Masterstudiengang "Drug Regulatory Affairs"


Biotechnological generics - a matter of science or science fiction? ***

Dr. Beate Hötzl (Abschlußjahr: 2003)

Biotechnological products were initially developed in the early 1980s and now represent one of the most booming special segments of the pharmaceutical market. In most cases these products are provided for chronic diseases and must be administered for life.

Biotechnological products are products derived from biotechnological techniques such as recombinant DNA technology. The resulting proteins are large molecules with complex structural features and - in many cases - microheterogeneities due to post-translational modifications, e.g. glycosylation. Due to the inherent variability of the biological process, the desired product often is not a single and homogeneous molecular population but a complex mixture of various isoforms of the protein.

Each biotechnological manufacturing process yields a unique product the quality of which is substantially determined by the manufacturing process and its consistency, the formulation, and the storage conditions. All of these issues define the product's safety and efficacy and are taken into account when assessing the in vivo behaviour of the product.

The manufacturing of a generic version implies a completely new process since the generic manufacturer has no insight into the original process. This includes a different host/vector system, different process steps, different facilities, and different equipment. The main risks associated are changes in immunogenicity, bioavailability, pharmacokinetics, and potency/bioactivity.

On the other hand, biotechnology is based on 20 years of experience in cloning and expression, in cell culture and purification, and in protein chemistry, with a large experience in efficacy and safety of biotechnological products. And it seems that at least similar products can be obtained through different processes. For example, three interferon beta products are available on the European and US market which differ significantly with regard to structural features and posology. However, all of these products are authorised for the same indication and thus seem to have appropriate profiles in terms of efficacy and safety, despite the existing differences.

In the US the vast majority of biotechnological products up to mid of 2003 had been approved by FDA's Center for Biologics Evaluation and Research under the Public Health Service Act to which the generic drug law was not applicable. Now, most of the biological/biotechnological products are reviewed under the jurisdiction of FDA's Center for Drug Evaluation and Research (CDER). CDER plans to issue a draft guidance on the abbreviated approval for "follow-on biologics".

In the EU an abridged application for biotechnological generics is already possible, and Directive 2003/63/EC, amending Annex I of Directive 2001/83/EC, now gives a legal basis to the concept of a "similar" biological product. However, the regulatory strategy for conventional chemical generics - demonstration of quality and bio-equivalence - has not generally been accepted for biotechnological products. The extent of data needed to prove efficacy and safety of a biotechnological generic may vary from a justification to one or more confirmatory studies. This will depend on the knowledge of the process and the product, the extent of characterisation of the product, the ability to detect differences, therapeutic area and available experience, and is dealt with on a case-by-case basis.

Authorities and manufacturers will have to work closely together, developing standards for assessing similar products with regard to structure and function, and establishing a database to allow a retrospective evaluation of existing cases. New techniques or the refinement of available tools may allow a more detailed characterisation of these complex molecules, and - together with new technologies such as Transgenics and Proteomics - may open new possibilities, even the possibility of demonstrating bio-equivalence.

If a biotechnological generic is defined as being "similar", the development is a matter of science, and the data needed will probably be less than for the originator product. However, regarding the comparability exercise necessary, the financial investment for the development of a biotechnological generic is still far beyond the investment needed for a conventional chemical generic. Especially in cases of highly complex proteins it may be quicker and easier to develop a biotechnological generic as a new entity rather than establishing a comparability exercise - taking advantage of the fact that the similarity to an approved product facilitates development, e.g. pre-clinical testing or dose ranging.

A comparability exercise for a biotechnological generic to be approved in the EU is developed.

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