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Terminology of the biopharmaceutical has faced a certain degree of chaos and anarchy for years and it is still in the developmental stages. Similar is the case of Biogenerics. All current terms related to Biogenerics have connotations and evoke preconceptions that may support, denigrate, or obfuscate anyone product under consideration. Biogenerics are as old as whatever you consider to be biopharmaceuticals. For example, various live vaccinia virus–based vaccines for smallpox prophylaxis have been available and considered therapeutically equivalent for more than 200 years. On the other hand, Biogenerics can be considered a recent phenomenon, with just a few on the market, if you take a rigorous regulatory view. Nowadays, there are more than 150 biopharmaceuticals in clinical use in western world. The patents on many recombinant DNA products have expired, or are due to expire, soon. In the case of classical drugs, expiration of patents opens the possibility of the introduction of generic products. Frost & Sullivan in a recent study analyzed the worldwide market for biogeneric products. It focuses on the United States, European, Asian, and the rest- of- The-world (row) markets. The research provides An interesting forecast: starting from 2011, the Market dimension of Biogenerics drugs in the USA And Europe only will be over 16 billion us $.However, the biogenerics market has been very slow to establish itself. The key reason is the lack of a Defined regulatory framework and uncertainty—on the part of manufacturers and regulators alike—regarding what biogenerics will look like and how they will reach the market.
Biogeneric products pose unique challenges from a clinical development/ Regulatory perspective. The concept of essential similarity does not Apply, requiring a variable combination of evidence to support quality, Safety and efficacy, depending on the product. Any pathway should fully address the patient safety considerations of medicines that are “similar to” or “comparable to” instead of “same as” the reference product. For example, there are currently three different companies who manufacture nine different types of insulin’s in 23 different presentations – and they are not interchangeable. Indeed, the FDA expressed its concerns with interchangeability in September 2006: “with protein products, as of today, the FDA has not determined how interchangeability can be established for complex proteins. Different large protein products, with similar molecular composition may behave differently in people and substitution of one for another may result in serious health outcomes, e.g., generation of a pathologic immune response.” (http://www.fda.gov/cder/news/biosimilars.htm) The European system recognizes that “by definition similar biological medicinal products are not generic medicinal products, since it could be expected that there may be subtle differences between similar biological medicinal products from different manufacturers or compared with reference products, which may not be fully apparent until greater experience in their use has been established.” (Guideline on similar biological medicinal products (chmp/437/04)) there is a further requirement that the products are clearly identified to support post-market monitoring. In addition, there is no evidence to support interchangeability in existing biologics, let alone a new class of biologics with different safety standards. Directive 2004/27/ec, amending directive 2001/83/ec, provides the legal Basis for the approval of 'similar biological medicinal products'(otherwise referred to as biosimilars or follow-on biologics).
Under the guidelines developed by EMEA, manufacturers may rely on the marketing authorization granted to a therapeutic protein when preparing a dossier for a biosimilar protein product. However, the guidelines establish that the manufacturer must adequately substantiate the quality, safety, and efficacy of the biosimilar product; these elements constitute the three main sections of any new drug application needed for product authorization in the EU. Each of these sections of the dossier must rely on the same innovator product. While the quality assessment for a biosimilar product is a comprehensive comparison against the innovator product, the application may be abbreviated in that the sponsor may not be required to repeat all efficacy and safety studies. The applicant will not be required to repeat these investigations if the physicochemical and in vitro characteristics of the two products can be adequately evaluated. In addition, the biosimilar product sponsor must demonstrate chemical comparability between the two products, a potentially difficult task depending on the innovator protein’s complexity and other product or manufacturing attributes. In fact, the EMEA guidelines point out that there will be some situations in which satisfactory equivalence cannot be demonstrated due to the complexity of the protein’s structure, the manufacturing process, and the effect of product differences on quality, safety, and efficacy. Where chemical comparability is not or cannot be demonstrated, a full complement of clinical and preclinical data will be necessary to support the dossier for the follow-on therapeutic product. While the EU guidelines may be difficult to satisfy, particularly for more complex therapies, they nevertheless provide sponsors with the opportunity for obtaining regulatory approval of a biosimilar therapeutic protein through an established regulatory framework. Recently, the European Commission, acting on a recommendation by the EMEA Committee on Medicinal Products for Human Use (CHMP) and following the established guidance documents, granted its first marketing authorization for follow-on biologic in April 2006 to Sandoz’s generic human growth hormone, Omnitrope. Omnitrope is a followon version of Pfizer’s Genotropin (somatropin recombinant).
The US FDA is still developing guidelines for "biosimilar" or "follow on" Biological products and has not been able to conclude what tests would constitute Demonstration of bioequivalence . Whereas these products are administered through Routes that provide lesser barriers in the entry of drug to the body, the differences are Related to antigenicity potential which needs a clinical evaluation; however, studies have Demonstrated that minute differences in the structure of protein drugs including Dimerization, 3 and 4`h degree structures and easily picked up in partitioning studies since these studies truly represent the thermodynamic potential which is readily changed even Where minor differences in the structures, often too small to be detected by even the most Sophisticated instruments; in most instances, the use of instrumentation itself disturbs the Structure enough to make the studies meaningless. This almost borders on the Heisenberg's principle of uncertainty. In early 2006, following the CHMP recommendations on Omnitrope and Valtropin, Senator Orrin Hatch (R-UT) and Representative Henry Waxman (D-CA) sent a letter to acting FDA Commissioner Andrew von Eschenbach urging FDA to issue guidance documents for follow-on insulin and human growth hormone (HGH) products. According to FDA, the Agency has had a draft of the guidance documents in final or near final form for some time. Over the past year, a number of events have placed increased pressure on the FDA to make substantive progress on developing a mechanism for reviewing and approving follow-on biologics: the development of a regulatory pathway in Europe; the authorization of a biosimilar product by the European Union; judicial intervention; and Congress sending signals regarding its intent to take direct action if FDA does not act imminently . The momentum is clearly building toward some regulatory movement on the generic biologics issue. FDA may seek to relieve some of this pressure through some incremental action, such as development of a regulatory pathway for a certain class of biologics, like insulin products or human growth hormone products. Alternatively, the Agency may take broader action by creating a
general pathway for most or all biologic products, but reserving final decisions on a specific pathway based on a product-by-product determination. The one certainty in all of this is that FDA will be taking some action on the issue of generic biologics in the not-too-distant future. Regulations on Biogenerics in India India follows a three-tier system of Institutional Bio Safety Committee (IBSC), Review Committee on Genetic Manipulation (RCGM) and Genetic Engineering Approval Committee (GEAC) for clearance and regulation of the recombinant products. Most of the biopharmaceuticals being produced in the country are biogenerics. All biogenerics cleared so far i.e. Hepatitis B vaccine, erythropoietin, GM-CSF, alpha interferon etc. have followed the approval procedure, which are a mix of the ones required for New Biological Entity (NBE) and generics. The molecules/vaccines have been cleared through three-tier mechanism adopting special abbreviated procedures and constituting special committees. This has been possible as the gold standard in the form of original products was available to evaluate the physicochemical and bioequivalence properties of these entities. How far these procedures may apply to new molecules is still to be seen. The first NBE that is going to face the approval system would be the anthrax vaccine. Hence, despite a large number of biogenerics being produced indigenously, the regulatory mechanisms are not very clear as to what has to be followed in case of biogenerics vis-à-vis NBE.
Evolution of regulatory changes • • • • • • • • • • 1998-2001, draft guidance for follow-on growth hormone and insulin 2002, transfer of therapeutic proteins and MAbs to CDER 2003, Omnitrope 505(b)(2) application (follow-on HGH) by Sandoz 2003, FDA follow-on biologics and proposed guidance 2004, citizen petitions from Genentech and Pfizer 2004, delayed approval of Omnitrope by FDA and EU. 2005, EMEA guideline for biosimilar products and product –specific Guidelines, Sandoz files law suite against FDA. 2006, EU CHMP’s positive opinion and eu commission approval of Omnitrope. 2006, USA federal judge’s ruling on FDA’s action toward sandoz’s Application. 2007, ____ FDA’s guidance or concept paper is awaited.
About the Author Mr. Ashish Agarwal is the founder- C.E.O of ONCO Life Sciences Pvt. Ltd. Established in 2005 Based at Pune, India. He is a first Generation Entrepreneur, a Gold medalist in pharmacy with a degree in Management. Contact: firstname.lastname@example.org
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