It can be said that biogenerics are as old as 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.

Currently, more than 150 biopharmaceuticals are used in clinics in western countries. The patents on many recombinant DNA products have expired and there are many due to expire soon. In the case of classical drugs, expiration of patents opens the possibility of introduction of generic products.

Frost & Sullivan in a recent study analyzed the global market for biogeneric products. The study focuses on biogeneric markets in the United States, Europe, Asia and other countries. The research forecasts that from 2011, the market dimension of biogenerics drugs in the USA and Europe will only be over $16 billion. Remember that the biogenerics market has been very slow to establish itself, largely due to lack of defined regulatory framework and uncertainty on the part of manufacturers and regulators.

Biogeneric products pose unique challenges from a clinical development/ regulatory perspective. For the biogeneric products, the concept of essential similarity does not apply but requires a variable combination of evidence to support quality, safety and efficacy of the product. However, 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 instance, there are currently three companies that manufacture nine types of insulins in 23 presentations. These insulins are not interchangeable. Indeed, the FDA had expressed its concerns of interchangeability in September 2006, saying, "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 other may result in serious health outcomes like generation of pathologic immune response."

By definition similar biological medicinal products are not generic medicinal products, recognizes the European system. 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. In addition, the products need to be clearly identified to support post-market monitoring. Also, 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, an amendment to directive 2001/83/ec, provides the legal basis for the approval of similar biological medicinal products (otherwise referred to as dissimilars or follow-on biologics).

Biogenerics: 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.

Under the guidelines of European Agency for the Evaluation of Medicinal Products (EMEA), manufacturers may rely on the marketing authorization granted to a therapeutic protein, while preparing a dossier for a biosimilar protein product.

However, the guidelines mandate the manufacturer to adequately substantiate the quality, safety and efficacy of the biosimilar product. Quality, safety and efficacy 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 of 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 biosimilar and innovator products can be adequately evaluated. In addition, sponsor of the biosimilar product 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 structure of protein, manufacturing process and 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 provide sponsors an opportunity to obtain regulatory approval for 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 to Sandoz's generic human growth hormone, Omnitrope in April 2006. 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 yet concluded what tests would constitute demonstration of bioequivalence. While these products are administered through routes that provide lesser barriers for the entry of drug in the body, the differences are related to antigenicity potential, which needs a clinical evaluation. However, studies have demonstrated minute differences in the structure of protein drugs, including dimerization 3 and 4`h degree structures. The difference in the structure was easily picked up in partitioning studies since these studies truly represent the thermodynamic potential.

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 the FDA to issue guidance documents for follow-on insulin and human growth hormone (HGH) products. Over the past year, a number of events, including development of a regulatory pathway in Europe, authorization of a biosimilar product by the European Union, judicial intervention and Congress' intent to take direct action if FDA does not act imminently, have placed increased pressure on the FDA to make substantive progress on developing a mechanism for reviewing and approving follow-on biologics. The momentum is clearly building some regulatory movement on the generic biologics issue. The US FDA may seek to relieve some of this pressure through certain incremental action, such as development of a regulatory pathway for a certain class of biologics like insulin products or human growth hormone products. The FDA may also take a 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.

Biogenerics regulations 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, Hepatitis B vaccine, erythropoietin, GM-CSF, alpha interferon etc, have followed the approval procedure required for new biological entity (NBE) and generics. The molecules/vaccines have been cleared through the three-tier mechanism adopting special abbreviated procedures and constituting special committees. This has been possible as the original products were available to evaluate the physico-chemical 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. Despite a large number of biogenerics being produced indigenously, the regulatory mechanisms are not very clear as to what has to be followed in the case of biogenerics vis-à-vis NBE.

(The author is founder and CEO of ONCO Life Sciences Pvt. Ltd. Pune, India)