Rheumatoid Arthritis

In recent years federal laws have been enacted to help provide more treatment options and possibly lower costs to patients for therapeutic biological products. You have likely heard or read about “biosimilars” on the U.S. drug market. But are you ready to make informed treatment decisions and answer patients’ questions about these new drugs?

Biosimilars are not “generic biologics.” Although the shared goal of making biosimilars and generic drugs available is to provide more treatment options, there are important differences between the two approval pathways. For instance, unlike generic drugs, which are “bioequivalent” to their reference listed drug, biosimilar products can be either “biosimilar” to or “interchangeable” with their reference product. The differences may seem subtle based on the terminology, but the differences are important, and health care professionals who prescribe, dispense, or administer these products will need to understand them – as well as other aspects of these new therapies.

To help busy health care professionals better understand biosimilar and interchangeable products, the FDA has created a free 1.5-hour continuing education program titled, FDA Overview of Biosimilar Products. The course describes the important characteristics of biological products, particularly their complexity. For instance, a single molecule of a biological product, such as a monoclonal antibody, can easily be many hundreds of times larger and much more complex than that of a “small molecule” drug such as aspirin. Their increased complexity is one reason they are regulated differently than generics – and why, in the case of biosimilars, the law allows some differences from the reference product in clinically inactive components. The CE course discusses the “inherent variability” in the production of all biological products – both reference and biosimilar – and how the FDA accounts for these differences in assessing safety and efficacy of the products. The course also provides detailed definitions of important terms – such as “biosimilar” and “interchangeable” – and an overview of the standards the FDA has established for reviewing and approving biosimilar and interchangeable products. It also outlines the FDA review and approval standards for biosimilars and interchangeable products to help practitioners be assured that these products have been demonstrated to be safe and effective treatment options for their patients.

Some of our most important and expensive drugs are biological products used to treat patients who have serious medical conditions that are often life threatening and usually life altering. In April 2016, the Food and Drug Administration approved Inflectra (infliximab-dyyb) to help treat certain patients with certain gastrointestinal disorders, such as Crohn’s disease, and for other indications such as treatment of psoriasis and rheumatoid arthritis. The product is approved but not yet marketed in the United States. However, last year, Zarxio (filgrastim-sndz) became the first biosimilar actually available in the U.S. marketplace – approved to help boost white blood cell production for patients with severe neutropenia as well as for patients receiving various cancer therapies. These products are “biosimilar” to already-approved biological products called “reference products.” Inflectra is biosimilar to the reference product, Remicade (infliximab), and Zarxio is biosimilar to Neupogen (filgrastim).

Use of safe and effective biosimilar and interchangeable biological products can potentially make treatment more affordable for patients in need and improve public health. As patients begin to ask about the use of biosimilar and interchangeable products, the FDA hopes this course will help prepare health care practitioners to make informed decisions on behalf of their patients.

Dr. Christl is Associate Director for Therapeutic Biologics at the Office of New Drugs, Center for Drug Evaluation and Research, FDA.

In recent years federal laws have been enacted to help provide more treatment options and possibly lower costs to patients for therapeutic biological products. You have likely heard or read about “biosimilars” on the U.S. drug market. But are you ready to make informed treatment decisions and answer patients’ questions about these new drugs?

Biosimilars are not “generic biologics.” Although the shared goal of making biosimilars and generic drugs available is to provide more treatment options, there are important differences between the two approval pathways. For instance, unlike generic drugs, which are “bioequivalent” to their reference listed drug, biosimilar products can be either “biosimilar” to or “interchangeable” with their reference product. The differences may seem subtle based on the terminology, but the differences are important, and health care professionals who prescribe, dispense, or administer these products will need to understand them – as well as other aspects of these new therapies.

To help busy health care professionals better understand biosimilar and interchangeable products, the FDA has created a free 1.5-hour continuing education program titled, FDA Overview of Biosimilar Products. The course describes the important characteristics of biological products, particularly their complexity. For instance, a single molecule of a biological product, such as a monoclonal antibody, can easily be many hundreds of times larger and much more complex than that of a “small molecule” drug such as aspirin. Their increased complexity is one reason they are regulated differently than generics – and why, in the case of biosimilars, the law allows some differences from the reference product in clinically inactive components. The CE course discusses the “inherent variability” in the production of all biological products – both reference and biosimilar – and how the FDA accounts for these differences in assessing safety and efficacy of the products. The course also provides detailed definitions of important terms – such as “biosimilar” and “interchangeable” – and an overview of the standards the FDA has established for reviewing and approving biosimilar and interchangeable products. It also outlines the FDA review and approval standards for biosimilars and interchangeable products to help practitioners be assured that these products have been demonstrated to be safe and effective treatment options for their patients.

Some of our most important and expensive drugs are biological products used to treat patients who have serious medical conditions that are often life threatening and usually life altering. In April 2016, the Food and Drug Administration approved Inflectra (infliximab-dyyb) to help treat certain patients with certain gastrointestinal disorders, such as Crohn’s disease, and for other indications such as treatment of psoriasis and rheumatoid arthritis. The product is approved but not yet marketed in the United States. However, last year, Zarxio (filgrastim-sndz) became the first biosimilar actually available in the U.S. marketplace – approved to help boost white blood cell production for patients with severe neutropenia as well as for patients receiving various cancer therapies. These products are “biosimilar” to already-approved biological products called “reference products.” Inflectra is biosimilar to the reference product, Remicade (infliximab), and Zarxio is biosimilar to Neupogen (filgrastim).

Use of safe and effective biosimilar and interchangeable biological products can potentially make treatment more affordable for patients in need and improve public health. As patients begin to ask about the use of biosimilar and interchangeable products, the FDA hopes this course will help prepare health care practitioners to make informed decisions on behalf of their patients.

Dr. Christl is Associate Director for Therapeutic Biologics at the Office of New Drugs, Center for Drug Evaluation and Research, FDA.

In recent years federal laws have been enacted to help provide more treatment options and possibly lower costs to patients for therapeutic biological products. You have likely heard or read about “biosimilars” on the U.S. drug market. But are you ready to make informed treatment decisions and answer patients’ questions about these new drugs?

Biosimilars are not “generic biologics.” Although the shared goal of making biosimilars and generic drugs available is to provide more treatment options, there are important differences between the two approval pathways. For instance, unlike generic drugs, which are “bioequivalent” to their reference listed drug, biosimilar products can be either “biosimilar” to or “interchangeable” with their reference product. The differences may seem subtle based on the terminology, but the differences are important, and health care professionals who prescribe, dispense, or administer these products will need to understand them – as well as other aspects of these new therapies.

To help busy health care professionals better understand biosimilar and interchangeable products, the FDA has created a free 1.5-hour continuing education program titled, FDA Overview of Biosimilar Products. The course describes the important characteristics of biological products, particularly their complexity. For instance, a single molecule of a biological product, such as a monoclonal antibody, can easily be many hundreds of times larger and much more complex than that of a “small molecule” drug such as aspirin. Their increased complexity is one reason they are regulated differently than generics – and why, in the case of biosimilars, the law allows some differences from the reference product in clinically inactive components. The CE course discusses the “inherent variability” in the production of all biological products – both reference and biosimilar – and how the FDA accounts for these differences in assessing safety and efficacy of the products. The course also provides detailed definitions of important terms – such as “biosimilar” and “interchangeable” – and an overview of the standards the FDA has established for reviewing and approving biosimilar and interchangeable products. It also outlines the FDA review and approval standards for biosimilars and interchangeable products to help practitioners be assured that these products have been demonstrated to be safe and effective treatment options for their patients.

Some of our most important and expensive drugs are biological products used to treat patients who have serious medical conditions that are often life threatening and usually life altering. In April 2016, the Food and Drug Administration approved Inflectra (infliximab-dyyb) to help treat certain patients with certain gastrointestinal disorders, such as Crohn’s disease, and for other indications such as treatment of psoriasis and rheumatoid arthritis. The product is approved but not yet marketed in the United States. However, last year, Zarxio (filgrastim-sndz) became the first biosimilar actually available in the U.S. marketplace – approved to help boost white blood cell production for patients with severe neutropenia as well as for patients receiving various cancer therapies. These products are “biosimilar” to already-approved biological products called “reference products.” Inflectra is biosimilar to the reference product, Remicade (infliximab), and Zarxio is biosimilar to Neupogen (filgrastim).

Use of safe and effective biosimilar and interchangeable biological products can potentially make treatment more affordable for patients in need and improve public health. As patients begin to ask about the use of biosimilar and interchangeable products, the FDA hopes this course will help prepare health care practitioners to make informed decisions on behalf of their patients.

Dr. Christl is Associate Director for Therapeutic Biologics at the Office of New Drugs, Center for Drug Evaluation and Research, FDA.

MAUI, HAWAII – The consensus among gastroenterologists with expertise in inflammatory bowel disease is that continuation of biologics or immunomodulators in affected women throughout pregnancy and breastfeeding poses no increased risks to the fetus – and therein lies a message for rheumatologists and obstetricians, Dr. Uma Mahadevan said at the 2016 Rheumatology Winter Clinical Symposium.

“The risk of uncontrolled disease must be weighed against the risk of medical therapy. And this is something that is often missed,” according to Dr. Mahadevan, professor of medicine and co–medical director of the Center for Colitis and Crohn’s Disease at the University of California, San Francisco.

Gastroenterologists – at least, those whose practices focus on inflammatory bowel disease (IBD) – have led the way within medicine in terms of establishing the safety of biologics and immunomodulators such as azathioprine in pregnant women with chronic inflammatory diseases and their babies. And having accomplished that, they have been ahead of the curve in terms of continuing such therapy throughout pregnancy and breastfeeding. That’s because active Crohn’s disease and ulcerative colitis are particularly common in women during their childbearing years. And a disease flare during pregnancy is associated with a markedly increased risk of preterm birth and other adverse outcomes.

Gastroenterologists’ longstanding interest in the safety to mother and fetus of continued use of effective, potent medications throughout pregnancy was the impetus for the ongoing prospective U.S. Pregnancy in Inflammatory Bowel Disease and Neonatal Outcomes (PIANO) study, now in its ninth year, with an enrollment of roughly 1,500 women with IBD. The study has included comparisons of outcomes of women on different medications during pregnancy versus unmedicated women.

In multiple publications, Dr. Mahadevan and other PIANO investigators have established that increased IBD activity adversely affects pregnancy outcomes, and that stabilization of disease and effective maintenance therapy throughout pregnancy is important. The PIANO group has demonstrated that IBD medication exposure well into the third trimester in patients in sustained remission was not associated with an increase in congenital anomalies, spontaneous abortions, intrauterine growth restriction, or low birth weight.

To the surprise of many gastroenterologists, the PIANO study has shown that women with Crohn’s disease generally have smoother pregnancies than do those with ulcerative colitis, who tend to get sicker and have more complications.

Since PIANO data show an increased rate of preterm birth and low birth weight in IBD patients on combination therapy with azathioprine plus a biologic throughout pregnancy, Dr. Mahadevan and others try to discontinue the azathioprine, even though the need for combination therapy is a marker for patients with more severe disease.

Anti-TNF-alpha use during third trimester

Of particular interest to rheumatologists, who rely heavily on many of the same biologic agents gastroenterologists use to treat IBD, the use of anti–tumor necrosis factor–alpha biologics in the third trimester was not associated with an increase in preterm birth or maternal disease activity in the third trimester or the first 4 months post partum. When women on certolizumab pegol (Cimzia) during the third trimester were excluded from the analysis, since this biologic uniquely does not cross the placenta at all, the most recent PIANO data show a modest yet statistically significant 35% increase in infections in infants at age 12 months whose mothers were on other biologics in the third trimester. But Dr. Mahadevan said she doesn’t yet consider this finding definitive.

“It’s still a small group of patients, and every year when we update the results the infant infection risk goes back and forth from statistically significant to nonsignificant. I think there’s a signal here; we just need to keep collecting more data,” she said.

Particularly reassuring is the finding that the offspring of PIANO participants who had in utero exposure to biologics and immunomodulators didn’t have any developmental delay, compared with unexposed babies, according to the validated Ages and Stages Questionnaire at ages 1, 2, 3, and 4 years and Denver Childhood Developmental Score at months 4, 9, and 12.

“These kids do great later in life. Actually, they have better scores than unexposed kids. Not to say that biologics make your kid smarter. It probably has to do with better IBD control,” Dr. Mahadevan said.

Effects while breastfeeding

Breastfeeding while on biologics or azathioprine didn’t adversely affect infant growth, infection rate, or developmental milestones. More specifically, levels of biologics in the mothers, babies, or cord serum were not associated with the likelihood of a neonatal intensive care unit stay, an increase in infant infections, or achievement of developmental milestones.

“Almost all the agents are detectable in breast milk, but only at the nanogram level. We tell all our patients on biologics they can breastfeed. It doesn’t matter when their last dose was, don’t worry about it,” the gastroenterologist said.

Importance of preconception counseling

Key practical lessons she has learned in taking care of large numbers of patients with severe IBD referred to her tertiary center include the importance of preconception counseling. A woman should stop methotrexate at least 3 months prior to conception. Providing information on medication safety and the risks of poorly controlled disease helps in adherence.

It’s best to communicate with the patient’s obstetrician about the importance of continuing her IBD therapy during pregnancy before she becomes pregnant.

“It’s better to have this discussion ahead of time and have a plan in place. Once a patient is pregnant it’s very difficult if her doula or someone else has told them to stop a medication to convince them to continue it,” said Dr. Mahadevan.

All women with IBD should be followed as high-risk pregnancies. Mode of delivery is at the discretion of the obstetrician unless the patient has an open rectovaginal fistula; even if it’s inactive, cesarean delivery is preferable in that situation, she said.

Steps taken in the third trimester

In the third trimester, she routinely sends a letter to the patient’s pediatrician requesting no live virus vaccines in the coming baby’s first 6 months – in the United States, that’s the rotavirus vaccine – if the infant was exposed in utero to a biologic other than certolizumab pegol, but that all other vaccines can be given on schedule. She also asks that the pediatrician monitor an exposed baby for infections.

“That being said, there have been 20-plus exposures to rotavirus vaccine in the first 6 months of life recorded in the PIANO registry in the infants of mothers on biologics and we haven’t seen any adverse events. So maybe the CDC is overstating the risk, but at this point the rule is still no live virus vaccines,” she said.

She tries to time her last dose of biologic agents during pregnancy as follows: at week 30-32 for infliximab or vedolizumab and week 36-38 for adalimumab or golimumab. As for certolizumab pegol, “they can take that on their way to labor and delivery,” she quipped.

“I give the next dose of a biologic agent soon after delivery, often while the patient is still in the hospital, 24 hours after vaginal delivery and 48 hours after a C-section, assuming no infection,” Dr. Mahadevan said.

The elements of her approach to management of the pregnant patient with IBD are in accord with a recent report, The Toronto Consensus Statements for the Management of Inflammatory Bowel Disease in Pregnancy, in which she participated (Gastroenterology. 2016 Mar;150[3]:734-57).

Rheumatologists’ habits with biologics in pregnancy

Dr. John J. Cush rose from the audience to observe that the situation in rheumatology with regard to biologics in pregnancy is quite a bit different from what’s going on in gastroenterology.

“I think a lot of rheumatologists don’t let their patients get pregnant on biologics for fear of what may happen. And that’s because they don’t know the data. I think you’ve shown very clearly that you can get pregnant on biologics and do well. But for many of us who do allow our patients to get pregnant on biologic monotherapy, the practice is to stop it once they get pregnant. The idea is we want them to be in a very deep remission to increase the odds of getting pregnant and having a successful pregnancy, but then we stop the drug and we assume the disease state is going to stay the same. Often, though, it doesn’t stay the same, it gets worse. Yet this is a common practice in rheumatology. What’s your response?” asked Dr. Cush, professor of medicine and rheumatology at Baylor University Medical Center, Dallas, and director of clinical rheumatology at the Baylor Research Institute.

“I think in IBD it’s very clear that patients with active disease in pregnancy do much, much worse,” Dr. Mahadevan replied. “They have preterm birth, they get very sick, they’re hospitalized and placed on steroids. So for us, the benefit is very clear. I don’t know the data in rheumatoid arthritis – whether active disease leads to increased complication rates – but I do know from colleagues that in the postpartum period women with poorly controlled rheumatoid arthritis can’t take care of their baby because their hands are so damaged. And that’s a big deal.

“So when you see that the drugs are not associated with an increased risk of birth defects and on monotherapy there’s no increase in infections and other complications, you’d think that in the right patient continuing treatment until the late third trimester would be the way to go, especially since if you’ve put the patient on a biologic it must mean she has severe disease,” the gastroenterologist observed.

Dr. Roy Fleischmann of the University of Texas, Dallas, asked why gastroenterologists don’t put all IBD patients of childbearing age on certolizumab pegol if they need biologic therapy, since it doesn’t cross the placenta.

“Maybe IBD is different, but our biologics don’t necessarily have the longest persistence,” Dr. Mahadevan replied. “If you start a woman on certolizumab pegol at age 20 the chances of her still being on it at 28 are probably pretty low.”

Conference director Dr. Arthur Kavanaugh, professor of medicine at the University of California, San Diego, asked if the message regarding management of IBD in pregnancy being put forth by Dr. Mahadevan and the IBD in Pregnancy Consensus Group has gained wide acceptance by gastroenterologists across the country.

“I think the people who do IBD as a concentrated practice, whether in private or academic practice, are very aware of this literature,” she said.

“In general, IBD has become more and more centered among a group of people who want to take care of IBD. If you look at the big private practices, they have a hepatitis C person, an IBD person, and everyone else just wants to scope. I think the message is getting across to non-IBD gastroenterologists, but there is some confusion because the Europeans are very firm about stopping biologics at 22 weeks’ gestation if the patient is in deep remission and we in North America continue treatment,” said Dr. Mahadevan.

Her work with the PIANO study is funded by the Crohn’s and Colitis Foundation of America. In addition, Dr. Mahadevan disclosed ties to more than half a dozen pharmaceutical companies.

bjancin@frontlinemedcom.com

MAUI, HAWAII – The consensus among gastroenterologists with expertise in inflammatory bowel disease is that continuation of biologics or immunomodulators in affected women throughout pregnancy and breastfeeding poses no increased risks to the fetus – and therein lies a message for rheumatologists and obstetricians, Dr. Uma Mahadevan said at the 2016 Rheumatology Winter Clinical Symposium.

“The risk of uncontrolled disease must be weighed against the risk of medical therapy. And this is something that is often missed,” according to Dr. Mahadevan, professor of medicine and co–medical director of the Center for Colitis and Crohn’s Disease at the University of California, San Francisco.

Gastroenterologists – at least, those whose practices focus on inflammatory bowel disease (IBD) – have led the way within medicine in terms of establishing the safety of biologics and immunomodulators such as azathioprine in pregnant women with chronic inflammatory diseases and their babies. And having accomplished that, they have been ahead of the curve in terms of continuing such therapy throughout pregnancy and breastfeeding. That’s because active Crohn’s disease and ulcerative colitis are particularly common in women during their childbearing years. And a disease flare during pregnancy is associated with a markedly increased risk of preterm birth and other adverse outcomes.

Gastroenterologists’ longstanding interest in the safety to mother and fetus of continued use of effective, potent medications throughout pregnancy was the impetus for the ongoing prospective U.S. Pregnancy in Inflammatory Bowel Disease and Neonatal Outcomes (PIANO) study, now in its ninth year, with an enrollment of roughly 1,500 women with IBD. The study has included comparisons of outcomes of women on different medications during pregnancy versus unmedicated women.

In multiple publications, Dr. Mahadevan and other PIANO investigators have established that increased IBD activity adversely affects pregnancy outcomes, and that stabilization of disease and effective maintenance therapy throughout pregnancy is important. The PIANO group has demonstrated that IBD medication exposure well into the third trimester in patients in sustained remission was not associated with an increase in congenital anomalies, spontaneous abortions, intrauterine growth restriction, or low birth weight.

To the surprise of many gastroenterologists, the PIANO study has shown that women with Crohn’s disease generally have smoother pregnancies than do those with ulcerative colitis, who tend to get sicker and have more complications.

Since PIANO data show an increased rate of preterm birth and low birth weight in IBD patients on combination therapy with azathioprine plus a biologic throughout pregnancy, Dr. Mahadevan and others try to discontinue the azathioprine, even though the need for combination therapy is a marker for patients with more severe disease.

Anti-TNF-alpha use during third trimester

Of particular interest to rheumatologists, who rely heavily on many of the same biologic agents gastroenterologists use to treat IBD, the use of anti–tumor necrosis factor–alpha biologics in the third trimester was not associated with an increase in preterm birth or maternal disease activity in the third trimester or the first 4 months post partum. When women on certolizumab pegol (Cimzia) during the third trimester were excluded from the analysis, since this biologic uniquely does not cross the placenta at all, the most recent PIANO data show a modest yet statistically significant 35% increase in infections in infants at age 12 months whose mothers were on other biologics in the third trimester. But Dr. Mahadevan said she doesn’t yet consider this finding definitive.

“It’s still a small group of patients, and every year when we update the results the infant infection risk goes back and forth from statistically significant to nonsignificant. I think there’s a signal here; we just need to keep collecting more data,” she said.

Particularly reassuring is the finding that the offspring of PIANO participants who had in utero exposure to biologics and immunomodulators didn’t have any developmental delay, compared with unexposed babies, according to the validated Ages and Stages Questionnaire at ages 1, 2, 3, and 4 years and Denver Childhood Developmental Score at months 4, 9, and 12.

“These kids do great later in life. Actually, they have better scores than unexposed kids. Not to say that biologics make your kid smarter. It probably has to do with better IBD control,” Dr. Mahadevan said.

Effects while breastfeeding

Breastfeeding while on biologics or azathioprine didn’t adversely affect infant growth, infection rate, or developmental milestones. More specifically, levels of biologics in the mothers, babies, or cord serum were not associated with the likelihood of a neonatal intensive care unit stay, an increase in infant infections, or achievement of developmental milestones.

“Almost all the agents are detectable in breast milk, but only at the nanogram level. We tell all our patients on biologics they can breastfeed. It doesn’t matter when their last dose was, don’t worry about it,” the gastroenterologist said.

Importance of preconception counseling

Key practical lessons she has learned in taking care of large numbers of patients with severe IBD referred to her tertiary center include the importance of preconception counseling. A woman should stop methotrexate at least 3 months prior to conception. Providing information on medication safety and the risks of poorly controlled disease helps in adherence.

It’s best to communicate with the patient’s obstetrician about the importance of continuing her IBD therapy during pregnancy before she becomes pregnant.

“It’s better to have this discussion ahead of time and have a plan in place. Once a patient is pregnant it’s very difficult if her doula or someone else has told them to stop a medication to convince them to continue it,” said Dr. Mahadevan.

All women with IBD should be followed as high-risk pregnancies. Mode of delivery is at the discretion of the obstetrician unless the patient has an open rectovaginal fistula; even if it’s inactive, cesarean delivery is preferable in that situation, she said.

Steps taken in the third trimester

In the third trimester, she routinely sends a letter to the patient’s pediatrician requesting no live virus vaccines in the coming baby’s first 6 months – in the United States, that’s the rotavirus vaccine – if the infant was exposed in utero to a biologic other than certolizumab pegol, but that all other vaccines can be given on schedule. She also asks that the pediatrician monitor an exposed baby for infections.

“That being said, there have been 20-plus exposures to rotavirus vaccine in the first 6 months of life recorded in the PIANO registry in the infants of mothers on biologics and we haven’t seen any adverse events. So maybe the CDC is overstating the risk, but at this point the rule is still no live virus vaccines,” she said.

She tries to time her last dose of biologic agents during pregnancy as follows: at week 30-32 for infliximab or vedolizumab and week 36-38 for adalimumab or golimumab. As for certolizumab pegol, “they can take that on their way to labor and delivery,” she quipped.

“I give the next dose of a biologic agent soon after delivery, often while the patient is still in the hospital, 24 hours after vaginal delivery and 48 hours after a C-section, assuming no infection,” Dr. Mahadevan said.

The elements of her approach to management of the pregnant patient with IBD are in accord with a recent report, The Toronto Consensus Statements for the Management of Inflammatory Bowel Disease in Pregnancy, in which she participated (Gastroenterology. 2016 Mar;150[3]:734-57).

Rheumatologists’ habits with biologics in pregnancy

Dr. John J. Cush rose from the audience to observe that the situation in rheumatology with regard to biologics in pregnancy is quite a bit different from what’s going on in gastroenterology.

“I think a lot of rheumatologists don’t let their patients get pregnant on biologics for fear of what may happen. And that’s because they don’t know the data. I think you’ve shown very clearly that you can get pregnant on biologics and do well. But for many of us who do allow our patients to get pregnant on biologic monotherapy, the practice is to stop it once they get pregnant. The idea is we want them to be in a very deep remission to increase the odds of getting pregnant and having a successful pregnancy, but then we stop the drug and we assume the disease state is going to stay the same. Often, though, it doesn’t stay the same, it gets worse. Yet this is a common practice in rheumatology. What’s your response?” asked Dr. Cush, professor of medicine and rheumatology at Baylor University Medical Center, Dallas, and director of clinical rheumatology at the Baylor Research Institute.

“I think in IBD it’s very clear that patients with active disease in pregnancy do much, much worse,” Dr. Mahadevan replied. “They have preterm birth, they get very sick, they’re hospitalized and placed on steroids. So for us, the benefit is very clear. I don’t know the data in rheumatoid arthritis – whether active disease leads to increased complication rates – but I do know from colleagues that in the postpartum period women with poorly controlled rheumatoid arthritis can’t take care of their baby because their hands are so damaged. And that’s a big deal.

“So when you see that the drugs are not associated with an increased risk of birth defects and on monotherapy there’s no increase in infections and other complications, you’d think that in the right patient continuing treatment until the late third trimester would be the way to go, especially since if you’ve put the patient on a biologic it must mean she has severe disease,” the gastroenterologist observed.

Dr. Roy Fleischmann of the University of Texas, Dallas, asked why gastroenterologists don’t put all IBD patients of childbearing age on certolizumab pegol if they need biologic therapy, since it doesn’t cross the placenta.

“Maybe IBD is different, but our biologics don’t necessarily have the longest persistence,” Dr. Mahadevan replied. “If you start a woman on certolizumab pegol at age 20 the chances of her still being on it at 28 are probably pretty low.”

Conference director Dr. Arthur Kavanaugh, professor of medicine at the University of California, San Diego, asked if the message regarding management of IBD in pregnancy being put forth by Dr. Mahadevan and the IBD in Pregnancy Consensus Group has gained wide acceptance by gastroenterologists across the country.

“I think the people who do IBD as a concentrated practice, whether in private or academic practice, are very aware of this literature,” she said.

“In general, IBD has become more and more centered among a group of people who want to take care of IBD. If you look at the big private practices, they have a hepatitis C person, an IBD person, and everyone else just wants to scope. I think the message is getting across to non-IBD gastroenterologists, but there is some confusion because the Europeans are very firm about stopping biologics at 22 weeks’ gestation if the patient is in deep remission and we in North America continue treatment,” said Dr. Mahadevan.

Her work with the PIANO study is funded by the Crohn’s and Colitis Foundation of America. In addition, Dr. Mahadevan disclosed ties to more than half a dozen pharmaceutical companies.

bjancin@frontlinemedcom.com

MAUI, HAWAII – The consensus among gastroenterologists with expertise in inflammatory bowel disease is that continuation of biologics or immunomodulators in affected women throughout pregnancy and breastfeeding poses no increased risks to the fetus – and therein lies a message for rheumatologists and obstetricians, Dr. Uma Mahadevan said at the 2016 Rheumatology Winter Clinical Symposium.

“The risk of uncontrolled disease must be weighed against the risk of medical therapy. And this is something that is often missed,” according to Dr. Mahadevan, professor of medicine and co–medical director of the Center for Colitis and Crohn’s Disease at the University of California, San Francisco.

Gastroenterologists – at least, those whose practices focus on inflammatory bowel disease (IBD) – have led the way within medicine in terms of establishing the safety of biologics and immunomodulators such as azathioprine in pregnant women with chronic inflammatory diseases and their babies. And having accomplished that, they have been ahead of the curve in terms of continuing such therapy throughout pregnancy and breastfeeding. That’s because active Crohn’s disease and ulcerative colitis are particularly common in women during their childbearing years. And a disease flare during pregnancy is associated with a markedly increased risk of preterm birth and other adverse outcomes.

Gastroenterologists’ longstanding interest in the safety to mother and fetus of continued use of effective, potent medications throughout pregnancy was the impetus for the ongoing prospective U.S. Pregnancy in Inflammatory Bowel Disease and Neonatal Outcomes (PIANO) study, now in its ninth year, with an enrollment of roughly 1,500 women with IBD. The study has included comparisons of outcomes of women on different medications during pregnancy versus unmedicated women.

In multiple publications, Dr. Mahadevan and other PIANO investigators have established that increased IBD activity adversely affects pregnancy outcomes, and that stabilization of disease and effective maintenance therapy throughout pregnancy is important. The PIANO group has demonstrated that IBD medication exposure well into the third trimester in patients in sustained remission was not associated with an increase in congenital anomalies, spontaneous abortions, intrauterine growth restriction, or low birth weight.

To the surprise of many gastroenterologists, the PIANO study has shown that women with Crohn’s disease generally have smoother pregnancies than do those with ulcerative colitis, who tend to get sicker and have more complications.

Since PIANO data show an increased rate of preterm birth and low birth weight in IBD patients on combination therapy with azathioprine plus a biologic throughout pregnancy, Dr. Mahadevan and others try to discontinue the azathioprine, even though the need for combination therapy is a marker for patients with more severe disease.

Anti-TNF-alpha use during third trimester

Of particular interest to rheumatologists, who rely heavily on many of the same biologic agents gastroenterologists use to treat IBD, the use of anti–tumor necrosis factor–alpha biologics in the third trimester was not associated with an increase in preterm birth or maternal disease activity in the third trimester or the first 4 months post partum. When women on certolizumab pegol (Cimzia) during the third trimester were excluded from the analysis, since this biologic uniquely does not cross the placenta at all, the most recent PIANO data show a modest yet statistically significant 35% increase in infections in infants at age 12 months whose mothers were on other biologics in the third trimester. But Dr. Mahadevan said she doesn’t yet consider this finding definitive.

“It’s still a small group of patients, and every year when we update the results the infant infection risk goes back and forth from statistically significant to nonsignificant. I think there’s a signal here; we just need to keep collecting more data,” she said.

Particularly reassuring is the finding that the offspring of PIANO participants who had in utero exposure to biologics and immunomodulators didn’t have any developmental delay, compared with unexposed babies, according to the validated Ages and Stages Questionnaire at ages 1, 2, 3, and 4 years and Denver Childhood Developmental Score at months 4, 9, and 12.

“These kids do great later in life. Actually, they have better scores than unexposed kids. Not to say that biologics make your kid smarter. It probably has to do with better IBD control,” Dr. Mahadevan said.

Effects while breastfeeding

Breastfeeding while on biologics or azathioprine didn’t adversely affect infant growth, infection rate, or developmental milestones. More specifically, levels of biologics in the mothers, babies, or cord serum were not associated with the likelihood of a neonatal intensive care unit stay, an increase in infant infections, or achievement of developmental milestones.

“Almost all the agents are detectable in breast milk, but only at the nanogram level. We tell all our patients on biologics they can breastfeed. It doesn’t matter when their last dose was, don’t worry about it,” the gastroenterologist said.

Importance of preconception counseling

Key practical lessons she has learned in taking care of large numbers of patients with severe IBD referred to her tertiary center include the importance of preconception counseling. A woman should stop methotrexate at least 3 months prior to conception. Providing information on medication safety and the risks of poorly controlled disease helps in adherence.

It’s best to communicate with the patient’s obstetrician about the importance of continuing her IBD therapy during pregnancy before she becomes pregnant.

“It’s better to have this discussion ahead of time and have a plan in place. Once a patient is pregnant it’s very difficult if her doula or someone else has told them to stop a medication to convince them to continue it,” said Dr. Mahadevan.

All women with IBD should be followed as high-risk pregnancies. Mode of delivery is at the discretion of the obstetrician unless the patient has an open rectovaginal fistula; even if it’s inactive, cesarean delivery is preferable in that situation, she said.

Steps taken in the third trimester

In the third trimester, she routinely sends a letter to the patient’s pediatrician requesting no live virus vaccines in the coming baby’s first 6 months – in the United States, that’s the rotavirus vaccine – if the infant was exposed in utero to a biologic other than certolizumab pegol, but that all other vaccines can be given on schedule. She also asks that the pediatrician monitor an exposed baby for infections.

“That being said, there have been 20-plus exposures to rotavirus vaccine in the first 6 months of life recorded in the PIANO registry in the infants of mothers on biologics and we haven’t seen any adverse events. So maybe the CDC is overstating the risk, but at this point the rule is still no live virus vaccines,” she said.

She tries to time her last dose of biologic agents during pregnancy as follows: at week 30-32 for infliximab or vedolizumab and week 36-38 for adalimumab or golimumab. As for certolizumab pegol, “they can take that on their way to labor and delivery,” she quipped.

“I give the next dose of a biologic agent soon after delivery, often while the patient is still in the hospital, 24 hours after vaginal delivery and 48 hours after a C-section, assuming no infection,” Dr. Mahadevan said.

The elements of her approach to management of the pregnant patient with IBD are in accord with a recent report, The Toronto Consensus Statements for the Management of Inflammatory Bowel Disease in Pregnancy, in which she participated (Gastroenterology. 2016 Mar;150[3]:734-57).

Rheumatologists’ habits with biologics in pregnancy

Dr. John J. Cush rose from the audience to observe that the situation in rheumatology with regard to biologics in pregnancy is quite a bit different from what’s going on in gastroenterology.

“I think a lot of rheumatologists don’t let their patients get pregnant on biologics for fear of what may happen. And that’s because they don’t know the data. I think you’ve shown very clearly that you can get pregnant on biologics and do well. But for many of us who do allow our patients to get pregnant on biologic monotherapy, the practice is to stop it once they get pregnant. The idea is we want them to be in a very deep remission to increase the odds of getting pregnant and having a successful pregnancy, but then we stop the drug and we assume the disease state is going to stay the same. Often, though, it doesn’t stay the same, it gets worse. Yet this is a common practice in rheumatology. What’s your response?” asked Dr. Cush, professor of medicine and rheumatology at Baylor University Medical Center, Dallas, and director of clinical rheumatology at the Baylor Research Institute.

“I think in IBD it’s very clear that patients with active disease in pregnancy do much, much worse,” Dr. Mahadevan replied. “They have preterm birth, they get very sick, they’re hospitalized and placed on steroids. So for us, the benefit is very clear. I don’t know the data in rheumatoid arthritis – whether active disease leads to increased complication rates – but I do know from colleagues that in the postpartum period women with poorly controlled rheumatoid arthritis can’t take care of their baby because their hands are so damaged. And that’s a big deal.

“So when you see that the drugs are not associated with an increased risk of birth defects and on monotherapy there’s no increase in infections and other complications, you’d think that in the right patient continuing treatment until the late third trimester would be the way to go, especially since if you’ve put the patient on a biologic it must mean she has severe disease,” the gastroenterologist observed.

Dr. Roy Fleischmann of the University of Texas, Dallas, asked why gastroenterologists don’t put all IBD patients of childbearing age on certolizumab pegol if they need biologic therapy, since it doesn’t cross the placenta.

“Maybe IBD is different, but our biologics don’t necessarily have the longest persistence,” Dr. Mahadevan replied. “If you start a woman on certolizumab pegol at age 20 the chances of her still being on it at 28 are probably pretty low.”

Conference director Dr. Arthur Kavanaugh, professor of medicine at the University of California, San Diego, asked if the message regarding management of IBD in pregnancy being put forth by Dr. Mahadevan and the IBD in Pregnancy Consensus Group has gained wide acceptance by gastroenterologists across the country.

“I think the people who do IBD as a concentrated practice, whether in private or academic practice, are very aware of this literature,” she said.

“In general, IBD has become more and more centered among a group of people who want to take care of IBD. If you look at the big private practices, they have a hepatitis C person, an IBD person, and everyone else just wants to scope. I think the message is getting across to non-IBD gastroenterologists, but there is some confusion because the Europeans are very firm about stopping biologics at 22 weeks’ gestation if the patient is in deep remission and we in North America continue treatment,” said Dr. Mahadevan.

Her work with the PIANO study is funded by the Crohn’s and Colitis Foundation of America. In addition, Dr. Mahadevan disclosed ties to more than half a dozen pharmaceutical companies.

bjancin@frontlinemedcom.com

GLASGOW – Treatment with tumor necrosis factor (TNF) inhibitors for rheumatoid arthritis is associated with a low risk of vasculitis-like events, according to a large analysis of data from the United Kingdom.

Investigators using data from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR-RA) found that the crude incidence rate was 16 cases per 10,000 person-years among TNF-inhibitor users versus seven cases per 10,000 person-years among users of nonbiologic disease-modifying antirheumatic drugs (nbDMARDs) such as methotrexate and sulfasalazine.

Although the risk was slightly higher among anti-TNF than nbDMARD users, the propensity score fully adjusted hazard ratio for a first vasculitis-like event was 1.27, comparing the anti-TNF drugs with nbDMARDs, with a 95% confidence interval of 0.40-4.04.

“This is the first prospective observational study to systematically look at the risk of vasculitis-like events” in patients with RA treated with anti-TNF agents, Dr. Meghna Jani said at the British Society for Rheumatology annual conference.

Dr. Jani of the Arthritis Research UK Centre for Epidemiology at the University of Manchester (England) explained that the reason for looking at this topic was that vasculitis-like events had been reported in case series and single-center studies, but these prior reports were too small to be able to estimate exactly how big a problem this was.

“Anti-TNF agents are associated with the development of a number of autoantibodies, including antinuclear antibodies and antidrug antibodies, and ANCA [antineutrophil cytoplasmic antibody],” she observed.

“We know that a small proportion of these patients may then go on to develop autoimmune diseases, some independent of autoantibodies,” she added. The most common of these is vasculitis, including cutaneous vasculitis.

Vasculitis is a somewhat paradoxical adverse event, she noted, in that it has been associated with anti-TNF therapy, but these drugs can also be used to treat it.

Now in its 15th year, the BSRBR-RA is the largest ongoing cohort of patients treated with biologic agents for rheumatic disease and provides one of the best sources of data to examine the risk for vasculitis-like events Dr. Jani observed. The aims were to look at the respective risks as well as to see if there were any particular predictive factors.

The current analysis included more than 16,000 patients enrolled in the BSRBR-RA between 2001 and 2015, of whom 12,745 were newly started on an anti-TNF drug and 3,640 were receiving nbDMARDs and were also biologic naive. The mean age of patients in the two groups was 56 and 60 years, 76% and 72% were female, with a mean Disease Activity Score (DAS28) of 6.5 and 5.1 and median disease duration of 11 and 6 years, respectively.

After more than 52,428 person-years of exposure and a median of 5.1 years of follow-up, 81 vasculitis-like events occurred in the anti-TNF therapy group. Vasculitis-like events were attributed to treatment only if they had occurred within 90 days of starting the drug. Follow-up stopped after a first event; if there was a switch to another biologic drug; and at death, the last clinical follow-up, or the end of the analysis period (May 31, 2015).

In comparison, there were 20,635 person-years of exposure and 6.5 years’ follow-up in the nbDMARD group, with 14 vasculitis-like events reported during this time.

A sensitivity analysis was performed excluding patients who had nail-fold vasculitis at baseline, had vasculitis due to a possible secondary cause such as infection, and were taking any other medications associated with vasculitis-like events. Results showed a similar risk for a first vasculitis event between anti-TNF and nbDMARD users (aHR = 1.05; 95% CI, 0.32-3.45).

Looking at the risk of vasculitis events for individual anti-TNF drugs, there initially appeared to be a higher risk for patients taking infliximab (n = 3,292) and etanercept (n = 4,450) but not for those taking adalimumab (n = 4,312) versus nbDMARDs, with crude incidence rates of 10, 17, and 11 per 10,000 person-years; after adjustment, these differences were not significant (aHRs of 1.55, 1.72, and 0.77, respectively, with 95% CIs crossing 1.0). A crude rate for certolizumab could not be calculated as there were no vasculitis events reported but there were only 691 patients enrolled in the BSRBR-RA at the time of the analysis who had been exposed to the drug.

“The risk of the event was highest in the first year of treatment, followed by reduction over time,” Dr. Jani reported. “Reassuringly, up to two-thirds of patients in both cohorts had manifestations that were just limited to cutaneous involvement,” she said.

The most common systemic presentation was digital ischemia, affecting 14% of patients treated with anti-TNFs and 14% of those given nbDMARDs. Neurologic involvement was also seen in both groups of patients (7% vs. 7%), but new nail-fold vasculitis (17% vs. 0%), respiratory involvement (4% vs. 0%), associated thrombotic events (5% vs. 0%), and renal involvement (2.5% vs. 0%) were seen in TNF inhibitor-treated patients only.

Ten anti-TNF–treated patients and one nbDMARD-treated patient needed treatment for the vasculitis-like event, and three patients in the anti-TNF cohort died as a result of the event, all of whom had multisystem organ involvement and one of whom had cytoplasmic ANCA-positive vasculitis.

Treatment with methotrexate or sulfasalazine at baseline was associated with a lower risk for vasculitis-like events, while seropositive status, disease duration, DAS28, and HAQ scores were associated with an increased risk for such events.

The BSRBR-RA receives restricted income financial support from Abbvie, Amgen, Swedish Orphan Biovitram (SOBI), Merck, Pfizer, Roche, and UCB Pharma. Dr. Jani disclosed she has received honoraria from Pfizer, Abbvie, and UCB Pharma.

GLASGOW – Treatment with tumor necrosis factor (TNF) inhibitors for rheumatoid arthritis is associated with a low risk of vasculitis-like events, according to a large analysis of data from the United Kingdom.

Investigators using data from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR-RA) found that the crude incidence rate was 16 cases per 10,000 person-years among TNF-inhibitor users versus seven cases per 10,000 person-years among users of nonbiologic disease-modifying antirheumatic drugs (nbDMARDs) such as methotrexate and sulfasalazine.

Although the risk was slightly higher among anti-TNF than nbDMARD users, the propensity score fully adjusted hazard ratio for a first vasculitis-like event was 1.27, comparing the anti-TNF drugs with nbDMARDs, with a 95% confidence interval of 0.40-4.04.

“This is the first prospective observational study to systematically look at the risk of vasculitis-like events” in patients with RA treated with anti-TNF agents, Dr. Meghna Jani said at the British Society for Rheumatology annual conference.

Dr. Jani of the Arthritis Research UK Centre for Epidemiology at the University of Manchester (England) explained that the reason for looking at this topic was that vasculitis-like events had been reported in case series and single-center studies, but these prior reports were too small to be able to estimate exactly how big a problem this was.

“Anti-TNF agents are associated with the development of a number of autoantibodies, including antinuclear antibodies and antidrug antibodies, and ANCA [antineutrophil cytoplasmic antibody],” she observed.

“We know that a small proportion of these patients may then go on to develop autoimmune diseases, some independent of autoantibodies,” she added. The most common of these is vasculitis, including cutaneous vasculitis.

Vasculitis is a somewhat paradoxical adverse event, she noted, in that it has been associated with anti-TNF therapy, but these drugs can also be used to treat it.

Now in its 15th year, the BSRBR-RA is the largest ongoing cohort of patients treated with biologic agents for rheumatic disease and provides one of the best sources of data to examine the risk for vasculitis-like events Dr. Jani observed. The aims were to look at the respective risks as well as to see if there were any particular predictive factors.

The current analysis included more than 16,000 patients enrolled in the BSRBR-RA between 2001 and 2015, of whom 12,745 were newly started on an anti-TNF drug and 3,640 were receiving nbDMARDs and were also biologic naive. The mean age of patients in the two groups was 56 and 60 years, 76% and 72% were female, with a mean Disease Activity Score (DAS28) of 6.5 and 5.1 and median disease duration of 11 and 6 years, respectively.

After more than 52,428 person-years of exposure and a median of 5.1 years of follow-up, 81 vasculitis-like events occurred in the anti-TNF therapy group. Vasculitis-like events were attributed to treatment only if they had occurred within 90 days of starting the drug. Follow-up stopped after a first event; if there was a switch to another biologic drug; and at death, the last clinical follow-up, or the end of the analysis period (May 31, 2015).

In comparison, there were 20,635 person-years of exposure and 6.5 years’ follow-up in the nbDMARD group, with 14 vasculitis-like events reported during this time.

A sensitivity analysis was performed excluding patients who had nail-fold vasculitis at baseline, had vasculitis due to a possible secondary cause such as infection, and were taking any other medications associated with vasculitis-like events. Results showed a similar risk for a first vasculitis event between anti-TNF and nbDMARD users (aHR = 1.05; 95% CI, 0.32-3.45).

Looking at the risk of vasculitis events for individual anti-TNF drugs, there initially appeared to be a higher risk for patients taking infliximab (n = 3,292) and etanercept (n = 4,450) but not for those taking adalimumab (n = 4,312) versus nbDMARDs, with crude incidence rates of 10, 17, and 11 per 10,000 person-years; after adjustment, these differences were not significant (aHRs of 1.55, 1.72, and 0.77, respectively, with 95% CIs crossing 1.0). A crude rate for certolizumab could not be calculated as there were no vasculitis events reported but there were only 691 patients enrolled in the BSRBR-RA at the time of the analysis who had been exposed to the drug.

“The risk of the event was highest in the first year of treatment, followed by reduction over time,” Dr. Jani reported. “Reassuringly, up to two-thirds of patients in both cohorts had manifestations that were just limited to cutaneous involvement,” she said.

The most common systemic presentation was digital ischemia, affecting 14% of patients treated with anti-TNFs and 14% of those given nbDMARDs. Neurologic involvement was also seen in both groups of patients (7% vs. 7%), but new nail-fold vasculitis (17% vs. 0%), respiratory involvement (4% vs. 0%), associated thrombotic events (5% vs. 0%), and renal involvement (2.5% vs. 0%) were seen in TNF inhibitor-treated patients only.

Ten anti-TNF–treated patients and one nbDMARD-treated patient needed treatment for the vasculitis-like event, and three patients in the anti-TNF cohort died as a result of the event, all of whom had multisystem organ involvement and one of whom had cytoplasmic ANCA-positive vasculitis.

Treatment with methotrexate or sulfasalazine at baseline was associated with a lower risk for vasculitis-like events, while seropositive status, disease duration, DAS28, and HAQ scores were associated with an increased risk for such events.

The BSRBR-RA receives restricted income financial support from Abbvie, Amgen, Swedish Orphan Biovitram (SOBI), Merck, Pfizer, Roche, and UCB Pharma. Dr. Jani disclosed she has received honoraria from Pfizer, Abbvie, and UCB Pharma.

GLASGOW – Treatment with tumor necrosis factor (TNF) inhibitors for rheumatoid arthritis is associated with a low risk of vasculitis-like events, according to a large analysis of data from the United Kingdom.

Investigators using data from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR-RA) found that the crude incidence rate was 16 cases per 10,000 person-years among TNF-inhibitor users versus seven cases per 10,000 person-years among users of nonbiologic disease-modifying antirheumatic drugs (nbDMARDs) such as methotrexate and sulfasalazine.

Although the risk was slightly higher among anti-TNF than nbDMARD users, the propensity score fully adjusted hazard ratio for a first vasculitis-like event was 1.27, comparing the anti-TNF drugs with nbDMARDs, with a 95% confidence interval of 0.40-4.04.

“This is the first prospective observational study to systematically look at the risk of vasculitis-like events” in patients with RA treated with anti-TNF agents, Dr. Meghna Jani said at the British Society for Rheumatology annual conference.

Dr. Jani of the Arthritis Research UK Centre for Epidemiology at the University of Manchester (England) explained that the reason for looking at this topic was that vasculitis-like events had been reported in case series and single-center studies, but these prior reports were too small to be able to estimate exactly how big a problem this was.

“Anti-TNF agents are associated with the development of a number of autoantibodies, including antinuclear antibodies and antidrug antibodies, and ANCA [antineutrophil cytoplasmic antibody],” she observed.

“We know that a small proportion of these patients may then go on to develop autoimmune diseases, some independent of autoantibodies,” she added. The most common of these is vasculitis, including cutaneous vasculitis.

Vasculitis is a somewhat paradoxical adverse event, she noted, in that it has been associated with anti-TNF therapy, but these drugs can also be used to treat it.

Now in its 15th year, the BSRBR-RA is the largest ongoing cohort of patients treated with biologic agents for rheumatic disease and provides one of the best sources of data to examine the risk for vasculitis-like events Dr. Jani observed. The aims were to look at the respective risks as well as to see if there were any particular predictive factors.

The current analysis included more than 16,000 patients enrolled in the BSRBR-RA between 2001 and 2015, of whom 12,745 were newly started on an anti-TNF drug and 3,640 were receiving nbDMARDs and were also biologic naive. The mean age of patients in the two groups was 56 and 60 years, 76% and 72% were female, with a mean Disease Activity Score (DAS28) of 6.5 and 5.1 and median disease duration of 11 and 6 years, respectively.

After more than 52,428 person-years of exposure and a median of 5.1 years of follow-up, 81 vasculitis-like events occurred in the anti-TNF therapy group. Vasculitis-like events were attributed to treatment only if they had occurred within 90 days of starting the drug. Follow-up stopped after a first event; if there was a switch to another biologic drug; and at death, the last clinical follow-up, or the end of the analysis period (May 31, 2015).

In comparison, there were 20,635 person-years of exposure and 6.5 years’ follow-up in the nbDMARD group, with 14 vasculitis-like events reported during this time.

A sensitivity analysis was performed excluding patients who had nail-fold vasculitis at baseline, had vasculitis due to a possible secondary cause such as infection, and were taking any other medications associated with vasculitis-like events. Results showed a similar risk for a first vasculitis event between anti-TNF and nbDMARD users (aHR = 1.05; 95% CI, 0.32-3.45).

Looking at the risk of vasculitis events for individual anti-TNF drugs, there initially appeared to be a higher risk for patients taking infliximab (n = 3,292) and etanercept (n = 4,450) but not for those taking adalimumab (n = 4,312) versus nbDMARDs, with crude incidence rates of 10, 17, and 11 per 10,000 person-years; after adjustment, these differences were not significant (aHRs of 1.55, 1.72, and 0.77, respectively, with 95% CIs crossing 1.0). A crude rate for certolizumab could not be calculated as there were no vasculitis events reported but there were only 691 patients enrolled in the BSRBR-RA at the time of the analysis who had been exposed to the drug.

“The risk of the event was highest in the first year of treatment, followed by reduction over time,” Dr. Jani reported. “Reassuringly, up to two-thirds of patients in both cohorts had manifestations that were just limited to cutaneous involvement,” she said.

The most common systemic presentation was digital ischemia, affecting 14% of patients treated with anti-TNFs and 14% of those given nbDMARDs. Neurologic involvement was also seen in both groups of patients (7% vs. 7%), but new nail-fold vasculitis (17% vs. 0%), respiratory involvement (4% vs. 0%), associated thrombotic events (5% vs. 0%), and renal involvement (2.5% vs. 0%) were seen in TNF inhibitor-treated patients only.

Ten anti-TNF–treated patients and one nbDMARD-treated patient needed treatment for the vasculitis-like event, and three patients in the anti-TNF cohort died as a result of the event, all of whom had multisystem organ involvement and one of whom had cytoplasmic ANCA-positive vasculitis.

Treatment with methotrexate or sulfasalazine at baseline was associated with a lower risk for vasculitis-like events, while seropositive status, disease duration, DAS28, and HAQ scores were associated with an increased risk for such events.

The BSRBR-RA receives restricted income financial support from Abbvie, Amgen, Swedish Orphan Biovitram (SOBI), Merck, Pfizer, Roche, and UCB Pharma. Dr. Jani disclosed she has received honoraria from Pfizer, Abbvie, and UCB Pharma.

GLASGOW – Switching patients on the anti–tumor necrosis factor drug Remicade to a biosimilar infliximab product resulted in good efficacy and tolerability with substantial cost savings in two real-world studies from the United Kingdom.

A total of 52 (88%) of 59 patients who had switched to the biosimilar infliximab CT-P13 (Inflectra) for the treatment of various indications for which Remicade is approved remained on the biosimilar after 10 months of follow-up and experienced comparable adverse events and similar levels of efficacy before and after switching, Dr. Lucy Parker of University Hospital Southampton NHS Foundation Trust reported at the British Society for Rheumatology annual conference. A second smaller study reported at the conference also showed similar results with the same infliximab biosimilar, which is also marketed as Remsima in Europe.

CT-P13 had efficacy, immunogenicity, and pharmacokinetic and pharmacodynamic parameters comparable to Remicade in 1-year follow-up data from the phase III randomized PLANETRAstudy (Arthritis Res Ther. 2016;18:82. doi: 10.1186/s13075-016-0981-6), but whether these study findings hold in a routine practice setting remains to be determined, Dr. Parker noted.

In Dr. Parker and colleagues’ study of data from the Southampton Biological Therapies Review Service, every patient was initially “seen in clinic and had the opportunity to speak to their consultant rheumatologist about the potential switchover from the originator drug to the new version,” she explained. Patients were then contacted directly by letter to explain the potential switch and given an information leaflet on Inflectra. They were also given access to a dedicated helpline number that could be used to re-explain the switch and discuss any concerns after switching had occurred.

In May 2015, all 59 patients being treated with Remicade were gradually switched over to the biosimilar version. Patients were reviewed after 3 months and then at 6-month intervals.

“Every single patient agreed to switch,” Dr. Parker observed. No patient used the helpline service or asked to talk with the consultant rheumatologist. One delegate noted during discussion that it was impressive that all patients agreed to switch, but Dr. Parker suggested that it was probably important that people were invited to switch rather being told that they would be switched. “If anyone had refused, then they would have been kept on Remicade,” she observed.

©BrianAJackson/Thinkstock.com

Dr. Parker noted that the patients were taking Remicade for various rheumatologic conditions, including 29 with rheumatoid arthritis (RA), 14 with ankylosing spondylitis (AS), 14 with psoriatic arthritis (PsA), and 2 with enteropathic arthritis. The mean age was 58.9 years, 51% of patients were female, mean disease duration was 18 years, and there was a mean of 5.7 years on Remicade before the switch. Patients had been diagnosed an average of 10 years before the first use of a biologic agent, 56% were also taking methotrexate, and 17% were on another disease-modifying antirheumatic drug (DMARD).

There was no significant difference in disease activity before or after switching, with respective mean 28-joint Disease Activity Scores of 3.4 and 3.3 and Bath Ankylosing Spondylitis Disease Activity Index scores of 3.7 and 3.6.

Dr. Parker noted that two 6-month periods before switching were compared to a 6-month period after switching and there were a similarly low number of cases reporting inefficacy, which was defined as any increase in symptoms or disease activity measure. Inefficacy was seen in one patient 12 months before the switch, two patients 6 months before the switch, and three patients after the switch. All three of the latter patients were switched back to Remicade, with one being then further switched to rituximab (Rituxan).

There were four adverse events in patients switched to the biosimilar versus three and four cases in the two 6-month periods before the switch. Adverse events after switching were widespread pain or myalgia and arthralgia after two infusions in two patients with PsA, multiple subjective symptoms such as dizziness and labile blood pressure and forgetfulness in another patient with PsA who also had these symptoms before the switch, and a case of chronic osteomyelitic foot infection in a patient with RA that also predated the switch. Biologic therapy was stopped in the RA patient, one of the PsA patients switched back to Remicade, and the other two were switched to ustekinumab (Stelara).

Dr. Parker reported that switching to the biosimilar has significantly cut the cost of treatment by £197,974 (about $291,000 USD) or 41.5% in their practice.

A team from St. George’s University Hospitals NHS Foundation Trust in London reported in a poster session similar findings after switching 31 patients to Remsima (Rheumatology [Oxford]. 2016;55[suppl 1]:i125-i126). Most switches occurred in RA patients (n = 18), followed by seven with AS and five with PsA. One patient did not switch following a consultant decision after the patient in question developed septic arthritis.

Dr. Ritu Malaiya and associates found equivalent efficacy responses in the vast majority of cases. Only one patient switched back to Remicade. Dr. Malaiya said that their experience of switching was, “on the whole, positive.” Effective planning and education of patients and staff around the switch was again considered vital and “instrumental to our early success,” the team reported. “Overall, patients were keen for others to benefit from more cost-effective drugs.”

Dr. Parker and Dr. Malaiya reported having no financial disclosures. Coauthors of the studies disclosed acting as consultants or receiving research grants from manufacturers of anti-TNF therapies.

GLASGOW – Switching patients on the anti–tumor necrosis factor drug Remicade to a biosimilar infliximab product resulted in good efficacy and tolerability with substantial cost savings in two real-world studies from the United Kingdom.

A total of 52 (88%) of 59 patients who had switched to the biosimilar infliximab CT-P13 (Inflectra) for the treatment of various indications for which Remicade is approved remained on the biosimilar after 10 months of follow-up and experienced comparable adverse events and similar levels of efficacy before and after switching, Dr. Lucy Parker of University Hospital Southampton NHS Foundation Trust reported at the British Society for Rheumatology annual conference. A second smaller study reported at the conference also showed similar results with the same infliximab biosimilar, which is also marketed as Remsima in Europe.

CT-P13 had efficacy, immunogenicity, and pharmacokinetic and pharmacodynamic parameters comparable to Remicade in 1-year follow-up data from the phase III randomized PLANETRAstudy (Arthritis Res Ther. 2016;18:82. doi: 10.1186/s13075-016-0981-6), but whether these study findings hold in a routine practice setting remains to be determined, Dr. Parker noted.

In Dr. Parker and colleagues’ study of data from the Southampton Biological Therapies Review Service, every patient was initially “seen in clinic and had the opportunity to speak to their consultant rheumatologist about the potential switchover from the originator drug to the new version,” she explained. Patients were then contacted directly by letter to explain the potential switch and given an information leaflet on Inflectra. They were also given access to a dedicated helpline number that could be used to re-explain the switch and discuss any concerns after switching had occurred.

In May 2015, all 59 patients being treated with Remicade were gradually switched over to the biosimilar version. Patients were reviewed after 3 months and then at 6-month intervals.

“Every single patient agreed to switch,” Dr. Parker observed. No patient used the helpline service or asked to talk with the consultant rheumatologist. One delegate noted during discussion that it was impressive that all patients agreed to switch, but Dr. Parker suggested that it was probably important that people were invited to switch rather being told that they would be switched. “If anyone had refused, then they would have been kept on Remicade,” she observed.

©BrianAJackson/Thinkstock.com

Dr. Parker noted that the patients were taking Remicade for various rheumatologic conditions, including 29 with rheumatoid arthritis (RA), 14 with ankylosing spondylitis (AS), 14 with psoriatic arthritis (PsA), and 2 with enteropathic arthritis. The mean age was 58.9 years, 51% of patients were female, mean disease duration was 18 years, and there was a mean of 5.7 years on Remicade before the switch. Patients had been diagnosed an average of 10 years before the first use of a biologic agent, 56% were also taking methotrexate, and 17% were on another disease-modifying antirheumatic drug (DMARD).

There was no significant difference in disease activity before or after switching, with respective mean 28-joint Disease Activity Scores of 3.4 and 3.3 and Bath Ankylosing Spondylitis Disease Activity Index scores of 3.7 and 3.6.

Dr. Parker noted that two 6-month periods before switching were compared to a 6-month period after switching and there were a similarly low number of cases reporting inefficacy, which was defined as any increase in symptoms or disease activity measure. Inefficacy was seen in one patient 12 months before the switch, two patients 6 months before the switch, and three patients after the switch. All three of the latter patients were switched back to Remicade, with one being then further switched to rituximab (Rituxan).

There were four adverse events in patients switched to the biosimilar versus three and four cases in the two 6-month periods before the switch. Adverse events after switching were widespread pain or myalgia and arthralgia after two infusions in two patients with PsA, multiple subjective symptoms such as dizziness and labile blood pressure and forgetfulness in another patient with PsA who also had these symptoms before the switch, and a case of chronic osteomyelitic foot infection in a patient with RA that also predated the switch. Biologic therapy was stopped in the RA patient, one of the PsA patients switched back to Remicade, and the other two were switched to ustekinumab (Stelara).

Dr. Parker reported that switching to the biosimilar has significantly cut the cost of treatment by £197,974 (about $291,000 USD) or 41.5% in their practice.

A team from St. George’s University Hospitals NHS Foundation Trust in London reported in a poster session similar findings after switching 31 patients to Remsima (Rheumatology [Oxford]. 2016;55[suppl 1]:i125-i126). Most switches occurred in RA patients (n = 18), followed by seven with AS and five with PsA. One patient did not switch following a consultant decision after the patient in question developed septic arthritis.

Dr. Ritu Malaiya and associates found equivalent efficacy responses in the vast majority of cases. Only one patient switched back to Remicade. Dr. Malaiya said that their experience of switching was, “on the whole, positive.” Effective planning and education of patients and staff around the switch was again considered vital and “instrumental to our early success,” the team reported. “Overall, patients were keen for others to benefit from more cost-effective drugs.”

Dr. Parker and Dr. Malaiya reported having no financial disclosures. Coauthors of the studies disclosed acting as consultants or receiving research grants from manufacturers of anti-TNF therapies.

GLASGOW – Switching patients on the anti–tumor necrosis factor drug Remicade to a biosimilar infliximab product resulted in good efficacy and tolerability with substantial cost savings in two real-world studies from the United Kingdom.

A total of 52 (88%) of 59 patients who had switched to the biosimilar infliximab CT-P13 (Inflectra) for the treatment of various indications for which Remicade is approved remained on the biosimilar after 10 months of follow-up and experienced comparable adverse events and similar levels of efficacy before and after switching, Dr. Lucy Parker of University Hospital Southampton NHS Foundation Trust reported at the British Society for Rheumatology annual conference. A second smaller study reported at the conference also showed similar results with the same infliximab biosimilar, which is also marketed as Remsima in Europe.

CT-P13 had efficacy, immunogenicity, and pharmacokinetic and pharmacodynamic parameters comparable to Remicade in 1-year follow-up data from the phase III randomized PLANETRAstudy (Arthritis Res Ther. 2016;18:82. doi: 10.1186/s13075-016-0981-6), but whether these study findings hold in a routine practice setting remains to be determined, Dr. Parker noted.

In Dr. Parker and colleagues’ study of data from the Southampton Biological Therapies Review Service, every patient was initially “seen in clinic and had the opportunity to speak to their consultant rheumatologist about the potential switchover from the originator drug to the new version,” she explained. Patients were then contacted directly by letter to explain the potential switch and given an information leaflet on Inflectra. They were also given access to a dedicated helpline number that could be used to re-explain the switch and discuss any concerns after switching had occurred.

In May 2015, all 59 patients being treated with Remicade were gradually switched over to the biosimilar version. Patients were reviewed after 3 months and then at 6-month intervals.

“Every single patient agreed to switch,” Dr. Parker observed. No patient used the helpline service or asked to talk with the consultant rheumatologist. One delegate noted during discussion that it was impressive that all patients agreed to switch, but Dr. Parker suggested that it was probably important that people were invited to switch rather being told that they would be switched. “If anyone had refused, then they would have been kept on Remicade,” she observed.

©BrianAJackson/Thinkstock.com

Dr. Parker noted that the patients were taking Remicade for various rheumatologic conditions, including 29 with rheumatoid arthritis (RA), 14 with ankylosing spondylitis (AS), 14 with psoriatic arthritis (PsA), and 2 with enteropathic arthritis. The mean age was 58.9 years, 51% of patients were female, mean disease duration was 18 years, and there was a mean of 5.7 years on Remicade before the switch. Patients had been diagnosed an average of 10 years before the first use of a biologic agent, 56% were also taking methotrexate, and 17% were on another disease-modifying antirheumatic drug (DMARD).

There was no significant difference in disease activity before or after switching, with respective mean 28-joint Disease Activity Scores of 3.4 and 3.3 and Bath Ankylosing Spondylitis Disease Activity Index scores of 3.7 and 3.6.

Dr. Parker noted that two 6-month periods before switching were compared to a 6-month period after switching and there were a similarly low number of cases reporting inefficacy, which was defined as any increase in symptoms or disease activity measure. Inefficacy was seen in one patient 12 months before the switch, two patients 6 months before the switch, and three patients after the switch. All three of the latter patients were switched back to Remicade, with one being then further switched to rituximab (Rituxan).

There were four adverse events in patients switched to the biosimilar versus three and four cases in the two 6-month periods before the switch. Adverse events after switching were widespread pain or myalgia and arthralgia after two infusions in two patients with PsA, multiple subjective symptoms such as dizziness and labile blood pressure and forgetfulness in another patient with PsA who also had these symptoms before the switch, and a case of chronic osteomyelitic foot infection in a patient with RA that also predated the switch. Biologic therapy was stopped in the RA patient, one of the PsA patients switched back to Remicade, and the other two were switched to ustekinumab (Stelara).

Dr. Parker reported that switching to the biosimilar has significantly cut the cost of treatment by £197,974 (about $291,000 USD) or 41.5% in their practice.

A team from St. George’s University Hospitals NHS Foundation Trust in London reported in a poster session similar findings after switching 31 patients to Remsima (Rheumatology [Oxford]. 2016;55[suppl 1]:i125-i126). Most switches occurred in RA patients (n = 18), followed by seven with AS and five with PsA. One patient did not switch following a consultant decision after the patient in question developed septic arthritis.

Dr. Ritu Malaiya and associates found equivalent efficacy responses in the vast majority of cases. Only one patient switched back to Remicade. Dr. Malaiya said that their experience of switching was, “on the whole, positive.” Effective planning and education of patients and staff around the switch was again considered vital and “instrumental to our early success,” the team reported. “Overall, patients were keen for others to benefit from more cost-effective drugs.”

Dr. Parker and Dr. Malaiya reported having no financial disclosures. Coauthors of the studies disclosed acting as consultants or receiving research grants from manufacturers of anti-TNF therapies.

Now that the Food and Drug Administration has approved Inflectra as the first biosimilar version of the anti–tumor necrosis factor-alpha agent Remicade, rheumatologists and patient advocacy groups are taking stock of how it may be used in practice, and what the future holds for biosimilar drugs, with so many questions still unanswered regarding price, substitution, and safety.

Joseph Riccio/Adirondack Health

Inflectra, approved in early April and given the generic name of infliximab-dyyb under the FDA’s nomenclature for biosimilar products, will have the same indications as Remicade. The agency extrapolated the clinical trial data that Inflectra’s South Korea–based manufacturer, Celltrion, submitted for rheumatoid arthritis and ankylosing spondylitis to all other indications for which Remicade is approved.

It’s currently unclear how the FDA will note which clinical data in Inflectra’s labeling come from Inflectra and which from Remicade, and the same concerns lie with future biosimilar approvals if their results are extrapolated to indications not tested to show biosimilarity in clinical trials.

Labeling questions

It’s concerning to rheumatologists and the patients who will be using them that biosimilars such as Inflectra are not subject to the same pivotal trial experience as the reference biologics on which they are based, according to Dr. Jonathan Krant, section chief of rheumatology for Adirondack Health Systems in Saranac Lake, N.Y., and medical director for CreakyJoints, a community of patients with arthritis and caregivers, and its larger parent nonprofit advocacy organization, the Global Healthy Living Foundation (GHLF).

While the unique regulatory requirements in the biosimilar approval pathway reduce development costs and could potentially make Inflectra’s average wholesale price 30% less than Remicade – as was the case when Inflectra was first on the market in Europe – it’s not known how reduced costs may affect the safety of biosimilars.

“It worries all of us that manufacturers may cut corners to manage the cost constraints imposed by managed care,” Dr. Krant said in an interview.

Given that U.S. rheumatologists don’t have experience with biosimilars, Dr. Krant is anticipating some push back. “I think some physicians are going to fight back and won’t want to prescribe them, even if mandated, because of concerns regarding patient safety,” he said.

In a written statement, Dr. Joan Von Feldt, president of the American College of Rheumatology, welcomed the potential benefits on access to care that cost-saving biosimilars may bring to the U.S. health care system, but also said that “the safety of our patients remains our highest priority. As such, we encourage the FDA to continue to apply distinct names for future biosimilars, and to maximize clarity in the labeling of biosimilars, specifically with respect to their interchangeable status and the origins (reference drug versus biosimilar) of clinical data upon which FDA approval is based.”

Inflectra met the FDA’s “very similar” criteria to be approved as a biosimilar by showing it has no clinically meaningful differences in terms of safety and effectiveness from Remicade, the agency said. According to FDA regulations, biosimilar products can have only minor differences in clinically inactive components and must have the same mechanism(s) of action (to the extent that it is known) and route(s) of administration, dosage form(s), and strength(s) as the reference product and can be approved only for the indication(s) and condition(s) of use that have been approved for the reference product.

However, it may not hold true that Inflectra will have the same efficacy and safety for all indications that Remicade had due to potential differences in the mechanism of action through which Remicade exerts its effect across indications, which in this case may apply to the indications for Crohn’s disease and ulcerative colitis.

Health Canada chose not to extrapolate the indications for Inflectra (known as Remsima in Canada) to Crohn’s disease and ulcerative colitis because of “observed differences in the level of afucosylation, Fc-gammaRIIIa receptor binding, and some in vitro antibody-dependent cell-mediated cytotoxicity (ADCC) assays” that could not rule out the possibility that Inflectra and Remicade differ in their ability to induce ADCC. Unlike the other indications for Remicade, Health Canada said “ADCC cannot be ruled out as a mechanism of action in the inflammatory bowel diseases. This position is supported by the observation that certolizumab pegol, another anti-TNF [anti–tumor necrosis factor] that lacks the ability to induce ADCC, displays only marginal efficacy in Crohn’s patients, compared with other anti-TNFs, namely infliximab.”

Other organizations suggest that extrapolation of indications is only appropriate when it is benefiting the patient to the greatest extent possible.

“GHLF is okay with extrapolation of indication unless the mechanism of action for the therapy is either scientifically or therapeutically outdated,” Stephen Marmaras, state and national advocacy manager for the GHLF, said in an interview. “Patients are okay with extrapolating data in order to expedite the approval process as long as you are extrapolating to best in class therapy for a particular indication. What [the GHLF is] saying is we want biosimilars to be an improvement on what we have, not the lowest common denominator. We shouldn’t be extrapolating indications data from products that aren’t considered to be the best product for that indication.”

“If we’re just judging on expediting the approval process for indications that are not considered to be really treated well by this particular drug, you have to always assume that the insurance company is going to go with the lowest common denominator,” he added. “What that could lead to, from a slippery-slope perspective, is the chipping away of the use of cutting-edge therapies.”

Substitution concerns

Inflectra was not approved as interchangeable with Remicade or other infliximab biosimilars. The FDA has yet to define the regulatory requirements for interchangeability that are necessary to meet the requirements of the Biologics Price Competition and Innovation Act of 2009. That Act states that an approved biosimilar “may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.”

A statement about implementation of the Act on the FDA website explains that for interchangeability, “a sponsor must demonstrate that the biosimilar product can be expected to produce the same clinical result as the reference product in any given patient and, for a biological product that is administered more than once, that the risk of alternating or switching between use of the biosimilar product and the reference product is not greater than the risk of maintaining the patient on the reference product.”

One of the biggest concerns that physicians have is that biosimilars will be substituted for the reference products without notification, Dr. Krant said. “State by state we’re looking at potential substitution rules which allow pharmacists to switch out these cheaper molecules for the reference product,” he said, and without timely notification, patients and rheumatologists won’t know whether it was the reference product or a biosimilar that was associated with an adverse event or loss of efficacy.

The ACR and patient advocacy organizations such as the GHLF are against forced switching of patients for nonmedical reasons. Patients’ and rheumatologists’ confidence in biosimilar safety will be key to their uptake and the overall expansion of access to biologics to more patients, Mr. Marmaras said.

Patient costs uncertain

Although rheumatologists hope that with biosimilars’ lower costs, access will expand, there is no guarantee it will do so by saving patients money.

“It’s a common misperception that a 30% decrease in the cost of a several thousand dollar-a-month drug is going to automatically open all the doors to access,” said Dr. Sean Fahey, a rheumatologist in Mooresville, N.C., and chair of the insurance subcommittee of the ACR’s Committee on Rheumatologic Care. “Most of my patients who use biologics do so either through copay cards from the pharmaceutical industry or through Medicare and a secondary [payer] covering their out-of-pocket costs for the infusible biologics. This is clearly saving the system money, which is important no doubt, but unless it’s significantly less expensive, it actually might not change the patient’s out-of pocket [cost] all that much.”

The patient assistance programs from biologics manufacturers that offer copay assistance, access hotlines, and administration benefits could be in jeopardy with the rise of biosimilars. Since the programs are bundled into the average wholesale price of the drug, the savings offered by the reduced wholesale price of biosimilars may squeeze them out, Dr. Krant said.

“There’s going to be a lot of hue and cry from the patients who cannot self-administer or have problems with compliance because of copays in the first place,” he predicted.

Another factor that could affect how much biosimilars such as Inflectra will be used is the amount of rebates or discounts that payers receive directly from the pharmaceutical manufacturers.

“We know for the Medicaid population what the average sales prices are, but for private payers, we don’t know if they’re giving 2%, 5%, 18%; we have no idea what the data are. This could affect how much market share Inflectra gets,” said Dr. Fahey, who is also president of the North Carolina Rheumatology Association.

It may be awhile before Inflectra is available on the U.S. market. In a statement following the approval of Inflectra, Remicade-maker Janssen said the “patents for Remicade remain valid and enforceable until September 2018. A commercial launch of Celltrion’s infliximab-dyyb in advance of this date would be an infringement of our patents, and we intend to defend our intellectual property rights.”

Janssen notes that its patient support program for Remicade “continues to offer a copay card for patients with commercial insurance that reduces the patient out-of-pocket cost to no more than $5 per infusion. Eligible uninsured and underinsured patients may be able to access Remicade through the Johnson & Johnson Patient Assistance Foundation.”

Pfizer, which owns the rights to marketing Inflectra in the United States, did not respond directly to a question about whether it would have a payment assistance program for Inflectra. “While we cannot comment on specific commercialization strategies at this time, we are working to bring these important therapies to market in the U.S. as quickly as possible,” said Rachel Hooper, Director of Public Affairs, West, for Pfizer.

It seems likely that once Inflectra does come to the market, new starts will account for many patients who will use the drug because of the lack of information available about whether there is, or is not, significant risk of immunogenicity with switching or loss of efficacy, Dr. Fahey said. “What is less certain is whether the payers will try to force us to move people from the Remicade brand to the infliximab biosimilar, and what the potential consequences of that is going to be.”

Dr. Krant, Dr. Fahey, and Mr. Marmaras had no relevant disclosures.

jevans@frontlinemedcom.com

Now that the Food and Drug Administration has approved Inflectra as the first biosimilar version of the anti–tumor necrosis factor-alpha agent Remicade, rheumatologists and patient advocacy groups are taking stock of how it may be used in practice, and what the future holds for biosimilar drugs, with so many questions still unanswered regarding price, substitution, and safety.

Joseph Riccio/Adirondack Health

Inflectra, approved in early April and given the generic name of infliximab-dyyb under the FDA’s nomenclature for biosimilar products, will have the same indications as Remicade. The agency extrapolated the clinical trial data that Inflectra’s South Korea–based manufacturer, Celltrion, submitted for rheumatoid arthritis and ankylosing spondylitis to all other indications for which Remicade is approved.

It’s currently unclear how the FDA will note which clinical data in Inflectra’s labeling come from Inflectra and which from Remicade, and the same concerns lie with future biosimilar approvals if their results are extrapolated to indications not tested to show biosimilarity in clinical trials.

Labeling questions

It’s concerning to rheumatologists and the patients who will be using them that biosimilars such as Inflectra are not subject to the same pivotal trial experience as the reference biologics on which they are based, according to Dr. Jonathan Krant, section chief of rheumatology for Adirondack Health Systems in Saranac Lake, N.Y., and medical director for CreakyJoints, a community of patients with arthritis and caregivers, and its larger parent nonprofit advocacy organization, the Global Healthy Living Foundation (GHLF).

While the unique regulatory requirements in the biosimilar approval pathway reduce development costs and could potentially make Inflectra’s average wholesale price 30% less than Remicade – as was the case when Inflectra was first on the market in Europe – it’s not known how reduced costs may affect the safety of biosimilars.

“It worries all of us that manufacturers may cut corners to manage the cost constraints imposed by managed care,” Dr. Krant said in an interview.

Given that U.S. rheumatologists don’t have experience with biosimilars, Dr. Krant is anticipating some push back. “I think some physicians are going to fight back and won’t want to prescribe them, even if mandated, because of concerns regarding patient safety,” he said.

In a written statement, Dr. Joan Von Feldt, president of the American College of Rheumatology, welcomed the potential benefits on access to care that cost-saving biosimilars may bring to the U.S. health care system, but also said that “the safety of our patients remains our highest priority. As such, we encourage the FDA to continue to apply distinct names for future biosimilars, and to maximize clarity in the labeling of biosimilars, specifically with respect to their interchangeable status and the origins (reference drug versus biosimilar) of clinical data upon which FDA approval is based.”

Inflectra met the FDA’s “very similar” criteria to be approved as a biosimilar by showing it has no clinically meaningful differences in terms of safety and effectiveness from Remicade, the agency said. According to FDA regulations, biosimilar products can have only minor differences in clinically inactive components and must have the same mechanism(s) of action (to the extent that it is known) and route(s) of administration, dosage form(s), and strength(s) as the reference product and can be approved only for the indication(s) and condition(s) of use that have been approved for the reference product.

However, it may not hold true that Inflectra will have the same efficacy and safety for all indications that Remicade had due to potential differences in the mechanism of action through which Remicade exerts its effect across indications, which in this case may apply to the indications for Crohn’s disease and ulcerative colitis.

Health Canada chose not to extrapolate the indications for Inflectra (known as Remsima in Canada) to Crohn’s disease and ulcerative colitis because of “observed differences in the level of afucosylation, Fc-gammaRIIIa receptor binding, and some in vitro antibody-dependent cell-mediated cytotoxicity (ADCC) assays” that could not rule out the possibility that Inflectra and Remicade differ in their ability to induce ADCC. Unlike the other indications for Remicade, Health Canada said “ADCC cannot be ruled out as a mechanism of action in the inflammatory bowel diseases. This position is supported by the observation that certolizumab pegol, another anti-TNF [anti–tumor necrosis factor] that lacks the ability to induce ADCC, displays only marginal efficacy in Crohn’s patients, compared with other anti-TNFs, namely infliximab.”

Other organizations suggest that extrapolation of indications is only appropriate when it is benefiting the patient to the greatest extent possible.

“GHLF is okay with extrapolation of indication unless the mechanism of action for the therapy is either scientifically or therapeutically outdated,” Stephen Marmaras, state and national advocacy manager for the GHLF, said in an interview. “Patients are okay with extrapolating data in order to expedite the approval process as long as you are extrapolating to best in class therapy for a particular indication. What [the GHLF is] saying is we want biosimilars to be an improvement on what we have, not the lowest common denominator. We shouldn’t be extrapolating indications data from products that aren’t considered to be the best product for that indication.”

“If we’re just judging on expediting the approval process for indications that are not considered to be really treated well by this particular drug, you have to always assume that the insurance company is going to go with the lowest common denominator,” he added. “What that could lead to, from a slippery-slope perspective, is the chipping away of the use of cutting-edge therapies.”

Substitution concerns

Inflectra was not approved as interchangeable with Remicade or other infliximab biosimilars. The FDA has yet to define the regulatory requirements for interchangeability that are necessary to meet the requirements of the Biologics Price Competition and Innovation Act of 2009. That Act states that an approved biosimilar “may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.”

A statement about implementation of the Act on the FDA website explains that for interchangeability, “a sponsor must demonstrate that the biosimilar product can be expected to produce the same clinical result as the reference product in any given patient and, for a biological product that is administered more than once, that the risk of alternating or switching between use of the biosimilar product and the reference product is not greater than the risk of maintaining the patient on the reference product.”

One of the biggest concerns that physicians have is that biosimilars will be substituted for the reference products without notification, Dr. Krant said. “State by state we’re looking at potential substitution rules which allow pharmacists to switch out these cheaper molecules for the reference product,” he said, and without timely notification, patients and rheumatologists won’t know whether it was the reference product or a biosimilar that was associated with an adverse event or loss of efficacy.

The ACR and patient advocacy organizations such as the GHLF are against forced switching of patients for nonmedical reasons. Patients’ and rheumatologists’ confidence in biosimilar safety will be key to their uptake and the overall expansion of access to biologics to more patients, Mr. Marmaras said.

Patient costs uncertain

Although rheumatologists hope that with biosimilars’ lower costs, access will expand, there is no guarantee it will do so by saving patients money.

“It’s a common misperception that a 30% decrease in the cost of a several thousand dollar-a-month drug is going to automatically open all the doors to access,” said Dr. Sean Fahey, a rheumatologist in Mooresville, N.C., and chair of the insurance subcommittee of the ACR’s Committee on Rheumatologic Care. “Most of my patients who use biologics do so either through copay cards from the pharmaceutical industry or through Medicare and a secondary [payer] covering their out-of-pocket costs for the infusible biologics. This is clearly saving the system money, which is important no doubt, but unless it’s significantly less expensive, it actually might not change the patient’s out-of pocket [cost] all that much.”

The patient assistance programs from biologics manufacturers that offer copay assistance, access hotlines, and administration benefits could be in jeopardy with the rise of biosimilars. Since the programs are bundled into the average wholesale price of the drug, the savings offered by the reduced wholesale price of biosimilars may squeeze them out, Dr. Krant said.

“There’s going to be a lot of hue and cry from the patients who cannot self-administer or have problems with compliance because of copays in the first place,” he predicted.

Another factor that could affect how much biosimilars such as Inflectra will be used is the amount of rebates or discounts that payers receive directly from the pharmaceutical manufacturers.

“We know for the Medicaid population what the average sales prices are, but for private payers, we don’t know if they’re giving 2%, 5%, 18%; we have no idea what the data are. This could affect how much market share Inflectra gets,” said Dr. Fahey, who is also president of the North Carolina Rheumatology Association.

It may be awhile before Inflectra is available on the U.S. market. In a statement following the approval of Inflectra, Remicade-maker Janssen said the “patents for Remicade remain valid and enforceable until September 2018. A commercial launch of Celltrion’s infliximab-dyyb in advance of this date would be an infringement of our patents, and we intend to defend our intellectual property rights.”

Janssen notes that its patient support program for Remicade “continues to offer a copay card for patients with commercial insurance that reduces the patient out-of-pocket cost to no more than $5 per infusion. Eligible uninsured and underinsured patients may be able to access Remicade through the Johnson & Johnson Patient Assistance Foundation.”

Pfizer, which owns the rights to marketing Inflectra in the United States, did not respond directly to a question about whether it would have a payment assistance program for Inflectra. “While we cannot comment on specific commercialization strategies at this time, we are working to bring these important therapies to market in the U.S. as quickly as possible,” said Rachel Hooper, Director of Public Affairs, West, for Pfizer.

It seems likely that once Inflectra does come to the market, new starts will account for many patients who will use the drug because of the lack of information available about whether there is, or is not, significant risk of immunogenicity with switching or loss of efficacy, Dr. Fahey said. “What is less certain is whether the payers will try to force us to move people from the Remicade brand to the infliximab biosimilar, and what the potential consequences of that is going to be.”

Dr. Krant, Dr. Fahey, and Mr. Marmaras had no relevant disclosures.

jevans@frontlinemedcom.com

Now that the Food and Drug Administration has approved Inflectra as the first biosimilar version of the anti–tumor necrosis factor-alpha agent Remicade, rheumatologists and patient advocacy groups are taking stock of how it may be used in practice, and what the future holds for biosimilar drugs, with so many questions still unanswered regarding price, substitution, and safety.

Joseph Riccio/Adirondack Health

Inflectra, approved in early April and given the generic name of infliximab-dyyb under the FDA’s nomenclature for biosimilar products, will have the same indications as Remicade. The agency extrapolated the clinical trial data that Inflectra’s South Korea–based manufacturer, Celltrion, submitted for rheumatoid arthritis and ankylosing spondylitis to all other indications for which Remicade is approved.

It’s currently unclear how the FDA will note which clinical data in Inflectra’s labeling come from Inflectra and which from Remicade, and the same concerns lie with future biosimilar approvals if their results are extrapolated to indications not tested to show biosimilarity in clinical trials.

Labeling questions

It’s concerning to rheumatologists and the patients who will be using them that biosimilars such as Inflectra are not subject to the same pivotal trial experience as the reference biologics on which they are based, according to Dr. Jonathan Krant, section chief of rheumatology for Adirondack Health Systems in Saranac Lake, N.Y., and medical director for CreakyJoints, a community of patients with arthritis and caregivers, and its larger parent nonprofit advocacy organization, the Global Healthy Living Foundation (GHLF).

While the unique regulatory requirements in the biosimilar approval pathway reduce development costs and could potentially make Inflectra’s average wholesale price 30% less than Remicade – as was the case when Inflectra was first on the market in Europe – it’s not known how reduced costs may affect the safety of biosimilars.

“It worries all of us that manufacturers may cut corners to manage the cost constraints imposed by managed care,” Dr. Krant said in an interview.

Given that U.S. rheumatologists don’t have experience with biosimilars, Dr. Krant is anticipating some push back. “I think some physicians are going to fight back and won’t want to prescribe them, even if mandated, because of concerns regarding patient safety,” he said.

In a written statement, Dr. Joan Von Feldt, president of the American College of Rheumatology, welcomed the potential benefits on access to care that cost-saving biosimilars may bring to the U.S. health care system, but also said that “the safety of our patients remains our highest priority. As such, we encourage the FDA to continue to apply distinct names for future biosimilars, and to maximize clarity in the labeling of biosimilars, specifically with respect to their interchangeable status and the origins (reference drug versus biosimilar) of clinical data upon which FDA approval is based.”

Inflectra met the FDA’s “very similar” criteria to be approved as a biosimilar by showing it has no clinically meaningful differences in terms of safety and effectiveness from Remicade, the agency said. According to FDA regulations, biosimilar products can have only minor differences in clinically inactive components and must have the same mechanism(s) of action (to the extent that it is known) and route(s) of administration, dosage form(s), and strength(s) as the reference product and can be approved only for the indication(s) and condition(s) of use that have been approved for the reference product.

However, it may not hold true that Inflectra will have the same efficacy and safety for all indications that Remicade had due to potential differences in the mechanism of action through which Remicade exerts its effect across indications, which in this case may apply to the indications for Crohn’s disease and ulcerative colitis.

Health Canada chose not to extrapolate the indications for Inflectra (known as Remsima in Canada) to Crohn’s disease and ulcerative colitis because of “observed differences in the level of afucosylation, Fc-gammaRIIIa receptor binding, and some in vitro antibody-dependent cell-mediated cytotoxicity (ADCC) assays” that could not rule out the possibility that Inflectra and Remicade differ in their ability to induce ADCC. Unlike the other indications for Remicade, Health Canada said “ADCC cannot be ruled out as a mechanism of action in the inflammatory bowel diseases. This position is supported by the observation that certolizumab pegol, another anti-TNF [anti–tumor necrosis factor] that lacks the ability to induce ADCC, displays only marginal efficacy in Crohn’s patients, compared with other anti-TNFs, namely infliximab.”

Other organizations suggest that extrapolation of indications is only appropriate when it is benefiting the patient to the greatest extent possible.

“GHLF is okay with extrapolation of indication unless the mechanism of action for the therapy is either scientifically or therapeutically outdated,” Stephen Marmaras, state and national advocacy manager for the GHLF, said in an interview. “Patients are okay with extrapolating data in order to expedite the approval process as long as you are extrapolating to best in class therapy for a particular indication. What [the GHLF is] saying is we want biosimilars to be an improvement on what we have, not the lowest common denominator. We shouldn’t be extrapolating indications data from products that aren’t considered to be the best product for that indication.”

“If we’re just judging on expediting the approval process for indications that are not considered to be really treated well by this particular drug, you have to always assume that the insurance company is going to go with the lowest common denominator,” he added. “What that could lead to, from a slippery-slope perspective, is the chipping away of the use of cutting-edge therapies.”

Substitution concerns

Inflectra was not approved as interchangeable with Remicade or other infliximab biosimilars. The FDA has yet to define the regulatory requirements for interchangeability that are necessary to meet the requirements of the Biologics Price Competition and Innovation Act of 2009. That Act states that an approved biosimilar “may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.”

A statement about implementation of the Act on the FDA website explains that for interchangeability, “a sponsor must demonstrate that the biosimilar product can be expected to produce the same clinical result as the reference product in any given patient and, for a biological product that is administered more than once, that the risk of alternating or switching between use of the biosimilar product and the reference product is not greater than the risk of maintaining the patient on the reference product.”

One of the biggest concerns that physicians have is that biosimilars will be substituted for the reference products without notification, Dr. Krant said. “State by state we’re looking at potential substitution rules which allow pharmacists to switch out these cheaper molecules for the reference product,” he said, and without timely notification, patients and rheumatologists won’t know whether it was the reference product or a biosimilar that was associated with an adverse event or loss of efficacy.

The ACR and patient advocacy organizations such as the GHLF are against forced switching of patients for nonmedical reasons. Patients’ and rheumatologists’ confidence in biosimilar safety will be key to their uptake and the overall expansion of access to biologics to more patients, Mr. Marmaras said.

Patient costs uncertain

Although rheumatologists hope that with biosimilars’ lower costs, access will expand, there is no guarantee it will do so by saving patients money.

“It’s a common misperception that a 30% decrease in the cost of a several thousand dollar-a-month drug is going to automatically open all the doors to access,” said Dr. Sean Fahey, a rheumatologist in Mooresville, N.C., and chair of the insurance subcommittee of the ACR’s Committee on Rheumatologic Care. “Most of my patients who use biologics do so either through copay cards from the pharmaceutical industry or through Medicare and a secondary [payer] covering their out-of-pocket costs for the infusible biologics. This is clearly saving the system money, which is important no doubt, but unless it’s significantly less expensive, it actually might not change the patient’s out-of pocket [cost] all that much.”

The patient assistance programs from biologics manufacturers that offer copay assistance, access hotlines, and administration benefits could be in jeopardy with the rise of biosimilars. Since the programs are bundled into the average wholesale price of the drug, the savings offered by the reduced wholesale price of biosimilars may squeeze them out, Dr. Krant said.

“There’s going to be a lot of hue and cry from the patients who cannot self-administer or have problems with compliance because of copays in the first place,” he predicted.

Another factor that could affect how much biosimilars such as Inflectra will be used is the amount of rebates or discounts that payers receive directly from the pharmaceutical manufacturers.

“We know for the Medicaid population what the average sales prices are, but for private payers, we don’t know if they’re giving 2%, 5%, 18%; we have no idea what the data are. This could affect how much market share Inflectra gets,” said Dr. Fahey, who is also president of the North Carolina Rheumatology Association.

It may be awhile before Inflectra is available on the U.S. market. In a statement following the approval of Inflectra, Remicade-maker Janssen said the “patents for Remicade remain valid and enforceable until September 2018. A commercial launch of Celltrion’s infliximab-dyyb in advance of this date would be an infringement of our patents, and we intend to defend our intellectual property rights.”

Janssen notes that its patient support program for Remicade “continues to offer a copay card for patients with commercial insurance that reduces the patient out-of-pocket cost to no more than $5 per infusion. Eligible uninsured and underinsured patients may be able to access Remicade through the Johnson & Johnson Patient Assistance Foundation.”

Pfizer, which owns the rights to marketing Inflectra in the United States, did not respond directly to a question about whether it would have a payment assistance program for Inflectra. “While we cannot comment on specific commercialization strategies at this time, we are working to bring these important therapies to market in the U.S. as quickly as possible,” said Rachel Hooper, Director of Public Affairs, West, for Pfizer.

It seems likely that once Inflectra does come to the market, new starts will account for many patients who will use the drug because of the lack of information available about whether there is, or is not, significant risk of immunogenicity with switching or loss of efficacy, Dr. Fahey said. “What is less certain is whether the payers will try to force us to move people from the Remicade brand to the infliximab biosimilar, and what the potential consequences of that is going to be.”

Dr. Krant, Dr. Fahey, and Mr. Marmaras had no relevant disclosures.

jevans@frontlinemedcom.com

Rosacea in women is linked with an increased risk for a wide variety of autoimmune disorders including type 1 diabetes, celiac disease, multiple sclerosis, and rheumatoid arthritis, according to a large population-based case-control study.

The finding expands the association of rosacea and autoimmune diseases beyond the previously reported associations with type 1 diabetes and celiac disease, reported Dr. Alexander Egeberg of Herlev and Gentofte Hospital, University of Copenhagen, and colleagues (J Am Acad Dermatol. 2016;74:667-72.)

“Remember that the absolute risk is still low; having rosacea does not guarantee that patients will develop other autoimmune diseases, and vice versa,” Dr. Egeberg said in an interview. “The links may provide insight into the pathogenesis of these diseases, and it will be interesting to see if systemic treatment of rosacea also affects the autoimmune diseases and the other way around.”

Using Danish registered health records, the researchers found 6,759 patients with rosacea, and matched them by age and sex to 33,795 control subjects. About two-thirds of the patients were women.

Compared with their matched controls, people with rosacea were at least twice as likely to have type 1 diabetes, celiac disease, and rheumatoid arthritis (odds ratio 2.6 for type 1 diabetes, 2.0 for celiac disease, and 2.1 for rheumatoid arthritis) and 1.65 times as likely to have multiple sclerosis. The differences, with the exception of rheumatoid arthritis, were statistically significant only in women.

The researchers said the broader association with autoimmune comorbidities is “intriguing” and suggests the genetic component of rosacea could be stronger than previously assumed with autoimmune inflammatory pathways contributing to the disease course. Because distinct rosacea subtypes (erythematotelangiectatic, papulopustular, phymatous, and ocular) could be associated with specific comorbidities, future association studies should attempt to stratify for clinical subtypes of rosacea, they noted.

Rosacea in women is linked with an increased risk for a wide variety of autoimmune disorders including type 1 diabetes, celiac disease, multiple sclerosis, and rheumatoid arthritis, according to a large population-based case-control study.

The finding expands the association of rosacea and autoimmune diseases beyond the previously reported associations with type 1 diabetes and celiac disease, reported Dr. Alexander Egeberg of Herlev and Gentofte Hospital, University of Copenhagen, and colleagues (J Am Acad Dermatol. 2016;74:667-72.)

“Remember that the absolute risk is still low; having rosacea does not guarantee that patients will develop other autoimmune diseases, and vice versa,” Dr. Egeberg said in an interview. “The links may provide insight into the pathogenesis of these diseases, and it will be interesting to see if systemic treatment of rosacea also affects the autoimmune diseases and the other way around.”

Using Danish registered health records, the researchers found 6,759 patients with rosacea, and matched them by age and sex to 33,795 control subjects. About two-thirds of the patients were women.

Compared with their matched controls, people with rosacea were at least twice as likely to have type 1 diabetes, celiac disease, and rheumatoid arthritis (odds ratio 2.6 for type 1 diabetes, 2.0 for celiac disease, and 2.1 for rheumatoid arthritis) and 1.65 times as likely to have multiple sclerosis. The differences, with the exception of rheumatoid arthritis, were statistically significant only in women.

The researchers said the broader association with autoimmune comorbidities is “intriguing” and suggests the genetic component of rosacea could be stronger than previously assumed with autoimmune inflammatory pathways contributing to the disease course. Because distinct rosacea subtypes (erythematotelangiectatic, papulopustular, phymatous, and ocular) could be associated with specific comorbidities, future association studies should attempt to stratify for clinical subtypes of rosacea, they noted.

Rosacea in women is linked with an increased risk for a wide variety of autoimmune disorders including type 1 diabetes, celiac disease, multiple sclerosis, and rheumatoid arthritis, according to a large population-based case-control study.

The finding expands the association of rosacea and autoimmune diseases beyond the previously reported associations with type 1 diabetes and celiac disease, reported Dr. Alexander Egeberg of Herlev and Gentofte Hospital, University of Copenhagen, and colleagues (J Am Acad Dermatol. 2016;74:667-72.)

“Remember that the absolute risk is still low; having rosacea does not guarantee that patients will develop other autoimmune diseases, and vice versa,” Dr. Egeberg said in an interview. “The links may provide insight into the pathogenesis of these diseases, and it will be interesting to see if systemic treatment of rosacea also affects the autoimmune diseases and the other way around.”

Using Danish registered health records, the researchers found 6,759 patients with rosacea, and matched them by age and sex to 33,795 control subjects. About two-thirds of the patients were women.

Compared with their matched controls, people with rosacea were at least twice as likely to have type 1 diabetes, celiac disease, and rheumatoid arthritis (odds ratio 2.6 for type 1 diabetes, 2.0 for celiac disease, and 2.1 for rheumatoid arthritis) and 1.65 times as likely to have multiple sclerosis. The differences, with the exception of rheumatoid arthritis, were statistically significant only in women.

The researchers said the broader association with autoimmune comorbidities is “intriguing” and suggests the genetic component of rosacea could be stronger than previously assumed with autoimmune inflammatory pathways contributing to the disease course. Because distinct rosacea subtypes (erythematotelangiectatic, papulopustular, phymatous, and ocular) could be associated with specific comorbidities, future association studies should attempt to stratify for clinical subtypes of rosacea, they noted.

A biosimilar version of the anti–tumor necrosis factor–alpha agent Remicade has been approved by the Food and Drug Administration, making it the first biosimilar drug approved by the agency for inflammatory diseases and just the second biosimilar it has approved.

The agency said in its April 5 announcement that the biosimilar drug, to be marketed as Inflectra, will have the same indications as Remicade: moderately to severely active Crohn’s disease in patients aged 6 years and older who have had an inadequate response to conventional therapy; moderately to severely active ulcerative colitis that has inadequately responded to conventional therapy; moderately to severely active rheumatoid arthritis in combination with methotrexate; active ankylosing spondylitis; active psoriatic arthritis; and chronic, severe plaque psoriasis.

Courtesy Wikimedia Commons/ FitzColinGerald/Creative Commons License

The drug, given the generic name of infliximab-dyyb under the agency’s nomenclature for biosimilar products, earned its approval as a biosimilar by showing it has no clinically meaningful differences in terms of safety and effectiveness from Remicade. According to FDA regulations, biosimilar products can have only minor differences in clinically inactive components and must have the same mechanism(s) of action (to the extent that it is known) and route(s) of administration, dosage form(s), and strength(s) as the reference product; and can be approved only for the indication(s) and condition(s) of use that have been approved for the reference product.

Inflectra’s approval is only as a biosimilar, not as an interchangeable product. The agency has yet to define the regulatory requirements for interchangeability that are necessary to meet the requirements of the Biologics Price Competition and Innovation Act of 2009. That Act states that an approved biosimilar “may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.” A statement about implementation of the Act on the FDA website explains that for interchangeability, “a sponsor must demonstrate that the biosimilar product can be expected to produce the same clinical result as the reference product in any given patient and, for a biological product that is administered more than once, that the risk of alternating or switching between use of the biosimilar product and the reference product is not greater than the risk of maintaining the patient on the reference product.”

Like Remicade, Inflectra will come with a boxed warning and a Medication Guide that describes important information about its uses and risks, which include serious infections (tuberculosis, bacterial sepsis, invasive fungal infections, and others), lymphoma and other malignancies, liver injury, blood problems, lupuslike syndrome, psoriasis, and in rare cases, nervous system disorders.

Inflectra is manufactured by Celltrion, based in South Korea, for Illinois-based Hospira. Inflectra’s label can be found here.

jevans@frontlinemedcom.com

A biosimilar version of the anti–tumor necrosis factor–alpha agent Remicade has been approved by the Food and Drug Administration, making it the first biosimilar drug approved by the agency for inflammatory diseases and just the second biosimilar it has approved.

The agency said in its April 5 announcement that the biosimilar drug, to be marketed as Inflectra, will have the same indications as Remicade: moderately to severely active Crohn’s disease in patients aged 6 years and older who have had an inadequate response to conventional therapy; moderately to severely active ulcerative colitis that has inadequately responded to conventional therapy; moderately to severely active rheumatoid arthritis in combination with methotrexate; active ankylosing spondylitis; active psoriatic arthritis; and chronic, severe plaque psoriasis.

Courtesy Wikimedia Commons/ FitzColinGerald/Creative Commons License

The drug, given the generic name of infliximab-dyyb under the agency’s nomenclature for biosimilar products, earned its approval as a biosimilar by showing it has no clinically meaningful differences in terms of safety and effectiveness from Remicade. According to FDA regulations, biosimilar products can have only minor differences in clinically inactive components and must have the same mechanism(s) of action (to the extent that it is known) and route(s) of administration, dosage form(s), and strength(s) as the reference product; and can be approved only for the indication(s) and condition(s) of use that have been approved for the reference product.

Inflectra’s approval is only as a biosimilar, not as an interchangeable product. The agency has yet to define the regulatory requirements for interchangeability that are necessary to meet the requirements of the Biologics Price Competition and Innovation Act of 2009. That Act states that an approved biosimilar “may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.” A statement about implementation of the Act on the FDA website explains that for interchangeability, “a sponsor must demonstrate that the biosimilar product can be expected to produce the same clinical result as the reference product in any given patient and, for a biological product that is administered more than once, that the risk of alternating or switching between use of the biosimilar product and the reference product is not greater than the risk of maintaining the patient on the reference product.”

Like Remicade, Inflectra will come with a boxed warning and a Medication Guide that describes important information about its uses and risks, which include serious infections (tuberculosis, bacterial sepsis, invasive fungal infections, and others), lymphoma and other malignancies, liver injury, blood problems, lupuslike syndrome, psoriasis, and in rare cases, nervous system disorders.

Inflectra is manufactured by Celltrion, based in South Korea, for Illinois-based Hospira. Inflectra’s label can be found here.

jevans@frontlinemedcom.com

A biosimilar version of the anti–tumor necrosis factor–alpha agent Remicade has been approved by the Food and Drug Administration, making it the first biosimilar drug approved by the agency for inflammatory diseases and just the second biosimilar it has approved.

The agency said in its April 5 announcement that the biosimilar drug, to be marketed as Inflectra, will have the same indications as Remicade: moderately to severely active Crohn’s disease in patients aged 6 years and older who have had an inadequate response to conventional therapy; moderately to severely active ulcerative colitis that has inadequately responded to conventional therapy; moderately to severely active rheumatoid arthritis in combination with methotrexate; active ankylosing spondylitis; active psoriatic arthritis; and chronic, severe plaque psoriasis.

Courtesy Wikimedia Commons/ FitzColinGerald/Creative Commons License

The drug, given the generic name of infliximab-dyyb under the agency’s nomenclature for biosimilar products, earned its approval as a biosimilar by showing it has no clinically meaningful differences in terms of safety and effectiveness from Remicade. According to FDA regulations, biosimilar products can have only minor differences in clinically inactive components and must have the same mechanism(s) of action (to the extent that it is known) and route(s) of administration, dosage form(s), and strength(s) as the reference product; and can be approved only for the indication(s) and condition(s) of use that have been approved for the reference product.

Inflectra’s approval is only as a biosimilar, not as an interchangeable product. The agency has yet to define the regulatory requirements for interchangeability that are necessary to meet the requirements of the Biologics Price Competition and Innovation Act of 2009. That Act states that an approved biosimilar “may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.” A statement about implementation of the Act on the FDA website explains that for interchangeability, “a sponsor must demonstrate that the biosimilar product can be expected to produce the same clinical result as the reference product in any given patient and, for a biological product that is administered more than once, that the risk of alternating or switching between use of the biosimilar product and the reference product is not greater than the risk of maintaining the patient on the reference product.”

Like Remicade, Inflectra will come with a boxed warning and a Medication Guide that describes important information about its uses and risks, which include serious infections (tuberculosis, bacterial sepsis, invasive fungal infections, and others), lymphoma and other malignancies, liver injury, blood problems, lupuslike syndrome, psoriasis, and in rare cases, nervous system disorders.

Inflectra is manufactured by Celltrion, based in South Korea, for Illinois-based Hospira. Inflectra’s label can be found here.

jevans@frontlinemedcom.com