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The Complexities of Biosimilars and the Regulatory Approval Process
Steven Lucio, PharmD, BCPS
Participating Faculty

The Complexities of Biosimilars and the Regulatory Approval Process

Steven Lucio, PharmD, BCPS
Created via the Biologics Price Competition and Innovation Act, the biosimilar class of drugs was conceived as an opportunity to introduce competition for commonly used biologics following loss of patent protection and market exclusivity, similar to the generic paradigm that has helped sustain access and innovation for more than 3 decades. The FDA approves a biosimilar after a manufacturer establishes that the product is highly similar to a previously approved originator biologic reference product without any clinically meaningful differences in safety, purity, and potency. Given the concerns about increasing healthcare costs and this new opportunity to reduce the expense associated with biologics, including many commonly used oncology medications, the use of biosimilars will likely increase as numerous stakeholders, including managed care organizations, begin to implement policies to encourage adoption. As biosimilars are a relatively new class of drugs, clinical, scientific, and regulatory aspects continue to evolve and improve. Understanding those various aspects can improve clinician acceptance and advance the science of biologics and biosimilars. In this report, various factors are addressed to improve the knowledge of biosimilars, including clinical, manufacturing, and cost considerations.
Am J Manag Care. 2018;24(11):-S0
Previously untreatable diseases can now be managed effectively in this medical era of tremendous innovation in pharmaceuticals, thus improving the quality of care and outcomes for patients. At the top of this list of novel and valuable therapies are the numerous biologic drugs used in oncology care, such as the hematopoietics; agents such as filgrastim and pegfilgrastim; and the monoclonal antibodies rituximab, bevacizumab, and trastuzumab. These therapies are extremely valuable in terms of the patient benefit they provide. Their value can also be characterized in the billions of dollars associated with their prescribing and use. Biologics dominate the top-selling drugs by sales in the United States and in other markets globally. In 2017, 11 of the top 15 best-selling pharmaceuticals (73%) were biologics.1

The correlation of commonly used medications and the expense of their use is not a novel concept, but an issue that has been managed for many decades via the generic drug approval process. After a period of patent protection and marketing exclusivity, competing suppliers receive approval for generic versions of previously licensed originator medications to preserve and expand the use of molecules, reduce the cost allocated to these treatments, and free overall healthcare dollars for the next iteration of new therapies. Unfortunately, the generic methodology for small-molecule drugs does not apply to the existing environment of biologics. Compared with small-molecule drugs, biologic drugs are much larger molecular weight molecules with complex biochemical structures (eg, peptides, proteins, antibodies, vaccines).2-4 Biological products are manufactured in living systems (eg, bacterial or yeast cell lines) or extracted from biological matrices (eg, blood and blood components). Perhaps most importantly, all biologic medications, unlike generic drugs, vary over their lifecycles, which makes the concept of an “identical” product inappropriate for this market. To understand how these inherent properties are managed to ensure the approval of highly similar products, even across oncology disease states, the concepts, processes, and regulatory requirements that exist to support the desired outcome of less expensive biologics of comparable safety and efficacy will be discussed.

Definitions/Descriptions and Regulatory Aspects

The potential for a biosimilar class of drugs came into existence via the Biologics Price Competition and Innovation Act (BPCIA) of 2009, itself a part of the Patient Protection and Affordable Care Act.5,6 The designation of biosimilars is defined in relation to a reference product in an FDA licensure application such that the biosimilar is “highly similar to the reference product” and that a biosimilar does not differ in a “clinically meaningful” way from the reference product with respect to “safety, purity, and potency.”5,7 The BPCIA created an abbreviated, yet extremely rigorous, regulatory approval pathway for biosimilars as a mechanism to promote innovation and competition in the development of biologics and to open an avenue to lower their cost.8 In practice, 2 phrases in the FDA’s working definition of a biosimilar are emphasized: “highly similar” and “no clinically meaningful differences.”7 These phrases highlight the fact that, unlike small-molecule generics, biosimilars are not identical to their reference products. Given the simplicity of their molecular structure and the well-defined processes for chemical synthesis, the active ingredient in a generic drug product is chemically identical to the brand name product.9 Given the consistency and simplicity of the molecular structure, the FDA usually classifies generic drugs as therapeutically equivalent when bioequivalence to the brand name product is established.9 This equivalence reinforces the concept that a generic drug is intended and expected to behave in the exact same way as its branded counterpart. On the other hand, this level of exactness does not exist for biologics, originator or biosimilar, given the size, complexity, and processes by which these pharmaceuticals are manufactured.3,10 As specified above, biologics are complex, high-molecular-weight molecules that are produced through a living organism, which introduces variations throughout the lifecycle of the biologic. Some variations in the molecular structure of a biologic are less consequential. However, other changes, such as in the primary amino acid sequence of the biologic or in the biologic compound, including posttranslational modifications, such as glycosylation and deamidation, could greatly alter the stability, functioning, and safety profile of these agents.11,12 Biologic manufacturing is closely monitored such that these changes do not result in negative patient outcomes over the lifecycle of the originator. Biosimilars, which are manufactured using different cell lines under different development conditions, will also vary. As a result, the focus of the biosimilar approval pathway is to provide similar assurance that these differences do not impact the clinical performance of the resulting product in relation to the originator brand biologic.11,12

When a biopharmaceutical company obtains approval for a new biological product, their product is recognized as the originator reference to which subsequent agents will be compared. Similar to small-molecule drugs, the manufacturer enjoys a period of market exclusivity for that biological product, and the length of that exclusivity period may vary depending on a host of factors, some of which will be described in subsequent sections of this activity. Given the enactment of the BPCIA and the construction of the related approval pathway, another manufacturer can now pursue development of a biosimilar once that period of exclusivity ends. The BPCIA and guidance documents from the FDA describe the streamlined approval approach for biosimilars.5,7 The FDA guidance on demonstrating biosimilarity recommends a stepwise approach for potential biosimilar products (Figure).7 To gain approval as a biosimilar, the manufacturer must demonstrate that their product does not differ in a “clinically meaningful” manner from the reference product. The biosimilar approval pathway, also known as a 351(k) application, is more targeted in that it requires fewer clinical studies compared with the reference biological product, which is intended to hopefully translate to lower costs—for the manufacturer, the provider, and most importantly, the patient.8 It must be noted, that while the clinical data requirement is reduced, the approval process is no less comprehensive or rigorous. Instead, the testing of a biosimilar includes a greater emphasis on analytical studies to demonstrate similarity with the biological reference product.8 Data from animal studies are still required to assess toxicity and from clinical studies to gauge efficacy, immunogenicity, and pharmacokinetics/pharmacodynamics.7,8 

One of the critical foundational elements of the biosimilar approval process is known as a “stepwise approach.” This concept conveys that each successive step of approval is focused on any unanswered regulatory questions from prior steps. This methodology supports that efficiency of approval in every succeeding step addresses “residual uncertainties” from previous sequences in the evaluation, thus supporting more targeted investigations as the process continues.

The other companion concept that supports the foundation of the biosimilar experience is that of the “totality of the evidence.” Each step of the approval mechanism is not evaluated in isolation, but instead is viewed in aggregate to form a total perspective of the biosimilar molecule, providing additional efficiencies that are scientifically sound and ideally lead to lower development cost.

The generic paradigm is greatly facilitated by the fact that competing versions of a small molecule medication share the same non-proprietary (ie, generic name) of the originator, thus making correlation between products much easier. This standard is different for biosimilars. Given concerns about the ease of pharmacovigilance and the potential for inadvertent substitution of highly similar, yet non-identical biologics, the FDA has finalized a strategy in which biosimilars, and ultimately all originator biologics, will have a modified non-proprietary name. For example, the branded biologic Remicade is also identified by its non-proprietary name of infliximab. Rather than being known simply by that designation, the approved biosimilars of Remicade are known respectively as infliximab-dyyb, infliximab-abda, and infliximab-qbtx. In this model “infliximab” represents the core name shared by the originator and the biosimilars which combined with a four letter, “devoid of meaning” suffix, creates a unique “proper” name for each biologic. Prior to finalization of this approach, the FDA approved one biosimilar, filgrastim-sndz, with a suffix that did convey a meaning, the product’s manufacturer. The FDA has since  continued to apply the devoid of meaning approach for biosimilars and even for newly approved, novel biologics. The presence of this modifier is relevant for accurate reflection and presentation of medication information in electronic medical records and computerized prescriber order entry systems.

A beneficial aspect for oncology practitioners is that the biosimilar paradigm is no longer just theoretical, but has actually resulted in the licensing of products via the pathway described above. The first biosimilars for oncology for the specific treatment of cancer, one for bevacizumab and one for trastuzumab, were approved in 2017, although neither is presently marketed due to originator patent protections and market exclusivities.13,14 However, filgrastim-sndz, a supportive care product, was the first biosimilar approved by the FDA and is increasingly used in place of the reference product, filgrastim.15,16 This specific experience has hopefully served to enlist additional trust in the biosimilar mechanism and prepare oncology physicians and other prescribers for an increasing pipeline of competing products. Still, recent information highlights the numerous practice areas that must continue to be addressed to facilitate the introduction and adoption of biosimilars and minimize any misunderstandings that could unnecessarily curtail use.17,18 In addition to the products that have reached the market, healthcare professionals (HCPs) should expect the approval of additional versions of those same molecules as well as oncology biosimilars for products including rituximab, cetuximab, and pegfilgrastim.19-23

Manufacturing and Assessment Methods

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