Over the last 20 years a new class of drugs has been developed and produced - safe and effective therapeutic proteins. These drugs, also called biotech pharmaceuticals, are manufactured by biotechnological procedures most often using recombinant DNA technology.
This scientific advance and the modern technology have opened up new avenues for the effective treatment of human diseases that were previously beyond the scope of the classical pharmaceuticals containing chemically synthesised compounds as active ingredients. The process for development of further innovative drugs using biotechnological technologies and procedures is still growing. It can be roughly estimated that at present more than 350 biotech pharmaceuticals and vaccines are undergoing preclinical and clinical tests with the view to offer new treatment options especially for neurodegenerative disorders and for cancer.
Considering this background of scientific and technological activities in the biotech area and recognising the fact that these innovative treatments are rather costly, it is surprising that up to now practically no "generic" copies of biotech pharmaceuticals have been granted marketing authorisation in Europe. EMEA has signalled the approval of only one generic version of a recombinant pharmaceutical, human growth hormone (Omnitrope), up to the end of January 2006. This is the first marketing authorisation for a copy of a biotech drug.
As demonstrated in the table, the patents of several biotech pharmaceuticals have expired or are about to expire this year. It is estimated that the expiration of patent protection will open up a market of about 23 billion Euro with annual growth rates of approximately 10%.
There are two important reasons for the rather slow progress in the development and filing of applications for copies of biotech pharmaceuticals: The technology of manufacturing and the regulatory framework.
Compared to the small molecules (chemical entities) of classical pharmaceuticals the active ingredients of drugs produced by biotechnological procedures (proteins) are much larger, have many more spatial structures and are much more diverse (heterogeneous) than chemical entities. Therefore the manufacturing process is a determining factor not only for the quality, but also for the safety and efficacy of the drug. Even very small process changes, such as small variations in temperature, cell culture conditions or even transport and storage conditions of inter-mediate and finished product, can result in significant differences in the toxicological and clinical properties.
Whereas generic copies of chemistry-based pharmaceuticals are identical to the original product and can be well characterised corresponding to the definitions of the EU Directive 2004/27/EC (March 2004), a comparable definition cannot be established for copies of biotech pharmaceuticals because of their nature and the complexity of the manufacturing process.
A typical manufacturing procedure for a chemical entity consists of 40 to 50 critical tests, whereas in a biotechnological procedure 250 or more critical tests must be performed. Manufacturers often develop product-specific proprietary standard tests or other assays to ensure that this process and product specifications are maintained throughout. As a consequence there will always be differences in the manufacturing process if different manufacturers produce the same biotech pharmaceutical, even if the same basic technology is used.
This situation has major implications for regulatory control. As a first consequence the definition of "biosimilar medicines" or biosimilars was created for follow-on versions (copies) of original biotech pharmaceuticals. The biosimilars should have the same mechanism of action as the originator product, the same quality, and they should exhibit the same safety and efficacy for the treatment of the same disease as the innovator`s product.
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After intensive discussions and deliberations starting around the year 2000, the European Union has established a legislative and regulatory pathway for the approval of biosimilars, which can be launched on the EU market after expiry of patent and data exclusivity. Currently, comparable legislation does not exist in the US, since the FDA has not started the discussion or issued any documents as a basis for consultation and discussion.
Prerequisite for approval in the EU is the appropriate testing of quality, safety and efficacy. This request is regulated by guidance documents issued by the European Medicines Agency (EMEA).
The key document is the "Guideline on similar biological products" (CHMP/43/04) valid since 30 October 2005. This guideline indicates that the classical generic approach is scientifically not appropriate for biological/biotechnology-derived products and specifies the "similar biological medicinal products" approach as a comparability exercise which has to be followed.
Whether a medicinal product would be acceptable using this approach depends on the state of art of analytical procedures, the manufacturing process employed, as well as clinical and regulatory experiences. It is not only the requirements for quality (Module 3) that must be fulfilled, safety and efficacy must also comply with the data requirements laid down in Annex I to Directive 2001/83/EC. Furthermore the requirements of the European Pharmacopoeia and additional relevant guidelines of CHMP and ICH must be considered.
Regulatory documents concerning proteins are: "Guideline on the comparability of medicinal products containing biotechnologically-derived proteins as active substance: qualityissues" (EMEA/CPMP/BWP/ 3207/00/Rev11) and "Guideline on the comparability of medicinal products containing biotechnologically derived proteins as active substance: non-clinical and clinical issues" (EMEA/CPMP/ 3097/02/Final).
Both guidelines address the requirements for a comparability exercise for changes in manufacturing procedure for a given product and for a product claimed to be similar to an authorised product. It is stressed that quality aspects may have a profound impact on safety and/or efficacy criteria and that a package of preclinical and/or clinical studies is required to qualify the respective product as biosimilar medicine.
For the practical use of these guidelines it should be kept in mind that all recommendations are provided with the reservation that, depending on the nature of the active substance and the technological procedure, a case-by-case evaluation and decision will be made by the authority to ensure the safety of the patient. In the event that satisfactory comparability is not shown, a full preclinical and clinical data package will be required. As a consequence of these unique features of biotechnologically derived medicinal products it is stronglyrecommended that advice is sought from experienced professionals before starting the development of a biosimilar medicinal product.
(The author is project leader Business Unit Pharma, RCC Ltd.)