NEWS & VIEWS THERAPY
Facing up to biosimilar agents —the ACR position Morton Scheinberg Refers to ACR Committee on Rheumatologic Care. American College of Rheumatology position statement – Biosimilars [online], https://www.rheumatology.org/Practice/Clinical/Position/Biosimilars_02_2015/.pdf (2015)
As patents expire for biologic reference products (innovators), biosimilar agents are joining the treatment landscape in rheumatology. Release of an ACR position statement on biosimilars prompts US rheumatologists to focus on issues relating to the clinical use of these agents and can also be helpful for rheumatologists in other regions where biosimilar agent regulatory processes are not yet fully implemented. Biologic therapies have revolutionized outcomes for patients with rheumatic diseases and are a major component of the current global pharmaceutical market. Early therapy with these agents is associated with reductions in work absenteeism, disability and hospitalizations, and has transformed the current standards of care in diseases such as rheumatoid arthritis, spondyloarthritis, psoriatic arthritis and, more recently, in systemic lupus erythematosus.1 The imminent expiration of patents for established biologic agents (innovators or reference products) has created an opportunity for biosimilar agents, also known as follow-on biologic agents, to enter the market and compete with established biologic agent brands for authorization by health authorities.2 Unfortunately, regulation of biosimilar agent authorization is not uniform worldwide, and in some regions can be quite variable. For instance, a Chinese version of an etanercept biosimilar agent, Yisaipu, was approved in Colombia using legislation covering similarity between the generic and biosimilar agent from chemical studies rather than clinical trial data.2 Although Yisaipu has been available in China for nearly a decade, little is known about its clinical use, and data regarding drug half-life, immunogenicity and incidence of adverse effects (such as tuberculosis) is lacking. Rheumatologists should be aware that biologic agents are more complicated and heterogeneous at the molecular level and are considerably larger than chemically- synthesized pharmaceuticals (for example, some biologic agents can have a molecular
mass on average 1,000 times greater than aspirin). The most common biologic agents used in patients with rheumatic conditions are monoclonal antibodies, large proteins for which the production of a perfect copy is considerably more complex than it is for small-molecule drugs. The complexity of biologic agents is compounded by the need for living cells for their production, meaning that techniques for produc ing the in novator—and consequently the biosimilar—can be technically-demanding and need to be closely monitored.3 The EU led the process of regulating the introduction of biosimilar agents and their requirements are now a benchmark for other countries.4 The infliximab biosimilar, distributed under the trade names Remsima or Infectra, is now available in several European countries and is the first ‘true’ biosimilar agent to be distributed in major markets. True biosimilars have similar structures to biologic agents, and have been
licensed after efficacy and safety evalu ation in clinical trials comparing them with the innovator.4 The upcoming approval and introduction of anti-TNF and B-cell depleting biosimilar agents for the treatment of rheumatic diseases has prompted the ACR to release a position statement on biosimilar agents.5 In this document, the ACR places major emphasis on the need for well-powered comparability clinical trials between the biosimilar agent and the innovator, so that efficacy and safety can be well defined before registration and licensing procedures are underway. The availability of clinical trial data also enables practicing rheumatologists to be confident that their patients are receiving a drug with the ‘same’ efficacy as before, for a lower cost. In other parts of the world, particularly in Latin America, ‘copies’ of anti-TNF agents were introduced into the market that would not be acceptable by ACR standards.5 Surprising as it may be, the licensed copies or biocopies available in these countries are priced in the range of the innovator, so one of the hallmarks of biosimilar agent competition advantages is absent. The ACR position paper also touches on practical aspects not fully addressed by EU policies, particularly regarding the need for the nomenclature of a biosimilar to be distinct from that of the innovator, so they can be clearly distinguished between to enable an effective process of pharmacovigilance to occur during post-marketing surveillance.5 It is worth emphasizing that the ACR statement also calls for post-marketing surveillance in both children and adults, and for long-term data on less common adverse effects.
Mike Watson Images/moodboard/Thinkstock
NATURE REVIEWS | RHEUMATOLOGY
ADVANCE ONLINE PUBLICATION | 1 © 2015 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS The controversial issue of therapy sub stitution (when patients receive a biosimilar instead of the prescribed innovator) or interchangeability is also discussed in the position paper. According to the ACR, the decision to substitute an innovator for a biosimilar agent lies with the physician; however, when substitution by the pharmacist is lawful, doctor and patient should immediately be made aware that a substitution has occurred, as the short dosing interval of many biologic agents means that adverse events in response to the biosimilar agent could occur soon after drug administration. This may not happen in countries where the health authorities decide that the innovator will no longer be provided and where it is substituted by the biosimilar agent or the intended copy. Although a discussion about interchangeability is included in the position statement, the document does not add the ACR’s final position on this, possibly because that direction should be provided by the regulators (the FDA). Nevertheless, the ACR places itself against indiscriminate interchangeability or to compulsory switching in patients that are stable to a different drug for cost-saving reasons.5 Although some agreement exists in support of biosimilar agent interchangeability in inflammatory arthritis, the same does not seem to happen in other diseases (for example, inflammatory bowel disease).6 The ACR statement does not discuss what might be the major driving force for the development of biosimilars—the ever increasing cost of new chemical and biological therapeutic agents. One of the main consequences of the development of biosimilars is an expected reduction
in price costs, although not to the same extent as it happened with the introduction of small-molecule generics. The first true biosimilar approved by the EMA, an infliximab similar, is associated with considerable reductions in reimbursement but, surprisingly, intended copies of etanercept released in Mexico and Colombia have only a modest 5% reduction in their fiscal cost.7 Release of this ACR position statement on biosimilars prompts us to focus on issues relating to the clinical use of biosimilar agents and calls for vigilance on that regard. Nevertheless, some important aspects for the rheumatologist in clinical practice, such as the immunogenicity of biosimilars and the development of antidrug antib odies, were not discussed. In the past decade, rheumatologists have learned a lot about the variability of efficacy between different biologic agents such as TNF inhibitors. If the mechanism of action of TNF inhibitors was solely dependent on its ability to neutralize TNF, individual patients would experience the same therapeutic benefit regardless of the TNF inhibitor prescribed. However, this is clearly not the case.8,9 Variability in efficacy might also occur when substituting an innovator for a biosimilar. The ACR position statement on biosimilars should help US-based rheumatologists in clinical practice to better understand the differences between a true biosimilar and an intended copy. The document provides advice on biosimilar nomenclature, on how to manage therapy substitution, and the risks of repeated switching. These same recommendations can also be helpful for rheumatologists in other regions of the world where biosimilar agent regulatory processes are not yet fully implemented.
2 | ADVANCE ONLINE PUBLICATION
Hospital Israelita Albert Einstein, Avenida Albert Einsten, 627/701 Morumbi, São Paulo, SP 05652-900, Brazil. [email protected] doi:10.1038/nrrheum.2015.57 Published online 28 April 2015 Acknowledgements The author thanks Amanda Malveira Guimarães for help while preparing the manuscript. Competing interests The author declares no competing interests. 1.
2.
3. 4.
5.
6.
7. 8.
9.
Strand, V., Kimberly, R. & Isaacs, J. D. Biologic therapies in rheumatology: lessons learned, future directions. Nat. Rev. Drug Discov. 6, 75–92 (2007). Scheinberg, M. A. & Kay, J. The advent of biosimilar therapies in rheumatology—“O brave new world”. Nat. Rev. Rheumatol. 8, 430–436 (2012). Schellekens, H. When biotech proteins go offpatent. Trends Biotechnol. 22, 406–410 (2004). Beck, A. & Reichert, J. M. Approval of the first biosimilar antibodies in Europe: a major landmark for the biopharmaceutical industry. MAbs 5, 621–623 (2013). ACR Committee on Rheumatologic Care. ACR position statement – Biosimilars [online], https://www.rheumatology.org/Practice/ Clinical/Position/Biosimilars_02_2015/.pdf (2015). Scheinberg, M. & Castaneda-Hernandez, G. Anti-tumor necrosis factor patent expiration and the risks of biocopies in clinical practice. Arthritis Res. Ther. 6, 501 (2014). Scheinberg, M. Biosimilars in Crohn’s disease. J. Crohns Colitis 8, 710 (2014). Finckh, A. Comparative effectiveness of biologic anti rheumatic therapies in rheumatoid arthritis after failure to respond to a first TNF inhibitor. J. Comp. Eff. Res. 6, 481–484 (2012). Schiff, M. H., von Kempis, J., Goldblum, R., Tesser, J. R. & Mueller, R. B. Rheumatoid arthritis secondary non-responders to TNF can attain an efficacious and safe response by switching to certolizumab pegol: a phase IV, randomised, multicentre, double-blind, 12-week study, followed by a 12-week open-label phase. Ann. Rheum. Dis. 73, 174–177 (2014).
www.nature.com/nrrheum © 2015 Macmillan Publishers Limited. All rights reserved
Facing up to biosimilar agents —the ACR position Morton Scheinberg Refers to ACR Committee on Rheumatologic Care. American College of Rheumatology position statement – Biosimilars [online], https://www.rheumatology.org/Practice/Clinical/Position/Biosimilars_02_2015/.pdf (2015)
As patents expire for biologic reference products (innovators), biosimilar agents are joining the treatment landscape in rheumatology. Release of an ACR position statement on biosimilars prompts US rheumatologists to focus on issues relating to the clinical use of these agents and can also be helpful for rheumatologists in other regions where biosimilar agent regulatory processes are not yet fully implemented. Biologic therapies have revolutionized outcomes for patients with rheumatic diseases and are a major component of the current global pharmaceutical market. Early therapy with these agents is associated with reductions in work absenteeism, disability and hospitalizations, and has transformed the current standards of care in diseases such as rheumatoid arthritis, spondyloarthritis, psoriatic arthritis and, more recently, in systemic lupus erythematosus.1 The imminent expiration of patents for established biologic agents (innovators or reference products) has created an opportunity for biosimilar agents, also known as follow-on biologic agents, to enter the market and compete with established biologic agent brands for authorization by health authorities.2 Unfortunately, regulation of biosimilar agent authorization is not uniform worldwide, and in some regions can be quite variable. For instance, a Chinese version of an etanercept biosimilar agent, Yisaipu, was approved in Colombia using legislation covering similarity between the generic and biosimilar agent from chemical studies rather than clinical trial data.2 Although Yisaipu has been available in China for nearly a decade, little is known about its clinical use, and data regarding drug half-life, immunogenicity and incidence of adverse effects (such as tuberculosis) is lacking. Rheumatologists should be aware that biologic agents are more complicated and heterogeneous at the molecular level and are considerably larger than chemically- synthesized pharmaceuticals (for example, some biologic agents can have a molecular
mass on average 1,000 times greater than aspirin). The most common biologic agents used in patients with rheumatic conditions are monoclonal antibodies, large proteins for which the production of a perfect copy is considerably more complex than it is for small-molecule drugs. The complexity of biologic agents is compounded by the need for living cells for their production, meaning that techniques for produc ing the in novator—and consequently the biosimilar—can be technically-demanding and need to be closely monitored.3 The EU led the process of regulating the introduction of biosimilar agents and their requirements are now a benchmark for other countries.4 The infliximab biosimilar, distributed under the trade names Remsima or Infectra, is now available in several European countries and is the first ‘true’ biosimilar agent to be distributed in major markets. True biosimilars have similar structures to biologic agents, and have been
licensed after efficacy and safety evalu ation in clinical trials comparing them with the innovator.4 The upcoming approval and introduction of anti-TNF and B-cell depleting biosimilar agents for the treatment of rheumatic diseases has prompted the ACR to release a position statement on biosimilar agents.5 In this document, the ACR places major emphasis on the need for well-powered comparability clinical trials between the biosimilar agent and the innovator, so that efficacy and safety can be well defined before registration and licensing procedures are underway. The availability of clinical trial data also enables practicing rheumatologists to be confident that their patients are receiving a drug with the ‘same’ efficacy as before, for a lower cost. In other parts of the world, particularly in Latin America, ‘copies’ of anti-TNF agents were introduced into the market that would not be acceptable by ACR standards.5 Surprising as it may be, the licensed copies or biocopies available in these countries are priced in the range of the innovator, so one of the hallmarks of biosimilar agent competition advantages is absent. The ACR position paper also touches on practical aspects not fully addressed by EU policies, particularly regarding the need for the nomenclature of a biosimilar to be distinct from that of the innovator, so they can be clearly distinguished between to enable an effective process of pharmacovigilance to occur during post-marketing surveillance.5 It is worth emphasizing that the ACR statement also calls for post-marketing surveillance in both children and adults, and for long-term data on less common adverse effects.
Mike Watson Images/moodboard/Thinkstock
NATURE REVIEWS | RHEUMATOLOGY
ADVANCE ONLINE PUBLICATION | 1 © 2015 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS The controversial issue of therapy sub stitution (when patients receive a biosimilar instead of the prescribed innovator) or interchangeability is also discussed in the position paper. According to the ACR, the decision to substitute an innovator for a biosimilar agent lies with the physician; however, when substitution by the pharmacist is lawful, doctor and patient should immediately be made aware that a substitution has occurred, as the short dosing interval of many biologic agents means that adverse events in response to the biosimilar agent could occur soon after drug administration. This may not happen in countries where the health authorities decide that the innovator will no longer be provided and where it is substituted by the biosimilar agent or the intended copy. Although a discussion about interchangeability is included in the position statement, the document does not add the ACR’s final position on this, possibly because that direction should be provided by the regulators (the FDA). Nevertheless, the ACR places itself against indiscriminate interchangeability or to compulsory switching in patients that are stable to a different drug for cost-saving reasons.5 Although some agreement exists in support of biosimilar agent interchangeability in inflammatory arthritis, the same does not seem to happen in other diseases (for example, inflammatory bowel disease).6 The ACR statement does not discuss what might be the major driving force for the development of biosimilars—the ever increasing cost of new chemical and biological therapeutic agents. One of the main consequences of the development of biosimilars is an expected reduction
in price costs, although not to the same extent as it happened with the introduction of small-molecule generics. The first true biosimilar approved by the EMA, an infliximab similar, is associated with considerable reductions in reimbursement but, surprisingly, intended copies of etanercept released in Mexico and Colombia have only a modest 5% reduction in their fiscal cost.7 Release of this ACR position statement on biosimilars prompts us to focus on issues relating to the clinical use of biosimilar agents and calls for vigilance on that regard. Nevertheless, some important aspects for the rheumatologist in clinical practice, such as the immunogenicity of biosimilars and the development of antidrug antib odies, were not discussed. In the past decade, rheumatologists have learned a lot about the variability of efficacy between different biologic agents such as TNF inhibitors. If the mechanism of action of TNF inhibitors was solely dependent on its ability to neutralize TNF, individual patients would experience the same therapeutic benefit regardless of the TNF inhibitor prescribed. However, this is clearly not the case.8,9 Variability in efficacy might also occur when substituting an innovator for a biosimilar. The ACR position statement on biosimilars should help US-based rheumatologists in clinical practice to better understand the differences between a true biosimilar and an intended copy. The document provides advice on biosimilar nomenclature, on how to manage therapy substitution, and the risks of repeated switching. These same recommendations can also be helpful for rheumatologists in other regions of the world where biosimilar agent regulatory processes are not yet fully implemented.
2 | ADVANCE ONLINE PUBLICATION
Hospital Israelita Albert Einstein, Avenida Albert Einsten, 627/701 Morumbi, São Paulo, SP 05652-900, Brazil. [email protected] doi:10.1038/nrrheum.2015.57 Published online 28 April 2015 Acknowledgements The author thanks Amanda Malveira Guimarães for help while preparing the manuscript. Competing interests The author declares no competing interests. 1.
2.
3. 4.
5.
6.
7. 8.
9.
Strand, V., Kimberly, R. & Isaacs, J. D. Biologic therapies in rheumatology: lessons learned, future directions. Nat. Rev. Drug Discov. 6, 75–92 (2007). Scheinberg, M. A. & Kay, J. The advent of biosimilar therapies in rheumatology—“O brave new world”. Nat. Rev. Rheumatol. 8, 430–436 (2012). Schellekens, H. When biotech proteins go offpatent. Trends Biotechnol. 22, 406–410 (2004). Beck, A. & Reichert, J. M. Approval of the first biosimilar antibodies in Europe: a major landmark for the biopharmaceutical industry. MAbs 5, 621–623 (2013). ACR Committee on Rheumatologic Care. ACR position statement – Biosimilars [online], https://www.rheumatology.org/Practice/ Clinical/Position/Biosimilars_02_2015/.pdf (2015). Scheinberg, M. & Castaneda-Hernandez, G. Anti-tumor necrosis factor patent expiration and the risks of biocopies in clinical practice. Arthritis Res. Ther. 6, 501 (2014). Scheinberg, M. Biosimilars in Crohn’s disease. J. Crohns Colitis 8, 710 (2014). Finckh, A. Comparative effectiveness of biologic anti rheumatic therapies in rheumatoid arthritis after failure to respond to a first TNF inhibitor. J. Comp. Eff. Res. 6, 481–484 (2012). Schiff, M. H., von Kempis, J., Goldblum, R., Tesser, J. R. & Mueller, R. B. Rheumatoid arthritis secondary non-responders to TNF can attain an efficacious and safe response by switching to certolizumab pegol: a phase IV, randomised, multicentre, double-blind, 12-week study, followed by a 12-week open-label phase. Ann. Rheum. Dis. 73, 174–177 (2014).
www.nature.com/nrrheum © 2015 Macmillan Publishers Limited. All rights reserved
