Formulary Selection Criteria for Biosimilars: Considerations for US Health-System Pharmacists

Pharmacists will play a key role in evaluating biosimilars for formulary inclusion in the United States. As defined by US law, a biosimilar is a biologic that is highly similar to its reference product, notwithstanding minor differences in clinically inactive components, and should not have clinically meaningful differences from its reference product in safety, purity, and potency. We review biosimilars and the current European Union and US regulatory pathways for biosimilars. Furthermore, we propose a checklist of considerations to ensure that US pharmacists thoroughly evaluate future biosimilars for formulary inclusion. Included in the checklist are considerations related to the availability of preapproval and postapproval safety and efficacy data; differences in product characteristics and immunogenicity between the biosimilar and reference product; manufacturer-related parameters that can affect a reliable supply of quality products; health-system and patient perspectives on product packaging, labeling, storage, and administration; costs and insurance coverage; patient education; interchangeability and differences in the range of indications; and evaluation of institutions’ information technology systems.Key Words: biologics, biosimilars, formulary, pharmacovigilance, reference productThe first biosimilar was licensed for use in humans in the European Union (EU) in 2006; since that time, a total of 11 distinct biosimilar products have been approved for marketing in the EU under 19 different trade names (2 have since been withdrawn) (1 As more patents for biologic drugs approach expiration, the number of biosimilars entering the market is expected to grow.^2,3 Yet, as the market awaits the first US biosimilar approval, questions remain about how this new class of drugs will be evaluated for incorporation into US formularies. In the US, the Biologics Price Competition and Innovation Act of 2009 (BPCI Act)—a part of the Affordable Care Act of 2009—provided for an abbreviated regulatory approval pathway for biosimilars.^4,5 As defined by the BPCI Act, a biosimilar is a biologic product that is highly similar to its reference product, notwithstanding minor differences in clinically inactive components; a biosimilar is to have no clinically meaningful differences from its reference product in terms of safety, purity, and potency. ⁴

Table 1.

Biosimilars authorized in the European Union^a

Biosimilar	Active substance	Manufacturerb	Marketing authorization holder/applicant
Granulocyte colony-stimulating factors
Biograstim	filgrastim	Sicor Biotech UAB	CT Arzneimittel GmbH
Filgrastim Hexal	filgrastim	Sandoz GmbH	Hexal AG
Filgrastim ratiopharmc	filgrastim	Sicor Biotech UAB	Ratiopharm GmbH
Grastofil	filgrastim	Intas Biopharmaceuticals Ltd.; Apotex Nederland BV	Apotex Europe BV
Nivestim	filgrastim	Hospira Zagreb	Hospira UK Ltd.
Ratiograstim	filgrastim	Sicor Biotech UAB	Ratiopharm GmbH
Tevagrastim	filgrastim	Sicor Biotech UAB	Teva Generics GmbH
Zarzio	filgrastim	Sandoz GmbH	Sandoz GmbH
Erythropoietins
Abseamed	epoetin alfa	Rentschler Biotechnologie GmbH; Lek Pharmaceuticals	Medice Arzneimittel Pütter GmbH & Co. KG
Binocrit	epoetin alfa	Rentschler Biotechnologie GmbH; Lek Pharmaceuticals	Sandoz GmbH
Epoetin Alfa Hexal	epoetin alfa	Rentschler Biotechnologie GmbH; Lek Pharmaceuticals	Hexal AG
Retacrit	epoetin zeta	Norbitec GmbH	Hospira UK Ltd.
Silapo	epoetin zeta	Norbitec GmbH	Stada Arzneimittel AG
Growth hormones
Omnitrope	somatropin	Sandoz GmbH	Sandoz GmbH
Valtropinc	somatropin	LG Life Sciences Ltd.	BioPartners GmbH
Follicle-stimulating hormone
Bemfola	follitropin alfa	Polymun Scientific Immunbiologische Forshung GmbH; Finox Biotech AG	Finox Biotech AG
Ovaleap	follitropin alfa	Merckle Biotec GmbH; Teva Pharmaceuticals; Europe BV	Teva Pharma BV
Anti-human tumor necrosis factor alpha 2 monoclonal antibody
Inflectra	infliximab	Celltrion Inc.	Hospira UK Ltd
Remsima	infliximab	Celltrion Inc.	Celltrion Healthcare Hungary Kft

Open in a separate window^aAs of September 3, 2014.^bThe same biosimilar from one manufacturer (eg, Sicor Biotech UAB) may be marketed under different brand names.^cMarketing authorization in the EU withdrawn at the request of the marketing authorization holder.Small-molecule generic drugs can be produced using well-defined chemical processes, but biologic drugs are typically large molecules with a complex structure that are manufactured in bioreactors using living cells.⁶ Because the details of manufacturing processes for biologic drugs are often proprietary to the innovator manufacturer, the processes for biosimilar production, such as cell culture, fermentation, and purification, must be independently developed by the biosimilar manufacturer.⁶ Consequently, there is potential for subtle differences between biosimilars and their reference products.^6–8 Thus, biosimilars will require more extensive evaluation than small molecule generic drugs⁹; the type and amount of clinical data required will be determined on a case-bycase basis.¹⁰The US Food and Drug Administration (FDA) approval pathway for biosimilars recommends a side-by-side comparison with an approved reference product that should include comparative analytic studies to characterize the product and to identify impurities, animal studies to assess toxicity, clinical studies to assess pharmacokinetics and/or pharmacodynamics and immunogenicity, and additional studies as needed to demonstrate safety and efficacy in the intended conditions of use.^10,11 Because this abbreviated approval pathway is based on demonstrated similarity to a well characterized, approved reference product, it is expected that some biosimilars will be approved with fewer patients studied and less clinical efficacy and safety data than were required for the reference product, but with more required analytical information (eg, structure and function).^12,13 However, based on the US definition of a biosimilar, clinical data are not anticipated to significantly differentiate a biosimilar from its reference product. According to the FDA’s interpretation of the BPCI Act, a biosimilar can be approved with fewer indications of use, fewer routes of administration, fewer product presentations, and different formulations and container closures than the reference product.¹⁴ Although no clinically relevant differences in safety or efficacy between a biosimilar and its reference products are permitted, there could be some differences in immunogenicity profiles that are not considered clinically relevant; in some cases, these differences may only become apparent through postapproval safety monitoring.¹⁰ Therefore, it is important for pharmacists to consider additional product- and manufacturer-related parameters when evaluating biosimilars for potential formulary inclusion.⁹Given the unique nature of biosimilars and their abbreviated regulatory pathway, formulary review and therapeutic interchange options will need to be considered for this class of medicines. This review provides an overview of biosimilars, offers insights into EU and US regulatory pathways for biosimilars, and recommends a checklist of considerations for pharmacists when evaluating biosimilars for inclusion in a US health-system formulary.