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, but they do have access to the commercialized innovator product. Differences in impurities and/or breakdown products can have serious health consequences as shown by a few instances in which manufacturing changes for innovator biologics have led to unforeseen adverse events. This has created a concern that copies of biologics might perform differently than the original branded version of the product. However, similar concerns also apply to any production changes by the maker of the original branded version, and there are internationally agreed procedures in the regulated markets to manage these changes (reference: ICH Q5E ). Subsequent versions of biologics have not been authorized in the US or the European Union through the simplified procedures allowed for small molecule generics. 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. 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 those that are interchangeable 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, Omntrope in May 2006 ). .
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.
- ↑ ICH Q5E: Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process
- ↑ EMEA Guideline on Similar Biological Medicinal Products, CHMP/437/04 London, 30 October 2005
- ↑ US Senate Committee on the Judiciary, Testimony of Dr. Lester Crawford, Acting Commissioner, FDA June 23, 2004
- ↑ Hearing: Assessing the Impact of a Safe and Equitable Biosimilar Policy in the United States. Subcommittee on Health Wednesday, May 2, 2007
- ↑ http://thomas.loc.gov/cgi-bin/query/F?c111:1:./temp/~c111YZ0mCN:e1761:
- ↑ FDA page on "Follow-On Protein Products: Regulatory and Scientific Issues Related to Developing"
- ↑ FDA Response to three Citizen Petitions against biosimilars
- ↑ EMEA guideline on similar biological medicinal products
- ↑ EMEA guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues
- ↑ EMEA guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues