Currently, “the most significant single cost problem” in medicine is clinical oncology; this is due to the rising incidence rates of cancer as baby-boomers age, and the fact that the cost of cancer chemotherapies and biologics is increasing faster than inflation. Together, these factors created a jump in the cost of chemotherapy, making cancer treatments an inevitable target for health care cost control efforts.1

One cost-control mechanism will be the approval and adoption of biosimilar drugs, also frequently referred to as “similar biotherapeutics,” “subsequent biologics,” and “follow-on biologics.”2  Biosimilars are also sometimes referred to as “generic” biopharmaceuticals, but this is misleading. Unlike generic versions of chemically synthesized drugs, which are intended to be exact molecular duplicates of their reference agents—and for which additional clinical testing for efficacy is therefore unnecessary—biologically produced biosimilars mimic larger, more complex, biologically derived molecules. Therefore, they are more likely to exhibit heterogeneity and small structural differences from reference biologics. Their safety, particularly immunogenicity, is therefore frequently cited as a concern.3

Regulating Biosimilars

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The United States Food and Drug Administration (FDA) definition of biosimilarity requires that there exist no “clinically meaningful differences between the biologic product and the reference product in terms of the safety, purity, and potency of the product.”4 While the FDA has not yet issued final guidance on biosimilars—and no company has yet applied for approval of a biosimilar agent in the United States—this definition indicates stricter regulatory approval criteria for biosimilars than generics, including a need for consideration of clinical research data to establish “interchangeability” with FDA-licensed reference biologics.4,5 Interchangeability is an empirical regulatory criteria that needs to be demonstrated to confirm biosimilarity.

United States Food and Drug Administration Definitions Relevant to Biosimilars

Generics: Homogenous medical chemicals, usually small-molecule compounds, whose bioequivalence to brand-name drugs has been empirically demonstrated.

Bioequivalence: The regulatory criteria for approval of generic drugs, involving empirical demonstration that a generic medication pharmacokinetically “performs in the same manner” as a reference medication, but not requiring duplication of clinical trials.12

Biosimilars: Complex and typically heterogeneous medicinal molecules of biologic origin, such as large-protein antibodies, but with safety and efficacy outcomes have been empirically demonstrated to be statistically “highly similar” to an FDA-licensed reference biologic product, despite “minor differences in clinically inactive components.”4

Interchangeability: Biologics are biosimilar to FDA-licensed reference medicines and “can be expected to produce the same clinical result as the reference product in any given patient.”4 To qualify as interchangeable, the safety risk or risk of diminished efficacy from “alternating or switching” between its use and the reference biologic must not exceed the risks associated with using the reference medication without switching.4

The Biologics Price Competition and Innovation Act (BPCIA) is intended to specify the criteria for biologics approval, however, includes the creation of an “abbreviated licensure pathway” for biopharmaceuticals that more closely resembles the approval requirements for generic drugs.4,6  Once approved by the FDA, the interchangeability of a biosimilar agent will allow product substitution by pharmacists without intervention by a prescribing clinician.4

Since 2008, European Union regulators have approved biosimilar erythropoiesis-stimulating agents and granulocyte colony-stimulating factors; conversely, these approvals have not yet occurred in the United States.2,5 The FDA has issued draft guidance on biologics, outlining the agency’s planned approach to biosimilar approvals under the BPCIA.3 The draft guidance indicates that regulators will adopt a “totality of the evidence” approach in reviewing biosimilar approval applications, assessing medications’ “complexity, formulation and stability,” and taking into consideration mechanisms of action, structure/function relationships, the clinical history of reference drugs, and manufacturing processes.7

In general, biosimilars must be sufficiently chemically, functionally, and clinically similar to their reference agents to ensure the relevance of reference agents’ efficacy and safety histories.3 This requires careful characterization and confirmation of structure, function, and immunogenicity—and in Europe, has led to the requirement that amino acid sequences for the biosimilar product be confirmed as identical to the reference agent.3

Biosimilars should require less clinical trial data overall than do novel biologics; clinical studies will need to be designed to establish noninferiority, resolve “residual uncertainty,” and to detect immunogenicity risks; these trials should not be used alone as the basis for regulatory approvals (Figures 1 and 2).8

Biosimilars in the United States: A Heated Debate

Over the next few years, the patents of several monoclonal antibodies—including rituximab, trastuzumab, and bevacizumab—will expire, thus generating market demand for less-expensive biosimilar agents.5

In 2012, the European Medicines Agency received its first application for a biosimilar infliximab, a monoclonal antibody used to treat rheumatoid arthritis.9