United States: FDA Goes Purple On Biologics And Biosimilars: Composes A Variation On A Theme Of Orange

Since the early 1980s, the pharmaceutical industry, as well as the pharmacy boards that control substitution at the state level, have relied on FDA's Orange Book to determine which drugs are not only approved, but also those generic versions that are therapeutically equivalent to the brand name product and may be substituted at the pharmacy level. With the passage in 2010 of the Biologics Price Competition and Innovation Act (BPCIA), the potential for the development of lower cost biosimilar versions of often very expensive brand name biologics products has been emerging. Indeed, the first biosimilar applications submitted to FDA were recently announced in July and August 2014 by both Sandoz and Celltrion. However, to date, there was no FDA list similar to the Orange Book of approved biologics that could serve as the reference product required for a biosimilar application. On September 9, 2014, FDA filled that void by announcing the creation of the Purple Book, which lists approved innovator biologic applications, and also includes a column to indicate not only when the biologic was first approved, but also a column in which the date that the 12-year exclusivity period mandated by the BPCIA will (or has) expired.

Avid readers of the Orange Book, however, will find the Purple Book very scanty in comparison. First, and not surprising, there are no approved biosimilars listed, as only two have been submitted and both of those in the last few months--the Sandoz and Celltrion applications as referred to above. Second, while the approved biologics are listed in alphabetical order by their non-proprietary names, most of the information regarding not only the date of first approval, but also the end of the 12-year exclusivity period has not yet been completed in the initial iterations of the Purple Book. FDA, however, cautions that the absence of the information should not be construed as indicating that the approved BLA in question is not entitled to exclusivity. The agency also made clear that it will be updating the list as necessary going forward.

The Purple Book has basically two chapters, referred to as lists. The first covers biologics that have been licensed through the Center for Drug Evaluation and Research (CDER), which, since June 2003, has had the responsibility of reviewing the vast majority of therapeutic protein products. The second chapter, or list, covers those BLAs that were licensed by the Center for Biologics Evaluation and Research (CBER). After June 2003, CBER retained jurisdiction over BLAs for vaccines, blood products, gene therapy, cell therapy, and several other types of product (click here for more information on the 2003 transfer to BLAs to CDER).

With respect to the yet-to-be launched birth of a biosimilar, the Purple Book does include a column to indicate whether the product is Interchangeable, to be indicated by a capital "I," or a biosimilar that has not been awarded interchangeability, to be noted by a capital "B."

The use of the "I" to denote an interchangeable biologic is consistent with comments this author previously made in a presentation in February 2014 to the 2nd Annual World Biosimilars and Biobetters Congress in Philadelphia. In a presentation on U.S. regulation of biosimilars, I advocated that it's time to start thinking about a biologic that FDA approves under the BPCIA as interchangeable to an innovator reference product without using the term "biosimilar." Rather, I asserted, the appropriate term should be to simply call them Interchangeable biologics, or "Interchangeables."

My nomenclature change suggestion reflects the key distinction that exists under the BPCIA between different types of biologics being developed under the BPCIA's abbreviated pathway. Initially, applicants will, according to FDA prior guidance, only be able to secure a finding of biosimilarity. Thereafter, an applicant, even with a licensed biosimilar, would have to do additional testing to show that its product is interchangeable. While we await FDA guidance on the details of how to prove interchangeability, if an applicant were successful in proving interchangeability, then, in my view, it would be appropriate to no longer refer to that product as a biosimilar, but as an Interchangeable to reflect the fact that FDA would have concluded, in so approving it, that the product can be used freely in place of the reference biologic product that formed the basis for the interchangeable application under § 351(k) of the Public Health Service Act.

Returning to the Purple Book, FDA appears to agree with this difference in terminology by adopting the "I" for an Interchangeable application approved under Section 351(k), as opposed to the "B" for a Biosimilar application that was approved without a finding of interchangeability.

Devotees of the Orange Book will not, however, find in the Purple Book the detailed information on patents that is required under the 1984 Drug Price Competition and Patent Term Restoration Act ("Hatch-Waxman"), for the simple reason that, unlike with Hatch-Waxman, the BPCIA's patent provisions operate outside of any substantive interaction with the FDA approval process for biosimilars. While this certainly does not signify that patents are not a key issue in the development of biosimilars, it does mean that a biosimilar application can go forward at FDA without the agency having to be concerned with the status of any pending patent litigation. Rather, the only possible FDA bar to approval of an otherwise complete and robust biosimilar application might be the terms of any exclusivity that the innovator product enjoys.

On the patent litigation side, however, it is important to keep in mind that FDA's acceptance of the biosimilar application filed by Sandoz and, ultimately when Celltrion's is accepted for filing*will serve as the trigger for patent litigation deadlines in the BPCIA. Within 20 days after FDA acceptance, the 351(k) applicant must provide a copy of the application and manufacturing information to the reference product sponsor. This, in turn, triggers the reference product sponsor's 60 day deadline to provide a list of patents to the biosimilar applicant. After two more 60-day periods for additional exchanges of the bases for a patent challenge, and the bases for patent enforcement and following a brief period of further negotiations, the reference product sponsor can file suit against the biosimilar applicant. Therefore, we anticipate the first biosimilar patent litigations under the BPCIA to be initiated in March or April of 2015.

Also missing from the Purple Book are those biologics that, for historical reasons, such as human growth hormone and recombinant insulin products, were approved not under the BLA provisions of the Public Health Service Act, but under the new drug application (NDA) provisions of the Federal Food, Drug, and Cosmetic Act (FFDCA). Under the BPCIA, a biosimilar application technically cannot be filed for a brand name biologic product that is approved under the NDA process. Rather, someone seeking to market a lower cost biologic based on showing similarity to an innovator biologic approved under an NDA also must submit an NDA, most likely under § 505(b)(2) of the FFDCA. Indeed, one of the first products approved in the United States that is in the nature of a "biosimilar" was secured under the 505(b)(2) NDA process in June 2006, when Sandoz secured approval of a version of Pfizer's Genotropin® via the 505(b)(2) process.

The launch of the Purple Book represents another key step forward in FDA's iterative approach to the regulation of biosimilars under the BPCIA. While, given the key differences between the regulatory regimes established by the BPCIA and Hatch-Waxman, the new reference will not spur as intense scrutiny as the Orange Book does for the small molecule generic drug approval process, its emergence further portends the day when a line will be added to the Purple Book announcing the first approval of a biosimilar under the BPCIA.

So stay tuned.

* Note: the Celltrion press release on its 351(k) application did not affirmatively state that FDA had accepted the Celltrion 351(k) application for filing. Rather, the company stated that it had "completed the filing procedure." Thus, we can not say for sure if Celltrion's application has reached that level of processing at FDA that it has been accepted for filing or is still in the initial review stage to see if it is sufficiently complete so as to be accepted for filing.

Disclaimer: This Alert has been prepared and published for informational purposes only and is not offered, nor should be construed, as legal advice. For more information, please see the firm's full disclaimer.

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