Science & Society
Biosimilars and the long game Farah Huzair1 and Dinar Kale2 1
Science Technology and Innovation Studies, School of Social and Political Sciences, University of Edinburgh, Old Surgeons Hall, High School Yards, Edinburgh EH1 1LZ, UK 2 The Open University, Development Policy and Practice, Faculty of Maths, Computing, and Technology, The Open University, Walton Hall, Milton Keynes MK7 6AA, UK
Despite greater certainty for biosimilar markets and regulation, the change that was seen in the small-molecule pharmaceuticals market with the rapid entrance of emerging-country generics suppliers will not be replicated exactly. The long game has yet to be played out, and recent changes in regulation, science, and production technology are likely to impact on future patterns of partnership and production.
Biosimilars gain in popularity Biosimilars, also known as ‘follow-on biologics’ and ‘subsequent entry biologics’, are medicines that exhibit a high degree of similarity to a reference product and are considered to be biologically and clinically comparable to another medicine that has already been authorised for use. The promise of biosimilars is being heralded in an era of ageing populations and escalating healthcare costs. As we approach expiry of the period of data-exclusivity on many original biologics, regulations and strategies are adapting to accommodate the expected efflux of biosimilars from pipelines [1]. Since the adoption of ‘similar biological medicinal product’ in EU pharmaceutical legislation in 2004, 21 biosimilars have been approved [2]. Greater clarity in the US has been arguably attained, and an abbreviated approval process for biosimilars is now detailed under section 351(k) of the Public Health Service Act. In July 2014 Sandoz became the first company to file for biosimilar approval in the US under the new 351(k) pathway. As countries around the world establish their own national guidelines, largely based on the World Health Organization (WHO) and European Medicines Agency (EMA) frameworks, it has been argued that regulatory uncertainty has finally been resolved. Emerging country suppliers of biosimilars can settle into their short game, using similar strategies to those used by small-molecule generics suppliers many years ago. We argue that the long game, in contrast, has yet to be played out. Lasting consequences that are unique for suppliers involved in biosimilar production stem from changes in regulation, science, and production technology. We survey current examples from each of these three domains, leading to the observation that biosimilars have emerged more slowly than expected [3].
Corresponding author: Huzair, F. ([email protected]). Keywords: biosimilar; follow-on biologic; subsequent entry biologic. 0167-7799/ ß 2015 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tibtech.2015.01.001
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Trends in Biotechnology, May 2015, Vol. 33, No. 5
Regulation, science, and production technologies are factors in the long game The potential for biosimilars to reduce healthcare costs depends on ‘interchangeability’ – exchanging one medicine for another that is expected to achieve the same clinical effect in a given clinical setting in any one patient, on the initiative or with the agreement of the prescriber [4]. Regulatory frameworks across the world have exhibited different approaches to the issue of interchangeability. Within the EU, substitution guidelines are subject to national decision-making and are not within the remit of the EMA. In the UK for example, the Association of the British Pharmaceutical Industry (ABPI) states that because biosimilars are not exact copies of their reference biological medicine, automatic substitution of one biological medicine for another could impact on patient safety and make pharmacovigilance more complicated. Similarly, Health Canada takes the view that Subsequent Entry Biologics (SEB) are new drugs that are not pharmaceutically or therapeutically equivalent to their reference products. They do not therefore support the automatic substitution of a SEB for its reference biologic drug and refer decision-making regarding therapeutic interchangeability to physicians [5]. However, in September 2014, the US FDA announced the publication of its ‘Purple Book’, which lists licensed biological products and interchangeable biosimilars [6] (an equivalent of its ‘Orange Book’, which lists small-molecule pharmaceuticals and their generic equivalents). Although the US has taken longer to issue guidance on biosimilars, interchangeability has become a potential game-changer, possibly making the US a more reliable market for suppliers of new biosimilars. Biosimilars are not all the same. They represent an extremely diverse group of medicines that include growth factors, cytokines, hormones, monoclonal antibodies (mAbs) and, potentially, vaccines. Early success in biosimilars centred on somatropins, which were produced using recombinant DNA. mAbs are very different, as the mechanism of action is usually complex and in many cases only partially understood. Licensed mAbs that will soon fall off the patent cliff have a reasonably well-established safety and efficacy profile and recognise known, validated targets. However, because there is normally no direct access to originator companies’ proprietary data, the developer of a mAb biosimilar has to retrieve the reference mAb, purify it, and reverse engineer a process to produce a copy. In other words, the development of a biosimilar mAb requires the establishment from scratch of a new manufacturing process for the molecule [7].
Science & Society
Trends in Biotechnology May 2015, Vol. 33, No. 5
Table 1. Three exemplary players compared Nature of firm Large firm moving from innovator drugs to biosimilars in a developed country Small or medium biotech firm
Traditional generics manufacturer in an emerging market
Regulatory factors (short-term uncertainty) Large generics manufacturers in developed countries have been the first to respond to US changes – the long game emerges Cost-challenges would encourage partnerships and collaborations with established players
Scientific factors (progress in therapeutic areas) Challenges of flexibility in moving between therapeutic areas. Advantages in clinical trials in specialist areas (e.g., oncology) Favours biotech firms which have flexibility and can quickly acquire expertise in new therapeutic areas
Uncertainty has delayed entry to developed-country markets, although generics firms have moved quickly in developing markets
Challenges in assimilating new scientific knowledge and conducting clinical trials in specialist areas
As with somatropins, mAbs require industrial know-how of sequencing, cloning, and fermentation. However, additional expertise is required in ‘humanising’ the protein and, if there is an intention to apply the mAb to oncology, how to trial the drug in an oncology setting, which differs from conducting clinical trials for other disease states. In June 2013 the EMA Committee for Medicinal Products for Human Use (CHMP) recommended the authorisation of Remsima as a biosimilar medicinal product containing infliximab. To support the authorisation, an extensive comparability exercise was carried out on two patient populations to observe the effects in patients with ankylosing spondylitis and rheumatoid arthritis [8]. A firm could accumulate a fair amount of specialised knowledge over time as it engages in mAb biosimilar production. Thus it is unsurprising that firms not only continue to specialise, but may also seek to develop a platform for innovative mAbs, or treatment for a range of related diseases. Conversely, specialised knowledge could turn a firm away from biologics altogether. Within oncology, for example, accumulated knowledge of the receptors and proteins in signalling pathways involved in particular cancers might encourage firms to only focus on small molecules, such as kinase inhibitors, that are shown to be effective in those signalling pathways. The long game for such firms might therefore not be about becoming a biosimilars player; it may be about being a player in a particular therapeutic class. Finally, we note the possible advance in production technologies. Older biologic drugs may be replaced eventually with biosimilars that have been produced more costeffectively. Such savings in cost may stem from more efficient methods of production, utilising optimised formulation, delivery modes, packaging variants, or improved service aspects. With improvements in technology and industrial production methods, it may then be possible to produce biosimilars with demonstrably reduced risk of adverse events and better safety profiles. These have been termed ‘biosuperiors’ or ‘biobetters’ [9]. Suppliers from emerging countries have been expected to play the short game, leveraging strategic expertise gained from reverse engineering and production of small-molecule generics in a new setting to quickly produce and contribute to the promise of biosimilars. The story will not be straight-
Technical factors (improvements allowing biobetters) Advantages when bringing biobetters to the market from experience with innovator drugs
Scaling-up is challenging for small/ medium biotech firms. Partnerships with larger firms and contract research organisations (CROs) are likely Expertise in scaling-up. Established route to market for biosimilars for the short game. Biobetters and the long game are challenging
forward. While emerging country suppliers have proven ability to compete in the generics market and some areas of the biosimilar market, challenges and delays are to be expected with the more-extensive studies that are necessary to establish comparability. As they gain experience and competence, they may in time compete in all areas and eventually with biobetters. Comparing the players Three types of idealised firm would feature in the biosimilars landscape (Table 1). We compare the advantages and challenges when faced with factors that will determine success in the short and long game. For large pharma firms situated within developed markets, and that have experience in bringing biologics with novel traits through clinical trials, we expect an accumulation of expertise that will serve in the long game. They will need to shift their focus from innovation to replication, developing strategies to transform expensive development and manufacturing processes into lean analogues. They will have to reduce the cost per unit dose and make the same amount of drug with fewer batches through higher fermentation titres, higher purification recoveries, and longer shelf-life formulations. A different set of challenges is faced by traditional generic manufacturers. Operating within particular therapeutic areas will require investment, otherwise firms will limit themselves to the short game. For mAbs in particular, they need new expertise to reverse-engineer the biologic, develop a stable and therapeutically-active cell line, and produce data for comparability tests. They also will need to develop manufacturing processes and infrastructure to meet specifications predictably and consistently at commercial scale [10]. Given the scale of these challenges for existing large firms, the appearance of biosimilars will be, and are being, accompanied by new partnerships, alliances, and collaborations as they look to devolve risk in the short term. Small and medium biotech firms can quickly assimilate new knowledge in science and have the adaptability to move across therapeutic areas. Working within partnerships and collaborative arrangements, small and medium biotechs will remain part of the long and short games of other players. 251
Science & Society Concluding remarks and future perspectives The change that was seen in the small-molecule pharmaceuticals market with the entrance of emerging country generics suppliers, is unlikely to be replicated after biologics fall off the impending patent cliff. Regulatory frameworks for biosimilars may not provide stable criteria for emerging country suppliers, and flexibility in approval criteria and case-by-case consideration makes international harmonisation more difficult to achieve. Biosimilar guidelines are designed to be living documents that are intended to adapt to progress in science and technology. The market might be a less-certain area in the short run until suppliers adapt to survive in this more dynamic regulatory environment. All in all, the ‘innovation system’ or ‘eco-system’ of actors is likely to further evolve, particularly in regard to the partnerships that link them. The strengths and capabilities needed for the long game are slowly being developed and will emerge as the long game is played out.
References 1 Huzair, F. and Kale, D. (2011) Emergence of the Biosimilar Sector and Opportunities of Developing Country Suppliers, Innogen 2 Generics and Biosimilars Initiative (2014) Biosimilars Approved in Europe, GaBi. Published online November 14, 2014. http://www. gabionline.net/Biosimilars/General/Biosimilars-approved-in-Europe
252
Trends in Biotechnology May 2015, Vol. 33, No. 5 3 Editorial (2013) Building a wall against biosimilars. Nat. Biotechnol. 31, 264 4 European Commission (2013) What You Need to Know About Biosimilar Medicinal Products (Consensus Information Document), European Commission 5 Health Canada (2010) Questions and Answers To Accompany the Final Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs), Health Canada. Published online May 27, 2010. http://www.hc-sc.gc.ca/dhp-mps/brgtherap/ applic-demande/guides/seb-pbu/01-2010-seb-pbu-qa-qr-eng.php 6 US Food and Drug Administration (2014) Purple Book: Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations, FDA. Published online January 27, 2015. http://www.fda.gov/Drugs/ DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ ucm411418.htm 7 Schneider, C.K. and Kalinke, U. (2008) Toward biosimilar monoclonal antibodies. Nat. Biotechnol. 26, 985–990 8 European Medicines Agency (2013) Assessment Report: Remsima. International Non-Proprietary Name: Infliximab, EMA. Published online June 27, 2013. http://www.ema.europa.eu/docs/en_GB/ document_library/EPAR_-_Public_assessment_report/human/002576/ WC500151486.pdf 9 Dorey, E. (2010) The next move in biopharma. Chemistry and Industry Magazine 24. Published online December 20, 2010. http://www.soci.org/ Chemistry-and-Industry/CnI-Data/2010/24/ The-next-move-in-biopharma 10 Lee, A. et al. (2011) Manufacturing strategies for biosimilars. Pharm. Technol. 35, 36
Biosimilars and the long game Farah Huzair1 and Dinar Kale2 1
Science Technology and Innovation Studies, School of Social and Political Sciences, University of Edinburgh, Old Surgeons Hall, High School Yards, Edinburgh EH1 1LZ, UK 2 The Open University, Development Policy and Practice, Faculty of Maths, Computing, and Technology, The Open University, Walton Hall, Milton Keynes MK7 6AA, UK
Despite greater certainty for biosimilar markets and regulation, the change that was seen in the small-molecule pharmaceuticals market with the rapid entrance of emerging-country generics suppliers will not be replicated exactly. The long game has yet to be played out, and recent changes in regulation, science, and production technology are likely to impact on future patterns of partnership and production.
Biosimilars gain in popularity Biosimilars, also known as ‘follow-on biologics’ and ‘subsequent entry biologics’, are medicines that exhibit a high degree of similarity to a reference product and are considered to be biologically and clinically comparable to another medicine that has already been authorised for use. The promise of biosimilars is being heralded in an era of ageing populations and escalating healthcare costs. As we approach expiry of the period of data-exclusivity on many original biologics, regulations and strategies are adapting to accommodate the expected efflux of biosimilars from pipelines [1]. Since the adoption of ‘similar biological medicinal product’ in EU pharmaceutical legislation in 2004, 21 biosimilars have been approved [2]. Greater clarity in the US has been arguably attained, and an abbreviated approval process for biosimilars is now detailed under section 351(k) of the Public Health Service Act. In July 2014 Sandoz became the first company to file for biosimilar approval in the US under the new 351(k) pathway. As countries around the world establish their own national guidelines, largely based on the World Health Organization (WHO) and European Medicines Agency (EMA) frameworks, it has been argued that regulatory uncertainty has finally been resolved. Emerging country suppliers of biosimilars can settle into their short game, using similar strategies to those used by small-molecule generics suppliers many years ago. We argue that the long game, in contrast, has yet to be played out. Lasting consequences that are unique for suppliers involved in biosimilar production stem from changes in regulation, science, and production technology. We survey current examples from each of these three domains, leading to the observation that biosimilars have emerged more slowly than expected [3].
Corresponding author: Huzair, F. ([email protected]). Keywords: biosimilar; follow-on biologic; subsequent entry biologic. 0167-7799/ ß 2015 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tibtech.2015.01.001
250
Trends in Biotechnology, May 2015, Vol. 33, No. 5
Regulation, science, and production technologies are factors in the long game The potential for biosimilars to reduce healthcare costs depends on ‘interchangeability’ – exchanging one medicine for another that is expected to achieve the same clinical effect in a given clinical setting in any one patient, on the initiative or with the agreement of the prescriber [4]. Regulatory frameworks across the world have exhibited different approaches to the issue of interchangeability. Within the EU, substitution guidelines are subject to national decision-making and are not within the remit of the EMA. In the UK for example, the Association of the British Pharmaceutical Industry (ABPI) states that because biosimilars are not exact copies of their reference biological medicine, automatic substitution of one biological medicine for another could impact on patient safety and make pharmacovigilance more complicated. Similarly, Health Canada takes the view that Subsequent Entry Biologics (SEB) are new drugs that are not pharmaceutically or therapeutically equivalent to their reference products. They do not therefore support the automatic substitution of a SEB for its reference biologic drug and refer decision-making regarding therapeutic interchangeability to physicians [5]. However, in September 2014, the US FDA announced the publication of its ‘Purple Book’, which lists licensed biological products and interchangeable biosimilars [6] (an equivalent of its ‘Orange Book’, which lists small-molecule pharmaceuticals and their generic equivalents). Although the US has taken longer to issue guidance on biosimilars, interchangeability has become a potential game-changer, possibly making the US a more reliable market for suppliers of new biosimilars. Biosimilars are not all the same. They represent an extremely diverse group of medicines that include growth factors, cytokines, hormones, monoclonal antibodies (mAbs) and, potentially, vaccines. Early success in biosimilars centred on somatropins, which were produced using recombinant DNA. mAbs are very different, as the mechanism of action is usually complex and in many cases only partially understood. Licensed mAbs that will soon fall off the patent cliff have a reasonably well-established safety and efficacy profile and recognise known, validated targets. However, because there is normally no direct access to originator companies’ proprietary data, the developer of a mAb biosimilar has to retrieve the reference mAb, purify it, and reverse engineer a process to produce a copy. In other words, the development of a biosimilar mAb requires the establishment from scratch of a new manufacturing process for the molecule [7].
Science & Society
Trends in Biotechnology May 2015, Vol. 33, No. 5
Table 1. Three exemplary players compared Nature of firm Large firm moving from innovator drugs to biosimilars in a developed country Small or medium biotech firm
Traditional generics manufacturer in an emerging market
Regulatory factors (short-term uncertainty) Large generics manufacturers in developed countries have been the first to respond to US changes – the long game emerges Cost-challenges would encourage partnerships and collaborations with established players
Scientific factors (progress in therapeutic areas) Challenges of flexibility in moving between therapeutic areas. Advantages in clinical trials in specialist areas (e.g., oncology) Favours biotech firms which have flexibility and can quickly acquire expertise in new therapeutic areas
Uncertainty has delayed entry to developed-country markets, although generics firms have moved quickly in developing markets
Challenges in assimilating new scientific knowledge and conducting clinical trials in specialist areas
As with somatropins, mAbs require industrial know-how of sequencing, cloning, and fermentation. However, additional expertise is required in ‘humanising’ the protein and, if there is an intention to apply the mAb to oncology, how to trial the drug in an oncology setting, which differs from conducting clinical trials for other disease states. In June 2013 the EMA Committee for Medicinal Products for Human Use (CHMP) recommended the authorisation of Remsima as a biosimilar medicinal product containing infliximab. To support the authorisation, an extensive comparability exercise was carried out on two patient populations to observe the effects in patients with ankylosing spondylitis and rheumatoid arthritis [8]. A firm could accumulate a fair amount of specialised knowledge over time as it engages in mAb biosimilar production. Thus it is unsurprising that firms not only continue to specialise, but may also seek to develop a platform for innovative mAbs, or treatment for a range of related diseases. Conversely, specialised knowledge could turn a firm away from biologics altogether. Within oncology, for example, accumulated knowledge of the receptors and proteins in signalling pathways involved in particular cancers might encourage firms to only focus on small molecules, such as kinase inhibitors, that are shown to be effective in those signalling pathways. The long game for such firms might therefore not be about becoming a biosimilars player; it may be about being a player in a particular therapeutic class. Finally, we note the possible advance in production technologies. Older biologic drugs may be replaced eventually with biosimilars that have been produced more costeffectively. Such savings in cost may stem from more efficient methods of production, utilising optimised formulation, delivery modes, packaging variants, or improved service aspects. With improvements in technology and industrial production methods, it may then be possible to produce biosimilars with demonstrably reduced risk of adverse events and better safety profiles. These have been termed ‘biosuperiors’ or ‘biobetters’ [9]. Suppliers from emerging countries have been expected to play the short game, leveraging strategic expertise gained from reverse engineering and production of small-molecule generics in a new setting to quickly produce and contribute to the promise of biosimilars. The story will not be straight-
Technical factors (improvements allowing biobetters) Advantages when bringing biobetters to the market from experience with innovator drugs
Scaling-up is challenging for small/ medium biotech firms. Partnerships with larger firms and contract research organisations (CROs) are likely Expertise in scaling-up. Established route to market for biosimilars for the short game. Biobetters and the long game are challenging
forward. While emerging country suppliers have proven ability to compete in the generics market and some areas of the biosimilar market, challenges and delays are to be expected with the more-extensive studies that are necessary to establish comparability. As they gain experience and competence, they may in time compete in all areas and eventually with biobetters. Comparing the players Three types of idealised firm would feature in the biosimilars landscape (Table 1). We compare the advantages and challenges when faced with factors that will determine success in the short and long game. For large pharma firms situated within developed markets, and that have experience in bringing biologics with novel traits through clinical trials, we expect an accumulation of expertise that will serve in the long game. They will need to shift their focus from innovation to replication, developing strategies to transform expensive development and manufacturing processes into lean analogues. They will have to reduce the cost per unit dose and make the same amount of drug with fewer batches through higher fermentation titres, higher purification recoveries, and longer shelf-life formulations. A different set of challenges is faced by traditional generic manufacturers. Operating within particular therapeutic areas will require investment, otherwise firms will limit themselves to the short game. For mAbs in particular, they need new expertise to reverse-engineer the biologic, develop a stable and therapeutically-active cell line, and produce data for comparability tests. They also will need to develop manufacturing processes and infrastructure to meet specifications predictably and consistently at commercial scale [10]. Given the scale of these challenges for existing large firms, the appearance of biosimilars will be, and are being, accompanied by new partnerships, alliances, and collaborations as they look to devolve risk in the short term. Small and medium biotech firms can quickly assimilate new knowledge in science and have the adaptability to move across therapeutic areas. Working within partnerships and collaborative arrangements, small and medium biotechs will remain part of the long and short games of other players. 251
Science & Society Concluding remarks and future perspectives The change that was seen in the small-molecule pharmaceuticals market with the entrance of emerging country generics suppliers, is unlikely to be replicated after biologics fall off the impending patent cliff. Regulatory frameworks for biosimilars may not provide stable criteria for emerging country suppliers, and flexibility in approval criteria and case-by-case consideration makes international harmonisation more difficult to achieve. Biosimilar guidelines are designed to be living documents that are intended to adapt to progress in science and technology. The market might be a less-certain area in the short run until suppliers adapt to survive in this more dynamic regulatory environment. All in all, the ‘innovation system’ or ‘eco-system’ of actors is likely to further evolve, particularly in regard to the partnerships that link them. The strengths and capabilities needed for the long game are slowly being developed and will emerge as the long game is played out.
References 1 Huzair, F. and Kale, D. (2011) Emergence of the Biosimilar Sector and Opportunities of Developing Country Suppliers, Innogen 2 Generics and Biosimilars Initiative (2014) Biosimilars Approved in Europe, GaBi. Published online November 14, 2014. http://www. gabionline.net/Biosimilars/General/Biosimilars-approved-in-Europe
252
Trends in Biotechnology May 2015, Vol. 33, No. 5 3 Editorial (2013) Building a wall against biosimilars. Nat. Biotechnol. 31, 264 4 European Commission (2013) What You Need to Know About Biosimilar Medicinal Products (Consensus Information Document), European Commission 5 Health Canada (2010) Questions and Answers To Accompany the Final Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs), Health Canada. Published online May 27, 2010. http://www.hc-sc.gc.ca/dhp-mps/brgtherap/ applic-demande/guides/seb-pbu/01-2010-seb-pbu-qa-qr-eng.php 6 US Food and Drug Administration (2014) Purple Book: Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations, FDA. Published online January 27, 2015. http://www.fda.gov/Drugs/ DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ ucm411418.htm 7 Schneider, C.K. and Kalinke, U. (2008) Toward biosimilar monoclonal antibodies. Nat. Biotechnol. 26, 985–990 8 European Medicines Agency (2013) Assessment Report: Remsima. International Non-Proprietary Name: Infliximab, EMA. Published online June 27, 2013. http://www.ema.europa.eu/docs/en_GB/ document_library/EPAR_-_Public_assessment_report/human/002576/ WC500151486.pdf 9 Dorey, E. (2010) The next move in biopharma. Chemistry and Industry Magazine 24. Published online December 20, 2010. http://www.soci.org/ Chemistry-and-Industry/CnI-Data/2010/24/ The-next-move-in-biopharma 10 Lee, A. et al. (2011) Manufacturing strategies for biosimilars. Pharm. Technol. 35, 36
