COMPARABILITY ASSESSMENTS

From a regulatory science perspective, therefore, what remains to be seen is whether, and if so, to what extent, the provisions of this new pathway governing highly similar biosimilars will affect comparability determinations for biological products regulated under traditional BLAs. Even before enactment of the new law, some signs seemed to be emerging that pre- and post-manufacturing change comparability assessments may be subjected to regulatory requirements that could approach those now codified for biosimilars. For example, in connection with Myozyme (alglucosidase alfa) for use in patients with Pompe disease, when the sponsor sought approval for product made at a significantly higher scale after completing a comprehensive comparability exercise, the FDA's initial review uncovered problems indicating the products were not comparable. The FDA's subsequent review found insufficient data to establish clinical comparability between the products. The FDA then requested that the sponsor submit a new BLA with clinical data to support separate licensure of the large-scale product as a new product, for which a new brand name, Lumizyme, was required, albeit with the same international nonproprietary name (INN), alglucosidase alfa.³

Traversing the 16-year history between the approvals of Avonex and Lumizyme, it would not be appropriate to suggest that either of them, or any of the comparability assessments in between, are necessarily harbingers of things to come. However, it certainly is clear from these and many other regulatory precedents that demonstrating comparability remains a sponsor's burden and one that needs to be met case-by-case on a data-driven basis. More broadly, depending on how the FDA evaluates biosimilar applications for highly similar biologics in the future, the biosimilars provisions of the BPCIA ultimately could become the foundation for one of the most transformative regulatory paradigm shifts in the years to come.

In the regulatory pathway itself and in the provisions delegating its implementation to scientific experts at the FDA, Congress established a regulatory pathway that generally enables sponsors to pursue development and approval of biosimilars that they have demonstrated to be highly similar to a previously licensed biologic.

It is not reasonable to apply that same conclusion, however, to the remaining nonregulatory BPCIA provisions. That is because much of the rest of the BPCIA is disproportionately focused on patent rights, including unprecedented disclosures to enable enforcement of patent rights, and unparalleled limitations on the exercise of patent rights. Unlike the relatively straightforward regulatory pathway-related provisions, which consume about three pages of legislative text, the patent provisions take double that amount of space to codify what can only be considered a convoluted process. Indeed, simply mapping out the patent challenge and enforcement process reveals that it is Kafkaesque in its disorienting complexities.

Exclusivity Provisions

Unfortunately, in the years of legislative debate leading up to enactment of the BPCIA, the emphasis from an intellectual property (IP) perspective was on provisions granting nonpatent exclusivity to originators who pioneer the development of innovative biologics. As if exclusivity were the only issue on the table, stakeholders on all sides of the debate often concentrated their advocacy on the period of years: Should it be 5 or 20, 7 or 14, 10 or 11 or 12? Reasonable arguments were presented on various sides of the issue, and Congress ultimately determined that 12 years was an appropriate nonpatent exclusivity period to incentivize R&D for biologics.

What was lost in the undue focus on this exclusivity period is that Congress codified an exclusivity regime unlike any other that preceded it. One of the most significant distinctions is that it provides for a flat 12-year period (plus pediatric exclusivity when attainable) running from the date of the original approval of the first BLA for a biological product. In practical terms, this means that, as of the day of enactment, there already were several dozen biologics that do not receive any nonpatent exclusivity, including blockbusters like Amgen's Enbrel, Epogen, and Neupogen; Genentech's Rituxan and Herceptin; and J&J's Procrit and Remicade. Moreover, Congress codified detailed provisions (so-called "anti-evergreening" prohibitions) that prevent exclusivity from being granted to slightly modified biologics that are not truly innovative.