The experience with biosimilar epoetins: Quality and therapeutic equivalence

For a number of reasons the classical generic approach cannot be extrapolated to therapeutic proteins. Protein pharmaceuticals are mostly large complex molecules and the current analytical methods do not allow their full characterization. In general, these proteins also show heterogeneity such as variations in glycosylation or protein clipping due to natural processes in the host cells needed for their production. Modifications can also be introduced during production, purification, formulation, and storage. In addition to these product-related impurities, host cells and (biological) materials used during production and purification, such as resins and monoclonal antibodies for affinity chromatography, may introduce process-related impurities. For these reasons regulatory systems for copies of therapeutic proteins were introduced in many parts of the world which made comparative clinical data obligatory. And because therapeutic proteins can never be shown to be identical the term biosimilars was introduced for this type of products to set them apart from generics. The first regulatory agency that has issued guidelines until now has been the European Medicine Evaluation Agency (EMEA) based on the EU legislation which became effective in November 2005. Clinical data have become mandatory for a marketing authorization submission to the EMEA for biosimilars, which like innovative biotechnology products, will need to be evaluated through a centralized procedure and not by national regulatory approval. The CHMP, the scientific committee of the EMEA, has issued a number of guidelines concerning the data required for marketing authorization, including a guideline regarding biosimilar epoetins. Until now two different epoetins, marketed under six different names, have been authorized in the EU based on the biosimilar regulations. As expected these biosimilars have shown difference in quality and biological/ clinical aspects but are therapeutically equivalent. Discussions are still going on concerning substitution, exchangeability and clustering with the original products in the reference price systems. An update will be given concerning these discussion and also of the results of the continuing monitoring of the quality of the different epoetins running at the department of biopharmaceutics of Utrecht University.