News Continued from page 260
FDA advisers recommend approval of biosimilar filgrastim
A
unanimous vote by members of FDA’s Oncologic Drugs Advisory Committee could pave the way for the marketing of the first FDA-approved biosimilar product in the United States. The January 7 vote signaled the advisers’ agreement that Sandoz’s EP2006— tentatively known as Zarxio—should be licensed as biosimilar to Amgen’s filgrastim reference product, Neupogen. The advisers agreed that Zarxio should be licensed for the five indications described in Neupogen’s current labeling. Janet Woodcock, director of FDA’s drugs division, called the January meeting “a very historic occasion.” “This is the first application under our new biosimilar pathway that’s been brought to an FDA advisory committee,” Woodcock said. But it won’t be the last. Woodcock said manufacturers are committed to bringing biosimilars to U.S. patients, and FDA expects to have “a number of meetings” to assess marketing applications for the products. Christopher Topoleski, ASHP’s director for federal regulatory affairs, said the
What’s in a name? FDA did not ask the advisers to discuss naming conventions for biosimilar products, although several public speakers at the January 7 meeting raised the topic. Some stakeholders favor unique nonproprietary names for the biologicals, unlike small-molecule generics, which have the same nonproprietary name as the reference product. Other stakeholders prefer that biosimilars not be given a nonproprietary name that differs from the reference product’s [see March 15, 2014, AJHP News]. ASHP’s Christopher Topoleski said ASHP is in the latter camp. “We do not support unique names, but we would support the same name with a suffix, if necessary,” he said. “It’s not necessarily so much about the name; it’s about being able to track the product appropriately.”
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organization is pleased with the outcome of the advisory meeting. “We have been supportive of the biosimilar pathway, we have been supportive of more choices in the market. We believe that this is a really good landmark,” Topoleski said. Biosimilars have been sold in the European Union since 2006. A total of 19 biosimilar products, including 8 versions of filgrastim, have active marketing authorization from the European Medicines Agency. FDA’s regulatory roadmap for licensing biosimilars was created through the Biologics Price Competition and Innovation Act of 2009. The act “created an abbreviated licensure pathway for biological products that are shown to be biosimilar to or interchangeable with an FDA-licensed reference product,” said Leah Christl, associate director for therapeutic biologics on FDA’s therapeutic biologics and biosimilars team. The terms biosimilar and interchangeable have distinct statutory meanings. Biosimilars must be highly similar to the reference product, with only minor differences in clinically inactive components. In addition, there must be no clinically meaningful differences in the safety, purity, and potency of a biosimilar and its reference product. Interchangeable products, in addition to meeting the biosimilarity criteria, “can be expected to produce the same clinical result as the reference product in any given patient,” Christl said. An applicant for an interchangeable product must further demonstrate that “the risk, in terms of safety or diminished efficacy, of alternating and switching between the use of the product and the reference product, is not greater than the risk of using the reference product without switching,” Christl said. By federal statute, an interchangeable product may be substituted for the refer-
Am J Health-Syst Pharm—Vol 72 Feb 15, 2015
ence product without the intervention of the healthcare provider who prescribed the reference product. Some advisers nevertheless questioned whether FDA will allow pharmacists or pharmacy benefits managers to substitute interchangeable biosimilars for their prescribed reference versions. “The concept of substitution is not something that the FDA oversees” but is instead regulated by state boards of pharmacy, Christl reminded the committee members. According to the National Conference of State Legislatures, eight states have passed biosimilar substitution laws. Most limit substitution to biosimilars that have been classified by FDA as interchangeable, and the laws typically include patient and prescriber consent and notification provisions that prevent automatic substitution [see May 15, 2013, AJHP News]. The Generic Pharmaceutical Association in December announced that it will advocate this year for state legislation that would specifically allow pharmacists to automatically substitute interchangeable biosimilars for prescribed reference products without notification requirements that would impose a “barrier” to substitution. Topoleski said ASHP “does not support any state legislation that would prohibit the substitution or that would hinder substitution” of interchangeagle biosimilars. He said an ASHP council may consider revising the organization’s official policy on substitution to reflect evolving language in state laws and an expected FDA guidance document on interchangeability. FDA has indicated that a biological product must first have demonstrated biosimilarity before the agency will consider a determination of interchangeability. But FDA acknowledged in a 2012 draft explanatory document for manufacturers that establishing interchangeability would be “difficult.” Mark McCamish, global head of development for Sandoz, noted that the Continued on page 264
News Continued from page 262
company has applied to market Zarxio as “a noninterchangeable biologic.” Even the lower standard of biosimilarity presented challenges to committee members, who normally evaluate comprehensive safety and efficacy data to determine whether to recommend that FDA approve a product. For biosimilars, safety and efficacy have already been established for the reference product. Safety and efficacy are presumed for the biosimilar if it closely resembles the reference product on the basis of limited analytical and clinical data. “We’re going to have to understand that we’re talking about a different kind of development program than the kind of development program that we would need for a new drug,” Woodcock reminded the committee members. The Sandoz filgrastim product that the committee reviewed has been licensed in the European Union since 2009, and the company presented findings from a wealth of analytical, human, and animal studies of the product, including postmarketing studies. The advisers’ sharpest questions about the Sandoz product pertained to a pharmacokinetics (PK) study comparing the timing of neutrophil level recovery during treatment with Neupogen or Zarxio. Neutrophil levels were essentially identical through day 10 in both groups but diverged through day 15 for the few study subjects who remained under evaluation because their neutrophil counts had not reached expected targets by day 10. FDA’s analysts concluded that the difference was not clinically meaningful. Filgrastim is a recombinant human granulocyte colony-stimulating factor that enhances neutrophil production. The FDA-approved indications in the labeling for Neupogen generally relate to the biological’s effects on neutropenia. After some debate, the advisers concurred with FDA’s overall assessment that the Sandoz product is biosimilar to Neupogen. “What really moved me was the very strong evidence shown by the sponsor
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for biosimilarity,” said Bernard F. Cole, professor of mathematics and statistics at the University of Vermont in Burlington. “Although there appears to be some possibility of small differences in some PK parameters, the clinical results demonstrate equivalence in the critically important [resolution] of severe neutropenia.” FDA did not announce when the agency will make a final decision about
the licensing application for Sandoz’s filgrastim product. The company stated that it currently markets biosimilar filgrasgim in more than 40 countries. —Kate Traynor DOI 10.2146/news150013
Study finds antimicrobial prescribing at discharge rife with errors
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harmacists on a hospital’s antimicrobial stewardship team say that medication errors at discharge that are related to antiinfective prescribing and use are surprisingly common and present an opportunity to improve transitional care. At The Brooklyn Hospital Center in New York, a one-month retrospective pilot study of patients discharged from the family medicine service found that medication errors occurred among 27% of patients leaving the hospital with a prescription for an antimicrobial. A six-month follow-up study, this time conducted during the discharge process, found an even higher rate—47%—said Christy Su, who led the research as part of a postgraduate year 2 pharmacy residency project in infectious diseases (ID). “With this project, we were able to highlight another high-risk population, which is those patients that are being discharged on antibiotics,” Su said in December. She presented the team’s findings last September at a poster session during the Interscience Conference on Antimicrobial Agents and Chemotherapy in Washington, D.C. The stewardship team found that 65 antiinfective drugs were prescribed for 45 patients during the six-month study. The team documented a total of 33 medica-
Am J Health-Syst Pharm—Vol 72 Feb 15, 2015
tion errors affecting 19 patients and made recommendations to the prescribers to rectify those errors. In all, the prescribers accepted 23 of these recommendations in 13 patients before discharge, thereby avoiding medication errors in 68% of the study population. The project used the National Coordinating Council for Medication Error Reporting and Prevention’s definition of a medication error: any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the healthcare professional, patient, or consumer. The errors were subcategorized as problems related to safety, efficacy, or regimen simplification. The team found that recommendations to resolve medication errors classified as safety-related were least likely to be accepted by the prescriber. Su said interventions to rectify such errors included the ordering of renal function testing, adjusting medication doses, or checking a patient’s leukocyte count to assess the response to antimicrobial therapy. In all, 6 of the 11 safety-related medication errors in this group pertained to the avoidance of unnecessary antimicrobials. “It pretty much means that a lot of physicians overtreat or may not necessarily follow recommendations to the
FDA advisers recommend approval of biosimilar filgrastim
A
unanimous vote by members of FDA’s Oncologic Drugs Advisory Committee could pave the way for the marketing of the first FDA-approved biosimilar product in the United States. The January 7 vote signaled the advisers’ agreement that Sandoz’s EP2006— tentatively known as Zarxio—should be licensed as biosimilar to Amgen’s filgrastim reference product, Neupogen. The advisers agreed that Zarxio should be licensed for the five indications described in Neupogen’s current labeling. Janet Woodcock, director of FDA’s drugs division, called the January meeting “a very historic occasion.” “This is the first application under our new biosimilar pathway that’s been brought to an FDA advisory committee,” Woodcock said. But it won’t be the last. Woodcock said manufacturers are committed to bringing biosimilars to U.S. patients, and FDA expects to have “a number of meetings” to assess marketing applications for the products. Christopher Topoleski, ASHP’s director for federal regulatory affairs, said the
What’s in a name? FDA did not ask the advisers to discuss naming conventions for biosimilar products, although several public speakers at the January 7 meeting raised the topic. Some stakeholders favor unique nonproprietary names for the biologicals, unlike small-molecule generics, which have the same nonproprietary name as the reference product. Other stakeholders prefer that biosimilars not be given a nonproprietary name that differs from the reference product’s [see March 15, 2014, AJHP News]. ASHP’s Christopher Topoleski said ASHP is in the latter camp. “We do not support unique names, but we would support the same name with a suffix, if necessary,” he said. “It’s not necessarily so much about the name; it’s about being able to track the product appropriately.”
262
organization is pleased with the outcome of the advisory meeting. “We have been supportive of the biosimilar pathway, we have been supportive of more choices in the market. We believe that this is a really good landmark,” Topoleski said. Biosimilars have been sold in the European Union since 2006. A total of 19 biosimilar products, including 8 versions of filgrastim, have active marketing authorization from the European Medicines Agency. FDA’s regulatory roadmap for licensing biosimilars was created through the Biologics Price Competition and Innovation Act of 2009. The act “created an abbreviated licensure pathway for biological products that are shown to be biosimilar to or interchangeable with an FDA-licensed reference product,” said Leah Christl, associate director for therapeutic biologics on FDA’s therapeutic biologics and biosimilars team. The terms biosimilar and interchangeable have distinct statutory meanings. Biosimilars must be highly similar to the reference product, with only minor differences in clinically inactive components. In addition, there must be no clinically meaningful differences in the safety, purity, and potency of a biosimilar and its reference product. Interchangeable products, in addition to meeting the biosimilarity criteria, “can be expected to produce the same clinical result as the reference product in any given patient,” Christl said. An applicant for an interchangeable product must further demonstrate that “the risk, in terms of safety or diminished efficacy, of alternating and switching between the use of the product and the reference product, is not greater than the risk of using the reference product without switching,” Christl said. By federal statute, an interchangeable product may be substituted for the refer-
Am J Health-Syst Pharm—Vol 72 Feb 15, 2015
ence product without the intervention of the healthcare provider who prescribed the reference product. Some advisers nevertheless questioned whether FDA will allow pharmacists or pharmacy benefits managers to substitute interchangeable biosimilars for their prescribed reference versions. “The concept of substitution is not something that the FDA oversees” but is instead regulated by state boards of pharmacy, Christl reminded the committee members. According to the National Conference of State Legislatures, eight states have passed biosimilar substitution laws. Most limit substitution to biosimilars that have been classified by FDA as interchangeable, and the laws typically include patient and prescriber consent and notification provisions that prevent automatic substitution [see May 15, 2013, AJHP News]. The Generic Pharmaceutical Association in December announced that it will advocate this year for state legislation that would specifically allow pharmacists to automatically substitute interchangeable biosimilars for prescribed reference products without notification requirements that would impose a “barrier” to substitution. Topoleski said ASHP “does not support any state legislation that would prohibit the substitution or that would hinder substitution” of interchangeagle biosimilars. He said an ASHP council may consider revising the organization’s official policy on substitution to reflect evolving language in state laws and an expected FDA guidance document on interchangeability. FDA has indicated that a biological product must first have demonstrated biosimilarity before the agency will consider a determination of interchangeability. But FDA acknowledged in a 2012 draft explanatory document for manufacturers that establishing interchangeability would be “difficult.” Mark McCamish, global head of development for Sandoz, noted that the Continued on page 264
News Continued from page 262
company has applied to market Zarxio as “a noninterchangeable biologic.” Even the lower standard of biosimilarity presented challenges to committee members, who normally evaluate comprehensive safety and efficacy data to determine whether to recommend that FDA approve a product. For biosimilars, safety and efficacy have already been established for the reference product. Safety and efficacy are presumed for the biosimilar if it closely resembles the reference product on the basis of limited analytical and clinical data. “We’re going to have to understand that we’re talking about a different kind of development program than the kind of development program that we would need for a new drug,” Woodcock reminded the committee members. The Sandoz filgrastim product that the committee reviewed has been licensed in the European Union since 2009, and the company presented findings from a wealth of analytical, human, and animal studies of the product, including postmarketing studies. The advisers’ sharpest questions about the Sandoz product pertained to a pharmacokinetics (PK) study comparing the timing of neutrophil level recovery during treatment with Neupogen or Zarxio. Neutrophil levels were essentially identical through day 10 in both groups but diverged through day 15 for the few study subjects who remained under evaluation because their neutrophil counts had not reached expected targets by day 10. FDA’s analysts concluded that the difference was not clinically meaningful. Filgrastim is a recombinant human granulocyte colony-stimulating factor that enhances neutrophil production. The FDA-approved indications in the labeling for Neupogen generally relate to the biological’s effects on neutropenia. After some debate, the advisers concurred with FDA’s overall assessment that the Sandoz product is biosimilar to Neupogen. “What really moved me was the very strong evidence shown by the sponsor
264
for biosimilarity,” said Bernard F. Cole, professor of mathematics and statistics at the University of Vermont in Burlington. “Although there appears to be some possibility of small differences in some PK parameters, the clinical results demonstrate equivalence in the critically important [resolution] of severe neutropenia.” FDA did not announce when the agency will make a final decision about
the licensing application for Sandoz’s filgrastim product. The company stated that it currently markets biosimilar filgrasgim in more than 40 countries. —Kate Traynor DOI 10.2146/news150013
Study finds antimicrobial prescribing at discharge rife with errors
P
harmacists on a hospital’s antimicrobial stewardship team say that medication errors at discharge that are related to antiinfective prescribing and use are surprisingly common and present an opportunity to improve transitional care. At The Brooklyn Hospital Center in New York, a one-month retrospective pilot study of patients discharged from the family medicine service found that medication errors occurred among 27% of patients leaving the hospital with a prescription for an antimicrobial. A six-month follow-up study, this time conducted during the discharge process, found an even higher rate—47%—said Christy Su, who led the research as part of a postgraduate year 2 pharmacy residency project in infectious diseases (ID). “With this project, we were able to highlight another high-risk population, which is those patients that are being discharged on antibiotics,” Su said in December. She presented the team’s findings last September at a poster session during the Interscience Conference on Antimicrobial Agents and Chemotherapy in Washington, D.C. The stewardship team found that 65 antiinfective drugs were prescribed for 45 patients during the six-month study. The team documented a total of 33 medica-
Am J Health-Syst Pharm—Vol 72 Feb 15, 2015
tion errors affecting 19 patients and made recommendations to the prescribers to rectify those errors. In all, the prescribers accepted 23 of these recommendations in 13 patients before discharge, thereby avoiding medication errors in 68% of the study population. The project used the National Coordinating Council for Medication Error Reporting and Prevention’s definition of a medication error: any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the healthcare professional, patient, or consumer. The errors were subcategorized as problems related to safety, efficacy, or regimen simplification. The team found that recommendations to resolve medication errors classified as safety-related were least likely to be accepted by the prescriber. Su said interventions to rectify such errors included the ordering of renal function testing, adjusting medication doses, or checking a patient’s leukocyte count to assess the response to antimicrobial therapy. In all, 6 of the 11 safety-related medication errors in this group pertained to the avoidance of unnecessary antimicrobials. “It pretty much means that a lot of physicians overtreat or may not necessarily follow recommendations to the
