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As the patents for biologic originator drugs expire, biosimilars are emerging as cost-effective alternatives within healthcare systems. Addressing various challenges in the clinical management of inflammatory bowel disease (IBD) remains crucial. To shed light on physicians' current knowledge, beliefs, practical approaches, and concerns related to biosimilar adoption-whether initiating a biosimilar, transitioning from an originator to a biosimilar, or switching between biosimilars (including multiple switches and reverse switching)-a global survey was conducted. Fifteen physicians with expertise in the field of IBD from 13 countries attended a virtual international consensus meeting to develop practical guidance regarding biosimilar adoption worldwide, considering the survey results. This consensus centered on 10 key statements covering biosimilar effectiveness, safety, indications, rationale, multiple switches, therapeutic drug monitoring of biosimilars, non-medical switching, and future perspectives. Ultimately, the consensus affirmed that biosimilars are equally effective and safe when compared to originator drugs. They are considered suitable for both biologic-naïve patients and those who have previously been treated with originator drugs, with cost reduction being the primary motivation for transitioning from an originator drug to a biosimilar., The consensus was supported by Sandoz.

Biosimilars are beginning to gain regulatory approval in the United States. Biosimilars are structurally near identical to the innovator and must demonstrate identical pharmacokinetics via the same binding affinity and biological function on assays. However, biologics are so complex that even the innovator company cannot produce exact duplicates; there is batch-to-batch variation. The International Psoriasis Council has outlined a biosimilarity index, which aims to standardize preclinical definitions of biosimilarity. Such an index, paired with post-approval monitoring, could provide a transparent, quantitative definition of biosimilarity. Such an index could increase trust in biosimilar medicines and the preclinical assessment process without increasing costs. As preclinical analyses are critical to biosimilar approval, manufacturers should devote proportionate resources to completing them. Dermatologists, who might reflexively look for indication-specific clinical data, might also shift their focus to preclinical variables. Finally, it should be noted that biosimilars provide more evidence of similarity than we have for different batches of the innovator product. Thus, any clinical testing standards, or lack thereof, for different batches of innovator products should also apply to biosimilars.

PurposeTo characterize current experiences with communication and decision-making practices when non-medical switching to a biosimilar trastuzumab is proposed or required by cancer center or insurer.MethodsWe developed and launched 60- and 51-item internet surveys to elicit US breast cancer patient and medical oncologist lived experiences with trastuzumab biosimilars and patient information needs and seeking practices. We recruited participants using social media and administered via REDCap in 2020-2021.Results143 breast cancer patients and 33 medical oncologists completed the surveys. 63.9% patients reported having switched to a trastuzumab biosimilar and 40.8% reported receiving no prior notification about switching. 44% of patients reported learning about biosimilars primarily through self-directed learning and 41% wanting more time to discuss with oncologist. None of the oncologists reported that the decision to switch a patient to a biosimilar was initiated by them, but rather more frequently by the insurer (45.2%). About 54.8% reported not receiving any pharmaceutical manufacturer material related to the selected biosimilar. Patients and oncologists diverged in their responses to items regarding patient opportunities to ask questions, adequacy of resources, effectiveness of treatment, patient worry, and magnitude of change.ConclusionThere is a need for tailored and effective patient and oncologist information and education on trastuzumab biosimilars, along with improved healthcare communication regarding switching. The discrepancy between patient-reported experiences and oncologist perceptions of the patient experience, suggests a lack of adequate information that may be a challenge not only to the uptake of trastuzumab biosimilars, but to the patient-oncologist relationship.

OBJECTIVE: The adalimumab originator Humira® introduced a new citrate-free formulation in 2016, before the patent expiry that occurred in the European Union in October 2018. Some of the adalimumab biosimilars that were subsequently marketed are citrate-free, while others are not. Since citrate as an excipient is associated with pain at the injection site, recent anecdotical reporting in Italy raised the issue of possible prescription biases related to the differences in formulation existing among the various adalimumab products. In this study, we analyzed the data obtained from the ‘Rete Nazionale di Farmacovigilanza’ (Pharmacovigilance National Network) to investigate whether, and to what extent, the differences in the formulation of the various adalimumab versions had an impact on the rate of injection site reactions reported in Italy in the period 2016-2019. MATERIALS AND METHODS: A search was conducted based on 3 search criteria: (1) time frame; (2) suspected drugs, and (3) adverse reaction type. Reports classified in the System Organ Class “Administration site conditions” were analyzed by year, product, and type of adverse event (whether including or not ‘pain’). Data were reported both as absolute numbers, as well as signaling rates, considering the consumption data expressed as defined daily doses (DDD). RESULTS: We found that: (1) The change in Humira® formulation introduced in august 2016 was followed by a decrease in the reports of injection site reactions (from 45 in 2016 to 12, 12 and 8 in 2017, 2018, and 2019, respectively); (2) after the introduction of biosimilars during 2018, in 2019 a marked shift in reporting toward biosimilars was observed (52 out of 60; 87%). CONCLUSIONS: While the decrease in Humira® reports is consistent with the improved tolerability of the new formulation, the huge increase in biosimilar reporting may be only in part explained by the differences in formulation and cannot be accounted for by a parallel increase in exposure, si

The therapeutic value of biologics is of extreme importance in the treatment of most major cancers. Biologics account for half of the oncologic pharmacology market. As the population of the United States ages, the demand for biologics is expected to increase. The future supply of biologics may be prohibited by cost. Biosimilar biologics are highly similar to existing Food and Drug Administration-licensed biologics and have the potential to meet biological demand. Market introduction of biosimilars at a lower cost than reference biologics creates an opportunity for reducing the nation’s financial burden. Despite the obvious gains from biosimilar use, adoption into clinical practice continues to lag. Numerous factors, including a lack of education on the part of prescribers, continue to hinder the widespread adoption of biosimilars into practice. The purpose of this integrative review is to examine the evidence surrounding biosimilar determination and ascertain if adult patients diagnosed with cancer can be treated with biosimilars as compared to reference biologics without a compromise in safety and efficacy throughout the course of therapy.

The International Society of Oncology Pharmacy Practitioners organized a workshop to create learning opportunities on biosimilars in pharmacy practice on 10 October 2019. The topics that were covered included (i) the development and testing of biosimilars, (ii) the challenges of bringing biosimilars to market, and (iii) real-world data on patient safety and perceptions during biosimilar implementation. The development of biosimilars can take up to eight years and the extensiveness of the process depends on several factors, such as the complexity of the production process and regulatory requirements. Compared to generic products of small-molecule drugs, there is a higher barrier to market entry for biosimilars, explaining the small number of biosimilars in the market. Appraisal of biosimilars for inclusion in hospital formularies is also different from the review process of originator biologics, where the former is usually institution-led and has fewer restrictions on use. When several biosimilar products are available, factors that should be considered besides cost are licensed indications, supply chain confidence, clinical data, and product attributes. Real-world data have shown that biosimilars are well-tolerated and have safety data that are comparable to that of the originator product. Oncology pharmacists from the United Kingdom, Kenya, and Canada also presented their respective experiences with biosimilar use. Different countries at varying stages of biosimilar implementation faced distinct challenges. Nevertheless, resources to assist biosimilar implementation can potentially be shared between different regions. International Society of Oncology Pharmacy Practitioners is well-positioned to foster professional cooperation at an international level to drive biosimilar implementation.

As patents on many high-selling biological medicines are expiring, non-innovator versions, such as biosimilars, may enter this multi-billion dollar market. This study aims to map patents and patent applications for innovator as well as biosimilar monoclonal antibodies in Europe, and investigates legal challenges associated with patenting the innovator product and alleged infringing activities, focusing on consequences for biosimilar developers. Via an exploratory literature review in PubMed and a database analysis in Darts-ip, Derwent Innovation, and Espacenet, an overview of basic patents and exclusivity rights for some of the best-selling biologicals is given, supplemented with a detailed analysis of patents taken during the medicine’s life cycle via three specific case studies (trastuzumab, bevacizumab, cetuximab). Case law was used to determine which patents were viewed by biosimilar developers as blocking market entry. For the selected monoclonal antibodies, the key protection instruments appeared to be the basic patent and the additional protection provided by a supplementary protection certificate. We observed that additional patents filed after the basic patent are hard to obtain and often insufficient in blocking market entry of biosimilars, but can in some cases be a substantial hurdle for biosimilar developers to overcome in patent litigation cases or to invent around, creating uncertainty on the launch date of a biosimilar on the market. These hurdles, however, seem to be surmountable, given that many cases were won by biosimilar developers. Also, biosimilars can be protected by filing new patents and these mainly pertain to new formulations.

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.

A pharmacodynamics (PD) and immunogenicity study was conducted to investigate biosimilarity of Pelmeg®, a pegfilgrastim biosimilar to EU‐authorized Neulasta®. The multiple‐dose, randomized, double‐blind, two‐sequence, and three‐period cross‐over study comprised 96 healthy male subjects, receiving Pelmeg (Test [T]) and Neulasta (Reference [R]) in a sequential manner (T‐T‐R vs R‐R‐T). Subjects were dosed with 3 mg pegfilgrastim, as this dose was previously shown to be in the ascending part of the dose‐response curve for PD. The primary PD endpoint was the area under the effect curve (AUEC0‐last) for absolute neutrophil count (ANC). The primary immunogenicity endpoint was proportion of anti‐drug antibody (ADA)‐positive subjects at the end of Period 2 (ie, after administration of two doses of the same study drug). Comparability was demonstrated for the PD endpoint, with the geometric mean ratio (T/R) of AUEC0‐last being 101.59%, with a corresponding 95% CI of [99.58; 103.63]. Of note, when using tighter acceptance limits (90.00%‐111.00%), comparability between test and reference was shown as well. Only two confirmed ADA positive samples were detected, one after treatment with Pelmeg and one after Neulasta. These had a low ADA titer, no filgrastim reactivity, and no neutralizing capacity. No clinically meaningful differences in safety between Pelmeg and Neulasta were observed. Overall, the results from this study confirmed the biosimilarity of Pelmeg and Neulasta for PD and immunogenicity, as shown already at the bioanalytical level and in the pivotal PK/PD study with Pelmeg., + ID der Publikation: unilu_47410 + Sprache: Englisch + Letzte Aktualisierung: 2021-03-08 13:09:21

A pharmacodynamics (PD) and immunogenicity study was conducted to investigate biosimilarity of Pelmeg®, a pegfilgrastim biosimilar to EU‐authorized Neulasta®. The multiple‐dose, randomized, double‐blind, two‐sequence, and three‐period cross‐over study comprised 96 healthy male subjects, receiving Pelmeg (Test [T]) and Neulasta (Reference [R]) in a sequential manner (T‐T‐R vs R‐R‐T). Subjects were dosed with 3 mg pegfilgrastim, as this dose was previously shown to be in the ascending part of the dose‐response curve for PD. The primary PD endpoint was the area under the effect curve (AUEC0‐last) for absolute neutrophil count (ANC). The primary immunogenicity endpoint was proportion of anti‐drug antibody (ADA)‐positive subjects at the end of Period 2 (ie, after administration of two doses of the same study drug). Comparability was demonstrated for the PD endpoint, with the geometric mean ratio (T/R) of AUEC0‐last being 101.59%, with a corresponding 95% CI of [99.58; 103.63]. Of note, when using tighter acceptance limits (90.00%‐111.00%), comparability between test and reference was shown as well. Only two confirmed ADA positive samples were detected, one after treatment with Pelmeg and one after Neulasta. These had a low ADA titer, no filgrastim reactivity, and no neutralizing capacity. No clinically meaningful differences in safety between Pelmeg and Neulasta were observed. Overall, the results from this study confirmed the biosimilarity of Pelmeg and Neulasta for PD and immunogenicity, as shown already at the bioanalytical level and in the pivotal PK/PD study with Pelmeg., + ID der Publikation: unilu_47410 + Sprache: Englisch + Letzte Aktualisierung: 2021-03-08 13:09:21

A pharmacodynamics (PD) and immunogenicity study was conducted to investigate biosimilarity of Pelmeg®, a pegfilgrastim biosimilar to EU‐authorized Neulasta®. The multiple‐dose, randomized, double‐blind, two‐sequence, and three‐period cross‐over study comprised 96 healthy male subjects, receiving Pelmeg (Test [T]) and Neulasta (Reference [R]) in a sequential manner (T‐T‐R vs R‐R‐T). Subjects were dosed with 3 mg pegfilgrastim, as this dose was previously shown to be in the ascending part of the dose‐response curve for PD. The primary PD endpoint was the area under the effect curve (AUEC0‐last) for absolute neutrophil count (ANC). The primary immunogenicity endpoint was proportion of anti‐drug antibody (ADA)‐positive subjects at the end of Period 2 (ie, after administration of two doses of the same study drug). Comparability was demonstrated for the PD endpoint, with the geometric mean ratio (T/R) of AUEC0‐last being 101.59%, with a corresponding 95% CI of [99.58; 103.63]. Of note, when using tighter acceptance limits (90.00%‐111.00%), comparability between test and reference was shown as well. Only two confirmed ADA positive samples were detected, one after treatment with Pelmeg and one after Neulasta. These had a low ADA titer, no filgrastim reactivity, and no neutralizing capacity. No clinically meaningful differences in safety between Pelmeg and Neulasta were observed. Overall, the results from this study confirmed the biosimilarity of Pelmeg and Neulasta for PD and immunogenicity, as shown already at the bioanalytical level and in the pivotal PK/PD study with Pelmeg., + ID der Publikation: unilu_47410 + Sprache: Englisch + Letzte Aktualisierung: 2021-03-08 13:09:21

A pharmacodynamics (PD) and immunogenicity study was conducted to investigate biosimilarity of Pelmeg®, a pegfilgrastim biosimilar to EU‐authorized Neulasta®. The multiple‐dose, randomized, double‐blind, two‐sequence, and three‐period cross‐over study comprised 96 healthy male subjects, receiving Pelmeg (Test [T]) and Neulasta (Reference [R]) in a sequential manner (T‐T‐R vs R‐R‐T). Subjects were dosed with 3 mg pegfilgrastim, as this dose was previously shown to be in the ascending part of the dose‐response curve for PD. The primary PD endpoint was the area under the effect curve (AUEC0‐last) for absolute neutrophil count (ANC). The primary immunogenicity endpoint was proportion of anti‐drug antibody (ADA)‐positive subjects at the end of Period 2 (ie, after administration of two doses of the same study drug). Comparability was demonstrated for the PD endpoint, with the geometric mean ratio (T/R) of AUEC0‐last being 101.59%, with a corresponding 95% CI of [99.58; 103.63]. Of note, when using tighter acceptance limits (90.00%‐111.00%), comparability between test and reference was shown as well. Only two confirmed ADA positive samples were detected, one after treatment with Pelmeg and one after Neulasta. These had a low ADA titer, no filgrastim reactivity, and no neutralizing capacity. No clinically meaningful differences in safety between Pelmeg and Neulasta were observed. Overall, the results from this study confirmed the biosimilarity of Pelmeg and Neulasta for PD and immunogenicity, as shown already at the bioanalytical level and in the pivotal PK/PD study with Pelmeg., + ID der Publikation: unilu_47410 + Sprache: Englisch + Letzte Aktualisierung: 2021-03-08 13:09:21

With the imminent arrival of oncology biosimilars in the therapeutic paradigm, stakeholders including a clinician, specialist nurse, patient advocate, regulator and economist provide their perspective on optimising the uptake of these new agents in the treatment of cancer. A number of key messages emerge, based on the discussion that took place during a session of the European Society for Medical Oncology's Annual Congress, ESMO Madrid 2017. First, for successful integration of biosimilars into the global healthcare paradigm, informing and educating the full scope of stakeholders, including clinicians, nurses, pharmacists and patients, is primordial. Success is dependent on providing solid evidence and ensuring all voices are heard. Second, for oncology medicines, much can be learnt from the growing experience of approved biosimilars in other disease indications, with success stories for patients, their healthcare providers and healthcare budgets alike. Finally, effective sustainability of the impact on healthcare budgets and the redirection of these savings require education and transparency

Los medicamentos han contribuido claramente a aumentar la calidad de vida. Pero para cumplir su función deben llegar a todos los pacientes. Los precios excesivos de los medicamentos innovadores dificultan el acceso de los pacientes a los mismos y ponen en riesgo la sostenibilidad de los Sistemas de salud. Estos precios se deben, sobre todo, a la opacidad que permiten las patentes. Tenemos una nueva oportunidad de aumentar la transparencia de la industria farmacéutica con la llegada de los biosimilares y con la reciente ley 9/2017 de Contratos del Sector Público., Medicines have clearly contributed to increase the quality of life. But to fulfill their function they must reach all patients. Excessive prices of innovative medicines make it difficult for patients to access them and put the sustainability of health systems at risk. health. These prices are due, above all, to the opacity allowed by patents. We have a new opportunity to increase the transparency of the pharmaceutical industry with the arrival of biosimilars and with the recent law 9/2017 of Public Sector Contracts.

Los medicamentos han contribuido claramente a aumentar la calidad de vida. Pero para cumplir su función deben llegar a todos los pacientes. Los precios excesivos de los medicamentos innovadores dificultan el acceso de los pacientes a los mismos y ponen en riesgo la sostenibilidad de los Sistemas de salud. Estos precios se deben, sobre todo, a la opacidad que permiten las patentes. Tenemos una nueva oportunidad de aumentar la transparencia de la industria farmacéutica con la llegada de los biosimilares y con la reciente ley 9/2017 de Contratos del Sector Público., Medicines have clearly contributed to increase the quality of life. But to fulfill their function they must reach all patients. Excessive prices of innovative medicines make it difficult for patients to access them and put the sustainability of health systems at risk. health. These prices are due, above all, to the opacity allowed by patents. We have a new opportunity to increase the transparency of the pharmaceutical industry with the arrival of biosimilars and with the recent law 9/2017 of Public Sector Contracts.

Funding. This review and article processing charges were funded by Pfizer Inc., Psoriasis is a chronic, inflammatory, lifelong disease with a high prevalence (afflicting approximately 1-5% of the population worldwide) and is associated with significant morbidity. The introduction of biologic therapies has improved the management of this disease. Multiple biologic medicines that block cytokine signaling, including tumor necrosis factor (TNF) antagonists (adalimumab, etanercept, and infliximab) and inhibitors of interleukin (IL)-17 (brodalumab, ixekizumab, and secukinumab), IL-23 (guselkumab), or IL-12/23 (ustekinumab), are approved for the treatment of psoriasis. Despite the clinical benefits associated with use of biologics in psoriasis, many patients are not treated with biologic therapy, and access to treatment may be limited for various reasons, such as high treatment costs. Patents for many biologics have expired or will soon expire, and biosimilar versions of these agents are available or in development. A biosimilar is a biological product that is highly similar to an approved biologic (i.e., originator or reference) product, and has no clinically meaningful differences in safety, purity, or potency when compared with the reference product. Biosimilars may offer less expensive treatment options for patients with psoriasis; they also may increase access to and address problems with underutilization of biologic therapy. Biosimilar development and approval follows a well-regulated process in many countries, with guidelines developed by the European Medicines Agency, US Food and Drug Administration, and World Health Organization. Currently, several anti-TNF biosimilars are available for use in patients with psoriasis, and other monoclonal antibodies are in development. This review provides dermatologists and those who treat and/or manage psoriasis with a working knowledge of the scientific principles of biosimilar development and approval. It also examines real-world experience with biosimilars available for or used in dermatology that will e

The paper applies a functional approach to the analysis of an emerging technology within an innovation system (IS) in a developing country. By doing so, the paper identifies the advantages and drawbacks of the approach through a dynamic analysis and highlights the life cycle of an IS within which a new technology is emerging. This is done empirically by analysing the emergence of biosimilars within the infant Turkish biotechnology system mainly from the perspective of firms. Our analysis of the Turkish case illustrates how the tool of functional approach could be valuable in understanding the dynamics of a technology in a developing country context. Policy suggestions and implications of the study are presented as concluding remarks., QC 20190205

The objective of this study is to apply therapeutic drug monitoring (TDM) as an objective tool to monitor the switch from infliximab innovator (INX) to infliximab biosimilar (INB) in our diverse rheumatic cohort in daily clinical practice. All rheumatic patients on INX treatment (Remicade®) and ≥18 years were switched to INB (Inflectra®) as part of routine care, but in a controlled setting. Patients were monitored by taking blood samples just before the first infusion of INB (T1), and after the second (T2), fourth (T3), and seventh (T4) infusion of INB. T4 reflects the patients’ status after ∼12 months. Infliximab trough levels, antibodies-to-infliximab (ATI), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and validated disease activity scores (if possible) were measured. Our population consisted of 27 patients with seven different rheumatic diseases who had received INX for 143 (58–161) months (median (IQR)). Half of the patients (52%) received concomitant immunosuppressives. We found widely varying infliximab levels, with only 56% within the proposed therapeutic range of 1–5 μg/mL. One patient had very high ATI levels (>880 au/mL), and two had low ATI levels (≤30 au/mL). After switching to INB, seven patients (26%) discontinued the therapy, partially due to subjective reasons. No difference in infliximab levels, CRP levels, and disease activity scores was found between the four time points (p ≥ 0.2460). In conclusion, no pharmacokinetic or clinical differences were found between INX and INB in our diverse rheumatic cohort. TDM is a helpful tool to monitor patients switching from INX to INB.

Introduction: Introducing biosimilar infliximab for the treatment in rheumatology (rheumatoid arthritis and ankylosing spondylitis) and inflammatory bowel disease (Crohn's disease and ulcerative colitis) may reduce treatment costs associated with biologics. This study aimed to investigate the budget impact of adopting biosimilar infliximab in five European countries, considering that the budget impact includes the adoption of biosimilar infliximab and the availability of biologic alternatives such as vedolizumab, biosimilar etanercept, biosimilar rituximab, and other relevant factors. Methods: An existing budget impact model was adapted to forecast the budget impact in the UK, Germany, France, Spain, and Italy. Epidemiological parameters were derived from published literature reviewed in July 2015. Current market shares of biologics were derived from Therapy Watch (2012/2013 data). Respondents in a Delphi panel, conducted in 2015 and consisting of several leading rheumatologists and gastroenterologists from different nationalities, were asked to forecast uptake of biosimilar infliximab and estimate the proportion of patients eligible for a particular type of biological treatment, including biosimilar infliximab. Scenario analyses assessed the influence of various factors, including price reductions, on the budget. Results: Uptake of biosimilar infliximab was particularly expected for naïve patients; switching patients that already received other biologics was not expected much. Market shares after 5 years of biosimilar infliximab were ~2% in rheumatology in all five countries and in gastroenterology ranged from 4% in France to over 30% in Italy. Except for France, budgets were expected to decrease for rheumatologic diseases. For gastroenterology, budgets were expected to decrease in Spain and Italy. Budgets were expected to increase substantially in the UK and Germany, due to the introduction of vedolizumab in the studied period. In France, budget was expected to sl

Biosimilar drugs must closely resemble the pharmacological attributes of innovator products to ensure safetyand efficacy to obtain regulatory approval. Glycosylation is one critical quality attribute that must be matched, but it is inherently difficult to control due to the complexity of its biogenesis. This usually implies that costly and time-consuming experimentation is required for clone identification and optimization of biosimilar glycosylation. Here, we describe a computational method that utilizes a Markov model of glycosylation to predict optimal glycoengineering strategies to obtain a specific glycosylation profile with desired properties. The approach uses a genetic algorithm to find the required quantities to perturb glycosylation reaction rates that lead to the best possible match with a given glycosylation profile. Furthermore, the approach can be used to identify cell lines and clones that will require minimal intervention while achieving a glycoprofile that is most similar to the desired profile. Thus, this approach can facilitate biosimilar design by providing computational glycoengineering guidelines that can be generated with a minimal time and cost.

Therapeutic proteins are rapidly becoming the most promising class of pharmaceuticals on the market due to their successful treatment of a vast array of serious diseases, such as cancers and immune disorders. Therapeutic proteins are produced using recombinant DNA technology. More than 60% of therapeutic proteins are posttranslationally modified following biosynthesis by the addition of N- or O-linked glycans. Glycosylation is the most common posttranslational modifications of proteins. However, it is also the most demanding and complex posttranslational modification from the analytical point of view. Moreover, research has shown that glycosylation significantly impacts stability, half-life, mechanism of action and safety of a therapeutic protein. Considering the exponential growth of biotherapeutics, this present review of the literature (2009-2015) focuses on the characterization of protein glycosylation, which has witnessed an improvement in methodology. Furthermore, it discusses current issues in the fields of production and characterization of therapeutic proteins. This review also highlights the problem of non-standard requirements for the approval of biosimilars with regard to their glycosylation and discusses recent developments and perspectives for improved glycan characterization., SCOPUS: re.j, info:eu-repo/semantics/published

Valderílio Feijó Azevedo,1,2 Ludmila Della Coletta Troiano,2 Natalia Bassalobre Galli,1 Alais Kleinfelder,1 Nathan M Catolino,1 Paulo Cesar Urbano Martins2 1Rheumatology Unit, Federal University of Paraná, 2Edumed Health Research and Biotech, Curitiba, Brazil Abstract: Adalimumab was the first fully humanized monoclonal antibody approved by the US Food and Drug Administration (FDA). Launched in 2003, the clinical efficacy and safety of adalimumab were assessed in various trials in rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, Crohn’s Disease, and ulcerative colitis, among others. At the global level, adalimumab is a major sales success among biologicals. It is still the greatest blockbuster among monoclonal antibodies. The date of its patent expiration paves the road for several potential biosimilars in various markets worldwide. This article discusses the current situation of molecules that are the main candidates to become adalimumab biosimilars. In addition, it also addresses the production processes, clinical studies, and relevant regulatory issues relative to the approval of those molecules, which must meet the challenge of demonstrating similar efficacy and safety to Humira®, but at a lower cost. Keywords: biosimilars, adalimumab, anti-TNF, biosimilarity

Monique Mantovani,1,2 Cecilia Sulzbacher Caruso,1 Fernanda Dell Antonio Facchini,1 Renata Pascon,1,3 Patrícia Ribeiro Vilaça Cagnacci,1 Vanda Dolabela de Magalhães1 1Department of Biotechnology, Eurofarma Laboratórios SA, São Paulo, SP, Brazil; 2Libbs Farmacêutica Ltda, Embu das Artes, SP, Brazil; 3Department of Biological Sciences, Federal University of São Paulo, Diadema, SP, Brazil Abstract: The registration of biosimilars requires comparison studies to reference products to guarantee their safety, purity, efficacy, and potency. In this study, we demonstrate the similarity of a filgrastim produced by Eurofarma (Fiprima®) and one produced by Amgen Inc. (commercialized by Hoffman-La Roche Ltd, Granulokine®) in terms of drug identity, structure, purity, and bioactivity. The methods used to compare both products were the following: peptide mapping, bidimensional electrophoresis, reduced and nonreduced polyacrylamide electrophoresis, Western blotting, reverse-phase high-performance liquid chromatography, size-exclusion high-performance liquid chromatography, far and near circular dichroism, fluorescence emission, X-ray crystallography, liquid chromatography–tandem mass spectrometry, matrix-assisted laser desorption/ionization-time of flight, receptor binding, and potency by in vitro cell proliferation. Biosimilarity to Granulokine was demonstrated in terms of identity, structure, purity, and bioactivity. Keywords: filgrastim, biosimilar, biopharmaceutical, G-CSF, comparability, neutropenia

Marceline Manka Fuh, Pascal Steffen, Hartmut Schlüter Mass Spectrometric Proteomics, Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Abstract: A continuously increasing number of therapeutic proteins are being released into the market, including biosimilars. In contrast to small organic drugs, therapeutic proteins require an extensive analysis of their exact chemical composition because of their complexity and proof of the absence of contaminants, such as host cell proteins and nucleic acids. Especially challenging is the detection of low abundant species of therapeutic proteins because these species are usually very similar to the target therapeutic protein. However, the detection of these species is very important for the safety of patients because a very small change of the exact chemical composition may cause serious side effects. In this review, we give a brief overview about the most important analytical approaches for characterizing therapeutic protein species and their contaminants and focus on the progress in this field during the past 3 years. Top-down mass spectrometry of intact therapeutic proteins in the future may solve many of the current problems in their analysis. Keywords: therapeutic protein species, biosimilars, liquid chromatography, mass spectrometry, capillary electrophoresis

Reginald Ewesuedo Pfizer Inc., Cambridge, MA, USA Abstract: The availability of biosimilars (also known as follow-on biologic or subsequent entry biologic, etc) is expected to improve access to health care and to provide more affordable alternatives to the reference products. However, despite this promise, based on publicly available information from clinical trial databases, there is apparent global disparity in participation (more so in oncology) and interest in the clinical development of proposed biosimilars. The disparity seems to be partly due to lack of access to biologics, as well as expectations of the development process and/or study objectives. There is inherent misalignment between the characterizations of the clinical studies, in the public domain, with regulatory guidance (eg, the use of “Phase” to describe a comparative study). There is also apparent non-appreciation of potential research opportunities afforded by the biosimilar development paradigm. It is imperative that key stakeholders required for the development of this class of drugs are adequately engaged and that they fully understand the development paradigm, if the promises of biosimilars are to be realized globally. Keywords: p-biosims, follow-on biologic, biologics, regulatory guidelines, clinical studies

Tommaso Gabbani, Simona Deiana, Siro Bagnoli, Vito Annese  Emergency Department, Division of Gastroenterology 2, AOU Careggi University Hospital, Florence, Italy Abstract: Biologics are defined as active substances derived from living cells or organisms with the aid of biotechnology methods. A similar biological medicinal product, commonly referred to as a biosimilar, is a copy version of an approved original biological medicine whose data protection has expired. The main advantage of biosimilars is to lower prices and create financial savings for health care systems. Adalimumab (Humira) is a human recombinant monoclonal antibody against tumor necrosis factor-α, licensed for the treatment of several rheumatologic diseases and inflammatory bowel diseases. The original biologic agent has worldwide sales of approximately 12.5 billion US dollars, but the patent will expire in 2016 for the US and in 2018 for Europe. Adalimumab biosimilar is already currently marketed and used in a clinical setting in India, but many other companies are testing adalimumab biosimilars in order to request authorization from the European Medicines Agency and the US Food and Drug Administration at the time of patent expiry. In this gold rush, the long-term safety and immunogenicity of these drugs are an issue, but the striking rise of pharmaceutical expenses makes these drugs highly attractive for health care systems and pharmaceutical companies. Keywords: adalimumab, IBD, biosimilar, biologics, Crohn's disease

Andy R Fry,1 Andrew J Krentz,2 Marcus Hompesch2 1Team Consulting Limited, Ickleton, Cambridge, UK; 2Profil Institute for Clinical Research, Chula Vista, CA, USA Abstract: Biosimilar insulins, also known as follow-on biologics, are modifications of an originator insulin that are intended to be clinically equivalent to the licensed product. For injectable insulins, or other peptides used in the management of diabetes, regular use of an insulin pen injector or other device to administer therapy is part of the patient's self-management regimen. By definition, the biosimilar product should have comparable pharmacokinetic and pharmacodynamic properties to the reference product. However, the device is the initial interaction for the patient rather than the product contained within. We consider the regulatory aspects of insulin device development. The options for manufacturers bringing a biosimilar insulin to market, including whether to outsource development of delivery devices, are explored. The structure of a device development program is outlined and issues of accuracy, safety, ease of use, and attractiveness of modern insulin delivery devices are discussed. Keywords: biosimilar insulin, delivery devices, diabetes mellitus&nbsp

When term of protection available for patents on biological medicine is over, biosimilar medicinal products appear as an alternative. Regulation, suitability, safety, efficacy, equity and cost, represent some highlights., La expiración de patentes de medicamentos biológicos permite a los biosimilares irrumpir como alternativa. Su regulación, idoneidad, seguridad, eficacia, el acceso en equidad y los costes, suponen algunos aspectos destacados

When term of protection available for patents on biological medicine is over, biosimilar medicinal products appear as an alternative. Regulation, suitability, safety, efficacy, equity and cost, represent some highlights., La expiración de patentes de medicamentos biológicos permite a los biosimilares irrumpir como alternativa. Su regulación, idoneidad, seguridad, eficacia, el acceso en equidad y los costes, suponen algunos aspectos destacados

Ashraf Mikhail , Christopher BrownRenal Unit, Morriston Hospital, Wales, UK Abstract: Biosimilars have been developed for several biologic therapeutic agents, including erythropoiesis-stimulating agents. Biosimilars cannot be assumed to be completely identical to the reference product. Several regulatory bodies have issued stringent guidelines to regulate the licensing of biosimilars. These guidelines, although share a unified aim of ensuring the safety and efficacy of biosimilars, show several differences. Such differences may reflect the difficulties facing regulatory bodies in defining a biosimilar, identifying sensitive means to assess equivalence in efficacy, and designing robust methodologies to monitor long-term safety. This review will discuss some of the aspects of differences in licensing requirements for biosimilars, comparing the European Medicines Agency guidelines and the American Food and Drug Administration guidelines. The pathway adopted by the manufacturer of a biosimilar (epoetin zeta) to gain licensing within the European market will be assessed, analyzing its compliance with the European Medicines Agency guidelines for the approval process. Since many patients are likely to be switched from original drugs to biosimilars in future, there is a need to establish strict guidelines on interchangeability and substitution of biosimilars and original products and to make it an integral part of the pre-registration assessment of any biosimilar in future. Eventually, long-term, observational post-marketing data will provide further reassurance on safety and tolerability of biosimilars. Keywords: biosimilars, erythropoiesis-stimulating agents, epoetin zeta, biologic therapeutic agents

Carlos Cuevas,1 Florian Deisenhammer,2 Xiaojun You,3 Mariano Scolnik,4 Regine Buffels,3 Bjørn Sperling,3 Francisco Flores-Ramírez,5 Miguel Macías-Islas,6 Sergio Sauri-Suárez7 On behalf of the MATRIX Investigator Group 1Specialty Hospital, Department of Neurology, National Medical Center Siglo XXI, Mexican Institute of Social Security, Mexico City, Mexico; 2Department of Neurology, University of Innsbruck, Innsbruck, Austria; 3Biogen, Cambridge, MA, USA; 4Biogen, Argentina, Buenos Aires, Argentina; 5Department of Internal Medicine–Neurology, Hospital Regional ISSSTE Monterrey, Monterrey, 6University Center for Health Sciences, University of Guadalajara, Guadalajara, 7Internal Medicine/Department of Neurology, National Medical Center, Mexico City, Mexico Abstract: MATRIX (Measuring neutralizing Antibodies in patients TReated with Interferon beta-1a IM in MeXico) was primarily a cross-sectional phase 4 study of patients with relapsing multiple sclerosis (RMS) that evaluated neutralizing antibody (NAb) frequency in Mexican and Colombian patients treated with intramuscular interferon (IFN) beta-1a in the form of Avonex® or the biosimilar drug Jumtab®. A secondary long-term retrospective observational evaluation of safety, tolerability, and relapses was also performed for patients in each arm of the study. In the cross-sectional portion of the study, patients with multiple sclerosis who had been treated with once-weekly Avonex (n=36) or Jumtab (n=29) self-injections as their first and only disease-modifying therapy for 1–3 years were retrospectively identified. The primary and secondary endpoints were proportion of patients with NAb levels >100 tenfold reduction units (TRU) and >20 TRU. The biological response to IFN beta-1a injections was assessed by change in serum neopterin levels and by pre- versus post-dose concentration difference. Safety, tolerability, and relapse-related

Uma Sinha-Datta, Srijit Khan, Dhananjay WadgaonkarFast Trak, GE Healthcare Life Science, John F Welch Technology Centre, Bangalore, IndiaAbstract: In the biosimilar eon, where various analytical platforms are needed to show biosimilarity, we demonstrate the use of surface plasmon resonance biosensor as a label-free interaction analysis tool to compare two therapeutic monoclonal antibodies (mAb1-i and mAb2-i) with their biosimilars (mAb1-B and mAb2-B1, B2, B3) based on kinetics, affinity, and thermal stability studies. We calculate active analyte concentration using Biacore systems' calibration-free concentration analysis method and demonstrate its importance for kinetic evaluation. The kinetic constants (ka and kd) and affinity constant (KD) of the mAbs for binding to specific antigens were evaluated. It was found that the biosimilars were very similar to their innovator with respect to binding to its antigen demonstrating functional similarity. To further confirm biosimilarity to the originator molecules, we conducted a thermal stability analysis of both mAbs using differential scanning calorimetry. This analysis showed good structural similarity in between innovator antibodies and biosimilars, with major Tm as 84.1°C (mAb1) and 72.8°C (mAb2), demonstrating structural similarity.Keywords: surface plasmon resonance, Biacore, kinetics, low level of ligand immobilization, calibration-free concentration analysis, bivalent analytes, active concentration

Brenda J Huneycutt,1 Earl Gillespie,2 Gillian R Woollett1 1FDA Regulatory Strategy and Policy, Avalere Health, LLC, Washington, DC, 2Health Advances, LLC, Weston, MA, USA Abstract: A number of biosimilars have been approved in highly regulated markets throughout the world. Biosimilar development follows its own unique path – relying primarily on analytics to compare a potential biosimilar to its reference product and giving a reduced, confirmatory role to clinical trials. In addition, the ability to extrapolate data to support approval for indications without a clinical trial gives this abbreviated pathway potential significant value. In fact, so far, all the approved biosimilars in Europe received approval for all the reference product's indications. However, this is not the case in other regions. Regulatory agencies of the highly regulated markets agree in general on many principles underlying biosimilar product development and approval, but differ in important aspects as reflected by the data burdens and approval decisions for four classes of products explored in this paper – somatropins, filgrastims, epoetins, and infliximabs. These case studies also highlight some biosimilar sponsor latitude as reflected in the varying clinical data packages submitted to the same regulatory agency for biosimilars to the same reference product. There also exists biosimilar sponsor latitude in deciding whether to use the biosimilar pathway at all or seek approval through the stand-alone biologics regulatory pathway. This, of course, is a commercial decision based on the weights each biosimilar sponsor gives to the various risks and benefits for each option, for each product, and for each market. Further, it remains an open question whether a single, biosimilar development plan for global commercialization can be used to satisfy each regulatory agency. Keywords: somatropin, filgrastim, epoetin, infliximab

Sarfaraz K NiaziTherapeutic Proteins International, LLC, Chicago, IL, USAAbstract: Biosimilar biological products are a safe and effective alternative to branded biological agents. One of the most common uses of the therapeutic protein filgrastim, a biological drug (recombinant human granulocyte-colony stimulating factor), is to reduce the occurrence and duration of severe neutropenia and its associated serious complications. TPI G-CSF, a filgrastim product under development by Therapeutic Proteins International, LLC, is a proposed biosimilar to Amgen's marketed filgrastim, Neupogen®. To evaluate bioequivalence, we conducted a double-blind, randomized, two-period crossover study that took place at a single center and had a washout period of at least 2 weeks. The pharmacokinetic endpoints (area under the concentration-time curve from time 0 to time of the last observed/measured non-zero concentration [AUC0-t], AUC from time 0 extrapolated to infinity [AUC0-inf], and maximum observed concentration [Cmax]) and the pharmacodynamic endpoints (baseline-corrected area under the effect curve from time zero to the last non-zero cell count data [AUEC0-t] and maximum observed effect [Emax]) for the absolute neutrophil count were compared after administration of a subcutaneous 5 µg/kg dose of TPI G-CSF or Neupogen® in 58 healthy adults. These 58 healthy subjects (72% male, 34.8±10.5 years, 77.1±14.1 kg) were randomly assigned to a treatment sequence group (TPI G-CSF-Neupogen® or Neupogen®-TPI G-CSF); subjects received a single subcutaneous injection of 5 µg/kg in each period. The 95% pharmacodynamic and 90% pharmacokinetic geometric confidence intervals of the ratio (TPI G-CSF/Neupogen®) of least-squares means from the analysis of variance of the natural log-transformed data for each parameter fell within the approved bioequivalence range of 80% to 125%. There were no serious adverse event

Anita Krishnan,1 Rustom Mody,1 Hemant Malhotra21Lupin Limited, Biotech Division, Maharashtra, India; 2Division of Medical Oncology, RK Birla Cancer Center, SMS Medical College Hospital, Jaipur, India Abstract: Biological product development for launch in multiple geographies with varied regulatory expectations would require a planned and focused strategy, involving the selection of the appropriate reference product, defining the extent of process and product characterization and design of nonclinical and clinical studies. The development for established markets like the European Union and the United States, which have precedence in regulatory pathways, may face very different challenges compared to emerging markets, many of which are still in the nascent stages of regulatory guidelines. A clear and concise understanding of the regulatory framework of each region and awareness of the limitations of health care policies, with an added knowledge of the local factors that influence the biosimilar market, would be desirable for a good business strategy. Herein it is attempted to outline the stages of regional guideline implementation in the various global locations and compare the variability in regulatory requirement between them. The factors that could potentially impact biosimilars business in these regions are also outlined. Finally, the prevailing competition between manufacturers of innovative and biosimilar drugs, which could influence the availability of lifesaving off-patent drugs for critical diseases and the advent of more effective, alternate, or next-generation molecules, is also briefly described. Keywords: guidelines, India, comparability, EMA, US FDA, WHO

Brian Bressler,1 Theo Dingermann2 1St Paul’s Hospital, University of British Columbia, Vancouver, BC, Canada; 2Institute of Pharmaceutical Biology, Frankfurt, Germany Abstract: Despite their enormous value for our health care system, biopharmaceuticals have become a serious threat to the system itself due to their high cost. Costs may be warranted if the medicine is new and innovative; however, it is no longer an innovation when its patent protection expires. As patents and exclusivities expire on biological drugs, biosimilar products defined as highly similar to reference biologics are being marketed. The goal of biosimilar development is to establish a high degree of biosimilarity, not to reestablish clinical efficacy and safety. Current sophisticated analytical methods allow the detection of even small changes in quality attributes and can therefore enable sensitive monitoring of the batch-to-batch consistency and variability of the manufacturing process. The European Medicines Agency (EMA), US Food and Drug Administration (FDA), and Health Canada have determined that a reduced number of nonclinical and clinical comparative studies can be sufficient for approval with clinical data from the most sensitive indication extrapolated to other indications. Extrapolation of data is a scientifically based principle, guided by specific criteria, and if approved by the EMA, FDA, and/or Health Canada is appropriate. Enablement of extrapolation of data is a core principle of biosimilar development, based on principles of comparability and necessary to fully realize cost savings for these drugs. Keywords: biosimilars, Inflectra, infliximab, pharmacoeconomics, Canada, Europe&nbsp

Shein-Chung Chow Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, USA Abstract: For assessing biosimilarity of biosimilar products, the US Food and Drug Administration (FDA) proposed a stepwise approach for providing totality-of-the-evidence of similarity between a proposed biosimilar product and a US-licensed (reference) product. The stepwise approach starts with an assessment of critical quality attributes (CQAs) that are relevant to clinical outcomes in structural and functional characterization in manufacturing process of the proposed biosimilar product. The FDA suggests that these critical quality–relevant attributes be identified and classified into three tiers depending their criticality or risk ranking. To assist the sponsors, the FDA also suggests some statistical approaches for the assessment of analytical similarity for CQAs from different tiers, namely equivalence test for Tier 1, quality range approach for Tier 2, and descriptive raw data and graphical comparison for Tier 3. In this paper, challenging issues to the FDA's recommended approaches are discussed followed by alternative methods for the assessment of analytical similarity (mainly for CQAs from Tier 1). Keywords: stepwise approach, critical quality attribute, CQA, equivalence test, quality range approach&nbsp

Wael M Ebied,1 Hytham M Ahmed,2 Fawzy A Elbarbry31SEDICO Pharmaceuticals, Merck & Co External Partner, 6th of October City, Cairo, 2Pharmaceutical Analysis Department, Faculty of Pharmacy, Damanhour University, Damanhour, Egypt; 3Pharmaceutical Sciences, School of Pharmacy, Pacific University Oregon, Hillsboro, OR, USAAbstract: Although management of chronic diseases has been a major challenge for health care systems in developed and developing countries, biopharmaceuticals have been successful in treating many life-threatening conditions. However, the high cost of these agents restricts their availability to countries where patients and/or health care systems are able to afford them. Licensing these biopharmaceuticals as biosimilars after expiration of their patents might increase access to such medicines at an affordable price in developing countries. South Egypt Drug Industries Company (SEDICO) is an Egyptian pharmaceutical company that has had the opportunity to manufacture some of these drugs. SEDICO biotechnology products, such as insulin, erythropoietin, streptokinase, angiokinase, follicle-stimulating hormone, aprotinin, filgrastim, and somatropin, have been available on the Egyptian market for more than 6 years. For this paper, erythropoietin, which has been investigated over a number of years, was chosen as a representative example of SEDICO biotechnology products. Our findings confirm that SEDICO erythropoietin can compete with the originator epoetins on the Egyptian market with high quality and at a lower cost.Keywords: biosimilars, developing countries, insulin, human growth hormone, erythropoietin, epoetin, Egypt

Martin K Kuhlmann,1 Andrea Schmidt2 1Department of Internal Medicine–Nephrology, Klinikum im Friedrichshain, Berlin, Germany; 2Sanofi, Frankfurt, Germany Abstract: More than 380 million people worldwide have diabetes, a disease that accounts for almost US$550 billion in global health care spending. The majority of patients with diabetes will require insulin replacement as part of their therapeutic regimen. In some countries, the approaching patent expiry dates for the long-acting insulin analog insulin glargine mean there is increasing interest in the potential of biosimilar insulins. However, the production and manufacturing of biosimilar insulins is a proprietary, complex, multistep process in which each stage can potentially introduce variability, possibly leading to adverse clinical and safety outcomes. Thus, marketing authorization in countries in which stringent regulatory requirements are in place requires manufacturers to demonstrate similarity in pharmacokinetic/pharmacodynamic properties, clinical efficacy, and adverse event and immunogenicity profiles, as well as provide proof of the quality of the production process between the biosimilar and the reference insulin product. A risk management plan and pharmacovigilance program may also be needed for the approval process. Regulatory guidelines for the introduction of biosimilar insulins differ between countries but are most developed for the European Union. As of the date of submission of this manuscript (April 30, 2014), no insulin or insulin analogs have received marketing authorization based on the European Union standards established for biosimilars; however, European Medicines Agency approval of a biosimilar glargine insulin is awaited for the end of 2014. In recent years several copies of the long-acting insulin glargine have been brought onto the market in countries such as India, the People’s Republic of China, Pakistan, Mexico, and Kenya without following a biosimilar pathway. I

Sanjay Bandyopadhyay, Mukesh Mahajan, Tulsi Mehta, Arun K Singh, Aashini Parikh, Ajit K Gupta, Pankaj Kalita, Mihir Patel, Sanjeev Kumar Mendiratta Zydus Research Centre, Biotech Division, Cadila Healthcare Ltd, The Zydus Group, Ahmedabad, Gujarat, India Abstract: ZRC-3197 has been developed indigenously by Cadila Healthcare Ltd as a biosimilar adalimumab of originator HUMIRA®. Biosimilarity has been demonstrated with a comprehensive set of state-of-the-art analytical techniques to characterize the physicochemical and functional properties of ZRC-3197 in comparison with originator HUMIRA®. The biosimilar ZRC-3197 showed indistinguishable primary and secondary structures with similar level of purity and heterogeneity as compared to that of the originator product. When analyzed, in parallel, the two products were observed to show a high degree of sameness of the carbohydrate structure and charge heterogeneity profile. Both biosimilar ZRC-3197 and the originator HUMIRA® appeared to show highly comparable key functional properties, as assessed by in vitro cell-based assay and surface plasmon resonance technique. The biosimilar ZRC-3197 exhibited highly similar tumor necrosis factor alpha neutralizing activity as well as binding affinity for FcγRIIIa receptor compared to that of the originator product. The biosimilar ZRC-3197 was observed to show similar level of efficacy and safety profile in rheumatoid arthritis patients, when submitted to a head-to-head double-blind trial, in India, with the originator (reference) product, HUMIRA®. Based on the demonstrated biosimilarity, market authorization has been granted for ZRC-3197, as a biosimilar of originator HUMIRA®, in India. Here, we report the characterization of physicochemical and functional properties of the biosimilar ZRC-3197 and originator HUMIRA®. Keywords: adalimumab, biosimilars, tumor necrosis factor (TNF)

Soba Tharmarajah,1,2 Abdulaziz Mohammed,3,4 Alaa Bagalagel,3,4 Karen MacDonald,2 Ivo Abraham2,3,5 1College of Pharmacy, University of Arizona, Tucson, AZ, USA; 2Matrix45, Tucson, AZ, USA; 3Center for Health Outcomes and PharmacoEconomic Research, College of Pharmacy, University of Arizona, Tucson, AZ, USA; 4College of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia; 5Department of Pharmacy Practice and Science, College of Pharmacy, University of Arizona, Tucson, AZ, USA Abstract: This second review of biosimilar granulocyte colony-stimulating factors approved by the European Medicines Agency evaluates the evidence on the clinical efficacy and safety of prophylaxis of (febrile) neutropenia with Zarzio® in chemotherapy-treated cancer patients relative to the originator product filgrastim (Neupogen®). Source documents include: publicly available documents of the European Medicines Agency; a published article reviewing the (preapproval) clinical development of EP2006 (Zarzio®); and published (postapproval) single-center experience reports on prophylaxis with Zarzio®, including two reports in the cancer setting and one in the setting of autologous peripheral blood stem cell mobilization. Also included is: a pooled analysis of these and other postapproval studies in the cancer setting that includes (interim) data from the two single cancer center reports; one additional single-center experience study; one completed study; and one ongoing multicenter postapproval study. Based on the available therapeutic equivalence and safety data, the clinical and safety outcomes of Zarzio® are likely to be similar to those of Neupogen®. Thus, Zarzio® and Neupogen® may be assumed interchangeable. Keywords: biosimilars, biosimilar pharmaceuticals, efficacy, safety, granulocyte colony stimulating factor, recombinant proteins

Wael M Ebied,1 Hytham M Ahmed,2 Fawzy A Elbarbry31SEDICO Pharmaceuticals, Merck & Co External Partner, 6th of October City, Cairo, 2Pharmaceutical Analysis Department, Faculty of Pharmacy, Damanhour University, Damanhour, Egypt; 3Pharmaceutical Sciences, School of Pharmacy, Pacific University Oregon, Hillsboro, OR, USAAbstract: Although management of chronic diseases has been a major challenge for health care systems in developed and developing countries, biopharmaceuticals have been successful in treating many life-threatening conditions. However, the high cost of these agents restricts their availability to countries where patients and/or health care systems are able to afford them. Licensing these biopharmaceuticals as biosimilars after expiration of their patents might increase access to such medicines at an affordable price in developing countries. South Egypt Drug Industries Company (SEDICO) is an Egyptian pharmaceutical company that has had the opportunity to manufacture some of these drugs. SEDICO biotechnology products, such as insulin, erythropoietin, streptokinase, angiokinase, follicle-stimulating hormone, aprotinin, filgrastim, and somatropin, have been available on the Egyptian market for more than 6 years. For this paper, erythropoietin, which has been investigated over a number of years, was chosen as a representative example of SEDICO biotechnology products. Our findings confirm that SEDICO erythropoietin can compete with the originator epoetins on the Egyptian market with high quality and at a lower cost.Keywords: biosimilars, developing countries, insulin, human growth hormone, erythropoietin, epoetin, Egypt

Paul D Chamberlain NDA Advisory Board, NDA Advisory Services Ltd, Surrey, UK Abstract: Clinical evaluation of comparative immunogenicity represents an important component of the European Union regulatory review process for candidate biosimilar products. The clinical evaluation is part of a multidisciplinary review that cross-refers to product quality attributes as well as preclinical and ongoing risk management considerations. Results from the monitoring of anti-drug antibody formation in relevant populations treated for an adequate period of time are interpreted in relation to clinically relevant endpoints, including pharmacokinetics, pharmacodynamics, efficacy, and safety parameters. The European Union regulatory standard for designation of biosimilarity requires a suitable weight of evidence, determined on a product-specific basis, to demonstrate that the immunogenicity associated with the biosimilar product does not lead to a higher negative impact on clinically relevant outcomes compared with the reference product. The experience gained during the 10-year period following the implementation of the European Union biosimilars pathway indicates that a suitably cautious approach was applied, insofar as no immunogenicity-related issues have emerged for the approved applications of the different biosimilar products. In some cases, product quality-related issues were identified in the preauthorization setting as being potentially relevant for heightened risk of immunogenicity and were duly taken into account for the biosimilarity decision. Some unresolved issues remain, most notably concerning the limitation of noninterventional post-marketing surveillance measures to monitor the potential for changes in immunogenicity over the longer term, eg, following introduction of changes in manufacture, formulation, or primary product container. Lack of standardization of bioanalytical methods precludes comparison of anti-drug antibody formation for different products that are

Alaa Bagalagel,1,2 Abdulaziz Mohammed,1,2 Karen MacDonald,3 Ivo Abraham1,3–5 1Center for Health Outcomes and PharmacoEconomic Research, University of Arizona, Tucson, AZ, USA; 2College of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia; 3Matrix45, Tucson, AZ, USA; 4Department of Pharmacy Practice and Science, College of Pharmacy, 5Department of Family and Community Medicine, College of Medicine, University of Arizona, Tucson, AZ, USA Abstract: In this second part of a series of three reviews of approved biosimilar erythropoietins, we review the evidence pertaining to the clinical efficacy and safety of SB309 relative to the originator product Eprex®/Erypo®. As in the first review, clinical efficacy is assessed with respect to the therapeutic equivalence of the biosimilar and originator product, while safety is evaluated in terms of immunogenicity, venous thromboembolism, and mortality. Seven studies in chronic renal failure and oncology populations are reviewed. In the renal setting, these include two randomized controlled trials on hemoglobin correction and maintenance in patients receiving long-term hemodialysis; open extension safety studies from both trials analyzed as a pooled database; a post hoc analysis on biosimilar and originator switching; a therapeutic equivalence study of subcutaneously administered SB309 and Eprex/Erypo; and a single-center experience study. In the cancer setting, one open-label non-controlled study is reported. Based on the available therapeutic equivalence and safety data, the clinical and safety outcomes of treatment with SB309 are likely to be similar to those of the originator product Eprex/Erypo. Both products can be considered interchangeable in the management of anemia for the approved indications. Patients transferred from reference product to biosimilar can be expected to show the same efficacy and safety outcomes. There is no evidence of the interchangeability of SB309 with other biosimila

Article reproduced (or made available) with permission of Practical Dermatology®, www.practicaldermatology.com., En el artículo se recoge la aplicación de los medicamentos biosimilares biotecnológicos) en patologías dermatológicas.

Article reproduced (or made available) with permission of Practical Dermatology®, www.practicaldermatology.com., En el artículo se recoge la aplicación de los medicamentos biosimilares biotecnológicos) en patologías dermatológicas.

Article reproduced (or made available) with permission of Practical Dermatology®, www.practicaldermatology.com., En el artículo se recoge la aplicación de los medicamentos biosimilares biotecnológicos) en patologías dermatológicas.