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. Biosimilars are also referred to as subsequent entry biologics (SEBs) in Canada.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. This has created a concern that copies of biologics might perform differently than the original branded version of the product. 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 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.[2] 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.[3] Additional Congressional hearings have been held,.[4] On March 17, 2009, the Pathway for Biosimilars Act was introduced in the House. Full text available [5] or see the Library of Congress website and search H.R. 1548. Since 2004 FDA has held a series of public meetings on biosimilars.[6] 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 cellbased 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.[8] 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 [9][10] 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. It is difficult and costly to recreate biologics because the complex proteins are derived from living organisms that are genetically modified. In contrast, small molecule drugs made up of a chemically based compound can be easily replicated and are considerably less expensive to reproduce. In order to be released to the public, biosimilars must be shown to be as close to identical to the parent biological product based on data compiled through clinical, animal and analytical studies. The results must demonstrate that they produce the same clinical results and are interchangeable with the referenced FDA licensed biological product already on the market. 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. BPCI ACT: The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) was originally sponsored and introduced on June 26, 2007 by Senator Edward Kennedy (D-MA). It was formally passed under the Patient Protection and Affordable Care Act (PPAC Act), signed into law by President Barak Obama on March 23, 2010. The BPCI Act was an amendment to the Public Health Service Act (PHS Act) to create an abbreviated approval pathway for biological products that are demonstrated to be highly similar (biosimilar) to a Federal Drug Administration (FDA) approved biological product. The BPCI Act is similar, conceptually, to the Drug Price

Competition and Patent Term Restoration Act of 1984 (also referred to as the "Hatch-Waxman Act") which created biological drug approval through the Federal Food, Drug, and Cosmetic Act (FFD&C Act). The BPCI Act aligns with the FDA's longstanding policy of permitting appropriate reliance on what is already known about a drug, thereby saving time and resources and avoiding unnecessary duplication of human or animal testing. DATA EXCLUSIVITY: Data exclusivity is an important piece of the amendment in the Patient Protection and Affordable Care Act for biosimilars. It is the period of time between FDA approval and an abbreviated filing for a biosimilar on the original producer's data. Data exclusivity is designed to preserve innovation and recognize the long, costly, and risky process involved while the innovator waits to gain FDA approval. The time allowed for data exclusivity is critical for the future of biologics. A number of provisions for data exclusivity in recent legislative proposals ranged up to 14 years, however, the passing of the PPAC Act guarantees a 12 year time period from the time of FDA approval. This is supposed to compensate for perceived shortcomings in patent protection for biologics. Data exclusivity extends from the date of product approval, and this protection period runs concurrently with any remaining patent term protection for the biologic. That is to say, data exclusivity provides additional protection to the innovator when the remaining patent length is shorter than the data exclusivity period at the time of approval (which can occur due to lengthy preclinical and clinical research required to obtain FDA approval), or to the extent that the patent term is circumvented by a biosimilar prior to its expiry.

The European Medecines Agency (EMEA) has issued draft guidelines on the development of "similar biological medicinal products", the so-called biosimilar medecines. The draft guideline follows two existing EMEA documents adopted in 2003 and aims at describing the EMEA approach to the development and approval of these products. The final guidelines will define what is a biosimilar medicine and will be a "user guide" for applicants that claim biosimilarity of their products. The aim of this guidelines follows the line of recent declarations by Thomas Lonngren, director general of the EMEA, who supports more detailed studies on potential health risks as a condition for new drug approvals. Any comments to the draft guideline should be sent to the EMEA Comparability Working Party Secretariat - Fax : +44 20 74 18 86 13 E-mail : susana.soobhujhun@emea.eu.int by end of February 2005.
What are biosimilar products ?

The draft guidelines explain that a company may choose to develop a new biological medicinal product claimed to be "similar" to an orginal reference medicinal product which has been granted a marketing authorisation in the EU. The guidelines also say that in this case, comparability studies are needed. Biosimilar medicines might also include vaccines and allergens. EuropaBio, the European Association of Bioindustries (which includes multinationals such as BASF, GlaxoSmithKline, Monsanto, Novartis, Procter & Gamble...) defines biosimilar products as second versions of biologic medicines that depend on the same mechanism of action and are intended to be used for the same therapeutic indication as the innovator product. They specify that biosimilar products are not chemical generics, and claim that a small change in the manufacturing process can indeed have an important impact on the efficacy and safety of a product.