News stories coming out of the conference reported how one pharma major after another announced plans to get into follow-ons, a surprising move for companies that, until now, based their reputations on innovation and not imitation.Maybe it shouldn't come as a great surprise, however, considering that recent technical innovations and regulatory advances are creating fertile ground for follow-on commercialization.
New analytics are making it possible (or will soon make it possible) to characterize proteins as they're being synthesized in the bioreactor. Advances in chromatography and mass spectroscopy allow manufacturers to detect variations in amino acids and glycan disposition within protein products that might alter their biophysical properties.The regulatory agencies are also advancing guidances for commercialization of complex biosimilar molecules, such as monoclonal antibodies (mAbs). But as the US pharma majors state their interest in biosimilars, it's important to note that US regulations lag behind Europe. Whereas the US held its first hearing on regulations for follow-ons in November 2010, the European Medicines Agency (EMA) had already developed a regulatory framework for follow-ons in 2003 and issued its first guidelines in 2005.
To be accurate, the medicines actually manufactured under the 2005 EMA guidelines are small, very well characterized molecules, such as recombinant human insulin. Recent debates on both sides of the Atlantic center on what constitutes proof of similarity for larger, complex biomolecules.
With the November 2010 release of two draft guidelines, one on similar biological medicinal products containing monoclonal antibodies, and the other on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use, EMA once again leads the way. The focus of the "biosimilarity exercise," notes the guideline on similar biological medicinal products, "is to demonstrate similar efficacy and safety compared to the reference product, not patient benefit per se, which has already been established by the reference product." And the tests EMA asks for—both in vivo and in vitro—are aimed at determining "all functional aspects of the mAb even though some may not be considered necessary for the mode of action in the clinic."
Together, the two guidelines ask manufacturers to evaluate differences between innovator and follow-on mAbs in process-related impurities due to differences in expression systems used by different manufacturers. They also address "less well characterized" impurities, differences in formulation, unusual excipients, post-translational modifications that can affect the conformation, aggregation, and ultimately the immunogenicity of the follow-on product. The guidelines go on to outline tests for pharmacodynamics, immunogenicity, and suggest an overall risk-based approach to follow-on mAb manufacturing.
Should EMA enact these regulations before FDA, which seems likely, European Union manufacturers will get a head start over their US counterparts in producing, testing, and marketing the follow-ons, which experience could put firms seeking to do business in the US at a competitive disadvantage in what promises to be a tight and competitive market. In light of pharma's expressed intent to manufacture follow-ons, the pressure is on regulators to get up to speed quickly—certainly before follow-ons are just so last year.
Michelle Hoffman is editorial director of Pharmaceutical Technology. Send your thoughts and story ideas to [email protected]