Shopping Cart

INTRODUCTION

Biologic drugs account for less than 1% of all prescriptions dispensed in the United States (U.S.), but they account for an estimated 28% of all prescription spending.¹ Patents are expiring for a number of blockbuster biologic drugs and the development of more affordable biosimilar drugs is of growing interest in the U.S.: given the high costs of biological drug products to patients and the health care system, the possibility for less expensive biologic agents is exciting. However, the development and regulation of biosimilar agents are considerably more complex than for small-molecule generic drugs. Before discussing specific developmental issues related to biosimilar products, a review of key terms and definitions associated with biological agents is necessary.

Key Terms and Definitions Related to Biological Products

Biological drug products, or biologics, (e.g., vaccines, blood and blood components, and allergenic products) may consist of proteins, sugars, nucleic acids, or cells/tissues; the purpose of these drug products is to prevent, treat, or cure a disease in humans. “Biologics” refers to an overarching category of drugs that includes 3 subcategories of products: originators, biosimilars, and interchangeables.^2-4

Reference biologics are also known as originators. The term “originator” encompasses any original, innovator biologic drug. It is against these originator products that future, related biologics are evaluated and compared. A biosimilar is a biologic agent that is highly similar to a respective originator product. A biosimilar should not have any clinically meaningful differences in purity, potency, or safety when compared to its originator. A biosimilar must have the same mechanism of action, route of administration, dosage form, and strength as its originator. Only minor differences in inactive ingredients are permitted. Biosimilars, by definition, are not considered generics. The term “generic” is reserved for small-molecule (chemical) drugs.^2-4

Interchangeables are biologics that meet additional requirements beyond what is required for biosimilars and, as such, they may be substituted for an originator without approval from the prescriber. An interchangeable should produce the same clinical result as its originator in any patient, and no difference in efficacy or safety should be apparent when alternating therapy between an interchangeable and its originator.^2-4

REGULATIONS ASSOCIATED WITH THE APPROVAL OF BIOSIMILAR PRODUCTS

Small-molecule drugs are approved under the Food, Drug, and Cosmetic Act (FD&C Act): the New Drug Application (NDA) for new drugs is defined in section 505(b) and the Abbreviated New Drug Application (ANDA) for generics is defined in section 505(j). Biological drug products are regulated and approved under the Public Health Service Act (PHS Act): section 351(a) outlines the Biologics License Application for new biologics and section 351(k) outlines the Biosimilar Biologics License Application for biosimilars. The biosimilar approval pathway was created as an amendment to the PHS Act by the Biologics Price Competition and Innovation Act when the Patient Protection and Affordable Care Act (PPACA) was passed in 2010.^3,5

For a new biologic to be approved under section 351(a) of the PHS Act, the manufacturer must complete a full evaluation of the drug’s efficacy and safety. For biosimilars to be approved under section 351(k), an abbreviated evaluation is required to provide evidence of similar efficacy and safety to that of the originator biologic; the approval process requires enough evidence to support that there are no clinically meaningful differences between the originator and the biosimilar. Both biological drug approval pathways require clinical trials.

The approval processes established for small-molecule drugs is considerably different than that for biological drug products. For a new small-molecule drug to be approved under the FD&C Act section 505(b) NDA pathway, a full evaluation of the drug’s efficacy and safety must be completed. For a generic version to be approved under the section 505(j) ANDA pathway, bioequivalence data, alone, is required. As such, no clinical trial beyond a bioequivalence study is required for the approval of a generic small-molecule drug (Table 1).⁵ It is important to note that some biologics are currently regulated under the FD&C Act for historical reasons (e.g., insulin products were developed and used decades before the biologics approval pathways were established), but all biologics will be regulated under the PHS Act by the year 2020.^2,6

Table 1. Comparison of Regulatory Pathways for Small-molecule Drugs and Biological Drug Products5
	Small-molecule drugs		Biological drugs
	Innovator	Generic	Originator		Biosimilar and interchangeable
Application type	New Drug Application	Abbreviated New Drug Application	Biologics License Application		Biosimilar Biologics License Application
Regulatory pathway	505(b) of the FD&C Act	505(j) of the FD&C Act	351(a) of the PHS Act		351(k) of the PHS Act
Data required	Efficacy and safety data	Bioequivalence data	Efficacy and safety data		Abbreviated comparability data; additional data required for interchangeable products
Abbreviations: FD&C Act = Food, Drug, and Cosmetic Act; PHS Act = Public Health Service Act.

STANDARDS FOR THE DEVELOPMENT OF BIOSIMILAR PRODUCTS

The development of biosimilars is based on a stepwise approach to demonstrate the totality of evidence: the results of each step influence the requirements for the next step in the process.⁷ The totality of evidence data package includes physicochemical characterization (structure), biological characterization (function), preclinical studies (animal data), clinical studies (human pharmacokinetics/pharmacodynamics [PK/PD], efficacy, and safety), and postmarketing pharmacovigilance. This stepwise comparison to the originator is based more heavily on preclinical data than on clinical studies (Figure 1).^7,8

Figure 1. Stepwise Approach to Demonstrating Biosimilarity7

The U.S. Food and Drug Administration (FDA) does not have a standard list of requirements for all biosimilar products; instead, each product is evaluated on an individual basis. The set of required studies will be different for and specific to each biosimilar candidate, depending on the level of uncertainty that remains following the completion of each “step.” Manufacturers are expected to tailor subsequent steps on the basis of any residual uncertainty from previous steps in order to resolve concerns regarding the comparability of the biosimilar with its originator product.^7,9 For example, if the biosimilar is highly comparable to the originator in terms of structure and function, then the FDA may only require targeted clinical studies to confirm biosimilarity since a high level of confidence already exists with the product. In contrast, if the biosimilar produces poor comparable data in terms of structure and function, then the FDA may require additional comparative clinical studies to assess PK/PD, efficacy, and safety parameters.³ The following provides a general summary of the steps associated with the biosimilar development process:

1. The foundation of evidence for biosimilar development is analytical data presenting how similar the biosimilar is to the originator product in terms of structure and function.⁷ On the basis of the results of the structure and function analyses, the biosimilar is categorized as not similar, similar, highly similar, or highly similar with fingerprint-like similarity. Products classified as highly similar or highly similar with fingerprint-like similarity meet the biosimilar standard, which allows the manufacturer to continue to the next step of the biosimilarity investigation.⁸
2. Animal studies must include toxicity studies. They may also include PK/PD and immunogenicity studies.⁷
3. PK/PD study results are reviewed to evaluate how similar, or different, the exposure-response profiles are between a biosimilar and its originator.⁹
4. Biologics have the potential to produce anti-drug antibodies, some of which may be neutralizing, anti-drug antibodies (i.e., antibodies that interfere with the drug’s ability to bind and/or elicit a targeted response). These anti-drug antibodies may also cause immune responses that may affect PK parameters and negatively impact the efficacy and safety of the biological drug product. Results from structure and function analyses and animal studies do not provide reliable data on the potential for immunogenicity in humans. Head-to-head comparative immunogenicity trials compare the levels of anti-drug antibodies and neutralizing anti-drug antibodies produced from exposure to the biosimilar to levels produced from exposure to the originator. These studies are ultimately performed to determine if there are differences in the incidence and/or severity of immune-related adverse events between a biosimilar and its originator.⁷
5. If residual uncertainty about biosimilarity remains following the first 4 steps (structure and function analyses, animal studies, PK/PD studies, and immunogenicity studies), then clinical trials will be necessary to address that uncertainty. However, the results from the analytical and preclinical studies may provide sufficient evidence to support a finding that there are no clinically meaningful differences between the biosimilar and the originator, rendering a comparative clinical trial unnecessary.^7,8 The main purposes of clinical trials, if deemed necessary, are to confirm that the biosimilar and the originator are highly similar and to resolve any remaining uncertainties about the biosimilarity. A clinical trial resulting in one product being superior or inferior compared to another would fail to meet the standards of biosimilarity.⁷ Numerous factors influence the type and extent of clinical study data necessary to verify biosimilarity, including:⁷
   • Complexity of the originator
   • Degree of structural and functional characterization of the biosimilar product
   • Comparative results of pre-clinical studies
   • Level of correlation between differences in structure, function, animal data, and PK/PD and differences observed in clinical outcomes
   • Knowledge of originator’s safety profile, clinical biomarkers, and clinical endpoints
   • Extent of clinical experience with the biosimilar
6. Finally, postmarketing surveillance, or pharmacovigilance, of biosimilars is recommended to ensure that the continued use of a biological product is effective and safe. It requires larger study populations than those used in the biosimilar development process to observe both rare adverse events and adverse events associated with long-term use. Thus, ongoing collection of postmarketing data concerning the effectiveness and safety of the biosimilar product is important to complete the biosimilar development process.⁷

BIOLOGICS AND BIOSIMILARS VERSUS SMALL-MOLECULE DRUGS AND GENERICS

The reason why biosimilars are not considered “generics” is because exact copies of biologics cannot be manufactured. Biological drug products are larger and more complex than small-molecule drugs, mainly due to the greater complexity associated with manufacturing biologics. To manufacture a biological drug product, a target gene is spliced into a vector (e.g., plasmid) that is subsequently inserted into living host cells (e.g., yeast, bacteria). If the host machinery produces the desired biological product, the cells are cultured and expanded to produce the biologic in mass quantities before it is extracted and purified.^9,10 In contrast, the active ingredients of small-molecule drugs can easily be replicated via predictable chemical reactions to produce exact copies of the active ingredient (i.e., generics).⁵ Key differences between biologics and small-molecule drugs are presented in Table 2. Biologics are large, complex products that are dependent upon the manufacturing process, sensitive to storage and handling conditions, and immunogenic; small-molecule drugs are smaller, simpler, more stable entities.⁵

Table 2. Comparison of Small-molecule Drugs and Biological Drug Products5
	Small-molecule drugs	Biological drugs
Size	Small; low molecular weight	Large; high molecular weight
Structure	Simple; well-characterized	Complex; incompletely characterized
Manufacturing	Chemical synthesis; reproducible chemical reactions produce identical replicas of active ingredient	Recombinant DNA technology; living system produces heterogeneous copies of active ingredient
Stability	Stable	Sensitive to external conditions
Immunogenicity potential	Low	High

Variability in biological drug products can potentially affect efficacy and safety. There are many ways in which variability can be introduced to a final biosimilar product and even in consecutive batches of the same biological drug product.^7,11 Since biologics are manufactured in living organisms, end-product variations may result from differences in protein structure folding (secondary, tertiary, and quaternary folding) and/or post-translational modifications (e.g., glycosylation).⁹

Originator biological products are manufactured using proprietary information and processes, which are not always made available to biosimilar manufacturers.¹² Therefore, the manufacturing process for a biosimilar is likely to be different from the process used to develop the originator.⁷ Biological drug products are highly dependent upon manufacturing processes, so manufacturing differences will be an inevitable source of product variation and a potential source of altered efficacy and safety profiles. Variations may, therefore, be introduced due to differences in the manufacturing processes employed by the manufacturer of a biosimilar compared to the processes of the manufacturer of the originator product (e.g., differences in host organism, culture media, extraction/purification methods), as well as any differences in manufacturing equipment.⁶

During the development process and/or during production of the final product, the manufacturing process may be changed for reasons such as improving product purity or increasing product yield. Since biological drugs are critically dependent on the manufacturing process, any change in the process must be accompanied by comparability testing data that demonstrate the manufacturing change will not alter product quality, efficacy, or safety. Analytical studies may be sufficient to show biosimilarity of the pre-change and post-change products, but some manufacturing process changes may require the addition of preclinical and clinical studies. Also, evidence of consistent product production with the new manufacturing process should be demonstrated by analyzing a sufficient number of batches.¹³

Issue: Potential Impact of the Biosimilar Approval Process on the Evaluation of Safety and Effectiveness

The amount of study required to secure approval for a biologic agent is not a trivial matter. On one hand, a sufficient amount of information related to structure and function, as well as clinical efficacy and safety outcomes, is clearly needed to establish the product as suitable for human use. On the other hand, the rigor required to bring a biosimilar to market has substantial implications on the time and costs incurred by a manufacturer in the developmental phase, ultimately influencing the cost of the product once it is available in the marketplace.¹⁴

As discussed, one important controversy regarding the adoption of the abbreviated biosimilar developmental pathway is related to the variability in the manufacturing processes between manufacturers. Due to inherent differences in manufacturing processes, differences will exist between a biosimilar and its originator product. Batch-to-batch variability is common for single biological products, so the clinical significance of variabilities between an originator and a biosimilar product can be debated. Because of these differences, however, some clinicians have questioned the ability of abbreviated developmental programs to identify clinically important safety and efficacy differences between products. One limitation of analytical studies used in the development of biosimilar products is that the studies measure specific variables that may not predict all biological activity in humans, which allows for the possibility of overlooking important characteristics of the biosimilar candidate that may signal safety issues or other problems.¹⁵ Repeated switching between a biosimilar and a reference originator product carries a theoretical risk for the development of immunogenicity. Factors that can contribute to the immunogenic profile of a biologic include the product’s characteristics, the underlying disease process, and patient-specific factors.¹⁶

Despite these potential concerns, the experience of biosimilar development in Europe is reassuring. Europe approves biosimilar agents through an abbreviated approval process to provide cost savings, and Europe’s collective experience has resulted in improved patient access to biologics without obvious compromise of therapeutic or safety outcomes.¹⁷

STANDARDS FOR INTERCHANGEABILITY

The designation of interchangeability for biosimilar products is regulated at the federal level by the FDA.⁵ A biological product that demonstrates no meaningful differences in immunogenicity or other safety measures when switching between itself and its originator (in addition to meeting the requisite standards of a biosimilar that are described above) will be designated as an interchangeable product to its reference originator biologic.² The types of clinical trial data required to demonstrate these additional standards for interchangeability have not yet been articulated by the FDA.^10,18

In 2014, the FDA published the Purple Book: it provides a list of all approved biologics and classifies medications as originators, biosimilars, or interchangeables.^4,19 It is essentially a version of the Orange Book for biological drug products; the Purple Book can be used to identify which biologic is biosimilar to or interchangeable with a given originator product.²⁰

The status of interchangeability is a legal designation made by the FDA. By definition, an originator may be substituted by an interchangeable without consultation with or approval from the prescriber.³ However, the ability to automatically substitute an interchangeable drug for a reference biologic is regulated at the state level.⁵ At the time of writing this lesson, no interchangeables have been approved by the FDA, but many states have moved forward with creating new laws to permit the automatic substitution of an interchangeable for a prescribed reference biologic by a pharmacist:²¹

• 23 states have enacted and signed biosimilar substitution statutes
• 7 states have filed bills that failed and/or were adjourned
• 6 states have pending legislation
• 1 state has passed legislation but is without state law

Although states are preparing for the advent of interchangeable biosimilars, concerns associated with the prospect of permitting automatic substitutions with interchangeable biosimilars have been raised. To discuss the issues related to substitution and interchangeability, a general understanding of the proposed naming system for biologics, biosimilars, and interchangeables is required.

Issue: Impact of the Future Naming System on Substituting Interchangeables

The FDA has not yet finalized the naming system for biologics and their biosimilars and interchangeables. The FDA has, however, proposed a naming system similar to that established by the World Health Organization.^4,22 For biologics and biosimilars, an arbitrary, unique 4-letter suffix is proposed to be added to the nonproprietary name. For example, the originator filgrastim is proposed to be changed to filgrastim-jcwp and the recently approved biosimilar filgrastim-sndz is proposed to be changed to filgrastim-bflm to reflect a more random suffix – one that is less attributable to the manufacturer.²³ For interchangeable biologics, there are 2 proposed naming systems: 1) an interchangeable would acquire the same 4-letter suffix as its originator; or 2) an interchangeable would obtain a unique 4-letter suffix distinct from its originator.⁴ The opinions of advocates for each naming option for interchangables are outlined in Table 3.²⁰

Table 3. Advantages of Proposed Naming Systems for Interchangeable Biologics20
Same 4-letter suffix	Different 4-letter suffix
Less confusion; can mitigate medication errors Less resistance to substitution; easier to accept designated status of interchangeability Current tracking and safety alert systems can recognize new products (e.g., National Drug Code)	Easier to track and associate adverse events and/or change in disease with correct product Facilitates accurate record-keeping of automatic substitutions (e.g., insurance-mediated switch) Lower costs due to marketing competition of different products

Olson²⁴ conducted a survey of U.S. prescribers that examined opinions toward medicines, including biologics. A portion of the survey focused on how the naming of drug products affects attitudes and beliefs. Overall, prescribers believed that if drugs (any drug, not just biologics) have the same nonproprietary name, they are structurally identical (72%), produce the same result in patients (68%), and can be safely switched to produce the same result in a patient (60%). Most (66%) prescribers believed the FDA should require distinct nonproprietary names for all biologic drugs and 11% did not (23% had no opinion). More than half (60%) of prescribers believed the suffix should be representative of the manufacturer (e.g., -sndz for Sandoz) and 9% believed the suffix should be random (32% had no opinion). When asked to quantify the importance of “dispense as written” authority on a scale of 1 to 10 (10 being very important), 35% of clinicians chose 10, 17% chose 9, 14% chose 8, 10% chose 7, 9% chose 6, and 9% chose 5. Additionally, prescribers reported that they believe it is important to be notified by a pharmacist when a different biologic is substituted for the one prescribed: 68% preferred to be notified before the substitution, 11% within 24 hours of the substitution, 10% within 1 week, and 4% within 1 month.

These survey data demonstrate that the majority of prescribers prefer distinct suffixes for interchangeable biologics. The majority of prescribers also believe that drugs with the same nonproprietary name are structurally identical, which is not true for biological drugs. Therefore, having different names for interchangeables may prevent prescribing and dispensing errors. The survey also revealed that the majority of prescribers wish to be notified about substitutions of interchangeable products. So, while it may be legal to substitute a biologic with an interchangeable without notification or consultation, pharmacists may be compelled to report such switches to prescribers. Since biologics are not exact-copy generics, communication between health care professionals and updates to patient health records about interchangeability and substitutions may assist with the next area of concern: pharmacovigilance monitoring.

Issue: Limitations of Current Pharmacovigilance Systems

Pharmacovigilance is the tracking and monitoring of a marketed drug’s effectiveness and safety. With abbreviated approval requirements for biosimilars, good postmarketing pharmacovigilance is particularly important. It is known that even well-conducted, robust clinical trials may not capture all possible adverse events, particularly rare events and/or adverse events with a long lag time. Likewise, smaller studies accepted as sufficient for the purposes of gathering comparative data for biosimilars will not likely capture all adverse events (e.g., immunogenicity) associated with biosimilar candidates.⁷

The importance of the future final naming system is also apparent when considering its impact on pharmacovigilance reporting. If interchangeables and biosimilars have the same nonproprietary name, health care professionals will need to establish a system that can accurately differentiate between agents (e.g., by National Drug Code) to appropriately associate clinical outcomes and adverse events with the correct biological product.⁴ Thus, the need for proper documentation of substitutions may support the policy of contacting prescribers at the time of substitution, even if it would be legal not to contact them.

Similar to current practices with small-molecule drugs and generics, patients could potentially be switched from one interchangeable to another multiple times due to changes in product availability, insurance coverage, or formulary restrictions, among other reasons. It is not clear if these multiple substitutions would result in an increased risk of immunogenicity or in decreased effectiveness. These unknowns could be studied using pharmacovigilance data, but only if there are accurate methods to track and attribute outcomes to the appropriate biological product in use.

In the U.S., postmarketing pharmacovigilance is conducted via spontaneous reporting systems and active surveillance systems. An example of a spontaneous reporting system is the FDA’s MedWatch Program, and an example of an active surveillance system is a retrospective analysis of medical records.²⁵

The FDA Adverse Event Reporting System (FAERS) (i.e., MedWatch) plays a major role in postmarketing pharmacovigilance. Both health care professionals and patients may voluntarily report adverse events to FAERS. Manufacturers, on the other hand, are required to report all notifications of any postmarketing adverse event.²⁶ Because little information is necessary to voluntarily submit an adverse event report via FAERS, there are several limitations to this reporting system. First, many reports are incomplete. Without all pertinent details (e.g., current medications, medical history), it is difficult to establish a direct causal relationship between the assumed drug product and the evident adverse event. That is, it is difficult to rule out other causes with the limited known information. Second, FAERS is a voluntary reporting system and it cannot be expected to capture all postmarketing adverse events. Thus, the incidence rate of any adverse event reported via FAERS cannot be calculated. Finally, reports for the same nonproprietary name are grouped together. Depending on the final naming system for biosimilars, it may be difficult to accurately associate the correct biological product with a reported adverse event.^25,26

The limitations associated with active surveillance systems are akin to the limitations of retrospective analyses. For example, without proper and accurate documentation, the biological product will not be correctly identified and associated with an adverse event. Most often, administrative and claims data are de-identified, leaving nonproprietary product names on patient medical records.²⁵

STANDARDS FOR EXTRAPOLATION OF INDICATIONS

After a biosimilar has been approved for an indication, the FDA may also approve extrapolation of its approval, without formal investigation, to any or all of the indications for which the originator is approved. Still, manufacturers are required to provide justification for extrapolation to each desired indication: the mechanism of action for each indication; the biosimilar’s PK/PD profile, immunogenicity risk, and toxicity in different patient populations; and any other potential factors of a condition or patient population that may alter the efficacy or safety of the biosimilar product.⁷

Issue: General Acceptance of Current Standards for Indication Extrapolation

The current era of evidence-based medicine has trained providers to make clinical decisions on the basis of robust clinical trial data. However, biosimilars are approved through an abbreviated process that is based on the totality of evidence (with little contribution from clinical data). Health care providers may, therefore, be less inclined to prescribe a biosimilar that has been extrapolated for a particular indication without evidence from clinical trials (i.e., robust head-to-head comparative randomized, controlled trials) to support such extrapolations.²⁷

It is important to note that data extrapolation is not a new concept and it has been performed for many years in other circumstances. For example, when a manufacturer develops a new subcutaneous formulation for an already-approved intravenous (IV) drug product, a single clinical trial is generally sufficient to extrapolate the data to many, or all, clinical indications for which the IV product is approved.²⁷

The justification for extrapolation may be more straightforward when the factors required for extrapolation are more closely aligned. That is, if the mechanism of action, for instance, is the same for all indications, then it is easier to extrapolate the data obtained from the totality of evidence used to approve the biosimilar for use in other indications. If, however, the biologic’s mechanism of action is complex (e.g., involving several receptors), it is difficult to decipher what contributes to the efficacy of the drug for each individual indication.²⁷

BIOSIMILAR PRODUCTS CURRENTLY AVAILABLE IN THE U.S.

There are several key differences in the developmental and approval processes between biosimilar drugs and small-molecule generics; these differences have led to issues affecting the clinical use and acceptance of some biological products. Despite the fact that many of the issues presented so far have not yet been fully resolved, the FDA has granted approval for several biosimilar products (Table 4).^28-31 The approved products (as of August 2016) and the clinical data used to support their approval are listed below.

Table 4. Summary of Currently Approved Biosimilar Products in the United States28-31
Biosimilar	Indications for use
Zarxio (filgrastim-sndz)	Decrease the incidence of infection‚ as manifested by febrile neutropenia‚ in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever Reduce the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia Reduce the duration of neutropenia and neutropenia-related clinical sequelae (e.g.‚ febrile neutropenia) in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation Mobilize autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis Reduce the incidence and duration of sequelae of severe neutropenia (e.g.‚ fever‚ infections‚ oropharyngeal ulcers) in symptomatic patients with congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia
Basaglar (insulin glargine injection; 100 units/mL)	Improve glycemic control in adults and pediatric patients with type 1 diabetes mellitus and in adults with type 2 diabetes mellitus
Inflectra (infliximab-dyyb)	Crohn's disease: Reduce signs and symptoms of disease Induce and maintain clinical remission in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy Reduce the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing disease Pediatric Crohn's disease: Reduce signs and symptoms of disease Induce and maintain clinical remission in pediatric patients with moderately to severely active disease who have had an inadequate response to conventional therapy Ulcerative colitis: Reduce signs and symptoms of disease Induce and maintain clinical remission and mucosal healing Eliminate corticosteroid use in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy Rheumatoid arthritis: Reduce signs and symptoms of disease Inhibit the progression of structural damage Improve physical function in patients with moderately to severely active disease in combination with methotrexate Ankylosing spondylitis: Reduce signs and symptoms in patients with active disease Psoriatic arthritis: Reduce signs and symptoms of active arthritis Inhibit the progression of structural damage Improve physical function Plaque psoriasis: Treatment of adult patients with chronic severe (i.e., extensive and /or disabling) plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate
Erelzi (etanercept-szzs)	Rheumatoid arthritis Polyarticular juvenile idiopathic arthritis in patients aged 2 years or older Psoriatric arthritis Ankylosing spondylitis Plaque psoriasis

Zarxio (filgrastim-sndz)

Zarxio (filgrastim-sndz) is a biosimilar of Neupogen (filgrastim) that was approved by the FDA on March 6, 2015.³² Zarxio was approved for the same 5 indications for which U.S.-licensed Neupogen is approved (Table 4); it also has the same dosing regimens and schedules as Neupogen. Structure and function studies demonstrated that Zarxio has the same amino acid sequence as the originator product, and it was deemed to be highly similar to Neupogen owing to the product’s physiochemical properties, biological activity, and receptor binding.³²

A key clinical trial was conducted to demonstrate similarity between filgrastim-sndz and the originator biologic in a breast cancer population.³³ The phase 3, randomized, double-blind clinical trial enrolled a total of 218 patients who received 5 mcg/kg/day filgrastim over 6 chemotherapy cycles. Participants were randomized 1:1:1:1 into 4 treatment arms. Patients in 2 of the treatment arms received 1 of the biological drug products only (biosimilar or reference originator product); patients in the other 2 treatment arms alternated agents with each treatment cycle (biosimilar then reference product or vice versa). The primary endpoint for the trial was duration of severe neutropenia during cycle 1. Ultimately, the trial found the biosimilar to be noninferior to the reference product, with severe neutropenia occurring for 1.17 ± 1.11 days in the biosimilar group (n = 101) and 1.20 ± 1.02 days in the originator group (n = 103). Additionally, no meaningful clinical differences in efficacy or safety were noted between products.³³

Basaglar (insulin glargine injection; 100 units/mL)

Basaglar (insulin glargine) was approved by the FDA in December of 2015, but it is not expected to be available in the U.S. market until December of 2016. Similar to Lantus, Basaglar is indicated for use as a long-acting basal insulin to improve glycemic control in adult and pediatric patients with type 1 diabetes mellitus and in adults with type 2 diabetes mellitus.³⁴ Basaglar was the first insulin product approved through an abbreviated approval pathway by the FDA (an NDA via the 505(b)(2) pathway). Because Lantus was approved by the FDA in the year 2000 – prior to establishment of the PPACA and the 351(k) pathway – Basaglar was not able to use this pathway for approval. Since Basaglar was approved as a new drug, it will not be considered interchangeable with Lantus.³⁴

Basaglar was evaluated in 2 key clinical trials that enrolled participants with type 1 and type 2 diabetes.^35,36 In both trials, improvements in hemoglobin A1C were seen with Basaglar and Lantus (p < 0.001) from baseline to the end of the studies.^35,36 Both studies also reported similar findings related to safety parameters, such as incidence of allergic reactions, changes in body weight, occurrence of hypoglycemia, and development of insulin antibodies.^35,36 Ultimately, no major efficacy or safety differences were noted between Basaglar and Lantus.

Inflectra (infliximab-dyyb)

In April 2016, the FDA announced the approval of Inflectra, a biosimilar to the tumor necrosis factor (TNF) inhibitor Remicade (infliximab).³⁷ As noted in Table 4, infliximab-dyyb was approved for the treatment of multiple conditions, including Crohn’s disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and chronic severe plaque psoriasis.³⁰ Infliximab-dyyb was approved by the FDA as a biosimilar, but not an interchangeable, product.³⁷

The approval of infliximab-dyyb was based on structural and functional characterization, animal study data, human PK/PD data, clinical immunogenicity data, and other clinical safety and efficacy data.³⁷ A variety of clinical trials have been performed in multiple conditions, such as ankylosing spondylitis³⁸ and rheumatoid arthritis,³⁹ that show similarities in efficacy and safety parameters between the biosimilar and the originator biologic.

Erelzi (etanercept-szzs)

Approval of the biosimilar Erelzi (etanercept-szzs) was announced in August 2016. This biosimilar to Enbrel (etanercept) was approved for all indications included in the originator product label (Table 4).³¹ The approval of etanercept-szzs marks the second approval of a biosimilar TNF inhibitor.

PHARMACOECONOMIC CONSIDERATIONS FOR BIOSIMILARS

As noted previously, biologics account for a small proportion of all prescriptions dispensed in the U.S., but they account for more than one quarter of all prescription spending.¹ On a worldwide scale, sales for biologics reached $157 billion in 2011 and some projections estimate that sales will exceed $200 billion in 2016.¹⁶ It is no wonder that savings associated with the use of biosimilars is of interest. While the success of generic small-molecule drugs to reduce health care costs is well established, the extent of savings that will be realized with the use of biosimilars will likely be much smaller (at least in terms of percent savings from the originator product price). There are several key reasons why biosimilar agents will never reach levels of price discounting achieved by small-molecule generics. First, development costs are considerably higher for biologic products than for small-molecule drugs due to the requirements for pre-clinical and clinical studies for biologics. Also, manufacturing costs are higher for biological products than for small-molecule drugs. Marketing of biosimilars also comes at high cost: manufacturers must communicate with prescribers and pharmacists since prescribing of biosimilars is performed largely by brand name; manufacturers of originator biologics have established relationships with prescribers and biosimilar manufacturers cannot replicate these key relationships without an investment of resources. Finally, clinician concerns about comparability between biosimilars and originator products may need to be addressed in post-launch studies. Overall, few biosimilar competitors are expected to enter the market due to the challenges of biosimilar development and marketing, resulting in less intense price competition.⁴⁰

A report from the FDA noted that, for generic small-molecule drugs, 10 or more competitors are required in the market to reach maximum savings, which is unlikely to occur for many biologics.¹ For example, in the European Union, where over 20 biosimilar products are available, the median price savings for the biosimilar epoetin alfa compared to its originator is approximately 35%.¹ Given the high costs of biologics, however, savings estimates can still yield large sums. Estimates of savings from biosimilar use over a 10-year period in the U.S. range from $25 billion to $100 billion.⁴⁰ While not as robust as savings realized with small-molecule generics, these estimates have enticed some benefits managers to include biosimilars within their formularies. In August 2016, CVS Health announced that Zarxio will be replacing Neupogen on its formulary.⁴¹ CVS Health will also be replacing Lantus on their formulary with the biosimilar insulin glargine product Basaglar.

There are costs associated with biosimilars beyond those calculated solely on drug prices, such as costs associated with health system challenges inherent to their use (Table 5).⁴² Issues related to formulary management, maintenance of order management and information systems, inventory management, and patient and provider education must be considered as biosimilar products make their way into the marketplace.

Table 5. Select Operational Challenges Associated with Biosimilars42
Domain	Considerations
Formulary analysis	Product approval pathway and data package Appropriate indications for use Indication extrapolation considerations Therapeutic interchange and use policies Transitions of care Payer mix
Order management & information systems	Differentiation of biosimilar and reference product in electronic systems to prevent inadvertent substitution and to facilitate pharmacovigilance Ordering of sets, protocols, and medication administration records Medication reconciliation
Inventory management	Buyer's need for adequate information (e.g., National Drug Code) Confirmation of whether both biosimilar and reference biologic are in stock Maintenance of product storage and handling conditions
Financial analysis	Pricing information comparison Staff management time Patient assistance and out-of-pocket expenses Determination of financial impact
Educational needs	Drug information and education (e.g., clinical data, policies) for all providers Patient education materials

CONCLUSION

Currently, only 4 biosimilar products are approved in the U.S., but many more are likely to be approved in the future. Biologics comprise a small percentage of medication use in the U.S., yet these agents account for immense costs. Biosimilars provide an avenue for more affordable options for both patients and the health care system as a whole, and issues surrounding the development and approval processes for biosimilars will likely be resolved with time. With biosimilars entering the U.S. market, pharmacists and other health care providers will be faced with a variety of challenges, including formulary and transitional care-related issues. Increased experience with biosimilars may assuage ongoing concerns regarding safety and effectiveness and will hopefully allow for increased access to biologics for patients in need.

REFERENCES

1. Sarpatwari A, Avorn J, Kesselheim AS. Progress and hurdles for follow-on biologics. N Engl J Med. 2015;372(25):2380-2382.
2. U.S. Food and Drug Administration. Sections 7001-7003 (Biologics Price Competition and Innovation Act of 2009) of the Patient Protection and Affordable Care Act (Public Law No. 111-148). http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ ucm216146.pdf. Accessed September 15, 2016.
3. U.S. Food and Drug Administration. Biosimilars: questions and answers regarding implementation of the Biologics Price Competition and Innovation Act of 2009. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation /Guidances/UCM444661.pdf. Published April 2015. Accessed September 15, 2016.
4. U.S. Food and Drug Administration. Nonproprietary naming of biological products. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformat ion/Guidances/UCM459987.pdf. Published August 2015. Accessed September 15, 2016.
5. Camacho LH, Frost CP, Abella E, et al. Biosimilars 101: considerations for U.S. oncologists in clinical practice. Cancer Med. 2014;3(4):889-899.
6. U.S. Food and Drug Administration. Frequently asked questions about therapeutic biological products. http://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredeveloped andapproved/approvalapplications/therapeuticbiologicapplications/ucm113522.htm. Updated July 7, 2015. Accessed September 15, 2016.
7. U.S. Food and Drug Administration. Scientific considerations in demonstrating biosimilarity to a reference product. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformat ion/Guidances/UCM291128.pdf. Published April 2015. Accessed September 15, 2016.
8. U.S. Food and Drug Administration. Clinical pharmacology data to support a demonstration of biosimilarity to a reference product. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformati on/Guidances/UCM397017.pdf. Published May 2014. Accessed September 15, 2016.
9. U.S. Food and Drug Administration. Quality considerations in demonstrating biosimilarity of a therapeutic protein product to a reference product. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformati on/Guidances/UCM291134.pdf. Published April 2015. Accessed September 15, 2016.
10. U.S. Food and Drug Administration. Biosimilars: additional questions and answers regarding implementation of the Biologics Price Competition and Innovation Act of 2009. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation /Guidances/UCM273001.pdf. Published May 2015. Accessed September 15, 2016.
11. Halim LA, Brinks V, Jiskoot W, et al. Quality and batch-to-batch consistency of original and biosimilar epoetin products. J Pharm Sci. 2016;105(2):542-550.
12. Graser D. Industry voices: biosimilars and trade secrets. http://www.fiercebiotech.com/r-d/industry-voices-biosimilars-and-trade-secrets. Published October 24, 2012. Accessed September 15, 2016.
13. U.S. Food and Drug Administration. Q5E comparability of biotechnological/biological products subject to changes in their manufacturing process. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation /guidances/ucm073476.pdf. Published June 2005. Accessed September 15, 2016.
14. Hirsch BR, Lyman GH. Biosimilars: are they ready for primetime in the United States? J Natl Comp Cancer Network. 2011;9(8):934-943.
15. Reinke T. Biosimilars might not measure up to health plan expectations. Manag Care. 2012;21(10):12-13.
16. Eleryan MG, Akhiyat S, Rengifo-Pardo M, Ehrlich A. Biosimilars: potential implications for clinicians. Clin Cosmet Investig Dermatol. 2016;9:135-142.
17. McCamish M, Woollett G. The state of the art in the development of biosimilars. Clin Pharmacol Ther. 2012;91(3):405-417.
18. Derbyshire M. Update on US state legislation on biosimilars substitution. Generics and Biosimilars Initiative Journal. 2015;4(2):95-97.
19. U.S. Food and Drug Administration. Purple Book: lists of licensed biological products with reference product exclusivity and biosimilarity or interchangeability evaluations. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDev elopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars /ucm411418.htm. Updated September 1, 2016. Accessed September 15, 2016.
20. Kim AP, Bindler RJ. The future of biosimilar insulins. Diabetes Spectr. 2016;29(3):161-166.
21. Cauchi R. State laws and legislation related to biologic medications and substitution of biosimilars. http://www.ncsl.org/research/health/state-laws-and-legislation-related-to-biologic-medications-and-substitution-of-biosimilars.aspx. Published July 12, 2016. Accessed September 15, 2016.
22. World Health Organization. Biological qualifier – an INN proposal. Available at http://www.who.int/medicines/services/inn/bq_innproposal201506.pdf.pdf. Published June 2015. Accessed September 15, 2016.
23. U.S. Food and Drug Administration. Designation of official names and proper names for certain biological products. https://www.federalregister.gov/articles/2015/08/28/2015-21382/designation-of-official-names-and-proper-names-for-certain-biological-products. Published August 28, 2015. Accessed September 15, 2016.
24. Alliance for Safe Biologic Medicines. Biosimilars – US prescribers and biosimilars naming. http://safebiologics.org/wp-content/uploads/2016/05/US-Prescribers-Biosimilars-Naming-2015.pptx. Published October 2015. Accessed September 15, 2016.
25. Grampp G, Felix T. Pharmacovigilance considerations for biosimilars in the USA. BioDrugs. 2015;29(5):309-321.
26. U.S. Food and Drug Administration. Questions and answers on FDA’s Adverse Event Reporting System (FAERS). http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Survei llance/AdverseDrugEffects/default.htm. Updated May 5, 2016. Accessed September 15, 2016.
27. Weise M, Kurki P, Wolff-Holz, et al. Biosimilars: the science of extrapolation. Blood. 2014;124(22):3191-3196.
28. Zarxio [package insert]. Princeton, NJ: Sandoz, Inc.; 2016.
29. Basaglar [package inert]. Indianapolis, IN: Lilly USA, LLC.; 2016.
30. Inflectra [package insert]. Lake Forest, IL: Hospira; 2016.
31. Erelzi [package insert]. Princeton, NJ: Sandoz, Inc.; 2016.
32. U.S. Food and Drug Administration. Filgrastim-sndz. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm436953.htm. Published March 6, 2015. Accessed September 15, 2016.
33. Blackwell K, Semiglazov V, Krasnozhon D, et al. Comparison of EP2006, a filgrastim biosimilar, to the reference: a phase III, randomized, double-blind clinical study in the prevention of severe neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy. Ann Oncol. 2015;26(9):1948-1953.
34. U.S. Food and Drug Administration. FDA approves Basaglar, the first “follow-on” insulin glargine product to treat diabetes. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm477734. htm. Published December 16, 2015. Accessed September 15, 2016.
35. Blevins TC, Dahl D, Rosenstock J, et al. Efficacy and safety of LY2963016 insulin glargine compared with insulin glargine (Lantus®) in patients with type 1 diabetes in a randomized controlled trial: the ELEMENT 1 study. Diabetes Obes Metab. 2015;17(8):726-733.
36. Rosenstock J, Hollander P, Bhargava A, et al. Similar efficacy and safety of LY2963016 insulin glargine and insulin glargine (Lantus®) in patients with type 2 diabetes who were insulin-naïve or previously treated with insulin glargine: a randomized, double-blind controlled trial (the ELEMENT 2 study). Diabetes Obes Metab. 2015;17(8):734-741.
37. U.S. Food and Drug Administration. FDA approves Inflectra, a biosimilar to Remicade. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm494227.htm. Published April 5, 2016. Accessed September 15, 2016.
38. Park W, Hrycaj P, Jeka S, et al. A randomized, double-blind, multicenter, parallel-group, prospective study comparing the pharmacokinetics, safety, and efficacy of CT-P13 and innovator infliximab in patients with ankylosing spondylitis: the PLANETAS study. Ann Rheum Dis. 2013;72(10):1605-1612.
39. Yoo DH, Hrycaj P, Miranda P, et al. A randomized, double-blind, parallel-group study to demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when coadministered with methotrexate in patients with active rheumatoid arthritis: the PLANETRA study. Ann Rheum Dis. 2013;72(1):1613-1620.
40. Mestre-Ferrandiz J, Towse A, Berdud M. Biosimilars: how can payers get long-term savings? Pharmacoeconomics. 2016;34(6):609-616.
41. Mangan D. CVS Health to replace higher-cost drugs on covered medication list for 2017. http://www.cnbc.com/2016/08/02/cvs-health-to-replace-higher-cost-drugs-on-covered-medication-list-for-2017.html. Published August 2, 2016. Accessed September 15, 2016.
42. Lucio SD, Stevenson JG, Hoffman JM. Biosimilars: implications for health-system pharmacists. Am J Health Syst Pharm. 2013;70(22):2004-2017.

Back to Top