Biosimilars in rheumatology: perspective and concerns

What all rheumatologists should know? Unlike traditional pharmaceuticals, biologic drugs are derived from living organisms. Recombinant DNA biotechnology has allowed large-scale production based on master cell banks from different sources. Many biologic drugs are used in internal medicine, for example insulin, growth hormone, erythropoietin, IFN-α and monoclonal antibodies [1]. In the past decade, rheumatology has been transformed with the introduction of monoclonal antibodies directed against cytokines involved in the pathogenesis of inflammatory arthritis, such as RA, AS and autoimmune diseases associated with arthritis such as psoriasis and IBD [2]. The first three anti-TNFs commercially available at the start of the past decade were etanercept, infliximab and adalimumab. These three became blockbuster drugs (with sales revenues of more than $US 1 billion annually) and have continued to do so for the past few years. Patents for biologics that were first marketed towards the end of 1980s are now beginning to expire, opening up the development of non-proprietary versions. However, the same regulatory process that controls the use of generic medication should not be applied for biosimilars. Government and industry are still evolving processes to deal with biosimilars. The manufacture of a biopharmaceutical product is complex and involves several steps of purification. The major differences are in the dimension of the compound and its synthesis, stability and immunogenicity. The first step is to introduce the gene for the required protein into a living cell line and then, through the final version of the product, several variations can occur, which are inherent to any biologic system so long as regulatory processes are in place for the development of a biosimilar from a synthetic product (based on a molecular structure). Minor changes in the production process can affect the safety and efficacy of the proposed biosimilar copy, which is usually not an issue for the production of synthetic molecules. The European Medicines Agency was the first to publish guidelines recognizing that specific regulatory processes were needed for the development of biosimilar-derived products where patents are expected to expire over the next few years [3]. The FDA, through the Patient Protection and Affordable Care Act, endorsed it into a law in 2010 and created a shorter licensing pathway where it is possible to show the presence of biosimilarity or interchangeability with an FDA-licensed biologic product. Besides the concerns of the manufacture of biosimilars, it is fundamental that rheumatologists are aware that demonstration of similarity with the innovator product during all critical steps of synthesis cannot be labelled as highly similar without proper clinical trials comparing the similar with the innovator. The similar then has to be powered to detect bioequivalence followed by an extensive post-license marketing period. Canadian rheumatologists expressed their concerns in a recent article that focused on patient safety and long-term outcomes [4–6]. In Latin America, the regulation of biosimilar agents varies considerably, but most of these countries are implementing specific requirements for the approval of biosimilars [7]. However, in some countries where regulations have not yet been established, intended copies of biologic products are already being registered for etanercept and rituximab. In Africa and Asia, although regulations have been implemented in several countries (similar to those in Latin America), registration of intended copies of rituximab and etanercept are already in place without any clinical trials in patients with RA (Table 1). Intended copies of biologics licensed without biosimilar regulations Intended copies of biologics licensed without biosimilar regulations In China, Shanghai CP Guojian Pharmaceutical Co. Ltd launched a new compound in 2006 that is supposedly a copy of etanercept. In the USA, patent expiry for etanercept was extended for another 17 years in 2011 so rheumatologists in the USA will see an etanercept biosimilar product later than other parts of the world. In India, a rituximab biosimilar was launched by a local manufacturer and is approved for the treatment of RA and lymphoma [8]. However, India is a semi-regulated market for biosimilars and only short trials are required to assess bioequivalence for licensing procedures. The first true biosimilar in rheumatology was registered in Korea in October 2012 and is a copy of infliximab. The trial that led to this license appears to be well done and powered to detect differences in efficacy and safety. It is now under review in Europe and Brazil as a validated biosimilar. Biosimilars will continue to be an area of interest through 2013 and 2014. Although no biosimilars have yet been approved for the treatment of inflammatory arthritis, Europe may possibly approve its first biosimilar monoclonal antibody product (infliximab) for the treatment of RA by the end of 2013. Rheumatologists should be concerned when true biosimilars become available, not only for safety and efficacy, but also for other issues such as immunogenicity of the biosimilar product and well-designed comparative trials. In the case of traditional chemical compounds, synthesis is initiated from commercially available substrates; this is not the case with biologic compounds. Cell lines used in biopharmaceutical production have unique features inherent to cell systems so that a biologic derived from different production systems can never be identical. Therefore head-to-head trials with adequate power are recommended, which is not the case with the copy of synthetic drugs. The immunogenicity issue was well illustrated when biosimilar epoietins were introduced in the market without proper attention to the possibility that the biosimilar could generate autoantibodies against the natural erythropoietin resulting in cases of drug-derived pure red cell aplasia mainly outside the USA [9, 10]. We believe that rheumatologists should be aware of two things in their respective countries. First, the biosimilar product can only really be classified as a biosimilar copy or an intended copy with proper head-to-head trials against the innovator. This information will most likely influence a rheumatologist’s prescription towards a branded product in favour of a biosimilar unless the reimbursement in their respective country affects the status of the originator brand [11]. Second, although in emerging markets the advent of biosimilars may reduce the high cost of biologic therapies for the patient, the practicing rheumatologist should be aware of the proper development of a biosimilar, as it may have been licensed using relaxed standards and may not be a truly bioequivalent biosimilar [12]. The bioequivalence of generic drugs is well established; however, when dealing with large biologic products, complex molecules and extensive glycosylation, a completely different kind of assessment is required, including laboratory testing to prevent production and clinical evaluation pitfalls [13]. Importantly, before prescribing a biosimilar, rheumatologists should be aware of whether the similarity between the intended copy and the innovator or originator is met and of the fundamental challenges that are required to be labelled a truly biosimilar product. Finally, one has to be careful about unproven molecules from foreign sources reaching countries as an alternative to the branded biologic with licensing pathways that would not usually meet FDA or EMEA standards. Disclosure statement: The authors have declared no conflicts of interest.