Pharmacology ConsultPublication Exclusive

Biosimilars may expand drug access, reduce costs, but still much to learn

Cancer is the major indication for six of the 10 best-selling biological products.

Meanwhile, the cost of cancer biologics in the United States has doubled from 2006 to 2012, increasing about 10% to 15% per year. The annual cost for some biologics now exceeds $200,000.

Patent expiration on biologics provides pharmaceutical companies with an opportunity to develop biosimilar products. The hope is biosimilars in oncology may offer one way to control cancer drug expenditure while simultaneously expanding patient access to vital treatments.

Jai N. Patel, PharmD
Jai N. Patel

However, concerns related to biosimilars’ safety and efficacy profiles remain, and the establishment of a regulatory pathway that allows for their development has been followed by calls for intense postmarketing pharmacovigilance.

Licensure pathway

The Affordable Care Act created an abbreviated licensure pathway for biological products that are demonstrated to be “biosimilar” to or “interchangeable” with an FDA-licensed biological product.

A biological product is considered to be “biosimilar” if data demonstrate that the product is highly similar to an already-approved biological product — notwithstanding minor differences in clinically inactive components — and there are no clinically meaningful differences in terms of safety, purity and potency.

Although an abbreviated new drug application for small molecule generic compounds simplifies the requirement for proof of safety and efficacy through demonstration of bioequivalence, a biosimilar also must demonstrate safety and efficacy in one of the primary indications of the reference product.

Based on the totality of evidence, a biosimilar still can be approved for the reference products’ other indications; thus, it is critical to consider the mechanism of action, pharmacokinetics/biodistribution and safety differences in each indication for different patient populations.

To meet the additional standard of interchangeability, an applicant also must demonstrate that the biosimilar can be expected to produce the same clinical result as the reference product in any given patient, and that the risk in terms of safety or diminished efficacy of alternating between the use of the biosimilar and the reference product is not greater than the risk of using the reference product alone.

Interchangeable products may be automatically substituted for the reference product by a pharmacist without the intervention of the prescribing health care provider; however, policies regarding automatic drug substitution are governed by state laws, which can vary significantly. Further, institutional pharmacy and therapeutics committees may conduct their own analyses based on safety and efficacy data, as well as cost considerations, to develop their own internal guidelines.

In March, filgrastim-sndz (Zarxio, Sandoz) became the first biosimilar approved in the United States.

Filgrastim-sndz is a leukocyte growth factor used primarily to decrease the incidence of infection — manifested by febrile neutropenia — in patients with nonmyeloid malignancies who also receive myelosuppressive anticancer drugs. It is approved for the same five indications as its reference product, filgrastim (Neupogen, Amgen).

Of note, filgrastim-sndz is approved only as a biosimilar, not as an interchangeable product.

Effects on access, costs

CMS recently published the final rule for the 2016 Physician Fee Schedule, in which biosimilars will be paid under Medicare Part B the same way it pays for generic drugs.

CMS hopes that the payment policy will encourage greater competition and improve the quality, price and access to biologic medicines.

Although traditional generics are 80% to 90% cheaper than the brand, biosimilars are expected to be only 20% to 25% cheaper given the complexity of developing these compounds.

Wholesale acquisition costs for a 300-µg syringe are $275.66 for filgrastim-sndz vs. $324.30 for filgrastim. For a 480-µg syringe, the cost is $438.98 for the biosimilar and $516.40 for the reference product.

It is unlikely that biosimilars will have the same economic impact on drug costs compared to small molecule generic drugs. The relative cost differential between a biosimilar and its reference product, coupled with general lack of large comparative trials, may dampen clinicians’ enthusiasm to utilize biosimilars.

Regardless, early data across all non–oncology-specific biosimilars suggest an estimated cost savings potential of up to $44.2 billion over 10 years. Actual savings will depend on payment arrangements, biosimilar nomenclature, interchangeability, competition and overall acceptability by key stakeholders.

Naming convention

According to the FDA’s guidance on biosimilar nomenclature — which has received both criticism and praise — the naming convention will include a core proper name and a designated four-letter suffix devoid of any meaning.

For interchangeable products, the FDA is considering whether the suffix should be unique or the same as its reference product.

Importantly, use of a shared core name will indicate a relationship among products, whereas placement of the identifier as a suffix should result in the biological products with the same core name being grouped together in electronic databases. The goal is to improve pharmacovigilance and to help minimize inadvertent substitution of biological products that the FDA has not determined to be interchangeable.

The Federal Trade Commission suggests that using different nonproprietary names from their branded counterparts may hinder price competition and cause physicians to mistakenly believe the drugs have clinically meaningful differences. Economic models suggest that price competition is more intense when the products are considered close substitutes and less intense when goods are more differentiated.

Pharmacy organizations have stated that — although using the same nonproprietary core name allows for a more uniform way to identify the drugs — suffixes still will distinguish the names from each other, thus undermining the efficiency of competitive products sharing the same active ingredient name and leading to coding and system inefficiencies.

Weighing price competition vs. inadvertent product use and the most appropriate naming convention will continue to be a major debate. Until sufficient pharmacovigilance of biosimilars is available, a designated suffix to differentiate products is required. Although the suffix should not be promotional as the FDA suggests, a meaningful suffix for biosimilars that are not interchangeable would make it easier to differentiate the biosimilar and reference product and help promote competition.

Assigning a unique suffix to each license holder also would allow simple identification of the manufacturer, satisfying pharmacovigilance to report safety events and still allow for a safeguard against inadvertent substitution. Ideally, biosimilars determined to be interchangeable should not have to be differentiated from the reference product, which would facilitate clinician use and patient access to cost-saving products.

Safety concerns and other potential obstacles

A consensus in the community seems that clinicians are reluctant to use the biosimilar for all indications approved for the reference product but not formally evaluated in clinical studies given the high stakes of cancer therapy. However, conducting comparative trials for all indications would not only delay approval and add significant costs to development, but also deprive patients of potentially significant cost savings.

Robust pharmacovigilance to track and accurately attribute adverse events is critical for biosimilars after approval due to their complexity and sensitivity to changes in manufacturing processes that can affect safety and efficacy (eg, immunogenicity).

For example, biologics can undergo glycosylation, which can be a significant cause of batch variability through modulation of stability, immunogenicity and biological activity. This is critical for biologics where structure–function relationships depend on drug–receptor interaction, such as interferons, antitumor necrosis factor and many targeted oncologics.

Economic factors will continue to play a major role in the incorporation of biosimilars into clinical practice. Institutions and payers will need to evaluate potential cost savings in the context of patient-assistance programs, 340B pricing, out-of-pocket cost incurred by the patient, and institutional costs associated with education and technology systems to facilitate tracking.

Conclusion

The FDA recently accepted Sandoz’s submission for approval of a biosimilar version of pegfilgrastim (Neulasta, Amgen), and biosimilars for monoclonal antibodies such as rituximab (Rituxan; Genentech, Biogen Idec) and bevacizumab (Avastin, Genentech) are in development.

Biosimilar approval and use is likely to gain in the coming years and may influence drug development strategies by pharmaceutical companies. With approximately half the development timeline for a biosimilar vs. biologic at about one-tenth the cost, the pharmaceutical industry may see a larger shift to the biosimilar playing field, and it is critical that the FDA establishes strict guidelines and thresholds for demonstrating biosimilarity.

Guidance and position statements from the FDA, Federal Trade Commission, pharmacy organizations and established national cancer societies may help clinicians, payers and providers understand key data relating to biosimilars and inform decisions regarding their use and place in clinical practice.

Lastly, health care providers and patients will play a key role in determining how biosimilars are integrated into treatment pathways. The results from a National Comprehensive Cancer Network survey suggest that overall interest in using biosimilars was moderate (35%) or high (27%) among physicians, nurses, and pharmacists; however, one-quarter reported needing additional information about biosimilars to make their decisions about use.

Education on biosimilar drug development and the approval process will be vital to the translation of these agents in clinical practice, with the ultimate goal of increasing drug access and reducing costs for patients and health care systems.

References:

Aapro M, et al. Generics and Biosimilars Initiative Journal. 2013;doi:10.5639/gabij.2013.0202.023.

Blackwell K, et al. Ann Oncol. 2015;doi:10.1093/annonc/mdv281.

CMS. Medicare program: Revisions to payment policies under the physician fee schedule and other revisions to Part B for CY 2016. Available at: www.federalregister.gov/articles/2015/11/16/2015-28005/medicare-program-revisions-to-payment-policies-under-the-physician-fee-schedule-and-other-revisions. Accessed on Dec. 28, 2015.

FDA. Nonproprietary naming of biological products: Guidance for industry. Available at: www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm459987.pdf. Accessed on Dec. 28, 2015.

Federal Trade Commission. In response to a request for comments on its guidance for industry on the “nonproprietary naming of biological products; Draft guidance for industry; availability.” Available at www.ftc.gov/system/files/documents/advocacy_documents/ftc-staff-comment-submitted-food-drug-administration-response-fdas-request-comments-its-guidance/151028fdabiosimilar.pdf. Accessed on Dec. 28, 2015.

Goldberg P. What’s in a suffix? FDA’s dilemma: How to name biologics. The Cancer Letter. 2015. Available at: www.cancerletter.com/articles/20150911_1. Accessed on Dec. 28, 2015.

Rak Tkaczuk KH, et al. Semin Oncol. 2014;doi:10.1053/j.seminoncol.2014.03.008.

Rand Corporation. The cost savings potential of biosimilar drugs in the United States. Available at: www.rand.org/content/dam/rand/pubs/perspectives/PE100/PE127/RAND_PE127.pdf. Accessed on Dec. 28, 2015.

Sandoz. FDA advisory committee briefing document. Zarxio (filgrastim). Available at: www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/oncologicdrugsadvisorycommittee/UCM428782.pdf. Accessed on Dec. 28, 2015.

For more information:

Jai N. Patel, PharmD, is chief of pharmacology research and phase 1 trials at Levine Cancer Institute at Carolinas HealthCare System, as well as adjunct assistant professor at UNC Eshelman School of Pharmacy. He also is a HemOnc Today Editorial Board member. He can be reached at jai.patel@carolinashealthcare.org.

Disclosure: Patel reports no relevant financial disclosures.

Cancer is the major indication for six of the 10 best-selling biological products.

Meanwhile, the cost of cancer biologics in the United States has doubled from 2006 to 2012, increasing about 10% to 15% per year. The annual cost for some biologics now exceeds $200,000.

Patent expiration on biologics provides pharmaceutical companies with an opportunity to develop biosimilar products. The hope is biosimilars in oncology may offer one way to control cancer drug expenditure while simultaneously expanding patient access to vital treatments.

Jai N. Patel, PharmD
Jai N. Patel

However, concerns related to biosimilars’ safety and efficacy profiles remain, and the establishment of a regulatory pathway that allows for their development has been followed by calls for intense postmarketing pharmacovigilance.

Licensure pathway

The Affordable Care Act created an abbreviated licensure pathway for biological products that are demonstrated to be “biosimilar” to or “interchangeable” with an FDA-licensed biological product.

A biological product is considered to be “biosimilar” if data demonstrate that the product is highly similar to an already-approved biological product — notwithstanding minor differences in clinically inactive components — and there are no clinically meaningful differences in terms of safety, purity and potency.

Although an abbreviated new drug application for small molecule generic compounds simplifies the requirement for proof of safety and efficacy through demonstration of bioequivalence, a biosimilar also must demonstrate safety and efficacy in one of the primary indications of the reference product.

Based on the totality of evidence, a biosimilar still can be approved for the reference products’ other indications; thus, it is critical to consider the mechanism of action, pharmacokinetics/biodistribution and safety differences in each indication for different patient populations.

To meet the additional standard of interchangeability, an applicant also must demonstrate that the biosimilar can be expected to produce the same clinical result as the reference product in any given patient, and that the risk in terms of safety or diminished efficacy of alternating between the use of the biosimilar and the reference product is not greater than the risk of using the reference product alone.

Interchangeable products may be automatically substituted for the reference product by a pharmacist without the intervention of the prescribing health care provider; however, policies regarding automatic drug substitution are governed by state laws, which can vary significantly. Further, institutional pharmacy and therapeutics committees may conduct their own analyses based on safety and efficacy data, as well as cost considerations, to develop their own internal guidelines.

In March, filgrastim-sndz (Zarxio, Sandoz) became the first biosimilar approved in the United States.

Filgrastim-sndz is a leukocyte growth factor used primarily to decrease the incidence of infection — manifested by febrile neutropenia — in patients with nonmyeloid malignancies who also receive myelosuppressive anticancer drugs. It is approved for the same five indications as its reference product, filgrastim (Neupogen, Amgen).

Of note, filgrastim-sndz is approved only as a biosimilar, not as an interchangeable product.

Effects on access, costs

CMS recently published the final rule for the 2016 Physician Fee Schedule, in which biosimilars will be paid under Medicare Part B the same way it pays for generic drugs.

CMS hopes that the payment policy will encourage greater competition and improve the quality, price and access to biologic medicines.

Although traditional generics are 80% to 90% cheaper than the brand, biosimilars are expected to be only 20% to 25% cheaper given the complexity of developing these compounds.

Wholesale acquisition costs for a 300-µg syringe are $275.66 for filgrastim-sndz vs. $324.30 for filgrastim. For a 480-µg syringe, the cost is $438.98 for the biosimilar and $516.40 for the reference product.

It is unlikely that biosimilars will have the same economic impact on drug costs compared to small molecule generic drugs. The relative cost differential between a biosimilar and its reference product, coupled with general lack of large comparative trials, may dampen clinicians’ enthusiasm to utilize biosimilars.

PAGE BREAK

Regardless, early data across all non–oncology-specific biosimilars suggest an estimated cost savings potential of up to $44.2 billion over 10 years. Actual savings will depend on payment arrangements, biosimilar nomenclature, interchangeability, competition and overall acceptability by key stakeholders.

Naming convention

According to the FDA’s guidance on biosimilar nomenclature — which has received both criticism and praise — the naming convention will include a core proper name and a designated four-letter suffix devoid of any meaning.

For interchangeable products, the FDA is considering whether the suffix should be unique or the same as its reference product.

Importantly, use of a shared core name will indicate a relationship among products, whereas placement of the identifier as a suffix should result in the biological products with the same core name being grouped together in electronic databases. The goal is to improve pharmacovigilance and to help minimize inadvertent substitution of biological products that the FDA has not determined to be interchangeable.

The Federal Trade Commission suggests that using different nonproprietary names from their branded counterparts may hinder price competition and cause physicians to mistakenly believe the drugs have clinically meaningful differences. Economic models suggest that price competition is more intense when the products are considered close substitutes and less intense when goods are more differentiated.

Pharmacy organizations have stated that — although using the same nonproprietary core name allows for a more uniform way to identify the drugs — suffixes still will distinguish the names from each other, thus undermining the efficiency of competitive products sharing the same active ingredient name and leading to coding and system inefficiencies.

Weighing price competition vs. inadvertent product use and the most appropriate naming convention will continue to be a major debate. Until sufficient pharmacovigilance of biosimilars is available, a designated suffix to differentiate products is required. Although the suffix should not be promotional as the FDA suggests, a meaningful suffix for biosimilars that are not interchangeable would make it easier to differentiate the biosimilar and reference product and help promote competition.

Assigning a unique suffix to each license holder also would allow simple identification of the manufacturer, satisfying pharmacovigilance to report safety events and still allow for a safeguard against inadvertent substitution. Ideally, biosimilars determined to be interchangeable should not have to be differentiated from the reference product, which would facilitate clinician use and patient access to cost-saving products.

Safety concerns and other potential obstacles

A consensus in the community seems that clinicians are reluctant to use the biosimilar for all indications approved for the reference product but not formally evaluated in clinical studies given the high stakes of cancer therapy. However, conducting comparative trials for all indications would not only delay approval and add significant costs to development, but also deprive patients of potentially significant cost savings.

Robust pharmacovigilance to track and accurately attribute adverse events is critical for biosimilars after approval due to their complexity and sensitivity to changes in manufacturing processes that can affect safety and efficacy (eg, immunogenicity).

For example, biologics can undergo glycosylation, which can be a significant cause of batch variability through modulation of stability, immunogenicity and biological activity. This is critical for biologics where structure–function relationships depend on drug–receptor interaction, such as interferons, antitumor necrosis factor and many targeted oncologics.

Economic factors will continue to play a major role in the incorporation of biosimilars into clinical practice. Institutions and payers will need to evaluate potential cost savings in the context of patient-assistance programs, 340B pricing, out-of-pocket cost incurred by the patient, and institutional costs associated with education and technology systems to facilitate tracking.

Conclusion

The FDA recently accepted Sandoz’s submission for approval of a biosimilar version of pegfilgrastim (Neulasta, Amgen), and biosimilars for monoclonal antibodies such as rituximab (Rituxan; Genentech, Biogen Idec) and bevacizumab (Avastin, Genentech) are in development.

PAGE BREAK

Biosimilar approval and use is likely to gain in the coming years and may influence drug development strategies by pharmaceutical companies. With approximately half the development timeline for a biosimilar vs. biologic at about one-tenth the cost, the pharmaceutical industry may see a larger shift to the biosimilar playing field, and it is critical that the FDA establishes strict guidelines and thresholds for demonstrating biosimilarity.

Guidance and position statements from the FDA, Federal Trade Commission, pharmacy organizations and established national cancer societies may help clinicians, payers and providers understand key data relating to biosimilars and inform decisions regarding their use and place in clinical practice.

Lastly, health care providers and patients will play a key role in determining how biosimilars are integrated into treatment pathways. The results from a National Comprehensive Cancer Network survey suggest that overall interest in using biosimilars was moderate (35%) or high (27%) among physicians, nurses, and pharmacists; however, one-quarter reported needing additional information about biosimilars to make their decisions about use.

Education on biosimilar drug development and the approval process will be vital to the translation of these agents in clinical practice, with the ultimate goal of increasing drug access and reducing costs for patients and health care systems.

References:

Aapro M, et al. Generics and Biosimilars Initiative Journal. 2013;doi:10.5639/gabij.2013.0202.023.

Blackwell K, et al. Ann Oncol. 2015;doi:10.1093/annonc/mdv281.

CMS. Medicare program: Revisions to payment policies under the physician fee schedule and other revisions to Part B for CY 2016. Available at: www.federalregister.gov/articles/2015/11/16/2015-28005/medicare-program-revisions-to-payment-policies-under-the-physician-fee-schedule-and-other-revisions. Accessed on Dec. 28, 2015.

FDA. Nonproprietary naming of biological products: Guidance for industry. Available at: www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm459987.pdf. Accessed on Dec. 28, 2015.

Federal Trade Commission. In response to a request for comments on its guidance for industry on the “nonproprietary naming of biological products; Draft guidance for industry; availability.” Available at www.ftc.gov/system/files/documents/advocacy_documents/ftc-staff-comment-submitted-food-drug-administration-response-fdas-request-comments-its-guidance/151028fdabiosimilar.pdf. Accessed on Dec. 28, 2015.

Goldberg P. What’s in a suffix? FDA’s dilemma: How to name biologics. The Cancer Letter. 2015. Available at: www.cancerletter.com/articles/20150911_1. Accessed on Dec. 28, 2015.

Rak Tkaczuk KH, et al. Semin Oncol. 2014;doi:10.1053/j.seminoncol.2014.03.008.

Rand Corporation. The cost savings potential of biosimilar drugs in the United States. Available at: www.rand.org/content/dam/rand/pubs/perspectives/PE100/PE127/RAND_PE127.pdf. Accessed on Dec. 28, 2015.

Sandoz. FDA advisory committee briefing document. Zarxio (filgrastim). Available at: www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/oncologicdrugsadvisorycommittee/UCM428782.pdf. Accessed on Dec. 28, 2015.

For more information:

Jai N. Patel, PharmD, is chief of pharmacology research and phase 1 trials at Levine Cancer Institute at Carolinas HealthCare System, as well as adjunct assistant professor at UNC Eshelman School of Pharmacy. He also is a HemOnc Today Editorial Board member. He can be reached at jai.patel@carolinashealthcare.org.

Disclosure: Patel reports no relevant financial disclosures.