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Biosimilars, also known as follow-on biologics, are biologic medical products whose active drug substance is made by a living organism or derived from a living organism by means of recombinant DNA or controlled gene expression methods.

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.[1] Biosimilars are also referred to as subsequent entry biologics (SEBs) in Canada.[2] 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 changes in manufacturing processes. Follow-on manufacturers do 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.

Approval processes[edit]

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.[3] In the US the Food and Drug Administration (FDA) held that new legislation was required to enable them to approve biosimilars to those biologics originally approved through the PHS Act pathway.[4] Additional Congressional hearings have been held,.[5] On March 17, 2009, the Pathway for Biosimilars Act was introduced in the House.[1] See the Library of Congress website and search H.R. 1548 in 111th Congress Session. Since 2004 the FDA has held a series of public meetings on biosimilars.[6][7]

The FDA gained the authority to approve biosimilars (including interchangeables that are substitutable with their reference product) as part of the Patient Protection and Affordable Care Act signed by President Obama on March 23, 2010 - none have yet been approved. The 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 [8]) .


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.

After the expiry of the patent of approved recombinant drugs (e.g. insulin, human growth hormone, interferons, erythropoietin, and more) any other biotech company can "copy" and market these biologics (thus called biosimilars).

However, because no two cell lines, developed independently, can be considered identical, biotech medicines cannot be fully copied. The European Medicines Agency, EMA, has recognized this fact, which has resulted in the establishment of the term "biosimilar" in recognition that, whilst biosimilar products are similar to the original product, they are not exactly the same.[9] Small distinctions in the cell line, in the manufacturing process or in 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[10][11] which requires substantial additional data to that required for chemical generics, although not as comprehensive as for the original biotech medicine. Originally the complexity of biological molecules led to requests for substantial efficacy and safety data for a biosimilar approval. This has been progressively replaced with a greater dependence on assays, from quality through to clinical, that show assay sensitivity sufficient to detect any significant difference in dose.[12] However, the safe application of biologics depends 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 innovator biologic product based on data compiled through clinical, animal, analytical studies and conformational status.[13] All these experimental data must demonstrate that they produce the same clinical results without any potential immunogenicity. EMA and FDA regulations as well as scientific considerations indicate that biosimilarity does not imply interchangeability.[14]

United States of America[edit]

BPCI Act[edit]

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 Barack 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 Food and 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. The FDA has released a total of four draft guidelines related to biosimilar or follow-on biologics development. Upon the release of the first three guidance documents the FDA held a public hearing on May 11, 2012. A summary of the key issues raised is available for review in the journal New Pharma Thinkers.[15]

Data exclusivity[edit]

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.[16] 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 pre-clinical 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.

Market implications[edit]

The 2012–2019 patent cliff.[17] Period of market exclusivity up to date of patent expiration for the Top 10 selling biologics for 2011. *Enbrel has been granted approval in 2011 for a patent filed in 1995, extending its patent life further 17 years.

The legal requirements of approval pathways, together with the costly manufacturing processes, escalates the developing costs for biosimilars that could be between 75–250 million USD per molecule.[17] This market entry barrier affects not only the companies willing to produce them but could also delay availability of inexpensive alternatives for public healthcare institutions that subsidize treatment for their patients. Even though the biosimilars market is rising, the price drop for biological drugs at risk of patent expiration will not be as great as for other generic drugs; in fact it has been estimated that the price for biosimilar products will be 65%-85% of their originators.[17] Biosimilars are drawing market's attention since there is an upcoming patent cliff, which will put nearly 36% of the 140bn USD market for biologic drugs at risk (as of 2011), this considering only the top 10 selling products.[17]


  1. ^ a b Nick, C (2012). "The US Biosimilars Act: Challenges Facing Regulatory Approval". Pharm Med 26 (3): 145–152. doi:10.1007/bf03262388. 
  2. ^ Blanchard, A., Helene D'Iorio and Robert Ford. "What you need to know to succeed: Key trends in Canada's biotech industry " Insights, spring 2010
  3. ^ EMEA Guideline on Similar Biological Medicinal Products, CHMP/437/04 London, 30 October 2005
  4. ^ US Senate Committee on the Judiciary, Testimony of Dr. Lester Crawford, Acting Commissioner, FDA June 23, 2004
  5. ^ Hearing: Assessing the Impact of a Safe and Equitable Biosimilar Policy in the United States. Subcommittee on Health Wednesday, May 2, 2007
  6. ^ FDA page on "Follow-On Protein Products: Regulatory and Scientific Issues Related to Developing"
  7. ^ FDA page on "Approval Pathway for Biosimilar and Interchangeable Biological Products Public Meeting"
  8. ^ FDA Response to three Citizen Petitions against biosimilars
  9. ^ EMEA guideline on similar biological medicinal products
  10. ^ EMEA guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues
  11. ^ EMEA guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues
  12. ^ Warren, JB (2013). "Generics, chemisimilars and biosimilars: is clinical testing fit for purpose?". Br J Clin Pharmacol 75 (1): 7–14. doi:10.1111/j.1365-2125.2012.04323.x. 
  13. ^ Wang, X. (June 1, 2014). "Higher-Order Structure Comparability: Case Studies of Biosimilar Monoclonal Antibodies". BioProcess International 12 (6): p.32–37. 
  14. ^ Declerck PJ (February 2013). "Biosimilar monoclonal antibodies: a science-based regulatory challenge". Expert Opin Biol Ther 13 (2): 153–6. doi:10.1517/14712598.2012.758710. PMID 23286777. 
  15. ^
  16. ^ 42 U.S.C. 262(k)(7)(A)
  17. ^ a b c d Calo-Fernández B, Martínez-Hurtado J (December 2012). "Biosimilars: Company Strategies to Capture Value from the Biologics Market". Pharmaceuticals 5 (12): 1393–1408. doi:10.3390/ph5121393.