The market for biogenerics is directly related to that of innovator biopharmaceuticals, whose sales have been on rise. Assuming a favourable regulatory environment for these products, the world market for generic biopharmaceuticals has the potential to touch $5.4 billion by 2008

Biopharmaceutical patent expirations are beckoning generic drug companies, but there are numerous hurdles to their commercialization. The biotechnological products are often patented and are strictly proprietary until patent expiry. Biogenerics can play a crucial role in providing less costly alternative to these products. The market for biogenerics is directly related to that of innovator biopharmaceuticals, whose sales have been on rise. Assuming a favourable regulatory environment for these products, the world market for generic biopharmaceuticals has the potential to touch $5.4 billion by 2008.

Definition and terminology
The term 'biogeneric' usually means a therapeutically equivalent version of a currently marketed recombinant DNA- derived protein product that is manufactured by a company that is independent from the originator company. By definition, these products are not duplicates of the originator product because the structural heterogeneity that is introduced during the manufacturing process is considered to preclude the demonstration of 'essential similarity'. Small changes in the manufacture of biologics medicinal products can dramatically affect the safety and efficacy of the therapeutic molecule. The very nature of a biologic means it is not possible for two different manufacturers to manufacture two identical biologics and therefore a generic biologic (biogeneric) cannot exist. "Biogenerics don't really exist" and the term is a misnomer because products are not identical. 'Follow-on biologics' or 'biosimilars' are scientifically more appropriate.

Current regulatory status
Since the European Union (EU), United States and Japan together constitute majority of the international market, current regula-tory status of these countries with respect to biogeneric products has been discussed below.

European position
The EU has a formally codified regulatory pathway for "similar biological medicinal products" in its pharmaceutical directive, and the European Medicines Agency, Evaluation of Medicines for Human Use (EMEA) has begun to formalize the process for approval of follow on biological products. The EU legislation provides a legal framework for biosimilars in which it is understood that such products will need less supporting data than had been required for the original reference product. The application should include data to justify differences from the reference product. The Committee forHuman Medicinal Products (CHMP) determines the exact data requirements on a product to product basis, according to the nature of product and its proposed therapeutic use. The development of detailed guidelines on dossier requirements for specific products is discouraged because this is thought to restrict the alternative scientifically valid approaches.

The EMEA guideline on similar biological medicinal products is the pivotal regulatory guideline on biogenerics and details key requirements for approval. This guideline for 'follow-on' biological products, aims to address product similarity along with quality, safety and efficacy issues. The same reference product is required to be used for all three parts of the dossier, i.e. quality, safety and effi-cacy aspects. The guideline addresses the general principles for clinical and non-clinical development and assessment of the marketing authorization applications of biogenerics, but not for comparability exercise for changes during development and post-authorization. Further, this guideline is to be considered in conjunction with all relevant current and future guidelines pertaining to biological medicinal products. The guideline requires following sets of studies to be carried out for approval of a biogeneric - Non-clinical, clinical, clinical safety and immunogenicity studies.

Non-clinical studies
Before going into clinical development, non-clinical studies are to be performed, with an aim to detect the differences in response of similar biological product and reference product. These ought to include both in vitro and in vivo studies.

Clinical studies
The clinical comparability exercise is a stepwise procedure that should begin with pharmacokinetic studies (PK), followed by pharmacodynamic studies (PD), PK/PD correlation and clinical efficacy trials. Combined PK/PD studies may provide useful information on the relationship between exposure and effect. Efficacy trials are necessary to demonstrate therapeutic equivalence.

Clinical safety and pharmacovigilance requirements
Even if the efficacy is shown to be comparable, the similar biological medicinal products may exhibit a different safety profile. Hence, the applicant requires to give detailed information on benefit to risk assessment.

Immunogenicity
An immune response to the product may have a significant impact on its clinical safety and efficacy. Neutralizing antibodies directly alter the pharmacodynamic effect, while any binding antibody may affect the pharmacokinetics. Testing for immunogenicity should be performed by assay methods with appropriate specificity and sensitivity.

American position
The Food and Drug Administration (FDA) has demonstrated leadership in creating a regulatory process for the demonstration of biologic product comparability, however, a pathway for the approval of biogenerics is still lacking. This apparent paradox is a consequence of a sequence of citizen petitions that are addressed to FDA, and are supported by active political lobbying. This has restricted the decision-making authority of the agency. FDA's decision to apply 505 (b) (2) approval route for products approved via Federal Food, Drug and Cosmetics Act (FD&C) has further added to confusion. The acceptance of the FDA in Sept 2003 of a hybrid dossier for a follow on version of recombinant hGH Omnitrop; provides a test case; however, this is also the subject of a citizen petition. Currently, the regulatory filing strategies that could lead to approval of a therapeutically equivalent biological product in the US are- (a) 505(b) (2) application, (b) biological license application, and (c) marketing authorization application via a centralized procedure.

The guidance documents have been ready for release since April 2004 and they reflect balanced views of FDA experts. However, intervention by various sections of the biopharmaceutical industry has caused a delay in their release as it has led to the need to broaden the scope. Although the Biotechnology Industry Organization (BIO) has opposed and has also been involved in a debate over the FDA's authority for approving follow-on biologicals, there is nothing in the Public Health Service Act that prevents the FDA from considering a dossier that contains adequate quality and non-clinical and clinical data to demonstrate comparability between a reference and a follow-on product. Thus it might not be necessary to create additional legislation for registration of biogenerics that were originally approved by either Central Drug Evaluation and Research or Central Biologics Evaluation and Research. Scientific reasons not withstanding, attempts to register biogenerics under the existing statutes are most likely to be delayed by legal challenges. Nevertheless, publication of FDA guidelines on biogenerics is inevitable, and a two-tiered approach is anticipated. Tier-one would outline the requirements for an abbreviated data package for approval while tier-two would contain a more rigorous characterization of approval requirements for inter-changeability.

Japanese scenario
In Japan, there is no legal framework in place for approval of a "biogeneric" or biosimilar". In 1984, the Ministry of Health, Labor and Welfare issued guidelines according to which "new drug" for purposes of data package are required for approval. The regulatory authorities considering biogenerics have been debating the issue of "comparability" as it applies to biologics. It is considered that it may be possible to evaluate relatively simple, low molecule, non-glycosolated proteins (e.g., hGH and insulin) as generic drugs but regulatory authorities have suggested that there is little likelihood of recognition of glycosolated proteins as generic drugs. Generic drugs are not widely used in Japan, but their use is on rise.

Obstacles to biogenerics
Although there are potential market opportunities for biogenerics, and any drug cost cut associated with biogenerics would be welcomed by governments and health care providers, a number of obstacles still remain. The approval by regulatory agencies, rather than the development of a biogeneric formulation is the bottleneck to their commercialization. The obstacles discussed here are the major reasons for delays in formulating and releasing an acceptable filing procedure by various regulatory authorities.

Scientific and technical hindrances
Unlike mainstream pharmaceuticals, extensive testing is not required for generics, thereby generics are much cheaper than innovator drugs. One of the factors that drove the rapid update of pharmaceutical generics in the US was the Hatch - Waxman Act (1984). This legislation allows a drug to gain approval without safety and efficacy trials if its active ingredient is identical to that of an innovator drug.

Because the biological product category was just emerging in 1984, it wasn't considered in drafting this legislation. Coincidentally, a limited number of biopharmaceuticals, including hGH and recombinant insulin product, are subject to approval under the FD&C, which falls under the Hatch Waxman umbrella. For those products the applicants have an access to drug approval by section 505(b) (2).

The manufacturing cost of biogenerics is much higherthan that for conventional small molecules pharmaceuticals. It is necessary to ensure production under full cGMP standards, which has added the need to meet the stringent requirements in case of a biological product. Biotech products are much harder to define chemically and their specifics may relate to the way in which they are expressed, purified and manufactured. Even minor modifications in a bio process, such as change in culture media or growth conditions, and cell lines used have a major impact on the end product. The dogma followed for biologicals is that the "process makes the product". Biotech drugs are much larger molecules than standard pharmaceutical products and this could result in a number of potential degradation products. Immunogenicity is one parameter that needs to be addressed by regulators because the immune system can detect even small changes in the 3-D structure of a molecule. In some cases, immunogenicity only becomes apparent after prolonged treatment and this indicates the necessity for lengthy clinical trials. Therefore, there are considerable safety obstacles to setting up a system for biogenerics that will resemble the current system for pharmaceutical generics.

Lack of specific regulatory guidelines
As of today, no specific regulations exist for biogenerics. Traditionally, regulatory authorities have considered biologicals as a category distinct from synthesized drugs. This has resulted in a situation of vagueness in regulations. Regulatory authorities in the US and Europe have been caught in the cross-fire between branded drugs and bio tech innovator companies, which want to block competition, and biogeneric firms, which want to profit by producing cheaper knock offs of the original drugs without conducting all the costly R& D and clinical testing done by the innovator. A pathway for approval is lacking mainly due to conflicts between Biotechnology Industry Organization (BIO) and Generic Pharmaceutical Association (GPhA). The BIO is assertive that the FDA doesn't have the authority for approving follow on biologics under any of the legal statutes that it administers. While generic pharmaceutical association argues that an abbreviated regulatory process is within the scope of current science. Generic players want FDA to make use of an existing abbreviated regulatory pathway to approve certain generic biopharmaceuticals that fall within the scope of Hatch - Waxman Act.

Due to current intellectual property scenario and the vigorous political lobby by commercial stakeholders, it is difficult to navigate the various product and process related patent restrictions. Another issue leading to ambiguity in deciding regulatory guidelines is the extent to which the regulators can rely on innovators data in their agency files to cut data requirements for generics. For chemical drugs that can be exactly copied, the product is not so process dependent, and copies can be produced through reverse engineering, good chemistry, tight specifications and Good Manufacturing Practices (GMP) for day to day consistency in actual production. For biological drugs there are always differences among different manufacturer's products, as "the process is the product and the product is the process".

The complexities of biological products extend into biogenerics, leading to difficulties in production and approval processes. The biogenerics market is difficult one to crack not only because of the complex biology and chemistry, but also due to dearth of regulatory guidelines. But for a company willing to take up the challenge, the prospects will be bright for years to come.

(Smiti Kumaris a post graduate research scholar, Aditya M Kaushal is a doctoral research scholar, and Arvind K. Bansal* is an associate professor, all in the Department of Pharmaceutical Technology (Formulations) at National Institute of Pharmaceutical Education and Research (NIPER), Punjab.)