Benefits and concerns related to biosimilars

As patents of the first introduced biological therapeutics in oncology have begun to expire, competing pharmaceutical companies are allowed to produce and market the same protein as the originator agent. This follows the pattern of the development of generics. However, biosimilars are fundamentally different from generics. Particularly in the field of oncology, the introduction of monoclonal antibodies has resulted in spectacular therapeutic advances by increasing the cure rate of early cancers and prolonging survival. Similar advances have occurred in rheumatology, haematology, neurology and other fields. Most therapeutic biologicals are monoclonal antibodies with molecular weights of around 140,000 Daltons [1]. Other peptides include hormones, growth factors and vaccines [2]. Most of those products are expensive and their broad application drains the financial resources of healthcare systems. Therefore, the development of biosimilars is expected to be mutually beneficial for both the pharmaceutical industry and society: pharmaceutical companies may enter a lucrative business, whereas payers reasonably expect lower prices for these costly but essential drugs.

Biosimilars are produced by recombinant DNA technology in living organisms as opposed to the chemical synthesis required for generics [3]. The complexity of the production process of biologicals, such as biosimilars, involves ultra-sensitive regulatory cellular processes, including not entirely predictable glucosylation of aminoacids residues. In addition, the spatial conformation of a large protein is further affected by the isolation and purification process. Consequently, only large pharmaceutical companies possess the capacity and the complex production plants required for the development of biosimilars. Variations of production technology and proprietary processing among various manufacturers inevitably render the end product, i.e. the biosimilar, not identical but similar to the prototype.

As biosimilars are not identical but a close approximation of the originator drug, a different set of regulatory rules are required for their approval [4]. The European Union was the first to create a registration and regulations agenda [5]. This initiative was followed by many other countries and eventually by the Food and Drug Administration of the US. With minor regional variations, a medicinal product can be universally approved as a biosimilar only if it passes the so-called ‘comparability exercise’ [4]. This series of testing involves analysis and comparison of the production methodology, physicochemical properties, biological properties, immunochemical properties, and profile of impurities. Eventually, a clinical study is required in order to prove equivalent clinical efficacy to the prototype. This is the ultimate step before approval and it implies that the candidate biosimilar has cleared all the previous comparability tests. These types of studies differ from the usual clinical trials, as they are not performed with the intention to benefit the patient by improving efficacy or reducing toxicity but only to demonstrate equivalence of the new product. Equivalence in one clinical outcome, such as response rate, suffices for the approval for all the indications of the originator drug. This justified assumption is termed extrapolation of indications.

Based on the above, biosimilars may enter the market after being tested in relatively small number of patients in a phase III study, usually numbering several hundreds. This fact raises concern about the possibilities of rare or delayed toxicities. Therefore, the marketing of therapeutic biosimilars is accompanied by a mandatory pharmacovigilance programme, which is imposed by regulators on producers [6]. Essential for a successful pharmacovigilance programme is the traceability of every batch of packaged biosimilar so that if an unexpected adverse reaction occurs it can be traced to its source. The establishment of pharmacovigilance is thought to appease the hesitation of skeptics regarding their use, as any adverse reaction, however improbable, will be captured.

It is evident that the development of biosimilars is a necessity for relieving the pharmaceutical cost of healthcare system and payers. A well-regulated environment that has already been set up in most countries seems to provide rigorous reassurance that public health is also protected. A well-functioning network of information flow and a good understanding of the needs of all parties involved, namely the patients, physicians, payers and manufacturers is more than essential.

Conflict of interest
The authors of the research paper [7] did not provide any conflict of interest statement.

Abstracted by Maria Karampola of the Department of Oncology, Interbalkan Medical Center, Thessaloniki, Greece.

Editor’s comment
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Biosimilars and interchangeability

References
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5. European Medicines Agency. Omnitrope [homepage on the Internet]. 2016 Jan 13 [cited 2016 Mar 18]. Available from: http://ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000607/human_med_000946.jsp&mid=WC0B01AC058001D124
6. European Medicines Agency [homepage on the Internet]. [cited 2016 Mar 18]. Available from: www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500003981.pdf
7. Emmanouilides CE1, Karampola MI2, Beredima M1.Biosimilars: Hope and concern. J Oncol Pharm Pract. 2015 Sep 21. pii: 1078155215603232. [Epub ahead of print]

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