Since in coming years more and more biopharmaceuticals will lose their patent protection, many pharmaceutical companies including biotechnology industry and generics manufacturers, as well as regulatory agencies, are becoming increasingly interested in biosimilars.
However, contrary to the small molecule medicines generics replication of biopharmaceuticals is somehow a complex and controversy issue. Biopharmaceuticals usually have large and complex molecular structures of protein nature which in many cases replication of these systems in order to produce “identical and similar” molecules are very difficult. Most of the times, small changes in the structure of the final molecule might create different safety and efficacy profile. Therefore changes in the manufacturing process can cause complications for potential biosimilars. New molecules could cause severe immunogenicity reactions. That is why evaluation of biosimilars becomes a serious challenge for both the scientific community and regulatory agencies.
Despite presence of biosimilars in some markets since years ago several highly regulated markets such as USA, until recently did not have any regulations for registration of these medicines. In 2004, European Medicine Agency (EMA) was the first well established regulatory authority to develop a comprehensive guideline for dealing with biosimilars. The main concept of “biosimilarity” in this guideline relies on a head to head demonstration of similarity of the new medicine from both physicochemical and biological activity point of view to a reference originator biopharmaceutical. Since then EMA has authorized more than 14 biosimilars for marketing in EU. Until 2010, the FDA lacked the legal authority to approve biosimilar medicines similar to what is already happening in EU. However, with new reform of health care system in USA, FDA has now the authority to review and approve “highly similar” biosimilar medicines.
WHO has published its first guideline for evaluation of biosimilars in 2010[7, 8]. This guideline also relies on a head to head demonstration of biosimilarity of a biosimilar with a registered biopharmaceutical. This head to head comparison involves both quality non-clinical and clinical aspects of the products. Clinical study should design in a way that would be able to demonstrate comparable safety and efficacy between biosimilar and reference biopharmaceutical.
However, there are some experts who believe that performing head to head preclinical and clinical trials between brand and biosimilar may not be necessary and in fact this might deprive patients of cost effectiveness treatment and compromise patients’ affordability. Some other researchers even believe that the clinical trials required by EMA to compare biosimilars and their corresponding originator product may even be a barrier for the development of future, more advanced biopharmaceuticals.
Highly regulated markets such as USA and EU have specific requirements for biosimilars regarding comparative studies proofing similar safety, efficacy, purity and potency for biosimilars and their brand comparator. Therefore developing biosimilars in these markets require substantial investments estimated in the range of 75–250 million USD. However, this might not be the case for marketing of biosimilars in less regulated markets. Therefore biosimilars in these markets could have different definitions. Although such products might have acceptable safety and efficacy profile based on local requirements they are not “biosimilars” as they have been defined by FDA, EMA or even WHO guidelines. As an example according to a published report, among several recombinant erythropoietins manufactured in Asia none was comparable with the originator product from structural point of view. However, according to the similar methodology, biosimilar erythropoietin marketed in EU was identical with originator. Therefore there is a very low chance for biosimilars developed outside of EU or USA to be approved by FDA or EMA as biosimilar medicine.
Although in many cases, following any change made in production process of biopharmaceuticals originators should ask for regulatory permission for marketing of their products, authorities even in EU or USA do not ask for new preclinical or clinical data in these cases. If the product fall within the variability of the originator molecule after manufacturing change then the new product would be considered “highly similar” to the originator molecule.
Surprisingly, FDA has recently used a non-clinical based approach for granting marketing authorization to the biosimilars. In 2010, FDA approved a generic Enoxaparin as a fully substitutable generic to Sanofi-Aventis Lovenox (Enoxaparin). In reviewing the Enoxaparin file, FDA used five criteria to establish “sameness” for these two products. None of them were pre-clinical or clinical data. In fact FDA used the analytical characterization to grant similarity status to the generic Enoxaparin.