Ankylosing spondylitis

BIRMINGHAM, ENGLAND – One in five people with ankylosing spondylitis could have comorbid fibromyalgia, according to data from the British Society for Rheumatology Biologics Register for Ankylosing Spondylitis (BSRBR-AS).

The analysis, which included more than 880 patients with axial spondyloarthritis (SpA), found that 20.7% met 2011 research criteria for the chronic pain condition.

The prevalence of fibromyalgia was similar when the modified New York (mNY) criteria were used to diagnose SpA, at 19.7%, but slightly higher at 25.2% when SpA patients met the Assessment of SpondyloArthritis international Society (ASAS) imaging criteria but not mNY criteria, and substantially lower at 9.5% when SpA patients met ASAS clinical criteria only.

Courtesy Dr. Gary J. Macfarlane

BIRMINGHAM, ENGLAND – One in five people with ankylosing spondylitis could have comorbid fibromyalgia, according to data from the British Society for Rheumatology Biologics Register for Ankylosing Spondylitis (BSRBR-AS).

The analysis, which included more than 880 patients with axial spondyloarthritis (SpA), found that 20.7% met 2011 research criteria for the chronic pain condition.

The prevalence of fibromyalgia was similar when the modified New York (mNY) criteria were used to diagnose SpA, at 19.7%, but slightly higher at 25.2% when SpA patients met the Assessment of SpondyloArthritis international Society (ASAS) imaging criteria but not mNY criteria, and substantially lower at 9.5% when SpA patients met ASAS clinical criteria only.

Courtesy Dr. Gary J. Macfarlane

BIRMINGHAM, ENGLAND – One in five people with ankylosing spondylitis could have comorbid fibromyalgia, according to data from the British Society for Rheumatology Biologics Register for Ankylosing Spondylitis (BSRBR-AS).

The analysis, which included more than 880 patients with axial spondyloarthritis (SpA), found that 20.7% met 2011 research criteria for the chronic pain condition.

The prevalence of fibromyalgia was similar when the modified New York (mNY) criteria were used to diagnose SpA, at 19.7%, but slightly higher at 25.2% when SpA patients met the Assessment of SpondyloArthritis international Society (ASAS) imaging criteria but not mNY criteria, and substantially lower at 9.5% when SpA patients met ASAS clinical criteria only.

Courtesy Dr. Gary J. Macfarlane

Infliximab-abda is the second infliximab biosimilar approved by the Food and Drug Administration, the agency announced April 21.

Infliximab-abda, to be marketed as Renflexis, is approved for all indications as the reference product, including Crohn’s diseases in adults and children, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis, according to the product label.

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On Twitter @denisefulton

Infliximab-abda is the second infliximab biosimilar approved by the Food and Drug Administration, the agency announced April 21.

Infliximab-abda, to be marketed as Renflexis, is approved for all indications as the reference product, including Crohn’s diseases in adults and children, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis, according to the product label.

[email protected]

On Twitter @denisefulton

Infliximab-abda is the second infliximab biosimilar approved by the Food and Drug Administration, the agency announced April 21.

Infliximab-abda, to be marketed as Renflexis, is approved for all indications as the reference product, including Crohn’s diseases in adults and children, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis, according to the product label.

[email protected]

On Twitter @denisefulton

As new rules about drug compounding get shaped, rheumatologists seek to protect their ability to combine injectable drugs – most commonly a steroid and a local anesthetic – in their own offices.

In a position statement sent to government agencies and members of Congress in February, the American College of Rheumatology voiced concerns that the practice, which it called “critical,” could become a casualty of drug-compounding regulations under revision by the United States Pharmacopeial Convention (USP), a nonprofit group whose standards are enforceable by state and federal regulators.

Carol Renner/NDSU

Steroid fiasco sparked rule revisions

The ACR’s concerns follow a tighter focus by state and federal agencies on drug compounding after a fungal meningitis outbreak in 2012 was traced to contaminated steroids produced in bulk by a compounding pharmacy.

More than 800 infections, 64 of them fatal, occurred after the New England Compounding Center in Framingham, Mass., sold contaminated methylprednisolone acetate that was used in epidural and intra-articular joint injections.

The following year Congress passed the Drug Quality and Security Act, which aims, in part, to prevent compounding pharmacies from engaging in what amounts to unregulated manufacturing.

As part of the law, the FDA created a list of drugs appropriate for compounding and a process by which larger compounding pharmacies must register with the FDA, and agree to inspections. The USP standards, meanwhile, address detailed technical and safety aspects of compounding and are enforceable by the FDA and state agencies.

“USP and FDA have had the ability to regulate compounding for over a decade, but only recently have the rules become actively enforced,” said Donald Miller, PharmD, of North Dakota State University, Fargo, who helped shape the ACR’s position statement on compounding with the help of rheumatologists in private practice.

“When you make guidelines for safety, they make sense, but then you can’t anticipate the way it’s going to affect individuals’ practice. And that’s where rheumatology got caught up,” said Dr. Miller, who was a member of the FDA Arthritis Advisory Committee in 2014-2016.

In-office mixing a top concern

Other specialties, including dermatology and immunology, also stand to be affected by various changes to compounding law and practice – and their societies have been active in voicing concerns.

Though the latest revisions of USP chapter 797, which impacts in-office mixing, are still being sorted out, it’s the No. 1 compounding-related concern for rheumatologists, Dr. Miller said.

Rheumatologists routinely mix an analgesic and a steroid for injection. The analgesic makes the steroids less viscous, and offers patients hours of immediate relief. They also add analgesics to hyaluronic acid injected for viscosupplementation. The mixing is usually conducted bedside, and the injections are administered right away.

Technically, combining these products amounts to sterile compounding, Dr. Miller explained. “And theoretically, under these rules, a physician could still do this, but they’d have to do it under a sterile hood like you find in a pharmacy, and that’s just not practical. It also becomes a matter of interpretation.”

USP chapter 797 sanctions in-office mixing for “immediate use” with individual patients – which is nearly always the case for the steroid injections used in rheumatology. But it’s unclear whether “immediate use” means emergency use only, or allows for routine use, as rheumatologists hope.

“One reason this came to rheumatology’s attention is that some state boards of medicine were inspecting and saying ‘Hey, you can’t do that,’ ” Dr. Miller said.

Pediatric issues

Pediatric rheumatologists, and adult rheumatologists who see children occasionally, use compounding pharmacies to create palatable oral medicines and adjusted doses of adult treatments.

They also use injections combining steroids with analgesics, and consider the addition of the analgesic a key aid to compliance.

“The biggest barrier we have is patient and parent anxiety about doing the procedure and the associated pain. We always administer our steroids mixed with lidocaine to help with the postprocedural discomfort,” said Adam Reinhardt, MD, chief of pediatric rheumatology at the University of Nebraska and Children’s Hospital and Medical Center in Omaha.

Relevance of rules

None of the rheumatologists interviewed questioned the need for tightened state and federal oversight of compounding practices overall – just the applicability of certain rules to their own practice.

Dr. Snow and Dr. Huffstutter noted that reports of infected joints – a potential result of a contaminated injection – are sporadic and rare. “There’s very little research in this, but [these types of injections] have been standard practice for decades,” Dr. Snow said.

Srikanth Mukkera, MD, a rheumatologist in Tupelo, Miss., agreed that “sporadic cases of joint infection do happen following injection, but it can be hard to show if an injection was the cause.”

Assuring that medicines are mixed only immediately prior to injection, and not stored, reduces the likelihood of contamination, Dr. Mukkera said. Moreover, he noted, epidural injections such as those that resulted in the 2012 meningitis outbreak carry different risks than those seen in intra-articular injections.

Dr. Miller, the lead author of the ACR statement, said that the rheumatologists on our committee “don’t know of anyone that’s had a knee or other joint infection from a contaminated injection. They feel that unless somebody finds some evidence of that, they should be allowed to continue” with their usual practice.

He said that he feels that the USP will ultimately heed the concerns of rheumatologists and hopefully provide a more relaxed interpretation of in-office compounding. “We’re hoping they’ll make some exceptions when they revise 797 standards or at least maybe leave room for organizations to create a best practice statement. We’ll see,” Dr. Miller said.

But this is in no way guaranteed. Dr. Huffstutter said he fears that, if the rules come to be interpreted more narrowly, even standard practices like reconstituting biologic drugs for infusion – something that’s also a routine part of in-office practice – could fall under the rubric of sterile compounding and come into question.

The quinacrine problem

A separate compounding-related issue in rheumatology is clinicians’ access to quinacrine, an antimalarial rheumatology drug that, while infrequently used, represents the only alternative to hydroxychloroquine for some lupus patients.

“There are no alternatives out there for hydroxychloroquine, so we need it as a backup,” Dr. Snow said. “If hydroxychloroquine isn’t an option, there’s nothing out there that we can use. There’s no easy replacement.”

Dr. Huffstutter said he currently had no patients on quinacrine. “It’s not very often that we use it, but in those patients that really need it, it can make a huge difference in how they do.”

Quinacrine is no longer manufactured commercially as a finished drug product but is available in a powder that compounding physicians put into 100-mg capsules. It is not on the FDA’s current list of drugs available for compounding except with special permission.

While the ACR has requested that the FDA add it the list of bulk drug substances that can be used in compounding, quinacrine remains off the list for now – and, providers say, hard to find.

Moreover, while rheumatologists may have previously been able to order and store quantities of quinacrine and other compounded nonsterile medications to dispense to their patients, they can no longer easily do so, as only the FDA-approved compounding “outsourcing facilities” are allowed to process larger orders; the rest can only respond to prescriptions for individual patients.

Dr. Miller said it’s likely that quinacrine will make it onto the FDA’s next list of bulk drugs available for compounding. “The FDA has kind of said, ‘Don’t worry about it,’ ” he said.

[email protected]

As new rules about drug compounding get shaped, rheumatologists seek to protect their ability to combine injectable drugs – most commonly a steroid and a local anesthetic – in their own offices.

In a position statement sent to government agencies and members of Congress in February, the American College of Rheumatology voiced concerns that the practice, which it called “critical,” could become a casualty of drug-compounding regulations under revision by the United States Pharmacopeial Convention (USP), a nonprofit group whose standards are enforceable by state and federal regulators.

Carol Renner/NDSU

Steroid fiasco sparked rule revisions

The ACR’s concerns follow a tighter focus by state and federal agencies on drug compounding after a fungal meningitis outbreak in 2012 was traced to contaminated steroids produced in bulk by a compounding pharmacy.

More than 800 infections, 64 of them fatal, occurred after the New England Compounding Center in Framingham, Mass., sold contaminated methylprednisolone acetate that was used in epidural and intra-articular joint injections.

The following year Congress passed the Drug Quality and Security Act, which aims, in part, to prevent compounding pharmacies from engaging in what amounts to unregulated manufacturing.

As part of the law, the FDA created a list of drugs appropriate for compounding and a process by which larger compounding pharmacies must register with the FDA, and agree to inspections. The USP standards, meanwhile, address detailed technical and safety aspects of compounding and are enforceable by the FDA and state agencies.

“USP and FDA have had the ability to regulate compounding for over a decade, but only recently have the rules become actively enforced,” said Donald Miller, PharmD, of North Dakota State University, Fargo, who helped shape the ACR’s position statement on compounding with the help of rheumatologists in private practice.

“When you make guidelines for safety, they make sense, but then you can’t anticipate the way it’s going to affect individuals’ practice. And that’s where rheumatology got caught up,” said Dr. Miller, who was a member of the FDA Arthritis Advisory Committee in 2014-2016.

In-office mixing a top concern

Other specialties, including dermatology and immunology, also stand to be affected by various changes to compounding law and practice – and their societies have been active in voicing concerns.

Though the latest revisions of USP chapter 797, which impacts in-office mixing, are still being sorted out, it’s the No. 1 compounding-related concern for rheumatologists, Dr. Miller said.

Rheumatologists routinely mix an analgesic and a steroid for injection. The analgesic makes the steroids less viscous, and offers patients hours of immediate relief. They also add analgesics to hyaluronic acid injected for viscosupplementation. The mixing is usually conducted bedside, and the injections are administered right away.

Technically, combining these products amounts to sterile compounding, Dr. Miller explained. “And theoretically, under these rules, a physician could still do this, but they’d have to do it under a sterile hood like you find in a pharmacy, and that’s just not practical. It also becomes a matter of interpretation.”

USP chapter 797 sanctions in-office mixing for “immediate use” with individual patients – which is nearly always the case for the steroid injections used in rheumatology. But it’s unclear whether “immediate use” means emergency use only, or allows for routine use, as rheumatologists hope.

“One reason this came to rheumatology’s attention is that some state boards of medicine were inspecting and saying ‘Hey, you can’t do that,’ ” Dr. Miller said.

Pediatric issues

Pediatric rheumatologists, and adult rheumatologists who see children occasionally, use compounding pharmacies to create palatable oral medicines and adjusted doses of adult treatments.

They also use injections combining steroids with analgesics, and consider the addition of the analgesic a key aid to compliance.

“The biggest barrier we have is patient and parent anxiety about doing the procedure and the associated pain. We always administer our steroids mixed with lidocaine to help with the postprocedural discomfort,” said Adam Reinhardt, MD, chief of pediatric rheumatology at the University of Nebraska and Children’s Hospital and Medical Center in Omaha.

Relevance of rules

None of the rheumatologists interviewed questioned the need for tightened state and federal oversight of compounding practices overall – just the applicability of certain rules to their own practice.

Dr. Snow and Dr. Huffstutter noted that reports of infected joints – a potential result of a contaminated injection – are sporadic and rare. “There’s very little research in this, but [these types of injections] have been standard practice for decades,” Dr. Snow said.

Srikanth Mukkera, MD, a rheumatologist in Tupelo, Miss., agreed that “sporadic cases of joint infection do happen following injection, but it can be hard to show if an injection was the cause.”

Assuring that medicines are mixed only immediately prior to injection, and not stored, reduces the likelihood of contamination, Dr. Mukkera said. Moreover, he noted, epidural injections such as those that resulted in the 2012 meningitis outbreak carry different risks than those seen in intra-articular injections.

Dr. Miller, the lead author of the ACR statement, said that the rheumatologists on our committee “don’t know of anyone that’s had a knee or other joint infection from a contaminated injection. They feel that unless somebody finds some evidence of that, they should be allowed to continue” with their usual practice.

He said that he feels that the USP will ultimately heed the concerns of rheumatologists and hopefully provide a more relaxed interpretation of in-office compounding. “We’re hoping they’ll make some exceptions when they revise 797 standards or at least maybe leave room for organizations to create a best practice statement. We’ll see,” Dr. Miller said.

But this is in no way guaranteed. Dr. Huffstutter said he fears that, if the rules come to be interpreted more narrowly, even standard practices like reconstituting biologic drugs for infusion – something that’s also a routine part of in-office practice – could fall under the rubric of sterile compounding and come into question.

The quinacrine problem

A separate compounding-related issue in rheumatology is clinicians’ access to quinacrine, an antimalarial rheumatology drug that, while infrequently used, represents the only alternative to hydroxychloroquine for some lupus patients.

“There are no alternatives out there for hydroxychloroquine, so we need it as a backup,” Dr. Snow said. “If hydroxychloroquine isn’t an option, there’s nothing out there that we can use. There’s no easy replacement.”

Dr. Huffstutter said he currently had no patients on quinacrine. “It’s not very often that we use it, but in those patients that really need it, it can make a huge difference in how they do.”

Quinacrine is no longer manufactured commercially as a finished drug product but is available in a powder that compounding physicians put into 100-mg capsules. It is not on the FDA’s current list of drugs available for compounding except with special permission.

While the ACR has requested that the FDA add it the list of bulk drug substances that can be used in compounding, quinacrine remains off the list for now – and, providers say, hard to find.

Moreover, while rheumatologists may have previously been able to order and store quantities of quinacrine and other compounded nonsterile medications to dispense to their patients, they can no longer easily do so, as only the FDA-approved compounding “outsourcing facilities” are allowed to process larger orders; the rest can only respond to prescriptions for individual patients.

Dr. Miller said it’s likely that quinacrine will make it onto the FDA’s next list of bulk drugs available for compounding. “The FDA has kind of said, ‘Don’t worry about it,’ ” he said.

[email protected]

As new rules about drug compounding get shaped, rheumatologists seek to protect their ability to combine injectable drugs – most commonly a steroid and a local anesthetic – in their own offices.

In a position statement sent to government agencies and members of Congress in February, the American College of Rheumatology voiced concerns that the practice, which it called “critical,” could become a casualty of drug-compounding regulations under revision by the United States Pharmacopeial Convention (USP), a nonprofit group whose standards are enforceable by state and federal regulators.

Carol Renner/NDSU

Steroid fiasco sparked rule revisions

The ACR’s concerns follow a tighter focus by state and federal agencies on drug compounding after a fungal meningitis outbreak in 2012 was traced to contaminated steroids produced in bulk by a compounding pharmacy.

More than 800 infections, 64 of them fatal, occurred after the New England Compounding Center in Framingham, Mass., sold contaminated methylprednisolone acetate that was used in epidural and intra-articular joint injections.

The following year Congress passed the Drug Quality and Security Act, which aims, in part, to prevent compounding pharmacies from engaging in what amounts to unregulated manufacturing.

As part of the law, the FDA created a list of drugs appropriate for compounding and a process by which larger compounding pharmacies must register with the FDA, and agree to inspections. The USP standards, meanwhile, address detailed technical and safety aspects of compounding and are enforceable by the FDA and state agencies.

“USP and FDA have had the ability to regulate compounding for over a decade, but only recently have the rules become actively enforced,” said Donald Miller, PharmD, of North Dakota State University, Fargo, who helped shape the ACR’s position statement on compounding with the help of rheumatologists in private practice.

“When you make guidelines for safety, they make sense, but then you can’t anticipate the way it’s going to affect individuals’ practice. And that’s where rheumatology got caught up,” said Dr. Miller, who was a member of the FDA Arthritis Advisory Committee in 2014-2016.

In-office mixing a top concern

Other specialties, including dermatology and immunology, also stand to be affected by various changes to compounding law and practice – and their societies have been active in voicing concerns.

Though the latest revisions of USP chapter 797, which impacts in-office mixing, are still being sorted out, it’s the No. 1 compounding-related concern for rheumatologists, Dr. Miller said.

Rheumatologists routinely mix an analgesic and a steroid for injection. The analgesic makes the steroids less viscous, and offers patients hours of immediate relief. They also add analgesics to hyaluronic acid injected for viscosupplementation. The mixing is usually conducted bedside, and the injections are administered right away.

Technically, combining these products amounts to sterile compounding, Dr. Miller explained. “And theoretically, under these rules, a physician could still do this, but they’d have to do it under a sterile hood like you find in a pharmacy, and that’s just not practical. It also becomes a matter of interpretation.”

USP chapter 797 sanctions in-office mixing for “immediate use” with individual patients – which is nearly always the case for the steroid injections used in rheumatology. But it’s unclear whether “immediate use” means emergency use only, or allows for routine use, as rheumatologists hope.

“One reason this came to rheumatology’s attention is that some state boards of medicine were inspecting and saying ‘Hey, you can’t do that,’ ” Dr. Miller said.

Pediatric issues

Pediatric rheumatologists, and adult rheumatologists who see children occasionally, use compounding pharmacies to create palatable oral medicines and adjusted doses of adult treatments.

They also use injections combining steroids with analgesics, and consider the addition of the analgesic a key aid to compliance.

“The biggest barrier we have is patient and parent anxiety about doing the procedure and the associated pain. We always administer our steroids mixed with lidocaine to help with the postprocedural discomfort,” said Adam Reinhardt, MD, chief of pediatric rheumatology at the University of Nebraska and Children’s Hospital and Medical Center in Omaha.

Relevance of rules

None of the rheumatologists interviewed questioned the need for tightened state and federal oversight of compounding practices overall – just the applicability of certain rules to their own practice.

Dr. Snow and Dr. Huffstutter noted that reports of infected joints – a potential result of a contaminated injection – are sporadic and rare. “There’s very little research in this, but [these types of injections] have been standard practice for decades,” Dr. Snow said.

Srikanth Mukkera, MD, a rheumatologist in Tupelo, Miss., agreed that “sporadic cases of joint infection do happen following injection, but it can be hard to show if an injection was the cause.”

Assuring that medicines are mixed only immediately prior to injection, and not stored, reduces the likelihood of contamination, Dr. Mukkera said. Moreover, he noted, epidural injections such as those that resulted in the 2012 meningitis outbreak carry different risks than those seen in intra-articular injections.

Dr. Miller, the lead author of the ACR statement, said that the rheumatologists on our committee “don’t know of anyone that’s had a knee or other joint infection from a contaminated injection. They feel that unless somebody finds some evidence of that, they should be allowed to continue” with their usual practice.

He said that he feels that the USP will ultimately heed the concerns of rheumatologists and hopefully provide a more relaxed interpretation of in-office compounding. “We’re hoping they’ll make some exceptions when they revise 797 standards or at least maybe leave room for organizations to create a best practice statement. We’ll see,” Dr. Miller said.

But this is in no way guaranteed. Dr. Huffstutter said he fears that, if the rules come to be interpreted more narrowly, even standard practices like reconstituting biologic drugs for infusion – something that’s also a routine part of in-office practice – could fall under the rubric of sterile compounding and come into question.

The quinacrine problem

A separate compounding-related issue in rheumatology is clinicians’ access to quinacrine, an antimalarial rheumatology drug that, while infrequently used, represents the only alternative to hydroxychloroquine for some lupus patients.

“There are no alternatives out there for hydroxychloroquine, so we need it as a backup,” Dr. Snow said. “If hydroxychloroquine isn’t an option, there’s nothing out there that we can use. There’s no easy replacement.”

Dr. Huffstutter said he currently had no patients on quinacrine. “It’s not very often that we use it, but in those patients that really need it, it can make a huge difference in how they do.”

Quinacrine is no longer manufactured commercially as a finished drug product but is available in a powder that compounding physicians put into 100-mg capsules. It is not on the FDA’s current list of drugs available for compounding except with special permission.

While the ACR has requested that the FDA add it the list of bulk drug substances that can be used in compounding, quinacrine remains off the list for now – and, providers say, hard to find.

Moreover, while rheumatologists may have previously been able to order and store quantities of quinacrine and other compounded nonsterile medications to dispense to their patients, they can no longer easily do so, as only the FDA-approved compounding “outsourcing facilities” are allowed to process larger orders; the rest can only respond to prescriptions for individual patients.

Dr. Miller said it’s likely that quinacrine will make it onto the FDA’s next list of bulk drugs available for compounding. “The FDA has kind of said, ‘Don’t worry about it,’ ” he said.

[email protected]

Women with rheumatoid arthritis or axial spondyloarthritis who stop treatment with tumor necrosis factor inhibitors when they become pregnant may be inviting disease flares during the pregnancy, according to a report published in Arthritis Research & Therapy.

To examine the frequency of rheumatoid arthritis (RA) and axial spondyloarthritis (axSpA) flares during pregnancy, researchers prospectively followed 136 women treated at the Center for Pregnancy in Rheumatic Diseases at Inselspital Bern (Switzerland) during a 5-year period. These patients – 75 with RA and 61 with axSpA – were assessed before conception, during each trimester, and 6-8 weeks postpartum for disease activity and medication use, said Stephanie van den Brandt, MD, of the department of rheumatology, immunology, and allergology at the University of Bern, and her associates.

©Photodisc/Thinkstock.com

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Women with rheumatoid arthritis or axial spondyloarthritis who stop treatment with tumor necrosis factor inhibitors when they become pregnant may be inviting disease flares during the pregnancy, according to a report published in Arthritis Research & Therapy.

To examine the frequency of rheumatoid arthritis (RA) and axial spondyloarthritis (axSpA) flares during pregnancy, researchers prospectively followed 136 women treated at the Center for Pregnancy in Rheumatic Diseases at Inselspital Bern (Switzerland) during a 5-year period. These patients – 75 with RA and 61 with axSpA – were assessed before conception, during each trimester, and 6-8 weeks postpartum for disease activity and medication use, said Stephanie van den Brandt, MD, of the department of rheumatology, immunology, and allergology at the University of Bern, and her associates.

©Photodisc/Thinkstock.com

[email protected]

Women with rheumatoid arthritis or axial spondyloarthritis who stop treatment with tumor necrosis factor inhibitors when they become pregnant may be inviting disease flares during the pregnancy, according to a report published in Arthritis Research & Therapy.

To examine the frequency of rheumatoid arthritis (RA) and axial spondyloarthritis (axSpA) flares during pregnancy, researchers prospectively followed 136 women treated at the Center for Pregnancy in Rheumatic Diseases at Inselspital Bern (Switzerland) during a 5-year period. These patients – 75 with RA and 61 with axSpA – were assessed before conception, during each trimester, and 6-8 weeks postpartum for disease activity and medication use, said Stephanie van den Brandt, MD, of the department of rheumatology, immunology, and allergology at the University of Bern, and her associates.

©Photodisc/Thinkstock.com

[email protected]

Two anti–tumor necrosis factor monoclonal antibodies, adalimumab and infliximab, showed evidence of being markedly more effective than the anti-TNF–receptor inhibitor etanercept at reducing the rate of anterior uveitis in patients with ankylosing spondylitis in a retrospective Swedish cohort study.

To compare the efficacy of the three TNF inhibitors, researchers analyzed data in nationwide Swedish population-based registries for 1,365 ankylosing spondylitis (AS) patients who initiated treatment during a 7-year period. Treatment began with adalimumab in 406 patients, infliximab in 605, and etanercept in 354, said Elisabeth Lie, MD, of the department of rheumatology and inflammation research at the University of Gothenburg (Sweden), and her associates.

Jonathan Trobe, M.D./Wikimedia Commons/CC BY-SA 3.0

Two anti–tumor necrosis factor monoclonal antibodies, adalimumab and infliximab, showed evidence of being markedly more effective than the anti-TNF–receptor inhibitor etanercept at reducing the rate of anterior uveitis in patients with ankylosing spondylitis in a retrospective Swedish cohort study.

To compare the efficacy of the three TNF inhibitors, researchers analyzed data in nationwide Swedish population-based registries for 1,365 ankylosing spondylitis (AS) patients who initiated treatment during a 7-year period. Treatment began with adalimumab in 406 patients, infliximab in 605, and etanercept in 354, said Elisabeth Lie, MD, of the department of rheumatology and inflammation research at the University of Gothenburg (Sweden), and her associates.

Jonathan Trobe, M.D./Wikimedia Commons/CC BY-SA 3.0

Two anti–tumor necrosis factor monoclonal antibodies, adalimumab and infliximab, showed evidence of being markedly more effective than the anti-TNF–receptor inhibitor etanercept at reducing the rate of anterior uveitis in patients with ankylosing spondylitis in a retrospective Swedish cohort study.

To compare the efficacy of the three TNF inhibitors, researchers analyzed data in nationwide Swedish population-based registries for 1,365 ankylosing spondylitis (AS) patients who initiated treatment during a 7-year period. Treatment began with adalimumab in 406 patients, infliximab in 605, and etanercept in 354, said Elisabeth Lie, MD, of the department of rheumatology and inflammation research at the University of Gothenburg (Sweden), and her associates.

Jonathan Trobe, M.D./Wikimedia Commons/CC BY-SA 3.0

The herpes zoster vaccine reduces the risk of shingles in older adults with autoimmune disease, even if they are taking immunosuppressants for their condition, but the protection begins to wane after about 5 years, a recent retrospective study found.

“There has been some concern that patients with autoimmune conditions might have a lower immunogenic response to herpes zoster vaccination, especially when treated with immunosuppressive medications such as glucocorticoids,” wrote Huifeng Yun, PhD, of the University of Alabama at Birmingham, and her colleagues.

copyright clsgraphics/iStockphoto.com

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The herpes zoster vaccine reduces the risk of shingles in older adults with autoimmune disease, even if they are taking immunosuppressants for their condition, but the protection begins to wane after about 5 years, a recent retrospective study found.

“There has been some concern that patients with autoimmune conditions might have a lower immunogenic response to herpes zoster vaccination, especially when treated with immunosuppressive medications such as glucocorticoids,” wrote Huifeng Yun, PhD, of the University of Alabama at Birmingham, and her colleagues.

copyright clsgraphics/iStockphoto.com

[email protected]

The herpes zoster vaccine reduces the risk of shingles in older adults with autoimmune disease, even if they are taking immunosuppressants for their condition, but the protection begins to wane after about 5 years, a recent retrospective study found.

“There has been some concern that patients with autoimmune conditions might have a lower immunogenic response to herpes zoster vaccination, especially when treated with immunosuppressive medications such as glucocorticoids,” wrote Huifeng Yun, PhD, of the University of Alabama at Birmingham, and her colleagues.

copyright clsgraphics/iStockphoto.com

[email protected]

SNOWMASS, COLO. – If you thought biosimilars would bring sharply reduced pricing compared with their parent agents, with resultant greater patient access to highly effective therapies for rheumatic diseases ... think again.

“The promise to our patients of biosimilars – greater access to treatments – is something I think we’re just not going to see, at least not here in the U.S.,” Michael E. Weinblatt, MD, declared at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

[email protected]
 

SNOWMASS, COLO. – If you thought biosimilars would bring sharply reduced pricing compared with their parent agents, with resultant greater patient access to highly effective therapies for rheumatic diseases ... think again.

“The promise to our patients of biosimilars – greater access to treatments – is something I think we’re just not going to see, at least not here in the U.S.,” Michael E. Weinblatt, MD, declared at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

[email protected]
 

SNOWMASS, COLO. – If you thought biosimilars would bring sharply reduced pricing compared with their parent agents, with resultant greater patient access to highly effective therapies for rheumatic diseases ... think again.

“The promise to our patients of biosimilars – greater access to treatments – is something I think we’re just not going to see, at least not here in the U.S.,” Michael E. Weinblatt, MD, declared at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

[email protected]
 

Administration of infliximab within 4 weeks of elective knee or hip arthroplasty did not have any significant effect on patients’ risk of serious infection after surgery, whereas the use of glucocorticoids increased that risk, in an analysis of a Medicare claims database.

“This increased risk with glucocorticoids has been suggested by previous studies [and] although this risk may be related in part to increased disease severity among glucocorticoid treated patients, a direct medication effect is likely. [These data suggest] that prolonged interruptions in infliximab therapy prior to surgery may be counterproductive if higher dose glucocorticoid therapy is used in substitution,” wrote the authors of the new study, led by Michael D. George, MD, of the University of Pennsylvania in Philadelphia.

Dr. George and his colleagues examined data from the U.S. Medicare claims system on 4,288 elective knee or hip arthroplasties in individuals with rheumatoid arthritis, inflammatory bowel disease, psoriasis, psoriatic arthritis, or ankylosing spondylitis who received infliximab within 6 months prior to the operation during 2007-2013 (Arthritis Care Res. 2017 Jan 27. doi: 10.1002/acr.23209).

The patients had to have received infliximab at least three times within a year of their procedure to establish that they were receiving stable therapy over a long-term period. The investigators also looked at oral prednisone, prednisolone, and methylprednisolone prescriptions and used data on average dosing to determine how much was administered to each subject.

“Although previous studies have treated TNF stopping vs. not stopping as a dichotomous exposure based on an arbitrary (and variable) stopping definition, in this study the primary analysis evaluated stop timing as a more general categorical exposure using 4-week intervals (half the standard rheumatoid arthritis dosing interval) to allow better assessment of the optimal stop timing,” the authors explained.

Stopping infliximab within 4 weeks of the operation did not significantly influence the rate of serious infection within 30 days (adjusted odds ratio, 0.90; 95% CI, 0.60-1.34) and neither did stopping within 4-8 weeks (OR, 0.95; 95% CI, 0.62-1.36) when compared against stopping 8-12 weeks before surgery. Of the 4,288 arthroplasties, 270 serious infections (6.3%) occurred within 30 days of the operation.

There also was no significant difference between stopping within 4 weeks and 8-12 weeks in the rate of prosthetic joint infection within 1 year of the operation (hazard ratio, 0.98; 95% CI, 0.52-1.87). Overall, prosthetic joint infection occurred 2.9 times per 100 person-years.

However, glucocorticoid doses of more than 10 mg per day were risky. The odds for a serious infection within 30 days after surgery more than doubled with that level of use (OR, 2.11; 95% CI, 1.30-3.40), while the risk for a prosthetic joint infection within 1 year of the surgery also rose significantly (HR, 2.70; 95% CI, 1.30-5.60).

[email protected]

Administration of infliximab within 4 weeks of elective knee or hip arthroplasty did not have any significant effect on patients’ risk of serious infection after surgery, whereas the use of glucocorticoids increased that risk, in an analysis of a Medicare claims database.

“This increased risk with glucocorticoids has been suggested by previous studies [and] although this risk may be related in part to increased disease severity among glucocorticoid treated patients, a direct medication effect is likely. [These data suggest] that prolonged interruptions in infliximab therapy prior to surgery may be counterproductive if higher dose glucocorticoid therapy is used in substitution,” wrote the authors of the new study, led by Michael D. George, MD, of the University of Pennsylvania in Philadelphia.

Dr. George and his colleagues examined data from the U.S. Medicare claims system on 4,288 elective knee or hip arthroplasties in individuals with rheumatoid arthritis, inflammatory bowel disease, psoriasis, psoriatic arthritis, or ankylosing spondylitis who received infliximab within 6 months prior to the operation during 2007-2013 (Arthritis Care Res. 2017 Jan 27. doi: 10.1002/acr.23209).

The patients had to have received infliximab at least three times within a year of their procedure to establish that they were receiving stable therapy over a long-term period. The investigators also looked at oral prednisone, prednisolone, and methylprednisolone prescriptions and used data on average dosing to determine how much was administered to each subject.

“Although previous studies have treated TNF stopping vs. not stopping as a dichotomous exposure based on an arbitrary (and variable) stopping definition, in this study the primary analysis evaluated stop timing as a more general categorical exposure using 4-week intervals (half the standard rheumatoid arthritis dosing interval) to allow better assessment of the optimal stop timing,” the authors explained.

Stopping infliximab within 4 weeks of the operation did not significantly influence the rate of serious infection within 30 days (adjusted odds ratio, 0.90; 95% CI, 0.60-1.34) and neither did stopping within 4-8 weeks (OR, 0.95; 95% CI, 0.62-1.36) when compared against stopping 8-12 weeks before surgery. Of the 4,288 arthroplasties, 270 serious infections (6.3%) occurred within 30 days of the operation.

There also was no significant difference between stopping within 4 weeks and 8-12 weeks in the rate of prosthetic joint infection within 1 year of the operation (hazard ratio, 0.98; 95% CI, 0.52-1.87). Overall, prosthetic joint infection occurred 2.9 times per 100 person-years.

However, glucocorticoid doses of more than 10 mg per day were risky. The odds for a serious infection within 30 days after surgery more than doubled with that level of use (OR, 2.11; 95% CI, 1.30-3.40), while the risk for a prosthetic joint infection within 1 year of the surgery also rose significantly (HR, 2.70; 95% CI, 1.30-5.60).

[email protected]

Administration of infliximab within 4 weeks of elective knee or hip arthroplasty did not have any significant effect on patients’ risk of serious infection after surgery, whereas the use of glucocorticoids increased that risk, in an analysis of a Medicare claims database.

“This increased risk with glucocorticoids has been suggested by previous studies [and] although this risk may be related in part to increased disease severity among glucocorticoid treated patients, a direct medication effect is likely. [These data suggest] that prolonged interruptions in infliximab therapy prior to surgery may be counterproductive if higher dose glucocorticoid therapy is used in substitution,” wrote the authors of the new study, led by Michael D. George, MD, of the University of Pennsylvania in Philadelphia.

Dr. George and his colleagues examined data from the U.S. Medicare claims system on 4,288 elective knee or hip arthroplasties in individuals with rheumatoid arthritis, inflammatory bowel disease, psoriasis, psoriatic arthritis, or ankylosing spondylitis who received infliximab within 6 months prior to the operation during 2007-2013 (Arthritis Care Res. 2017 Jan 27. doi: 10.1002/acr.23209).

The patients had to have received infliximab at least three times within a year of their procedure to establish that they were receiving stable therapy over a long-term period. The investigators also looked at oral prednisone, prednisolone, and methylprednisolone prescriptions and used data on average dosing to determine how much was administered to each subject.

“Although previous studies have treated TNF stopping vs. not stopping as a dichotomous exposure based on an arbitrary (and variable) stopping definition, in this study the primary analysis evaluated stop timing as a more general categorical exposure using 4-week intervals (half the standard rheumatoid arthritis dosing interval) to allow better assessment of the optimal stop timing,” the authors explained.

Stopping infliximab within 4 weeks of the operation did not significantly influence the rate of serious infection within 30 days (adjusted odds ratio, 0.90; 95% CI, 0.60-1.34) and neither did stopping within 4-8 weeks (OR, 0.95; 95% CI, 0.62-1.36) when compared against stopping 8-12 weeks before surgery. Of the 4,288 arthroplasties, 270 serious infections (6.3%) occurred within 30 days of the operation.

There also was no significant difference between stopping within 4 weeks and 8-12 weeks in the rate of prosthetic joint infection within 1 year of the operation (hazard ratio, 0.98; 95% CI, 0.52-1.87). Overall, prosthetic joint infection occurred 2.9 times per 100 person-years.

However, glucocorticoid doses of more than 10 mg per day were risky. The odds for a serious infection within 30 days after surgery more than doubled with that level of use (OR, 2.11; 95% CI, 1.30-3.40), while the risk for a prosthetic joint infection within 1 year of the surgery also rose significantly (HR, 2.70; 95% CI, 1.30-5.60).

[email protected]

The Food and Drug Administration has proposed a regulatory path for biosimilar biologics that are interchangeable with the reference product, paving the way for a new generation of less-expensive versions of these unique drugs.

But bringing an interchangeable biosimilar to market won’t be easy. The bar for interchangeability will be high, requiring that manufacturers prove switching between the new and older products is safe. And clinicians, while cautiously optimistic, aren’t thrilled with the industry payoff that could come with the designation: freedom for insurance companies and pharmacies to switch products at the dispensing level without requiring a new prescription.

The draft FDA guidance for industry, “Considerations in Demonstrating Interchangeability With a Reference Product,” arises from the Biologics Price Competition and Innovation Act of 2009. That section of the Affordable Care Act provides for abbreviated approval pathways for biological products that are demonstrated to be “highly similar” (biosimilar) to or “interchangeable” with an FDA-approved biological product.

The difference between these appellations is subtle but critical to the regulatory process – and perhaps to patient safety. Regulators recognize that the structure of these large, highly complex molecules can never precisely replicate the reference product. But to be labeled a “biosimilar,” developers must prove that the new product functions essentially the same; there can be no clinically meaningful differences in terms of safety, purity, and potency. Unlike a generic medication, a biosimilar can’t be substituted for its reference product at the pharmacy level. If a physician wants the patient on that biosimilar, the script must specify it.

Interchangeables jump a higher regulatory bar

An “interchangeable biosimilar,” though, would have to jump a higher regulatory bar. Not only must it produce the same clinical result as the reference product, it also must be benignly interchangeable with it, conferring no additional risk if a patient switches from the reference to the biosimilar and back again. A pharmacist could, if permitted by state law, substitute an interchangeable product for the reference product without going through the prescriber.

Like biosimilars, interchangeable products need not be tested in every disease for which the reference drug is approved, according to the document. Once they are proved safe for one indication, those data can be extrapolated to allow approval for the other indications as well. Nor do biosimilars need to prove efficacy per se, as their molecular similarity to the reference product ensures that they bind to the same receptor and exert the same therapeutic effect.

The biosimilar/interchangeable market has been slow to take off in the United States. There are no approved interchangeable biosimilars, and only four biosimilars – three of which were approved in 2016:

• Sandoz’ filgrastim-sndz (Zarxio).

• Pfizer’s and Celltrion’s infliximab-dyyb (Inflectra).

• Sandoz’ etanercept-szzs (Erelzi).

• Amgen’s adalimumab-atto (Amjevita).

Switching studies is the key to achieving the interchangeable designation, according to the FDA document. They must include at least two full switches between the candidate product and the reference product, which must be licensed in the United States.

But because these products are so structurally diverse, the FDA isn’t imposing a one-size-fits-all process on them. Instead, the molecular complexity and immunogenicity of each product will dictate its approval requirements.

Those with relatively low structural complexity, high molecular similarity to the reference product, and a low incidence of immunogenic adverse events may only need a single switching study to achieve the “interchangeability” designation.

The bar will be higher for a product with high structural complexity that is not as similar to the reference product, or which has been associated with immunogenic adverse events. For this product, FDA might also require extensive safety postmarketing data for the product as a licensed biosimilar, as well as a switching study.

Pharmacokinetics, pharmacodynamics, immunogenicity, and safety will be the primary endpoints of a switching study. Efficacy data are not necessary but can be used as supportive endpoints. Any safety signals in a switching study would raise regulatory eyebrows whether they came from the candidate product or the reference product. Since the study replicates what could happen if the two were used sequentially, it makes little difference from which product the event might arise.

“If an apparent difference in immune response or adverse events is noticed between the switching and nonswitching arms of the study ... it would raise concerns as to whether the proposed interchangeable product is interchangeable, regardless of whether the proposed interchangeable product or the reference product or the switching of the two products actually caused the event,” the document notes.

The E.U. vs. U.S. experience

The United States is only now getting a taste of what has become common fare in the European Union, said Angus Worthing, MD, chair of the American College of Rheumatology’s Government Affairs Committee. The European Medicines Agency approved its first biosimilar in 2006. Since then, 23 such drugs have come on the market, at an average price of about 30% less than the reference drug. Prices for some drugs have dropped as much as 70% in countries in which national health care systems abandoned the reference product in favor of the competing biosimilar, Dr. Worthing said in an interview.

“But the U.S. doesn’t have a national health care system, so it won’t work like that here.” In fact, he noted, brand-new data show that Medicare actually paid 22% more for the infliximab biosimilar Inflectra than it did for Remicade in the last quarter of 2016.

It’s not immediately apparent why this is the case, but it’s probably related to company discounts and rebates on these very expensive drugs. According to the report in Inside Health Policy, Janssen Biotech may have increased its discount on the drug to compete with Inflectra’s launch price of 15% below Remicade’s wholesale cost. Prices won’t moderate as much in the United States as in the European Union until several biosimilars of the same class appear, Dr. Worthing said.

There have already been allegations that big pharma manipulates international and national pricing to reduce biosimilar competition.

In June, Russian biotech company Biocad filed a lawsuit in New York charging Roche/Genentech with price fixing. The suit alleges that the companies cut the cost of three cancer drugs (Avastin, Herceptin, and Rituxan/MabThera) in Russia, where Biocad markets biosimilars for each. At the same time, Biocad alleges, the companies raised U.S. prices on those drugs to make up for the money they were losing on the Russian market.

Nonmedical switching raises concerns

Academic medical societies and clinicians interviewed for this article view the proposed approval pathway with cautious optimism. While acknowledging the potential benefit of reducing the costs of prohibitively expensive drugs, they uniformly insist that patient safety – not economic pressure – should be the driving force here.

“I was initially skeptical, and I do believe that we need very close pharmacovigilance in monitoring these for safety,” said Gideon Smith, MD, PhD, a dermatologist at Massachusetts General Hospital, Boston. “But there has been huge uptake of these products in the E.U., and the data are so extensive that we can be reasonably confident these drugs are effective, and no good reason to believe the safety will be any different.”

He is not as comfortable with the prospect of pharmacy-level substitution of an interchangeable biosimilar with the reference product – a feeling that other clinicians echoed.

“I think this is a fundamental issue that should have been dealt with on a federal level. Physicians should always be involved in the decision,” said Dr. Smith, who spoke at an FDA advisory committee meeting last summer on behalf of the American Academy of Dermatology (AAD).

*This article was updated 1/31/2017.

[email protected]

On Twitter @alz_gal

The Food and Drug Administration has proposed a regulatory path for biosimilar biologics that are interchangeable with the reference product, paving the way for a new generation of less-expensive versions of these unique drugs.

But bringing an interchangeable biosimilar to market won’t be easy. The bar for interchangeability will be high, requiring that manufacturers prove switching between the new and older products is safe. And clinicians, while cautiously optimistic, aren’t thrilled with the industry payoff that could come with the designation: freedom for insurance companies and pharmacies to switch products at the dispensing level without requiring a new prescription.

The draft FDA guidance for industry, “Considerations in Demonstrating Interchangeability With a Reference Product,” arises from the Biologics Price Competition and Innovation Act of 2009. That section of the Affordable Care Act provides for abbreviated approval pathways for biological products that are demonstrated to be “highly similar” (biosimilar) to or “interchangeable” with an FDA-approved biological product.

The difference between these appellations is subtle but critical to the regulatory process – and perhaps to patient safety. Regulators recognize that the structure of these large, highly complex molecules can never precisely replicate the reference product. But to be labeled a “biosimilar,” developers must prove that the new product functions essentially the same; there can be no clinically meaningful differences in terms of safety, purity, and potency. Unlike a generic medication, a biosimilar can’t be substituted for its reference product at the pharmacy level. If a physician wants the patient on that biosimilar, the script must specify it.

Interchangeables jump a higher regulatory bar

An “interchangeable biosimilar,” though, would have to jump a higher regulatory bar. Not only must it produce the same clinical result as the reference product, it also must be benignly interchangeable with it, conferring no additional risk if a patient switches from the reference to the biosimilar and back again. A pharmacist could, if permitted by state law, substitute an interchangeable product for the reference product without going through the prescriber.

Like biosimilars, interchangeable products need not be tested in every disease for which the reference drug is approved, according to the document. Once they are proved safe for one indication, those data can be extrapolated to allow approval for the other indications as well. Nor do biosimilars need to prove efficacy per se, as their molecular similarity to the reference product ensures that they bind to the same receptor and exert the same therapeutic effect.

The biosimilar/interchangeable market has been slow to take off in the United States. There are no approved interchangeable biosimilars, and only four biosimilars – three of which were approved in 2016:

• Sandoz’ filgrastim-sndz (Zarxio).

• Pfizer’s and Celltrion’s infliximab-dyyb (Inflectra).

• Sandoz’ etanercept-szzs (Erelzi).

• Amgen’s adalimumab-atto (Amjevita).

Switching studies is the key to achieving the interchangeable designation, according to the FDA document. They must include at least two full switches between the candidate product and the reference product, which must be licensed in the United States.

But because these products are so structurally diverse, the FDA isn’t imposing a one-size-fits-all process on them. Instead, the molecular complexity and immunogenicity of each product will dictate its approval requirements.

Those with relatively low structural complexity, high molecular similarity to the reference product, and a low incidence of immunogenic adverse events may only need a single switching study to achieve the “interchangeability” designation.

The bar will be higher for a product with high structural complexity that is not as similar to the reference product, or which has been associated with immunogenic adverse events. For this product, FDA might also require extensive safety postmarketing data for the product as a licensed biosimilar, as well as a switching study.

Pharmacokinetics, pharmacodynamics, immunogenicity, and safety will be the primary endpoints of a switching study. Efficacy data are not necessary but can be used as supportive endpoints. Any safety signals in a switching study would raise regulatory eyebrows whether they came from the candidate product or the reference product. Since the study replicates what could happen if the two were used sequentially, it makes little difference from which product the event might arise.

“If an apparent difference in immune response or adverse events is noticed between the switching and nonswitching arms of the study ... it would raise concerns as to whether the proposed interchangeable product is interchangeable, regardless of whether the proposed interchangeable product or the reference product or the switching of the two products actually caused the event,” the document notes.

The E.U. vs. U.S. experience

The United States is only now getting a taste of what has become common fare in the European Union, said Angus Worthing, MD, chair of the American College of Rheumatology’s Government Affairs Committee. The European Medicines Agency approved its first biosimilar in 2006. Since then, 23 such drugs have come on the market, at an average price of about 30% less than the reference drug. Prices for some drugs have dropped as much as 70% in countries in which national health care systems abandoned the reference product in favor of the competing biosimilar, Dr. Worthing said in an interview.

“But the U.S. doesn’t have a national health care system, so it won’t work like that here.” In fact, he noted, brand-new data show that Medicare actually paid 22% more for the infliximab biosimilar Inflectra than it did for Remicade in the last quarter of 2016.

It’s not immediately apparent why this is the case, but it’s probably related to company discounts and rebates on these very expensive drugs. According to the report in Inside Health Policy, Janssen Biotech may have increased its discount on the drug to compete with Inflectra’s launch price of 15% below Remicade’s wholesale cost. Prices won’t moderate as much in the United States as in the European Union until several biosimilars of the same class appear, Dr. Worthing said.

There have already been allegations that big pharma manipulates international and national pricing to reduce biosimilar competition.

In June, Russian biotech company Biocad filed a lawsuit in New York charging Roche/Genentech with price fixing. The suit alleges that the companies cut the cost of three cancer drugs (Avastin, Herceptin, and Rituxan/MabThera) in Russia, where Biocad markets biosimilars for each. At the same time, Biocad alleges, the companies raised U.S. prices on those drugs to make up for the money they were losing on the Russian market.

Nonmedical switching raises concerns

Academic medical societies and clinicians interviewed for this article view the proposed approval pathway with cautious optimism. While acknowledging the potential benefit of reducing the costs of prohibitively expensive drugs, they uniformly insist that patient safety – not economic pressure – should be the driving force here.

“I was initially skeptical, and I do believe that we need very close pharmacovigilance in monitoring these for safety,” said Gideon Smith, MD, PhD, a dermatologist at Massachusetts General Hospital, Boston. “But there has been huge uptake of these products in the E.U., and the data are so extensive that we can be reasonably confident these drugs are effective, and no good reason to believe the safety will be any different.”

He is not as comfortable with the prospect of pharmacy-level substitution of an interchangeable biosimilar with the reference product – a feeling that other clinicians echoed.

“I think this is a fundamental issue that should have been dealt with on a federal level. Physicians should always be involved in the decision,” said Dr. Smith, who spoke at an FDA advisory committee meeting last summer on behalf of the American Academy of Dermatology (AAD).

*This article was updated 1/31/2017.

[email protected]

On Twitter @alz_gal

The Food and Drug Administration has proposed a regulatory path for biosimilar biologics that are interchangeable with the reference product, paving the way for a new generation of less-expensive versions of these unique drugs.

But bringing an interchangeable biosimilar to market won’t be easy. The bar for interchangeability will be high, requiring that manufacturers prove switching between the new and older products is safe. And clinicians, while cautiously optimistic, aren’t thrilled with the industry payoff that could come with the designation: freedom for insurance companies and pharmacies to switch products at the dispensing level without requiring a new prescription.

The draft FDA guidance for industry, “Considerations in Demonstrating Interchangeability With a Reference Product,” arises from the Biologics Price Competition and Innovation Act of 2009. That section of the Affordable Care Act provides for abbreviated approval pathways for biological products that are demonstrated to be “highly similar” (biosimilar) to or “interchangeable” with an FDA-approved biological product.

The difference between these appellations is subtle but critical to the regulatory process – and perhaps to patient safety. Regulators recognize that the structure of these large, highly complex molecules can never precisely replicate the reference product. But to be labeled a “biosimilar,” developers must prove that the new product functions essentially the same; there can be no clinically meaningful differences in terms of safety, purity, and potency. Unlike a generic medication, a biosimilar can’t be substituted for its reference product at the pharmacy level. If a physician wants the patient on that biosimilar, the script must specify it.

Interchangeables jump a higher regulatory bar

An “interchangeable biosimilar,” though, would have to jump a higher regulatory bar. Not only must it produce the same clinical result as the reference product, it also must be benignly interchangeable with it, conferring no additional risk if a patient switches from the reference to the biosimilar and back again. A pharmacist could, if permitted by state law, substitute an interchangeable product for the reference product without going through the prescriber.

Like biosimilars, interchangeable products need not be tested in every disease for which the reference drug is approved, according to the document. Once they are proved safe for one indication, those data can be extrapolated to allow approval for the other indications as well. Nor do biosimilars need to prove efficacy per se, as their molecular similarity to the reference product ensures that they bind to the same receptor and exert the same therapeutic effect.

The biosimilar/interchangeable market has been slow to take off in the United States. There are no approved interchangeable biosimilars, and only four biosimilars – three of which were approved in 2016:

• Sandoz’ filgrastim-sndz (Zarxio).

• Pfizer’s and Celltrion’s infliximab-dyyb (Inflectra).

• Sandoz’ etanercept-szzs (Erelzi).

• Amgen’s adalimumab-atto (Amjevita).

Switching studies is the key to achieving the interchangeable designation, according to the FDA document. They must include at least two full switches between the candidate product and the reference product, which must be licensed in the United States.

But because these products are so structurally diverse, the FDA isn’t imposing a one-size-fits-all process on them. Instead, the molecular complexity and immunogenicity of each product will dictate its approval requirements.

Those with relatively low structural complexity, high molecular similarity to the reference product, and a low incidence of immunogenic adverse events may only need a single switching study to achieve the “interchangeability” designation.

The bar will be higher for a product with high structural complexity that is not as similar to the reference product, or which has been associated with immunogenic adverse events. For this product, FDA might also require extensive safety postmarketing data for the product as a licensed biosimilar, as well as a switching study.

Pharmacokinetics, pharmacodynamics, immunogenicity, and safety will be the primary endpoints of a switching study. Efficacy data are not necessary but can be used as supportive endpoints. Any safety signals in a switching study would raise regulatory eyebrows whether they came from the candidate product or the reference product. Since the study replicates what could happen if the two were used sequentially, it makes little difference from which product the event might arise.

“If an apparent difference in immune response or adverse events is noticed between the switching and nonswitching arms of the study ... it would raise concerns as to whether the proposed interchangeable product is interchangeable, regardless of whether the proposed interchangeable product or the reference product or the switching of the two products actually caused the event,” the document notes.

The E.U. vs. U.S. experience

The United States is only now getting a taste of what has become common fare in the European Union, said Angus Worthing, MD, chair of the American College of Rheumatology’s Government Affairs Committee. The European Medicines Agency approved its first biosimilar in 2006. Since then, 23 such drugs have come on the market, at an average price of about 30% less than the reference drug. Prices for some drugs have dropped as much as 70% in countries in which national health care systems abandoned the reference product in favor of the competing biosimilar, Dr. Worthing said in an interview.

“But the U.S. doesn’t have a national health care system, so it won’t work like that here.” In fact, he noted, brand-new data show that Medicare actually paid 22% more for the infliximab biosimilar Inflectra than it did for Remicade in the last quarter of 2016.

It’s not immediately apparent why this is the case, but it’s probably related to company discounts and rebates on these very expensive drugs. According to the report in Inside Health Policy, Janssen Biotech may have increased its discount on the drug to compete with Inflectra’s launch price of 15% below Remicade’s wholesale cost. Prices won’t moderate as much in the United States as in the European Union until several biosimilars of the same class appear, Dr. Worthing said.

There have already been allegations that big pharma manipulates international and national pricing to reduce biosimilar competition.

In June, Russian biotech company Biocad filed a lawsuit in New York charging Roche/Genentech with price fixing. The suit alleges that the companies cut the cost of three cancer drugs (Avastin, Herceptin, and Rituxan/MabThera) in Russia, where Biocad markets biosimilars for each. At the same time, Biocad alleges, the companies raised U.S. prices on those drugs to make up for the money they were losing on the Russian market.

Nonmedical switching raises concerns

Academic medical societies and clinicians interviewed for this article view the proposed approval pathway with cautious optimism. While acknowledging the potential benefit of reducing the costs of prohibitively expensive drugs, they uniformly insist that patient safety – not economic pressure – should be the driving force here.

“I was initially skeptical, and I do believe that we need very close pharmacovigilance in monitoring these for safety,” said Gideon Smith, MD, PhD, a dermatologist at Massachusetts General Hospital, Boston. “But there has been huge uptake of these products in the E.U., and the data are so extensive that we can be reasonably confident these drugs are effective, and no good reason to believe the safety will be any different.”

He is not as comfortable with the prospect of pharmacy-level substitution of an interchangeable biosimilar with the reference product – a feeling that other clinicians echoed.

“I think this is a fundamental issue that should have been dealt with on a federal level. Physicians should always be involved in the decision,” said Dr. Smith, who spoke at an FDA advisory committee meeting last summer on behalf of the American Academy of Dermatology (AAD).

*This article was updated 1/31/2017.

[email protected]

On Twitter @alz_gal

Two recent reports that provide opposing evidence about the potential for inflammatory bowel disease patients to develop articular manifestations after starting vedolizumab raise questions for future studies to answer in regard to a plausible mechanism for the adverse event and its relative importance.

The two reports, one a case series of 5 patients with inflammatory bowel disease (IBD) who developed articular manifestations after beginning vedolizumab (Entyvio) and the other a prospective cohort study of 53 patients with IBD who started vedolizumab without any subsequent cases of induction or flare of arthritis and/or sacroiliitis, came to somewhat different conclusions about the beneficial or paradoxical effects of vedolizumab’s blockade of the alpha4beta7 receptor on articular manifestations of IBD.

The five-patient cases series reported by Gaëlle Varkas, MD, a doctoral student at the University of Ghent, Belgium, and her colleagues consisted of five IBD patients, aged 26-50 years, who developed either new onset or an exacerbation of sacroiliitis or arthritis soon after starting vedolizumab. All but one of the patients was female (Ann Rheum Dis. 2016 Nov 29. doi: 10.1136/annrheumdis-2016-210233). In these patients, the investigators said, vedolizumab did not “seem to show any efficacy in and might even induce arthritis and/or sacroiliitis.”

The first was a 50-year-old woman who had progressive back pain with MRI-confirmed bilateral sacroiliitis about 2 months after beginning vedolizumab. The second patient, a 28-year-old woman with no previous history of spondyloarthropathy, had lower limb pain, a painful left shoulder, and arthritis of one wrist. Ultrasound examination confirmed intercarpal effusions and synovial hyperproliferation.

The third patient was 30 years old and male. He had both ankylosing spondylitis and Crohn’s disease, and experienced arthralgias, elevated C-reactive protein, and MRI-confirmed axial skeletal inflammation 4 weeks after starting vedolizumab.

The fourth patient was a 47-year-old woman with no previous history of spondyloarthropathy who developed MRI-confirmed sacroiliitis after beginning vedolizumab. The fifth patient, a 26-year-old woman, developed polyarticular joint pain after starting vedolizumab. Examination of this patient showed synovitis and enthesitis of multiple joints of the appendicular skeleton.

In discussion, Dr. Varkas and her colleagues noted that “one of the many hypotheses is that integrins and adhesion molecules play a role in the interception of recirculating activated lymphocytes between the gut and the synovial membrane due to the inhibition of the alpha4beta7 integrin homing at the level of the gut.” However, the investigators also acknowledged that other hypotheses may also account for their findings. “Alternatively, in the presence of vedolizumab, cellular recruitment may be mediated by yet to be determined adhesion molecules. This recirculation theory might explain the short mean interval of 64 days between vedolizumab initiation and the expression of symptoms.”

Another group, publishing its prospective cohort study in a letter, had different findings (Ann Rheum Dis. 2017 Jan 17. doi: 10.1136/annrheumdis-2016-211011).

“Although the hypotheses proposed by the authors to explain such events sounds reasonable,” wrote Ambrogio Orlando, MD, and his coauthors, their experience of the effect of vedolizumab on spondyloarthritis differed.

In the report on 53 patients who began treatment with vedolizumab at Villa Sofia-Cervello Hospital, Palermo, Italy, where Dr. Orlando and his associates work, almost all (96%) had been steroid dependent and 81% had been treated with at least one tumor necrosis factor inhibitor. About two-thirds had completed the induction phase of vedolizumab treatment during follow-up, which lasted a mean of 2.6 months. Of the 14 patients (26%) who had active IBD-associated spondyloarthropathy when starting vedolizumab, 6 (46.2%) saw “a sharp clinical benefit after the initiation of vedolizumab,” wrote Dr. Orlando and his colleagues. Five of these six patients experienced clinical remission of gut symptoms by 12 weeks of therapy.

Dr. Orlando and his colleagues wrote that “our preliminary prospective data indicate a potential benefit of vedolizumab on IBD-associated spondyloarthropathy.”

Looking for mechanistic reasons for this apparent benefit, Dr. Orlando and his collaborators wrote that “the previous demonstration of alpha4beta7 in the joint and the recent evidence of the upregulation of mucosal vascular address in cell adhesion molecule (MadCAM-1) in the high endothelial venules of bone marrow in patients with active axial SpA seem to strengthen the hypothesis of a beneficial rather than a paradoxical effect of alpha4beta7 blockade on articular manifestations of IBD.”

Two authors of the case series reported relationships with multiple pharmaceutical companies, as did Dr. Orlando and two other authors of the letter describing the prospective study.

[email protected]

On Twitter @karioakes

Two recent reports that provide opposing evidence about the potential for inflammatory bowel disease patients to develop articular manifestations after starting vedolizumab raise questions for future studies to answer in regard to a plausible mechanism for the adverse event and its relative importance.

The two reports, one a case series of 5 patients with inflammatory bowel disease (IBD) who developed articular manifestations after beginning vedolizumab (Entyvio) and the other a prospective cohort study of 53 patients with IBD who started vedolizumab without any subsequent cases of induction or flare of arthritis and/or sacroiliitis, came to somewhat different conclusions about the beneficial or paradoxical effects of vedolizumab’s blockade of the alpha4beta7 receptor on articular manifestations of IBD.

The five-patient cases series reported by Gaëlle Varkas, MD, a doctoral student at the University of Ghent, Belgium, and her colleagues consisted of five IBD patients, aged 26-50 years, who developed either new onset or an exacerbation of sacroiliitis or arthritis soon after starting vedolizumab. All but one of the patients was female (Ann Rheum Dis. 2016 Nov 29. doi: 10.1136/annrheumdis-2016-210233). In these patients, the investigators said, vedolizumab did not “seem to show any efficacy in and might even induce arthritis and/or sacroiliitis.”

The first was a 50-year-old woman who had progressive back pain with MRI-confirmed bilateral sacroiliitis about 2 months after beginning vedolizumab. The second patient, a 28-year-old woman with no previous history of spondyloarthropathy, had lower limb pain, a painful left shoulder, and arthritis of one wrist. Ultrasound examination confirmed intercarpal effusions and synovial hyperproliferation.

The third patient was 30 years old and male. He had both ankylosing spondylitis and Crohn’s disease, and experienced arthralgias, elevated C-reactive protein, and MRI-confirmed axial skeletal inflammation 4 weeks after starting vedolizumab.

The fourth patient was a 47-year-old woman with no previous history of spondyloarthropathy who developed MRI-confirmed sacroiliitis after beginning vedolizumab. The fifth patient, a 26-year-old woman, developed polyarticular joint pain after starting vedolizumab. Examination of this patient showed synovitis and enthesitis of multiple joints of the appendicular skeleton.

In discussion, Dr. Varkas and her colleagues noted that “one of the many hypotheses is that integrins and adhesion molecules play a role in the interception of recirculating activated lymphocytes between the gut and the synovial membrane due to the inhibition of the alpha4beta7 integrin homing at the level of the gut.” However, the investigators also acknowledged that other hypotheses may also account for their findings. “Alternatively, in the presence of vedolizumab, cellular recruitment may be mediated by yet to be determined adhesion molecules. This recirculation theory might explain the short mean interval of 64 days between vedolizumab initiation and the expression of symptoms.”

Another group, publishing its prospective cohort study in a letter, had different findings (Ann Rheum Dis. 2017 Jan 17. doi: 10.1136/annrheumdis-2016-211011).

“Although the hypotheses proposed by the authors to explain such events sounds reasonable,” wrote Ambrogio Orlando, MD, and his coauthors, their experience of the effect of vedolizumab on spondyloarthritis differed.

In the report on 53 patients who began treatment with vedolizumab at Villa Sofia-Cervello Hospital, Palermo, Italy, where Dr. Orlando and his associates work, almost all (96%) had been steroid dependent and 81% had been treated with at least one tumor necrosis factor inhibitor. About two-thirds had completed the induction phase of vedolizumab treatment during follow-up, which lasted a mean of 2.6 months. Of the 14 patients (26%) who had active IBD-associated spondyloarthropathy when starting vedolizumab, 6 (46.2%) saw “a sharp clinical benefit after the initiation of vedolizumab,” wrote Dr. Orlando and his colleagues. Five of these six patients experienced clinical remission of gut symptoms by 12 weeks of therapy.

Dr. Orlando and his colleagues wrote that “our preliminary prospective data indicate a potential benefit of vedolizumab on IBD-associated spondyloarthropathy.”

Looking for mechanistic reasons for this apparent benefit, Dr. Orlando and his collaborators wrote that “the previous demonstration of alpha4beta7 in the joint and the recent evidence of the upregulation of mucosal vascular address in cell adhesion molecule (MadCAM-1) in the high endothelial venules of bone marrow in patients with active axial SpA seem to strengthen the hypothesis of a beneficial rather than a paradoxical effect of alpha4beta7 blockade on articular manifestations of IBD.”

Two authors of the case series reported relationships with multiple pharmaceutical companies, as did Dr. Orlando and two other authors of the letter describing the prospective study.

[email protected]

On Twitter @karioakes

Two recent reports that provide opposing evidence about the potential for inflammatory bowel disease patients to develop articular manifestations after starting vedolizumab raise questions for future studies to answer in regard to a plausible mechanism for the adverse event and its relative importance.

The two reports, one a case series of 5 patients with inflammatory bowel disease (IBD) who developed articular manifestations after beginning vedolizumab (Entyvio) and the other a prospective cohort study of 53 patients with IBD who started vedolizumab without any subsequent cases of induction or flare of arthritis and/or sacroiliitis, came to somewhat different conclusions about the beneficial or paradoxical effects of vedolizumab’s blockade of the alpha4beta7 receptor on articular manifestations of IBD.

The five-patient cases series reported by Gaëlle Varkas, MD, a doctoral student at the University of Ghent, Belgium, and her colleagues consisted of five IBD patients, aged 26-50 years, who developed either new onset or an exacerbation of sacroiliitis or arthritis soon after starting vedolizumab. All but one of the patients was female (Ann Rheum Dis. 2016 Nov 29. doi: 10.1136/annrheumdis-2016-210233). In these patients, the investigators said, vedolizumab did not “seem to show any efficacy in and might even induce arthritis and/or sacroiliitis.”

The first was a 50-year-old woman who had progressive back pain with MRI-confirmed bilateral sacroiliitis about 2 months after beginning vedolizumab. The second patient, a 28-year-old woman with no previous history of spondyloarthropathy, had lower limb pain, a painful left shoulder, and arthritis of one wrist. Ultrasound examination confirmed intercarpal effusions and synovial hyperproliferation.

The third patient was 30 years old and male. He had both ankylosing spondylitis and Crohn’s disease, and experienced arthralgias, elevated C-reactive protein, and MRI-confirmed axial skeletal inflammation 4 weeks after starting vedolizumab.

The fourth patient was a 47-year-old woman with no previous history of spondyloarthropathy who developed MRI-confirmed sacroiliitis after beginning vedolizumab. The fifth patient, a 26-year-old woman, developed polyarticular joint pain after starting vedolizumab. Examination of this patient showed synovitis and enthesitis of multiple joints of the appendicular skeleton.

In discussion, Dr. Varkas and her colleagues noted that “one of the many hypotheses is that integrins and adhesion molecules play a role in the interception of recirculating activated lymphocytes between the gut and the synovial membrane due to the inhibition of the alpha4beta7 integrin homing at the level of the gut.” However, the investigators also acknowledged that other hypotheses may also account for their findings. “Alternatively, in the presence of vedolizumab, cellular recruitment may be mediated by yet to be determined adhesion molecules. This recirculation theory might explain the short mean interval of 64 days between vedolizumab initiation and the expression of symptoms.”

Another group, publishing its prospective cohort study in a letter, had different findings (Ann Rheum Dis. 2017 Jan 17. doi: 10.1136/annrheumdis-2016-211011).

“Although the hypotheses proposed by the authors to explain such events sounds reasonable,” wrote Ambrogio Orlando, MD, and his coauthors, their experience of the effect of vedolizumab on spondyloarthritis differed.

In the report on 53 patients who began treatment with vedolizumab at Villa Sofia-Cervello Hospital, Palermo, Italy, where Dr. Orlando and his associates work, almost all (96%) had been steroid dependent and 81% had been treated with at least one tumor necrosis factor inhibitor. About two-thirds had completed the induction phase of vedolizumab treatment during follow-up, which lasted a mean of 2.6 months. Of the 14 patients (26%) who had active IBD-associated spondyloarthropathy when starting vedolizumab, 6 (46.2%) saw “a sharp clinical benefit after the initiation of vedolizumab,” wrote Dr. Orlando and his colleagues. Five of these six patients experienced clinical remission of gut symptoms by 12 weeks of therapy.

Dr. Orlando and his colleagues wrote that “our preliminary prospective data indicate a potential benefit of vedolizumab on IBD-associated spondyloarthropathy.”

Looking for mechanistic reasons for this apparent benefit, Dr. Orlando and his collaborators wrote that “the previous demonstration of alpha4beta7 in the joint and the recent evidence of the upregulation of mucosal vascular address in cell adhesion molecule (MadCAM-1) in the high endothelial venules of bone marrow in patients with active axial SpA seem to strengthen the hypothesis of a beneficial rather than a paradoxical effect of alpha4beta7 blockade on articular manifestations of IBD.”

Two authors of the case series reported relationships with multiple pharmaceutical companies, as did Dr. Orlando and two other authors of the letter describing the prospective study.

[email protected]

On Twitter @karioakes