BIOSIMILAR: WHAT IT IS NOT Fernando de Mora, MBA, PhD
Professor of Pharmacology Dept. of Pharmacology, Therapeutics and Toxicology Universitat Autònoma de Barcelona, Barcelona (Spain)
Running head: Biosimilar concept
Keywords: biobetter, biologic, biosimilar, biotechnology-derived medicine, generic, nonoriginal biologic, regulation, stand-alone
Wordcount: 3.604 Figures: 2 Tables: 0
Corresponding author address / contact details: Fernando de Mora Dpto. de Farmacología (Edificio V) Universidad Autónoma de Bellaterra (Campus Bellaterra) 08193 Bellaterra (Barcelona) / Spain
Phone: +34 935813320 Email: [email protected] This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/bcp.12656
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SUMMARY A biosimilar is a high-quality biological medicine shown to be equivalent to an original product. The European Medicines Agency (EMA) paved the way in the regulatory arena by creating a safeguarding framework for biosimilars development. Biosimilar is thus a regulatory term that alludes to the evidence-based studies required to demonstrate such equivalence. They are therefore not innovative products, but the pathway laid down by the EMA for their approval represented a new paradigm. This has brought some confusion, and has casted doubts among healthcare professionals about the scientific evidence behind their authorization. Many papers have been published to clarify the concept, and to reassure those professionals, but misconceptions still arise frequently. Unfortunately, this prevents biosimilars from deploying their full therapeutic added value. This paper is intended to approach those misconceptions from a new angle; by explaining what a biosimilar is not…and why. A biosimilar is neither a generic, nor an original product. It is not a biobetter or a ―stand-alone‖. Therefore, it should not be managed as such therapeutically, commercially, or from a healthcare policy viewpoint. The EMA’s criteria were acknowledged by other agencies, but a significant regulatory gap with a vast majority of regulatory bodies still remains. This leaves room for the so-called non-original biologics (NOB) to be launched in many regions. Raising awareness of what a biosimilar is, and what it is not, will generate trust among healthcare professionals in biosimilars, and will ultimately benefit patients.
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TEXT
Background: the biosimilar scenario The expression ―similar biological medicinal product‖ was coined by the European Commission (EC) and was officially used for the first time in a 2001 Commission’s Directive as amended [1]. It was then shortened to ―biosimilar‖ in a 2005 overarching European Medicines Agency (EMA) guideline [2]. A word also adopted by the US Food and Drug Administration (FDA) years later [3], and increasingly used among healthcare professionals. However, too often mistakingly. There are two principal sources of confusion. The first is related to the very concept. Although the term biosimilar is now defined with considerable accuracy by updated EMA guidelines, and excellent scientific papers [7-9], it may be thought of straightforwardly as a biological medicine shown to be equivalent to a reference original biological product. The second source of confusion refers to the studies needed to demonstrate such equivalence. Questioning the studies undertaken to prove similarity under the EC legal basis, accounts for the slow penetration rate of such products in Europe [4-6], despite being the most experienced region in terms of biosimilars regulation and utilization. Biosimilar is thus a regulatory concept with clinical implications. Its incorrect use, or a biased understanding, causes an enormous harm to the patient. Indeed, one of biosimilars’ added value is their contribution to the sustainability of healthcare systems, and to the access of more patients to otherwise often unaffordable treatments. This article is neither intended to analyze the clinical and socio-economical impact of such medicines [10, 11], nor to thoroughly revise the EMA biosimilars guidance [12, 13]. It is rather intended to help clinicians and scientists interpret the biosimilar concept by going beyond the boundaries of the regulatory language and by using a different approach; by defining what a biosimilar is not. Through this process of elimination, we hope to reassure patients, doctors, pharmacists, nurses and healthcare professionals in general, including healthcare administrators, that the granting of marketing authorization to a biosimilar product in the European Union (EU) is a result of logical thinking based on current scientific evidence. Clinical pharmacologists are in an advantageous position to acknowledge it, given the fact that they gather a unique expertise that combines knowledge
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about regulation and science of drug development, a medical education background, and daily collaboration with medical specialists exposed to biosimilar products. We thus advocate a contribution of clinical pharmacologists to such reassurance. (Figure 1 provides an overview of the conceptual discrimination laid down in this paper).
A biosimilar is not a generic Unlike biologics, the manufacture of chemically-synthesized medicinal products (or smallmolecule drugs, as they are commonly called) such as ibuprofen, atorvastatin, and methotrexate for example, does not require cells, animals or complex biological systems. A chemicallysynthesized medicinal product that is equivalent to another in terms of quality, efficacy, and safety is known as a generic drug product [16]. Generics and biosimilars differ considerably with respect to the studies taken to demonstrate equivalence towards a reference product. When no biological sources are involved in the manufacture of a medicinal product, it is possible in general to produce a structurally virtually identical active substance in spite of changes in the manufacturing conditions. When developing a generic, a company can thus, both synthesize the same compound and carry out analytical studies to acknowledge such molecular identity. Once this has been demonstrated, only a bioequivalence study in humans is needed to prove therapeutic equivalence (Figure 2). This is achieved through a comparative bioavailability (pharmacokinetic) study that shows that the rate and extent to which the active substance reaches the circulation is equivalent in both drugs. If so, it can then be assumed on scientific grounds that both, the original and the generic candidate products will share the safety and the efficacy profile [16]. Little or none of the above holds for biosimilars. The regulatory pathway pursued to demonstrate equivalence is generally longer and more complex for biosimilar than for generic candidates, because of the inherent variability to biotech products. A biosimilar is a biological product (or biologic), i.e. a product, the active substance of which is produced by, or extracted from, a biological source, and that needs for its characterization and the determination of its quality, a combination of physico-chemical-biological testing, together with the production process and its
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control (1). The list of biologics is long and growing. Of note are erythropoietin (EPO), interferons, granulocyte colony-stimulating factor (GCSF), either pegylated or not, insulin, growth hormone (somatropin), blood derivatives such as coagulation factors, low-molecularweight heparins (LMWH), vaccines, and numerous monoclonal antibodies. Most of the biologics currently available are biotechnology-derived medicinal products, or simply biotech medicines; i.e. biological medicines whose production requires prior genetic modification or molecular engineering. For example, factor VIII, used to treat hemophilia, can be extracted from human blood without the need for engineering [14], or be produced in genetically modified cells [15]. Furthermore, most biotechnological medicines currently available are recombinant proteins, a category that includes recombinant monoclonal antibodies, rHu-EPO, rHu-insulin, rHusomatropin, rHu-GCSF (i.e. filgrastim), rHu-interferons, etc. Proteins are large, structurally and functionally complex molecules. In addition to the inherent variability to biological products, recombinant therapeutic proteins are highly sensitive to environmental conditions during production, storage and/or use (unstable). Their composition is thus microheterogeneous, i.e. the product comprises a diversity of molecular isoforms. This implies that batch-to-batch variation is a particular problem for original biotech products; notably when its manufacturing process is subject to modifications, however minor (e.g. changes in pH, temperature, production volume, etc.) [17]. Such molecular conformational changes may in turn impact in the biological medicine’s efficacy and/or safety [17, 18]. Regulatory measures have been taken for companies to ascertain that procedural modifications do not have relevant therapeutic implications [19, 20].
Accordingly, although thanks to modern-day technology it is now possible to reliably replicate a complex recombinant protein, comparability studies beyond just molecular equivalence and bioequivalence are needed to exclude any significant difference between a biosimilar candidate and its original product counterpart [21]. When embarking on the development of a biosimilar, a pharmaceutical company faces two main hurdles:
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The difficulty of exactly mimicking the molecular structure of the original biological product, and of replicating its microheterogeneous composition, by means of a new production process
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The unavailability of a single analytical test that can unequivocally demonstrate the structural equivalence of both products
Based on these facts, EMA guidance advocates thorough head-to-head structural and biological activity studies between the reference product and the biosimilar candidate [13]. Such early quality studies provide the most sensitive comparability set of assays for picking up potential differences (Figure 2). In other words, if the combined structural and functional comparability assessment does not reveal a significant divergence, it is highly improbable that subsequent trials in patients would uncover any difference in safety and/or efficacy [22]. In spite of this, based on the ―totality of evidence‖ assessment, further comparative clinical studies in patients are usually required to confirm comparable efficacy, and address key safety concerns such as immunogenicity. Head-to-head nonclinical and bioequivalence studies are also required, and, finally, an active post-marketing surveillance plan (pharmacovigilance) needs to be put in place [12, 23].
The EMA has thus established a rational scientifically-based regulatory framework that ensures that a biosimilar candidate is indeed equivalent to the original product in terms of quality, safety and efficacy, and hence in its benefit-to-risk balance. Such framework is much more demanding that that required for generic products (Figure 2). In fact, in economic terms, the investment needed to develop a fully fledged biosimilar is generally between 20 and 100 times that required for a generic [24]. Hence, the terms biosimilar and generic should not be used interchangeably, and it is inaccurate to refer to a biosimilar as a biogeneric, since the latter would imply that insufficiently stringent development requirements would have been followed.
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A biosimilar is not an original product The term ―biologic‖ (or ―biotech product‖) is often set against the term ―biosimilar‖. Even stakeholders, in an attempt to simplify matters, erroneously draw a distinction between both concepts [25-27]. This discredits to some extent the value of biosimilars, because a biosimilar is in fact a biologic. What may be distinguished are the concepts ―original biologic‖ and ―similar biologic‖ (i.e. biosimilar). Whether a biologic is classified as an original product or as a biosimilar is just related to the degree of innovation of the product and/or its therapeutic application. Briefly, an original product may be either a new molecular entity, or a slightly modified existing molecule. To some extent the level of innovation correlates with the level of uncertainty of the risk-to-benefit outcome. In turn, the level of uncertainty will drive the applicable regulatory criteria, i.e. the type and number of studies that the product will be required to undergo during its development. In brief, a fully new compound/target needs to be subject to a full characterization, and preclinical assessment prior to enter clinical R&D, but above all, to a very extensive clinical development program, i.e. a so-called complete dossier will need to be built (Figure 2). In contrast, a biosimilar is aimed at replicating a well known reference original medicinal product. It is intended to contain essentially the same active substance as the original product, to come in the same pharmaceutical form, and to be administered via the same route at the same dose for the same, or fewer, indications. Indeed a pharmaceutical company planning to develop a biosimilar starts out with several advantages. It knows the primary structure (i.e. the amino acid sequence) of the original product, and its expected biological activity, it can acquire the reference product to analyze its composition, and assess in detail structurally and functionally, its batch-to-batch variation, and above all, it has access to a wide range of real world clinical data on the original product’s safety and efficacy. These historical data help determine what evidence and which studies will be required for the biosimilar candidate. Regulators responsible for deciding whether a biosimilar candidate is indeed equivalent, have an extensive knowledge of the original reference product that often reaches beyond publicly available information. The company can therefore draw on this pool of knowledge to design a highly customized evidence-based development plan, certain phases of which can be tailored to
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the characteristics of the original product, and to the knowledge that has been amassed over the years while still ensuring the necessary guarantees. The importance of the clinical experience with the reference product is clearly illustrated by the case of an original EPO [28]. Problems associated with immunogenicity, and its possible adverse consequences only became fully evident with the use of the original product. Serious problems detected with the innovative product as a result of an apparently irrelevant change in the production process (reformulation) alerted the regulatory authorities to the need to establish strict requirements regarding the evaluation of immunogenicity for both original and biosimilar EPO products. In fact, immunogenicity needs to be assessed for any biosimilar candidate, and the duration and the nature of this assessment for the most part relies on the clinical experience with the corresponding reference product [29].
It may be technically complex to replicate the molecular structure of a biologic but, once this has been confidently achieved and demonstrated, the uncertainty regarding its pharmacological behavior is appreciably lower than for any innovative product. Therefore, by its own nature, a biosimilar bears a significantly lower risk for humans and higher chance of successfully completing clinical phases. The regulatory requirements need to be customized accordingly. As brought up earlier, the burden of the demonstration of equivalence therefore lies in the very exhaustive analytical comparison (quality studies), because, given its sensitivity, any possible structural or functional difference is most likely to be picked up during this initial comparability exercise. Accordingly, the module that addresses quality attributes is considerably more extensive for biosimilars than for original products (Figure 2). It is thus scientifically sound, and ethical, not to require for biosimilar candidates a complete dossier, but rather a customized development program. The goal of biosimilar studies is not to demonstrate safety and efficacy per se, but rather to prove that safety and efficacy are comparable to the originator’s. Hence, the clinical trials needed in the light of a biosimilar development, may differ substantially from those requested for an innovative product. For instance, the number of phase III patients recruited, the clinical endpoints assessed, or the indications tested, may vary from the reference product [22]
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A biosimilar is neither a biobetter nor a “stand-alone” As discussed above, the more innovative the biopharmaceutical seeking marketing authorization, the more demanding will the regulators be in requiring proof and guarantees that the product’s benefits outweighs its risks. On the contrary, biosimilars are not innovative in terms of therapeutic target, indication, administration route or regimen (certain technological innovation might be introduced to improve production or formulation). Not all products, however, fall into the fully innovative or the biosimilar extremes.
Biobetter versus biosimilar Although the boundaries are sometimes fuzzy, and the subject is a constant source of debate, a biological product whose active ingredient or formulation is slightly modified in some way to improve efficacy, or ameliorate its therapeutic regimen, cannot be developed as a biosimilar. As protein technology advances, the practice of altering molecules to achieve favorable pharmacokinetic or pharmacodynamic variations will become more common [30, 31]. For instance, improving a drug’s half-life or its potency changes the dosing regimen, but does not change the therapeutic target or indication. In such cases, it would appear reasonable for the company to perform head-to-head studies with the unaltered product to demonstrate the alleged clinical benefits. The goal of this comparison, clearly, should not be to demonstrate equivalence, but to prove that the new product is clinically superior in some respect. The product would therefore not qualify for a biosimilar application. Products of this type are typically called biobetters, for obvious reasons. However, to my knowledge this is not a regulatory term, the distinction between biobetters and biosimilars is pertinent, as the two types of products are too frequently lumped together. Technologically, the field is still highly experimental. Insulin analogs (as opposed to natural insulins), and darbepoetin (as opposed to EPO) were in fact pioneering biobetters. In the coming years, we are likely to see an increasing number of minor modifications to recombinant proteins claiming to improve the therapeutic attributes of their original counterpart.
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―Stand-alone‖ versus biosimilar application Eporatio is an erythropoietin that was approved by the European Commission in 2009 [32]. Because it is a rHuEPO, its amino acid sequence is identical to that of original products containing human EPO, and also to that of more recent biosimilars. In spite of not bearing a new active substance, Eporatio is not a biosimilar, because the pharmaceutical company that developed the drug chose not to undertake that regulatory path, i.e. not to experimentally demonstrate that Eporatio was comparable to an original product. For commercial reasons, or perhaps following regulators’ recommendations based on preliminary comparability data, a pharmaceutical company may decide not to pursue the biosimilar regulatory pathway despite the apparent similarity with a biological already in the market. Instead it chooses a ―stand-alone‖ application, which is envisaged by the EMA as an alternative in its recently adopted overarching Guideline on Similar Biological Medicinal Products [33]. It should be noted that stand-alone application is a very ample concept that includes any request relying on its own data for approval, i.e. not making reference to the dossier of another medicinal product. Eporatio is therefore another EPO whose authorization was not based on the demonstration of equivalence to an original reference EPO.
The distinction between biobetter and ―stand-alone‖ can in some cases be arbitrary. In fact, both qualify to some extent as original products. In any case, although in such circumstances the company has not set out to replicate an existing product, because these products share targets and indications, and because they are analogous in other respects to existing products, they are sometimes wrongly assumed to be biosimilars.
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A biosimilar is not a Non-Original Biological (NOB) As already mentioned, the EC paved the way in issuing a biosimilars legal framework (1), and EMA guidance for the approval of biosimilars, based on the principle of comparability laid down in 1998 (34). The groundwork laid by the EMA helped institutions such as the World Health Organization (WHO), and a few reference regulatory bodies to establish their own requirements and criteria, which are in essence analogous to the European agency’s. Although the trend among other national regulatory agencies that evaluate marketing authorization dossiers for biotechnological medicinal products is to embrace the standards established by the EMA, many such agencies are not compliant with the evidence-based standards set up by European authorities. Scientific evidence drives the need for EMA-like standards, and less stringent requirements may constitute a risk for patients.
While the biopharmaceutical industry is clearly dominated by companies from the most developed countries, several emerging economies in Latin America and Asia (e.g. Brazil, Argentina, Mexico, India, and China) have gained ground in biotechnological know-how. This growing strength has triggered national debates that have led to the adoption of legal measures, and the publication of guidelines in these and other countries to regulate the development of products claimed to be analogous to original biologics. Although in some cases the regulatory measures established mirror the intentions of the EMA, they often do not yet meet its standards, and, perhaps more troublingly, they are not always diligently applied. This regulatory gap allows for biologics whose biosimilarity has not been proved on the basis of sound science-based regulatory guidance, to receive marketing authorization. For this reason, some products approved in countries beyond the EU, the US, Canada, Japan, Australia, and possibly other regions, are increasingly being referred to as non-original biologicals (NOB), or non-comparable biologicals [4].
Studies of some NOB licensed in countries with a less stringent regulation have uncovered considerable structural differences with respect to original products [35, 36] that would not have
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passed muster in Europe. It is possible that the identified structural differences will have an impact on safety or efficacy, but it is often difficult to prove it, for one because the pharmacovigilance systems in many of these countries are inadequate or nonexistent. Nonetheless, studies monitoring and analyzing the immunogenic capacity of some of these NOB point to troubling differences with respect to the mirrored original products [37, 38]. Some authors have also called these products ―intended copies‖ to suggest either that their equivalence has not been successfully demonstrated, or that the studies used to demonstrate their comparability may be insufficiently rigorous. Patients administered NOB face a greater risk than they would with either original products or with EU-authorized biosimilars. South Korea deserves mention as an economy with a growing biotech industry. The South Korean pharmaceutical company Celltrion was the first to successfully develop a biosimilar to Remicade [39]. The active substance is infliximab, an anti-TNF monoclonal antibody used to treat rheumatoid arthritis and Crohn’s disease among other diseases. With this approval, two milestones were reached: Celltrion became the first company to achieve marketing authorization for a biosimilar to a monoclonal antibody, and the Asian biotech industry gained a foothold as a supplier to highly regulated markets. This sets the stage for other companies from emerging countries to follow, but for the time being, the biosimilar scenario is dominated by companies from leading economies.
NOB should therefore not be called biosimilars. Some healthcare professionals in the EU have expressed fear regarding the possible entry of NOB. Such fear is unfounded; a NOB, as it stands, would not make its way towards patients in the EU. The EMA, with its rigorous standards, would not approve them, nor probably would Canada, Australia, Japan, or the United States, as they have similar requirements to Europe.
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CONCLUDING REMARKS No biopharmaceutical product—whether original or biosimilar—is risk-free, but when a biosimilar is granted marketing authorization in a highly-regulated region such as the EU, the approval is founded on a solid science-based development process that ensures a comparable risk-to-benefit balance [40]. Hence, a biosimilar approved under the auspices of the EMA, or a regulatory body with similar criteria, is simply another high quality biological that, once authorized, follows its own therapeutic and commercial track. There are no grounds to believe that the use of a biosimilar carries more risks for the patient than that of the corresponding reference original product. Since the first biosimilar was authorized in 2006 by the EC, no clinical alerts have raised red flags about the established EMA biosimilar pathway. This should not come as a surprise since the Agency has put in place stringent evidence-based criteria strongly focused on ensuring patient’s safety [40]. Thinking otherwise has unfairly caused a negative impact on the prescription of biosimilars, and has ultimately affected or delayed the access of more patients to biological therapies. Extending the reach of biosimilars is as socially and economically desirable as fostering biopharmaceutical innovation—and the introduction of biosimilars does undoubtedly contribute to such innovation. Beyond the slow penetration, a misconception as to how biosimilars are studied and what they represent may further undermine their therapeutic added value. Indeed, misinterpreting the biosimilar concept is not just a terminology matter. Biosimilars are neither generics nor ―stand-alones‖ or biobetters, and should not be managed as such from a therapeutic, a commercial, an economic, or a healthcare policy perspective. A biosimilar, by its very nature, is not an innovative product, but it still is viewed as an innovative concept by many because it represented a considerable shift of paradigm. Raising awareness of what biosimilars are, and what they are not, generates trust among healthcare professionals in these products. Clinical pharmacologists are ideally positioned to contribute to such trust.
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Figure 1 Conceptual discrimination between biosimilar and non-biosimilars on the basis of regulatory and non-regulatory criteria Only products claimed to be highly similar to a reference original biologic, and whose similarity is demonstrated through a thorough EMA-like comparability exercise** should qualify as biosimilars (this figure is not intended to be an accurate account of the available alternative regulatory pathways).
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Figure 2 Comparative EMA requirements for biosimilar development versus studies envisaged for generics, original products, and possibly biologics after manufacturing changes. The regulatory requirements rely to a large extent on the background knowledge sustaining the product development. In the case of a fully original biologic application, there is no accumulated evidence prior to undertaking the development program; hence a complete dossier will be requested. It is to note that, given the particularly high sensitivity of structural and biological activity studies for picking up potential differences, the biosimilar quality module is the most extensive. Finally, it has to be borne in mind that this is a general framework; the actual specific requirements will need to be established on a case-by-case basis.
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Professor of Pharmacology Dept. of Pharmacology, Therapeutics and Toxicology Universitat Autònoma de Barcelona, Barcelona (Spain)
Running head: Biosimilar concept
Keywords: biobetter, biologic, biosimilar, biotechnology-derived medicine, generic, nonoriginal biologic, regulation, stand-alone
Wordcount: 3.604 Figures: 2 Tables: 0
Corresponding author address / contact details: Fernando de Mora Dpto. de Farmacología (Edificio V) Universidad Autónoma de Bellaterra (Campus Bellaterra) 08193 Bellaterra (Barcelona) / Spain
Phone: +34 935813320 Email: [email protected] This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/bcp.12656
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SUMMARY A biosimilar is a high-quality biological medicine shown to be equivalent to an original product. The European Medicines Agency (EMA) paved the way in the regulatory arena by creating a safeguarding framework for biosimilars development. Biosimilar is thus a regulatory term that alludes to the evidence-based studies required to demonstrate such equivalence. They are therefore not innovative products, but the pathway laid down by the EMA for their approval represented a new paradigm. This has brought some confusion, and has casted doubts among healthcare professionals about the scientific evidence behind their authorization. Many papers have been published to clarify the concept, and to reassure those professionals, but misconceptions still arise frequently. Unfortunately, this prevents biosimilars from deploying their full therapeutic added value. This paper is intended to approach those misconceptions from a new angle; by explaining what a biosimilar is not…and why. A biosimilar is neither a generic, nor an original product. It is not a biobetter or a ―stand-alone‖. Therefore, it should not be managed as such therapeutically, commercially, or from a healthcare policy viewpoint. The EMA’s criteria were acknowledged by other agencies, but a significant regulatory gap with a vast majority of regulatory bodies still remains. This leaves room for the so-called non-original biologics (NOB) to be launched in many regions. Raising awareness of what a biosimilar is, and what it is not, will generate trust among healthcare professionals in biosimilars, and will ultimately benefit patients.
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TEXT
Background: the biosimilar scenario The expression ―similar biological medicinal product‖ was coined by the European Commission (EC) and was officially used for the first time in a 2001 Commission’s Directive as amended [1]. It was then shortened to ―biosimilar‖ in a 2005 overarching European Medicines Agency (EMA) guideline [2]. A word also adopted by the US Food and Drug Administration (FDA) years later [3], and increasingly used among healthcare professionals. However, too often mistakingly. There are two principal sources of confusion. The first is related to the very concept. Although the term biosimilar is now defined with considerable accuracy by updated EMA guidelines, and excellent scientific papers [7-9], it may be thought of straightforwardly as a biological medicine shown to be equivalent to a reference original biological product. The second source of confusion refers to the studies needed to demonstrate such equivalence. Questioning the studies undertaken to prove similarity under the EC legal basis, accounts for the slow penetration rate of such products in Europe [4-6], despite being the most experienced region in terms of biosimilars regulation and utilization. Biosimilar is thus a regulatory concept with clinical implications. Its incorrect use, or a biased understanding, causes an enormous harm to the patient. Indeed, one of biosimilars’ added value is their contribution to the sustainability of healthcare systems, and to the access of more patients to otherwise often unaffordable treatments. This article is neither intended to analyze the clinical and socio-economical impact of such medicines [10, 11], nor to thoroughly revise the EMA biosimilars guidance [12, 13]. It is rather intended to help clinicians and scientists interpret the biosimilar concept by going beyond the boundaries of the regulatory language and by using a different approach; by defining what a biosimilar is not. Through this process of elimination, we hope to reassure patients, doctors, pharmacists, nurses and healthcare professionals in general, including healthcare administrators, that the granting of marketing authorization to a biosimilar product in the European Union (EU) is a result of logical thinking based on current scientific evidence. Clinical pharmacologists are in an advantageous position to acknowledge it, given the fact that they gather a unique expertise that combines knowledge
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about regulation and science of drug development, a medical education background, and daily collaboration with medical specialists exposed to biosimilar products. We thus advocate a contribution of clinical pharmacologists to such reassurance. (Figure 1 provides an overview of the conceptual discrimination laid down in this paper).
A biosimilar is not a generic Unlike biologics, the manufacture of chemically-synthesized medicinal products (or smallmolecule drugs, as they are commonly called) such as ibuprofen, atorvastatin, and methotrexate for example, does not require cells, animals or complex biological systems. A chemicallysynthesized medicinal product that is equivalent to another in terms of quality, efficacy, and safety is known as a generic drug product [16]. Generics and biosimilars differ considerably with respect to the studies taken to demonstrate equivalence towards a reference product. When no biological sources are involved in the manufacture of a medicinal product, it is possible in general to produce a structurally virtually identical active substance in spite of changes in the manufacturing conditions. When developing a generic, a company can thus, both synthesize the same compound and carry out analytical studies to acknowledge such molecular identity. Once this has been demonstrated, only a bioequivalence study in humans is needed to prove therapeutic equivalence (Figure 2). This is achieved through a comparative bioavailability (pharmacokinetic) study that shows that the rate and extent to which the active substance reaches the circulation is equivalent in both drugs. If so, it can then be assumed on scientific grounds that both, the original and the generic candidate products will share the safety and the efficacy profile [16]. Little or none of the above holds for biosimilars. The regulatory pathway pursued to demonstrate equivalence is generally longer and more complex for biosimilar than for generic candidates, because of the inherent variability to biotech products. A biosimilar is a biological product (or biologic), i.e. a product, the active substance of which is produced by, or extracted from, a biological source, and that needs for its characterization and the determination of its quality, a combination of physico-chemical-biological testing, together with the production process and its
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control (1). The list of biologics is long and growing. Of note are erythropoietin (EPO), interferons, granulocyte colony-stimulating factor (GCSF), either pegylated or not, insulin, growth hormone (somatropin), blood derivatives such as coagulation factors, low-molecularweight heparins (LMWH), vaccines, and numerous monoclonal antibodies. Most of the biologics currently available are biotechnology-derived medicinal products, or simply biotech medicines; i.e. biological medicines whose production requires prior genetic modification or molecular engineering. For example, factor VIII, used to treat hemophilia, can be extracted from human blood without the need for engineering [14], or be produced in genetically modified cells [15]. Furthermore, most biotechnological medicines currently available are recombinant proteins, a category that includes recombinant monoclonal antibodies, rHu-EPO, rHu-insulin, rHusomatropin, rHu-GCSF (i.e. filgrastim), rHu-interferons, etc. Proteins are large, structurally and functionally complex molecules. In addition to the inherent variability to biological products, recombinant therapeutic proteins are highly sensitive to environmental conditions during production, storage and/or use (unstable). Their composition is thus microheterogeneous, i.e. the product comprises a diversity of molecular isoforms. This implies that batch-to-batch variation is a particular problem for original biotech products; notably when its manufacturing process is subject to modifications, however minor (e.g. changes in pH, temperature, production volume, etc.) [17]. Such molecular conformational changes may in turn impact in the biological medicine’s efficacy and/or safety [17, 18]. Regulatory measures have been taken for companies to ascertain that procedural modifications do not have relevant therapeutic implications [19, 20].
Accordingly, although thanks to modern-day technology it is now possible to reliably replicate a complex recombinant protein, comparability studies beyond just molecular equivalence and bioequivalence are needed to exclude any significant difference between a biosimilar candidate and its original product counterpart [21]. When embarking on the development of a biosimilar, a pharmaceutical company faces two main hurdles:
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The difficulty of exactly mimicking the molecular structure of the original biological product, and of replicating its microheterogeneous composition, by means of a new production process
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The unavailability of a single analytical test that can unequivocally demonstrate the structural equivalence of both products
Based on these facts, EMA guidance advocates thorough head-to-head structural and biological activity studies between the reference product and the biosimilar candidate [13]. Such early quality studies provide the most sensitive comparability set of assays for picking up potential differences (Figure 2). In other words, if the combined structural and functional comparability assessment does not reveal a significant divergence, it is highly improbable that subsequent trials in patients would uncover any difference in safety and/or efficacy [22]. In spite of this, based on the ―totality of evidence‖ assessment, further comparative clinical studies in patients are usually required to confirm comparable efficacy, and address key safety concerns such as immunogenicity. Head-to-head nonclinical and bioequivalence studies are also required, and, finally, an active post-marketing surveillance plan (pharmacovigilance) needs to be put in place [12, 23].
The EMA has thus established a rational scientifically-based regulatory framework that ensures that a biosimilar candidate is indeed equivalent to the original product in terms of quality, safety and efficacy, and hence in its benefit-to-risk balance. Such framework is much more demanding that that required for generic products (Figure 2). In fact, in economic terms, the investment needed to develop a fully fledged biosimilar is generally between 20 and 100 times that required for a generic [24]. Hence, the terms biosimilar and generic should not be used interchangeably, and it is inaccurate to refer to a biosimilar as a biogeneric, since the latter would imply that insufficiently stringent development requirements would have been followed.
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A biosimilar is not an original product The term ―biologic‖ (or ―biotech product‖) is often set against the term ―biosimilar‖. Even stakeholders, in an attempt to simplify matters, erroneously draw a distinction between both concepts [25-27]. This discredits to some extent the value of biosimilars, because a biosimilar is in fact a biologic. What may be distinguished are the concepts ―original biologic‖ and ―similar biologic‖ (i.e. biosimilar). Whether a biologic is classified as an original product or as a biosimilar is just related to the degree of innovation of the product and/or its therapeutic application. Briefly, an original product may be either a new molecular entity, or a slightly modified existing molecule. To some extent the level of innovation correlates with the level of uncertainty of the risk-to-benefit outcome. In turn, the level of uncertainty will drive the applicable regulatory criteria, i.e. the type and number of studies that the product will be required to undergo during its development. In brief, a fully new compound/target needs to be subject to a full characterization, and preclinical assessment prior to enter clinical R&D, but above all, to a very extensive clinical development program, i.e. a so-called complete dossier will need to be built (Figure 2). In contrast, a biosimilar is aimed at replicating a well known reference original medicinal product. It is intended to contain essentially the same active substance as the original product, to come in the same pharmaceutical form, and to be administered via the same route at the same dose for the same, or fewer, indications. Indeed a pharmaceutical company planning to develop a biosimilar starts out with several advantages. It knows the primary structure (i.e. the amino acid sequence) of the original product, and its expected biological activity, it can acquire the reference product to analyze its composition, and assess in detail structurally and functionally, its batch-to-batch variation, and above all, it has access to a wide range of real world clinical data on the original product’s safety and efficacy. These historical data help determine what evidence and which studies will be required for the biosimilar candidate. Regulators responsible for deciding whether a biosimilar candidate is indeed equivalent, have an extensive knowledge of the original reference product that often reaches beyond publicly available information. The company can therefore draw on this pool of knowledge to design a highly customized evidence-based development plan, certain phases of which can be tailored to
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the characteristics of the original product, and to the knowledge that has been amassed over the years while still ensuring the necessary guarantees. The importance of the clinical experience with the reference product is clearly illustrated by the case of an original EPO [28]. Problems associated with immunogenicity, and its possible adverse consequences only became fully evident with the use of the original product. Serious problems detected with the innovative product as a result of an apparently irrelevant change in the production process (reformulation) alerted the regulatory authorities to the need to establish strict requirements regarding the evaluation of immunogenicity for both original and biosimilar EPO products. In fact, immunogenicity needs to be assessed for any biosimilar candidate, and the duration and the nature of this assessment for the most part relies on the clinical experience with the corresponding reference product [29].
It may be technically complex to replicate the molecular structure of a biologic but, once this has been confidently achieved and demonstrated, the uncertainty regarding its pharmacological behavior is appreciably lower than for any innovative product. Therefore, by its own nature, a biosimilar bears a significantly lower risk for humans and higher chance of successfully completing clinical phases. The regulatory requirements need to be customized accordingly. As brought up earlier, the burden of the demonstration of equivalence therefore lies in the very exhaustive analytical comparison (quality studies), because, given its sensitivity, any possible structural or functional difference is most likely to be picked up during this initial comparability exercise. Accordingly, the module that addresses quality attributes is considerably more extensive for biosimilars than for original products (Figure 2). It is thus scientifically sound, and ethical, not to require for biosimilar candidates a complete dossier, but rather a customized development program. The goal of biosimilar studies is not to demonstrate safety and efficacy per se, but rather to prove that safety and efficacy are comparable to the originator’s. Hence, the clinical trials needed in the light of a biosimilar development, may differ substantially from those requested for an innovative product. For instance, the number of phase III patients recruited, the clinical endpoints assessed, or the indications tested, may vary from the reference product [22]
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A biosimilar is neither a biobetter nor a “stand-alone” As discussed above, the more innovative the biopharmaceutical seeking marketing authorization, the more demanding will the regulators be in requiring proof and guarantees that the product’s benefits outweighs its risks. On the contrary, biosimilars are not innovative in terms of therapeutic target, indication, administration route or regimen (certain technological innovation might be introduced to improve production or formulation). Not all products, however, fall into the fully innovative or the biosimilar extremes.
Biobetter versus biosimilar Although the boundaries are sometimes fuzzy, and the subject is a constant source of debate, a biological product whose active ingredient or formulation is slightly modified in some way to improve efficacy, or ameliorate its therapeutic regimen, cannot be developed as a biosimilar. As protein technology advances, the practice of altering molecules to achieve favorable pharmacokinetic or pharmacodynamic variations will become more common [30, 31]. For instance, improving a drug’s half-life or its potency changes the dosing regimen, but does not change the therapeutic target or indication. In such cases, it would appear reasonable for the company to perform head-to-head studies with the unaltered product to demonstrate the alleged clinical benefits. The goal of this comparison, clearly, should not be to demonstrate equivalence, but to prove that the new product is clinically superior in some respect. The product would therefore not qualify for a biosimilar application. Products of this type are typically called biobetters, for obvious reasons. However, to my knowledge this is not a regulatory term, the distinction between biobetters and biosimilars is pertinent, as the two types of products are too frequently lumped together. Technologically, the field is still highly experimental. Insulin analogs (as opposed to natural insulins), and darbepoetin (as opposed to EPO) were in fact pioneering biobetters. In the coming years, we are likely to see an increasing number of minor modifications to recombinant proteins claiming to improve the therapeutic attributes of their original counterpart.
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―Stand-alone‖ versus biosimilar application Eporatio is an erythropoietin that was approved by the European Commission in 2009 [32]. Because it is a rHuEPO, its amino acid sequence is identical to that of original products containing human EPO, and also to that of more recent biosimilars. In spite of not bearing a new active substance, Eporatio is not a biosimilar, because the pharmaceutical company that developed the drug chose not to undertake that regulatory path, i.e. not to experimentally demonstrate that Eporatio was comparable to an original product. For commercial reasons, or perhaps following regulators’ recommendations based on preliminary comparability data, a pharmaceutical company may decide not to pursue the biosimilar regulatory pathway despite the apparent similarity with a biological already in the market. Instead it chooses a ―stand-alone‖ application, which is envisaged by the EMA as an alternative in its recently adopted overarching Guideline on Similar Biological Medicinal Products [33]. It should be noted that stand-alone application is a very ample concept that includes any request relying on its own data for approval, i.e. not making reference to the dossier of another medicinal product. Eporatio is therefore another EPO whose authorization was not based on the demonstration of equivalence to an original reference EPO.
The distinction between biobetter and ―stand-alone‖ can in some cases be arbitrary. In fact, both qualify to some extent as original products. In any case, although in such circumstances the company has not set out to replicate an existing product, because these products share targets and indications, and because they are analogous in other respects to existing products, they are sometimes wrongly assumed to be biosimilars.
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A biosimilar is not a Non-Original Biological (NOB) As already mentioned, the EC paved the way in issuing a biosimilars legal framework (1), and EMA guidance for the approval of biosimilars, based on the principle of comparability laid down in 1998 (34). The groundwork laid by the EMA helped institutions such as the World Health Organization (WHO), and a few reference regulatory bodies to establish their own requirements and criteria, which are in essence analogous to the European agency’s. Although the trend among other national regulatory agencies that evaluate marketing authorization dossiers for biotechnological medicinal products is to embrace the standards established by the EMA, many such agencies are not compliant with the evidence-based standards set up by European authorities. Scientific evidence drives the need for EMA-like standards, and less stringent requirements may constitute a risk for patients.
While the biopharmaceutical industry is clearly dominated by companies from the most developed countries, several emerging economies in Latin America and Asia (e.g. Brazil, Argentina, Mexico, India, and China) have gained ground in biotechnological know-how. This growing strength has triggered national debates that have led to the adoption of legal measures, and the publication of guidelines in these and other countries to regulate the development of products claimed to be analogous to original biologics. Although in some cases the regulatory measures established mirror the intentions of the EMA, they often do not yet meet its standards, and, perhaps more troublingly, they are not always diligently applied. This regulatory gap allows for biologics whose biosimilarity has not been proved on the basis of sound science-based regulatory guidance, to receive marketing authorization. For this reason, some products approved in countries beyond the EU, the US, Canada, Japan, Australia, and possibly other regions, are increasingly being referred to as non-original biologicals (NOB), or non-comparable biologicals [4].
Studies of some NOB licensed in countries with a less stringent regulation have uncovered considerable structural differences with respect to original products [35, 36] that would not have
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passed muster in Europe. It is possible that the identified structural differences will have an impact on safety or efficacy, but it is often difficult to prove it, for one because the pharmacovigilance systems in many of these countries are inadequate or nonexistent. Nonetheless, studies monitoring and analyzing the immunogenic capacity of some of these NOB point to troubling differences with respect to the mirrored original products [37, 38]. Some authors have also called these products ―intended copies‖ to suggest either that their equivalence has not been successfully demonstrated, or that the studies used to demonstrate their comparability may be insufficiently rigorous. Patients administered NOB face a greater risk than they would with either original products or with EU-authorized biosimilars. South Korea deserves mention as an economy with a growing biotech industry. The South Korean pharmaceutical company Celltrion was the first to successfully develop a biosimilar to Remicade [39]. The active substance is infliximab, an anti-TNF monoclonal antibody used to treat rheumatoid arthritis and Crohn’s disease among other diseases. With this approval, two milestones were reached: Celltrion became the first company to achieve marketing authorization for a biosimilar to a monoclonal antibody, and the Asian biotech industry gained a foothold as a supplier to highly regulated markets. This sets the stage for other companies from emerging countries to follow, but for the time being, the biosimilar scenario is dominated by companies from leading economies.
NOB should therefore not be called biosimilars. Some healthcare professionals in the EU have expressed fear regarding the possible entry of NOB. Such fear is unfounded; a NOB, as it stands, would not make its way towards patients in the EU. The EMA, with its rigorous standards, would not approve them, nor probably would Canada, Australia, Japan, or the United States, as they have similar requirements to Europe.
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CONCLUDING REMARKS No biopharmaceutical product—whether original or biosimilar—is risk-free, but when a biosimilar is granted marketing authorization in a highly-regulated region such as the EU, the approval is founded on a solid science-based development process that ensures a comparable risk-to-benefit balance [40]. Hence, a biosimilar approved under the auspices of the EMA, or a regulatory body with similar criteria, is simply another high quality biological that, once authorized, follows its own therapeutic and commercial track. There are no grounds to believe that the use of a biosimilar carries more risks for the patient than that of the corresponding reference original product. Since the first biosimilar was authorized in 2006 by the EC, no clinical alerts have raised red flags about the established EMA biosimilar pathway. This should not come as a surprise since the Agency has put in place stringent evidence-based criteria strongly focused on ensuring patient’s safety [40]. Thinking otherwise has unfairly caused a negative impact on the prescription of biosimilars, and has ultimately affected or delayed the access of more patients to biological therapies. Extending the reach of biosimilars is as socially and economically desirable as fostering biopharmaceutical innovation—and the introduction of biosimilars does undoubtedly contribute to such innovation. Beyond the slow penetration, a misconception as to how biosimilars are studied and what they represent may further undermine their therapeutic added value. Indeed, misinterpreting the biosimilar concept is not just a terminology matter. Biosimilars are neither generics nor ―stand-alones‖ or biobetters, and should not be managed as such from a therapeutic, a commercial, an economic, or a healthcare policy perspective. A biosimilar, by its very nature, is not an innovative product, but it still is viewed as an innovative concept by many because it represented a considerable shift of paradigm. Raising awareness of what biosimilars are, and what they are not, generates trust among healthcare professionals in these products. Clinical pharmacologists are ideally positioned to contribute to such trust.
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COMPETING INTERESTS
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http://www.icmje.org/coi_disclosure.pdf and declares: no support from any organisation for the submitted work; work as a speaker and/or consultant with Bayer, Roche, Hospira, Oli Med, Sandoz and Salupharma in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work".
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Figure 1 Conceptual discrimination between biosimilar and non-biosimilars on the basis of regulatory and non-regulatory criteria Only products claimed to be highly similar to a reference original biologic, and whose similarity is demonstrated through a thorough EMA-like comparability exercise** should qualify as biosimilars (this figure is not intended to be an accurate account of the available alternative regulatory pathways).
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Figure 2 Comparative EMA requirements for biosimilar development versus studies envisaged for generics, original products, and possibly biologics after manufacturing changes. The regulatory requirements rely to a large extent on the background knowledge sustaining the product development. In the case of a fully original biologic application, there is no accumulated evidence prior to undertaking the development program; hence a complete dossier will be requested. It is to note that, given the particularly high sensitivity of structural and biological activity studies for picking up potential differences, the biosimilar quality module is the most extensive. Finally, it has to be borne in mind that this is a general framework; the actual specific requirements will need to be established on a case-by-case basis.
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