>Magister Scientiae - MSc / The introduction of biosimilars to health care markets across the globe has had some success in increasing competition and improving the cost of healthcare. While savings are important for driving the biosimilar uptake, this is not the only consideration for the growth of biosimilars onto emerging markets. A systematic review of the literature to assess the growth of biosimilars onto the emerging market was conducted using the following data sources: PubMed, Website of the Generics and Biosimilars Initiative (GaBI) journal, ProQuest, Google Scholar. Studies that provided evidence of biosimilars onto the emerging market through surveys and other sources of existing data were included. The systematic review process followed Wichor et al. (2018) and the PRISMA checklist (PRISMA, 2009). The search strategy for the review provided a total of 71studies, which underwent title, abstract and full text review to give 20 articles that fit the inclusion criteria for the aimed study. A quality assessment was conducted on the 20 articles and by using the Hawker et al. (2002) quality tool and directed research questions to set variables, the data analysis of 13 articles emerged. The included studies agreed on the growth of biosimilars onto the emerging market and on the switch to biosimilars to improve access to therapies. However, International Nonproprietary Name (INN) and physician confidence were still considered as hurdles. The two most successful drivers of the growth of biosimilars onto the emerging market based on this review was certainly the regulation of the process followed by the cost of biosimilars. To conclude, data analysis of 13 articles determined that the general perception of using biosimilars in emerging markets is positive. However, for successful integration into routine healthcare and uptake into these markets, there must be a direct focus on the regulation of Biosimilars

New methods for drugs analysis, disease diagnosis, and protein analysis by using modern mass spectrometry are developed in this thesis. In drugs analysis, we develop a rapid assessment of molecular similarity between an extremely complex innovator product and a candidate biosimilar by mass spectrometry. Protease digestion combined with Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry were successfully used to peptides mapping and de novo peptides sequencing. Overall ion signals obtained by MALDI-TOF/MS were processed by two multivariate statistics including principle component analysis (PCA) and hierarchical clustering analysis. Based on the variances of the peptide profile, innovator product and normally synthesized biosimilar were grouped on the PCA score plot, while impure biosimilar or abnormally synthesized biosimilar were distinctly separated. The results of hierarchical cluster analysis also revealed high conformity between innovator product and normally synthesized biosimilar. Abnormally synthesized products, as a set of quality controller, could be discriminated from innovator product favorably. Another quality control strategy developed in this study is building classification model, batches of product is successfully evaluated. Furthermore, the similarity of molecular weight distribution between these complex drugs is determined. Another target of drug analysis is to develop a vital analytical method to directly detect the peptides synthesized on the resin. Except an organic solvent is transformed to disperse the resin-peptides samples, no other sample pretreatments are required before the MS detection. When using conventional destructive analytical methods to characterize masses of compounds on the solid supports, acid hydrolysis or acid cleavage of the peptide molecules depart from insoluble resin is required. In consequence, side-reactions such as de-blocked or de-protected cause additional fragments in the system, and determination of the intermediates or products are confusing and difficult. Unlike these acid release methods, the molecular weight information of the intact peptide molecules can be obtained in our direct analyses system, and sample consumption is also great reduced. Moreover, our strategy performed the analysis in the ambient environment is more straightforward for real-time monitor reaction and quality control than those techniques in high vacuum system. This direct non-destructive on-line monitoring method would allow following step by step peptide solid-phase synthesis be well quality controlled. In the disease diagnose part, MALDI-TOF mass spectrometry combined with statistics were used to perform semi-quantitative albuminuria diagnoses. Based on the fact that the contributions of singly, doubly, triply, and quadruply charged albumin ions from the samples were inflected according to the concentration change. The severity of albuminuria of patients can be estimated by 2D peaks distribution (peaks ranking by p-value) or supervised principal component analysis (PCA). In protein analysis study, we use liquid electrospray laser desorption ionization mass spectrometry (liquid-ELDI/MS) to directly characterized the proteins stored in different solutions containing acids, bases, buffers, organic solvents, or detergents without extra sample pretreatment. A drop of the sample solution was applied on a stainless steel plate., and then the surface of the sample drop was irradiated with a pulsed laser. The laser energy absorbed by the metal plate and surrounding solvent led to the desorption of protein molecules or the formation of fine droplets containing protein molecules. The desorbed protein species were then post-ionized within an electrospray plume to generate the ESI-like protein ions. Since no pH or composition adjustment of the sample solution is needed, this technique is useful for rapid and high throughput screening of the proteins in a solution to check their integrality after storage or prior to further biochemical treatment. In addition,, native and denatured conformation of the proteins can be distinctly examined by using acid-free and organic solvent-reduced ESI solutions in liquid-ELDI.

Reumatoid artrit (RA) är en typ av reumatisk sjukdom där uttalad inflammation uppstår i flertalet leder tillsammans med smärta och stelhet. Inflammationen uppkommer som resultat av en autoimmun reaktion. I Sverige har ungefär 1 % av befolkningen RA och sjukdomen är 2–3 gånger vanligare hos kvinnor än hos män. Adalimumab (Humiraâ) är en TNF-hämmare som används vid behandling av RA. Humira är en humaniserad monoklonal antikropp som binder till TNF och neutraliserar de effekter som TNF utövar och reducerar på så vis symtom samt bromsar progressionen av RA. Under 2018 beräknas Humira utsättas för konkurrens av biosimilarer, vilka innehåller en version av den verksamma substansen som finns i det biologiska referensläkemedlet. För att en biosimilar ska godkännas krävs det att de bland annat har jämförbar effekt och säkerhet som referensläkemedlet. Syftet med denna litteraturstudie var att undersöka om biosimilarer till adalimumab är lika effektiva och säkra vid behandling av RA som det biologiska referensläkemedlet Humira. De fem artiklar som analyserats i denna litteraturstudie hittades via sökning i databasen PubMed med sökorden “rheumatoid arthritis”, “adalimumab” och “biosimilar”. Totalt gav detta 38 träffar varav 5 artiklar valdes ut. Enligt de resultat som sågs i denna litteraturstudie kan det konstateras att de fem biosimilarer som undersökts hade likvärdig effekt som referensläkemedlet adalimumab (Humiraâ) vid behandling av RA. Fyra av fem studier visade även att immunogenicitet mellan biosimilar och Humira var likvärdig. Liknande biverkningar förekom i båda behandlingsgrupper och behandling med en biosimilar gav inte fler eller allvarligare biverkningar än behandling med Humira. Lansering av biosimilar till adalimumab kommer troligtvis leda till lägre behandlingskostnader och därmed till att fler patienter kan få möjlighet till behandling. / Rheumatoid arthritis (RA) is a type of rheumatic disease where pronounced inflammation occurs in several joints along with pain and stiffness. The inflammation occurs as a result of an autoimmune reaction. In Sweden, approximately 1% of the population has RA and the disease is 2-3 times more common among women than men. One of the proinflammatory cytokines that plays a major role in RA is tumor necrosis factor (TNF). TNF is produced primarily by macrophages in the synovial membrane and has been shown to regulate release of other cytokines like IL-1 and IL-6. TNF also contributes to the release of metalloproteases from fibroblasts, reduced synthesis of proteoglycan from chondrocytes and to monocytes differentiate into osteoclasts. In this way, TNF contributes to joint destruction. Adalimumab (Humiraâ) is a TNF-inhibitor used in the treatment of RA. Humira is a humanized monoclonal antibody that binds to TNF and neutralizes the effects that TNF exerts and thus reduces symptoms and inhibits the progression of RA. In 2018, Humira is expected to be exposed to biosimilars competition. Biosimilars contains a version of the active substance in the biological reference drug and in order for a biosimilar to be approved it is necessary that they have comparable effect and safety as the reference drug. The purpose of this literature study was to investigate whether biosimilars to adalimumab are as effective and safe in the treatment of RA as the biological reference drug Humira. The five articles analyzed in this literature study were found through a search in the PubMed database with the words "rheumatoid arthritis", "adalimumab" and "biosimilar". In total, this resulted in 38 hits, of which 5 were selected. According to the results seen in this literature study, it can be noted that the five biosimilars investigated had similar effect as the reference drug adalimumab (Humira) in the treatment of RA. Four out of five studies also showed that the immunogenicity between the biosimilar and Humira was similar. Similar side effects occurred in both treatment groups and treatment with a biosimilar did not give more or more serious side effects than treatment with Humira. The launch of biosimilar adalimumab is likely to result in lower treatment costs and cost savings, as a result of the price competition that may occur between biosimilar adalimumab and the reference drug Humira. How much the cost will fall is hard to predict, but if there is a 58% reduction previously seen with other launched biosimilars, it can result in a cost saving of SEK 635 million. However, the amount of price reduction remains to be seen.

Medicamentos biológicos são obtidos a partir de fluidos biológicos ou tecidos de origem animal por procedimentos biotecnológicos e, a partir do vencimento das suas patentes, surge a possibilidade da produção de suas cópias, os chamados biossimilares. Este tema, além de polêmico, por ainda apresentar divergências de entendimento da classe científica, também engloba 4 das 5 classes terapêuticas de medicamentos mais vendidas, e apresenta evolução crescente no mercado farmacêutico. Com o aumento da demanda, cresce o interesse na produção de medicamentos biológicos de alta qualidade, com a mesma eficácia, porém a preços mais baixos. Dessa forma, é possível entender a responsabilidade das regulamentações, principalmente no que diz respeito aos biossimilares, a fim de que eles respeitem os requisitos mínimos necessários para serem comparáveis ao seu medicamento biológico novo. Assim, este trabalho teve como objetivo avaliar questões técnico-regulatórias e os requisitos de qualidade para registro de medicamentos biológicos e biossimilares humanos frente a diferentes Autoridades Sanitárias mundiais. A análise foi baseada em três moléculas biológicas, sendo a clássica heparina e moléculas novas, filgrastim e infliximabe. Foi constatado que na teoria, a legislação brasileira é baseada em regulamentos internacionais, especialmente da Federal and Drug Administration (FDA) e European Medicines Agency (EMA), e que na prática, o Brasil tem se mostrado mais conservador na extrapolação de indicação e na aprovação dos biossimilares. Ainda, foi possível notar que independente do país, as Farmacopeias ainda necessitam de aprimoramento com relação a este tema, pois em sua maioria, não existe padronização dos parâmetros e testes a serem realizados. Pesquisa demonstrou que o conhecimento sobre biossimilares ainda não está consolidado entre profissionais médicos e que, portanto, há necessidade de programas para esclarecimentos, com a finalidade de estimular seu uso, quando possível e com custos mais interessantes. / Biological drugs are obtained from biological fluids or animals tissues by biotechnological procedures and, from the expiration of their patents, the possibility of producing their \"copies\", the so-called biosimilars, arises. In addition to being a controversial subject, as it still presents divergences of understanding by the scientific class, it also encompasses 4 of the 5 therapeutic classes of best-selling drugs, and it presents an increasing evolution in the pharmaceutical market. As demand increases, interest in the production of high-quality biological drugs with the same effectiveness, but at lower prices, also increases. In this way, it is possible to understand the responsibility of regulations, especially with regard to biosimilars, so that they comply with the minimum requirements needed to be comparable to their reference biological medicine. Thus, the objective of this project was to evaluate technical and regulatory topics, as well as quality requirements for the registration of human biological and biosimilar medicines under the perspective of different Health Authorities around the world. The analysis was based on three biological molecules, being the classic heparin and new molecules, filgrastim and infliximab. It was found that in theory, Brazilian regulation is based on international regulations, especially the Federal and Drug Administration (FDA) and the European Medicines Agency (EMA), and that in practice, Brazil has been more conservative in the extrapolation of indication and approval of biosimilars. Also, it was possible to note that, regardless the country, Pharmacopoeias still need to be improved for this topic, since in general, there is no standardization of the parameters and tests to be performed. Research showed that the knowledge about biosimilars is not yet consolidated among doctors and that, therefore, there is a need for clarification programs, with the purpose of stimulating their use, when possible and at lower costs.

The equivalence assessment usually consists of three tests and is often conducted through a three-arm clinical trial. The first two tests are to demonstrate the superiority of the test treatment and the reference treatment to placebo, and they are followed by the equivalence test between the test treatment and the reference treatment. The equivalence is commonly defined in terms of mean difference, mean ratio or ratio of mean differences, i.e. the ratio of the mean difference of the test and placebo to the mean difference of the reference and placebo. In this dissertation, the equivalence assessment for both continuous data and discrete data are discussed. For the continuous case, the test of the ratio of mean differences is applied. The advantage of this test is that it combines a superiority test of the test treatment over the placebo and an equivalence test through one hypothesis. For the discrete case, the two-step equivalence assessment approach is studied for both Poisson and negative binomial data. While a Poisson distribution implies that population mean and variance are the same, the advantage of applying a negative binomial model is that it accounts for overdispersion, which is a common phenomenon of count medical endpoints. The test statistics, power function, and required sample size examples for a three-arm equivalence trial are given for both continuous and discrete cases. In addition, discussions on power comparisons are complemented with numerical results. / Statistics

Submitted by Emil Gludsted (emil.gludsted2014@gvmail.br) on 2016-12-19T21:20:10Z No. of bitstreams: 1 MPGI Thesis - Emil Brohl Gludsted - Dec'19 2016 vf.pdf: 3020698 bytes, checksum: 358ae13dcfdff17ec0c5c1b1a639c91d (MD5) / Rejected by Josineide da Silva Santos Locatelli (josineide.locatelli@fgv.br), reason: Dear Emil, The pages before introduction must to be considered, however, but they can’t appear (example, if there were 8 pages before introduction, then the first page to be numbered is 9 – Introduction), The epigraph must to be before the abstract. on 2016-12-20T10:49:17Z (GMT) / Submitted by Emil Gludsted (emil.gludsted2014@gvmail.br) on 2016-12-20T19:52:24Z No. of bitstreams: 2 MPGI Thesis - Emil Brohl Gludsted - Dec'19 2016 vf.pdf: 3020698 bytes, checksum: 358ae13dcfdff17ec0c5c1b1a639c91d (MD5) MPGI Thesis - Emil Brohl Gludsted - Dec'20 2016 vf.pdf: 2957721 bytes, checksum: 148202567b3f2d2bd77107e5c9ea53ac (MD5) / Rejected by Josineide da Silva Santos Locatelli (josineide.locatelli@fgv.br), reason: Emil, There was just two change to do, but the thesis is the same way. All the pages must to be considerated, but the numbers must to start (appear) in the introduction. So, if your work has 11 pages before the introduction, the number on the introduction must to be 12. The epigraph must to be before the abstract, the sequence is: epigraph, abstract and resumo. on 2016-12-21T11:15:58Z (GMT) / Submitted by Emil Gludsted (emil.gludsted2014@gvmail.br) on 2016-12-21T12:26:05Z No. of bitstreams: 1 MPGI Thesis - Emil Brohl Gludsted - Dec'21 2016 vf.pdf: 2957630 bytes, checksum: 1ff24b2e9893e6d5bdcb3d6f7e5f5f9e (MD5) / Approved for entry into archive by Josineide da Silva Santos Locatelli (josineide.locatelli@fgv.br) on 2016-12-21T13:52:43Z (GMT) No. of bitstreams: 1 MPGI Thesis - Emil Brohl Gludsted - Dec'21 2016 vf.pdf: 2957630 bytes, checksum: 1ff24b2e9893e6d5bdcb3d6f7e5f5f9e (MD5) / Made available in DSpace on 2016-12-22T13:14:35Z (GMT). No. of bitstreams: 1 MPGI Thesis - Emil Brohl Gludsted - Dec'21 2016 vf.pdf: 2957630 bytes, checksum: 1ff24b2e9893e6d5bdcb3d6f7e5f5f9e (MD5) Previous issue date: 2016-12-07 / Type 2 diabetes is a progressive disease projected to grow tremendously in prevalence. Basal insulin analogues used to be the most efficacious treatment and last step in therapeutic intensification. Today, demographic, economic and epidemiologic transitions have placed pressure on healthcare systems and payers’ budgets. Three imminent threats require the basal insulin regimen to rethink how value can be addressed in the market: mounting institutional pricing pressure, biosimilar competition and, new innovative anti-diabetic drug classes with the potential to delay insulinization. Products aspiring to compete in the basal insulin regimen must avoid commoditization and steer clear of new threats. This paper identifies seven strategies and tactics to successfully address value in the diabetes market and particularly in the basal insulin regimen: 1) cost-based advantage and price competition; 2) value-based pricing; 3) risk-sharing agreements; 4) redifferentiation and post-approval evidence generation; 5) combination products carrying complementary mechanisms of action; 6) treating comorbidities and adjacent diseases; and, 7) indicating for patient sub-populations. / A diabetes tipo 2 é uma doença progressiva cuja projeção é crescer tremendamente em prevalência. Análogos de insulina basal eram considerados o tratamento mais eficaz, e utilizados em último instância durante a intensificação terapêutica. Hoje, transições demográficas, econômicas e epidemiológicas tem colocado pressão nos sistemas de saúde e no orçamento dos usuários. Três iminentes ameaças levam o regime de insulina basal à necessidade de repensar a maneira como seu valor é apresentado ao mercado: crescente pressão institucional sobre os preços, competição de biosimilares e novas classes medicamentos inovadores anti-diabetes com o potencial de atrasar a insulinização. Produtos que buscam competir no regime de insulina basal devem evitar a comoditização e esquivar-se de novas ameaças. Este trabalho identifica sete estratégias e táticas para apresentar de maneira bem sucedida valor no mercado de diabetes e particularmente no regime de insulina basal: 1) vantagem baseada em custo e competição por preço; 2) precificação baseada em valor; 3) acordos de compartilhamento de riscos; 4) rediferenciação e geração de evidencias pós-aprovação; 5) produtos combinados que apresentam mecanismos complementares de ação; 6) tratamento de co-morbidades e doenças adjacentes; e, 7) indicação para pacientes de determinados sub-grupos da população.

No / Biosimilar pharmaceuticals are complex biological molecules that have similar physicochemical properties to the originator therapeutic protein. They are produced by complex multi-stage processes and are not truly equivalent. Therefore, for a biosimilar to be approved for market it is important to demonstrate that the biological product is highly similar to a reference product. This includes its primary and higher order structures and its aggregation behaviour. Representative lots of both the proposed biosimilar and the reference product are analysed to understand the lot-to-lot variability of both drug substances in the manufacturing processes. Whilst it is not easy to characterise every variation of a protein structure at present additional analytical technologies need to be utilised to ensure the safety and efficacy of any potential biosimilar product. We have explored the use of Taylor dispersion analysis (TDA) to analyse such batch to batch variations in the model protein, bovine serum albumin (BSA) and compared the results to that obtained by conventional dynamic light scattering analysis (DLS). Inter and intra batch differences were evident in all grades of BSA analysed. However, the reproducibility of the TDA measurements, enabled the stability and reversibility of BSA aggregates to be more readily monitored. This demonstrates that Taylor dispersion analysis is a very sensitive technique to study higher order protein states and aggregation. The results, here, also indicate a correlation between protein purity and the physical behaviour of the samples after heat shocking. Here, the protein with the highest quoted purity resulted in a reduced increase in the measured hydrodynamic radius after heat stressing, indicating that less unfolding/aggregation had occurred. Whilst DLS was also able to observe the presence of aggregates, its bias towards larger aggregates indicated a much larger increase in hydrodynamic radii and is less sensitive to small changes in hydrodynamic radii. TDA was also able to identify low levels of larger aggregates that were not observed by DLS. Therefore, given the potential for immunogenicity effects that may result from such aggregates it is suggested that TDA may be suitable in the evaluating detailed batch to batch variability and process induced physical changes of biopharmaceuticals and biosimilars.

O objetivo do projeto foi desenvolver linhagens celulares para um anticorpo terapêutico anti-hTNFα e comprovar sua funcionalidade. Os genes anti-hTNFα foram clonados em células CHO para seleção da população estável mista, demonstrando expressão de anticorpo com reconhecimento de hTNFα em estrutura tridimensional. A população de transfectantes de maior produtividade específica foi escolhida para geração de linhagem monoclonal utilizando a tecnologia robótica ClonePix FL. Não houve diferença estatística entre o anti-hTNFα purificado e o produto de referência na cinética de ligação ao TNFα e reconhecimento diferencial por FcγRs em ensaios por SPR O ensaio de atividade funcional mostrou que o anti-TNFα desenvolvido pôde neutralizar a citotoxicidade induzida em células L929 e inibir a expressão de ELAM-1 em HUVEC. Os resultados finais permitiram identificar os três melhores clones, estáveis por 60 gerações. A comparabilidade entre o anti-TNFα desenvolvido e a referência permite admiti-lo como não inferior, um dos requisitos para o desenvolvimento de biossimilar. / The aim of the project was to develop a therapeutic anti-hTNFα antibody and evaluate its functionality. The anti-hTNFα synthezised genes were cloned into CHO cells and stable pools were selected, producing antibodies able to hTNFα three-dimensional structure recognition. The stable pools displaying higher antibody yields were the source for the generation of monoclonal lineage by ClonePix FL robotic technology. The clones selection proceeded using different criteria as cell density, specific productivity, fed-batch performance, kinetics measured by surface plasmonic resonance, hTNFα binding through ELISA, western-blotting and SPR, FcγRs binding by SPR. Besides, a small number of clones was tested in functional assays by the impairment of cytotoxicity of hTNFα over L929 cells and the inhibition of ELAM-1 expression by HUVEC. The long term stability testing allowed to finally select 3 top clones, not inferior to adalimumab reference by the above criteria.

O objetivo do projeto foi desenvolver linhagens celulares para um anticorpo terapêutico anti-hTNFα e comprovar sua funcionalidade. Os genes anti-hTNFα foram clonados em células CHO para seleção da população estável mista, demonstrando expressão de anticorpo com reconhecimento de hTNFα em estrutura tridimensional. A população de transfectantes de maior produtividade específica foi escolhida para geração de linhagem monoclonal utilizando a tecnologia robótica ClonePix FL. Não houve diferença estatística entre o anti-hTNFα purificado e o produto de referência na cinética de ligação ao TNFα e reconhecimento diferencial por FcγRs em ensaios por SPR O ensaio de atividade funcional mostrou que o anti-TNFα desenvolvido pôde neutralizar a citotoxicidade induzida em células L929 e inibir a expressão de ELAM-1 em HUVEC. Os resultados finais permitiram identificar os três melhores clones, estáveis por 60 gerações. A comparabilidade entre o anti-TNFα desenvolvido e a referência permite admiti-lo como não inferior, um dos requisitos para o desenvolvimento de biossimilar. / The aim of the project was to develop a therapeutic anti-hTNFα antibody and evaluate its functionality. The anti-hTNFα synthezised genes were cloned into CHO cells and stable pools were selected, producing antibodies able to hTNFα three-dimensional structure recognition. The stable pools displaying higher antibody yields were the source for the generation of monoclonal lineage by ClonePix FL robotic technology. The clones selection proceeded using different criteria as cell density, specific productivity, fed-batch performance, kinetics measured by surface plasmonic resonance, hTNFα binding through ELISA, western-blotting and SPR, FcγRs binding by SPR. Besides, a small number of clones was tested in functional assays by the impairment of cytotoxicity of hTNFα over L929 cells and the inhibition of ELAM-1 expression by HUVEC. The long term stability testing allowed to finally select 3 top clones, not inferior to adalimumab reference by the above criteria.

Le coût des biomédicaments impacte lourdement le fardeau financier déjà important imposé par la polyarthrite rhumatoïde (PR) à la société. Le but de ce travail était de rechercher les motivations de la prescription des médicaments biosimilaires en rhumatologie, tout particulièrement pour prendre en charge les patients atteints de PR. Les travaux effectués ont permis d’estimer les économies annuelles réalisables en France avec le médicament biosimilaire de l’infliximab à 13,6 millions d’EUR, pour la seule prise en charge de la PR. Par ailleurs, une enquête menée auprès des rhumatologues et pharmaciens a permis d’identifier les principaux enjeux liés à l’utilisation de ces médicaments. Enfin, le suivi de leur utilisation en région Grand Est entre 2015 et 2016 rend compte de leur utilisation encore modeste. La mise sur le marché régulière de médicaments biosimilaires, combinée à l’expérience croissante des acteurs et aux dispositifs d’incitation mis en place, devraient permettre de faire progresser la part d’utilisation de ces médicaments dans les prochaines années, et de s’assurer qu’ils tiennent bien leurs engagements sur le plan des économies réalisées. / Biological drugs are associated with high procurement costs and heavily impact the financial burden imposed by rheumatoid arthritis on society. The purpose of this work was to investigate the benefits of using biosimilar drugs in rheumatoid arthritis patients. This work showed the introduction of biosimilar infliximab could lead to substantial annual cost savings of up to €13.6 million nationally, to treat rheumatoid arthritis patients only. Moreover, a biosimilar survey involving rheumatologists and pharmacists allowed us to identify the main issues at stake. Finally, the monitoring of their use in Grand Est region between 2015 and 2016 account for their relatively low utilization rate. The regular launch of new biosimilar medicines, together with growing experience of healthcare players and incentive policies, should allow to increase biosimilar uptake in the future, and also to make sure they meet well their commitments in terms of savings generated.