Commentary
Biosimilars: A consideration of the regulations in the United States and European union

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Abstract

Biosimilars are defined as biological products that are highly similar to a reference product, notwithstanding minor differences in clinically inactive components. Biosimilars show no clinically meaningful differences in safety, purity, and potency of the product in comparison to the reference product. With the ever looming patent expiry of some major high cost biologics, biosimilar production is becoming ever more lucrative to companies. Europe (EU) set the precedent, followed by the United States (US) in early 2012, for the approval process for biosimilars. Therefore, the purpose of this paper is to explore the nature of the regulatory processes in the US and EU and to determine the requirements of each in the approval process of a biosimilar. The current Food and Drug Administration (FDA) and European Medicines Agency's (EMA) guidance documents for biosimilars were reviewed revealing a need for further clarifications, as well as specifically addressing Celltrion's and Sandoz's application for approval for the biosimilars infliximab and filgrastim, respectively. Currently, the FDA and EMA focus on comparability in terms of the clinical, pharmacokinetic (PK)/pharmacodynamic (PD), preclinical, biological activity, and physiochemical characterization results, as well as requiring a robust and consistent manufacturing process. Both the EU and US have prepared guidance documents for biosimilars that will result in biotherapeutics that are as safe and efficacious as the innovator product but the necessity exists to globally harmonize international nonproprietary naming nomenclature and clarify how the concept of pharmacovigilance, extrapolation, and interchangeability will be handled and regulated in the future.

Introduction

As many biopharmaceuticals approach the end of their patent life, the development and approval of a “generic” version for these original innovator biologics becomes appealing to the biotechnology industry, especially in the US where previously no tested direct pathway for biosimilar approval existed. With twelve innovator biologics (e.g., Neulasta, Remicade, etc.) with a global sales revenue of $67 billion set to undergo patent expiration by 2020, the potential global market for emerging biosimilars is obviously an appealing niche for companies looking to add capital and products to their pipeline (Generics and Biosimilars Initiative, 2012) (Table 1). Thus, many companies have started pursuing their own versions of previously approved innovator biologics to gain a portion of the market share once patent life has expired. Therefore, an impending influx of biosimilars into the market place will soon be seen.

Biosimilars are defined as biological products that are highly similar to a reference product, notwithstanding minor differences in clinically inactive components. The product shows no clinically meaningful differences in safety, purity, and potency compared to the reference product (U.S. Department of Health and Human Services, 2012a, U.S. Department of Health and Human Services, 2012b, U.S. Department of Health and Human Services, 2012c)). However, with the emergence of biosimilars also comes the need for crucial new regulations. The existing regulations that govern the approval pathways for generic products aren't appropriate for biosimilars due to the inherent variability associated with the production methods utilized by different companies and even different facilities within the same company.

Biologics are made through manipulation of living organisms via recombinant DNA technology to produce specific proteins. These proteins can be 200 to 1000 times larger than a small molecule drug and are complex heterogeneous proteins with more variable molecular weights than small molecule drugs (AMGEN., 2014, Schellekens, 2009). Furthermore, biologics are highly dependent on the manufacturing steps and handling undertaken in the production line. Protein structural changes include oligomerization, modification of the protein primary sequence, glycosylation patterns or the conformational state (Schellekens, 2009). Production of the same protein by different methods or in different facilities can lead to variable and unique final products, each having a different and distinctive safety, efficacy, and purity profile (Schellekens, 2009). Moreover, biosimilars are not identical copies of the innovator biologic and therefore cannot be considered true “generics”. Biosimilars are similar to but are not exactly the same as the original. Basic differences in methodology potentially can exist between competing companies due to the proprietary nature of the manufacturing line and strategies utilized by these competitors. Even minor alterations in the production process can lead to microheterogeneity, which is defined as slight changes in molecular structure, stability, and production cell line behavior, growth conditions, vectors, and purification processes (Fig. 1). For these reasons, the process of creating biosimilars is challenging.

To date, companies have gained approval via differing pathways for biosimilars in the US as well as in Europe (EU) (Table 2). The first biosimilar to be approved for use in the EU was Omnitrope (somatropin), a biosimilar version of Pfizer Pharmaceutical's Genotropin (somatropin) (Ahmed et al., 2012). Genotropin, an injectable recombinant human growth hormone, is used to treat growth hormone deficiency in pediatric and adult patients (Ahmed et al., 2012). Omnitrope was also approved for use in the US, but not as a biosimilar to Genotropin, because the US did not have framework in place for biosimilars at that time (Ahmed et al., 2012). Omnitrope (somatropin) was therefore approved under section 505(b) (2) of the FD&C Act in 2006 (Chow et al., 2011). In response to a need for a clear approval pathway to assist the pharmaceutical industry in identifying the information necessary to support biosimilar applications, and clarification of the scientific and regulatory principles used to evaluate those applications, the FDA released draft guidance documents for the approval of biosimilars in early 2012 (U.S. Department of Health and Human Services, 2012a, U.S. Department of Health and Human Services, 2012b, U.S. Department of Health and Human Services, 2012c, U.S. Department of Health and Human Services, 2014)).

Due to the unique challenges of manufacturing biosimilars, regulatory considerations are continuing to evolve in the US and EU, where both the FDA and EMA have prepared guidance documents for the approval of biosimilars. The EMA outlines product-specific approval pathways based on biological classification. In contrast, the FDA currently relies on a risk-based, case-by-case, totality-of-evidence approach (Fig. 2, Fig. 3). Moreover, pharmacovigilance programs in the EU mandate postmarketing safety monitoring to address immunogenicity and adverse events (Calvo and Zuñiga, 2014). However, the FDA has yet to release finalized guidance documents in the US specifically addressing biosimilar pharmacovigilance requirements (Camacho et al., 2014). Without appropriate pharmacovigilance monitoring guidelines in place in the US, tracking and attributing adverse events and immunogenicity to a specific biosimilar may be impossible and lead to an inaccurate determination of the related adverse event's root cause.

Although both the FDA and EMA's guidance documents provide the framework for biosimilar submissions, four important questions remain unanswered, mostly in the US. First, guidance regarding pharmacovigilance, specifically in the US, is yet to be fully addressed. The need exists for guidelines which address a robust pharmacovigilance program in the US to provide for accurate adverse event root cause determination. Second, how biosimilars are to be named in comparison to the innovator product needs to be considered both in the EU and US. A direction should ideally, be taken toward global harmonization in support of effective pharmacovigilance programs. Third, clarification on how extrapolation of indications needs to be provided, particularly in the US. Clarification in this regard to extrapolation is especially true where the absence of a direct clinical data comparison for all indications between the innovator and biosimilars is present. Fourth, the necessary requirements to prove interchangeability must be clarified. Interchangeability guidance should be detailed in the EU where a total lack of guidance exists at the EMA level. Guidelines in the US have yet to be finalized detailing interchangeability. Without clear direction, the pharmaceutical industry may not provide enough data in a biosimilars submission, leading to delayed regulatory approval and an increased cost and time to the manufacturer, ultimately leading to a more expensive biosimilar for the consumer.

In this review, basic principles of biosimilar manufacturing are discussed, along with accompanying potential sources of biosimilar microheterogeneity. Furthermore, an overview of the guidance outlining the approval process for biosimilars in both the EU and US is provided. Examples of biosimilars that have been approved will be described, including Celltrion's biosimilar for infliximab, the first approval of a biosimilar monoclonal antibody in the EU, and Sandoz's biosimilar for filgrastim, a granulocyte colony-stimulating factor representing the first 351(k) approved biosimilar in the US. Finally, regulatory opinions regarding the nuances between the FDA and EMA are presented with respect to pharmacovigilance programs, naming strategies, extrapolation of indications, and interchangeability strategies. Information presented in this review supports the need for finalized and/or clarified guidance specifically addressing pharmacovigilance safety monitoring in the US, a direction toward global harmonization for biosimilar naming in the EU and US in support of robust pharmacovigilance programs, detailed extrapolation requirements in the US, and interchangeability requirements that are scientifically justified through clinical data in the US.

Section snippets

Microheterogeneity of biosimilars

Unlike generic small molecule pharmaceuticals where the active pharmaceutical ingredients are exact copies of the originator product, biosimilars are not identical copies to the innovator biologic. Therefore, biosimilars can essentially be thought of as snowflakes. As no two snowflakes are identical nor is a biosimilar and its corresponding innovator product. Due to the complexity of the structure of the biologics, as well as the nature of the differences in the manufacturing process,

Regulatory considerations for biosimilars

Regulations regarding the approval of biosimilars differ slightly between the US and EU. Obviously, the guidelines that govern the approval of low molecular weight (LMW) generics, which have identical active ingredients, will not suffice for biological products due to differences in manufacturing, amino acid sequence, impurities, stability, and/or side effects. The following section discusses the EU and the US with regard to their corresponding regulatory approval process for biosimilars.

Celltrion: creation of a biosimilar

In order for a biopharmaceutical to be considered a biosimilar, it must show comparability in several categories. These categories include physico-chemical characterization, PK/PD, pre-clinical comparisons, clinical safety and efficacy, immunogenicity, biological activity, purity, stability, as well as showing robust and consistent manufacturing. Because manufacturing facilities utilize different processes than that of the innovator company in the development of a biosimilar, producing a

Sandoz: paving the way for biosimilars in the US

Filgrastim, a granulocyte colony-stimulating factor, used to reduce the duration of neutropenia in patients undergoing chemotherapy or bone marrow transplantation, and for mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis (Food and Drug Administration, 2015a, Food and Drug Administration, 2015b). Sandoz, a Novartis company, gained the FDA Oncologic Drugs Advisory Committee's recommendation for approval on Jan. 7, 2015 for EP2006,

Regulatory opinions

With the variations in protein composition and manufacturing practices, a one-size-fits-all approach to the biosimilar approval pathway clearly is not possible with the current existing technology and characterization practices. Because the EMA has had a pathway for the approval of biosimilars since 2005, this agency's guidelines are considered the gold standard for the authorization for biosimilar products (Wang and Chow, 2012). The FDA has only approved one biosimilar under the new regulatory

Conclusion

As more and more biologics reach the end of patent life, the development of biosimilars becomes increasingly more attractive to companies. The EMA provided the framework in 2005 and laid the foundation upon which the manufacturing and approval of both safe and efficacious biosimilars could be achieved. Since then, 19 biosimilars have been approved in the EU under the current regulation, and more are currently under review. The first biosimilar mAb was approved by the EMA in 2013, setting the

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