which in turn can be disseminated by the relevant professional societies more locally., Conclusion: This study revealed that, despite strong EU-level regulatory biosimilar guidance, guidance about biosimilars, and their use differs considerably across Member States. This heterogeneity, together with the absence of a clear EU-wide position on interchangeability, may instill uncertainty among stakeholders about the appropriate use of biosimilars in practice. Regulators should strive for a clear and common EU scientific position on biosimilar interchangeability to bridge this gap and unambiguously inform policy makers, healthcare professionals, and patients. Furthermore, there is a clear opportunity to expand information at the national level, and leverage EU-developed information materials more actively in this regard., Competing Interests: IH, SS, PD, and AV are the founders of the KU Leuven Fund on Market Analysis of Biologics and Biosimilars following Loss of Exclusivity (MABEL Fund). AV is involved in consulting, educational work and speaking engagements for a number of companies, i.e., AbbVie, Accord, Amgen, Biogen, Effik, EGA, Pfizer/Hospira, Fresenius-Kabi, Mundipharma, Roche, Novartis, Sandoz, Boehringer Ingelheim. SS was involved in a stakeholder roundtable on biologics and biosimilars sponsored by Amgen, Pfizer, and MSD, and he has participated in advisory board meetings for Amgen, Pfizer, and Sandoz. He has contributed to studies on biologics and biosimilars for Hospira, Celltrion, Mundipharma, and Pfizer; and he has had speaking engagements for Amgen, Celltrion and Sandoz. PD participated at advisory board meetings for AbbVie, Amgen, Hospira, and Samsung Bioepis and is on the Speakers' Bureau of AbbVie, Celltrion, Hospira, Merck Serono, and Roche. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Barbier, Mbuaki, Simoens, Declerck, Vulto and Huys.)

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., (© 2022. The Author(s).)

Background and objectives: Biosimilar medicines have been on the European market for 15 years. Despite the extensive and positive experience with biosimilars across Europe, their uptake remains limited in Belgium. One of the possible factors limiting uptake in clinical practice is the inadequate understanding and lack of trust in biosimilars among patients. This study aimed to assess the level of knowledge and perceptions about biosimilar medicines among Belgian patients in the ambulatory care. Methods: This study consisted of online questionnaires among Belgian patients in the ambulatory care (i.e., rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, Crohn's disease, ulcerative colitis, diabetes mellitus type I and II). The results were collected between December 2020 and February 2021. The data were analyzed with descriptive and inferential statistics. Results: In total, 657 patients across all disease areas of interest participated in this study. Only 38% of patients had heard of biosimilars before. Of those patients, most (58%) were aware that biosimilars are as safe and effective as their reference product. The vast majority of respondents (68%) would agree with transitioning to a biosimilar if their physician prescribed it, only 3% would never agree with a transition to a biosimilar. If a physician would propose to change their current originator biological therapy with its biosimilar, nearly all patients (95%) want their physician to explain the decision and inform them. For additional information about biosimilars, Belgian patients prefer brochures or folders (41%), or available resources on the internet (35%). Physicians were indicated as the preferred source of information (95%), followed by pharmacists (51%), academia (39%), and patient associations (35%). Most patients require information regarding the safety and efficacy (78%), price and reimbursement (64%), and the clinical development process (56%) of the biosimilar. Conclusion: Belgian patients require information about biosimilar medicines. However, most patients are open and positive towards transitioning their current biological therapy with its biosimilar if sufficiently supported by their healthcare providers., Competing Interests: This research project is funded by the Belgian National Institute for Health and Disability Insurance (NIHDI). SS, IH and AV have founded the KU Leuven Fund on Market Analysis of Biologics and Biosimilars following Loss of Exclusivity (MABEL). SS was involved in a stakeholder roundtable on biologics and biosimilars sponsored by Amgen, Pfizer and MSD; he has participated in advisory board meetings for Pfizer, Sandoz and Amgen; he has contributed to studies on biologics and biosimilars for Hospira (together with AV and IH), Celltrion, Mundipharma and Pfizer, and he has had speaking engagements for Amgen, Celltrion and Sandoz. AV is involved in consulting, advisory work and speaking engagements for a number of companies, a. o. AbbVie, Accord, Amgen, Biogen, EGA, Effik Benelux, Pfizer/Hospira, Mundipharma, Roche, Sandoz. PVW acted as health care consultant to public and private organizations, including pharmaceutical companies and their professional associations. All other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Vandenplas, Barbier, Simoens, Van Wilder, Vulto and Huys.)

More than ten years after the first biosimilars were authorized for use in the European Union, Belgium still experiences limited competition from biosimilars, as exemplified by low market shares. Achieving high biosimilar market shares is not necessarily a goal in itself, as cost savings are also realized by mandatory price reductions on originator medicines in Belgium. However, we believe that biosimilars play a role in ensuring the long-term sustainability of the off-patent biologicals market. It is therefore crucial to list what has been done and what is needed to support the Belgian government in establishing a policy framework for a competitive off-patent biologicals market. We provide a comprehensive overview of the Belgian biosimilar market, including existing hurdles for biosimilar use in Belgium. Based on these hurdles and supplemented with learnings from other European countries, we propose practical recommendations that can be implemented to overcome them. Several Belgian stakeholders had the opportunity to comment on these recommendations. Specifically, we suggest to evolve towards a long-term consistent, integrated policy framework via i) the creation of a proactive and transparent climate supporting a level playing field for both biosimilar and reference product, including public dissemination of how savings at the level of the Belgian healthcare system are used, ii) investment in educational activities, including raising awareness of societal responsibility, iii) enforcement of the practical implementation of public procurement law, and iv) the development of incentives for physicians, who are key stakeholders in the Belgian off-patent biologicals market.