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Introduction

Within the last 2 decades, innovative biologic medicines have formed the basis for a number of standards of therapeutic care for many diseases, including cancer and autoimmune diseases.¹ In 2014, 4 of 9 approved cancer drugs were biologics and by the middle of 2015, 4 more were approved. However, the therapeutic success of these products has been accompanied by high cost. The average cost of biologics for the treatment of oncologic disease doubled within the last decade. Furthermore, although 4% of the United States (U.S.) patient population use biologic drugs, it represents approximately 25% of overall drug expenditures.¹ Many of these biologic products are reaching patent expiration, which will allow for the potential introduction of more biosimilar products of the reference biologic product (branded biologic) to the market. With the inherent complexities associated with the manufacturing, handling, and use of these products, pharmacists must be knowledgeable and be ready to play a pivotal role in safe usage. This activity is a review of biosimilars and their potential impact on pharmacy practice.

The Nature of Biologics and Biosimilars

Biologic products are derived from living cell organisms using biologic manufacturing processes. Unlike small molecular nonbiologic medications, biologic products have large complex protein structures that are not easily characterized and are immunogenic.² The U.S. Food and Drug Administration (FDA) defines a biosimilar product as a biological product that is highly similar to an already FDA-approved biological product, regardless of minor differences in the clinical inactive components, and without meaningful clinical differences from the reference product. The active component of the biosimilar product is similar to that of the biologic reference medicine and it is generally used at the same dose to treat the same disease. The synonymous names for biosimilars in the literature include similar biologic products, follow-up biologics, subsequent entry biologics, second entry biologics, biogenerics, multisource products, and off-patent products.^3-5

Biosimilars Are Not Generics

Generic drugs are copies of brand name small-molecule drugs with the same dosage form, strength, quality, safety profile, route of administration, and indication for use. Generic products have the same active ingredient as the brand name small molecule, with a quantifiable number of contaminants. A biosimilar product is neither a generic nor an original product and should not be managed as such therapeutically, commercially, or from a health care policy viewpoint.^6,7 Biosimilar is a regulatory designation that denotes that evidence-based studies demonstrate the high similarity of a biosimilar product to the reference standard. Biosimilars are high quality biologic agents that have been demonstrated to be similar to the original reference product, but not identical, and do not guarantee therapeutic equivalency.⁸ Biologics are derived from living cells consisting of large, highly complex molecular entities that may be difficult to fully characterize. The inherent variability of the biologic system and the manufacturing process produces a biologic product with variable properties (microheterogeneity), even among different batches of the same product. Because of unavoidable differences in the manufacturing processes of a biosimilar and the reference product, the biosimilars and the reference product may not be entirely identical; however, the amino acid sequence is expected to be the same and only small differences in the pattern of the molecule may be acceptable. ⁹ The European and U.S. regulatory agencies, the European Medicines Agency (EMA) and the FDA, created the framework to ensure the highest standards, quality, and integrity for the development and use of biosimilars.

Biologic and Biosimilar Development

Numerous production steps are involved in the manufacturing of biologic products. These production steps include modifying the selected gene of interest, inserting the gene in a specified cell line or host for the expressed purpose of replicating the cell line and increasing protein expression, harvesting the protein products from the cell line, and purification of the selected protein.¹⁰ There are complexities and difficulties associated with all aspects of production during the manufacturing process. These complexities and difficulties may impact the quality of the produced products, including complex and large molecules with complex 3-dimensional structures, use of cell systems for production, and variation in the biologic products as the result of changes during protein production.¹⁰ These production difficulties often translate into a profound variation in both intra- and interindividual responses and complications with the use of biologic agents.

Biologic and biosimilar products are FDA approved and licensed under the Public Health Services Act (PHSA), while small-molecular drugs are FDA approved and licensed under the Federal Food, Drug, and Cosmetic Act (FDCA).^11,12 A Biologic License Application (BLA) is processed through section 351(a) of the PHSA. The Biologics Price Competition and Innovation Act of 2009 (BCPI Act) (part of the Patient Protection and Affordable Care Act of 2010 [PPACA]) amended the PHSA to provide the pathway for approving biologic products. The exclusivity period for the reference product essentially ensures that a 351(k) application may not be submitted until 4 years after the first licensure of the reference product and the FDA may not approve a 351(k) application until 12 years after the licensure of the reference product.¹³

Therapeutic Categories of Biosimilars Development

Since the introduction of biologic products, their use has continuously increased over the last several decades and is expected to represent 50% of the top 20 selling drugs by 2016.¹⁴ As the patents for these expensive branded biologic products expire, the pressure for cheaper biosimilars for these reference products will increase. The key therapeutic categories of biosimilars development in the U.S. include proteins (erythropoietin), growth factors (filgrastim) , and monoclonal antibodies (rituximab), to name a few.¹⁵

Erythropoietin (EPO) is a 165-amino acid glycoprotein with a molecular weight of 30 kDa.¹⁶ Erythropoietin is produced mainly in the human kidney; but, erythropoietin produced with recombinant DNA technology is used clinically to treat anemia in patients with chronic renal failure, as well as cancer patients. It is also used to reduce the need for blood transfusion in adults with mild anemia or before major surgery for those who are expected to have complications. EPO is the leading class of biologics in use in terms of sales and market share.

Filgrastim is a recombinant version of human granulocyte colony-stimulating factor (G-CSF) used clinically to treat patients with neutropenia caused by chemotherapy, HIV, or severe, repeated infections.¹⁷ Its activity is the same as that of endogenous human G-CSF, but filgrastim is produced in Escherichia coli and, thus, is not glycosylated and has an added N-terminal methionine. A biosimilar form of filgrastim is logical because of the availability of E coli, the large market share for the reference drug ($1.2 billion in 2014), and patent expirations are due.¹⁸

Monoclonal antibodies (mAb) are large glycoprotein molecules composed of 4 polypeptide heavy and light chains, with an approximate molecular weight of 150 kDa. The complexity of the mAb biosimilar compared with the referenced biologic product makes any attempts to establish similarity between antibodies in both products during clinical trials very challenging, even when careful consideration is given to the production processes. Adding to this challenge are the various patents protecting all production processes. The increased complexity and less understood mechanisms of action of most mAb antibodies will also lead to more requirements for clinical studies.¹⁹ Several oncology biosimilar products, including alemtuzumab, bevacizumab, panitumumab, ritiximab, and trastuzumab, are currently in preclinical or clinical development phases. The EMA has issued a draft document discussing the immunogenicity assessment requirements for monoclonal antibodies, highlighting the critical value of the immunogenicity data generated from clinical studies.²⁰

Biosimilar Filgrastim

Filgrastim is a human G-CSF with activity on hematopoietic cells. G-CSF binds to specific cell surface receptors and regulates neutrophil production, progenitor proliferation, and differentiation, producing multi-lineage effects on neutrophil granulocytes.^21,22 Filgrastim expressly promotes proliferation and maturation of neutrophil granulocytes. It also affects phagocytic activity, cellular metabolism, and antibody-dependent killing. ²²

Unlike small-molecule generics, biosimilars require extensive nonclinical and clinical comparability studies. Comparability studies were required for the approval of filgrastim-sndz, the first approved biosimilar in the U.S. The studies were conducted using the reference filgrastim product. Comparability was assessed regarding the single indication for which Neupogen is approved, which is the reduction of chemotherapy-induced neutropenia (CIN). Efficacy was assessed in a comparative study involving patients with breast cancer who are at high risk of CIN. Supportive studies provided safety data from patients with CIN and concomitant lung cancer and non-Hodgkin lymphoma. Comparable efficacy was established on the basis of pharmacokinetic and pharmacodynamic studies. Safety was established in a noncomparative study involving patients with breast cancer who were at high risk for CIN.

The clinical use of biosimilar filgrastim in the U.S. is similar to that of the branded product. Filgrastim-sndz was approved for febrile neutropenia in the treatment of non-myeloid and acute-myeloid malignancy, severe neutropenic disorders, and radiation injury of bone marrow, as well as being used as an aid in the delivery of chemotherapy to maintain dose intensity, to support dose-dense chemotherapy, peripheral blood progenitor cells (PBPC) in both patients with cancer and healthy donors, to support engraftment and neutrophil recovery after stem-cell transplantation, for the treatment of severe chronic neutropenia and to maintain neutrophil counts or reverse neutropenia in patients infected with human immunodeficiency virus.²² Filgrastim-sndz is indicated for adults and children to shorten the duration of neutropenia and reduce the incidence of febrile neutropenia following the receipt of cytotoxic chemotherapy.²²

Biosimilars Efficacy and Safety Concerns

Many concerns have been raised about the efficacy and safety of biosimilar products. These concerns are related to pharmaceutical quality, safety of use, and their interchangeability with the branded reference product. Indeed, the potential for a low quality, substandard product exists because there are several major steps involved in the manufacturing of biosimilar products. These production steps include modifying the selected gene of interest, inserting the gene in a specified cell line or host for the expressed purpose of replicating the cell line and increasing protein expression, harvesting the protein products from the cell line, and purification of the selected protein.¹⁰ There are complexities and difficulties associated with all aspects of the production stages in the manufacturing process. These complexities and difficulties may impact the quality of the biologic.¹⁰ Production difficulties often translate into a profound variation in both intra- and interindividual responses and complications with the use of biologic agents. Thus, there are concerns about these similar but not identical medications, their interchangeability and indication extrapolation, especially if the biosimilar is used for indications and or by populations for which there are no clinical data to represent major drawbacks for their usage.^23,24

Furthermore, concerns have been raised about safety data provided during the approval process that have been deemed insufficient, especially data about immunogenicity.^25,26 The potential for immunogenicity from the use of biosimilar products increases with changes in the amino acid sequence of the biosimilar when compared with the branded reference biologic agent. There are 3 different types of immune reactions, each having varying consequences. These reactions include the formation of antibodies that can neutralize the biosimilar agent, rendering it therapeutically ineffective. Secondly, the immune reaction may have no perceivable clinical reaction. Thirdly, and rarely, the immune reaction can lead to a life-threatening response. The immunogenicity of biologic agents may be unpredictable and unexpected. Finally, the need for strict postmarketing surveillance is evident and there are concerns that the current naming and labeling of biosimilars and the manufacturer-based reporting of adverse events may be inadequate and detrimental.

The Regulatory Environment: What to Expect

The Biologics Price Competition and Innovation Act of 2009 (BCPI Act) was enacted as a part of the Patient Protection and Affordable Care Act of 2010.²⁷ The BCPI Act amended the PHSA to create an abbreviated pathway for the approval of biologic products demonstrated to be biosimilar to, or interchangeable with, an FDA-licensed branded reference biologic product. The BCPI Act is similar to the abbreviated new drug application (ANDA) process established through the 1984 Hatch-Waxman amendment to the FDCA that created generic drug program approvals for small molecular drugs.²⁸ The intent of the law was to lower the cost of biologics and give patients access to crucial biologic therapies that they need and otherwise may not be able to afford because of high cost. The BCPI Act allows for the submission of a BLA for a biosimilar or interchangeable biologic to a branded reference biologic product. It requires that the biosimilar application sponsoring organization submit evidence that demonstrates that the biologic product is biosimilar to the branded reference biologic product, utilizes the same mechanism of action for the proposed indications of use, and uses the same route of administration, dosage form, and strength.

Impact of Biosimilars on Pharmacy Practice

The emergence of biosimilars has revealed several issues for the pharmacist to consider in practice. The major issues that will influence pharmacy practice include product selection, cost, supply, labeling, interchangeability, substitution, and indication extrapolation, state laws, as well as pharmacy personnel and patient education and pharmacovigilance.²⁹

Issues that will impact the pharmacist's ability to select a product for dispensing would be the following: how and when a pharmacist should select an approved biosimilar instead of the brand name reference biologic product and to what extent a pharmacist will have the authority to switch among biosimilars in the same class. For small-molecule therapies, pharmacists have generally selected generic alternatives because they are considered to be identical and therapeutically equivalent and, therefore, interchangeable, with few exceptions, and state laws have provided the authority for such substitutions. Since biosimilars are not identical to the branded reference biologic product, the concept of interchangeability has been defined by the FDA.

The BCPI Act allowed the FDA to approve biosimilars and established the following 2 distinct standards: biosimilarity and interchangeability. The 2012 FDA draft guidance clarified the data sets that are required to demonstrate biosimilarity. Drug candidates require unique sets of analytical and nonclinical data, as well as clinical pharmacology and immunogenicity studies to demonstrate biosimilarity, and may require additional clinical studies prior to approval if deemed necessary.¹⁰ An FDA-approved biosimilar product with a designation of interchangeability with the brand name reference biologic product must provide evidence of the same clinical result after use by any given patient and that it poses no additional risks for switching between the biosimilar and brand name reference biologic product.²⁷ Only products that the FDA designate as interchangeable will be allowed as substitution for the reference biologic. Furthermore, because interchangeability designations are currently a latter consideration in the approval process, the clinical data currently required as part of the biosimilar review process limit the number and range of biosimilars that have an interchangeability designation at the present, as well as potentially in the near future.³⁰ Comparable to the Orange Book for small-molecule generics, the FDA Purple Book is an important and useful compendia listing of all FDA-approved biological products. It also contains information regarding whether a biosimilar is an interchangeable product.³¹

FDA approval of a biosimilar may include using some, or all, of the labeled indications from the brand name reference biologic product, which will be determined by the data submitted. It is important to note that biosimilars may not automatically receive FDA approval for all the indications of the brand name reference biologic product and the indication extrapolation for a nonapproved indication requires demonstrated scientific data for justification and to prove that the 2 products can be safely substituted for one another without causing adverse health outcomes, such as a pathological immune response, after switching. Indication extrapolation may provide the means for the appropriate use of a biosimilar product that optimizes efficacy, safety, cost, and access. Data that may be used to justify indication extrapolation include physicochemical and clinical factors of the brand name reference biologic product, such as the mechanism of action, specific receptors for each indication, differences in safety and immunogenicity for different patient populations, as well as data from biosimilar products, is imperative. A possible framework for indication extrapolation consideration is to assess factors pertaining to the patient population, disease state, and end points, in combination with biosimilar data, to determine if indication extrapolation is not possible or if extrapolation is possible for some indications or all indications. The drawbacks of indication extrapolation for clinicians include potential risks, the uncertainty that the benefits outweigh the risks, and the uncertainty of payers' coverage for therapy.³²

States are beginning to regulate the nature of biosimilar substitutions, including documentation of substitutions and patient and prescriber communications.³³ Eighteen states, as of November 2015, including California, Colorado, Delaware, Georgia, Massachusetts, New Jersey, Virginia, Illinois, Indiana, Idaho, Florida, Louisiana, Tennessee, Texas, Utah, North Dakota, and Oregon, Washington, have enacted laws with conditions under which a pharmacist may substitute only FDA-designated interchangeable biosimilar biologic products for a prescribed brand name reference biologic product (readers are encouraged to visit www.ncsl.org for updates). The prescriber has the right to request that the specific product prescribed be dispensed. The pharmacist must notify the patient about the substitution at the time of dispensing; record the information in an interoperable electronic health record system for prescriber access, or inform the prescriber after the fact; record specified information on the label and dispensing record; and maintain a 3-year record, consistent with current law. All states are expected to enact similar laws in the future.

Additional issues that will impact biosimilar product selection include naming, cost, supply considerations, packaging, and storage. Currently, the most controversial issue is the naming strategy, which has thus far produced many proposals without a consensus.^34-36 The import benefits of a biosimilar naming strategy can be described as follows: identify its connection to the reference product (therapeutic category, dosing); differentiate products one from another (support for pharmacovigilance and proper attribution of outcomes or adverse drug events [ADEs]); avoid sound-alike and look-alike names (error prevention), and aid product tracing (counterfeit prevention). The current naming proposals include the following: 1) using totally different names (preferred by the reference biologic manufacturer); 2) using same United State Adopted Name (USAN) as the reference biologic; 3) using a unique suffix attached to the reference product USAN (may create issues with computer codes as the result of truncation); and 4) using a unique prefix, attached to the reference biologic (i.e., supported by the Institute for Safe Medication Practices [ISMP] and the Hematology/Oncology Pharmacy Association [HOPA]). The FDA guidance document recommends the use of names that include generic name of the reference biologic product followed by a suffix to indicate the particular biosimilar origin or manufacturer. The drawback to this naming strategy is that it will generate multiple names for same biosimilar products from several manufacturers, which may lead to errors with substitution, prescribing, compounding, and administration, as well as negatively impacting substitution, reimbursement, and postmarketing surveillance.

The pharmacist is critical in terms of appropriately educating other health care providers and patients about the use of biosimilars. Pharmacists should be aware of the manufacturing process, properties of biosimilars, and substitution and interchangeability of biosimilars, as well as state laws governing the substitution and notification requirements and pharmacovigilance programs. Pharmacists play important role in educating patients about all relevant issues regarding the safe use of these products.

Biosimilar pharmacovigilance programs are essential to identifying, characterizing, and minimizing the risks associated with the use of biosimilars. There are multiple contributing risk factors associated with the use of biosimilars. These risks are associated with the manufacturing process, naming of the approved biologics, and associated errors that may result when the name is incorporated into the medical record and computerized drug codes.

Pharmacovigilance programs for biosimilar products are necessary for monitoring postmarketing surveillance. At a minimum, the pharmacovigilance program goal is to safeguard patient safety by detecting rare events associated with products and provide a mechanism to document and report issues. All health care providers have a duty to minimize the risks to patients from the use of biosimilar products. Thus, health care provider participation in a pharmacovigilance program is a professional responsibility. Effective communication among all health care providers is necessary to ensure the success of any pharmacovigilance program. Pharmacovigilance programs include the FDA Adverse Event Reporting System (FAERS) through the MedWatch program, Risk Evaluation and Mitigation Strategies (REMS), and Risk Management Programs to reduce medication errors. The MedWatch program allows both health care providers and consumers to report serious adverse drug reactions and issues related to the use of drugs and medical devises to the FDA.³⁷ In addition, manufacturers are also required to submit reports of adverse event reports to the FDA.

Drawback of Biosimilars Pharmacovigilance

Adverse event reports are collected by manufacturers from a variety of sources, based on currently accepted surveillance practices. This process relies on the voluntary participation of the health care community, which is not always consistent and often results in underreporting. Further, the quality of reports varies and the medication suspected of causing the adverse event is not always fully identified.^29,36 Tracing adverse events associated with biologics will be challenging because the event may not manifest immediately; so, reporting may occur weeks or months later and most likely after the product packaging has been discarded. Consequently, adverse event reporting may depend on the patient's memory or the medical record.^37,38 Finally, inconsistencies associated with labeling and the identification of biosimilars may increase medication errors and limit accurate tracing of reported adverse events.

The Horizon for Biosimilars in the United States

By 2020 the estimated cost of biologics used in the U.S. will be about $253 billion.¹ This will particularly significant for the medical specialties that use biologics most frequently, such as oncology and rheumatology. The introduction of biosimilars has the potential to produce substantial cost reductions and savings. Current estimates indicate that biosimilars will provide meaningful savings overall. Many biologic reference products are approaching patent expiration in the coming years. This will inherently create opportunities for the expansion and introduction of biosimilar products into the U.S. markets. The future pipeline for biosimilars, especially in cancer therapy, may include biosimilars for erythropoietin alfa, pegfilgrastim, adalimumab, bevacizumab, and trastuzumab agents, whose patents are expiring (Table 1).

Table 1. Examples of Leading U.S. Biologics Products Patent Expiration Dates

Products	Indication	Patent Expiration Date
Neulasta (Pegfigrastim)	Neutropenia	10/2015
Epogen (Erythropoietin alpha)	Anemia	5/2015
Herceptin (Trastuzumab)	Cancer	5/2019
Gleevec (Imatinib)	Cancer	7/2015
Avastin (Bevacizumab)	Cancer	2/2018
Humira (Adalimumab)	Arthritis	12/2016

Reimbursements for biosimilars will be a major consideration for both patients and payers. U.S. payers are preparing strategies to evaluate and determine coverage based on a number of factors, such as pricing, potential for interchangeability, switching, and the number and quality of competitors in the market, because of the expected growth in the U.S. biosimilar market by 2020.¹ Biosimilars will most likely not be treated like the small-molecule generics of the originator biologics; reports suggest that payers may be reimbursing, generally, at a lower rate.¹ Tier assignment of a branded reference biologic product and its biosimilars will impact the use of biosimilars, the relative market share of the branded reference biologic product to its biosimilars, and the market share of plan-favored biosimilars over excluded or disfavored biosimilars. A major question to resolve is how payers will assign biosimilars to formulary tiers. Also some therapeutic segments have more significance than others when it comes to benefit design and contracting. Thus, it is likely that payers will focus on some categories before others. Another complexity is that payers may contract with a manufacturer across a therapeutic segment; so decisions made for one segment could impact competition overall. Finally, payer benefit designs, coverage policies, and prescriber bundling will evolve, impacting the commercial success of existing and newly approved biosimilars.¹

Conclusion

The market share for biologics therapeutic agents will continue to grow into the foreseeable future. Pharmacists have the professional obligation to be educated about the manufacturing process, the safety and efficacy profiles and the federal and state laws governing the use of these products. The pharmacist's role will be pivotal in the selection and appropriate use of these therapeutic agents.

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