Biosimilars: An Emerging Category of Biologic Drugs for Emergency Medicine Practitioners

Katelyn Sylvester 0 Megan Rocchio 0 Nahal Beik 0 John Fanikos 0 0 K. Sylvester (&) M. Rocchio N. Beik J. Fanikos Department of Pharmacy Services, Brigham and Women's Hospital , 75 Francis Street, Boston, MA 02115, USA Biologics are the fastest growing segment of annual United States (US) drug expenditure. Biologics are complex proteins derived from living sources that are important therapy for a variety of diseases. The US is now poised to introduce biosimilars, which are copies of biologics that are not manufactured by the innovator company and are approved under an abbreviated regulatory process. Biosimilars are intended to offer comparable safety and efficacy to the reference biologic at a lower cost. Because of the complexity of producing biologics, the manufacturing process for biosimilars may differ from that of the reference biologic, which may result in subtle changes in biological characteristics and clinical activity. Questions exist regarding whether these slight differences allow the products to be interchanged with the reference product and if unique adverse events will occur with use. While the Biologics Price Competition and Innovation Act outlined the abbreviated approval pathway for biosimilars, guidance from the US Food and Drug Administration (FDA) is needed on specific details of the approval process. The FDA has recently provided guidance about the scientific and quality requirements for demonstrating biosimilarity, but a number of unanswered questions still remain, including concerns about immunogenicity, product naming, and the exact cost savings from biosimilars. Emergency Medicine practitioners must have a sound understanding of these issues to ensure patient safety and avoid complications in care. - Annual spending on prescription medications is forecasted to reach $372 billion in the United States (US) and $1.2 trillion worldwide by 2016 [1]. Biologics, medications synthesized through biotechnology, are the fastest growing segment of the pharmaceutical market. Biologics are generated by cells or living organisms through recombinant deoxyribonucleic acid (DNA) technology, controlled gene expression, or antibody production, and encompass a wide range of substances, including hormones, vaccines, growth factors, blood products, monoclonal antibodies, and advanced technology products (e.g., proteinantibody combinations, gene therapy biological products) [2]. The FDA approved the first biologic human insulin (Humulin) in 1982 [3]. Since then, the pharmaceutical industry has developed many biologics for the treatment of acute life-threatening diseases, such as cancer and cardiovascular illness, and for chronic conditions like diabetes, anemia, rheumatoid arthritis, and multiple sclerosis, and for rare genetic conditions, such as Gauchers disease and Fabry disease. Health providers are now trying to balance the pressures of prescribing these agents early, when the disease course may be prevented or modified, with the challenges of patient and insurer affordability. After 30 years on the market, the patents on many of these recombinant biologics will soon expire (Table 1) [4, 5] and the US pharmaceutical marketplace is now poised for the introduction of biosimilars. It is therefore important for Emergency Medicine practitioners, including physicians, physician assistants, nurses, and pharmacists to understand the issues surrounding these agents to ensure optimum patient care. Table 1 Biologics, therapeutic uses, global sales, and patent expiration Hepatitis B, hepatitis C Interferon beta 1a Interferon beta 1a JIA juvenile idiopathic arthritis, G-CSF granulocyte-colony stimulating factor Biosimilars are simply described as copies of biologics that are not manufactured by the innovator company and are approved under an abbreviated regulatory process. Because it is not possible to copy a biologic in the precise manner that small molecules can be replicated, the term generic biologic is inappropriate. Therefore, a variety of other terms have been used for these products, such as follow-on biologics, biogenerics, and postpatent biologics. During the last several years, and especially after the introduction of the legislation described below, the term biosimilar has become the standard term, but definitions are not standardized. Recently, a more detailed consensus definition was proposed: A biosimilar is a copy version of an already authorized biological medicinal product with demonstrated similarity in physicochemical characteristics, efficacy and safety, based on a comprehensive comparability exercise [6]. Scope and Impact Global biologics sales amounted to approximately $93 billion in 2009 and are expected to be worth more than $167 billion by 2015 [7]. Biologics sales are expected to continue to grow at least twice as fast as those of conventional, chemical based, small-molecule medications. By 2016, ten biologics are expected to occupy the top 20 positions in pharmaceutical industry sales. The top six biologics already consume 43 % of the drug budget for Medicare Part B [8]. As a result of this clinical and commercial success, pharmaceutical companies have invested heavily in the development of biologics. Approximately 30 % of the industrys research and development pipeline is composed of biologics [2, 9]. The goals for encouraging the development of generic biologics are the same as those for encouraging generic small-molecule drugs, which is to reduce costs by fostering price competition and provide patients with access to treatment at an affordable price. Generic drug use is common [10]. In 2011, approximately 80 % of the four billion drug prescriptions issued in the US were dispensed using generic medications. Estimated savings to the consumer and to the US health-care system from generic drug use reached $193 billion in 2011. The introduction of generic biologics or biosimilars is projected to generate $9 to $12 billion in savings for the US Medicare program during the next decade [11, 12]. The manufacturing process for biologics is more complex than the chemical synthesis used for conventional small-molecule Table 2 Comparison of small-molecule medications and biololgics Table 3 Demonstrated differences in biologics Antibody production Antibody production Molecular difference or cause Antibody production causing anemia (pure red blood cell aplasia) Change in stabilizer from human serum albumin to glycine and polysorbate 80 pharmaceuticals (Table 2) [13]. The production of biologics and their subsequent pharmacologic activity are dependent on the manufacturing processes, which, in turn, are very sensitive to changes in production [14]. Any changes occurring to the expression systems used for production, culture conditions (e.g., temperature and nutrients), equipment, purification and processing, formulation, storage, or packaging may result in subtle changes in the biological characteristics, clinical activity, and toxicity profile (Table (...truncated)