Biosimilar

Biosimilars or Follow-on biologics are terms used to describe officially-approved subsequent versions of innovator biopharmaceutical products made by a different sponsor following patent and exclusivity expiry on the innovator product. Reference to the innovator product is an integral component of the approval.

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 fermentation and purification process,nor to the active drug substance. They do have access to the commercialized innovator product. Differences in impurities and/or breakdown products can have serious health implications. The same concern applies to the reference product when manufacturing changes are made. Concerns have been expressed that copies of biologics might perform differently than the original branded version of the product, but none have yet been demonstrated (this is currently an important but nonetheless hypothetical concern). Consequently only a few subsequent versions of biologics have been authorized in the US through the simplified procedures allowed for small molecule generics, namely Menotropins (January 1997) and Enoxaparin (July 2010), and a further eight biologics through the so-called 505(b)(2) pathway. The European regulatory authorities led with a specially-adapted approval procedure to authorize subsequent versions of previously approved biologics, termed "similar biological medicinal products" - often called biosimilars for short. This procedure is based on a thorough demonstration of "comparability" of the "similar" product to an existing approved product. In the US the Food and Drug Administration held that new legislation was required to enable them to approve biosimilars to those biologics originally approved through the PHS Act pathway. Additional Congressional hearings have been held,. On March 17, 2009, the Pathway for Biosimilars Act was introduced in the House. Full text available or see the Library of Congress website and search H.R. 1548. Since 2004 FDA has held a series of public meetings on biosimilars .

FDA was given the authority to approve biosimilars, including interchangeable that are substitutable with their reference product,as part of the Patient Protection and Affordable Care Act signed by President Obama March 23, 2010 - none have yet been approved. FDA has previously approved biologic products using comparability, for example, Omnitrope in May 2006, but this like Enoxaparin was also to a reference product, Genotropin, originally approved as a biologic drug under the FD&C Act ) .

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 . 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 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 ( December 2009), 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.

References

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