Clinical Data and Regulatory Issues of Biosimilar Products

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Supplements and Featured Publications, Clinical and Managed Care Implications of Biosimilars: Evaluating the Science and Challenges to Upta, Volume 21, Issue 16 Suppl

Biologics are a fast-growing segment of pharmaceutical development. Many are effective in the treatment of illnesses such as cancers, rheumatoid arthritis, and multiple sclerosis. Biologics encompass a range of compounds, including recombinant hormones, growth factors, monoclonal antibodies, recombinant vaccines, and blood products. Many of these drugs are facing patent expiration, and pharmaceutical research is focusing on the development of generic substitutes, or “biosimilars.” Because biologics generally exhibit high molecular complexity, the process of development and approval of biosimilars is complicated. Unlike standard smallmolecule generics where an identical drug copy is expected, variations in biosimilars may be inherent because the sponsor does not have knowledge of the originator’s processes. Because of this intricacy, regulatory requirements are needed to ensure biosimilarity, comparability, and interchangeability with respect to efficacy and safety. Clinician awareness of the similarities and differences between original biopharmaceuticals and biosimilars, as well as their impact on efficacy and safety, is imperative. Am J Manag Care. 2015;21:S320-S330

As patents for leading biologic products expire, the FDA’s March 2015 approval of the first biosimilar product in the United States1 is expected to help usher in a new wave of biosimilar products. It is widely anticipated that biosimilars, once available, will offer physicians and their patients more product-related options for a host of serious and chronic illnesses, including cancer and autoimmune disorders, at a potentially lower cost when compared with original biologic products. This will improve access to these expensive therapies and reduce the overall costs of healthcare.

The success of biosimilars in lowering costs and improving patient access to treatment options will largely depend on how well these products are accepted by clinicians, payers, and patients. Because biosimilars are not identical to their original biologic reference products, many clinicians, including specialists and pharmacists, still have questions regarding their safety and efficacy in actual clinical practice. In addition, specific FDA guidance is still evolving, especially regarding the issue of interchangeability between a biosimilar and its reference biologic product.

This article will explain what biosimilars are and how they differ from their reference biologic products and generic small-molecule pharmaceutical agents. We will examine the current approval process for biosimilars in Europe and the United States, and how the European experience with biosimilars, to date, can inform us about the potential use of biosimilars in the United States. Specific concerns regarding the clinical uptake of these products, as well as current and evolving regulatory factors that could impact the future of biosimilar availability and usage in the United States, will also be discussed.

Biosimilars and Biologics

A biosimilar can be defined as a biopharmaceutical agent that is similar, but not identical to, the original or reference biopharmaceutical product or biologic.2 It is expected that biosimilars will not have meaningful differences in clinical efficacy and safety compared with the reference product. For this reason, biosimilars are sometimes referred to as follow-on or copy versions of the originator biologic product.

From a regulatory perspective, biosimilars are produced by a different manufacturer than that of the originator product; they are developed through an abbreviated regulatory process.3 A biologic, which is usually a therapeutic protein, is a pharmaceutical agent or product derived from living cells or organisms and consists of relatively large, often highly complex molecular entities that may be difficult to fully characterize.4 Biologics are generally polypeptides (glycoproteins) and/or nucleic acids; they often have indications for use in serious and chronic diseases.5,6 Table 15 summarizes the main differences between small-molecule chemical drugs and biologic drugs.

Since the introduction of recombinant human insulin in 1982, the use of biologics has continued to increase, and they have become an essential element of many cancer and supportive care treatments. 7,8 Increasingly, they are also used to treat a range of autoimmune, neurologic, and inflammatory conditions, such as rheumatoid arthritis and multiple sclerosis. In 2000, only 1 of the top 10 drugs, by sales, was a biologic product; by 2008, half were biologics.9 In 2013, biopharmaceuticals accounted for 22% of sales in large pharmaceutical companies; this is expected to increase to 32% by 2023.10

Large numbers of patients now rely on biologics to treat and manage chronic, potentially life-threatening and/ or debilitating conditions and their significant costs, and biosimilars are seen as a potential solution to provide lower-cost alternatives to high-priced branded biologics. Consequently, biosimilars have gained increased attention in recent years among payers. Lower costs are, in turn, expected to provide patients with greater levels of access to these critical treatments. According to one estimate, the United States could save $250 billion between 2014 and 2024, if 11 of the likeliest biosimilars reach the market.11

Biosimilars will likely face competition from new biologics in the same therapeutic class, including incremental improvements to existing reference products.12 Some manufacturers may develop so-called biobetters, a biologic that seeks to establish superiority in one or more aspects of its clinical profile, compared with the originator product,13 as a strategy against the use of less expensive biosimilars. A biobetter contains the same basic protein or targets the same receptor but may include structural changes, bi-functional targeting, or an improved formulation, which may result in improved efficacy and/or safety.

Differences Between Biosimilars and Small-Molecule Generics

With traditional or small-molecule pharmaceutical products, the active substance in the generic or copy product is identical to that of the brand name or originator reference product.2 Biologics are much larger and more complex molecules; therefore, they cannot be fully characterized and copied exactly, so biosimilars are not generic or identical versions of the innovator pharmaceuticals.

Composition Differences

Small-molecule generics have relatively uncomplicated chemical structures that are made up of basic atomic units, such as carbon, hydrogen, and oxygen, and their weight ranges from a few hundred to a few thousand daltons.6,8 In contrast, biologics, including biosimilars, are typically complex proteins or monoclonal antibodies and are much larger, ranging from about 10,000 to several hundred thousand daltons.6 A biosimilar will typically have the same amino acid sequence as its innovator product, but because of protein folding and glycosylation, it may have slight differences in structure.4

Small-molecule generics are synthesized through predictable chemical processes and can be completely characterized by existing analytical methods, making it possible to ensure that the active drug in the generic product is identical to the reference product.8 Current analytical techniques do not allow the final structure of a biosimilar product to be fully characterized, so there cannot be complete structural equivalence to the reference product.8 However, the characterization of important “quality attributes” related to structure and function can be compared to assess the similarity between products.

Manufacturing Differences

There are also significant differences in manufacturing processes. Small-molecule generics are developed using relatively simple chemical reactions; because the end product will be identical, any changes made to the process will likely be negligible. In contrast, the manufacturing processes for producing biologics are very complex and involve multiple stages of expression, production, purification, and validation of the final product.8 These processes often include targeting and isolating gene sequences, cloning the gene sequence, and using DNA vectors to transfer the targeted DNA into an expression system. Different biologics and biosimilar manufacturers may use different protein sources, bioreactors, and extraction and purification processes.2 Small changes in the manufacturing process for a biosimilar may alter the final structure and function of the protein.8 In addition, biosimilar manufacturers do not have access to information on innovator product manufacturing processes that are proprietary; therefore, it is impossible for a biosimilar manufacturer to precisely replicate the manufacturing process for any protein product.2 Therefore, the biosimilar cannot be exactly the same as the 1reference product. The standard for approval by the FDA requires that the biosimilar is “highly similar to an FDA-approved biological product, known as a reference product, and has no clinically meaningful differences in terms of safety and effectiveness from the reference product.”


Regulatory Differences

In the United States, small-molecule drugs are regulated according to the Federal Food, Drug, and Cosmetic Act that was enacted in 1938. This act was modified in 1984 under the Hatch-Waxman Act to allow for the expedited approval of generic medications through an Abbreviated New Drug Application (ANDA) process.15 Small-molecule generic medications, approved through the ANDA process, are usually designated as pharmaceutical equivalents and bioequivalent, which means they can be substituted for the brand product.

Biologics were initially regulated by the Biologics Control Act of 1902 and were later revised and codified into the Public Health Services (PHS) Act in 1944.15 In March 2010, as part of the Affordable Care Act, the Biologics Price Competition and Innovation (BPCI) Act of 2009, which established an abbreviated licensure pathway for biosimilars for the first time in the United States, was signed into law by President Obama.16

The BPCI Act defines a biosimilar as a product for which clinical study or studies are sufficient “to demonstrate safety, purity, and potency for one or more appropriate conditions of use for which the reference product is licensed.”16 The FDA can approve a biosimilar only if it has the same mechanism of action, route of administration, dosage form, and strength as the reference product. The biosimilar also must have no clinically meaningful differences in safety and effectiveness, and approval will be only for the indications and conditions of use that have been approved for the reference product.1 However, a biosimilar can be approved with fewer routes of administration than the reference product, and under the BPCI Act, the indications for FDA approval of a biosimilar do not necessarily have to include all of the licensed uses of the innovator reference product.16 These can vary based on the biosimilar sponsor’s application and the extent to which clinical trial information supports extrapolation across multiple indications.

Manufacturers seeking biosimilar approval must file a 351(k) application with the FDA. Since 2012, the FDA has issued, and subsequently revised, draft guidance documents outlining the general approach it will use in determining biosimilarity to a reference product.17 The approach continues to evolve.18,19

Regulatory Pathways for Biosimilar Approval: the European Experience

To understand more about the FDA’s approach to approving and regulating biosimilars in the United States, it is helpful to first look at the European Union, which has had a regulatory pathway in place for these products for more than a decade and accounts for about 80% of the global spending on these molecules.6 The European Medicines Agency (EMA) first established a regulatory pathway for the approval of biosimilars in 2005, and the first biosimilar, a version of a human growth hormone (somatropin), was approved by the EMA in 2006.6 Another key milestone for biosimilars in Europe occurred in September 2013, when final marketing authorization was granted to a biosimilar version of infliximab, the first monoclonal antibody (a class comprising agents of greater complexity) to receive biosimilar status in the European Union.6

As of the date of this writing, 21 biosimilar products were on the market in Europe.20 Of these, 19 are currently on the market, with two being withdrawn for commercial reasons. All have an established safety record—none of these products has had to be recalled or removed from the European market due to regulatory or safety concerns. One reason European Union-approved biosimilars have had such a good track record is because the EMA has taken a conservative approach in approving biosimilars.21,22 The EMA has issued a series of guidelines to the industry over the years and continues to build on them to specify what data and other information will be expected from manufacturers in order to approve a biosimilar. The initial overarching guidelines were published in 2005 and were followed by subsequent guidelines in 2006 that outlined quality standards, as well as what kind of clinical and non-clinical information manufacturers would need to provide to gain biosimilar status.23 In addition to providing overarching biosimilar guidance, the EMA has issued specific annexes or class guidances that describe what studies and data must be provided to gain biosimilar status for several select categories of biologics, including epoetin, granulocyte colony-stimulating factor (G-CSF), human growth hormone, heparin/ low-molecular weight heparin (LMWH), interferons, monoclonal antibodies, and insulins.

Similarities and Differences Between the EMA and FDA Biosimilar Approval Approaches

As previously mentioned, the United States still lags behind Europe in developing and implementing a biosimilar approval pathway. The FDA’s approach to regulating biosimilars, to date, has followed a relatively conservative and cautious approach similar to that used by the EMA. Unlike the EMA, however, the FDA has not provided specific requirements manufacturers must follow; instead, the guidance documents, which will be discussed more in detail later in this article, describe general principles the agency will expect manufacturers to adhere to when seeking biosimilar approval.17

There are several notable differences between the FDA’s approach to biosimilars and that of the EMA.21,22 First, the EMA requires all biosimilar product manufacturers to provide a specific risk management or pharmacovigilance plan for its product before receiving approval. On the other hand, the FDA, to date, has no such explicit requirement for biosimilar manufacturers, and it is not clear if the agency will require it at a future date. Second, the FDA has not developed annexes with specific data and/or study requirements for select categories of biologics, as the EMA has done. Additionally, the FDA has not approved follow-on LMWH and insulin products through the biosimilar pathway, as the EMA has; the FDA has, however, approved them as generic products through the more established ANDA process.

It is important to understand that biologic products approved through the biosimilar pathway in the European Union may be approved in the United States under a different FDA regulatory pathway altogether; therefore, those products may not be categorized as biosimilars in the United States. For example, in 2014, for the treatment of severe neutropenia in select patients with nonmyeloid malignancies, the FDA approved the G-CSF tbo-filgrastim, but because it was approved through the FDA’s full Biologics License Application (BLA) approval pathway, 351(a), it is not classified as a biosimilar in the United States.24 Table 225-28 summarizes the different FDA-approved biologic approval pathways that are used in the United States for the various G-CSF products currently on the market.


Arguably, the most important difference between the EMA’s and the FDA’s respective biosimilar approval pathways involves the issue of interchangeability. In the European Union, the EMA does not grant the interchangeable designation for biosimilars.21,22 In contrast, under the BPCI Act, the FDA is specifically authorized to grant interchangeability status to biosimilars; the BPCI Act defines interchangeable to mean that the biosimilar “is expected to produce the same clinical results in any given patient,” adding that “the biologic product may be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product.”8 For biologics administered more than once to a patient, the risks in terms of safety and efficacy of switching between the use of the reference product and the biosimilar must be equal to the risk of only using the reference product.8 Although the FDA is authorized to grant interchangeability status to biosimilars, the agency has not issued guidance or requirements on what studies or data biosimilar manufacturers will need to provide to receive interchangeable product status. Additionally, the FDA grant did not award interchangeability status to the first biosimilar approved in March 2015. Further comparison on the differences in approval characteristics between the United States and European Union can be seen in Table 3.21,22

FDA Guidance on Biosimilars

Unlike small-molecule generic drugs that only require pharmacokinetic studies demonstrating bioequivalence, the FDA indicates in its draft 2012 guidance document, and a subsequent 2015 update, that it will use “a totality of the evidence approach” in reviewing applications for biosimilar products, which is consistent with the agency’s longstanding approach to evaluating scientific evidence.29 The FDA stresses that manufacturers submitting applications for biosimilar product approval will need to meet high standards; the agency already has guidance limiting the variation in biologic products that occurs when there are manufacturing changes in reference products, commonly referred to as manufacturing drift. The guidance provides a framework to evaluate the differences in the manufacturing process that will be introduced by developers of biosimilars. “Demonstrating that a proposed product is biosimilar to a reference product typically will be more complex than assessing the comparability of a product before and after manufacturing changes made by the same manufacturer,” the agency states. “FDA anticipates that more data and information will be needed to establish biosimilarity than would be needed to establish that a manufacturer’s post-manufacturing change product is comparable to the pre-manufacturing change product.”

The FDA also provides the following high-level guidance29:

  • Manufacturers should use a stepwise approach to demonstrate biosimilarity. This approach can include a comparison of the proposed product and the reference product regarding structure, function, animal toxicity, human pharmacokinetics (PK) and pharmacodynamics (PD), clinical immunogenicity, and clinical efficacy and safety, as well as effectiveness.
  • In evaluating biosimilars, the agency will look at general scientific principles used to conduct comparative structural analyses, functional assays, animal testing, human PK and PD studies, clinical immunogenicity assessments, and comparative clinical studies, including clinical study design issues.
  • The FDA will consider the complexities of therapeutic protein products, including manufacturing process considerations and the use of data.In other words, there is no standard template the FDA will apply to the approval of all biosimilars. Rather, the FDA will work with each biosimilar manufacturer to develop an overall plan to demonstrate biosimilarity and will determine which additional studies are needed at each step in the process.

In other words, there is no standard template the FDA will apply to the approval of all biosimilars. Rather, the FDA will work with each biosimilar manufacturer to develop an overall plan to demonstrate biosimilarity and will determine which additional studies are needed at each step in the process.

The Complexities of Biosimilar Production and Approval

The complex and variable nature of biologics and biosimilars presents numerous challenges for manufacturers and for regulatory bodies, such as the EMA and FDA, that oversee the approval process. Several specific areas warrant discussion.


As discussed earlier, differences in manufacturing processes, protein sources used, extraction methods, and purification processes result in heterogeneity, or differences in biopharmaceutical products. Heterogeneity does not necessarily present safety or efficacy issues. The “similar but not identical” paradigm is not new to biotechnology, and even consecutive batches of originator products are never identical to each other (ie, manufacturing drift). Structural differences between a biosimilar and its reference product are generally acceptable if it can be shown that the differences would not impact clinical performance. One such difference that has been accepted by the EMA is an increased level of phosphorylated high mannose-type structures in a biosimilar epoetin alfa compared with the reference product; this is because the biosimilar applicant could prove that these are common glycoforms of recombinant erythropoietins and cytokines, and a large variety of nonlysosomal proteins from human plasma.4

In Europe, one analysis of 2 separately marketed biosimilar epoetin products showed that they differed in their protein content, isoform profiles, and in vivo potency.24 However, a subsequent population-based analysis showed that in clinical practice, the epoetin doses administered were quite similar compared with the originator product.

Nevertheless, wide variability in product composition and bioactivity has been observed and documented in products produced outside of the United States and Europe. In 1 study comparing 11 epoetin proteins from Korea, Argentina, China, and India, isoform distribution varied, and there were substantial deviations from specifications for in vivo bioactivity.2 For these reasons, regulatory guidelines governing biosimilars must account for these differences and require that rigorous pharmacovigilance programs be put in place.2

Safety and Efficacy Concerns/Immunogenicity

Because of their size and complexity, biologics are readily recognized by the body’s immune system, which can induce a range of immunologic responses, some of which can result in substantial clinical consequences, including loss of efficacy (neutralizing antibodies), the potential for anaphylaxis, and infusion reactions.6 For these reasons, immunogenicity is cited as a primary concern with using biosimilars, especially for biologics for which immune responses have been linked to serious safety issues.4 The most quoted example is pure red cell aplasia, which is caused by cross-reacting neutralizing antibodies against erythropoietin; this occurred secondary to a manufacturing change with a reference epoetin product in Europe. However, it illustrates how an apparently small manufacturing change can result in significant clinical consequences.

Immunogenicity can be influenced by patient-, disease-, or product-related factors. Because patient- and disease-related factors are already known from experience gained by the innovator product, focus must be placed on potential product-related factors when evaluating biosimilars for possible immunogenicity safety issues,4 which include manufacturing factors and structural alterations, such as aggregation or impurities and contaminants. Even small differences can impact immunogenicity, and current analytical or animal data cannot predict immune response in humans. Therefore, immunogenicity data are necessary before licensing a biosimilar.

Bioequivalence Assessments

The abbreviated process for approval of small-molecule generic medicines involves a relatively simple bioequivalence study to show that the generic product has similar pharmacokinetic properties to the innovator compound.21 In contrast, the abbreviated approval process for a biosimilar is much more complex, as there is no single test that can be used to determine biosimilarity. It usually starts with physicochemical characterization of the biosimilar compared with the reference product. A variety of analytical methods are used to evaluate the complex structure of these biologic compounds, including primary structure and posttranslational modifications such as glycosylation and phosphorylation. Following that are studies of similarity to the reference product in both PK and PD properties in humans. Assuming that these first evaluations indicate there is substantial similarity between the biosimilar and the reference product, further clinical studies are conducted to evaluate potential immunogenicity, as well as a safety and efficacy evaluation with a clinically relevant and sensitive end point that would be expected to detect meaningful differences.4,6,17,29

Clinical Factors Impacting Uptake of Biosimilars

Clinicians and some medical societies have voiced concerns about biosimilars regarding quality, safety (including immunogenicity), and interchangeability with the reference product, including questions about clinical efficacy and safety in extrapolated indications for which no formal clinical studies have been performed with the biosimilar.4 These concerns are discussed in more detail below.

Quality Concerns

Manufacturing production complexities have led to concerns about the potential for low quality or substandard biosimilar products.4 Based on the European experience to date, this fear is largely unfounded because the manufacturing process for a biosimilar must comply with the same quality requirements as any new biologic: manufacturers must demonstrate that their production process can consistently produce a high-quality product.4 Because the manufacturing process must include state-of-the-art scientific knowledge, biosimilar manufacturers may have more advanced processes in place compared with original processes used by the older originator products.4

The Indication Extrapolation Conundrum

Extrapolation of data is an established scientific and regulatory principle that has been used for many years. Even in situations where major changes are made to the manufacturing process of originator biologics, clinical data are typically generated in one indication and may then be extrapolated to another indication, taking into account the overall information gained from performing a comparability exercise for determining biosimilarity. Such exercises can include an extensive comparison of the physicochemical and functional characteristics of the molecules, including glycosylation within the molecular structure and receptor binding, using current analytical tools.30

With biosimilars, if the relevant mechanism of action of the active substance and the target receptor(s) involved in the tested and extrapolated indication(s) are the same, extrapolation is usually not problematic. However, extrapolation is more difficult to justify when the mode of action is complex and involves multiple receptors or binding sites; in such cases, additional data are generally necessary.30

In Europe, several biosimilars of filgrastim were approved based on extrapolated data, with strong scientific arguments supporting the use of extrapolation in these cases. Even so, several medical societies have criticized the extrapolation of data to stem cell mobilization and collection in healthy donors, and they have warned against the use of biosimilar filgrastim in the treatment of neutropenia and for the mobilization of peripheral blood progenitor cells. Similarly, biosimilar versions of epoetin, which were approved after rigorous studies by the EMA for the treatment of renal anemia and chemotherapyinduced anemia, have been called into question by some on the grounds that safety data were missing for the high doses required in cancer patients.30

Even when the scientific evidence supports extrapolation of data, by both additional studies and rigorous regulatory review, as the European experience shows, many clinicians are still skeptical of expert assessments regarding biosimilar safety and efficacy and are reluctant to embrace biosimilars. An EMA Working Party on Similar Biological Medicinal Products is currently attempting to clarify this issue within Europe.31

Interchangeability Concerns

The question of interchangeability, or whether a biosimilar product can be substituted for the reference biologic product, remains one of the most difficult issues to resolve. When 2 generic drugs are proven as bioequivalent, they are considered to be interchangeable with the reference product and with other generics, but this is not the case with biosimilars. Two independently developed biopharmaceuticals demonstrated to be bioequivalent may not have identical quality attributes, making it so they cannot be considered interchangeable in the absence of additional clinical data showing otherwise.5

In the European Union, the EMA does not make determinations regarding interchangeability and therapeutic substitution; instead, those determinations are left to the regulatory bodies of individual countries and to the discretion of treating providers. Whether a pharmacist can automatically substitute a biosimilar for a reference product is determined by each individual European Union state. Regulations in individual countries differ widely and have a major impact on the uptake of biosimilars.4

As of the date of this writing, the FDA has not issued final guidance in a number of key areas, including naming and interchangeability. Interchangeability is considered key to encouraging manufacturers to file biosimilar product applications and to give prescribers more confidence in using biosimilars. At a US Senate subcommittee hearing held September 17, 2015, FDA Center for Drug Evaluation and Research Director Janet Woodcock countered criticism from some congressional members by saying that the agency needs to “get the science right” first.32 During the hearing, Woodcock could not estimate when the FDA will publish these specific guidelines on interchangeability given the complicated authorization process; however, she indicated the FDA would likely issue a new guidance document, in late 2015, on “Statistical Approaches to Evaluation of Analytical Similarity Data to Support a Demonstration of Biosimilarity.”

Other FDA guidance designed to assist in addressing questions of interchangeability in the long-term are starting to emerge. On August 27, 2015, the FDA published new draft guidance on the non-proprietary naming of biologic products.33 Specifically, the agency proposes that reference products and biosimilar products have an international nonproprietary name that shares the name of the reference product, plus an FDA-designated 4-character suffix unique to each product. For example, the name of a reference product could be replicamab-cznm, and a biosimilar to that product could be replicamab-hixf.34 This naming convention is designed to make it easier to track each specific product for postmarketing pharmacovigilance purposes across all settings of care.

In the draft guidance, the FDA states that it is still considering whether the nonproprietary name for an interchangeable product should include a unique suffix, or if it should share the same suffix as its reference product (ie, the nonproprietary name of both the reference product and the interchangeable product could be replicamab-cznm). The FDA is soliciting public comment on the draft guidance, including suggestions for alternate ways to improve active pharmacovigilance systems.33

Another significant FDA regulatory development occurred in September 2014 when the agency released its first version of the “Purple Book,”35 which is meant to be the biologic equivalent of the FDA’s “Orange Book,” which is widely used to determine which small-molecule drug products are substitutable to each other. The Purple Book will list biosimilar and interchangeable biologic products licensed in the United States under section 351(k) of the PHS Act under the reference product to which biosimilarity or interchangeability was demonstrated. Additionally, the resource lists all reference biologic products licensed under section 351(a), side-by-side with all corresponding biosimilars and interchangeable products licensed under section 351(k), and it will be updated periodically when the FDA licenses a biologic product under section 351(a) or section 351(k) of the PHS Act and/or makes a determination regarding date of first licensure for a biologic product licensed under section 351(a) of the PHS Act.36

Clinical Uptake of Biosimilars: the European Experience

If Europe is a good indicator of biosimilar acceptance, then biosimilar uptake in the United States may be modest; there are, however, reasons to believe that the US experience will be different. In Europe, initial acceptance of biosimilars has been relatively slow, even though the rate of adoption continues to increase. Several medical societies in Europe have issued statements expressing concern over the use of biosimilars in extrapolated indications,30 in spite of the fact that Europe has had an abbreviated biosimilar approval pathway in place for more than 10 years and an established safety track record among the 21 biosimilars approved in the European Union to date. The EMA Working Party on Similar Biological Medicinal Products is working to evaluate the safety of extrapolating biosimilar use to other indications.

Depending on differences in local pricing and reimbursement policies, regulatory policy, and stakeholder influence and perceptions regarding use, clinical uptake varies in individual European countries. Germany and France combined account for the majority of biosimilar market share in the region (34% and 17%, respectively), while usage in Spain and the United Kingdom has started to increase. Biosimilar G-CSFs would appear to have achieved the highest level of within-class uptake, accounting for 25% of all European G-CSF sales.6

Healthcare and Biosimilar Uptake in the United States: What to Expect

Historically, many physicians who may have initially been hesitant to prescribe generics, in lieu of brand name drugs, eventually became more comfortable with these products as they established a longer track record of safety over time.

Because biosimilars are new to the US market, there is relatively sparse information available on US physician acceptance and planned uptake of biosimilars, and what is available presents a mixed picture. One analysis found that 70% of physician survey respondents were likely to prescribe biosimilars to a new patient; a majority (69%) said that they were comfortable switching an existing patient from the originator biologic to a biosimilar. It should be noted, however, that this was based on a very small survey sample of physicians who were knowledgeable on the topic of biosimilars.12 Safety and efficacy, followed by out-of-pocket costs to patients, immunogenicity, and price of treatment, were the most important considerations for both physicians and payers regarding biosimilars, according to this analysis.37

In July 2015, the American Society of Clinical Oncology updated its 2006 clinical practice guideline on the use of hematopoietic CSFs in cancer patients who are undergoing chemotherapy.38 The updated guidelines, published in the Journal of Clinical Oncology, specifically cite biosimilars as acceptable. The choice of agent depends on convenience for the patient, cost, and the patient’s clinical situation. Additionally, a survey of oncologists indicated high or moderate levels of interest in using biosimilars.8 However, many US physicians and physician groups continue to voice concerns about the safety and efficacy of biosimilars. The American College of Rheumatology issued a position statement in February 2015 outlining concerns, mostly regarding substitution: it stated that only prescribing providers should be allowed to substitute a biosimilar and objected to compulsory switching of stable patients to a different medication, including a biosimilar, for cost savings without advance prescriber consent. In addition, it said that biosimilars should have distinct names to distinguish them from each other and their reference products and that clinical trials and postmarketing surveillance studies of biosimilars need to be performed in children and adults.39

As debate about the appropriate use of biosimilars continues, it will be important for those making formulary decisions to pay close attention to the emerging biosimilar landscape. Physicians and pharmacists will play a key role in evaluating biosimilars for formulary inclusion in the United States.24 Many health systems already have therapeutic interchange programs in place for a variety of biologic agents.6 Griffith and colleagues have created a detailed list of issues that should be considered when evaluating biosimilars for formulary inclusion, including specific areas related to safety and efficacy (such as product characteristics and clinical data), manufacturer considerations (such as the probability of product shortages), and economic considerations (such as product reimbursement and the availability of patient assistance programs).24

State Legislative and Regulatory Activity

The focus on biosimilar entry combined with concerns regarding interchangeability has prompted some states to take legislative measures. By July 27, 2015, a total of 15 states had enacted biosimilar substitution laws, while additional bills were filed or pending in another 15 states and Puerto Rico.40 Although the provisions in these bills vary, common threads include the following:

  • All products considered for substitution must be approved by the FDA as interchangeable.
  • The prescriber may prevent substitution by writing “DAW” (dispense as written).
  • The prescriber must be notified of any allowable substitution made at the pharmacy.
  • The individual patient must be notified that a substitution was made (and in some states, patient consent would be required).
  • The pharmacist and physician must retain records of substituted biologic medications.

Many of these laws were prompted by concerns that traditional state statutes regulating generic drugs could be misapplied to new biosimilar products that are not identical to the reference product; hence, some states have acted to amend these older laws or add new sections and language to address the medical and chemical characteristics of biologics and biosimilars.40

Patients and Use of Biosimilars

There may be variability in physician willingness to prescribe biosimilars to existing patients compared with patients who have not been treated previously with an originator biologic.12 In addition, certain sub-populations of patients may not necessarily be immediate candidates to switch to a biosimilar product if they are considered to be especially vulnerable to having an unwanted immune response; patients who fall in this category include pediatric patients and immunocompromised patients.41 Finally, physicians may feel more comfortable prescribing biosimilars or extrapolating indications for products that have a specific biomarker (ie, neutrophil count with G-CSF) compared with those that don’t have an easily measureable biomarker (ie, rituximab).30

Because biosimilars are more complex than generic small molecules, the need for patient education will be magnified. The FDA has a page on its website explaining basic principles about biosimilars to consumers; this will need to be supplemented at the patient-provider level with more indepth instructions and support, depending on the patient’s disease state, economic factors, and other variables.42


Biosimilars have the potential to offer physicians, as well as their patients, more therapeutic options for a range of serious illnesses at a potentially lower cost than the innovator reference biologics, which offer potential benefits for clinicians, patients, and payers alike. Biosimilars are already widely accepted in many parts of the world, including the European Union, where such products have had an established safety track record for a decade. Although the United States has lagged behind Europe in terms of having a biosimilar regulatory approval pathway in place, the FDA’s March 2015 approval of the first biosimilar product in the United States is viewed as a watershed event, and many applications for biosimilars are currently in development or under consideration by the FDA.

The ability of biosimilars to lower costs and improve patient access will depend largely on how well biosimilars are accepted by clinicians, payers, and patients. Many clinicians, including physicians and pharmacists, still have questions about the safety and efficacy of biosimilars in actual clinical practice, particularly around extrapolation of indications. There is also confusion around interchangeability and product substitution. Until the FDA issues more specific guidance for the industry, clinicians, payers, and patients are likely to evaluate each new biosimilar product on a case-by-case basis. Payers are likely to adopt reimbursement and formulary management approaches that will encourage adoption of biosimilars. Education of physicians, other healthcare providers, and patients, combined with ongoing evaluation and publication of clinical studies, scientific data, and FDA guidance, will be critical in gaining broad acceptance and uptake of biosimilars.

Author affiliation: University of Michigan, Ann Arbor; Visante, Inc, St. Paul, Minnesota.

Funding source: This activity is supported by an independent educational grant from Boehringer Ingelheim Pharmaceuticals, Inc.

Author disclosure: Dr Stevenson reports being a consultant and advisory board member for Amgen and is employed by Visante.

Authorship information: Concept and design, analysis and interpretation of data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content.

Address correspondence to:

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