In view of the success of generic small molecule pharmaceuticals in competing with their branded equivalents, it’s not surprising that many parties want to bring lower-cost copies of biopharmaceuticals to market as well. A significant impediment has been the perception that the complexity of biopharmaceutical agents (biologics) makes it impossible to ensure that a purported copy, or follow-on biologic (FOB), is really identical to the original.
After years of debate about the very concept of FOBs, the federal government in March 2010 took a huge step toward making FOBs a reality by enacting the Biologics Price Competition and Innovation Act. The act created the long-awaited statutory framework for U.S. FDA evaluation and approval of FOBs.
Given that 2010 worldwide sales of biologics approached the $100 billion mark and several of these agents are due to come off patent in the next five years, the act is likely to have profound consequences in the biotechnology and healthcare sectors. The act is intended to encourage innovation and to promote price competition by being responsive to the needs of both the biologic license application (BLA) holder who originally developed and marketed the biologic (the reference product) and the FOB applicant who wishes to compete by offering a similar product at a lower price, without having to do full-scale clinical trials.
The act outlines two pathways whereby FOB applicants can seek approval: 1) as biosimilar to the reference product, where the FOB is deemed highly similar to the reference product; and 2) as interchangeable with the reference product, where the FOB is deemed essentially identical. Clearly, the standards for interchangeable will be especially stringent, but in both categories it is expected that considerable scrutiny will be placed on criteria used to demonstrate equivalence of the FOB to the sponsor/reference product.
Biosimilarity and Bioequivalence
In November 2010, FDA held a public hearing to solicit input on 1) scientific and technical factors it should consider in determining whether the biological product is highly similar to the reference product; 2) scientific and technical factors it should consider in determining what studies are appropriate for assessing the nature and impact of actual or potential structural differences between the proposed biosimilar product and the reference product; 3) the range of structural differences between a proposed biosimilar product and the reference product consistent with the standard “highly similar;” and 4) criteria FDA should apply to determine whether animal and/or clinical studies are unnecessary for submission of a FOB application.
Of significance to protein-based FOBs in particular, FDA had earlier identified three properties of therapeutic proteins that, in its opinion, cannot be sufficiently measured at this time, but that are deemed important for understanding the behavior of protein drugs: post-translational modifications, “higher-order” structures, and protein aggregates. Methods used to investigate these properties are likely to be crucial for the FOB approval process for protein-based FOBs, which are expected to constitute a significant component of the marketplace.