A biosimilar (also known as follow-on biologic or subsequent entry biologic) is a biologic medical product which is copy of an original product that is manufactured by a different company. Biosimilars are officially approved versions of original "innovator" products, and can be manufactured when the original product's patent expires. 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. 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. 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. Additional Congressional hearings have been held,. On March 17, 2009, the Pathway for Biosimilars Act was introduced in the House. 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.
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. On March 6 2015, the US FDA approved Sandoz’s Zarxio (filgrastim-sndz), the first biosimilar product approved in the US. 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 ). Sandoz’s Zarxio is biosimilar to Amgen’s Neupogen (filgrastim), which was originally licensed in 1991. This is the first product to be passed under the Biologics Price Competition and Innovation Act of 2009 (BPCI Act), which was passed as part of Obamacare. But Zarxio was approved as a biosimilar, not as an interchangeable product, the FDA notes. And under the BPCI Act, only a biologic that has been approved as an “interchangeable” may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product. The FDA said its approval of Zarxio is based on review of evidence that included structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data and other clinical safety and effectiveness data that demonstrates Zarxio is biosimilar to Neupogen.
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, Monoclonal antibody and more) any other biotech company can "copy" and market these biologics (thus called biosimilars).
Every biological (or biopharmaceutical products) displays a certain degree of variability, even between different batches of the same product, which is due to the inherent variability of the biological expression system and the manufacturing process. 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. 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.
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. 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. 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.
United States of America
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.
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 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.
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. 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. 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.
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- 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
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- EMEA guideline on similar biological medicinal products
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- 42 U.S.C. 262(k)(7)(A)
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