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Clinical comparability and European biosimilar regulations
Abstract
Clinical trials required by European regulators to compare biosimilar products with corresponding biologic brands are
surplus to requirements and may even be a barrier for the development of biosimilars of more complicated biologics.
... At the onset of the biosimilar market entrance, many medical societies suggested watchful use of biosimilars. Accumulated evidence has been reassuring and the first wave of biosimilar agents has exceeded 5 years in use, albeit they were small proteins, not monoclonal antibodies [37][38][39]. ...
... As mentioned above, the manufacturing process of a biosimilar is overwhelmingly more complex, expensive and time-consuming when compared to generics: estimates point to a 7-8-year period from early development to approval at a cost of US$100-250 million, as opposed to a 2-3-year period at a cost of US$1-4 million for generics, although developmental expenses with biosimilars will tend to decrease in the near future [37,53]. Consequently, manufacturers venturing in the biosimilar market are fewer and price reductions are expected to reach on average only 30 % of originator price, as opposed to a 70-80 % reduction for generics [54,55]. ...
Despite representing a breakthrough in the treatment of immune-mediated rheumatic diseases, the direct costs of biotechnological therapies represent a burden to healthcare budgets worldwide. Furthermore, several studies demonstrated that socioeconomically constrained countries have poorer access to these therapies and this has consequences on the optimal management of rheumatic patients. Experience with small peptide biosimilars like filgrastim and epoetin confirmed significant cost savings but revealed variable market uptake. In this report, we summarize the available budget impact models and discuss possible determinants of the pharmacoeconomic performance of antirheumatic biosimilar drugs.
... In 2009, EMA started with providing individual protocol assistance and scientific consultations to companies to avoid slowdown of the development of biosimilar mAbs (European Medicines Agency, 2015b). Even with the published guideline, the evaluation is very much case-by-case and the developer has the opportunity to propose novel study techniques (Schellekens and Moors, 2010;EMA, 2012a). During the public consultation period of the EMA guideline on biosimilar mAbs, industry and regulatory representatives made comments, while the medical profession did not take this opportunity to be involved in designing the guidelines (Ebbers et al., 2012a). ...
... The historical market approval of biosimilars shows a caseby-case approach and approval of the marketing authorization application based on the available test data and the intellectual judgment of the EMA (Schellekens and Moors, 2010). Profound knowledge of and experience with the regulatory requirements, in combination with EMA Scientific advice/Protocol assistance, will help a company to adjust the biosimilar mAb development process to these requirements and overcome this barrier for the EMA regulatory pathway. ...
Background: In 2014, six of the top ten blockbuster medicines were monoclonal antibodies. This multibillion-dollar market with expiring patents is the main driver for the development of biosimilar mAbs. With the ever-increasing cost of healthcare and the economic pressure to reduce or sustain healthcare expenses, biosimilars could be instrumental in reducing costs for medication and increasing patient access to treatment.
Objectives: The aim of this study is to identify and describe the barriers to market access of biosimilar mAbs in the European Union and to analyze how these barriers could be overcome.
Methods: A narrative literature review was carried out using the databases PubMed, Embase, and EconLit. Studies were published in English or Dutch. Additionally, the reference list of the articles was checked for relevant studies. Articles and conference papers known to the authors were included as well. Articles were also identified by searching on the website of the Generics and Biosimilars Initiative (GaBI) journal.
Results: Six barriers were identified based on available literature: The manufacturing process, the regulatory process, intellectual property rights, lack of incentive, the impossibility of substitution, and the innovator's reach. These six barriers are presented as a possible framework to study the market access of biosimilar mAbs. Based on the literature search, recommendations can be made to overcome these barriers: (i) invest initially in advanced production processes with the help of single-use technology, experience or outsourcing (ii) gain experience with the regulatory process and establish alignment between stakeholders (iii) limit patent litigation, eliminate evergreening benefits, build out further the unitary patent and unified patent litigation system within the EU (iv) create demand-side policies, disseminate objective information (v) change attitude toward biosimilar switching/substitution, starting with physician, and patient education (vi) differentiate the biosimilar by service offerings, use an appropriate comparator in cost-effectiveness analyses.
Conclusions: Barriers to the market access of biosimilar mAbs could be reduced when more transparency and communication/education is used in all steps toward market access in order to increase the trust in biosimilar mAbs by all stakeholders. Only then biosimilar mAbs will be able to fully capture their cost saving potential.
... The requirement of comparability for approving the production of biosimilars has been criticized by some authors, for example, by Schellekens and Moors (2010), who state that while with classic generics the comparative data are assumed to be surrogate for clinical trials, in the case of biosimilars, clinical data remain mandatory; thus, the question regarding the need for comparative data emerges. Furthermore, the European guidelines from EMEA state that some differences between the innovator and the reference are admitted as long as the clinical data show no negative effects. ...
... This is another reason for questioning the relevance of a comparison between biosimilars and reference products. In conclusion, according to Schellekens and Moors (2010), the comparability of biosimilar and reference products should not be mandatory, even if it might be useful for manufacturers to set specifications for their production and purification and to validate their production methods and analytical tools for marketing purposes. On the other hand, according to the author, dropping the obligation to make a comparison will make it easier to develop more complex biosimilars. ...
The issue of comparative effectiveness research (CER) is assessed from an ethical point of view by comparison with the main ethical frameworks and by analysis of some of the relevant institutional documents. Two main conclusions emerge from the study: no ethical framework seems able to objectively and definitively assess CER; no institutional document, neither national nor international, has specifically assessed the ethical implications of CER. Nevertheless, this vacuum regarding CER raises relevant ethical concerns, thus revealing the necessity and urgency of an ethical evaluation of CER.
... The following years, the FDA approved other clinical indications for administering rhGH. For the first time, the European Medicine Agency (EMA) published a series of special regulatory guidelines for the production and development of biosimilar rhGH in 2006 [12,13]. Therefore, based on that, 12-month safety and effectiveness studies are needed to compare biosimilar products with the approved reference drug regarding tolerance, quality and effectiveness. ...
... The following years, the FDA approved other clinical indications for administering rhGH. For the first time, the European Medicine Agency (EMA) published a series of special regulatory guidelines for the production and development of biosimilar rhGH in 2006 [12,13]. Therefore, based on that, 12-month safety and effectiveness studies are needed to compare biosimilar products with the approved reference drug regarding tolerance, quality and effectiveness. ...
Objectives:
This study is designed in order to compare the efficacy and safety of recombinant human growth hormone (rhGH) with the reference brand.
Methods:
According to the inclusion criteria, 85 people in 13 Iranian centers were randomly selected to receive biosimilar Somatropin (Somatin®) (44 people) and reference Somatropin (Norditropin®) (41 people) at a dose of 35 µg/kg/d, seven days/week for 12 months. The primary outcomes included height velocity (HV) was measured during 12 months of treatment.
Results:
The two intervention groups' Height changes were similar. The mean HV was 10.96 cm/year in the biosimilar group and 10.05 cm/year in the reference groups after 12 months. Estimates of the lower bounds of 95% CI for mean height differences in the biosimilar intervention group compared to the reference intervention group did not exceed the 2 cm margin. Therefore, the non-inferiority of biosimilar intervention compared to the brand product is verified. Common ADRs in both groups were nausea in two patients (2.4%), diarrhea in two patients (2.4%), increased body temperature in one patient (1.2%), and headache in one patient (1.2%).
Conclusions:
The finding of this study indicated that Somatin® and Norditropin® have comparable efficacy and safety profiles.
Clinical trial registration:
www.IRCT.ir IRCT20171122037571N1.
... In summary, the clinical comparability exercise starts with pharmacokinetic and/or pharmacodynamic studies, and comparative clinical efficacy and safety trials may still follow. An important step is to document the side effects and to take into consideration the evaluation of immunogenicity for which comparable profiles for the biosimilar and the reference are also required for the clinical safety data assessment [38,39]. Apart from comparing the quality attributes of both medications, establishing the similarity in biological activity and safety of the biosimilar involves utilizing relevant and sensitive in vitro assays. ...
By definition, biosimilar medicinal products are biological medicinal products that are similar to other biological medicinal products that are already on the market—the reference medicinal products. Access to biosimilar medicines is a current reality. However, to achieve this goal, it is extremely important to consistently and scientifically substantiate the regulatory requirements necessary for biosimilar medicines when accessing the market. Based on an analysis of the raw materials and the type of methods used in the manufacturing processes of biological medicines, it is known that this tends to be more complex for the quality of the finished product than the manufacture of molecules obtained through a chemical process. It is then relevant to highlight the main differences between both products: biological medicines manufactured using biotechnology and the current generics containing active pharmaceutical ingredients (APIs) obtained from synthetic processes. Once arriving at the approval process of these medicinal products, it is imperative to analyse the guidance documents and the regulatory framework that create the rules that allow these biosimilar medicinal products to come to the market. The present review aimed at documenting comparatively the specific provisions of European legislation, through the European Medicines Agency (EMA), as well as the legislation of the United States of America, through the Food and Drug Administration (FDA). This was then translated into a critical appraisal of what concerns the specific criteria that determine the favourable evaluation of a biosimilar when an application for marketing authorisation is submitted to different regulatory agencies. The gathered evidence suggests that the key to the success of biosimilar medicines lies in a more rigorous and universal regulation as well as a greater knowledge, acceptance, and awareness of health professionals to enable more patients to be treated with biological strategies at an earlier stage of the disease and with more affordable medicines, ensuring always the safety and efficacy of those medicines.
... Clinical data is essential in the case of biosimilars [33] and these products undergo three main phases, namely: ...
Biologics are medicines primarily derived from living systems and produced through recombinant DNA (rDNA) and monoclonal technologies. Generic version of biologics with improved efficacy and safety is called biosimilar. Patent and copyright expiration of biological products permits the entry of biosimilars. Synthesis of biosimilars involves two main processes, such as monoclonal antibodies and rDNA technology, and characterized by various methods such as posttranslational modification, mass spectrometry, peptide mapping, three-dimensional (high-order) structure, X-ray crystallography, ion mobility spectrometry, and hydrogen deuterium exchange mass spectrometry. Though both generic and biosimilar products follow the same regulatory approval, the requirements are not the same due to the variability in composition and instability. Hence, it is essential to develop pharmacokinetic and pharmacodynamic data to support the efficacy and safety data on biosimilars. This review summarizes the recent updates on biosimilars, synthesis, characterization, and current market status. Brief information on the role of biosimilars in multiple sclerosis is also provided in the review.
... Clinical data is essential in the case of biosimilars [33] and these products undergo three main phases, namely: ...
Biologics are medicines primarily derived from living systems and produced through recombinant DNA (rDNA) and monoclonal technologies. Generic version of biologics with improved efficacy and safety is called biosimilar. Patent and copyright expiration of biological products permits the entry of biosimilars. Synthesis of biosimilars involves two main processes, such as monoclonal antibodies and rDNA technology, and characterized by various methods such as posttranslational modification, mass spectrometry, peptide mapping, three-dimensional (high-order) structure, X-ray crystallography, ion mobility spectrometry, and hydrogen deuterium exchange mass spectrometry. Though both generic and biosimilar products follow the same regulatory approval, the requirements are not the same due to the variability in composition and instability. Hence, it is essential to develop pharmacokinetic and pharmacodynamic data to support the efficacy and safety data on biosimilars. This review summarizes the recent updates on biosimilars, synthesis, characterization, and current market status. Brief information on the role of biosimilars in multiple sclerosis is also provided in the review.
... A common global trend in regulatory guidelines introduced since has been the use of extensive physicochemical and biological characterization techniques to demonstrate comparability, with confirmation by clinical studies. In some jurisdictions, demand for extensive clinical trials has been challenged as being too cautious and hindering the development of biosimilars [6]. In a step that would facilitate the objective of affordable healthcare, the EMA proposed a criterion for waiver of clinical trial requirement, publishing a concept paper on granulocyte colony-stimulating factor for the revision of the current guidelines [7]. ...
Background
Biotherapeutics are protein products generated using recombinant DNA technology and manufactured in prokaryotic or eukaryotic cells. It is often said that “the process is the product” and thereby the effect of the manufacturing process is etched on the final product in the form of its heterogeneity. For any biotherapeutic, the acceptable range of the critical quality attributes is defined based on the expected impact of a specific variation on the product stability, safety, and efficacy. For a biosimilar to receive regulatory approval, the manufacturer must demonstrate analytical and clinical comparability with the originator product. As this is mandatory, every biosimilar manufacturer performs this exercise for each biosimilar product under development. However, few reports of thorough evaluation of the quality of biosimilar products are available in the literature.Objective
We examined the structural and functional comparability of biosimilars of trastuzumab, a humanized monoclonal antibody biotherapeutic. The originator product, Herclon (Roche), was compared with four marketed biosimilars: Trasturel from Reliance Life Sciences, Canmab from Biocon, Vivitra from Zydus Ingenia, Hertraz from Mylan.Methods
Structural comparability was established using mass spectrometry and spectroscopic techniques such as Fourier transform infrared spectroscopy, differential light scattering, circular dichroism, and fluorescence spectroscopy. Stability was compared by performing accelerated thermal stress studies. Functional comparability was established via surface plasmon resonance and biological assays such as antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity.ResultsWith respect to comparability, one biosimilar exhibited significant differences in multiple attributes, such as lower percentage of monomer content and main charge variant species, lower percentage of aglycosylated glycoform G0, and lower estimated potency values.Conclusions
Overall, the results indicated general similarity with respect to structure and function, but we found variations with respect to size heterogeneity, charge heterogeneity, and glycosylation pattern in each of the biosimilars.
... Biosimilar manufacturers are using state-of-the-art technologies. Technology that has evolved since the launch of the innovator biologics may offer additional conveniences to patients and healthcare providers [21] • Substantial cost-benefit: Cost of biosimilar products is still relatively high unlike, generics. Developing a biosimilar product is expensive and time-consuming process (approximately 8-10 years to introduce a biosimilar in the market). ...
As the first biologics produced by recombinant deoxyribonucleic acid (DNA) technology were approved in the late 1980s and consequently the exclusive marketing rights of most of these biological medicinal products have expired or will expire very shortly, it is quite evident that biosimilars are being developed and marketed in developed as well as developing countries in line with these expiries. Hence, there is an explosion of published papers and scientific programs on biological medicinal products and biosimilar insulins in the last decade or so. Each of these papers or scientific programs generated more questions than providing clinically useful answers. The specific aim of the medical literature or scientific programs were blurred due to lot of attention (created by the innovators) directed towards confusing terminologies, past mishaps with biosimilars (in the era with the absence of regulatory guidelines for biosimilars) diverting our attention from the matters relevant to clinicians and patients. One of the principle reason behind this phenomenon has been our poor understanding of the manufacturing process, regulatory pathways, and study endpoints involved in developing a biosimilar in the present era. This drawback resulted in a nonsystematic approach in analyzing the biosimilars and apparently resulting in confusion. This review attempts at demystifying certain facets of frequently encountered information on biosimilars and acquire a personal understanding on the same, rather than depending on conflicting versions floated at different continuing medical educations (CMEs) and Diabetes Congresses.
... 4 The active substance of a biosimilar and that of its reference medicine are essentially the same biological substance, but they do have differences due to the complexity of their nature and the methods of production, 1 which do not affect the safety or the effectiveness of the medicine. 5 The aim of developing biosimilar medicines was to reduce the price of the medicines and to promote competition in the pharmaceutical market. 6 Biosimilars can only be authorised once the period of exclusivity of the reference biological medicine has expired. 1 In the European Union (EU), the first biological product patents expired in 2001, and it was not until several years later, in 2006, that the EMA approved the first biosimilar. ...
Objectives
To assess the degree of readability and the length of the package leaflets of biosimilars.
Setting
The package leaflets analysed were downloaded from the European Medicines Agency (EMA) website.
Participants
The study sample included the package leaflets written in English of all the biosimilars that were authorised by the EMA on 31 August 2017, and whose content was available via the internet on that date (n=35).
Design
This was a cross-sectional analytical study. The readability of the package leaflets of all biosimilars authorised by the EMA in August 2017 was determined applying the Flesch and Flesch-Kincaid formulas. The influence of the following variables on the readability and length was also analysed: package leaflet section, type of biosimilar, date of first authorisation of the biosimilar and type of medicine.
Results
A considerable variation of the package leaflets length was found (3154±803). The readability of all the package leaflets overtook the recommended value for health-related written materials taking into account Flesch-Kincaid Index, and none of the package leaflets were easy to understand according to the Flesch Index. Statistically significant differences (p<0.05) were observed between the sections of package leaflets in readability indices and length. The most difficult sections to understand were those related with the therapeutic indication of medicine and the possible side effects.
Conclusions
Package leaflets for authorised biosimilars may not fulfil the function for which they were designed. The competent organisations could be informed about the possible negative effect on the use of this type of medicines.
... Although several years had passed since the biosimilars analyzed in this study were subject to comparative analysis required to obtain market authorization, the filgrastims retained their high biosimilarity. Any slight differences present between the products are recognized as typical of biological molecules [19], and may be attributed to the most up-to-date methods being used in the production of biosimilars [20]. The most evident difference observed in this study for filgrastims was the one in the CD spectrum of Product D (Zarzio). ...
Background:
Filgrastim, a recombinant human granulocyte colony-stimulating factor (rhG-CSF) produced in Escherichia coli, is indicated for treatment of neutropenia-related conditions in cancer patients. It has been marketed as Neupogen since 1991. In 2006, biosimilar rhG-CSF products have been approved in the European Union (EU).
Objective:
The aim of this study was to compare quality attributes of the originator filgrastim with its three biosimilars which came from the EU market in 2014 to verify whether their similarity is maintained since their market approval.
Methods:
Spectrophotometric analysis was used to determine protein content in analyzed products. Chromatographic and electrophoretic analyses were applied to verify the presence of high and low-molecular weight impurities. Secondary and tertiary structure of the drugs were investigated with circular dichroism and intrinsic fluorescence. Finally, biological activity of the drugs was assessed using cell proliferation assay.
Results:
All products displayed protein content close to the label concentration with a ±6% variation. Two oxidized forms and a deamidated form were present at <0.5%. Levels of dimers and other high molecular-weight impurities were similar except for one product, which contained higher amount of the dimer. Profiles and levels of process-related impurities were comparable. The three-dimensional conformation of the molecules with respect to exposed tryptophan residues were similar. The relative potencies of the products were comparable to the reference standard with a ±2% variation.
Conclusions:
This study shows that a high level of similarity is maintained among originator and three biosimilar filgrastims up to 5 years from their first registration in the EU.
... The process for biosimilar approval in Europe was established prior to that of the United States. The European Medicine Agency (EMEA) and the associated Committee for Medicinal Products for Human Use (CHMP) evaluate data gathered by pharmaceutical companies seeking approval for prospective biosimilars [3] . ...
Biosimilars are a growing drug class designed to be used interchangeably with biologics. Biologics are created in living cells and are typically large, complex proteins that may have a variety of uses. Within the field of gastroenterology alone, biologics are used to treat inflammatory bowel diseases, cancers, and endocrine disorders. While biologics have proven to be effective in treating or managing many diseases, patient access is often limited by high costs. The development of biosimilars is an attempt to reduce treatment costs. Biosimilars must be nearly identical to their reference biologics in terms of efficacy, side effect risk profile, and immunogenicity. Although the manufacturing process still involves production within living cells, biosimilars undergo fewer clinical trials than do their reference biologics. This ultimately reduces the cost of production and the cost of the biosimilar drug compared to its reference biologic. Currently, seven biosimilars have been approved by the United States Food and Drug Administration (FDA) for use in Crohn’s disease, ulcerative colitis, and colorectal cancer. There are other biologics involved in treating gastroenterologic diseases for which there are no FDA approved biosimilars. Although biosimilars have the potential to reduce healthcare costs in chronic disease management, they face challenges in establishing a significant market share. Physician comfort in prescribing reference biologics instead of biosimilars and patient reluctance to switch from a biologic to a biosimilar are two common contributing factors to biosimilars’ slow increase in use. More time will be needed for biosimilars to establish a larger and more consistent market share compared to their reference biologics. Additional data confirming the safety and efficacy of biosimilars, increased number of available biosimilars, and further cost reduction of biosimilars will all be necessary to improve physician confidence in biosimilars and patient comfort with biosimilars.
... En el año 2005, la EMA estableció los lineamientos para la aprobación de biosimilares a través de un proceso de registro que requiere estudios clínicos abreviados, y en años posteriores presentó varias guías generales y específicas. Aun publicados los lineamientos, la evaluación es caso por caso y las firmas que desarrollan biosimilares tienen la posibilidad de proponer nuevas técnicas analíticas para la evaluación (Schellekens, et al., 2010). Esta estrategia regulatoria busca conciliar los intereses de los principales gobiernos europeos que buscan limitar el crecimiento de sus presupuestos de salud encontrando vías para extender la cobertura de los mismos, con los de los grandes grupos biofarmacéuticos que buscan, por su parte, proteger sus mercados. ...
... Manufacturers of reference medicines have also adapted their production methods but have older technologies as a basis, due in part to the financial and regulatory impact of making changes to their methods. 12,13 The technical quality of biosimilar epoetins has thus been shown to exceed that of the reference medicines in some attributes; for example, Binocrit ® was shown to have lower levels of certain impurities compared with the reference medicine. 14 ...
Patent expirations for several biological products have prompted the development of alternative versions, termed ‘biosimilars’, which have comparable quality, safety and efficacy to a licensed biological medicine (also referred to as the ‘reference’ medicine). The first biosimilars developed in oncology were the supportive-care agents filgrastim and epoetin. Binocrit® (HX575) is a biosimilar version of epoetin alfa, indicated in the oncology setting for the treatment of chemotherapy-induced anemia (CIA). The process for development and approval of Binocrit® as a biosimilar included extensive analytical characterization and comparison with the reference epoetin alfa. This was followed by a clinical development program comprising phase I pharmacokinetic/pharmacodynamic studies to show bioequivalence to the reference medicine and a confirmatory phase III study to confirm therapeutic effectiveness in CIA. Since its approval, Binocrit® has been extensively used and studied in real-world clinical practice. The accumulated data confirm that Binocrit® is an effective and well-tolerated option for the treatment of CIA in patients with cancer.
... All epoetin products were found to be of high quality, although there was some degree of variation among products and batches, confirming the ''similar but not identical'' paradigm of biologicals. Of note, biosimilar manufacturers are able to take advantage of state-of-the-art methodologies, which may not be used by manufacturers of reference medicines due to the financial and regulatory impact of changing from older processes [22]. ...
Biosimilars are biological medicines that are approved via stringently defined regulatory pathways on the basis that comparable safety, efficacy, and quality have been demonstrated to their reference medicine. The advantage of biosimilar drugs is that they may be less expensive than the reference medicine, allowing for greater patient access and cost savings in already stretched healthcare budgets. Biosimilar epoetins have been available in Europe for a decade. Complementing in vitro and preclinical characterization, and pharmacokinetic/pharmacodynamic studies, clinical trials provided the additional data needed to reassure European authorities that biosimilar epoetins were sufficiently similar to the reference epoetin to warrant approval. Post-approval, real-world studies have provided further evidence that biosimilar epoetins are an effective and well-tolerated option for the treatment of renal anemia, with ongoing pharmacovigilance and observational studies monitoring for any unexpected long-term signals that have not been identified in clinical development studies. As the evidence and experience with these products increase, many of the initial concerns are being alleviated. Nephrologists can be increasingly confident that European Medicines Agency-approved biosimilars offer high-quality, affordable, effective alternatives to existing reference medicines used to treat renal anemia, and may help yield cost savings and improve patient access.
... Biosimilar manufacturers are able to take advantage of technological improvements and use state-of-the-art systems to produce and purify biosimilar proteins. This contrasts with manufacturers of reference medicines, who may be locked in to older technologies due to the financial and regulatory impact of making changes to their methods [9]. Indeed, studies have shown the quality of biosimilar epoetins and the reference medicine to be equally as good or, in some cases, they have shown the biosimilars to have lower levels of certain impurities [10,11]. ...
High-quality, safe, and effective biosimilars have the potential to increase access to biological therapies worldwide and to reduce cancer care costs. The European Medicines Agency (EMA) was the first regulatory authority to establish legislative procedures for the approval of biosimilars when they published their guidelines on similar biological medicinal products in 2005. Biosimilar epoetins were first approved in 2007, and a wealth of data has been collected over the last decade. Two biosimilar epoetins (under five commercial names) have been approved by the EMA so far. The availability of epoetin biosimilars generated discussion among the oncology community regarding prescribing these products, their efficacy, and their safety. These agents are approved only if they are shown in extensive analytical and clinical testing to have comparable quality, safety, and efficacy to the reference medicine, and real-world studies provide further data that biosimilar epoetins are an effective and well-tolerated option for the treatment of chemotherapy-induced anemia in patients with cancer. Other countries have adopted similar regulatory pathways to those in Europe and have approved epoetin biosimilars. The now extensive European experience with biosimilar epoetins should reassure regulators from other territories.
... [4][5] In some jurisdictions, demand for extensive clinical trials have been challenged as being too cautious and hindering the development of biosimilars. 6 In a forward-looking step, the EMA has recently released a concept paper to revise the clinical requirements for granulocyte colony stimulating factor, thereby proposing criteria that would allow waiver of the clinical trial requirement for a biosimilar. 7 Recently, the US Food and Drug Administration (FDA) has released guidance on clinical pharmacological data to support a demonstration of biosimilarity to a reference product, indicating the possibilities to perform only selected clinical studies when comparative analytical characterization indicates a "highly similar proposed biosimilar with fingerprint-like similarity". ...
Biosimilars are products that are similar in terms of quality, safety, and efficacy to an already licensed reference/ innovator product and are expected to offer improved affordability. The most significant source of reduction in the cost of development of a biosimilar is the reduced clinical examination that it is expected to undergo as compared to the innovator product. However, this clinical relief is predicated on the assumption that there is analytical similarity between the biosimilar and the innovator product. As a result, establishing analytical similarity is arguably the most important step towards successful development of a biosimilar. Here, we present results from an analytical similarity exercise that was performed with five biosimilars of Ristova® (rituximab, Roche), a chimeric mouse/ human monoclonal antibody biotherapeutic, that are available on the Indian market. The results show that, while the biosimilars exhibited similarity with respect to protein structure and function, there were significant differences with respect to size heterogeneity, charge heterogeneity and glycosylation pattern.
... This is obviously a somewhat simplistic analysis, with all the limits that implies, since neither the various problems nor the various bioethical arguments are watertight compartments. The close interconnections are perfectly exemplifi ed by the debate concerning the procedures for authorising the marketing of biosimilars [4,5]. These procedures involve both 'collective' organisational issues (including questions of justice) and 'individual' clinical issues (which embrace such aspects as risk-benefi t ratios). ...
... Therefore, it is not expected that, in the demonstration of biosimilarity, quality attributes such as protein structure and posttranslational modifications measured in comparative physiochemical and functional studies will be identical between the biosimilar and reference product, but highly similar. It has, on the contrary, been argued that deviations from the technology of the innovator may actually be desirable 9, 34 . This is because since the introduction of the first recombinant DNA-derived therapeutic proteins, the technology to produce and purify these products has greatly improved. ...
Therapeutic protein drugs are an important class of medicines serving patients most in need of novel therapies. Recently approved recombinant protein therapeutics have been developed to treat a wide variety of clinical indications, including cancers, autoimmunity/inflammation, exposure to infectious agents, and genetic disorders. The latest advances in protein-engineering technologies have allowed drug developers and manufacturers to fine-tune and exploit desirable functional characteristics of proteins of interest while maintaining (and in some cases enhancing) product safety or efficacy or both. In this review, we highlight the emerging trends and approaches in protein drug development by using examples of therapeutic proteins approved by the U.S. Food and Drug Administration over the previous five years (2011–2016, namely January 1, 2011, through August 31, 2016).
... These rhEPO therapeutics often contain identical protein backbone sequence, albeit decorated with differential PTMs due to different conditions in their production. Technically, it is very important, yet challenging, to quantify the similarity of these therapeutics in a robust and reproducible way [29][30][31] . We here introduce a biosimilarity score to describe the level of structural similarity of three rhEPO therapeutics, demonstrating its usage in direct assessment of the similarity of therapeutic glycoproteins. ...
Many biopharmaceutical products exhibit extensive structural micro-heterogeneity due to an array of co-occurring post-Translational modifications. These modifications often effect the functionality of the product and therefore need to be characterized in detail. Here, we present an integrative approach, combining two advanced mass spectrometry-based methods, high-resolution native mass spectrometry and middle-down proteomics, to analyse this micro-heterogeneity. Taking human erythropoietin and the human plasma properdin as model systems, we demonstrate that this strategy bridges the gap between peptide-and protein-based mass spectrometry platforms, providing the most complete profiling of glycoproteins. Integration of the two methods enabled the discovery of three undescribed C-glycosylation sites on properdin, and revealed in addition unexpected heterogeneity in occupancies of C-mannosylation. Furthermore, using various sources of erythropoietin we define and demonstrate the usage of a biosimilarity score to quantitatively assess structural similarity, which would also be beneficial for profiling other therapeutic proteins and even plasma protein biomarkers. © 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
... Whether these biologic and biosimilar molecules can be considered interchangeable is still a matter of controversy and, though there are certain criteria set by regulating authorities, these are often not clearly defined. 3 The current biologic and biosimilar brands of rituximab available in India differ in their molecular separation properties and adequate comparative studies to determine their relative biological effects do not exist. 4 Another point which deserves mention is "interchangeability" of biologic agents. ...
... Perhaps the most telling statement regarding the maturation of the field is that the EU, as of March 2005, had approved six biosimilars and recently one was approved in the United States [3] . These are biologicals that are comparable in quality, safety, and efficacy to a reference product [5]. Isolated small-molecular entities from natural products have also been a productive source of drugs. ...
... One compared the efficacy and safety of HX575 and Erypo® via IV administration to patients with anaemia secondary to chronic renal insufficiency (CRI), with 314 patients in the HX575 arm and 164 in the Erypo® arm. A second study evaluated the efficacy and safety of HX575 in 114 patients with chemotherapy-induced anaemia [Kramer, 2008;Schellekens and Moors, 2010]. ...
The loss of patents covering many biopharmaceutical/biological agents in the mid 1990s led to the introduction of a new generation of drugs: biosimilars. These new agents, produced by living cells just as the originator drugs, are chemically highly similar to endogenous human proteins; characterized by three-dimensionally complex, high molecular weight compounds. Among the first biosimilars used in haematology-oncology were erythropoietin and granulocyte colony-stimulating factor. After five years of use in clinical practice, the efficacy and safety profile of biosimilars approved by the European Medicines Agency is excellent. Over the next year or two, biosimilar monoclonal antibodies (MoAbs) will become available; the first will be rituximab and trastuzumab. Not only are MoAbs more complex in terms of molecular weight and number of amino acids than the first biosimilars, but they are also anticancer drugs, not merely supportive treatments like their predecessors. This opens up important questions. How are regulatory agencies to assess their clinical efficacy, immunogenicity and safety? Is the neoadjuvant clinical setting the best to evaluate them? What will regulatory agencies decide in terms of switching an originator molecule for a biosimilar or extrapolating efficacy results from one pathology to another? Once biosimilars of rituximab and trastuzumab are approved, several challenging issues will need to be addressed such as how to maintain appropriate pharmacovigilance, how to extrapolate across indications, and issues concerning automatic substitution. There is currently no consensus in any of these areas. This review addresses all these issues: new challenges that the oncology community will face in the near future.
... This concept paper resulted in a guideline in 2003. However, the issue remained very controversial for scientific and legal reasons [11,12]. The legal uncertainty was removed by the revision of Directive 2001/83/ EC of the European Parliament and of the Council, which came into force in 2005 [13]. ...
In the EU, the EMA has been working with biosimilars since 1998. This experience is crystallized in the extensive set of guidelines, which range from basic principles to details of clinical trials. While the guidance may appear complicated, it has enabled the development of biosimilars, of which 21 have managed to get marketing authorization. Currently marketed biosimilars in the EU have a good track record in safety and traceability. No biosimilars have been withdrawn from the market because of safety concerns. The most controversial issues with biosimilars are immunogenicity and extrapolation of therapeutic indications. The available data for these topics do not raise concerns among EU regulators. Interchangeability and substitution are regulated by individual EU member states.
... Of course, EMA rules on pharmacovigilance for biosimilars are very strict, asking for a very detailed risk management plan [56], this plan being considered even more important if extrapolation is accepted. Of course, agreement with EMA's opinion is not universal, and some experts clearly question the concept575859. In fact, considering the same original data (furnished by the manufacturer), Health Canada reached a different opinion and, while approving CT-P13 for ankylosing spondylitis and rheumatoid arthritis, did not consider adequate the extrapolation to Crohn's disease and ulcerative colitis, because differences in afucosylation could affect pathophysiological routes important in IBD [60]. ...
The goal is to review the most recent literature about biosimilars in inflammatory bowel disease (IBD), with emphasis on controversial regulatory issues.
Although biosimilars have been in use in Europe since 2005, the recent approval of CT-P13 (Remsima, Inflectra), a biosimilar of the reference infliximab (Remicade), by the European Medicines Agency (EMA) and several regulatory agencies has become a widely discussed topic in IBD, rheumatology, and other areas. Biologics are the main drivers of cost in current IBD units, and biosimilars can reduce prices thus increasing the availability of this type of treatment. The guidelines for evaluation of biosimilars are considerably different from those of the reference biologics, regulatory agencies relying on detailed in-vitro studies for defining 'high similarity', and requiring many fewer clinical data. 'High similarity' is considered sufficient for clinical trials, as the new molecule is demonstrated so structurally similar to the reference one that no significant difference in efficacy or safety is expected. Two trials in ankylosing spondylitis and rheumatoid arthritis gave no evidence of real difference and provided the required pharmacokinetic and PD data. The main controversy remains in the 'extrapolation' of indications, accepted by EMA but not by Health Canada. Position statements from several scientific societies and some expert's reviews have expressed concerns to the concept of extrapolation without direct IBD clinical evidence, whereas EMA experts have published detailed reviews supporting extrapolation.
Biosimilars in IBD are here to stay. New data are awaited to settle the controversy of extrapolation, but only the complex behavior of markets will show whether biosimilars fuel competition and extend access to biologics with significant cuts in drug costs.
Hematopoiesis is an intricate, well-regulated, and homeostatic multistep process that allows immature precursor cells in the bone marrow to proliferate, differentiate, mature, and become functional blood cells that transport oxygen and carbon dioxide; contribute to host immunity; and facilitate blood clotting. In the early 1900s, scientists recognized the presence of circulating factors that regulate hematopoiesis. Scientific progress was slow until it became possible to purify sufficient quantities to evaluate the characteristics and biologic potential of the isolated materials. The introduction of recombinant DNA technology triggered a flurry of studies and an information explosion, which confirmed that hematopoiesis is mediated by a series of hematopoietic growth factors that act individually and in various combinations involving complex feedback mechanisms. Today, many hematopoietic growth factors have been isolated; some have been studied extensively, and a few have been manufactured for clinical use. In this chapter, the HGF molecular structure and mechanism of action, its main pharmacokinetic and pharmacodynamic properties, as well as the clinical indications and main toxicities are described.
Biotherapeutics and their biosimilar versions have been flourishing in the biopharmaceutical market for several years. Structural and functional characterization is needed to achieve analytical biosimilarity through the assessment of critical quality attributes as required by regulatory authorities. The role of analytical strategies, particularly mass spectrometry-based methods, is pivotal to gathering valuable information for the in-depth characterization of biotherapeutics and biosimilarity assessment. Structural mass spectrometry methods (native MS, HDX-MS, top-down MS, etc.) provide information ranging from primary sequence assessment to higher order structure evaluation. This review focuses on recent developments and applications in structural mass spectrometry for biotherapeutic and biosimilar characterization.
Biotechnology is a growing field that can lead to sustainable progression in terms of economic development, environmental protection in accordance to the needs of public health. The bloom in healthcare biotechnology sector has put forward infinite prospects that can further nurture healthcare system. Considering the international data, there is a high concentration of businesses in Europe and the United States and shows a promising upward trend for the future. The chapter has identified some of the important areas of application in modern healthcare biotechnology and relevant challenges in implementation as well as loopholes to be filled for improvement. Biopharmaceuticals are the third generation of drugs that have applications in the cure of harmful human maladies as a miracle of modern techniques of biotechnology. However, the hurdles related to commercialization, research and development (R&D), and inexpensive nature of these treatments still get in the way of its promotion in healthcare. Similar issues are associated with development and deployment of vaccines that though save lives but come with safety concerns. Botanical drugs assure to alleviate the “dry spell” overpowering the pharmaceutical hub, but the present regulatory framework regarding herbal medication is suboptimal because it fails to incite thorough efforts to R&D of effective drugs from botanical sources. Furthermore, big data analytics has combined power of various healthcare data sources, a very useful tool in refining the healthcare system. Genomic science is readily shifting from research labs to biobanks and further to the clinical setting due to progress in data analytics. Moreover, big data facilitates the development of precision medicine and clinical practice. Omics-based technology and systems biology has considerably expanded the scope of opportunities but comes with the challenges of data security and handling. Finally, nanomedicine is the face of tomorrow's medical intervention that can revolutionize present therapies. Sustainability of healthcare industry can be promoted by encouraging new biotech business and transfer of technology. Healthcare biotech has the potential to improve the health outcomes and reduce the health inequities at a global scale; however, the complete realization of the potential benefits of this science will need sustained and concerted effort and ingenuity over a long period of time.
Los medicamentos biosimilares vienen siendo comercializados en el territorio regulatorio europeo desde hace trece años. Su comercialización no ha estado exenta de múltiples críticas, especialmente las confusiones en torno a su errónea equiparación con los medicamentos genéricos y las dudas generadas en cuanto a su posibilidad de intercambiabilidad y sustitución. En este trabajo exponemos que, gracias al desarrollo de los medicamentos biosimilares, se introduce competencia en el mercado farmacéutico y se fomenta la innovación en el sector sanitario. Además, dado que los medicamentos biosimilares se distribuyen a unos precios más económicos con respecto a los medicamentos biológicos originales, también facilitan la accesibilidad de los tratamientos a los pacientes y contribuyen a la sostenibilidad de los sistemas sanitarios públicos.
During the past few decades, immunotherapy has become a clinical reality, and an ever-increasing number of cancer patients are receiving immunologic intervention(s). The therapeutic focus has been on the development of interventions that initiate or boost an existing immune response against a patient’s tumor. Indeed, in 2013, the clinical success of immunotherapy was recognized by the editors of Science Magazine with the designation of “Breakthrough of the Year” [1]. Nonetheless, we have only just begun to understand and develop the potential of immunotherapy. Ongoing clinical studies are testing the safety and efficacy of biologic, molecular, and cellular therapeutic regimens either as stand-alone interventions or in combination with standard of care therapy. Immunoaugmenting drugs have been used to treat disease since early in the twentieth century when William B. Coley treated cancer patients with mixed bacterial toxins [2]. These studies stimulated the clinical use of microbial substances, such as Bacillus Calmette-Guérin (BCG) (bladder cancer, United States), Krestin, Picibanil and lentinan (gastric and other cancers, Japan), and Biostim and Broncho-Vaxom (recurrent infections, Europe). While these unsophisticated drugs can induce various immunopharmacological activities, their use is associated with regulatory obstacles due to impurity, lot-to-lot variability, unreliability, and adverse side effects. Similarly, traditional herbal medicines (Asia) can act as a source of active substances for immunotherapy but require purification, characterization, and synthetic production of the active moieties. Purified entities derived from natural products that are in “routine” clinical use includes Bestatin®, Taxol®, FK-506, rapamycin, deoxyspergualin, and cyclosporine, all of which are derived from natural products. The current immunotherapy focus is on the use of monoclonal antibodies such as checkpoint inhibitors and recombinant proteins (cytokines), although the utility of these drugs can be limited due to immunotoxicity and pharmacological deficiencies. However, there remains a potential utility for biological response modifiers (BRM) due to their ability to induce multiple cytokines for immune augmentation and hematopoietic restoration.
Background
Biological products comprise a most complex and diverse types of drugs that are made by living cells. The use of biological products has increased significantly in recent decades and has contributed significantly to improving the efficacy of treatment in many diseases. Patent protection for pharmaceutical products, including biological products, generally expires about 20 years after development. Expiration of patents of biological innovative medicines allows regulatory authorities to approve copies of such medicines called similar biological products (biosimilar) and to enter in clinical use. Biosimilar products are comparable but not identical with innovator biological products and are not a generic version of the innovator biological product. While biosimilars are subjected to rigorous characterization and clinical trials to demonstrate their safety and efficacy, in the case of biosimilars certain regulatory requirements apply for registration. Biosimilars are very complex and large molecules and minor changes in the manufacturing process can have important implications in their safety and efficacy profiles. To ensure that biosimilar reaches their potential in clinical application, intensive Pharmacovigilance system and risk management plan must be established to demonstrate the true similarity between the biosimilar products and original biological products. Biosimilars are part of the growing sector of the pharmaceutical industry and normally used by human beings, since manufacturers of biosimilars face some challenges in regulatory approval and manufacturing of biosimilars in European Union.
Objectives
The current manuscript will provide the information regarding the regulation of Biosimilars products with biosimilar guidelines and challenges faces by manufacturers during approved and manufacturing of biosimilar products in European Union, provide the status of approval and rejected biosimilars by EMA
Conclusion
Biosimilars may reduce costs when patent protection of biological products expires and compared to the original products, savings are not as large as seen with traditional generics. In the coming years, there will be an increasing number of biological and biosimilar products available on the market, highlighting the need for specific short- and long-term post-marketing surveillance programs for these medicines. It is essential to understand how the concept of compatibility, interchangeability will be managed and regulated in the future. An important aspect for future a high quality, clinical and non-clinical studies will be conducted to evaluate the safety and efficacy of biosimilars. Scientific guidelines on biosimilar issued by the EMA that established a process for demonstrate similarity between a biosimilar product and the innovator reference product.
Hematopoiesis is an intricate, well-regulated, and homeostatic multistep process that allows immature precursor cells in the bone marrow to proliferate, differentiate, mature, and become functional blood cells that transport oxygen and carbon dioxide; contribute to host immunity; and facilitate blood clotting. In the early 1900s, scientists recognized the presence of circulating factors that regulate hematopoiesis. Scientific progress was slow until it became possible to purify sufficient quantities to evaluate the characteristics and biologic potential of the isolated materials. The introduction of recombinant DNA technology triggered a flurry of studies and an information explosion, which confirmed hematopoiesis is mediated by a series of hematopoietic growth factors (HGF) that acts individually and in various combinations involving complex feedback mechanisms. Today, many HGF have been isolated; some have been studied extensively, and a few have been manufactured for clinical use. In this chapter, the HGF molecular structure and mechanism of action, its main pharmacokinetic and pharmacodynamic properties, as well as the clinical indications and main toxicities are described.
The ever-increasing cost of healthcare together with our improved understanding of biotech therapeutic drugs has fueled the rise of biosimilars. A step towards achieving the successful development of a biosimilar is to establish analytical similarity with the innovator drug. This is necessary so as to avail the significant reduction in clinical data required for achieving regulatory approval. A key concern is the limited understanding of how the different quality attributes (QA) affect its safety and efficacy profile. India has successfully demonstrated its ability to make affordable, high-quality pharmaceutical products for the world, particularly the small molecule generics. This fact is validated by the trend that the share of Indian made pharmaceutical products in the US market has been constantly increasing and is presently more than 30%. The question is if India can successfully replicate its success, in manufacturing complex biotherapeutic products. This chapter explores India’s journey in the field of biosimilar manufacturing with an emphasis on the regulatory aspect. Followed by a concise overview of the evolution of global regulatory guidelines, the Indian framework has been discussed in detail. Major changes introduced in the latest guidelines for similar biologics (2016) have been highlighted. Insight into the key developments related to clinical experiences and thereby addition of more sophisticated platforms to the analytical armory in the past decade for characterization of biosimilars has been given. Two recently published case studies on analytical platform approach used to establish similarity for microbial (GCSF) and mammalian product (Rituximab), in the Indian marketplace, using an array of advanced, orthogonal, high-resolution analytical methods, have been discussed. Finally, the importance post-approval pharmacovigilance as a feedback mechanism to update and improve existing regulatory framework has been outlined.
Anemia, defined as an abnormally low concentration of blood hemoglobin, can develop as a result of multiple different disease processes. Its association with adverse outcomes irrespective of its cause underscores the importance of anemia. Therapeutic strategies to correct anemia range from replacement of red blood cells in the form of blood transfusions to various medical interventions designed to correct the underlying pathophysiology of low blood hemoglobin level. Broadly, anemia can develop as a result of either the destruction of red blood cells, or their inadequate generation. This chapter provides a broad overview of various therapies used to treat anemia developing as a result of the inadequate generation of red blood cells.
The issue of comparative effectiveness research (CER) is assessed from an ethical point of view by comparison with the main ethical frameworks and by analysis of some of the relevant institutional documents. Two main conclusions emerge from the study: no ethical framework seems able to objectively and definitively assess CER; no institutional document, neither national nor international, has specifically assessed the ethical implications of CER. Nevertheless, this vacuum regarding CER raises relevant ethical concerns, thus revealing the necessity and urgency of an ethical evaluation of CER.
In September 2014, Colombia issued standards for the evaluation of biological drugs within the framework of the marketing authorization process. The Colombian approach explicitly includes a fast track for evaluating competing biologicals, which caused great national and international controversy. This article explains the context that justifies the need for this fast-track approach, critically analyzes comparability as a paradigm for the evaluation of biogenerics, and shows that Colombia's position is not isolated and is based on global regulatory trends.
Biosimilars remain a hot topic in rheumatology, and some physicians are cautious about their application in the real world. With many products coming to market and a wealth of guidelines and recommendations concerning their use, there is a need to understand the changing landscape and the real clinical and health-economic potential offered by these agents. Notably, rheumatologists will be at the forefront of the use of biosimilar monoclonal antibodies/soluble receptors. Biosimilars offer cost savings and health gains for our patients and will play an important role in treating rheumatic diseases. We hope that these lower costs will compensate for inequities in access to therapy based on economic differences across countries. Since approved biosimilars have already demonstrated highly similar efficacy, it will be most important to establish pharmacovigilance databases across countries that are adequate to monitor long-term safety after marketing approval.
Hematopoiesis is an intricate, well-regulated, and homeostatic multistep process that allows immature precursor cells in the bone marrow to proliferate, differentiate, mature, and become functional blood cells that transport oxygen and carbon dioxide; contribute to host immunity; and facilitate blood clotting. In the early 1900s, scientists recognized the presence of circulating factors that regulate hematopoiesis. It took approximately 50 years to develop in vitro cell culture systems in order to definitively prove that the growth and survival of early blood cells require the presence of specific circulating factors, called hematopoietic growth factors (HGF). The presence of many HGF with different targets at extremely small amounts in blood, bone marrow, and urine confounded the search for a single HGF with a specific activity. Scientific progress was slow until it became possible to purify sufficient quantities to evaluate the characteristics and biologic potential of the isolated materials. The introduction of recombinant DNA technology triggered a flurry of studies and an information explosion, which confirmed hematopoiesis is mediated by a series of HGF that acts individually and in various combinations involving complex feedback mechanisms. Today, many HGF have been isolated; some have been studied extensively, and a few have been manufactured for clinical use.
This chapter provides a philosophical and practical approach to biophysical studies performed during the product life cycle from molecule selection to licensure. It discusses the common biophysical methods for assessing folded structure, size heterogeneity, association state, aggregation, and subvisible particulates. Case examples are included to demonstrate the use of different types of biophysical methods in addressing product-specific questions. The limitations and advantages of the methods are outlined as the basis for their selection and for inclusion in the license application. Since significant expertise and cost are involved in conducting and interpreting most biophysical methods and data, the effort to gain biophysical knowledge needs to be balanced with the value of the information obtained in advancing products to the market.
Development of biosimilars requires an evaluation of comparability to the innovator biopharmaceutical product that includes a wide-ranging and rigorous analytical component, while the requirements for nonclinical and clinical studies of biosimilar candidates are less extensive. For innovator biologics, in vivo studies are largely designed to establish comprehensive safety, efficacy and an appropriate risk–benefit ratio; however, for biosimilars, the emphasis is shifted to establishing similarity of safety and efficacy and thus the in vivo strategies are fundamentally different. For early nonclinical testing there is still a need to ensure appropriate safety prior to entry into clinical trials, but the extent of safety data previously generated for innovator products allows for a much more focused and streamlined approach to preclinical safety evaluation. Efficient strategies have evolved as we have gained experience with the first generation of biosimilars and these strategies will continue to evolve as new and more complex biologics come off patent and enter development as biosimilar candidates. This chapter will discuss class-specific scientific considerations for early nonclinical characterization, including pharmacology, pharmacokinetics, pharmacodynamics, and safety, as well as lessons learned from developing first-generation biosimilars.
This paper engages with the complex relationship between innovation and human health and the role of regulation in bringing the two together, and, in doing so, facilitating inclusive innovation in emerging economies. After outlining the contested role of regulation, we provide two case studies: regenerative medicine regulation in Argentina, and medical devices regulation in India. While these empirically-based case studies examine different scientific sectors in different jurisdictions and therefore have different contextual foundations, they demonstrate the important link between regulatory policies and the successful promotion of innovation. Through them we challenge the oft-repeated complaint that regulation stifles innovation, demonstrating that both a lack of regulation (Argentina) and poorly conceived regulation (India) are equally damaging to innovation, to actor wellbeing, and, ultimately, to human health. We argue that devising new forms of regulation can facilitate increased innovation and thus improved technological (and economic) competitiveness (ie: social/regulatory innovation can lead to improved technological/scientific innovation).
Biosimilar drugs or drugs which are similar to reference biological drugs represent a new treatment option within the biological treatment. They are already the standard biotherapeutics option in some fields of medicine, in others as in diabetology, remain to be evaluated. The article presents the definition of biosimilar drugs and summarizes the therapeutic benefits and attitudes of agencies for drug control in the United States and Europe.Key words: biosimilar drugs - biotherapy - diabetology.
Glatiramer acetate is a disease-modifying drug approved for the treatment of relapsing-remitting multiple sclerosis. Since its discovery almost four decades ago, and in particular since the observation of its beneficial clinical effects in the late 1980s and early 1990s, numerous data have been generated and contribute pieces of a puzzle to help explain the mechanism of action of glatiramer acetate. Two major themes have emerged, namely (i) the induction of glatiramer acetate-reactive TH2 immunoregulatory cells, and (ii) the stimulation of neurotrophin secretion in the central nervous system that may promote neuronal repair.
The imminent expiry of patents on biological medicinal products, such as epoetin alfa in 2006, has significant implications for nephrology in Australia. The purpose of this review is to examine the differences between biosimilars (similar biological medicinal products) and generic low molecular weight (chemical) drugs. The approach that regulatory agencies, including the European Medicines Agency (EMEA) and the Therapeutic Goods Administration (TGA), are taking towards biosimilars is also discussed. Biosimilars differ from generic chemical drugs in many important ways, including the size and complexity of the active substance, the nature of the starting materials (cell banks, tissues and other biological products), and the complexity of the manufacturing processes. Therefore, it has been acknowledged by the EMEA that established legal and regulatory principles of 'essential similarity' that are applied to standard chemical generics cannot be readily applied to biosimilars. One of the key areas of concern with the introduction of biosimilars into the field of nephrology will be guaranteeing the safety and efficacy of biosimilars. New manufacturers will need to ensure that their biopharmaceutical has a similar efficacy and safety profile to the innovator product through more extensive clinical trials than the limited testing done for generic versions of low molecular weight chemical medicines.
New biotechnology and drug discovery technologies are facilitating the rapid expansion of the clinical drug chest, empowering clinicians with a better understanding of disease as well as novel modalities for treating patients. Important research tools and themes include genomics, proteomics, ligand-receptor interaction, signal transduction, rational drug design, biochips, and microarrays. Emerging drug classes include monoclonal antibodies, cancer vaccines, gene therapy, antisense strands, enzymes, and proteins. In this article, we review these topics and illustrate their potential impact by presenting an overview of promising drugs in the pipeline. Clinicians who use these novel treatments must become familiar with these trends.
The imminent patent expiration of many biopharmaceutical products will produce the possibility for generic versions of these therapeutic agents (i.e. biosimilars). However, there are a number of issues that will make approval of biosimilars much more complicated than the approval of generic equivalents of conventional pharmaceuticals. These issues centre on the intrinsic complexity of biopharmaceutical agents, which are recombinant proteins in most cases, and the heterogeneity of proteins produced by different manufacturing processes (i.e. differences in host cells, purification and processing, formulation and packaging). The increased occurrence of antibody (Ab)-mediated pure red cell aplasia (PRCA) associated with a change in the formulation of one particular epoetin-alpha product highlights the potential for increased immunogenicity of recombinant proteins with different formulations, or those manufactured by different processes. Thus, verification of the similarity to or substitutability of biosimilars with reference innovator biopharmaceutical products will require much more than a demonstration of pharmacokinetic similarity, which is sufficient for conventional, small molecule generic agents. Regulatory requirements for the approval of biosimilars have not yet been fully established, but preliminary guidelines from the European Agency for the Evaluation of Medicinal Products (EMEA) state that the complexity of the product, the types of changes in the manufacturing process, and differences in quality, safety and efficacy must be taken into account when evaluating biosimilars. For most products, results of clinical trials demonstrating safety and efficacy are likely to be required. In addition, because of the unpredictability of the onset and incidence of immunogenicity, extended post-marketing surveillance is also important and may be required.
Glatiramer acetate is a disease-modifying drug approved for the treatment of relapsing-remitting multiple sclerosis. Since its discovery almost four decades ago, and in particular since the observation of its beneficial clinical effects in the late 1980s and early 1990s, numerous data have been generated and contribute pieces of a puzzle to help explain the mechanism of action of glatiramer acetate. Two major themes have emerged, namely (i) the induction of glatiramer acetate-reactive TH2 immunoregulatory cells, and (ii) the stimulation of neurotrophin secretion in the central nervous system that may promote neuronal repair.
- Y Avidor
- N J Mabjeesh
- H Matzkin
Avidor, Y., Mabjeesh, N.J. & Matzkin, H. South Med. J.
96, 1174-1186 (2003).
- European Parliament
- Council
European Parliament and Council. Off. J. Eur. Union 47,
34–57 (2004).
- H Schellekens
Schellekens, H. Nephrol. Dial. Transplant. 20, 31–36
(2005).
- J E Toblli
- G Cao
- L Oliveri
- M Angerosa
- Port
Toblli, J.E., Cao, G., Oliveri, L. & Angerosa., M. Port. J.
Nephrol. Hypert. 23, 53-63 (2009).
Guideline on similar biological medicinal products. (EMEA, London
- Anonymous
Anonymous. Guideline on similar biological medicinal
products. (EMEA, London, 2005; accessed 4 March
2008). <http://www.emea.europa.eu/pdfs/human/
biosimilar/043704en.pdf>
4. Anonymous. Guideline on similar biological medicinal
- D J Crommelin
Crommelin, D.J. et al. Eur. J. Hosp. Pharm. Sci. 1,
11-17 (2005).
<http://www. emea.europa.eu/pdfs/human/opinion/19089606en. pdf> 32. Anonymous. Questions and answers on the withdrawal of the marketing authorisation application for Insulin Human Rapid Marvel; Insulin Human Long Marvel; Insulin Human 30/70 Mix Marvel
- Anonymous
Anonymous. Questions and answers on recommendation
for refusal of marketing application for alpheon. (EMEA,
London, 2006; accessed 3 March 2008). <http://www.
emea.europa.eu/pdfs/human/opinion/19089606en.
pdf>
32. Anonymous. Questions and answers on the withdrawal
of the marketing authorisation application for Insulin
Human Rapid Marvel; Insulin Human Long Marvel;
Insulin Human 30/70 Mix Marvel. (EMEA, London;
2008; accessed 28 February 2008). <http://www.emea.
europa.eu/humandocs/PDFs/EPAR/insulinhumanrapidm
arvel/419308en.pdf>
Anonymous. Questions and answers on the withdrawal of the marketing authorisation application for Insulin Human Rapid Marvel
- Anonymous
Anonymous. Questions and answers on recommendation
for refusal of marketing application for alpheon. (EMEA,
London, 2006; accessed 3 March 2008). <http://www.
emea.europa.eu/pdfs/human/opinion/19089606en.
pdf>
32. Anonymous. Questions and answers on the withdrawal
of the marketing authorisation application for Insulin
Human Rapid Marvel; Insulin Human Long Marvel;
Similar biological medicinal products containing biotechnology-derived proteins as active substance: Non-clinical and clinical issues
- Anonymous
Anonymous. Guideline on similar biological medicinal
products containing biotechnology-derived proteins as
active substance: quality issues. (EMEA, London, 2006;
Annex to guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues guidance on similar medicinal products containing somatropin
- Anonymous
Anonymous. Annex to guideline on similar biological
medicinal products containing biotechnology-derived
Questions and answers on recommendation for refusal of marketing application for alpheon
- Anonymous
Questions and answers on the withdrawal of the marketing authorisation application for Insulin Human Rapid Marvel; Insulin Human Long Marvel; Insulin Human 30/70 Mix Marvel
- Anonymous
Annex to guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues guidance on similar medicinal products containing recombinant granulocyte-colony stimulating factor
- Anonymous