Biosimilar

Biosimilars or Follow-on biologics are terms used to describe copies of innovator biopharmaceutical products.

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Unlike the more common "small-molecule" drugs, biologics generally exhibit high molecular complexity, and may be quite sensitive to manufacturing process changes. The follow-on manufacturer does not have access to the originator's molecular clone and original cell bank, nor to the exact fermention and purification process. Finally, nearly undetectable differences in impurities and/or breakdown products are known to have serious health implications. This has created a concern that copies of biologics might perform differently than the original branded version of the drug. So copies of biologics are not authorized in the US or the European Union through the simplified procedures allowed for small molecule generics. In the EU a specially-adapted approval procedure has been authorized for certain protein drugs, termed "similar biological medicinal products". This procedure is based on a thorough demonstration of "comparability" of the "similar" product to an existing approved product.^[1] In the US the FDA has taken the position that new legislation will be required to address these concerns.^[2] Additional Congressional hearings have been held,^[3] but no legislation had been approved as of May 2007.

Background

Cloning of human genetic material and development of in vitro biological production systems has allowed the production of virtually any recombinant DNA based biological substance for eventual development of a drug. Monoclonal antibody technology combined with recombinant DNA technology has paved the way for tailor-made and targeted medicines. Gene- and cell-based therapies are emerging as new approaches.

Recombinant therapeutic proteins are of a complex nature ( composed of a long chain of amino acids, modified amino acids, derivatized by sugar moieties, folded by complex mechanisms). These proteins are made in living cells ( bacteria, yeast, animal or human cell lines). The ultimate characteristics of a drug containing a recombinant therapeutic protein are to a large part determined by the process through which they are produced: choice of the cell type, development of the genetically modified cell for production, production process, purification process, formulation of the therapeutic protein into a drug.

Since the expiry of the patent of the first approved recombinant drugs (e.g. insulin, human growth hormone, interferons, erythropoietin, and more ) ‘copying’ and marketing of these biologics (thus called biosimilars) can be offered by any other biotech company.

However, because no two cell lines, developed independently, can be considered identical, biotech medicines cannot be fully copied. This is recognised by the European Medicines Agency, EMEA, and has resulted in the establishment of the term “biosimilar” in recognition of the fact that, whilst biosimilar products are similar to the original product, they are not exactly the same ^[4]. Small distinctions in the cell line, the manufacturing process or the surrounding environment can make a major difference in side effects observed during treatment, i.e. two similar biologics can trigger very different immunogenic response. Therefore, and unlike chemical pharmaceuticals, substitution between biologics, including biosimilars, can have clinical consequences and does create putative health concerns.

Biosimilars are subject to an approval process ^[5][6] which requires substantial additional data to that required for chemical generics, although not as comprehensive as for the original biotech medicine. However, the safe application of biologics is also dependent on an informed and appropriate use by healthcare professionals and patients. Introduction of biosimilars also requires a specifically designed pharmacovigilance plan.

Currently ( August 2007), ambiguities concerning naming, regional differences in prescribing practices, regional differences in legally defined rules with respect to substitution are important points that still need to be resolved to ensure a safe use of biosimilars.

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