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Recognizing and Addressing Challenges to the Adoption of Trastuzumab Biosimilars and HER2-Targeted Therapies
Jeremy Whalen, PharmD, BCOP
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Managed Care Considerations for Navigating Biosimilar and HER2-Directed Therapies for the Treatment of HER2-Positive Breast Cancer

Recognizing and Addressing Challenges to the Adoption of Trastuzumab Biosimilars and HER2-Targeted Therapies

Jeremy Whalen, PharmD, BCOP
Oncology biologics are one of the fastest-growing segments of pharmaceutical development, bringing more options to patients, including those with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The advent of multiple oncology biosimilars is affecting this patient population, as 5 trastuzumab biosimilars had been FDA approved as of the end of 2019; only 2, however, have been commercially marketed. Trastuzumab serves as the foundation for treatment for patients with HER2-positive breast cancer. HER2-targeted antibody–drug conjugates have been developed to enhance efficacy, improve safety, and/or create more convenient administration. Three biologic drug entities have been approved using trastuzumab, including 2 antibody–drug conjugates and a subcutaneous trastuzumab formulation that includes hyaluronidase. More products are being developed, so biosimilars and other HER2-targeted therapies may further disrupt the biologic market. Many challenging questions surround the adoption of oncology biosimilars, including regulatory pathways, efficacy, safety, cost-benefit, and comparability. The Biologics Price Competition and Innovation Act established an abbreviated regulatory approval pathway for biosimilars to create a catalyst for innovation and competition in the biologics market and to lower the costs of biologics. Challenges to adoption of therapeutic oncology biosimilars continue in the United States and include a lack of directed education to providers and patients, residual concerns regarding efficacy and safety, and practices including “pay-for-delay.” The uptake of oncology biosimilars is also affected by multiple issues stemming mainly from cost of care, including drug cost, patient access, formulary inclusion, and treatment management algorithms. Managed care organizations and payers need to be familiar with the biosimilar approval process, the concerns of stakeholders (eg, providers and patients), and factors influencing HER2-directed therapies, including the use of biosimilars and antibody–drug conjugates in today’s market.

Am J Manag Care. 2020;26:S23-S31.
Trastuzumab, a humanized monoclonal antibody (mAb) that is a human epidermal growth factor receptor 2 (HER2) receptor antagonist, is a biologic drug that serves as a foundation of the treatment of HER2-positive breast cancer in the neoadjuvant, adjuvant, and metastatic settings.1 Additional trastuzumab indications include HER2-overexpressing metastatic gastric and gastroesophageal junction adenocarcinoma and cancers that are identified based on diagnostic testing.2 For each year between 2014 and 2018, trastuzumab experienced annual worldwide sales of approximately $7 billion.3,4 With the end of trastuzumab’s US market exclusivity in 2019, biosimilars of the drug are expected to capture some of the market share. As of December 2019, 5 biosimilars of trastuzumab had been approved by the FDA, although only 2 are commercially available to date.5 However, the manufacturer of trastuzumab has subsequently developed and marketed 2 additional HER2-directed therapies with some overlapping indications with the reference product: ado-trastuzumab emtansine (Kadcyla), a conjugate of the mAb and a microtubule inhibitor; and a combination product, trastuzumab/hyaluronidase-oysk (Herceptin Hylecyta).6-8 Fam-trastuzumab deruxtecan-nxki (Enhertu), a HER2-directed mAb with a topoisomerase inhibitor conjugate, was also approved in late 2019, adding to the armamentarium.9 As the availability of trastuzumab biosimilars and HER2-directed therapies increases, managed care professionals will face challenges that are primarily based on cost of care and can impact patient access, formulary decisions, and clinical care plans. To address those challenges, managed care professionals should understand the regulatory pathways for approval of biologics and biosimilars as well as understand the concept of antibody drug-conjugates.

FDA Biosimilars Regulatory Pathway


The FDA regulates the approval of drugs through a variety of mechanisms. With the era of biologics and the passing of the Biologics Price Competition and Innovation Act (BPCIA), 3 pathways have been authorized for the approval of biologics: (1) the full 351(a) Biologics License Application (BLA) pathway, (2) an abbreviated 351(k) pathway for biosimilars, and (3) the 351(k)(4) pathway for interchangeable biosimilars.10 This article will provide an overview of the nuances of these regulatory pathways, presenting them in comparison with the small-molecule drug approval pathway. The intent is to improve managed care professionals’ understanding of biosimilars, including those used for oncology applications; HER2 antibody–drug conjugates will also be reviewed. With the current US approval of 5 biosimilars, a subcutaneous trastuzumab/hyaludronidase product, and 2 HER2 antibody–drug conjugates, this timely information will be useful in the context of treatment of HER2-positive breast cancer.

Small-molecule Generic Approval (Hatch-Waxman Amendments)

A perspective on small-molecule generic drugs is helpful because the law creating small-molecule generic drugs was a model for the law creating biosimilars. In addition, knowledge of the differences between small-molecule generics and biosimilars is necessary to properly educate patients and healthcare professionals. The term “generic drug” refers to “a medication created to be the same as an existing approved brand-name drug in dosage form, safety, strength, route of administration, quality, and performance characteristics.”11 The brand-name and generic drugs in question contain an active pharmaceutical ingredient (API) that can be synthesized chemically. By virtue of chemical synthesis, the API in a brand-name drug product and a corresponding generic drug product are identical. This key point is one of the major differentiating factors between generics and biosimilars.

The Drug Price Competition and Patent Term Restoration Act (colloquially referred to as the Hatch-Waxman Amendments) was passed in 1984 to establish a regulatory mechanism for the approval of small-molecule generic drugs as a means to rein in high drug prices.12-14 To prompt competition in the prescription drug marketplace, the Hatch-Waxman Amendments “established bioequivalence as the basis for approving generic copies of drug products”15 through the streamlined regulatory pathway called the abbreviated new drug application (ANDA), which was originally developed by the FDA in 1969.14 Generic drug applications submitted through the ANDA process do not generally require original preclinical or clinical safety and efficacy data to gain FDA approval. The generic drug manufacturer must conduct clinical pharmacokinetic (PK) studies or, in certain instances, in vitro dissolution studies to demonstrate bioequivalence.16 Thus, the generic drug applicant would have to establish that their product’s API is identical to that of the brand-name product and that their product is bioequivalent.13,15 Bioequivalence is determined if no significant differences in the rate and extent of absorption are demonstrated with the generic product compared with those of the brand-name product.

The goal of the Hatch-Waxman Amendments to lower drug prices has been successfully met. The addition of generic products to the market puts downward pressure on drug prices, with the greatest effects seen after 2 or 3 generic manufacturers introduce products.17 Market research has shown that 6 months after a generic drug is launched, the generic products can capture 75% or more of the brand-name market share at a price discount of 40% or more.18

BPCIA of 2009

The BPCIA of 2009, which was a part of the Patient Protection and Affordable Care Act, codified the biosimilar class of drugs under the Public Health Services (PHS) Act.10 The BPCIA also established an abbreviated regulatory approval pathway for biosimilars to spur innovation and competition in the biologics market as a means to lower the costs of biologics.19-21 While the Hatch-Waxman Amendments were an inspiration for the BPCIA, there are several key differences between the laws.14,19 One obvious distinction is that the BPCIA covers biologics, whereas the Hatch-Waxman Amendments addresses small-molecule drugs. The approach to FDA authority is substantially different between each legislation. With Hatch-Waxman, the FDA was required to create regulations that specify the types of data necessary for the ANDA process. However, as set out by the BPCIA, the FDA is not bound to a pre-established set of data for approvals via the streamlined 351(k) pathway, which has resulted in a stepwise, totality-of-evidence approach described by an FDA guidance document for industry in which the amount of clinical and preclinical data is determined on a case-by-case basis.19,22 Under Hatch-Waxman, a single approval mechanism based on bioequivalence was created, whereas the BPCIA created 2 approval categories: biosimilar and interchangeable biosimilar. Market exclusivity of generic drugs and biosimilars differ as well. The first generic drug of a brand-name product benefits from 180 days of market exclusivity, whereas the first interchangeable biosimilar of a reference biologic would have interchangeable market exclusivity for 1 year under the BPCIA.19,22,23 A summary of the major differences between the Hatch-Waxman Amendments and the BPCIA are listed in Table 1.19

To further discuss the differences among an original biologic and its biosimilars and antibody–drug conjugates, a few definitions are helpful. The reference biologic or reference product is the original biologic that was approved and licensed under section 351(a) of the BPCIA (ie, the full BLA).10,20,21,24 A biologic is deemed a biosimilar if it was approved and licensed under section 351(k) of the BPCIA.10 A biosimilar is highly similar to the reference product, notwithstanding minor differences in clinically inactive components, and there are no clinically meaningful differences in terms of safety, purity, and potency.10,22 Additionally, the biosimilar must have the same route of administration, dosage form, and strength as the reference product. An interchangeable biosimilar is a product within a subset of biosimilars, as the interchangeable biosimilar would be approved and licensed under subsection 351(k)(4) of the BPCIA.10 The makers of an interchangeable biosimilar, in addition to satisfying the biosimilar requirements, must demonstrate that their product would produce the same clinical result as the reference product in any given patient. They must also demonstrate that switching between the interchangeable and reference product in a single patient would not increase the risk of safety issues or diminished efficacy compared with using the reference biologic product alone.10,25 The FDA has concluded that a product approved as an interchangeable biosimilar may be substituted for the reference product without consulting the prescriber, similar to the current practice with small-molecule generics. To date, no applications have been made for an interchangeable biosimilar following the FDA’s final ruling in May 2019. Other HER2-targeted therapies, including HER2 antibody–drug conjugates, are licensed under the full 351(a) BLA process.26-28 The Food, Drug, and Cosmetic Act (FD&C Act) 505(b)(1) and 505(b)(2) pathways have been used for certain biologics, most prominently, insulin products. Notably, as of March 23, 2020, biologics approved under the FD&C Act will be deemed biologics under the PHS Act.29

FDA Approval Process

The BPCIA does not mandate, within the legislation, the specific parameters that the FDA must use to evaluate and approve biosimilars or interchangeable biosimilars,19,22 so the FDA has developed a number of guidance documents for the industry.30 The FDA’s guidance on demonstrating biosimilarity describes its perspective on the stepwise and totality-of-evidence approach.22 The stepwise approach identifies 3 categories of studies, which are depicted in Figure 131: comparative quality studies, comparative nonclinical studies, and comparative pharmacology and clinical studies.22,31

Studies Comparing Biosimilar With Reference Product

The comparative quality studies focus on characterizing and comparing the physicochemical, structural, and functional properties of the proposed biosimilar in relation to the reference product. Many of the biologics and biosimilars—particularly those used in oncology, including trastuzumab and its biosimilars (Table 25)—are mAbs.31

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