Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Clinical requirements for the development of biosimilar products ***

Dr. Katja Schepper (Abschlußjahr: 2007)

Language: English

As global sales of biologic products are growing rapidly this market represents a significant target for generic companies. The term “biosimilar product” is a new European term which came-up with the 2004 review of EU legislation. Biosimilar products can be regarded as a generic version of biologically or biotechnologically derived products situated in-between the pure generic approach and a full new application. The first biosimilar product in the EU was Somatotropin / Sandoz (Omnitrope®). In the EPAR of Omnitrope® a definition of the term “biosimilar product” can be found.

Due to several reasons in the USA the opportunities for the development of generic versions of biological products are much less developed : currently there is no approval pathway for biosimilar products in the USA. The FDA is considering a hybrid application between the regular NDA and the ANDA for particular biological products, which would include consideration of data from the innovator product and the potential for provision of additional data by the biosimilar applicant. But so far, in the USA the majority of biologics are approved after submission of a full Biologic License Application (BLAs) and there is currently no approval pathway for biosimilars of BLAs.

Contrary to the USA a legal framework for biosimilars exits in the EU since the review of EU legislation. Directive 2004/27/EC displaced the term “essential similarity” by two new terms: “generic medicinal products” and “similar biological medicinal product”. For authorization of all biotechnology products including biosimilars the centralized procedure is mandatory. The type and quantity of data needed depends on a case-by-case assessment. According to Directive 2003/63/EC, the usual generic approach is not sufficient. For the demonstration of the similar nature of two biological products, additional data regarding the toxicological and clinical profile have to be provided. The following three essential guidelines give advice for the pre-clinical and clinical sections of the biosimilar dossier:

• EMEA/CHMP/437/04
• EMEA/CPMP/3097/02 to be replaced by EMEA/CHMP/BMWP/101695/06 (draft)
• EMEA/CHMP/BMWP/42832/2005 and its four product specific annexes regarding epoeitin, G-CSF, human insulin and somatropin.

Additionally, there are two draft guidelines regarding the specific concerns of

• immunogenicity (EMEA/CHMP/BMWP/14327/06) and
• LMWH (EMEA/CHMP/BMWP/496286/06).

According to this new legislation it may not be necessary to repeat all safety and efficacy studies of the originator if the biosimilar applicant can demonstrate that it is possible to characterize the product in detail with respect to physico-chemical properties and in vitro activity and comparability can be shown from a chemical-pharmaceutical perspective.
All pre-clinical and clinical studies should be comparative in nature and should be designed to detect differences in response between the biosimilar and the reference product and not just the response per se. The comparability exercise requires not only a comparable physico-chemical profile but also pre-clinical and clinical trials showing similarity between biosimilar and reference product. The chosen reference product must be a medicinal product authorized in the Community, on the basis of a complete dossier. The same reference product should be used throughout the whole comparability program.

Pages 60, Annexes pages 6