Biogenerics Feature

 

Biogenericsand Regulatory Affairs

Although the individual products within the protein families are heterogenous, these protein product classes represent established markets with proven value of the therapeutic proteins. As such, many companies were attracted to use their technology for products with improved features, i.e. efficacy, safety, convenience or price leading to a fully packed pipeline of next generation products.

The stakeholders in the R&D activities related to these seven established protein product classes plus to that of thrombopoiesis stimulating agents are:

Innovator companies of first generation protein products;

• Biogeneric companies in regulated markets;
• Biogeneric companies in non-regulated or “off-patent” markets;
• Drug delivery companies;
• Device companies;
• Next generation innovator companies.

Patent expiry for first generation protein products such as human growth hormone, insulin and G-CSF has already commenced, predominantly first in Europe and then in the US , and is progressively advancing to other territories and protein products. Patent expiration, thus, reduces the risk of law suites for patent infringement and stimulated companies to copy the success story of small molecule generics with biologics. Follow-on versions of previously approved recombinant biotechnology products most commonly are termed “ biogenerics ”, but equivalent terms are “ biosimilars ” or similar biological medicinal products in the terminology of the EMEA and follow-on versions of biologics (“ follow-on biologics ”, FoBs) in the terminology of the FDA.

While the development of a small molecule generic typically costs between US$ 2 and 5 mln, biogeneric costs are at least ten-fold higher due to more severe requirements in manufacturing and clinical development. This will prevent manufacturers and marketers of biogeneric proteins to sell the products as cheap as small molecule generics at price discounts of more than 50 %.. In fact, Novartis announced to sell its biogeneric Omnitrope at a 25 % discount (Wall Street Journal; June 1, 2006, page D8).

The first biogeneric protein approved in the European Union, the USA and in Australia is Sandoz’ Omnitrope, a generic equivalent of Pfizer’s Genitrope, a human growth hormone. Sandoz’ NDA submitted to the FDA did not include phase II dose-finding studies and contained less toxicology. The NDA relied on demonstration of similarity to an approved product rather than clinical data for one of its indications. FDA acted within the confines of section 505(b)(2) of the Food, Drug, and Cosmetic Act )FDCA) which governs regulation of drugs filed under NDA. FDA stated that it had no statutory authority to address follow-on biologics governed by the Public Health Service Act (PHS).

In contrast, the European Medicines Evaluation Agency (EMEA) published a set of final guidelines on similar biological medicinal products ( link ) which came into effect on June 1, 2006 (or July 1, 2006 in the case of erythropoietin). The guidelines give guidance on quality, non-clinical and clinical issues. There are four product specific annexes for insulin, somatropin (hGH), erythropoietin and G-CSF which give guidance on specific non-clinical and clinical issues. A concept paper for interferon alpha is under consultation.

Guideline Similar Biological Medicinal Products: http://www.emea.eu.int/pdfs/human/biosimilar/043704en.pdf

Guideline Non-Clinical and Clinical Issues: http://www.emea.eu.int/pdfs/human/biosimilar/4283205en.pdf

Guideline Quality Issues: http://www.emea.eu.int/pdfs/human/biosimilar/4934805en.pdf

Insulin annex: http://www.emea.eu.int/pdfs/human/biosimilar/3277505en.pdf

G-CSF annex: http://www.emea.eu.int/pdfs/human/biosimilar/3132905en.pdf

Somatropin (hGH) annex: http://www.emea.eu.int/pdfs/human/biosimilar/9452805en.pdf

EPO annex: http://www.emea.eu.int/pdfs/human/biosimilar/9452605en.pdf

Concept paper Interferon alpha: http://www.emea.eu.int/pdfs/human/biosimilar/724106en.pdf

The EMEA also finalized its New Framework for Scientific Advice & Protocol Assistance ( link ) which provides several improvements including faster delivery of advice (within 40 to 70 days), broader scope for requesting advice and more involvement of experts from the pre-submission phase. In addition, a 90 % fee reduction applies for micro, small and medium size companies. The new Framework will come into effect as of July 1, 2006 and will help to clarify open questions related to the development of biogenerics.

Apart from the European and US regulatory developments, first biogeneric R&D activities are reported in Japan (EPO), but the regulatory situation is not yet transparent.

Biogeneric development activities so far focus on copycats of first generation protein products, but in the case of hGH slow release versions of biogeneric hGH are in advanced clinical development in EU and US territories. Indian companies are already working on pegylated versions of biogeneric proteins and also started with development of biogeneric antibodies (rituximab).