Bio Generics Regulation

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Biogenerics – a worldwide perspective 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 va
   Biogenerics – a worldwide perspectiveT erminology of the biopharmaceutical has faced a certain degree of chaosand anarchy for years and it is still in the developmental stages. Similar isthe case of Biogenerics. All current terms related to Biogenerics haveconnotations and evoke preconceptions that may support, denigrate, orobfuscate anyone product under consideration.Biogenerics are as old as whatever you consider to be biopharmaceuticals.For example, various live vaccinia virus–based vaccines for smallpoxprophylaxis have been available and considered therapeutically equivalent formore than 200 years. On the other hand, Biogenerics can be considered arecent phenomenon, with just a few on the market, if you take a rigorousregulatory view.Nowadays, there are more than 150 biopharmaceuticals in clinical use inwestern world. The patents on many recombinant DNA products haveexpired, or are due to expire, soon. In the case of classical drugs, expirationof patents opens the possibility of the introduction of generic products.Frost & Sullivan in a recent study analyzed the worldwide market forbiogeneric products. It focuses on the United States, European, Asian, andthe rest- of- The-world (row) markets. The research provides An interestingforecast: starting from 2011, the Market dimension of Biogenerics drugs inthe USA And Europe only will be over 16 billion us $.However, thebiogenerics market has been very slow to establish itself. The key reason isthe lack of a Defined regulatory framework and uncertainty—on the part of manufacturers and regulators alike—regarding what biogenerics will look likeand 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 andefficacy, depending on the product. Any pathway should fully address thepatient 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 manufacturenine different types of insulin’s in 23 different presentations – and they arenot interchangeable. Indeed, the FDA expressed its concerns withinterchangeability in September 2006: “with protein products, as of today,the FDA has not determined how interchangeability can be established forcomplex proteins. Different large protein products, with similar molecularcomposition may behave differently in people and substitution of one foranother may result in serious health outcomes, e.g., generation of apathologic immune response.” ( European system recognizes that “by definition similar biologicalmedicinal products are not generic medicinal products, since it could beexpected that there may be subtle differences between similar biologicalmedicinal products from different manufacturers or compared with referenceproducts, which may not be fully apparent until greater experience in theiruse has been established.” (Guideline on similar biological medicinal products(chmp/437/04)) there is a further requirement that the products are clearlyidentified to support post-market monitoring. In addition, there is noevidence to support interchangeability in existing biologics, let alone a newclass 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 orfollow-on biologics).  Under the guidelines developed by EMEA, manufacturers may rely on themarketing authorization granted to a therapeutic protein when preparing adossier for a biosimilar protein product. However, the guidelines establishthat the manufacturer must adequately substantiate the quality, safety, andefficacy of the biosimilar product; these elements constitute the three mainsections of any new drug application needed for product authorization in theEU. Each of these sections of the dossier must rely on the same innovatorproduct. While the quality assessment for a biosimilar product is acomprehensive comparison against the innovator product, the applicationmay be abbreviated in that the sponsor may not be required to repeat allefficacy and safety studies. The applicant will not be required to repeat theseinvestigations if the physicochemical and in vitro characteristics of the twoproducts can be adequately evaluated. In addition, the biosimilar productsponsor must demonstrate chemical comparability between the two products,a potentially difficult task depending on the innovator protein’s complexityand other product or manufacturing attributes. In fact, the EMEA guidelinespoint out that there will be some situations in which satisfactory equivalencecannot be demonstrated due to the complexity of the protein’s structure, themanufacturing process, and the effect of product differences on quality,safety, and efficacy. Where chemical comparability is not or cannot bedemonstrated, a full complement of clinical and preclinical data will benecessary to support the dossier for the follow-on therapeutic product.While the EU guidelines may be difficult to satisfy, particularly for morecomplex therapies, they nevertheless provide sponsors with the opportunityfor obtaining regulatory approval of a biosimilar therapeutic protein throughan established regulatory framework. Recently, the European Commission,acting on a recommendation by the EMEA Committee on Medicinal Productsfor Human Use (CHMP) and following the established guidance documents,granted its first marketing authorization for follow-on biologic in April 2006 toSandoz’s generic human growth hormone, Omnitrope. Omnitrope is a follow-on 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 wouldconstitute Demonstration of bioequivalence . Whereas these products areadministered through Routes that provide lesser barriers in the entry of drugto the body, the differences are Related to antigenicity potential which needsa clinical evaluation; however, studies have Demonstrated that minutedifferences in the structure of protein drugs including Dimerization, 3 and4`h degree structures and easily picked up in partitioning studies since thesestudies truly represent the thermodynamic potential which is readily changedeven Where minor differences in the structures, often too small to bedetected by even the most Sophisticated instruments; in most instances, theuse of instrumentation itself disturbs the Structure enough to make thestudies meaningless. This almost borders on the Heisenberg's principle of uncertainty.In early 2006, following the CHMP recommendations on Omnitrope andValtropin, Senator Orrin Hatch (R-UT) and Representative Henry Waxman(D-CA) sent a letter to acting FDA Commissioner Andrew von Eschenbachurging FDA to issue guidance documents for follow-on insulin and humangrowth hormone (HGH) products. According to FDA, the Agency has had adraft 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 onthe FDA to make substantive progress on developing a mechanism forreviewing and approving follow-on biologics: the development of a regulatorypathway in Europe; the authorization of a biosimilar product by the EuropeanUnion; judicial intervention; and Congress sending signals regarding itsintent to take direct action if FDA does not act imminently . The momentumis clearly building toward some regulatory movement on the generic biologicsissue. FDA may seek to relieve some of this pressure through someincremental action, such as development of a regulatory pathway for acertain class of biologics, like insulin products or human growth hormoneproducts. Alternatively, the Agency may take broader action by creating a
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