Biosimilars and Follow-on Biologics

Pharmacists need to be experts on follow-on biologics (FOBs), including biosimilars, so they can provide education to health professionals about safe prescribing

and use, which ultimately affects patient care. Seamless interchangeability among biosimilars and FOBs may not be permissible under the law, or as appropriate, as it is with brand and generic chemically derived drugs.¹

Several biologic patents expire in the next few years, and other manufacturers will offer alternatives with reduced costs. Health care practitioners will encounter many questions as biosimilars and FOBs enter the market. Many prescribers may not fully understand the differences between a biosimilar and the reference licensed biologic product.

Experts anticipate a 20% to 30% price reduction on biosimilars compared with the reference biologic, a price drop that would be necessary to create a viable biosimilar market through increased patient access.^2-5 Payers anticipate biosimilars, and FOBs will be part of a strategy to reduce drug prices.

Depending on market dynamics and the competitive landscape, price reductions may come directly from the list price, rebates, or a combination of both. Some believe this represents a compelling business opportunity.² Meanwhile, patients and providers face a challenge understanding immunogenicity, interchangeability, and pharmacy substitutions related to biosimilars.

Differing biologic formulations may pose concerns for efficacy and safety due to changes in manufacturing processes, protocols, packaging, and cold storage delivery.^5,6 Keeping this in mind, pharmacists will be important contributors to the biosimilar and FOB information cascade shared with prescribers and patients as they make product decision choices.

FOLLOW-ON BIOLOGICS VS GENERICS

There are important differences between biologics and biosimilars compared with chemically derived small molecules and their generics. First, biologics are produced in living cells or organisms and may comprise any virus, therapeutic serum, toxin, antitoxin, or analogous product, including therapeutic proteins that are not chemically synthesized polypeptides.^7-9 These biologic products are typically used in the prevention, treatment, or cure of a disease. The first biologic product approved as a “drug” in 1982 was Humulin R (recombinant human insulin) from Eli Lilly and Company.10 Today, biopharmaceuticals include vaccines, blood products, allergenic extracts, human cells and tissues, gene therapies, and more.¹¹

Second, biologics differ from chemical drugs because they are larger, more complex molecules manufactured from living cells or organisms, susceptible to instability from external conditions, and associated with immunologic properties.⁷ A biosimilar is highly similar to an already approved licensed biologic molecule in which the manufacturing process details are proprietary information. This is the reason why manufacturers of a proposed biosimilar must develop an entirely new process that can lead to small differences in structure, stability, impurities, and excipients compared with the reference biologic.^1,2,12-14 Approval processes require that these changes have no clinically meaningful significance. Therefore, biosimilars are similar to the reference biologic, not identical, so they are not generically equivalent.^2,15

KEY TERMINOLOGY

Different terminology describes biosimilars and FOBs, and it is important for pharmacists to understand how the terms relate to federal and state regulations. In the United States, biosimilars are approved under Section 351 of the Public Health Service Act (PHS Act). Interchangeability is an FDA regulatory designation that the manufacturer requests, suggesting that a biosimilar draft a higher level of regulation than biosimilarity. However, specific FDA guidance on interchangeability has not yet been finalized. At least 35 states have passed legislation regarding the rules for biosimilar substitution (ncsl.org/research/health/state-laws-and-legislation-related-to-biologic-medications-and-substitution- of-biosimilars.aspx). Therefore, substitution occurs at the pharmacy and is regulated by state legislatures.

States may define the practice of substitution so that the pharmacist is able to substitute an FDA-licensed interchangeable biosimilar for a referenced biologic or vice versa without direct prescriber consult based on state-specific regulations.^1,2,14 Interchangeability refers to a decision by a regulatory authority, based on scientific data submitted by the manufacturer, that the biosimilar product is appropriate for substitution for the reference biological product under local laws and pharmacy practices.^2,9,16,17

Switching occurs when the prescriber chooses to change a patient’s therapy from a registered licensed biologic to a biosimilar product, or vice versa.⁹ Additional terms of importance include “not similar,” “similar,” “highly similar,” and “highly similar with fingerprint-like similarity.” These categories described by the FDA further quantify the degree of similarity between 2 products.⁸ In the United States, some follow-on biologics may be similar versions of already approved listed drugs upon which the new drug application (NDA) is filed under section 505(b)(2) of the Food, Drug, and Cosmetic Act. Biologics filed through the 505(b)(2) pathway are also obligated to meet safety and efficacy requirements as defined by the FDA.^16,18 Biosimilars and FOBs are not generics; therefore, they are not “bioequivalent” to the listed drug relied upon. For biologics, 2 products manufactured by different companies (without technology transfer) cannot be said to contain the identical active ingredient or to be bioequivalent.^2,7

REGULATORY CONSIDERATIONS

351(k) Pathway

Biosimilar regulations continue to evolve, but pharmacists should be familiar with some regulatory pathways currently in place. The 351(k) pathway is an abbreviated pathway for licensing of products shown to be biosimilar to an FDA-approved reference product.¹⁹ Zarxio (filgrastim-sndz), the first approved biosimilar in the United States, went through this pathway.^19,20 The totality-of-evidence approach is used to demonstrate biosimilarity and requires structural and functional characterization, nonclinical evaluation, human pharmacokinetics (PK) and pharmacodynamics (PD) data, clinical immunogenicity data, and comparative clinical study data. Clinically meaningful differences could include a difference in the expected range of safety, purity, or potency of the proposed product and the reference product. In contrast, slight differences in rates of occurrence of certain adverse events (AEs) between the 2 products ordinarily would not be considered a clinically meaningful difference.¹⁵

505(b)(2) Pathway

Alternatively, the 505(b)(2) pathway is used in cases where the listed drug relied upon made its application under section 505. These submissions require an NDA and have been used by insulins, calcitonin, and human growth hormone.¹⁸ In 2010, the Affordable Care Act (ACA) required all biologics and biosimilars to file a biologics license application (BLA) and previously approved products to be subject to a transition period until 2020. Between now and 2020, similar biologics will either be filed under the 351(k) pathway or the 505(b)(2) pathway pending transition to a biologics or biosimilar designation on March 23, 2020.²¹ Basaglar (insulin glargine injection) was recently approved and filed through the 505(b)(2) pathway.⁷

THE PURPLE BOOK

Since the introduction of biologic licensing under the PHS Act, the FDA introduced a new resource, The Purple Book. This resource provides lists of licensed biological products with reference product exclusivity and biosimilarity or interchangeability evaluations. Besides providing key dates and lists of reference products, a portion of The Purple Book assigns 1 of 2 grades to biologics, biosimilar (B) or interchangeable (I) to the reference product. Interchangeable would require additional data for approval compared with a biosimilar designation.^22,23 This resource is meant to closely model The Orange Book, which describes the therapeutic equivalence and safety between 2 related drug products.²² The Purple Book will add all new biologic products approved through the 351(k) pathway, with the first entry being Zarxio (filgrastim-sndz).^20,23 Biopharmaceuticals submitted for approval through the 505(b)(2) pathway are not yet reflected in The Purple Book. However, as of March 23, 2020, these products will be transitioned to obtain their BLA previously mentioned under 351 and, hence, they will be defined in the resource.²¹ Meanwhile, pharmacists will have to pay close attention to regulations around biologic products.

NAMING AND LABELING

Within the 351(k) pathway, there are still many questions regarding biosimilar naming and labeling in the United States. The FDA has asked for input on draft guidances on biosimilar naming and labeling.²⁴ On August 28, 2015, the FDA announced the availability of a draft guidance, entitled “Nonproprietary Naming of Biological Products.” The draft guidance describes current thinking on the need for biologic products licensed under the PHS Act to bear a nonproprietary name that includes an FDA-designated suffix.²⁴ This guidance has been applied to Zarxio (filgrastim-sndz), the first biosimilar approved in March 2015.²³ Inflectra (infliximab-dyyb) is the second example of an approved biosimilar in the United States.²⁵

An approach to streamline naming could be to decide that the nonproprietary names are similar, but not the same. Utilizing the same nonproprietary name could imply the product is identical and approved for all of the same indications, whereas the biosimilar could be approved only for a subset of the reference biologic’s indications.^1,4,5,26 Therefore, each product would hold its own brand name to further help to prevent confusion on which product should be dispensed.

Prescribers and pharmacists need to prepare for the adoption of biosimilars in practice to support their patients appropriately. As previously mentioned, biosimilars are not interchangeable unless specifically requested by the manufacturer and approved by the FDA under the higher regulatory standard of interchangeability.

If a regulatory authority determines the biosimilar to be interchangeable, this would allow for direct substitution. Pharmacists will then have to know which products can be directly substituted and those that would require prescriber consultation. Additionally, pharmacists must follow individual state regulations. Prescribers will want accurate documentation of which biosimilar their patient is utilizing.²⁷ Although complicated, this provides an opportunity for pharmacists to be a valued source of education to prescribing health care professionals. Pharmacists can be the local biosimilar experts and implement sound pharmacovigilance practices, as well as have the knowledge of niche therapeutic options and potential cost advantages for patients, prescribers, and health care systems.

Basaglar (insulin glargine injection) was recently approved through a 505(b)(2)) submission with no differentiation in the non-proprietary name associated with Lantus (Sanofi; Paris, France). Biologics manufactured by different companies (without technology transfer) are not identical despite having the same primary amino acid structure or being bioequivalent.^2,7 The 2 molecules are not considered bioequivalent, resulting in 2 products that are not automatically substitutable unless listed as such in The Orange Book. Prescribers maintain the option to transition patients from one product to the other as a matter of choice, but should do so when prescribing by brand name to enable management of potential clinical and safety issues that may occur. Somatropin, a growth hormone, marketed under several brand names, has the same nonproprietary name resulting in similar challenges.²

If biosimilars and FOBs are not prescribed by their brand name, pharmacists and prescribers should be aware of the potential confusion that may be generated by electronic medical records, e-prescribing, prescription dispensing practices, AE reporting, and patient discussions. When a prescription is written for the nonproprietary name, pharmacists should verify with the prescriber of the intended brand. To further complicate matters, Merck and Mylan are anticipated to seek approval of their versions of insulin glargine sometime in the near future.

IMMUNOLOGIC CONSIDERATIONS

There are a number of factors that can influence the development of an immune response from a biologic or biosimilar, and they can be product-, patient-, or treatment-related.²⁸ The body has the ability to detect foreign proteins and produce (neutralizing) antibodies. Therefore, the immunologic profile of a biosimilar or an FOB should be more important than cost considerations when determining their place in therapy.

Payers may desire interchangeable biologic products analogous to AB-rated bioequivalent generics, but product complexity complicates this circumstance. Small changes in the manufacturing process or product excipients may impact the PD and PK, efficacy, structure, stability, impurities, immunogenicity, and AEs associated with the biotherapeutic.^7,12 One must remember that biologics are inherently immunogenic. An example of this was Coagulation Factor VIII. This biotherapeutic clearly showed a link between the manufacturing process and the product profile. A degradation product of factor VIII led to increased immunogenicity.²⁹

Despite issues pertaining to complexity and risk, biosimilar or FOB agents can safely be produced using different manufacturing processes and protocols. Health care professionals facilitating patient care should be properly educated on the background of biotechnological manufacturing and how these processes can differ between manufacturers.

BIOSIMILARS AND FOLLOW-ON BIOLOGICS IN PRACTICE SITES

Pharmacists need to prepare for the introduction of biosimilars and FOBs for use in both the institutional and outpatient settings. Starting with hospital formularies, the adoption of these products will have different challenges to overcome compared with chemical drugs. This will continue into the outpatient setting, where payer formularies and product availability may differ from the prescribing institution. The more complex adoption into a health-system formulary may require clarity of past manufacturing issues, supply chain availability, patient monitoring, and increased provider and patient education. The institutional setting may need to invest resources into evaluating and monitoring the use of the reference product over that of a single, or even multiple, FOB products.

As the medication expert, pharmacists have the opportunity to offer guidance in all stages and areas of biologic use. This is especially true as collaborative practice agreements and pharmacist credentialing and certifications continue to develop. Prescribers will need to appreciate how better access to biotherapeutics may impact patient adherence to treatment regimens and begin taking steps now to address these potential issues.^12,19 Patient adherence may also be affected by device ease of use, patient support programs, and product affordability.¹² Patient perceptions of biosimilar and FOB therapeutics will be a barrier if the patient perceives these alternatives as inferior to the reference product. If they are providing meaningful patient education, pharmacists must be knowledgeable about a biotherapeutic’s efficacy, immunogenicity, and AEs that may be uncommon compared with the listed drug relied upon.¹² Postmarketing surveillance also is critical to confirm the regulatory decision of biosimilarity, and it is important for the pharmacist to report AEs in conjunction with the prescriber’s responsibility.

PATIENT COST IMPACT

As previously stated, experts anticipate that a 20% to 30% price reduction from the reference biologic would create a viable biosimilar and FOB market through increased patient access. This has the potential to impact what a patient pays out-of-pocket (OOP). Reductions in list price will impact patients in benefit design, such as high-deductible plans and co-insurance, where OOP costs are determined by a percentage of a medication’s list price instead of a fixed co-pay. For example, a patient who is in a high-deductible plan will pay 100% of the list price for each prescription until they reach their OOP benefit maximum, which can be as high as $6500 for a single plan and $13,000 for a family plan, as mandated by the ACA. For a patient with coinsurance, their OOP may be 10% or 20% of the list price. Therefore, the introduction of biosimilars and FOBs may impact the patient’s cost, whereby if the biosimilar list price or the FOB price is lower than the reference product, the patient’s OOP costs will be lower.

In benefit designs where patient OOP is a fixed co-pay, price concessions from manufacturers may not impact a patient’s OOP expenses. Considering all the factors discussed, pharmacists have the opportunity to proactively direct patients and prescribers to the lower-priced biologic.

DISCUSSION

Biopharmaceuticals offer management options and solutions for a vast number of conditions and diseases. Ultimately, they help improve patient lives. Increasing availability of biosimilars and FOBs should increase prescriber choice of, and patient access to, biotherapeutics. Improving prescriber confidence in biosimilars and FOBs will help to overcome negative patient perceptions that may mirror what generics faced when initially compared with brand thereapeutics.¹² Prescriber education on immunogenicity profiles and clarity on product names and documentation will demand interprofessional communication in the process. Payers may dictate access to different products, and it will be up to the health care team to be knowledgeable of available options. Products may not be interchangeable based on approval status, so the pharmacist has a responsibility to ensure the accuracy and appropriateness of their patient’s regimen. If pharmacists understand the regulations and biosimilar/FOB marketplace, they will be able to offer pertinent recommendations to prescribers and meaningful consultation to patients.

Michael McShea, RPh, graduated from the University of South Carolina, College of Pharmacy with his BS in Pharmacy. His experiences span marketing, account management, hospital and retail pharmacy, long term care, and diabetes and hospital account sales. He joined Eli Lilly & Co. in 1989 and is currently in Channel Strategy focusing on the Endocrine platform. His responsibilities include identifying and understanding the environment and capabilities in various traditional Trade and emerging Specialty Channels, including distribution and pharmacy, as well as the evolving capabilities of the organizations and vendor partners actively participating in those channels. He is also currently a member of the advisory panel for Specialty Pharmacy Times and Pharmacy Times. He places importance on connecting patients with product within the pharmacy channel to ultimately enhance patient experiences and care in support of improved patient outcomes.

Mark Borns, PharmD, graduated from The Ohio State University in 2016 with his Doctorate of Pharmacy and also has a BS in Pharmaceutical Sciences. He is currently a Visiting Scientist Fellow at Eli Lilly and Company in Indianapolis, Indiana, focused in Global Pricing, Reimbursement and Access. He is devoted to the value of biopharmaceutical innovation and the importance of patient access to medications.

Roy Daniel Pollom, MD, received his MD from Indiana University School of Medicine in 1977 and completed his residency in Internal Medicine in 1980. For the last 15 years, Dr. Pollom worked at Diabetes, Internal Medicine & Endocrinology, a multi-physician group practice at Community Health Network in Indianapolis, Indiana, specializing in the care of children and adults with diabetes. Additionally, he served as Medical Director at the Indiana Heart Hospital providing leadership in the management of diabetes and hyperglycemia in hospitalized patients with cardiovascular disease. His work with cardiovascular and peripheral vascular surgeons helped to establish evidence-based glycemic guidelines to improved outcomes in surgical patients. He joined Eli Lilly & Co. as a Sr. Medical Advisor in 2013 after more than 30 years of treating people with diabetes in private practice. His areas of expertise include type 1 and type 2 diabetes management, diabetes in pregnancy, continuous insulin pump and glucose sensor technology, stress hyperglycemia management during hospitalization and electronic glucose data analysis.

References

• T.McGuire,Armada 2016,Opportunities, Challenges and Clinical Adoption of Biosimilars Updates for Specialty Pharmacy
• Andes S, Bockello M, Larson C, et al. Trends in Biosimilars Report. Amgen. 2015.
• Creating Viable Biosimilars Market. Drug Store News. 17 March 2014 http://www.drugstorenews.com/article/creating-viable-biosimilars-market. Accessed: 13 Aug 2015.
• Lucio S. Biosimilars: Overview and Outlook. Presented at: ASHP Midyear Clinical Meeting and Exposition; December 2014; Anahein, CA. Accessed: 3 August 2015.
• Lucio S. Biosimilars: Implications for health system pharmacists; AJHP Accessed: 25 Mar 2016
• DeVries JH, Gough SC, Kiljanski J, Heinemann L. Biosimilar insulins: a European perspective. Diabetes Obes Metab. 2015 May; 17(5):445-451. doi: 10.1111/dom.12410.
• Kroon L, Li E, Segal A, Stevenson J. Biosimilar Insulins: Issues and Considerations Before Clinical Use. Presented at: ASHP Midyear Clinical Meeting and Exposition; December 2014; Anaheim, CA. Accessed: 3 Aug 2015.
• US Food and Drug Administration. Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product. 2014. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM397017.pdf. Accessed: 18 Aug 2015.
• US Food and Drug Administration. Information for Consumers (Biosimilars). 2015. http://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/therapeuticbiologicapplications/biosimilars/ucm241718.htm. Accessed: 18 Aug 2015.
• Celebrating a Milestone: FDA's Approval of First Genetically-Engineered Product. http://www.fda.gov/AboutFDA/WhatWeDo/History/ProductRegulation/SelectionsFromFDLIUpdateSeriesonFDAHistory/ucm081964.htm. April 4 2009. Accessed: 18 August 2015.
• FDA Basics - What is a biological product? http://www.fda.gov/AboutFDA/Transparency/-Basics/ucm194516.htm. Accessed: 18 Aug 2015.
• Edelman S, Polonsky WH, Parkin CG. Biosimilar insulins are coming: what they are, what you need to know. Curr Med Res Opin. 2014; 30(11):2217-2222.
• Owens DR, Landgraf W, Schmidt A, Bretzel RG, Kuhlmann MK. The emergence of biosimilar insulin preparations--a cause for concern? Diabetes Technol Ther. 2012 Nov; 14(11):989-996. doi: 10.1089/dia.2012.0105.
• Lutz R. Biosimilar Substitution A Primer for Pharmacists. Pharmacy Times. 2015 Jul 16.
• US Food and Drug Administration. Guidance for industry: Scientific considerations in demonstrating biosimilarity to a reference product. 2012. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm291128.pdf. Accessed: 18 Aug 2014
• US Food and Drug Administration. Information on Biosimilars http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/default.htm
• BioPharma Reporter 11.20.2015. New Jersey permits pharmacy-level substitution
• The Food and Drug Law Institute, Monograph series, The 505(b)(2) New Drug Application Process: The Essential Primer; Volume 1, Number 6; June 2010
• Koutnik-Fotopoulos E. Impact of Biosimilars on Stakeholders. First Report Managed Care. May 2015. http://www.firstreportnow.com/articles/impact-biosimilars-stakeholders. Accessed: 13 Aug 2015.
• FDA approves first biosimilar Zarxio (filgrastim-sndz) from Sandoz. http://www.biosimilarnews.com/fda-approves-first-biosimilar-zarxio-filgrastim-sndz-from-sandoz. Accessed: 18 Aug 2015.
• Sherman R. Biosimilar Biological Products. U.S. Food and Drug Administration. http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UCM292463.pdf. Accessed: 15 Feb 2012.
• Biosimilars. Purple Book. Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations. Accessed: 30 Jun 2016.
• Gaffney A. Zarxio, First Biosimilar Approved in the US, Added to FDA’s New ‘Purple Book.’ Regulatory Affairs Professionals Society. http://www.raps.org/Regulatory-Focus/News/2015/04/16/21984/Zarxio-First-Biosimilar-Approved-in-the-US-Added-to-FDAs-New-Purple-Book/. 16 April 2015.
• Non Proproprietaty Naming of Biological Product; Draft Guidance for Industry; Availability. A notice by the Food and Drug Administration on 08/28/2015. https://www.federalregister.gov/articles/2015/08/28/2015-21383/nonproprietary-naming-of-biological-products-draft-guidance-for-industry-availability
• Press Announcements _ FDA approves Inflectra, a biosimilar to Remicade
• Li E. Provider Considerations on Biosimilar Adoption and Usage. WorldCongress February, 2015
• Dolinar R. Biosimilars Ahead, Proceed with Caution. Alliance for Safe Biologic Medicines. BIOtechNOW. 2012 May 5.
• Arraztio A. Immunogenicity in biotherapeutics and biosimilars. Being bio-reactive. 8 June 2014. http://being-bioreactive.com/2014/08/06/immunogenicity-in-biotherapeutics-and-biosimilars/. Accessed: 25 Aug 2015.
• Josić D, Buchacher A, Kannicht C, et al. Degradation products of factor VIII which can lead to increased immunogenicity. Vox Sang. 1999; 77 Suppl 1:90-99.