Safety Issues of Biosimilar Products

Biologics are complex molecules that are manufactured using living cells and used in the treatment of several chronic inflammatory diseases and cancer [1]. As biosimilars offer the potential for lower acquisition costs versus the originator biologic, evaluating the economic implications of the introduction of biosimilars is of interest [2]. As the costs of biologics are high, biosimilars offer the potential of greater choice and value, increased patient access to treatment, and the potential for improved outcomes [3]. By providing more-affordable treatment options and introducing price competition to the market, biosimilar medicines can generate significant savings. The cumulative savings between 2016 and 2020 in the EU5 and the USA are estimated to range between 49 billion Euros and 98 billion Euros [4]. The Biologics Price Competition and Innovation Act (BPCIA) grants 12 years of exclusivity to originator or reference biologics; therefore, by law, the FDA cannot approve a biosimilar until this period has elapsed [2,5]. Patents for many branded biologics will expire during the next few years, allowing biosimilars manufacturers to seek FDA approval for generic versions of these agents [2]. The Biologics Price Competition and Innovation Act (BPCIA), which is part of the patient protection and affordable care act, were passed to facilitate the entry of biosimilar drugs into the market [6]. There has been an increasing trend toward the approval of biosimilars in the USA and the EU. The original goal of legislation to approve biosimilars through a fast-track process that would lead to more competition and price reductions is starting to be realized [7]. According to the BPCIA, a biologic product is deemed biosimilar to the already approved, originator biologic if the available data show that it is highly similar to the reference product, “notwithstanding minor differences in clinically inactive components, and there are no clinically significant differences between the biologic product and the reference product in terms of safety, purity, and potency of the product” [8-10]. Approval of biosimilars requires comprehensive assessment of all stages of the research and development process, including evaluation of analytical, preclinical and clinical data, to establish bio-similarity to their reference products. The goal of biosimilar comparability studies is not to re-establish efficacy and safety for the proposed biosimilar, but to demonstrate similarity to the reference product [11,12]. The biosimilar development pathway consists of a comprehensive comparability exercise between the biosimilar candidate and the reference product, primarily focusing on data from analytical studies. Clinical studies for biosimilar candidates follow a different design to those for a new biological, as the aim is not to independently establish clinical benefit, but to confirm bio-similarity between the two agents [4]. Physician awareness and perceptions towards biosimilars are important factors in their adoption to clinical practice [11]. A biosimilar applicant has to provide a considerably larger package of comparative data than a generic applicant to ensure that the biosimilar can indeed rely, for the purpose of licensing, on the efficacy and safety experience gained with the reference product. While for a generic, the demonstration of similar in vitro dissolution and in vivo bioavailability (so-called bioequivalence) is sufficient to conclude therapeutic equivalence with the reference product, for a biosimilar, comparable physicochemical, biological and functional characteristics as well as efficacy and safety/immunogenicity with the reference product must be demonstrated. In addition, unlike generics, any extrapolation to other indications of the reference product must be scientifically justified [12]. The approval of biosimilars is a highly regulated and detailed process. The European Medicines Agency (EMA) and the US FDA guidance documents stipulate that a biosimilar manufacturer must perform a series of extensive similarity assessments in order to demonstrate bio-similarity to the reference product, and to ultimately gain regulatory approval or licensure [13]. Difference between generic biotech and biosimilar products are: a) Biologic medicines are not made using a set of standard materials, but are developed using unique biological systems and living cells. As a result, the active ingredient is impossible to recreate exactly and the selected cell lines from which the biologic medicine originates are unique to each manufacturer b) The manufacturing process for biologic medicines is generally more complex than manufacturing processes for chemical drugs. Unlike small molecule drugs, biologic medicines are produced in genetically-engineered living cells that are sustained in a highly-controlled environment. Abdul Kader Mohiuddin*