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Current Market and Regulatory Landscape of Biosimilars
Valkal Bhatt, PharmD
Participating Faculty

Current Market and Regulatory Landscape of Biosimilars

Valkal Bhatt, PharmD
The introduction of biologic therapies has improved the treatment landscape for multiple diseases, particularly in the areas of oncology, rheumatology, and endocrinology. Although they are effective, biologics are associated with increased costs that result in economic burden for healthcare professionals and patients. Biosimilars are biologic medical products that are almost an identical copy of the original product. There are differences in the regulatory requirements for the original biologic product and a biosimilar, as biosimilars gain FDA approval through an abbreviated approval pathway. The incorporation of these products into the US market will potentially result in improved patient access and decreased healthcare costs. There are barriers, such as lack of familiarity, that affect the use of biosimilars. Strategies to overcome these barriers are essential to improve the uptake of these products in the United States.
Am J Manag Care. 2018;24:-S0
The introduction of biologic medications has significantly improved the outcomes of many difficult-to-treat diseases, particularly within the oncology, rheumatology, and endocrinology therapeutic areas. Many biologics, however, are highly expensive medications, which presents a significant economic burden for patients, providers, and the healthcare system overall. Biosimilars, biologic medications containing a highly similar active ingredient compared with the reference product, have the potential to reduce healthcare expenditures and improve access to potentially life-saving medications.

As biosimilars continue to advance, identifying strategies to optimally incorporate these agents into clinical practice is critical. Educating healthcare professionals (HCPs) on biosimilars and the regulatory and approval process is imperative to evidence-based decision making and patient access to optimized care.

Historical Landscape

Historically, FDA approval of generic chemical drugs was allowed by the Drug Price Competition and Patent Term Restoration Act of 1984, also known as the Hatch-Waxman Act.1 The act is credited with lowering the cost of drugs and expanding the generic drug industry in the United States.1 Cost savings are achieved by generics through avoiding the enormous expenses of drug research, clinical trials, and development and marketing efforts amassed by brand-name manufacturers.

The FDA Center for Drug Evaluation and Research (CDER) regulates prescription brand name and generic drugs, over-the-counter drugs, and biologics.1 FDA approval of a generic drug requires proof of identical chemical structure and pharmacokinetic equivalence to the original product, allowing the generic manufacturer to reference the safety and efficacy data for the FDA-approved brand drug while abiding by manufacturing and reporting standards.1 Traditional generic pharmaceuticals are not required to be evaluated in an independent clinical trial because the law permits clinical data to be extrapolated from the reference product.1 Chemical drugs are regulated by the FDA using a new drug application (NDA) or an abbreviated new drug application (ANDA) under the Federal Food, Drug, and Cosmetic Act (FFDCA). This established framework provides a mechanism for the approval of generic chemical drugs.

The first biologics were developed by the industry during this time of regulatory debate and development. Human insulin (Humulin-R) was approved by the FDA in 1982, becoming the first human biologic to enter the US market. Following were human growth hormone (Protropin) in 1985, alpha interferon (Intron-A) in 1986, tissue plasminogen activator (Activase) in 1987, and erythropoietin (Epogen) in 1989.1

Originally, certain biologics were regulated as chemical drugs under the FFDCA rather than the Public Health Service Act (PHSA).1 Congress gave the FDA authority over the marketing of insulin in 1941. During this time, biologics, such as insulin, were extracted from animals, becoming known as the “natural source.”1 The National Institutes of Health (NIH) managed the natural source biologics with a small group being the exception, including insulin, glucagon, human growth hormone, hyaluronidase, urokinase, and several hormones that were under the authority of the FDA. The FDA lacked the authority, however, to approve biosimilars as patents for biologics expired. As a result, the US biologics market lacked the competition seen between chemical brand-name and generic drugs.1

The NIH regulated most biological products until 1972, when the responsibility was completely transferred to the FDA. Currently, biologic agents are regulated under the PHSA (rather than the FFDCA), requiring a biologics license application (BLA) to obtain licensure for marketing by the FDA.1 Although the Hatch-Waxman Act provided a pathway of approval for generic drugs under the FFDCA, the PHSA lacked a defined regulatory framework for biosimilars.1 Manufacturers were effectively blocked from submitting follow-on applications for biologics licensed under the PHSA, and were instead limited to a niche group of said natural source biologics previously approved under the FFDCA.1

Abbreviated Approval Pathway for Biosimilars and Interchangeability

The current established legal pathway for the approval of biosimilars was achieved through the Biologics Price Competition and Innovation Act (BPCIA), signed by President Barack Obama on March 23, 2010.1 The BPCIA was enacted as Title VII of the Affordable Care Act (ACA, P.L. 111-148). It established an abbreviated pathway for regulatory approval of biosimilars (the 351 [k] pathway), allowing the FDA discretion for marketing approval with less-extensive testing, as clinical safety and efficacy of the biologic molecule is already demonstrated by the innovator.1 Under the act, the biosimilar sponsor is required to show that a biosimilar candidate has no clinically significant differences, aside from minor differences in clinically inactive components between it and the reference-biologic in terms of safety, purity, and potency. The sponsor is also required to demonstrate that the biosimilar is expected to produce the same clinical effect as the reference-biologic. Thus, an approved biosimilar should not be expected to differ from the reference-biologic in safety and efficacy.

There are key differences in regulatory requirements for approval of a reference-biologic, compared with the requirements for the approval of a biosimilar. The manufacturer of the reference-biologic is required to produce analytics on the drug’s composition and formula.2 They must also undertake preclinical testing to identify toxicities and demonstrate therapeutic effects in an animal model. Clinical trials from phase 1 studies of the pharmacokinetics to phase 2 and phase 3 safety and efficacy studies hold the highest cost burden for these manufacturers and are necessary to demonstrate therapeutic benefit without excess toxicity for target disease.2 In contrast, most of the cost burden for a biosimilar manufacturer rests on the analytics of the drug composition and formula, confirming the high similarity to the reference-biologic.2 Although demonstrating similarity to the reference-biologic in terms of primary structure is straightforward, doing so for higher orders of structure (secondary, tertiary, and quaternary) is very challenging. Post-translational modifications must be identical or highly similar and variations due to oxidation and deamination warrant consideration.2 Such variables, however, are inherent to all biologics and can theoretically have a significant impact on clinical safety and efficacy parameters (with both biologics and biosimilars).

Antigen binding and avidity of the biosimilar must also match that of the reference-biologic as determined by in vitro studies. Such studies provide data on biosimilar functions associated with antigen binding (Fab) fragment (neutralization and receptor activation) as well as functions associated with fragment crystallizable region (Fc): apoptosis, antibody-dependent, cell-mediated, and complement-dependent cytotoxicity. Of equal importance are assays on antigen binding: Fc receptor for IgG (Fcy receptor), neonatal Fc receptor, and complement components.2

Randomized controlled trials (RCTs) for biosimilars exist to reaffirm data following the physiochemical and in vitro analyses.2 If all data from physiochemical and in vitro studies imply the biosimilar and reference-biologic are equivalent, clinical efficacy is assumed. Biosimilars of this nature may require a single pharmacokinetic study to demonstrate equivalence and a single RCT to establish equivalence to the reference-biologic in clinical safety, efficacy, and immunogenicity.

Extrapolation is established in the totality of evidence presented in placebo-controlled phase 3 RCTs and functional data of the biosimilar in each condition for which licensure is sought. Such data packages may include the pharmacokinetics and biodistribution of the product in different patient populations, immunogenicity in different patient populations, and any differences in expected toxicities in each condition of use.3 Although study populations in RCTs should represent the indications sought for approval, extrapolation between indications is normal if a common mechanism exists and equivalence is displayed in a single indication.2

Biosimilars may be further evaluated to determine interchangeability with the reference-biologic. Interchangeability is defined, under the BPCIA, as meeting a high standard of similarity to the reference-biologic and the biosimilar has no clinically meaningful difference.3 Additionally, the interchangeable product is expected to produce the same clinical result as the reference-biologic. For a product administered more than once to an individual, the risk (in terms of safety and reduced efficacy) of alternating between use of biosimilar and reference-biologic is not greater than the risk of using the reference-biologic only.3 To gain marketing approval as interchangeable, the FDA additionally requires one or more switching studies evaluating the effects of switching patients between biosimilar and reference-biologic to monitor any changes in safety events and establish interchangeability of products.3 A sponsor may seek licensure for a proposed interchangeable biosimilar in fewer than all conditions of use as the reference-biologic is licensed; it is recommended, however not required, by the FDA to seek licensure for all conditions of use held by the reference-biologic if able.3

As with all biologics, quality and purity of biosimilars are subject to changes in the manufacturing process due to modernization of equipment, changes in scaling, or improving efficiency. The International Conference on Harmonization Q5E tripartite comparability guidelines use comparability analyses to determine if a biologic medicine retains similar quality before and after changes in manufacturing processes.4 Such guidelines allow marketing to continue under the current product label without the need to conduct a clinical development program analyzing the product before and after manufacturing changes. Molecular changes in the product must be shown to have no impact on efficacy, safety, and immunogenicity. If analytical differences are observed and there is a questionable relation to efficacy and safety, a combination of nonclinical, clinical, and/or analytical studies may be warranted.5 

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