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ORLANDO – Regardless of what you think about using biosimilars, chances are you won’t be able to avoid using them if you already use biologics.
That’s according to Dr. David T. Rubin, codirector of the Digestive Diseases Center at the University of Chicago. “They’re coming and they will influence our practice, ” he told a clinical track audience at a conference on inflammatory bowel disease.
Before exploring how these medications may change how you treat patients, here’s a look at what they are and how they’re brought to market.
First, a little basic science review of small-molecule medications vs. biologic ones. Small-molecule agents are simple structures, which are stable enough to be replicated, do not tend to cause immunogenicity, and require very little in the way of testing for quality assurance.
By contrast, biologic medicines, including monoclonal antibodies, are complex structures – in some cases, highly complex – that are replicable, but often with a high degree of difficulty. Unlike small-molecule medicines, biologic drugs cannot be mass produced and require almost 250 sophisticated tests to ensure quality. They are less stable and can trigger an immunogenic response. The manufacturing process for biologics is so precise that the slightest disturbance in development can affect whether the medication is functional.
As a result, the typical development timeline for these medications is between 7 and 8 years, with costs running as high as $250 million each. Currently, there are more than 650 recombinant therapeutics in development worldwide, more than half of which are in the preclinical stage. The top original products being copied are adalimumab at 13, and infliximab with 9. Meanwhile, at least five as-of-yet unpublished studies are looking at how these potential adalimumab and infliximab biosimilars perform in inflammatory bowel disease (IBD), Dr. Rubin said. Biosimilars are used worldwide, primarily in Europe and Asia.
But when these biosimilars reach our shores, don’t call them generics. “I encourage you to not use that term, even when discussing them with patients,” Dr. Rubin said. Still, because the Food and Drug Administration says that a biosimilar should have no greater risk for adverse events or diminished efficacy compared with the original biologic just as with generics, pharmacists are within their rights to substitute biosimilars for original biologics without prescriber intervention.
That’s why, “There must be pharmacovigilance with biosimilars, just like with generics, after the drug is brought to market,” Dr. Rubin said.
Biosimilars are also not “biobetters,” medications that have modifications added to the original biologic product in order to improve their clinical performance. While biobetters can be patented, they do not have legal or regulatory status, however, because they are considered new drugs.
The FDA defines biosimilars as a biological product that is highly similar to the reference product, with no clinically meaningful safety, purity, or potency differences from the reference product.
Early in 2015, the biosimilar filgrastim-sndz (Zarxio TM, Sandoz-Novartis), which has been available in Europe since 2009, entered the U.S. market. With its biosimilarity to Filgrastim (Sandoz-Novartis), the medication’s primary indications are for various cancers and chronic neutropenia.
To help expedite bringing the medications to market, FDA guidance data requirements for biosimilars is abbreviated when compared with that for biologics. Rather than ask developers to conduct clinical trials, developers must provide at least one comparative study between the biosimilar and its original, according to the original drug’s indication. There also is what Dr. Rubin called a “weighted reliance” on analytical similarity to the original. In addition, no phase II dose-ranging studies are required. Indication extrapolation is also possible, meaning that safety and efficacy data leading to a biosimilar being approved for say, rheumatoid arthritis, could also be applied to Crohn’s disease.
So, what does all this mean for your patients? It depends upon in which state you practice: Even when a recombinant product meets the FDA criteria, whether or not a patient can be placed on a biosimilar comes down to state regulation. At present, 19 states have passed laws as to how and when biosimilars can be swapped out, most of them stipulating that a patient be notified when it occurs. Physicians maintain their rights to ask pharmacists to “dispense as written,” but since biosimilars are cheaper than their originals, you won’t necessarily get around mounting pressure from third-party payers to contain costs.
Dr. Rubin said this potential friction between insurers and physicians could result in delays with adverse effect on the patient. “If the insurance company says they prefer another agent over the one a patient is receiving, we all know about the unexpected delays that can occur when switching.”
Dr. Rubin predicted that the logistics of prescribing will be complicated by pharmaceutical marketing efforts. He noted the similar names of Remsima (Hospira) vs. Remicade (Janssen), Inflectra (Hospira) vs. infliximab generic. “It could be confusing for all of us.”
The question of how the drug will fare once inside the patient is still a matter of debate.
“The major issue is immunogenicity ... it’s impossible to predict in vitro,” said Dr. Brian Feagan, a copanelist with Dr. Rubin, and a professor of medicine at the University of Western Ontario in London, Canada. “Immunogenicity is determined by product-related factors, and a lot of clinical ones such as immunosuppression, coadministration, route of administration, disease-specific factors.”
The only way to truly determine the impact on immunogenicity of interchangeability, whether because of third-party payer stipulations or physician’s choice, is to do multiple switching trials, said Dr. Feagan.
But Dr. Stephen B. Hanauer, the Clifford Joseph Barborka Professor of Medicine in Gastroenterology and Hepatology at Northwestern University (Chicago), said that’s not likely to happen. “There’s no time for that as the FDA regulatory evaluation proceeds,” he said in an interview.
“The trial would take 2 years to accomplish, would need large numbers of patients in order to identify potential small differences, and would be too expensive.” All of which would defeat the purpose of the expedited approval process, Dr. Hanauer said, because the decision by Congress to give biosimilars the green light was to reduce cost.
On the other hand, said Dr. Feagan, the experiment on switching probably has already been done. That’s because despite what he referred to as efforts by pharmaceutical manufacturers to reassure physicians there is no drift from the original product, heterogeneity is inevitable.
These iterative qualities, according to Dr. Hanauer, essentially make the original products into biosimilars of themselves. Add to that, he said that depending upon the company used to perform the assays to determine immunogenicity, the range of results can vary widely, and you end up having to learn to live with a certain amount of uncertainty. “I’m not afraid of biosimilars,” Dr. Hanauer said while discussing biosimilars during an audience question time at the meeting.
“We are a little bit timid about biosimilars, but my sense is we will find our comfort level in the next few years, and we will start using them frequently,” Dr. Miguel Regueiro, medical director of the IBD Center at the University of Pittsburgh, said in an interview. “I think immunogenicity to biosimilars will be the same immunogenicity to the innovative biologics, but I don’t think we’re going to be comfortable with interchanging a biosimilar with a[n] original biologic because of the potential immunogenicity that can occur by switching between agents.”
Whether biosimilars can be used in place of their originals, said both Dr. Feagan and Dr. Hanauer, will come down to how extrapolated data is interpreted.
“I think the biggest debate the FDA is going to have [when indicating biosimilars for IBD] is overextrapolation,” Dr. Hanauer said in the interview. Since the FDA does not require clinical trials for biosimilars, but relies upon analytics instead, and because there are far less clinical data for biologics in IBD than there are for diseases such as rheumatoid or psoriatic arthritis, manufacturers will turn to those studies to demonstrate efficacy between originals and recombinants. “If 99.9% of the analytic assays and the clinical data in rheumatoid arthritis are virtually the same, I would assume that the data in inflammatory bowel disease is going to be virtually the same.”
However, at least in Canada, that was not the opinion of regulators who decided against approving the extrapolation of infliximab clinical data for indicating its biosimilar in IBD, but did allow extrapolation of the data for rheumatoid arthritis. “Health Canada decided that the antibody-dependent, cell-mediated cytotoxicity was different for IBD,” said Dr. Feagan.
Predicting the primacy of cost over keeping patients in remission, but at least for now, Dr. Rubin said the question of cost is “huge. Based on the European and Asian experience, the day one of these new products becomes available, the price of the existing therapies drops anywhere from 15% to 30%.”
Recent data places the cost of remission in the United States using infliximab at about $15,000.
Dr. Regueiro said these market forces are a good thing. “I don’t look at biosimilars in a negative context whatsoever. I think they are a necessary part of health care reform. Cost is definitely a driver, and that’s not bad.”
The meeting was sponsored by the Crohn’s & Colitis Foundation of America. Dr. Rubin has financial and consulting relationships with AbbVie, Janssen, Takeda, and numerous other pharmaceutical companies. Dr. Feagan has numerous relationships with pharmaceutical companies, including Abbott, Janssen, Teva, and others. Dr. Hanauer has served on the board of AbbVie and has financial relationships with numerous other pharmaceutical manufacturers. Dr. Regueiro did not have any disclosures relevant to this story.
On Twitter @whitneymcknight
This article was updated 1/6/16.
ORLANDO – Regardless of what you think about using biosimilars, chances are you won’t be able to avoid using them if you already use biologics.
That’s according to Dr. David T. Rubin, codirector of the Digestive Diseases Center at the University of Chicago. “They’re coming and they will influence our practice, ” he told a clinical track audience at a conference on inflammatory bowel disease.
Before exploring how these medications may change how you treat patients, here’s a look at what they are and how they’re brought to market.
First, a little basic science review of small-molecule medications vs. biologic ones. Small-molecule agents are simple structures, which are stable enough to be replicated, do not tend to cause immunogenicity, and require very little in the way of testing for quality assurance.
By contrast, biologic medicines, including monoclonal antibodies, are complex structures – in some cases, highly complex – that are replicable, but often with a high degree of difficulty. Unlike small-molecule medicines, biologic drugs cannot be mass produced and require almost 250 sophisticated tests to ensure quality. They are less stable and can trigger an immunogenic response. The manufacturing process for biologics is so precise that the slightest disturbance in development can affect whether the medication is functional.
As a result, the typical development timeline for these medications is between 7 and 8 years, with costs running as high as $250 million each. Currently, there are more than 650 recombinant therapeutics in development worldwide, more than half of which are in the preclinical stage. The top original products being copied are adalimumab at 13, and infliximab with 9. Meanwhile, at least five as-of-yet unpublished studies are looking at how these potential adalimumab and infliximab biosimilars perform in inflammatory bowel disease (IBD), Dr. Rubin said. Biosimilars are used worldwide, primarily in Europe and Asia.
But when these biosimilars reach our shores, don’t call them generics. “I encourage you to not use that term, even when discussing them with patients,” Dr. Rubin said. Still, because the Food and Drug Administration says that a biosimilar should have no greater risk for adverse events or diminished efficacy compared with the original biologic just as with generics, pharmacists are within their rights to substitute biosimilars for original biologics without prescriber intervention.
That’s why, “There must be pharmacovigilance with biosimilars, just like with generics, after the drug is brought to market,” Dr. Rubin said.
Biosimilars are also not “biobetters,” medications that have modifications added to the original biologic product in order to improve their clinical performance. While biobetters can be patented, they do not have legal or regulatory status, however, because they are considered new drugs.
The FDA defines biosimilars as a biological product that is highly similar to the reference product, with no clinically meaningful safety, purity, or potency differences from the reference product.
Early in 2015, the biosimilar filgrastim-sndz (Zarxio TM, Sandoz-Novartis), which has been available in Europe since 2009, entered the U.S. market. With its biosimilarity to Filgrastim (Sandoz-Novartis), the medication’s primary indications are for various cancers and chronic neutropenia.
To help expedite bringing the medications to market, FDA guidance data requirements for biosimilars is abbreviated when compared with that for biologics. Rather than ask developers to conduct clinical trials, developers must provide at least one comparative study between the biosimilar and its original, according to the original drug’s indication. There also is what Dr. Rubin called a “weighted reliance” on analytical similarity to the original. In addition, no phase II dose-ranging studies are required. Indication extrapolation is also possible, meaning that safety and efficacy data leading to a biosimilar being approved for say, rheumatoid arthritis, could also be applied to Crohn’s disease.
So, what does all this mean for your patients? It depends upon in which state you practice: Even when a recombinant product meets the FDA criteria, whether or not a patient can be placed on a biosimilar comes down to state regulation. At present, 19 states have passed laws as to how and when biosimilars can be swapped out, most of them stipulating that a patient be notified when it occurs. Physicians maintain their rights to ask pharmacists to “dispense as written,” but since biosimilars are cheaper than their originals, you won’t necessarily get around mounting pressure from third-party payers to contain costs.
Dr. Rubin said this potential friction between insurers and physicians could result in delays with adverse effect on the patient. “If the insurance company says they prefer another agent over the one a patient is receiving, we all know about the unexpected delays that can occur when switching.”
Dr. Rubin predicted that the logistics of prescribing will be complicated by pharmaceutical marketing efforts. He noted the similar names of Remsima (Hospira) vs. Remicade (Janssen), Inflectra (Hospira) vs. infliximab generic. “It could be confusing for all of us.”
The question of how the drug will fare once inside the patient is still a matter of debate.
“The major issue is immunogenicity ... it’s impossible to predict in vitro,” said Dr. Brian Feagan, a copanelist with Dr. Rubin, and a professor of medicine at the University of Western Ontario in London, Canada. “Immunogenicity is determined by product-related factors, and a lot of clinical ones such as immunosuppression, coadministration, route of administration, disease-specific factors.”
The only way to truly determine the impact on immunogenicity of interchangeability, whether because of third-party payer stipulations or physician’s choice, is to do multiple switching trials, said Dr. Feagan.
But Dr. Stephen B. Hanauer, the Clifford Joseph Barborka Professor of Medicine in Gastroenterology and Hepatology at Northwestern University (Chicago), said that’s not likely to happen. “There’s no time for that as the FDA regulatory evaluation proceeds,” he said in an interview.
“The trial would take 2 years to accomplish, would need large numbers of patients in order to identify potential small differences, and would be too expensive.” All of which would defeat the purpose of the expedited approval process, Dr. Hanauer said, because the decision by Congress to give biosimilars the green light was to reduce cost.
On the other hand, said Dr. Feagan, the experiment on switching probably has already been done. That’s because despite what he referred to as efforts by pharmaceutical manufacturers to reassure physicians there is no drift from the original product, heterogeneity is inevitable.
These iterative qualities, according to Dr. Hanauer, essentially make the original products into biosimilars of themselves. Add to that, he said that depending upon the company used to perform the assays to determine immunogenicity, the range of results can vary widely, and you end up having to learn to live with a certain amount of uncertainty. “I’m not afraid of biosimilars,” Dr. Hanauer said while discussing biosimilars during an audience question time at the meeting.
“We are a little bit timid about biosimilars, but my sense is we will find our comfort level in the next few years, and we will start using them frequently,” Dr. Miguel Regueiro, medical director of the IBD Center at the University of Pittsburgh, said in an interview. “I think immunogenicity to biosimilars will be the same immunogenicity to the innovative biologics, but I don’t think we’re going to be comfortable with interchanging a biosimilar with a[n] original biologic because of the potential immunogenicity that can occur by switching between agents.”
Whether biosimilars can be used in place of their originals, said both Dr. Feagan and Dr. Hanauer, will come down to how extrapolated data is interpreted.
“I think the biggest debate the FDA is going to have [when indicating biosimilars for IBD] is overextrapolation,” Dr. Hanauer said in the interview. Since the FDA does not require clinical trials for biosimilars, but relies upon analytics instead, and because there are far less clinical data for biologics in IBD than there are for diseases such as rheumatoid or psoriatic arthritis, manufacturers will turn to those studies to demonstrate efficacy between originals and recombinants. “If 99.9% of the analytic assays and the clinical data in rheumatoid arthritis are virtually the same, I would assume that the data in inflammatory bowel disease is going to be virtually the same.”
However, at least in Canada, that was not the opinion of regulators who decided against approving the extrapolation of infliximab clinical data for indicating its biosimilar in IBD, but did allow extrapolation of the data for rheumatoid arthritis. “Health Canada decided that the antibody-dependent, cell-mediated cytotoxicity was different for IBD,” said Dr. Feagan.
Predicting the primacy of cost over keeping patients in remission, but at least for now, Dr. Rubin said the question of cost is “huge. Based on the European and Asian experience, the day one of these new products becomes available, the price of the existing therapies drops anywhere from 15% to 30%.”
Recent data places the cost of remission in the United States using infliximab at about $15,000.
Dr. Regueiro said these market forces are a good thing. “I don’t look at biosimilars in a negative context whatsoever. I think they are a necessary part of health care reform. Cost is definitely a driver, and that’s not bad.”
The meeting was sponsored by the Crohn’s & Colitis Foundation of America. Dr. Rubin has financial and consulting relationships with AbbVie, Janssen, Takeda, and numerous other pharmaceutical companies. Dr. Feagan has numerous relationships with pharmaceutical companies, including Abbott, Janssen, Teva, and others. Dr. Hanauer has served on the board of AbbVie and has financial relationships with numerous other pharmaceutical manufacturers. Dr. Regueiro did not have any disclosures relevant to this story.
On Twitter @whitneymcknight
This article was updated 1/6/16.
ORLANDO – Regardless of what you think about using biosimilars, chances are you won’t be able to avoid using them if you already use biologics.
That’s according to Dr. David T. Rubin, codirector of the Digestive Diseases Center at the University of Chicago. “They’re coming and they will influence our practice, ” he told a clinical track audience at a conference on inflammatory bowel disease.
Before exploring how these medications may change how you treat patients, here’s a look at what they are and how they’re brought to market.
First, a little basic science review of small-molecule medications vs. biologic ones. Small-molecule agents are simple structures, which are stable enough to be replicated, do not tend to cause immunogenicity, and require very little in the way of testing for quality assurance.
By contrast, biologic medicines, including monoclonal antibodies, are complex structures – in some cases, highly complex – that are replicable, but often with a high degree of difficulty. Unlike small-molecule medicines, biologic drugs cannot be mass produced and require almost 250 sophisticated tests to ensure quality. They are less stable and can trigger an immunogenic response. The manufacturing process for biologics is so precise that the slightest disturbance in development can affect whether the medication is functional.
As a result, the typical development timeline for these medications is between 7 and 8 years, with costs running as high as $250 million each. Currently, there are more than 650 recombinant therapeutics in development worldwide, more than half of which are in the preclinical stage. The top original products being copied are adalimumab at 13, and infliximab with 9. Meanwhile, at least five as-of-yet unpublished studies are looking at how these potential adalimumab and infliximab biosimilars perform in inflammatory bowel disease (IBD), Dr. Rubin said. Biosimilars are used worldwide, primarily in Europe and Asia.
But when these biosimilars reach our shores, don’t call them generics. “I encourage you to not use that term, even when discussing them with patients,” Dr. Rubin said. Still, because the Food and Drug Administration says that a biosimilar should have no greater risk for adverse events or diminished efficacy compared with the original biologic just as with generics, pharmacists are within their rights to substitute biosimilars for original biologics without prescriber intervention.
That’s why, “There must be pharmacovigilance with biosimilars, just like with generics, after the drug is brought to market,” Dr. Rubin said.
Biosimilars are also not “biobetters,” medications that have modifications added to the original biologic product in order to improve their clinical performance. While biobetters can be patented, they do not have legal or regulatory status, however, because they are considered new drugs.
The FDA defines biosimilars as a biological product that is highly similar to the reference product, with no clinically meaningful safety, purity, or potency differences from the reference product.
Early in 2015, the biosimilar filgrastim-sndz (Zarxio TM, Sandoz-Novartis), which has been available in Europe since 2009, entered the U.S. market. With its biosimilarity to Filgrastim (Sandoz-Novartis), the medication’s primary indications are for various cancers and chronic neutropenia.
To help expedite bringing the medications to market, FDA guidance data requirements for biosimilars is abbreviated when compared with that for biologics. Rather than ask developers to conduct clinical trials, developers must provide at least one comparative study between the biosimilar and its original, according to the original drug’s indication. There also is what Dr. Rubin called a “weighted reliance” on analytical similarity to the original. In addition, no phase II dose-ranging studies are required. Indication extrapolation is also possible, meaning that safety and efficacy data leading to a biosimilar being approved for say, rheumatoid arthritis, could also be applied to Crohn’s disease.
So, what does all this mean for your patients? It depends upon in which state you practice: Even when a recombinant product meets the FDA criteria, whether or not a patient can be placed on a biosimilar comes down to state regulation. At present, 19 states have passed laws as to how and when biosimilars can be swapped out, most of them stipulating that a patient be notified when it occurs. Physicians maintain their rights to ask pharmacists to “dispense as written,” but since biosimilars are cheaper than their originals, you won’t necessarily get around mounting pressure from third-party payers to contain costs.
Dr. Rubin said this potential friction between insurers and physicians could result in delays with adverse effect on the patient. “If the insurance company says they prefer another agent over the one a patient is receiving, we all know about the unexpected delays that can occur when switching.”
Dr. Rubin predicted that the logistics of prescribing will be complicated by pharmaceutical marketing efforts. He noted the similar names of Remsima (Hospira) vs. Remicade (Janssen), Inflectra (Hospira) vs. infliximab generic. “It could be confusing for all of us.”
The question of how the drug will fare once inside the patient is still a matter of debate.
“The major issue is immunogenicity ... it’s impossible to predict in vitro,” said Dr. Brian Feagan, a copanelist with Dr. Rubin, and a professor of medicine at the University of Western Ontario in London, Canada. “Immunogenicity is determined by product-related factors, and a lot of clinical ones such as immunosuppression, coadministration, route of administration, disease-specific factors.”
The only way to truly determine the impact on immunogenicity of interchangeability, whether because of third-party payer stipulations or physician’s choice, is to do multiple switching trials, said Dr. Feagan.
But Dr. Stephen B. Hanauer, the Clifford Joseph Barborka Professor of Medicine in Gastroenterology and Hepatology at Northwestern University (Chicago), said that’s not likely to happen. “There’s no time for that as the FDA regulatory evaluation proceeds,” he said in an interview.
“The trial would take 2 years to accomplish, would need large numbers of patients in order to identify potential small differences, and would be too expensive.” All of which would defeat the purpose of the expedited approval process, Dr. Hanauer said, because the decision by Congress to give biosimilars the green light was to reduce cost.
On the other hand, said Dr. Feagan, the experiment on switching probably has already been done. That’s because despite what he referred to as efforts by pharmaceutical manufacturers to reassure physicians there is no drift from the original product, heterogeneity is inevitable.
These iterative qualities, according to Dr. Hanauer, essentially make the original products into biosimilars of themselves. Add to that, he said that depending upon the company used to perform the assays to determine immunogenicity, the range of results can vary widely, and you end up having to learn to live with a certain amount of uncertainty. “I’m not afraid of biosimilars,” Dr. Hanauer said while discussing biosimilars during an audience question time at the meeting.
“We are a little bit timid about biosimilars, but my sense is we will find our comfort level in the next few years, and we will start using them frequently,” Dr. Miguel Regueiro, medical director of the IBD Center at the University of Pittsburgh, said in an interview. “I think immunogenicity to biosimilars will be the same immunogenicity to the innovative biologics, but I don’t think we’re going to be comfortable with interchanging a biosimilar with a[n] original biologic because of the potential immunogenicity that can occur by switching between agents.”
Whether biosimilars can be used in place of their originals, said both Dr. Feagan and Dr. Hanauer, will come down to how extrapolated data is interpreted.
“I think the biggest debate the FDA is going to have [when indicating biosimilars for IBD] is overextrapolation,” Dr. Hanauer said in the interview. Since the FDA does not require clinical trials for biosimilars, but relies upon analytics instead, and because there are far less clinical data for biologics in IBD than there are for diseases such as rheumatoid or psoriatic arthritis, manufacturers will turn to those studies to demonstrate efficacy between originals and recombinants. “If 99.9% of the analytic assays and the clinical data in rheumatoid arthritis are virtually the same, I would assume that the data in inflammatory bowel disease is going to be virtually the same.”
However, at least in Canada, that was not the opinion of regulators who decided against approving the extrapolation of infliximab clinical data for indicating its biosimilar in IBD, but did allow extrapolation of the data for rheumatoid arthritis. “Health Canada decided that the antibody-dependent, cell-mediated cytotoxicity was different for IBD,” said Dr. Feagan.
Predicting the primacy of cost over keeping patients in remission, but at least for now, Dr. Rubin said the question of cost is “huge. Based on the European and Asian experience, the day one of these new products becomes available, the price of the existing therapies drops anywhere from 15% to 30%.”
Recent data places the cost of remission in the United States using infliximab at about $15,000.
Dr. Regueiro said these market forces are a good thing. “I don’t look at biosimilars in a negative context whatsoever. I think they are a necessary part of health care reform. Cost is definitely a driver, and that’s not bad.”
The meeting was sponsored by the Crohn’s & Colitis Foundation of America. Dr. Rubin has financial and consulting relationships with AbbVie, Janssen, Takeda, and numerous other pharmaceutical companies. Dr. Feagan has numerous relationships with pharmaceutical companies, including Abbott, Janssen, Teva, and others. Dr. Hanauer has served on the board of AbbVie and has financial relationships with numerous other pharmaceutical manufacturers. Dr. Regueiro did not have any disclosures relevant to this story.
On Twitter @whitneymcknight
This article was updated 1/6/16.
EXPERT ANALYSIS FROM 2015 ADVANCES IN IBD
