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A biosimilar is a biological medicine that enters the market subsequent to expiration of the patent of an original reference product and its similarity to the reference medicine exhibits ‘no clinically meaningful differences in terms of quality, safety and efficacy’.1 In practice, patents protect a reference product for 10 years after its approval before registration for a similar biological medicine can be applied for.1 The term ‘biosimilar’ is recognised by all regulators, but synonyms include ‘similar biotherapeutic product’ (WHO) and ‘subsequent-entry biologic’ (Canada).2 Biopharmaceutical agents are derived from living cells or organisms and are usually complex proteins. Therefore, regulators are establishing novel specific approval pathways for biosimilars that differ from those for chemical generics. Since the first approval in 2005, several biosimilars of somatropin (human growth hormone), filgrastim (granulocyte colony-stimulating factor, G-CSF) and epoetin (erythropoietin) have become available in Europe. Currently, 12 biosimilars are authorised in the European market, and numerous others, including monoclonal antibodies (mAbs), have applied for authorisation.3 ,4 This subject has received increasing attention in gastroenterology, because the patent on infliximab is due to expire and regulatory approval for two biosimilar infliximabs have already been filed for to the European Medicines Agency (EMA). One of these molecules is already available for patient care in South Korea.4 ,5
The driving force behind biosimilar development
Biological agents are currently in widespread use for the treatment of chronic inflammatory diseases. As recently as in 2000, only two of the world's top 10 grossing drugs were biological agents. In 2012, estimates are that seven are biological agents, of which adalimumab and infliximab lead the list.6 The long duration of development and high manufacturing costs are cited as the main contributors to the high cost of biological agents. For example, the average yearly cost of infliximab treatment for Crohn's disease in a single patient is estimated to be €15 000.7 Therefore biosimilars, which are usually priced 15–30% below their reference products in Europe, may become less costly alternatives to innovator biological agents.
Biosimilars and chemical generics: apple and pear
Chemically synthesised drugs are usually small molecules (eg, omeprazole is 345 Da and acetylsalicylic acid is 180 Da in size), whose structures are well known, stable and reproducible and have low potential for immunogenicity. In contrast, biopharmaceutical agents are large (eg, infliximab is 149 000 Da and interferon-α is 19 000 Da), fragile molecules with a highly complex, three-dimensional structure. Most importantly, biopharmaceutical agents are engineered in and produced by living cells, which determine the overall structure and post-translational modifications, resulting in a major potential source of manufacturing heterogeneity. As a result, the development of biological agents—from identification of the target to marketing—takes an average of 10–12 years, and the complex manufacturing process is associated with approximately 2.5 times higher costs than chemical drugs.8 ,9 Consequently, biosimilars have a completely different nature from chemical generics, and regulatory strategies for chemical generics are not appropriate for biosimilars.
Biosimilars: identical, similar or dissimilar?
Production of biosimilars is associated with several challenges. First, molecular heterogeneity of biological agents results from the complex interplay of the primary, secondary and higher-order structures. In addition, intra- and inter-molecular interactions and post-translational modifications result in millions of chemical forms. For example, antibodies are highly glycosylated in their Fc region. The type and degree of glycosylation has a major influence on interaction with Fc receptors, and such changes in the glycosylation pattern could have unpredictable effects on efficacy and safety.10 Second, currently available high-tech analytical tools remain limited in their capacity to characterise all possible chemical variants of biological products. Accordingly, the absence of detectable differences could be misinterpreted as evidence of biosimilarity.11 Third, the final biosimilar product is determined by the manufacturing process, where all steps are required to be consistent and reliable. However, even after patent expiration, biosimilar companies do not have access to the manufacturing process of the innovator products, since these are trade secrets. The manufacturing process includes several steps, namely the vector, the host cell expression system, the cell expansion procedure (growth medium, method of expansion), the protein recovery mechanism (eg, filtration and centrifugation), the purification process and the formulation of the therapeutic protein into a drug.12 Therefore, owing to the vast molecular structural heterogeneity, and differences in manufacturing, biosimilars are highly unlikely to be identical with their reference products. Alterations in receptor binding, stability, pharmacokinetics and immunogenicity may result in altered safety or clinical efficacy. Therefore biosimilars require distinct, stringent regulatory approval processes.
Fourth, manufacturing drift or incremental differences among multiple biopharmaceutical agents—either original products or biosimilars—may occur after changes in manufacturing over the years of production.13 Consequently, after demonstration of biosimilarity at the time of approval, a biosimilar and a reference drug could potentially diverge over time to a point where they are no longer deemed similar. To prevent this, EMA provides principles for assessing comparability of biological products before and after changes in the manufacturing process.14 In our opinion, demonstration of comparability between multiple biosimilars and the initial biosimilar product is therefore also necessary.
There is a clear distinction between biosimilars and second- or later-generation biological agents. The latter, such as adalimumab and golimumab, are structurally different from the first-generation compound, in this case infliximab, and they are developed independently, so physicochemical properties and clinical efficacy are not evaluated against the reference product. The term ‘biobetter’ is applicable when there is evidence for a clinically relevant advantage over the first-generation product.2 ,15
The international non-proprietary name (INN) is the official name given to a pharmaceutical substance, as designated by the WHO. The generic adaptations of chemical medicines are assigned the same name, as they are identical copies of the reference products. However, as biosimilars are not identical, not only their brand names, but also their INN labelling should be unique, as recommended by the WHO, possibly including the deviations from the innovator products.16 We are in favour of this WHO approach. However, in Europe, a biosimilar erythropoietin (HX575) is approved under the INN ‘epoetin alfa’, despite a different glycosylation pattern from the reference product.
Unavoidable structural heterogeneity and differences in manufacturing have raised concerns about identity, efficacy and purity, immunogenicity, safety and interchangeability of biosimilars.17
Features of structural heterogeneity may have unpredictable clinical implications. As an example, when a biosimilar tissue plasminogen activator product was compared with the innovator compound in India, a 2.5-fold difference in glycosylation occupancy was found, which affects clot lysis and may compromise bioequivalence.18
Efficacy and purity
A study comparing 11 marketed epoetin alfa products from four different countries (Korea, Argentina, China, India) demonstrated variability in the isoform distribution and significant diversions from the specification for in vivo bioactivity (71–226%). Most remarkably, five products failed to comply with their own specifications.19 A similar study examined quality parameters of 16 commercial biosimilar brands of three biopharmaceutical agents from the Indian market (recombinant human pegylated G-CSF, recombinant human G-CSF, recombinant human erythropoietin). A marked lack of comparability between biosimilars and innovator products was found, and a significant difference in the level of purity was observed.20 In contrast, two EMA-approved biosimilar erythropoietins (Binocrit and Retacrit) were shown to have quality that was similar to, or better than, the reference originator product (Eprex).21 These examples further emphasise the importance of adequate regulation pathways regarding biosimilar production.
An undesirable immune response is a serious safety concern for biological agents and biosimilars and may also impair efficacy.22 The development of drug antibodies is influenced by patient-related factors (genetic background, age, disease type and activity, coadministration of immunosuppressive agents) as well as product-related factors (dosing, mode and timing of administration, product aggregation and denaturation).23 ,24 The interplay of these factors for a given product is not predictable in the laboratory and thus cannot exclusively be evaluated by empirical studies. After a manufacturing modification of a subcutaneously administered innovator epoetin (Eprex), a dramatic increase in the incidence of pure red cell aplasia occurred from 1998 to 2003 such that over 200 cases were reported in chronic renal failure.25 This epidemic was later attributed to the replacement of human serum albumin as a stabiliser with the synthetic detergent, polysorbate 80 and glycine, which enhanced leaching of organic compounds from rubber stoppers in the drug syringes.26 These substances acted as an adjuvant, resulting in an immune response against membrane-bound erythroblasts in the bone marrow, which caused red cell aplasia. More recently, in an investigational clinical trial comparing the subcutaneously administered biosimilar, epoetin alfa HX575, and Eprex in 337 patients, two cases of neutralising antibodies were reported.27 Evidence suggests that tungsten contamination during the manufacturing of the syringes mediated epoetin aggregation, which resulted in antibody formation, a phenomenon that may cause pure red cell aplasia.28 In summary, multiple examples exist that underscore the importance of adequately evaluating the potential immunogenicity of a biosimilar both by in vitro methods and in the clinic.
Interchangeability refers to switching a patient from an innovator biopharmaceutical agent to a biosimilar (or vice versa) by the treating physician. Although switching between biological medicines raises potential safety concerns, on the basis of 58 clinical trials collectively including 12 039 patients, safety has not been shown to be compromised when switching between biopharmaceutical agents.29 ,30 However, these data did not supply evidence on biosimilar mAbs. Therefore we suggest that interchangeability of mAbs should be evaluated on an individual basis by the treating specialist and should not be routinely recommended. Substitution or replacement of biological agents at the pharmacy level in order to deliver the most economical treatment should not be recommended, since this practice would hamper the necessary strict pharmacovigilance programmes.31
Biosimilar approval pathways
The approval of a chemical generic only requires an abridged process that focuses on chemical and manufacturing methods and uses a pharmacokinetic study, performed in healthy volunteers, to establish therapeutic equivalence to the reference product. However, the approval of biosimilars has required the development of new regulatory standards that continue to evolve.
In Europe, all biopharmaceutical agents must be authorised by the EMA, which established an initial pathway for the approval of biosimilars in 2005.32 Assessment of biosimilar applications is carried out according to guidelines of the Committee for Human Medicinal Products (CHMP) of the EMA. The guidelines, including a separate guideline for biosimilar mAbs which came into effect on 1 December 2012, establish the necessary studies to show similarity of the new agent to the original and determine the production quality requirements.33 The first step of mAb development is demonstration of comparability to the reference product with regard to pharmacokinetic properties using methods that are ‘sensitive enough to detect differences in the concentration–activity relationship between the biosimilar and the reference product’.33 Pharmacodynamic evaluations may contribute to this comparability exercise. These studies determine whether further comparability studies on similar clinical efficacy need to be performed in an adequately powered, randomised, parallel group comparative clinical trial. Clinical safety is monitored during the pharmacokinetic evaluation and the clinical comparability study. Furthermore, strict pharmacovigilance is required. On the basis of EMA guidelines, biosimilars of human growth hormone, erythropoietin and G-CSF (table 1) have been approved. Conversely, the EMA has rejected applications for Alpheon, a biosimilar interferon-α 2a, because of concerns over manufacturing technique and quality control.3
In the USA, the Hatch–Waxman Act of 1984 standardised procedures for generic chemical drugs through an Abbreviated New Drug Application. Biopharmaceutical agents and biosimilars of insulin and human growth hormone have previously been approved under the authority of the Public Health Service Act and Section 505 of the Federal Food, Drug and Cosmetic Act. However, the regulation of biosimilars has also resulted in new legislation in the USA. The Biologics Price Competition and Innovation Act of 2009, which was signed into law in the Patient Protection and Affordable Care Act in 2010 as part of the health reform, gave the Food and Drug Administration (FDA) the authority to approve biosimilars in an abbreviated licensure process. This also enabled the FDA to decide on a case-by-case basis how much testing is needed to compare a biosimilar with an FDA-licensed reference product to obtain approval.34 The clause on data exclusivity guarantees a 12-year period from the time of FDA approval of an innovator compound to when approval for a biosimilar could be applied for. To date, no products have been approved by this novel procedure.
Health Canada has developed the most rigorous process for approval of biosimilars. While the EMA and FDA allow approval for several disease indications for a single biosimilar based on extrapolation of the efficacy data for the original compound, approval across indications is not granted by Health Canada. Furthermore, interchangeability of compounds is not endorsed, and equivalence designs are advocated for clinical studies. Rigorous pharmacovigilance programmes, similar to those for the original compound, are also required.33 ,35–37
Biosimilars in inflammatory bowel disease (IBD): present and future
Biosimilar monoclonal antibodies have been approved in India and South Korea, and further candidates may soon reach Western markets.15 The EMA has accepted the first regulatory filings for two biosimilar mAbs on biosimilar infliximabs.4 Although the EMA does not identify companies, the first application is known to have been filed by Celltrion, and the patent on infliximab is estimated to expire in Europe between 2013 and 2015 depending on the country.38 Meanwhile, Reliance Life Sciences, India announced in October that the evaluation of their biosimilar infliximab is in the clinical phase. Celltrion's biosimilar infliximab (CT-P13, Remsima) is already being marketed in South Korea, where it was approved for all indications of the reference product, including the treatment of IBD. Surprisingly, Celltrion applied to the EMA to approve their biosimilar, CT-P13, under the INN ‘infliximab’. The phase I clinical trial (PLANETAS) was carried out in patients with ankylosing spondylitis, whereas equivalence in safety and efficacy to infliximab was demonstrated in a phase III study (PLANETRA) during coadministration of methotrexate in patients with rheumatoid arthritis.39 The use of CT-P13 for IBD indications was therefore extrapolated from the results of rheumatological trials.
However, special considerations need to be taken into account regarding the use of biosimilar mAbs to treat IBD. First, the dose of infliximab for IBD, 5 mg/kg, differs from that used for rheumatoid arthritis, 3 mg/kg. Second, compared with rheumatic diseases, anti-tumour necrosis factor (TNF) medication is more often used as monotherapy in IBD. The presence of drug antibodies to infliximab or adalimumab correlates with shorter duration of response and higher incidence of infusion reactions.40 ,41 On the other hand, immunosuppressive agents are known to reduce the risk of the development of neutralising antibodies against anti-TNFs.42 Thus, the concomitant use of methotrexate in the phase III study may compromise the validity of extrapolation of safety and efficacy data. Third, the exact downstream effects that are responsible for efficacy of anti-TNF medication and selective costimulation modulation in the various disease states are unknown. Infliximab, etanercept and abatacept all show efficacy in rheumatoid arthritis, but neither etanercept nor abatacept have been shown to be efficacious in IBD.43 ,44 In vitro studies show substantial mechanistic differences among the anti-TNF drugs that are currently used.45 As a consequence, pharmacodynamic markers as surrogate end points for efficacy, such as the absolute neutrophil count for G-CSF therapy, are lacking for TNF antagonists. In summary, extrapolation across indications is not well established for biosimilars; therefore we do not support approval across indications.
The technical aspects of designing clinical trials of biosimilars for the treatment of IBD warrant careful consideration. Non-inferiority trials are probably the most practicable option, despite inherent methodological and feasibility challenges, requiring a large number of patients and being subject to type I errors. These trials should be of sufficient duration to assess the comparability of both induction therapy and immunogenicity; therefore 6 months seems reasonable. Trial designs that feature re-randomisation—either sequentially randomised induction followed by maintenance in randomised responders or open label induction followed by randomisation of responders—are probably not feasible because of concerns about sensitisation given that patients would be randomly assigned to the biosimilar or reference product in maintenance therapy after exposure to either during induction. Thus a ‘treat right through design’ is probably an optimal configuration.
Biopharmaceutical agents are becoming increasingly important with the expiration of innovator product patents. The expected benefit of biosimilar mAbs is reduction of costs, which will provide better access to biopharmaceutical agents. However, the safety and efficacy of these products must be ensured by strict regulatory requirements. In Europe, the EMA has developed scientifically based, stringent guidelines for the authorisation of biosimilars, which have been adapted by Canadian and US regulators. In contrast, regulatory requirements are markedly reduced in developing countries, such as India, which is one of the leading contributors to the world biosimilar market.46 Optimally a balance should be maintained that ensures safe and effective products for patients and encourages both innovation and competition. In the meantime, physicians require a clear view of this rapidly evolving landscape and will need to be familiar with the benefits and concerns regarding the biosimilar concept.
Contributors KBG performed the literature search and drafted and revised the paper. RK contributed to drafting the ‘Biosimilar approval pathways’ section. GRvdB, CYP, ML and VJ performed additional literature searches and revised the draft paper. SPLT, WJS and BGF contributed with thorough revisions to the draft. GRAMD supervised the preparation of the paper and made the final revisions.
Competing interests GRvdB has received consulting fees from Abbott Laboratories and lecture fees from Abbott Laboratories, Merck Sharp & Dohme and Ferring Pharmaceuticals. He has received research grants from Abbott Laboratories and Ferring Pharmaceuticals. CYP has received unrestricted research grants from Abbott Netherlands, Dr Falk Pharma Benelux, Schering-Plough Netherlands and Tramedico Netherlands and has been on advisory boards for Abbott and Glaxo Smith Kline. ML has served as a speaker for Abbott, Merck Sharp & Dohme and Ferring Pharmaceuticals. SPLT has received consulting fees from Abbott, Asahi-Kasei, Bristol-Myers Squibb, Cosmo Technologies, Coronado Biosciences, Ferring Pharmaceuticals, Genentech, Genzyme Corp, Glaxo Smith Kline, Janssen, Lexicon Pharmaceuticals, Merck Research Laboratories, Millennium Pharmaceuticals, Nisshin Kyorin Pharmaceuticals, Novartis, Novo Nordisk, NPS Pharmaceuticals, PDL Biopharma, Pfizer, Procter and Gamble, Santarus, Schering Plough, Shire Pharmaceuticals, Sigmoid Pharma Ltd, Tillotts Pharma AG, TxCell SA, UCB Pharma and Warner Chilcott UK Ltd, research grants from Abbott, Genentech, Glaxo Smith Kline, Janssen, Novartis, Pfizer, Procter and Gamble, Shire Pharmaceuticals and UCB Pharma, and payments for lectures/speakers bureaux from Abbott, Janssen, Ferring Pharmaceuticals and Warner Chilcott, but holds no stock/stock options. WJS has received consulting fees from Abbott Laboratories, ActoGeniX NV, AGI Therapeutics Inc, Alba Therapeutics Corporation, Albireo, Alfa Wasserman, Amgen, AM-Pharma BV, Anaphore, Astellas Pharma, Athersys, Inc, Atlantic Healthcare Limited, Axcan Pharma (now Aptalis), BioBalance Corporation, Boehringer-Ingelheim Inc, Bristol Meyers Squibb, Celegene, Celek Pharmaceuticals, Cellerix SL, Cerimon Pharmaceuticals, ChemoCentryx, CoMentis, Cosmo Technologies, Coronado Biosciences, Cytokine Pharmasciences, Eagle Pharmaceuticals, Eisai Medical Research Inc, Elan Pharmaceuticals, EnGene, Inc, Eli Lilly, Enteromedics, Exagen Diagnostics, Inc, Ferring Pharmaceuticals, Flexion Therapeutics, Inc, Funxional Therapeutics Limited, Genzyme Corporation, Genentech (now Roche), Gilead Sciences, Given Imaging, Glaxo Smith Kline, Human Genome Sciences, Ironwood Pharmaceuticals (previously Microbia Inc), Janssen (previously Centocor), KaloBios Pharmaceuticals, Inc, Lexicon Pharmaceuticals, Lycera Corporation, Meda Pharmaceuticals (previously Alaven Pharmaceuticals), Merck Research Laboratories, MerckSerono, Millennium Pharmaceuticals (subsequently merged with Takeda), Nisshin Kyorin Pharmaceuticals Co, Ltd, Novo Nordisk A/S, NPS Pharmaceuticals, Optimer Pharmaceuticals, Orexigen Therapeutics, Inc, PDL Biopharma, Pfizer, Procter and Gamble, Prometheus Laboratories, ProtAb Limited, Purgenesis Technologies, Inc, Receptos, Relypsa, Inc, Salient Pharmaceuticals, Salix Pharmaceuticals, Inc, Santarus, Schering Plough Corporation (acquired by Merck), Shire Pharmaceuticals, Sigmoid Pharma Ltd, Sirtris Pharmaceuticals, Inc (a GSK company), SLA Pharma (UK) Ltd, Targacept, Teva Pharmaceuticals, Therakos, Tillotts Pharma AG (acquired by Zeria Pharmaceutical Co, Ltd), TxCell SA, UCB Pharma, Viamet Pharmaceuticals, Vascular Biogenics Ltd (VBL), Warner Chilcott UK Ltd and Wyeth (now Pfizer). He has received lecture fees from Abbott Laboratories, Bristol Meyers Squibb and Janssen (previously Centocor). He has received research support from Abbott Laboratories, Bristol Meyers Squibb, Genentech, Glaxo Smith Kline, Janssen (previously Centocor), Millennium Pharmaceuticals (now Takeda), Novartis, Pfizer, Procter and Gamble Pharmaceuticals, Shire Pharmaceuticals and UCB Pharma. GRAMD has received consultancy fees from Abbott Laboratories, Actogenix, Boerhinger Ingelheim, Centocor, Cosmo Technologies, Engene, Ferring Pharmaceuticals, Glaxo Smith Kline, Jansen Biologics, Millenium Pharmaceuticals, Mitsubishi Pharma, Merck Research Laboratories, Novo Nordisk, PDL Biopharma, Pfizer, Schering Plough, SetPoint, Shire Pharmaceuticals, Sigmoid Pharma Ltd, Takeda, Teva, Tillotts Pharma and UCB Pharma, research grants from Abbott Laboratories, Jansen Biologics, Given Imaging, MSD, DrFalk Pharma, Photopill, speaking honoraria from Abbott Laboratories, Jansen Biologics, Tillotts, Tramedico, Ferring, MSD, UCB, Norgine and Shire, and has stock options from Engene Inc.
Provenance and peer review Commissioned; externally peer reviewed.
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