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World Journal of Pharmaceutical Research Sen Et Al World Journal of Pharmaceutical Research Sen et al. World Journal of Pharmaceutical SJIF ImRepactsearch Factor 6.805 Volume 5, Issue 9, 1841-1866. Review Article ISSN 2277– 7105 BIOSIMILARS AS BIOACTIVE MOLECULAR CLONE 1Prof. Dr. Dhrubo Jyoti Sen*, 2Jahangir Nabi, 2Pooja Raj and 2Jainik Khamar 1Department of Pharmaceutical Chemistry, Shri Sarvajanik Pharmacy College, Gujarat Technological University, Arvind Baug, Mehsana-384001, Gujarat, India. 2Delhi Institute of Pharmaceutical Sciences & Research (DIPSAR), Mehrauli-Badarpur Road, Puspvihar, Sector-3, New Delhi-110017, India. ABSTRACT Article Received on 24 July 2016, Biologics are 200 to 1,000 times the size of a small molecule (generic) Revised on 12 August 2016, drug and far more structurally complex. Additionally, biologics and Accepted on 01 Sept 2016 biosimilars are manufactured in living cells, then extracted and DOI: 10.20959/wjpr201610-7121 purified, whereas small molecule drugs and generics are manufactured purely via chemical synthesis. These fundamental differences in *Corresponding Author complexity and large-scale manufacturing are at the core of why Prof. Dr. Dhrubo Jyoti Sen Department of biosimilars are not equal to generics. Biologics and biosimilars are Pharmaceutical Chemistry, produced in living cells with a multi-step process. Initially, a basic Shri Sarvajanik Pharmacy protein structure is ―translated‖ from a DNA sequence and then College, Gujarat modifications, including changes and additions, are made to that basic Technological University, protein structure. These later changes and additions are called post- Arvind Baug, Mehsana- 384001, Gujarat, India. translational modifications. The impact of post-translational modifications on a product is similar to the impact of a farming environment on growing tomatoes. The look and taste of the same type of tomatoes will vary in different farm environments because of the quality of the soil, use of fertilizers, type of irrigation and weather elements like rain, air, sunlight. Similarly, differences in biological systems (e.g., type of living cell with slightly different cellular environments) used to manufacture biosimilars may cause different types and levels of modifications, which in turn may affect the quality, safety or effectiveness of the product. So, whereas a generic can be identical to a small molecule reference product, biosimilars cannot and are not required to be exactly like the biologic reference product. Given the expected differences, regulatory authorities have outlined robust data requirements to demonstrate similarity. Biosimilar manufacturers will generally need to generate data from lab testing, non-clinical testing and www.wjpr.net Vol 5, Issue 9, 2016. 1841 Sen et al. World Journal of Pharmaceutical Research clinical testing to show that the biosimilar they have developed will provide the same therapeutic benefit and risks to patients as the reference product. KEYWORDS: Darbepoetin alfa, Etanercept, Epoetin alfa, Somatropin, Trastuzumab, Adalimumab, Pegfilgrastim, Filgrastim, Infliximab, Rituximab, Bevacizumab, Lispro, Glargine. INTRODUCTION The Patient Protection and Affordable Care Act (Affordable Care Act), signed into law by President Obama on March 23, 2010, amends the Public Health Service Act (PHS Act) to create an abbreviated licensure pathway for biological products that are demonstrated to be ―biosimilar‖ to or ―interchangeable‖ with an FDA-licensed biological product. This pathway is provided in the part of the law known as the Biologics Price Competition and Innovation Act (BPCI Act). Under the BPCI Act, a biological product may be demonstrated to be ―biosimilar‖ if data show that, among other things, the product is ―highly similar‖ to an already-approved biological product. Figure-1: Similar A biosimilar product is a biological product that is approved based on a showing that it is highly similar to an FDA-approved biological product, known as a reference product and has no clinically meaningful differences in terms of safety and effectiveness from the reference product. Only minor differences in clinically inactive components are allowable in biosimilar products. An interchangeable biological product is biosimilar to an FDA-approved reference product and meets additional standards for interchangeability. An interchangeable biological product may be substituted for the reference product by a pharmacist without the intervention of the health care provider who prescribed the reference product. FDA requires licensed biosimilar and interchangeable biological products to meet the Agency‘s rigorous standards www.wjpr.net Vol 5, Issue 9, 2016. 1842 Sen et al. World Journal of Pharmaceutical Research of safety and efficacy. That means patients and health care professionals will be able to rely upon the safety and effectiveness of the biosimilar or interchangeable product, just as they would the reference product.[1] Figure-2: Biosimilar A biosimilar (also known as follow-on biologic or subsequent entry biologic) is a biologic medical product which is almost an identical 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 with generic drugs of the more common small-molecule type, 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, although they do have access to the commercialized innovator product. Overall, it is harder to ascertain fungibility between generics and innovators among biologics than it is among totally synthesized and semi-synthesized drugs, which is why the name "biosimilar" was coined to differentiate these drugs from small-molecule generics. A simple analogy is that it is harder to say that two wines are "sufficiently interchangeable", because of differences in yeast strain, weather, grape harvest, or terroir, than it is to say that two soda pops are "sufficiently interchangeable" because they contain the same flavoring powder and salts. Drug related authorities such as European Medicines Agency (EMA), Food and Drug Administration (FDA) and Health Canada hold their own guidance on requirements for demonstration of the similar nature of two biological products in terms of safety and efficacy. According to them, analytical studies that demonstrate that the biological product is highly www.wjpr.net Vol 5, Issue 9, 2016. 1843 Sen et al. World Journal of Pharmaceutical Research similar to the reference product notwithstanding minor differences in clinically inactive components, animal studies (including the assessment of toxicity) and a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) are sufficient to demonstrate safety, purity and potency in one or more appropriate conditions of use for which the reference product is licensed and intended to be used and for which licensure is sought for the biological product. In case of a monoclonal antibody-containing medicinal product, such as Remsima, extensive physicochemical and biological characterization for it and its reference product Remicade (Infliximab) was conducted in order to demonstrate their highly similar properties. Consequently, EMA has granted a marketing authorisation for only a few biosimilars since 2006 including a monoclonal antibody which is recently approved. Meanwhile, on March 6, 2015, the FDA approved the United States's first biosimilar product, the biosimilar of filgrastim called filgrastim-sndz (trade name Zarxio) by Sandoz. Figure-3: Infliximab biosimilar Figure-4: Filgrastim biosimilar www.wjpr.net Vol 5, Issue 9, 2016. 1844 Sen et al. World Journal of Pharmaceutical Research The European regulatory authorities led with a specially adapted approval procedure to authorize subsequent versions of previously approved biologics, termed "similar biological medicinal products", or biosimilars. This procedure is based on a thorough demonstration of "comparability" of the "similar" product to an existing approved product. In the United States, 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. 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. The FDA has previously approved biologic products using comparability, for example, Omnitrope (Somatropin) in May 2006, but this like Enoxaparin (Heparin) was also to a reference product, Genotropin, originally approved as a biologic drug under the FD&C Act.[2] Figure-5: Omnitrope On March 6, 2015, Zarxio obtained the first approval of FDA. 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
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