Biosimilar therapeutic agents: issues with bioequivalence and immunogenicity

Abstract

European patents on a number of therapeutic biopharmaceutical agents will expire in 2004 and 2005. These agents and others recently past patent expiry include recombinant human growth hormone, alpha and gamma interferons, streptokinase, interleukin (IL)-2, insulin, glucerase, plasminogen activator, granulocyte colony-stimulating factor, and erythropoietin. Patent expiry for these products opens the door for the development and marketing of generic versions of these drugs, also known as biosimilars or follow-on biologics. The successful introduction of biosimilars into the pharmaceutical market will depend on the establishment of regulatory guidelines that have been adapted for approval of these generic biopharmaceutical agents. Recombinant therapeutic proteins differ significantly from classic small drug molecules, such as diazepam and prednisone, in their size, molecular heterogeneity and complexity, and methods of manufacture. In contrast with classic drugs, it is currently impossible to fully predict the biological characteristics of therapeutic proteins using physicochemical methods. For these reasons, guidelines for demonstrating bioequivalence of biosimilars with approved innovative products must be specially tailored to the characteristics of these molecules. The criteria for regulatory approval of biosimilars differ from those used to evaluate follow-on versions of classic drugs. During the revision of European (EU) legislation concerning medicinal products, the controversial regulatory and patent issues for marketing of biosimilars led to revamping of the regulations by the European Parliament in May of 2004 [1,2]. The revised regulations provide a clearer and more expedient route for developing and testing generic products within the period of protected data exclusivity (8 years for the reference product), and guidance regarding when generics may be sold following expiration of the reference product patent. There is much at stake in establishing regulatory guidelines for approval of biosimilars in terms of the total potential market for these products (approximately US $20 billion, or 24 billion Euros, by 2005) [3]. In addition to the standard demonstration of safety and efficacy, development and marketing approval of biosimilars are complicated by several factors, including: the technically complex methods required to manufacture and characterize biopharmaceutical proteins; susceptibility of these proteins to physical and chemical degradation during and after manufacture; and the observed immunogenicity of several approved biologics such as recombinant streptokinase [4], interferon-beta [5], GM-CSF [6], hirudin, interleukin (IL)-2 [7] and, more recently, epoetin alfa [8], which can lead to neutralization of these biologic agents and lack of efficacy or sometimes severe, adverse reactions. Immunologic safety will be an increasingly important criterion for evaluating the safety of biosimilars, especially in light of the recently observed increase in cases of antibody (Ab)-mediated pure red cell aplasia (PRCA) [9,10]. These cases have been associated primarily with subcutaneous (SC) administration of epoetin alpha (Eprex®, Ortho Biologics LLC, Manati, Puerto Rico), which was reformulated in 1998. Establishing proper and comprehensive guidelines for biosimilars is further complicated by the absence of clear-cut criteria and methods for determining their potential immunogenicity. Preclinical in vitro or in vivo surrogate markers of immunogenicity are not always available or representative of immune responses in patients [11]. Therefore, the definitions for bioequivalence of biosimilars with approved products will likely differ from definitions used for bioequivalence of classic drugs [12,13]. The pharmaceutical and biotechnology industries have different viewpoints from generic drug manufacturers on what is required for evaluating the safety and efficacy of biosimilars for regulatory approval [14,15]. Innovator companies explain that the complexities of manufacture and process validation, the intrinsic heterogeneity of biopharmaceutic products, and the potential immunogenicity of products manufactured by different processes preclude reliance on in vitro surrogates of activity alone for evaluating substitutability of biosimilars [14]. For these reasons, innovator companies maintain that full-fledged clinical trials are required to demonstrate the substitutability and safety/efficacy of biosimilar products. In contrast, manufacturers of biogeneric products argue that surrogate in vitro or in vivo assays that mimic the absorption kinetics and dose–response of reference drugs may be sufficient to demonstrate bioequivalence of biosimilars. These assays can be performed in the absence of large, controlled clinical studies, which are required for approval of pioneer drugs [10,15]. The situation with demonstrating immunologic safety is more problematic, especially with products with a low incidence of immunogenicity. The European Committee for Human Medicinal Products (CHMP) states that the potential immunogenicity of biosimilar products should be evaluated at the preclinical and clinical stages using validated state-of-art techniques, including animal models, physicochemical methods, and computer algorithms [12,16]. However, the lack of standardization of assays for detecting Abs against therapeutic proteins is a major hurdle because of differences in procedure and calibration, assay sensitivity, and other factors [16]. For example, the potential immunogenicity of erythropoiesis-stimulating agents (ESAs), including epoetin, is confounded by the undefined mechanism of the Ab response to these recombinant proteins, with respect to contributing product characteristics or any predisposing patient factors. There is a need for an appropriate in vivo model to fully evaluate the immunogenicity of new ESAs or biosimilars because of the potential development of an immunopathology such as Ab-mediated PRCA [10]. Such a deleterious consequence of treatment underscores the need to unequivocally demonstrate immunologic safety for ESAs and their biosimilars in addition to the classic parameters of safety, efficacy, and bioequivalence [11]. The ultimate proof of immunologic safety of ESAs and other therapeutic proteins will come from results of clinical studies and post marketing analyses [10]. In conclusion, the development of Ab-mediated PRCA in patients receiving reformulated erythropoietin underscores the problems associated with maintaining safety and efficacy of approved products following changes in manufacture. Alterations in protein structure or stability can result in serious reactions in patients or loss of therapeutic efficacy. For these reasons, rigorous criteria must be established by the medical, manufacturing, and regulatory communities to protect patients from adverse immune responses to therapeutic recombinant proteins, in general, and biosimilars in particular. These same criteria will also help to establish standards of manufacture and process validation that can be used by all biopharmaceutical manufacturers. Ultimately, these criteria will ensure the safety and efficacy of biosimilars while reducing the potential for immune neutralization of therapeutic proteins or severe treatment-related complications.