BIOSIMILARS: SCIENCE TO MARKET

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Dissertation-MSc. Biotechnology, Bioprocessing and Business Management

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BIOSIMILARS: SCIENCE TO MARKET

  1. 1. MSc Biotechnology, Bioprocessing And Business Management 2010-2011 BIOSIMILARS: SCIENCE TO MARKET 1055902 Supervisor: Dr. Neil Porter Word Count: 15,169A dissertation submitted in part fulfillment of the Degree of MSc. Biotechnology, Bio processing and Business Management, University of Warwick, September 2011 i
  2. 2. AcknowledgementI would like to take this opportunity to thank my supervisor Dr. Neil Porter, for his invaluableinsight and guidance throughout my dissertation.I would like to thank Dr. Crawford Dow, Dr. Steve Hicks and Dr. Charlotte Moonan for theirassistance and Adrienne Davis for her continuous support and encouragement throughout theyear.Finally, I would like to thank my parents and friends, without whom this piece of thesis wouldnot have been possible. i
  3. 3. TABLE OF CONTENTSList of Tables ............................................................................................................................................ vList of Figures:.......................................................................................................................................... viExecutive Summary................................................................................................................................ viii1. Introduction: ........................................................................................................................................ 1 1.1 Biopharmaceuticals: ....................................................................................................................... 1 1.2 Biopharmaceutical Market:............................................................................................................. 42. Biosimilars: .......................................................................................................................................... 6 2.1 Terminology disputes: .................................................................................................................... 7 2.2 Differences between Biosimilars & Generic Drugs:.......................................................................... 8 2.2.1 Product differences: ............................................................................................................... 10 2.2.2 Manufacturing differences: .................................................................................................... 10 2.3 Manufacturing Process: ................................................................................................................ 13 2.3.1 Challenges: ............................................................................................................................. 13 2.3.2 Selection of platform: ............................................................................................................. 15 2.3.3 Purification:............................................................................................................................ 16 2.3.4 Formulation: .......................................................................................................................... 163. Biosimilars legislation & Regulations: ................................................................................................. 18 3.1 Regulatory framework Europe: ..................................................................................................... 19 3.1.1 Product specific guidelines: .................................................................................................... 24 3.1.2 Immunogenicity: .................................................................................................................... 26 3.1.3 Extrapolation:......................................................................................................................... 27 3.2 EU Biosimilar approval process: .................................................................................................... 28 3.2.1 Common technical document:................................................................................................ 28 3.3 United States Regulatory framework: ........................................................................................... 30 ii
  4. 4. 3.4 Global Landscape:......................................................................................................................... 314. Case Study-Biosimilar Insulin: ............................................................................................................. 33 4.1 Manufacturing: ............................................................................................................................. 33 4.2 EMEA requirements: ..................................................................................................................... 34 4.3 Marvel’s Insulin rejection: ............................................................................................................. 35 4.3.1 Quality Aspects: ..................................................................................................................... 36 4.3.2 Non clinical aspects: ............................................................................................................... 36 4.3.3 Clinical Aspects:...................................................................................................................... 365. Market Analysis: ................................................................................................................................ 37 5.1 Biosimilars On market:.................................................................................................................. 37Table 5.2: Unsuccessful biosimilar applications in the EU. Source: Greer, F.M., 2011.............................. 39 5.2 Market Size & Growth: ................................................................................................................. 40 5.3 Market potential:.......................................................................................................................... 40 5.4 Regional market analysis: ............................................................................................................. 42 5.5 Biologic class market analysis: ...................................................................................................... 43 5.6 Market Opportunities: .................................................................................................................. 45 5.6.1 Patent expiry: ......................................................................................................................... 47 5.7 Market share: ............................................................................................................................... 54 5.8 Sales: ............................................................................................................................................ 56 5.9 market Drivers: ............................................................................................................................. 56 5.9.1 Cost Savings (Global health care): ........................................................................................... 566. Issues & Challenges: ........................................................................................................................... 60 6.1 Cost of Product development: ...................................................................................................... 60 6.1.1 US region ............................................................................................................................... 61 6.2 Manufacturing Facility: ................................................................................................................. 61 iii
  5. 5. 6.3 Substitution: ................................................................................................................................. 62 6.4 Market exclusivity:........................................................................................................................ 62 6.5 Innovator Strategies: .................................................................................................................... 64 6.6 Profitability of biosimilars: ............................................................................................................ 66 6.7 Marketing: .................................................................................................................................... 677. Conclusion: ........................................................................................................................................ 68References: ............................................................................................................................................ 71 iv
  6. 6. LIST OF TABLESTable 1.1: Comparison of the size of the chemical and biological medicine 2Table 1.2: Biopharmaceutical market, estimated value and forecast 2009-2015 in 5US$billionTable 2.1: Biosimilars Terminology. 7Table 2.2: Small molecule generics v/s biosimilars. 9Table 2.3: Definitions of biological and chemical pharmaceuticals. 9Table 2.4: comparison of generics, biosimilars & biologics. 11Table 2.5: Biopharmaceutical processing with prokaryotic and eukaryotic expression 15systems.Table 3.1. Format of the dossier- modules of the CTD. 29Table 5.1: Biosimilars approved by the EU. 38Table 5.2: Unsuccessful biosimilar applications in the EU. 39Table 5.3: Total World Biosimilar Market Potential 2006-2013 41Table 5.4: World Biosimilar Market Potential by Region 2006-2013 43Table 5.6: The world market potential for Biosimilars by Biological Class (EPO, G-CSF, 44insulin, Interfereon, alpha, others) 2006-2013.Table 5.7: Estimates of treatment cost per patient of selected biopharmaceuticals. 47Source: Crandall, 2009.Table 5.8: Blockbuster biological drugs set to lose patent protection per year through 492015. Source: Emmerich, R. (2010)Table 5.9: Interferons on market and patent expiries. Source: 50Table 5.10: Multiple sclerosis drugs on the market and patent expiries. 52Table 5.11: Recombinant insulin products on the market and patent expiries 53Table 5.12: Bbiosimilar companies sales and market share 55Table 6.1: Interferons on market and patent expiries 65 v
  7. 7. LIST OF FIGURES:Fig 1.1: Differences in complexity (biotech’s interferon)-a protein naturally produced in 3our body versus Traditional AsprinSource …………………Fig 1.2: Evolution of the biologics market 2009-2015. 5Fig 2.1: Biologic from production to drug use 14Fig 3.1: Regulatory guidelines. 19Fig 3.2: Market exclusivity. 25Fig 4.1: Post fermentation steps in manufacturing process 34Fig 5.1: World Biosimilar Market potential by region 2006-2013, products with currently 42expired patents.Fig 5.2: Expected Biosimilar market split in 2015 45Fig 5.3: Forecast of the global biosimilar market value in $billion: 2008-12 46Fig 5.4: Number and value of biological drugs set to lose patent protection per year 48through 2015Fig 5.6: Predicted market share of multiple sclerosis drugs (2007-2017) 51Fig 5.7: Estimated patent expiry dates of selected proteins 54Fig 5.8. Market Share of biosimilars in the off patent biologics market. 55Fig 6.1: Patent protection and market exclusivity for top biologics losing patent 64protection prior to 2018 vi
  8. 8. ABBREVIATIONSEMEA – European Medicine AgencyFDA – Food and Drug AdministrationEBE - European Biopharmaceutical EnterprisesEU – European UnionICH- International Conference on HarmonizationCHMP-Committee For Medicinal Products For Human UseBLA- Biologic License ApplicationDNA-Deoxyribo Nucleic AcidCMC- Chemistry Manufacturing and ControlsCTD- Common Technical Document vii
  9. 9. EXECUTIVE SUMMARY According to the definition, biosimilars are different versions of existing brandedbiologics, which have received legal approval and which gain access to the market after thedemonstration of pre-clinical and clinical data proving their similarity to the reference product. Due to their complex structure and nature as well as their complicated manufacturingprocess biosimilars have become the subject of rigid regulatory frameworks currently in theEuropean Union and to be followed by the rest of the world. The aim of this dissertation is to offer a wide spectrum view of biosimilars in general butalso in comparison to traditional generic chemical drugs. In order to do this, an overview of the current regulatory frameworks focusing on EU andUS will be presented in relation to the manufacturing process and subsequently the approvalprocess. Following this, an analysis of the market of biosimilars is offered addressing issues suchas market opportunities and drivers as well as the challenges faced. viii
  10. 10. 1. INTRODUCTION: The first generation of the biopharmaceuticals which are manufactured by the use ofrecombinant technologies were launched in the 1980s and most of these products have eitheralready lost patent protection or are about to lose patent protection in the near future.Biopharmaceuticals presently demand premium pricing due to various factors such as high costof manufacturing, superior safety and efficacy profiles and limited competition from otherbiopharmaceutical companies. Since 1982 the global biopharmaceutical market has developedsignificantly and was estimated to be worth $125 billion in 2010 (Greer, 2011). Significant market opportunities for generic companies are provided by the expiry of thepatents first generation of biopharmaceutical/biotechnological products. Second-entry (follow-on) biopharmaceutical/biotechnological products have a more complex route to the market ascompared to the generic versions of chemically-synthesized active ingredients. The differentterminology that is used to describe "biologically similar drugs" indicates the complexities in thisarea. The generic industry tends to regard the biological similar drugs as the biogenerics, but theresearch based industry argues that it is not possible to replicate precisely the biological processfor large molecules therefore, due to the nature of their production process; the generic of thebiopharmaceutical cannot exist (Marchant, 2007).1.1 BIOPHARMACEUTICALS: The biological medicines (biologic pharmaceuticals or biologics or biopharmaceuticals)are the medicines which are produced using a living system or organism (EuropaBio 2005). Thedivision of drugs that are generated from biological sources and which include gene therapy,vaccines, antibodies and other therapeutic products derived through biotechnology are calledas biologics or biopharmaceuticals (Wang, 2011). Biopharmaceuticals are also considered as any substance used for the treatment ormanagement of diseases or injuries and is produced by natural organisms or recombinanttechniques consisting of proteins or other products derived from living organisms (Crandall, 1
  11. 11. 2009). Using biotechnology, biopharmaceuticals are produced, which are medical drugs.Biopharmaceuticals are proteins which include antibodies, nucleic acids (DNA, RNA or antisenseoligonucleotides) which are used for therapeutic or in vivo diagnostic purposes and areproduced by means other than direct extraction from a native (non-engineered) biologicalsource. Through a distinctive process biopharmaceuticals are produced, where various types ofbioreactors are used in which the microbial cells are cultured to produce proteins (Pandey, R. K.et al., 2011). The first biopharmaceutical product approved for therapeutic use was recombinanthuman insulin (rHI), which also goes by the trade name Humulin. Humulin was developed byGenentech and marketed by Eli Lilly & Co. in 1982. The chemical medicines are usually organic molecules whose molecular structure can beunfailingly assessed and they are produced by a defined chemical pathway (Fox, 2010). Inlaboratory the chemical medicines are defined by simple analytical methods. The conventionalchemical medicines are different in various ways to the biological medicines. One of theapparent differences is the size of the biopharmaceuticals; the molecules of thebiopharmaceutical are much larger, have more complex spatial structures and are to a greatextent heterogeneous than the small molecules which make up chemical medicines (Table 1.1). Table 1.1: Comparison of the size of the chemical and biological medicines. Source: EuropaBio,2005 2
  12. 12. This makes it intricate to characterize biopharmaceuticals in a conventional way byanalyzing their individual components as is done for chemical medicines. A biopharmaceuticalproduct is molecule which is typically a protein with a complicated three dimensional structureconsisting of chain of hundreds of amino acids. Due the large size (Fig 1.1) and structure of themolecules, the biopharmaceuticals are administered in injection form, whereas the chemicalmedicines with small molecules come in pill form. . Fig 1.1: Differences in complexity (biotech’s interferon)-a protein naturally produced in our body versus Traditional AsprinSource: EuropaBio (2005) Biological and Biosimilar Medicines. The productions conditions must be strictly controlled for the manufacturing ofbiopharmaceuticals as they are very sensitive to the production processes. There is anoccurrence of complex post-translational modifications such as glycosylation and pegylation tothe protein, so even the small change in the manufacturing process could have a major impacton biological activity. If compared in the terms of production quality tests, there are over 2000production quality tests for the manufacture of a biological drug and only an average of 200required for small molecule drugs (Pandey et al, 2011). 3
  13. 13. 1.2 BIOPHARMACEUTICAL MARKET: The biopharmaceuticals represent one of the most dynamic and potential segments ofthe pharmaceutical sector and it has rapidly expanded over the past few years withcompounded growth rates which are beyond double digit figures, which are greater than theperformance of the overall pharmaceutical market (Taylor, 2009). In the field of biomedicine,the biopharmaceuticals are well established and they have opened new avenues of therapyoptions specifically in disease areas where earlier there were no therapies, or only insufficienttherapies were available (Kresse, 2009). Since the early 1980s biopharmaceuticals have been a rising part of the pharmaceuticalsector. Biopharmaceuticals is one of the rapidly growing sectors in pharmaceutical industry,growing at an average rate of 18-20% since 2007 (Crandall, 2009). There are manybiopharmaceuticals in the approval pipeline and it was projected that in 2010 for the marketplace, 50% of drugs will be the result of biotechnology. There are some 165 biopharmaceuticalproducts which have gained approval. The total sales of recombinant protein-based drugs were$54.5 billion in 2007 and in 2012 the sales are estimated to increase to $75.8 billion (Kresse,2009). Worldwide there are more than 400 new biopharmaceuticals under development or inclinical trials and it has been recently estimated that biopharmaceutical sales will expand by 15-20% annually in the future (Horikawa et.al, 2009). The biopharma market overall is forecasted togrow at nearly 7% CAGR through to 2015 (Table 1.2), with MAbs (Monoclonal Antibodies)showing higher growth of 9% (Evers, 2010). The biopharmaceutical market majorly comprisesof monoclonal antibodies, therapeutic proteins and vaccines. In terms of market size,therapeutic proteins are the leaders (Fig 1.2), but Monoclonal Antibodies (mAbs) are the fastestgrowing sector. MAbs (Monoclonal Antibodies) represents three quarters of the biologic marketand expected to dominate. Vaccines will have a steady growth rate and will hold their marketshare. Therapeutic proteins are estimated to grow steadily but their growth rate will slightlydecline as compared to other product groups (Fig 1.2) (Evers, 2010). 4
  14. 14. 2009-$117bn 2015-$170bn 52% 46% 38% 33% 15% 16% Proteins Vaccines MabsFig 1.2: Evolution of the biologics market 2009-2015. Source: Evers, P. (2010) The Future of the BiologicalsMarket. Table 1.2: Biopharmaceutical market, estimated value and forecast 2009-2015 in US$billion Source: Evers, P. (2010) The Future of the Biologicals Market. 5
  15. 15. 2. BIOSIMILARS: The patent protection for most of the first- generation biopharmaceuticals began toexpire in 2004, opening the door to the so called ‘biosimilars’. A biosimilar is a medicine that issimilar but not identical to a biological medicine that has already been authorized (the‘biological reference medicine’) (Zuniga & Calvo, 2009). The biosimilars are also called follow-on biologics (FOB) or Subsequent Entry Biologicswhich refer to the “generic” version of biologics or biopharmaceutical products that areproduced and sold on the market after the patents on the innovator’s biologics are expired.However, the nomenclature of biosimilars is not universal (Wang, 2011). Many definitions have been provided for “Biosimilars” by various authors. Thebreakdown of the term “Biosimilars” can be done for the better understanding of the concept.They are “biological medicinal products” which as the name suggests are similar to theapproved biological medicinal products in respect to quality, safety and efficacy. Theseapproved products are reference novel products which are already licensed and marketed. Afterthe reference product has lost patent protection and data/market exclusivity the independentapplicant can launch the biosimilar product after the approval. For the authorization of thebiosimilar product for marketing the applicant of the biosimilar producer or developer shouldfollow the procedure of regulations proving the similarity with the reference product. Thecomplex biological products are difficult to characterize completely, therefore the focus of the“biosimilar” approach is generally on highly purified products consisting recombinant proteinsas the active pharmaceutical ingredient. According to the (Kresse, 2009) the approach is notapplicable to products which are derived from blood or plasma, immunologicals and otherupcoming therapies like gene or cell therapies. But the regulation bodies are prepared to acceptadditional classes of compounds like polysaccharides such as low-molecular weight heparins. 6
  16. 16. 2.1 TERMINOLOGY DISPUTES: There has been extreme confusion among the regulatory bodies and countries about theterminology which could be applied to the biopharmaceuticals/biologics that could be probablyaccesible generically due to loss of patent protection and market exclusivity of the originaltherapeutic protein (Crandall, 2009). The complexity of the biopharmaceutical industry and the science behind it leads tosignificant controversies with reference to definitions, terminology and issues related tobiopharmaceuticals in terms of products, technologies, companies. Biopharmaceutical arecomplex medicines as compared to the small molecule chemical drugs as they aremanufactured by the usage of living organisms. Biopharmaceuticals possess complex nature,size and complexity therefore they usually cannot be technically classified to the same extent asthe conventional chemical drugs (Taylor, 2009). As it is complicated to provide a concisedefinition for a biopharmaceutical, it is particularly tricky to define a generic biopharmaceuticalgiven the complexity of the products derived from biotechnology. Table 2.1 illustrates thedifferent names which are used in various regions of the world to describe genericbiopharmaceuticals. Table 2.1: Biosimilars Terminology. Source: Taylor P., 2009. 7
  17. 17. Most of the things associated with the concept of the biosimilars is controversial, eventhe language related to the products. The term “biogenerics” is preferred by GPhA (GenericPharmaceutical Association), the generic industry trade group, as it indicates the possibility ofinterchangeability and also improves the view of the public of generics as being as safe andeffective as the original product. Contrary to this belief the innovator companies approach isdifferent and use the term “follow –on biologics” (FOB). Different countries and regulatorybodies of those countries make use of different terminology for generic biopharmaceuticals.The European Union has the most established regulatory system for generic biopharmaceuticalscalled EMA and this system makes use of the term “biosimilars.” The United States has switchedfrom the term “follow on protein product” to “follow-on biologic” to cover different kinds ofbiologic product. Follow-on biologic is also considered as an umbrella term which covers bothbiosimilars (i.e. products not having potential to substitute reference product) and biogenerics(i.e. products having potential to substitute reference product) (Clark, 2009). At initial phasesmost products have no proof of interchangeability and the European Union has an establishedregulatory pathway as compared to the rest of the world which uses the term “biosimilar”which will obliviously influence the regulatory system of United States and other countries.2.2 DIFFERENCES BETWEEN BIOSIMILARS & GENERIC DRUGS: Generic Medicines are the medicines which contain active substances whose safety andefficacy are well established. Generic medicines must demonstrate that same dose of thegeneric and reference product behave in the body in the exact same way which determines thebioequivalence of the generic drug with that of the reference product (Zuniga & Calvo, 2009).Quality in terms of the controls and standards for all manufacturing, preparation and processingof the product should be maintained by the generic drug at the same standard to the referenceproduct. The generic drugs are generally considered as interchangeable with the referenceproduct because they are therapeutically equivalent to the reference product. The marketapplication procedure is relatively simple for generic medicines as there is no requirement ofresults of clinical trials or the results of non clinical data like toxicological and pharmacologicaltests. On the contrary it is completely opposite in the case of similar biological medicinal 8
  18. 18. products (biosimilars) whose development procedure is complicated like all thebiopharmaceutical products. For the biosimilar products the generic approach is not applicabledue to factors such as the unique manufacturing process for each product and complexity of theproducts derived through biotechnology (Table 2.2) (Zuniga & Calvo, 2009). Table 2.3 providesthe definitions of the generic drug, biopharmaceutical and biosimilars. Table 2.2: Small molecule generics v/s biosimilars. Source: Chen, 2009. Table 2.3: Definitions of biological and chemical pharmaceuticals. Source: Crommelin et al., 2005. 9
  19. 19. 2.2.1 PRODUCT DIFFERENCES: The small molecule drugs called as chemical drugs due to their nature are able tocharacterize chemically and this facilitates the generic manufacturers to evade the effort andadditional cost associated with clinical and non clinical evaluation and thereby proving theirproduct to be bioequivalent to the originator. The requirement of the accurate threedimensional structures is necessary for the biological activity of the biopharmaceuticals, as thisstructure helps in the interaction of the biopharmaceutical with other molecules like receptorson cell surfaces, binding proteins and nucleic acids. During drug development there are variousprofiles which should be fulfilled such as pharmacokinetic and pharmacodynamic profiles,Clinical safety and efficacy profile all of which are influenced by the three dimensional structureof biopharmaceutical, by the degree and location of its glycosylation sites, by its isoform profileand by the degree of aggregation. The biosimilar product in order to prove equivalent to theoriginator product has to have all these characteristics in addition to the primary (chemical)structure to be identical to the original product and this makes the biosimilar different fromchemical generics which can be fully described by its chemical structure (Crommelin, 2005).2.2.2 MANUFACTURING DIFFERENCES: The manufacturing of the low molecular weight pharmaceuticals (chemical drugs) isdone by the sequence of controlled and conventional chemical reactions of the recognizedchemical reagents. Contrary to the chemical drugs, the biopharmaceuticals are manufacturedor produced by the harvesting of the proteins from the living cells which often results in theadditional secretion of various other substances along with the protein of interest (Table 2.4).There is a general misunderstanding that biopharmaceutical product manufacturing is thesimple process of inserting the gene of interest in an appropriate cell line. Howeverbiopharmaceutical manufacturing is a complex process which requires the attention of variouscritical factors such as complex size and the three dimensional structures of biopharmaceuticals,the unpredictable nature of the biological reactions with respect to chemical reactions, various 10
  20. 20. secondary modification processes such as glycosylation, and potential chances of denaturation,aggregation and degradation (Crommelin et al., 2005). Table 2.4: comparison of generics, biosimilars & biologics. Source: Accenture (2009) There are several stages involved in the production of the biopharmaceuticals which couldaffect the final product. 11
  21. 21.  The characteristic of the protein product is determined by the selection of the host cell and the sequence of genes that codes for the desired protein. A master cell bank is established for protein production by extensive cell screening and selection process and two master cell banks are never precisely the same During the fermentation process the fermentor, components of the culture medium and physical conditions at which the cells are cultured on the large scale affects the protein which is produced and it also affects behavior properties in the body. Purification is the critical step in manufacturing as various related proteins, DNA and other purities are produced along with the protein of interest any change in the process could affect the purity of the product. A range of analytical techniques is used to examine different characteristics of the protein product. Even the advanced analytical tools are not sufficient to analyze product characteristic that may change the clinical safety and efficacy. On the other hand by using only few analytical techniques the low molecular weight compounds can be completely characterized in terms of structure. The product should be stored cautiously due to the fact that if not stored in optimal conditions, the product will lose its integrity.The manufacturing of the biopharmaceutical is a more complex process as compared to thesmall chemical synthetic drugs and to make exact reproduction of the innovator biologicmolecule is almost impossible (Greer, 2011). Every stage of the biopharmaceuticalmanufacturing process is critical because the slightest change in the process can havesubstantial change in the product and its efficacy in patients. The innovator faces a challenge tomaintain consistent batch to batch of biologic product in spite of possessing the patentinformation and years of experience with the manufacturing process. Biosimilars cannot beconsidered as regular generics as it is highly unlikely to manufacture a “copy” version ofbiological products using the manufacturing process which is considerably different from theinnovators manufacturing process (Greer, 2011). 12
  22. 22. 2.3 MANUFACTURING PROCESS: Biosimilar development constitutes of three important steps such as ChemistryManufacturing and Controls (CMC), preclinical and clinical trials. The traditional generic drugsare approved under an abbreviated pathway through the Hatch-Waxman Act of 1984. Thispathway is not applicable to the biosimilars as they come under biologics which are governed bydifferent laws and regulations. The ICH Common Technical Document (CTD) has a module 3 onquality which describes the CMC requirements for the biosimilars. The European Union followsthe CTD format for submission of application and it will be used by the U.S., when the regulatorypathway is put into place.2.3.1 CHALLENGES: To develop a biosimilar from scratch is a relatively tough task as the biosimilardevelopers have no access to the proprietary information of the innovators product’smanufacturing process or specification of the product. Generally biosimilars development hasto go through a series of steps such as the authorized marketed biologic product should be firstrecognized by the biosimilar developer and used as the reference biologic product or innovatorsproduct. The second step is to then carry out a thorough characterization of the referenceproduct. The manufacturing process of the biosimilar is developed from the data which isgenerated from the characterization of the reference product. This data will also be utilized forthe comparability exercise which is performed to prove the bioequivalence between thebiosimilar and reference product. Due to the lack of access to the innovators manufacturingprocess the biosimilar product is manufactured from entirely different and new process ascompared to the innovator manufacturing process. The new process developed by biosimilarsmanufacturers may use and carry out production process in different culture system andequipments like fermentor (Chen, 2009). The challenges faced by the biosimilar as well as the innovator manufactures are thesame when it comes to the biopharmaceutical/ biologics production. Specifically there are twochallenges: Firstly there should be a robust manufacturing process which produces a consistent 13
  23. 23. product which has to be tested to be same in the preclinical and clinical studies. The secondchallenge is to maintain product reproducibility in terms of scale up of the process with samesite or when manufacturing occurs at different sites. These two challenges are never easily metby the manufacturers for instance the studies on innovators epoietin alpha with that of theepoietin which is manufactured outside the U.S. and European Union have differences in termsof purity, efficacy and biological activity. This example indicates that slight change in themanufacturing process will result in the change in the biological activity of the product (Sharma,2007). Fig 2.1 illustrates the flow from drug production to the administration. Fig 2.1: Biologic from production to drug use Source: Chen, B., 2009 14
  24. 24. 2.3.2 SELECTION OF PLATFORM : The development of the CMC is initiated by the selection of the production platform orthe expression system (Table 2.5). Depending on the type of protein to be manufactured anappropriate technology is selected. The yeast expression system along with batch fermentationis selected for the production of small peptides and proteins. The mammalian expressionsystem is selected as it provides the higher yields and reliable purification results and used forthe production of the monoclonal antibodies, complex proteins which contains disulphidebonds and require glycosylation. Several stages in manufacturing are crucial and have influenceon the properties of the end product. Therefore after the selection and establishment of the cellline which is crucial, a specific DNA sequence which codes for protein of interest is inserted(Chen, 2009). Then extensive cell screening and appropriate methods are used to form a mastercell bank, so high levels of sterility and identity of the cells could be maintained. Throughoutthe manufacturing process the cells are cultured under definite conditions so as to getoptimized results in terms of production and secretion of protein of interest. The structuralcharacteristics of the proteins are decided by the culture conditions in the mammalian cellsystem and in the bacterial system they are later defined in the purification process (Sharma,2007). Table 2.5: Biopharmaceutical processing with prokaryotic and eukaryotic expression systems. Source: Sharma, 2007 15
  25. 25. 2.3.3 PURIFICATION: Impurities are unacceptable in the biologics manufacturing as impurities in the finalproduct could have clinical consequences. The process of purification has to get rid of all theimpurities which include cell proteins by host cells, DNA contamination, medium components,viruses and other by products without causing any damage to the protein of interest. Thereshould be proper selection of the desired protein forms with suitable glycosylation and removalof damaged forms in the purification process. Biosimilar manufacturers do not have access tothe purification process information of the innovator which leads to the differences in the purityand protein structure. It is important for the biosimilar manufacturers to compromise on theyield when it comes to purity as the purity leads to safety and efficacy status which is theultimate aim of the biosimilar. For instance in the erythropoietin purification, for the optimumbiological activity only the isoforms which are highly glycosylated are selected (Sharma, 2007).2.3.4 FORMULATION: The therapeutic performance and conformational stability of the biologic drug isassociated with composition of the formulation and choice of the container. These factors areresponsible for the protein degradation and aggregation. After going through composition offormulation then sterile filtration and filling into the final container the final product is formed.Components of the formulation consist of basic buffer which is for proper pH control and saltwhich provides the isotonic adjustment. In order to avoid proteins from being absorbed to thesurface of containers or hydrophobic surfaces, surfactants are used in the formulation. In theend container and closure reliability should be thoroughly checked for sterility. Biologics are theheterogeneous mixtures which are not pure substances. Biologic products are produced underthe current Good Manufacturing Practice guidelines and to make sure they are producedaccording to the predefined specifications there are various assays which could check the purityand authenticity of the product. The biologics are sensitive to environmental changes such astemperature, storage, handling and sunlight. For instance insulin vials exposed to temperature 16
  26. 26. more than 40C results in transformation of the product and increased chances ofimmunogenicity and loss of biological activity (Sharma, 2007). 17
  27. 27. 3. BIOSIMILARS LEGISLATION & REGULATIONS: The regulatory bodies have recognized the fact that the manufacturing process is criticalin the production of biopharmaceuticals and variations in the process could lead to significantdifferences in product characteristics which cannot be fully determined by the analyticalcharacterization. So the manufacturing process is considered and made part of thedetermination of the product quality along with other testing protocols carried to determinesimilarity. Therefore protein products which are manufactured by the independentmanufactures would never be identical to the innovator product, but at maximum would besimilar to innovator molecule possessing the same clinical attributes despite of not being thesame molecule (Kresse, 2009). An ideal legal and regulatory process which allows the approval of the biosimilarproducts has to attain equilibrium between various factors which involve the facility for marketentry for biosimilars, competition for products which have lost patent protection, to promoteresearch and development and provide incentives, and finally the most important is to evadeany risk associated with patient safety. Though it is considered that advent of biosimilars willlead to reduction of redundant or even unethical clinical trials of animals as well as human andbiosimilars will propose economic benefits but biosimilars do not bring any innovative medicalprogress as the original product is already available proving effective and safe to the patients.Therefore the approval pathway for biosimilars should ensure that appropriate standards ofsame level as innovative products should be maintained. Usually it is agreed that the regulatorypathway for traditional low molecular generic drugs is not suitable for biologic orbiopharmaceutical medicines. There are initiatives and regulatory pathways already establishedor under development in various regions of the world (Kresse, 2009). Biosimilars are licensed and marketed in various regions of the world including the lessregulated markets such as India, China and South Korea. The category of the products which aremarketed in these regions include interferons, EPOs, growth hormones, enzymes, interleukins,monoclonal antibodies etc. As compared to these less regulated markets there is a significantlyless number of biosimilar products available on the European market with only few categories 18
  28. 28. of products such EPO, filgrastim and somatropin. On the other side, however, there is theestablishment of a highly developed framework of regulations in the European Union for theapproval of biosimilar products. The regulatory framework of Europe by the EMA (EuropeanMedicines Agency) (earlier called as EMEA, terms used alternatively in this report) hasinfluenced the regulatory authorities in other countries like Unites States, Japan and Canadawhich will work on the similar lines (Zuniga & Calvo, 2009).3.1 REGULATORY FRAMEWORK EUROPE: The regulatory framework and process for the biosimilar product approval is defined bythe European Directive 2001/83/EC which is modified by Directive 2003/63/EC and Directive2004/27/EC. These Directives provide detailed specific guidelines which have to be followed bythe biosimilar developers. These guidelines include an overarching guideline (Box 1) and alsoother broad guidelines which are associated with quality of the product and clinical and nonclinical data which is to be provided by the biosimilar applicant (Fig 3.1). EMEA has also providedproduct specific guidelines and are also in the course of developing supplementary guidelineswhich will upgrade the main guidelines as new information is continuously added and found.Box 2 states the guidelines which are being issued in the European Union in reference tobiosimilars. Fig 3.1: Regulatory guidelines. Source: Kox, S., 2009 19
  29. 29. Box 1: Summary of biosimilar overarching guideline (EMEA/CHMP/437/04) Source: Taylor, P., 2009. 20
  30. 30. Box 2: Summary of biosimilar overarching guideline (EMEA/CHMP/437/04)PD= Publication date; ED= Effective Date. Source: Taylor, P., 2009. 21
  31. 31. As per the legislation the Committee for Medicinal Products for Human Use (CHMP) ofthe European Medicines Agency (EMEA) has discretion to develop guidelines which determinethe amount of clinical trials required as per the product (Chu & Pugatch, 2009). The pharmaceutical products resulting from biotechnology are registered in Europealone through a centralized procedure which results in a European Union license. The EuropeanUnion license is valid in all the member countries of EU (Zuniga & Calvo, 2009). The biosimilar developers for the marketing authorization of the product have to fulfill thefollowing requirements which are set by EMEA: Data on the comparability studies should be provided between the applicant biosimilar product and reference innovative medical product. Non clinical studies data which are generally required in limited details as compared to applications for the innovative product. To prove safety and efficacy of the biosimilar product clinical studies are required. An obligation to provide post market pharmacovigilance arrangements as part of the approval process (Zuniga & Calvo, 2009). EMEA has developed biosimilar regulatory guidelines with major distinctions from thegeneric medicines approval process considering the fact that biosimilars are not expected to beidentical to the innovator biologic medicines. The fact that conventional generics are differentfrom biosimilars is recognized by European legislation and mentioned in the Article 10(4) of EUDirective 2001/83/EC which has been modified by Directive 2004/27/EC (Kresse, 2009). Establishing bioequivalence alone of the biosimilars to the innovator biologic is not sufficientto get market approval. The basic fundamental idea behind the guidelines is that the biologicalactivity of the biosimilars cannot be determined if the active substance is different from theinnovative biologic. Analyzing the pharmacokinetic properties of the biosimilars will not offersatisfying results on whether the similar but not identical nature of the active substances haslead to changes in clinical safety and efficacy profile. Therefore the biosimilar applicant todemonstrate the similar product quality, safety and efficacy profile to the innovator biologic has 22
  32. 32. to perform further clinical and non clinical studies according to the EMEA clinical and nonclinical guidelines (Box 3) to acquire market approval (Fox, 2010). Box 3: Summary of Biosimilars Clinical & non clinical Guideline Principles for MEA/CHMP/42832/05 Source: Zuniga & Calvo, 2009 23
  33. 33. 3.1.1 PRODUCT SPECIFIC GUIDELINES: Apart from general regulatory guidance issued for all biosimilar categories, EMEA hasadditionally issued guidelines which are specific to the product class such as EPO, G-CSF, humansoluble insulin, somatropins, low molecular weight heparin and interferon alpha. The guidelinesfor other product category such as monoclonal antibodies or biosimilar medicinal productscontaining monoclonal bodies have been in the stages of finalization. The Biosimilars MedicinalProducts Working Party (BMWP) is in the process of preparation of the guidelines for the SimilarBiological Medicinal Products containing Follitropin alpha and beta-Interferon. Currentlyaccording to the EMA (2010) there is also revision and maintenance of the existing overarching,non-clinical and Clinical guidelines by Biosimilars Medicinal Products Working Party (BMWP). The product specific guidelines explain in details the extent and type of studies, both interms of clinical and non clinical, which should be carried out and presented to the regulators toobtain approval for the product. The guidelines not only expect the biosimilar product to be safeand effective but also to be comparative in nature and most importantly to identify variation inresponse between the biosimilar and innovative biologic. It is of important concern that theminute differences of biosimilars to innovative product with reference to quality are notacceptable by the guidelines and even if they are anticipated then proper explanation regardingthe implications caused by the variation should be provided. As per the guidelines, it is crucialthat the biosimilar applicant demonstrates that the quality, safety and efficacy of the biosimilarare similar to that of the innovators biologic it seeks to copy. The attributes of the biosimilarsshould display equivalence and cannot be worse, better or different from the innovator biologicproduct. If the biosimilar is different or better than the original biologic, which is not analternative as it implies there is lack of similarity, then the biosimilar product may have to bewithdrawn from the application process, would get rejected or have to apply for new productapplication necessitating a need to pursue a full stand alone pathway (Fox, 2010). Given that the data submitted by the biosimilar applicant are less than the innovator,the approach of the EMEA to acquiring authorization of a biosimilar, in that, there is nostandard data set which is applicable to all classes of biologics, is sensible. There is a variation 24
  34. 34. among different classes of biologics in terms of benefit and risk profile, whether surrogatemarkers are available and validated, adverse events possible and clinical indications. EMEAprovides product class specific guidelines that suggest the data and studies which are supposedto be conducted but does not provide the exact equivalence margins. Therefore the guidelinesdo not lay down set standards for approval and there is possibility to maneuver when it comesto settling exact standards for approval of any biosimilar (Fox, 2010). The Regulatory pathway for biosimilars in the European Union was in effect from 2005and since then there have been 14 biosimilar approvals and 7 products received negativeopinion or were rejected by the EMEA (Fig 3.1 & 3.2). The biosimilar applicant requires clinicalstudies consisting of 200 to 500 subjects which depend on the product class of the biosimilar. Incontrast the innovator biologics have to conduct clinical trials on thousands of subjects toachieve a range of clinical indications. This indicates the extent of reduction of clinical trials forthe biosimilar applicant (Fox, 2010). Fig 3.2: market exclusivity. Adapted from Kox, S., 2009 25
  35. 35. 3.1.2 IMMUNOGENICITY: The generic drugs are different from the biosimilars in various aspects and one criticalaspect is their capability to produce immune response. A change in immunogenicity profile is ofmost important concern as it can have enormous consequence on the product safety (Zuniga &Calvo, 2010). The implications which are caused by immunogenicity are difficult to predict. Theformation of antibodies can either have harmless clinical effects or can result into seriousdiseases and some cases considerable adverse events. Immunogenicity effects can be explainedby the example of Eprex which is an EPO product marketed by Johnson & Johnson in theEuropean Union with no significant immunogenic concerns for almost 10 years prior to 1998when regulatory bodies requested for change in the product. Johnson & Johnson modified theEprex formulation by interchanging human serum albumin with polysorbate 80 and glycinewhich resulted in pure red-cell aplasia (PRCA). Pure red-cell aplasia is a severe type of anemia.The antibodies which are produced due to Eprex neutralize all the exogenous rHuEPO and alsocross react with endogenous erythropoietic proteins which results into ineffectivenesserythropoiesis and serum EPO is not detectable. J&J later found out that the polysorbate 80 inthe single use syringes reacted with rubber stoppers to leach plasticizers which triggered theimmune reaction and caused PRCA. In 2003 there was 90% reduction in PRCA by changinguncoated rubber stoppers to Teflon coated rubber stoppers (Chen, 2009). The EMA approval process in association to immunogenicity concerns with biosimilarproducts can be explained with clinical and non clinical testing and comparability decision of thebiosimilar product Retacrit® with the innovator product Eprex®/Erypo®. The applicant offered adatabase of studies which was considered as sufficient by the EMA which consisted of a reporton studies of clinical immunogenicity within a time period of twelve month taking data from 227subjects with renal anemia which was later updated to additional 585 subjects. The toxicity,pharmacokinetic and pharmacodynamic analysis and biologics safety and efficacy are oftenaffected due to anti-drug antibody (ADA) reactions. The safety issues are also related withneutralizing ADA (nADA). In case of Retacrit® and reference product Eprex® the serum sampleswere acquired for the determination of ADA before dosing and through the safety studies. A 26
  36. 36. validated radioimmunoprecipitation assay was used for the testing of the Anti-EPO antibodieswhich indicated that there was a low occurrence of ADA in the subjects which were treatedeither with the biosimilar Retacrit® or the innovator product and also no patients who wereADA positive showed signs of PRCA. These results indicated that there was no need for theNADA tests, but for post marketing surveillance a validated nADA testing was available. TheEMA has not concluded on the specific value of the predictive immunology but its usage isrecommended. For example the transgenic mouse models could be helpful to estimateprobable immunogenicity of the protein in question. Generally in preclinical immunogenicity itis difficult to recognize that the estimations are relevant without clinical data to validatepreclinical assessments (Barbosa, 2011). The European biosimilar regulatory pathway has specific consideration towards thebiosimilars immunogenicity issues and post marketing activity to identify potential concerns.The estimation of immunogenicity of biosimilars cannot be determined by only preclinical trials.As a result clinical trials along with a post marketing surveillance plan are mandatory for theauthorization of biosimilars (Zuniga & Calvo, 2009). In context to the persistent chronictreatment, there is a requirement of immunogenicity data for about a year of treatment beforeauthorization (EMEA/CHMP/BMWP/42832/05).3.1.3 EXTRAPOLATION: With the appropriate justification, as per the relevant guidelines, the extrapolation ofclinical data, for indications for which the drug has not been evaluated in clinical trials, has beenallowed for biosimilars. According to guidelines provided by the EU, extrapolation is notallowed, but is considered on a case by case basis based on various factors such as complexity ofthe product and mechanism of action etc. CHMP guidelines allow extrapolation based onknown mechanism of action and the sensitive indication where, if significant differences wouldexist between biosimilar and the reference product, they would be detected in that particularpopulation (Ruiz & Calvo, 2010). The extrapolation of safety is not approved for any indications.EMEA has approved recombinant granulocyte –colony stimulating factor for the reduction in 27
  37. 37. neutropenia after cancer chemotherapy, but the approval of other indications of referenceproduct were made by extrapolation considering that mechanism of action of biosimilar is thesame. (Zuniga & Calvo, 2010).3.2 EU BIOSIMILAR APPROVAL PROCESS: According to the European Directive 2004/27/EC the conducting of the comparabilitystudies between the biosimilar and the reference product is necessary but the requirements forprobable test are not addressed. The comparability exercise is of various types which includephysiochemical, biological, Pre-clinical and clinical. The reference biologic product underconsideration must be a medical licensed product on the basis of the complete document as perthe necessities of article 8 of Directive 2001/83/EC modified by Directive 2001/83/EC (Zuniga &Calvo, 2010). The reference product chosen to compare with the applicant should be samethroughout the comparability programme. Comparability should be in terms of product qualityand manufacturing process as the safety and efficacy of the product is directly associated to themanufacturing process.3.2.1 COMMON TECHNICAL DOCUMENT: The biosimilar applications should be made completely in agreement with the CommonTechnical Document (CTD) presentation (CPMP/ICH/2887/99). It is structured into five differentmodules which biosimilar applicants have to follow as shown in Table 3.1. The information tobe provided is not restricted to first 3 modules, but additional data will be required. Generallythe supplemental data is determined on a case by case basis in relation to specific scientificguidelines (Directive 2003/63/EC) (Zuniga & Calvo, 2010). 28
  38. 38. Table 3.1. Format of the dossier- modules of the CTD. Source: Zuniga & Calvo, 20093.2.1.1 MODULE 1: In module 1 a brief document is to be submitted comprising information about thedetails of the product, the manufacturing process involved, raw materials used, and its activesubstance. It also involves other information about the comparability exercise such as changesmade during development which would affect the safety and efficacy and detailed descriptionof the reference product.3.2.1.2 MODULE 2: Module 2 expects the data on normal requirements which includes the general idea andsynopsis of the quality, clinical and non-clinical data.3.2.1.3 MODULE 3: A complete quality document which provides information on chemical, pharmaceuticaland biologic information is required for biosimilars. In addition to this information,comparability studies should be provided as per the guidelines of EMEA. 29
  39. 39. 3.2.1.4 MODULE 4: The non-clinical studies to determine the differences and similarities between theapplicant product and reference product are to be demonstrated in module 4. It is crucial toidentify the biological product characteristics of the biosimilar based on studies related tophysiochemical and biological characterization.3.2.1.5 MODULE 5: To demonstrate the safety and efficacy of the biosimilar at the clinical level the studiesconducted at non clinical level are not sufficient. It is essential to submit the design of theclinical program to the regulatory agency. The extent of the biosimilar trial depends on thespecific class of the product (Zuniga & Calvo, 2010). The approval of the biosimilars in the European Union will lead into formation andpublication of public report which is called European Public Assessment Report (EPAR). TheEPAR is designed for the public and is written in collaboration with the biosimilar applicant. Themain purpose of the report is to explain and provide the transparency of the biosimilarapplication and regulatory process involved during the approval period (Zuniga & Calvo, 2009).3.3 UNITED STATES REGULATORY FRAMEWORK: The Regulations framework of Biologics in the United States is regulated by Public HealthService Act (PHSA), but for few exceptions such as insulin and human growth hormone whichcome under the Food Drug and Cosmetics Act (FDCA). FDCA has a regulatory pathway for thegeneric drugs of the conventional chemical drugs, but PHSA does not have any approval systemfor the generic versions of biologics (Clark, 2009). According to the standards of FDCA, thebiological drugs are authorized on the basis of identity, effectiveness and purity rather than onefficacy and safety. Even though there are no biosimilar approval options by the PHSA, there arestill few biosimilar products out in the United States market. For example Omnitrope by Sandoza biosimilar version of recombinant human growth hormone which is similar to Genotropin byPfizer was authorized by the FDA in 2006 for the United States. The approval of Omnitrope was 30
  40. 40. made through a New Drug Application (NDA) which used the route 505(b) (2). This route isdifferent from the generic approach which is called as Abbreviated New Drug Application(ANDA) in various ways such as there is no need for sameness which gives room for satisfactorysimilarity. The applicant using the 505(b) (2) route can use the available research which impliesthat the FDA without citing the trade secrets of Pfizer could evaluate Sandoz’s Omnitrope (Clark,2009). The complicated biosimilar products such as interferons cannot be approved through thisregulatory pathway. President Obama approved the “Patient Protection and Affordable Healthcare Act” inMarch 2010. The main objective of this act was to form legislation by designing a regulatorypathway which will save healthcare cost and creating a flexible route for the approval certainbiologic which reduces the cost of development. The 351 (k) route is the new regulatorypathway for biosimilars which is provided by the Biologics Price Competition and Innovation Act(BPCIA) as part of the Affordable Care Act. According to the pathway the biosimilar should becompared to the single innovative reference product which is authorized under 351 (a) route.Two types of products will be provided by this pathway, Biosimilar and Interchangeablebiosimilar. For obtaining the interchangeable biosimilar approval exact guidelines andrequirements are under discussion. The manufacturers should also comply with patentdisclosure arrangements as per the act. The authority of describing the guidelines for regulatoryframework is given to FDA and they have not yet revealed data requirement for approval(Greer, 2011).3.4 GLOBAL LANDSCAPE: International Conference on Harmonization (ICH) aims to synchronize the approvalprocess and regulatory requirements of drug or biologics in the United States, EU and Japan.Biosimilar regulatory framework is already established in EU and Japan but the legislation is stillunder discussion in US (Chen, 2009). There is establishment of the regulatory pathway have taken place in various countriesof the world such as Brazil, Taiwan, Mexico, Argentina, India, Canada and South Africa. There is 31
  41. 41. a direct acceptance of the guidelines of EMEA in Australia and on similar basis regulation areestablished in Malaysia, Japan and Turkey. The approval pathways followed by variouscountries are not clear in terms of scientific reasoning, therefore the World Health Organization(WHO) adopted a guideline to evaluate similar biologic products which will result in availabilityof the regulated biosimilar products worldwide (Kresse, 2009). 32
  42. 42. 4. CASE STUDY-BIOSIMILAR INSULIN: In general biologics are complex molecules to produce and biosimilar insulins presentspecial challenges. Their therapeutic window is narrow and the accuracy of their dosing isdependent on the product formulation and quality of the administrative device. Therefore forthese specific reasons EMA has issued strict guidelines which the biosimilar applicant mustfollow to receive approval of the biosimilar soluble insulin (Sauer, T. and Kramer, I., 2010).4.1 MANUFACTURING: The recombinant human insulin production is a highly complicated process (Fig 4.1). Thefirst step is the isolation of the human insulin gene which has specific sequence which codes forthe human insulin. After the isolation the gene is attached to the vector and then it is insertedinto a host cell which is generally E.coli or a yeast species. The recombinant cells which areformed are screened which results in the formation of the master cell bank, then furthercultured and fermented. After fermentation the protein which is produced is isolated, purifiedand is folded in order to form secondary structure. To achieve biologically active insulin, thesecondary structure is enzymatically cleaved. Different adsorption and chromatographictechniques are employed for the purification of the recombinant insulin. To prevent the insulinfrom losing its biological activity or avoid aggregation of the product and bacterial growth, thepurified product is subjected to crystallization, lyophilization and formulated by addition ofother compounds such as protamine is added for long acting formulation (Marre & Kuhlmann,2010). If there is any change in the various sequential process of insulin production such aschange in vector selection or change in formulation will result in an insulin product which will beidentical to the innovator insulin product in terms of structure and amino acid sequence but itsclinical properties will differ from the innovator product. 33
  43. 43. Fig 4.1: Post fermentation steps in manufacturing process. Source: (Marre, M. & Kuhlmann, M., 2010)4.2 EMEA REQUIREMENTS: For the market approval of the soluble insulin biosimilars, EMEA has laid down specificguidelines which explain the requirements to be fulfilled by the applicant. As per the guidelineslike all the biosimilars, insulin as a biosimilar product should be analyzed with the comparativetechnique to prove equivalence with the reference product. For biosimilar insulin approval thepreclinical studies are required which consist of in vitro pharmacodynamic studies, in vitroaffinity bioassays and receptor binding assay for insulin as well as IGF-1. 34
  44. 44. The requirement of EMEA is at least one pharmacokinetic single dose crossover study inpatients suffering from type 1 diabetes by subcutaneous administration to compare thebiosimilar with the reference product. To check the biosimilar insulins hypoglycaemic responseprofile, clinical activity must be determined in pharmacodynamic study designed as a doubleblind crossover, hyperinsulinaemic, euglycaemic clamp study (Sauer and Kramer, 2010). Forbiosimilar insulin clinical efficacy trial is not needed but there is a requirement of clinical safetystudy. For at least the period of 12 months, the insulin product immunogenicity should beinspected through the clinical studies. Six months of comparative phase should be included inthe clinical trials. To detect any clinically important immunogenicity that may occur in the longterm, the developers should design a pharmacovigilance plan (Marre & Kuhlmann, 2010).4.3 MARVEL’S INSULIN REJECTION: Marvel Life Sciences Ltd in March 2007 submitted a biosimilars application for marketapproval of recombinant insulin in three different formulations. Marvel Life Sciences Ltdpresented their data from their studies intended to show the similarity between Marvel’s insulinand the reference insulin product in experimental models and in humans. The consequence ofMarvel’s insulin on the blood sugar levels was studied in Twenty-four healthy volunteers withthat of the reference insulin product and these studies were presented to the EMEA. Anotherimportant study was also presented which involved 526 diabetes mellitus patients who eitherreceived Marvel’s insulin or reference insulin for the period of 12 months. There were various issues found by CHMP regarding the data and application submittedby Marvel Life Sciences. CHMP found that data on many critical aspects of the application werenot enough and unclear. Review of the application was done by EMEA, considering theapplication CHMP formed a conclusion that the three formulations of biosimilar insulins byMarvel Life Sciences Ltd were not comparable with the reference insulin. The CHMP rejectedMarvel’s insulin on the grounds of Quality, Clinical and Non-Clinical aspects. 35
  45. 45. 4.3.1 QUALITY ASPECTS: The Proper evaluation of the application was not possible because sufficient amount ofdata was not submitted on the development and manufacture of the drug substance as well asthe drug product. There was confusion whether the reference product used for thecomparability exercise was valid or not. The explanation provided for the process likefermentation, harvesting, purification and modification in the application were not in completedetails. The comparability exercises to detect impurities in the insulin product to that of thereference product were not adequate to draw a conclusion that Marvel’s insulin was biosimilarto the reference insulin. There was a huge confusion that the dossier submitted duringapplication was unable to specify two different presentations of the drug product (vials andcartridges).The important details such as drug substance batch number, size and site ofmanufacture and details of where the batches have been used for clinical and pre-clinical trialswere absent in the dossier (Joshi, 2009).4.3.2 NON CLINICAL ASPECTS: Based on the data submitted, the committee was not able to review the comparability ofMarvel’s insulin with the reference product due to insufficient explanation.4.3.3 CLINICAL ASPECTS: The pharmacodynamic studies did not provide the result of lowering the blood glucoselevel as compared to the reference product. The sufficient pharmacokinetic studies were notcarried out such as single dose crossover comparative studies by the use of subcutaneousinjection as per the guidelines. The immunogenicity of the insulin product was not completelyevaluated and validated. Additionally the pharmacovigilance plan presented in the dossier wasnot up to the requirement of the EMEA guidelines (Joshi, 2009). Due to inadequate studies and lack of well presented data in January 2008 it wasdeclared by the EMEA that Marvel Life Sciences Ltd have withdrawn applications for all threeinsulin formulations (Marre & Kuhlmann, 2010). 36
  46. 46. 5. MARKET ANALYSIS: The focus of the market analysis in this thesis is based on major markets such as theUnited States and the European Union.5.1 BIOSIMILARS ON MARKET: The expiration of patents of a number of first generation of biologics has led to theapproval of various biosimilar drugs by the European Medicines Agency (then EMEA, now EMA)in Europe. EU in 2003 held discussions on the follow on biologic recombinant proteins conceptand then later the guidelines on biosimilars were established and took effect in 2005. TheCommittee for Medicinal Products for Human Use (CHMP) according to the guidelines forbiosimilars requires complete characterization in terms of physical, chemical and biological ofthe biosimilar product as compared to the reference product. To prove the safety and efficacyof the biosimilar product widespread characterization, clinical and non clinical data is requiredbut as per the guidelines the amount of data required will be less than the application of theinnovators drug (Greer, 2011). Omnitrope, a biosimilar version of somatropin was the firstbiosimilar drug to get approval from the EMEA in April 2006. Another Human growth hormonecalled Valtropin was approved by EMA immediately two weeks after the approval of Omnitrope.Table 5.1 illustrates that to date the EMA has approved 14 biosimilars products which includethe versions of somatropin, EPO and filgrastim. Nine different biosimilar companies havesuccessfully launched 7 biosimilar molecules under 14 different trade names (EBE 2010). 37
  47. 47. Table 5.1: Biosimilars approved by the EU. Source: Greer, F.M., 2011 Table 5.2 shows that several applications such as interferon alpha-2a and insulinreceived negative opinion and some applications were not successful, either rejected orwithdrawn voluntarily. 38
  48. 48. Table 5.2: Unsuccessful biosimilar applications in the EU. Source: Greer, F.M., 2011 In the United States there is no legislation for a clear regulatory approval pathway forbiosimilars but still Omnitrope, a biosimilar version of somatropin was authorized by the use ofthe Abbreviated New Drug Application (ANDA) process under the Hatch-Waxman Act followingEU approval (Horikawa et.al, 2009). There were various biosimilars approvals before Omnitropewhich didn’t achieve to receive as much attention as Omnitrope. These approvals includedifferent recombinant biologic drugs with trade names such as Glucagen, Hylenex, Hydase andAmphadase. Fortical by Unigene which is similar to Miacalcin by Novartis used for the treatmentof osteoporosis was the first biosimilar recombinant DNA product to be authorized by FDA bythe 505(b) (2) route under NDA (Clark, 2009). 39
  49. 49. 5.2 MARKET SIZE & GROWTH: The patent expirations from the year 2009 through 2013 are expected to trigger thebattle the approval and production of biosimilars (Crandall, 2009). The potential of the totalworldwide market for the biosimilar products is quite significant amounting up to several billiondollars annually. Significant opportunity for the biosimilars market is also created as thebiologics worth $25 billion are expected to go off-patent by 2016 (Business Insights Ltd, 2009).The biologic market has outperformed the pharmaceutical market which is driven by high pricesfor the therapies which cannot be managed by traditional drugs. In 2007 Biologics contributedmore than 10% of the global pharmaceutical revenues. The annual rate of growth for thebiologics is growing at the rate of 12%-13% which is almost double the global pharmaceuticalindustry rate of growth (Business Insights Ltd, 2009). The growth of the biosimilars market is also fueled by the rapid penetration of the novelbiologics in the global pharmaceutical markets and the gradual expiry of the patents of thenovel biologics. There was 5.9% growth in the global biosimilars market in 2007 to reach thevalue of approximately $1 billion (Business Insights Ltd, 2009). The growth of the biosimilars willbe majorly driven by the four drug classes - erythropoietin (EPO), filgrastim, human GrowthHormone (hGH) and insulin in the future. The revenues from the biosimilars are currently lessbecause one of the profitable markets, such as the U.S. is facing regulatory restrictions but afterthe regulatory framework is established there will be a number of products which could havemarket authorization and thereby increasing the revenues and size of the biosimilar market(Crandall, 2009).5.3 MARKET POTENTIAL: There is a range of reports which provide estimates on worldwide biosimilars marketfigures and forecast. As this market is highly speculative the range of figures and estimatesprovided by the various reports vary. 40
  50. 50. The total global biosimilar market potential for the period of 2006-2013 is forecasted forthe currently expired patents by Crandall (2009) which indicates that by the year 2013 therevenues generated would be $358 million at the 17.0 percent growth rate and for the period of2006-2013 the compound annual growth rate would be 32.5% (Table 5.3). Table 5.3: Total World Biosimilar Market Potential 2006-2013 (Products with currently expired patents).Source : Crandall M., 2009. Fig 5.1 represents the steady growth of the global biosimilar market and its potentialwith currently expired patents. 41
  51. 51. Fig 5.1: World Biosimilar Market potenatial by region 2006-2013, products with currently expired patents. Source: Crandall, 2009.5.4 REGIONAL MARKET ANALYSIS: The European Union and the U.S. are the major markets for the sales and revenuegeneration from the biosimilars. As compared to any other region worldwide the products inthe U.S. perform better in reference to sales and the drug approval in the U.S. generally sets thestandard for the approval abroad. Marketers consider that the U.S. market is generally mostfavorable. Lack of regulation is holding back the biosimilar market from expanding in the U.S.Although in the U.S. there is no clear developed pathway for the authorization and approval ofthe biosimilars as compared to other countries, currently only few approvals of biosimilars canbe seen for the regions other than the U.S. There is some progress with a range of biosimilarsapprovals in markets such as Eastern Europe, Asia and South America but still the sales revenuesare quite less as compared to the major markets such as the U.S. and Europe. Novartis, is themain competitor in the biosimilar market, as this company has made progress in early phase of 42
  52. 52. the market. In less regulated and less developed markets like India, Rituxan and Neupogen aresubstituted by the generic counterparts (Crandall, 2009). Table 5.4 shows the distribution ofmarket potential for biosimilars in major markets such as Europe and the United states and therest of the world from currently expired patents. Table 5.4: World Biosimilar Market Potential by Region 2006-2013 (Products with currently expired patents). Source: Crandall M., 2009.5.5 BIOLOGIC CLASS MARKET ANALYSIS: Table 5.6 shows the forecast for market potential and revenue generated from individualproduct categories which are currently marketed. The biosimilar versions of the blood productslike erythropoietin and G-CSF are in great demand in the global biosimilars market. Salesrevenues generated from these products alone in the period of 2008 were estimated to be $62million (Crandall, 2009). This sales figure consists of the sales of the products in the EuropeanUnion as well as in the less regulated market throughout the world where relaxed laws of 43
  53. 53. biosimilars exist. Despite of the fact that insulin is the favorable for biosimilar production due tothe reasonably less complex manufacturing process, the sales of the biosimilar insulin isrelatively low as compared to the total market of insulin. Another key product in biosimilarproducts is HGH which is favorable for production in the U.S. and Europe, but the sales resultsare much lower than predicted by producers. Global sales for the biosimilar HGH is about$15million for the year 2008 and with the growth rate of 21.9% during the projected period(Crandall, 2009). The category of biosimilar drugs which involves autoimmune and oncologyproducts shows a rapid growth with sales estimated to be $39 million throughout 2008(Crandall, 2009). The accessibility of the monoclonal antibodies and multiple sclerosistherapeutic biosimilar versions is found in regions of the world where there is less regulationand the patent laws are not strict. Table 5.6: The world market potential for Biosimilars by Biological Class (EPO, G-CSF, insulin, Interfereon, alpha, others) 2006-2013. This forecast includes currently marketed classes only. Source: Crandall M., 2009. 44
  54. 54. It has been reported by (Emmerich, 2010) that by the year 2015 the European andUnited States biosimilar market size could reach US$ 10 billion. The monoclonal antibody (mAB)segment is anticipated to generate most revenues. The Biosimilars’ largest market share isexpected from the revenues generated from mAB such as Remicade and Rituxan. Fig 5.2indicates the predicted market share among various classes of biosimilar drugs by 2015. Themarket is dominated by various companies which will lead in variation in market penetrationbetween products. For example biosimilar insulin market penetration is considered lowbecause the market is dominated by other three originator companies and on top of thatadvanced injection system is required for insulin. Fig 5.2: Expected Biosimilar market split in 2015 Source: Emmerich, R. (2010)5.6 MARKET OPPORTUNITIES: The global biosimilar sales estimates (Fig 5.3) were reported by Clark (2009) for a periodof five years ending in 2012. The estimates provided in the report were based on biosimilaractivities in Europe as the US market, due to lack of regulatory framework, is not likely to showany momentum during this period. Even though the biosimilar market value would be around$13 billion for the period 2009-2012 which is quite considerable, this biosimilar market is 45
  55. 55. actually predicted to represent only a small percentage of total pharmaceutical and genericsales of the future. Fig 5.3: Forecast of the global biosimilar market value in $billion: 2008-12. Source: Clark, T.D., 2009 The prices of the biosimilar products will generally be 20% to 30% less than thecorresponding innovator products. The average price of biologic could be $16,425 p.a. which isaround 20 times the cost of the chemical generics (Emmerich, 2010). As compared to the 90%savings from traditional generics the savings of 30% from biosimilars is not significant, but, ifconsidering a situation where the treatment of the metastatic cancer through the biologic drugcan cost up to $200,000 a year, savings of mere 30% amounts to much more than a 90% savingson a drug which costs $1000 (Emmerich, 2010). The biologic drugs are expensive at an averagedaily cost of $45 or 22 times that of conventional drugs. Table 5.7 provides the estimates of thetreatment cost per patient of selected biopharmaceuticals. The first wave of thebiopharmaceutical drugs accounting up to $10 billion market have already lost patentprotection and by 2018 further biopharmaceutical drugs of $20 billion market will lose patentprotection (Clark, 2009). These figures and circumstances has led to immense interest towardsthe market opportunities generated by the biosimilars industry. 46
  56. 56. Table 5.7: Estimates of treatment cost per patient of selected biopharmaceuticals. Source: Crandall, 2009.5.6.1 PATENT EXPIRY: The expiry or pending expiry of patents of the biopharmaceuticals products such asinterferons, human growth hormone and epoietins is the most serious problem faced by thebiopharmaceutical industry. The expiry of patents of many blockbuster biologic products hascreated immense market opportunities for biosimilar industry in markets where the innovatorcompanies are already established. When it comes to patent protection, there are numerouspatents which are generally issued by the innovator companies for specific APIs (ActivePharmaceutical Ingredient The extent to which the innovator companies can go to protect andextend patent protection of these patents poses extreme difficult issues for the prospectivebiosimilar companies (Taylor, 2009). In the United States the Congressional Budget Office has estimated that out of the $40billion exhausted on the biopharmaceutical products in 2007, the products which contributed to 47
  57. 57. the three quarters of the spending will lose patent protection by the year 2019. The governmentinitiatives will be benefited by the cost reductions through the period of 2010-2019 whichwould amount up to $9.1 to $11.7 billion and during this period the private insurance programswould experience 0.2% reduction in premiums (Clark, 2009). Reports have mentioned that there are major opportunities for the biosimilarmanufacturers during the period of 2010 to 2015 as throughout this period 45 biologic drugspatent will expire and their value is more than $60 billion in global sales (Emmerich, 2010). Fig5.4 shows the number of biologic drugs set to lose patent protection per year during the periodof 2010 to 2015 and annual global sales. Fig 5.4: Number and value of biological drugs set to lose patent protection per year through 2015 Source: Emmerich, R. (2010) 48
  58. 58. Table 5.8 shows that the blockbuster biologic drugs such as Enbrel, Remicade, Rituxanwith the global sales in billions lose the patent protection in major markets like US and Europefrom 2012 to 2015. Table 5.8: Blockbuster biological drugs set to lose patent protection per year through 2015. Source: Emmerich, R. (2010)5.6.1.1 PATENT EXPIRY BY BIOPHARMACEUTICAL CLASS:5.6.1.1.1 ERYTHROPOIETINS (EPO S ): The biologic drugs have different classes based on the therapy areas. In theerythropoietins (EPOs) category there are many products which have been repeatedly reportedto have gone off patent in December 2004. First generation EPOs by Amgen such as Epogen(epoetin alfa) and Johnson & Johnson’s Procit and Eprex have gone off patent. It has beenreported that Amgen is also involved in patent disputes on various development patents of EPOwith Wyeth, Roche. Various disputes are resolved but the terms and agreements are notdisclosed which could indicate that parties resolved disputes by cross licensing their patents(Taylor, 2009).5.6.1.1.2 INTERFERONS ALPHA (2A & 2B): Interferons Alpha market segment has two fundamental products Pegasys andPegIntron. The usages of these two products are done in the treatment of hepatitis Cfrequently with the combination of ribavirin. Standard interferon products such as Roferon(interferon-ά 2a) and Intron-A (interferon-ά 2b) which were introduced before Pegasys and 49
  59. 59. PegIntron are still marketed but are not as effective as PEGylated products (Pegasys andPegIntron) and so they are prescribed to a lesser extent than PEGylated products(Taylor, 2009). Table 5.9 shows the expiry dates of the patents of major Interferon Alpha productswhich currently exist on the market and indicates use of improved method such as pegylation asa strategy to lengthen the market exclusivity following the expiry of patents of the standardinterferon products as both the standard and pegylated interferon products are from samecompanies. Table 5.9: Interferons on market and patent expiries. Source: Taylor, P. (2009)5.6.1.1.3 INTERFERONS BETA (1A & 1B): Some most important patents have recently expired of a class of biopharmaceuticalswhich constitute of interferons (beta-1a and beta-1b). For the treatment of Relapsing/RemittingMultiple Sclerosis the principal product used is Avonex which belongs to key group ofinterferons and is manufactured by Biogen Idec. For the production of beta interferon there arevarious companies which have pending patent applications or issued patents in the UnitedStates, Europe and other major market and countries and these patents are regarded as theTaniguchi patents. There also some other patents which are called as Roche patents and theRentschler patents which are pending patent applications or issued patents for interferon betaby the companies EMD Serono Pfizer and Bayer. Biogen Idec has access to rights in differentcountries and markets of the world such as United States, Europe and Japan for production andmarketing of Avonex as per the Taniguchi, Roche and Rentschler issued patents (Taylor, 2009). 50
  60. 60. The Taniguchi patents are going off patent in the United States in 2013 and they havealready expired in other parts of the world. The Roche patents have expired in most countries ofthe world and they will expire in May 2008 in the United States. The European Union Rentschlerpatents expire in July 2012. Other interferon beta-1a products such as Betaferon (Betaseron) byBayer and Rebif by company Merck Sereno for multiple sclerosis have lost patent protection inthe United States in 2007 and most European Union countries in 2008. In a couple of years timethe pricing and sales of Betaferon (Betaseron) would be significantly affected due to the expiryof the patents in Europe. Table 5.10 summarizes the currently available multiple sclerosis dugson market and patent expiry dates of these products. Fig 5.6 shows the predicted market shareof the multiple sclerosis drugs on market which would lose market share due to the entry of thebiosimilar version of the multiple sclerosis drug. Fig 5.6: Predicted market share of multiple sclerosis drugs (2007-2017) Source: (Taylor, 2009). 51
  61. 61. Table 5.10: Multiple sclerosis drugs on the market and patent expiries. Source: Taylor P., 2009.5.6.1.1.4 HUMAN INSULIN AND INSULINS ANALOGUES: Insulin products such as Humulin and Novolin are used for the treatment of diabetes.These insulin products are structurally identical to the naturally occurring insulin in humanpancreas. Later on insulin analogues were available in the market such as Lantus, Humalog,NovoLog, Levemir and Apidra which are modified to make their properties better than naturalhuman insulin (Taylor, 2009). Table 5.11 shows that the original recombinant insulin productssuch as Humulin and Novolin first launched in the market have lost their patent protection inthe year 2001 and 2002 respectively, but the insulin analogs which were introduced later willexpire during the 2013 to 2018 period. 52
  62. 62. Table 5.11: Recombinant insulin products on the market and patent expiries. Source: Taylor P., 2009.5.6.1.1.5 MONOCLONAL ANTIBODIES ( M AB): Monoclonal Antibodies are an important category in the biopharmaceuticals consistingof complex proteins which have a wide range of therapeutic applications such as cancer,rheumatoid arthritis, asthma and psoriasis. Monoclonal Antibodies products have generatedsales revenue which is more than $21 billion in 2007. The Mab drug or product which firstsucceeded commercially in the market and generated significant revenues was Rituxan as itproved to be effective than most of the other therapies available on the market. Consideringthe success of the Rituxan the drug developers launched various other Mab products such asAvastin, Herceptin, Remicade, Humira and Erbitux. The innovator companies manufacturingMab are going to face competition from the biosimilar developers as major Mab products areabout to go off patent from 2012 (Taylor, 2009). Fig 5.7 illustrates the patent positions of theleading biopharmaceutical products which are already expired or are about to lose patentprotection in the near future. 53
  63. 63. Fig 5.7: Estimated patent expiry dates of selected proteinsSource: Taylor, 2009.5.7 MARKET SHARE: The current market share of the biosimilars contributes to only a small part of the salesvolume of the biologic drugs which are gone off patent. It has been reported that since 2005only 25% of the biologic drugs have their patent status as expired and this indicates theopportunity of more than $20 billion sales for biosimilars (Emmerich, 2010). The Indian and Chinese biosimilar manufactures have launched more than 50 biosimilarproducts in less regulated markets which is significantly high as compared to the US andEuropean manufactures (Emmerich, 2010). Fig 5.8 shows the market share for biosimilars in theoff patent biologics market. In the biologics market 23% of the biologic have gone off patentand out of these 23%, the biosimilars market share is less than 5% which indicates the attractivemarket opportunity for biosimilars to expand. 54
  64. 64. Fig 5.8. Market Share of biosimilars in the off patent biologics market. Source: Emmerich, R., 2010 Table 5.12 illustrates that the biosimilar market is quite small in the regulated marketswith less than 20 biosimilar products in the market. Table 5.12: Bbiosimilar companies sales and market share. Source: Emmerich, 2010. 55

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