As noted in our previous client alert, FDA Accepts First Biosimilar Application Filed under Section 351(k) of the Public Health Service Act, Sandoz Inc. (“Sandoz”) filed the first biosimilar application under the Biologics Price Competition and Innovation Act (“BPCIA”) on July 24, 2014 for a biosimilar version of Amgen Inc.’s (“Amgen”) Neupogen® (filgrastim). The FDA issued a Briefing Document for the Oncologic Drugs Advisory Committee Meeting held January 7, 2015 concluding that Sandoz’s biosimilar, referred to as EP2006 in the FDA’s Briefing Document, is highly similar to and has no clinically meaningful differences from Neupogen®.

The FDA concluded, based on Sandoz’s analytical data, that EP2006’s clinical product lots are highly similar to Neupogen® [1] despite minor differences in the clinically inactive components. (Briefing Document at p. 8.) Further, the proposed commercial drug EP2006 product was also found to be analytically highly similar to Neupogen® with the exception of the protein content, which was slightly lower. (Id.) Interestingly, the FDA did not seem concerned about the lower protein content and attributed the lower protein content to a manufacturing issue that could be resolved by manufacturing and control strategies. (Id.) The FDA also concluded that there are “no clinically meaningful differences” between EP2006 and Neupogen® based on Sandoz’s clinical development program and a comparative clinical study, which used clinical product lots of EP2006 that did not suffer from the lower protein content of commercial EP2006. (Id. at p. 9.)

However, the FDA noted that Sandoz used EU–approved Neupogen® instead of US–approved Neupogen® in some clinical studies. (Id. at p. 8.) As a result, Sandoz was required to scientifically justify the relevance of the comparison data with EU–approved Neupogen® by establishing an adequate scientific bridge. (Id. at pp. 8–10.) Sandoz did so by conducting analytical pair-wise comparisons of EP2006, US–licensed Neupogen®, and EU–approved Neupogen® that show that all three products meet the requirements for analytical similarity. (Id. at p. 10.) Although the FDA determined that Sandoz’s bridging studies were sufficient, it expressly noted that EP2006 has a reactively simple structure and lacks post-translational modifications. (Id. at 28.) This caveat appears to caution potential biosimilar applicants against assuming that similar bridging studies will be sufficient for other biologics. The several references by the FDA to the simple structure of the biosimilar seem to be an attempt by the FDA to caution other applicants against using Sandoz’s submitted studies as a benchmark for all other biosimilar applications.

Notably, Sandoz’s studies did not fully examine all five indications of Neupogen®. However, the FDA recommended that EP2006 be licensed for all five indications.  Specifically, the FDA found that the results of Sandoz’s extensive PD and PK similarity studies (extensive in terms of the number of trials and the doses of EP2006 and Neupogen®) support a finding of no clinically meaningful differences in the effectiveness of EP2006 and Neupogen® for all five indications for which Neupogen® is approved. (Id. at p. 60.) The FDA’s recommendation is an example of “extrapolation,” which the FDA permits “if the proposed product meets the statutory requirements for licensure as a biosimilar product under section 351(k) of the PHS Act based on, among other things, data derived from a clinical study sufficient to demonstrate safety, purity, and potency in an appropriate condition of use, the potential exists for the biosimilar product to be licensed for one or more additional conditions of use for which the reference product is licensed,” provided that the applicant provides “sufficient scientific justification for extrapolating clinical data” for each condition of use for which licensure is being sought. (Draft Guidance: Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 (Feb. 2012) at p. 9.) The FDA’s apparent willingness to use sufficiently justified extrapolation to approve a biosimilar for indications not fully studied could result in decreased costs for biosimilar applicants and also increase the speed at which a biosimilar applicant could complete the studies required for a successful biosimilar application.

Also of note is the FDA’s decision to use Sandoz’s product descriptor EP2006 instead of the brand name Zarxio®. (Id. at fn 1.) During the January 7, 2015 Oncologic Drugs Advisory Committee meeting (“ODAC Meeting”) an FDA representative explained that Zarxio® was not used by the FDA because it has not been approved as a proprietary designation for the biologic. However, no explanation was given for why the FDA did not refer to the product as filgrastim. This appears to be an indication that the FDA is leaning toward assigning unique identifiers for biosimilars instead of having biosimilars share a nonproprietary name with the reference product as is done with traditional generic drugs. However, one ODAC committee member did remark after voting to approve EP2006 that in his opinion EP2006 is filgrastim and as such should have the same name.

Several concerns were raised during the ODAC Meeting, including whether pharmacists will be able to dispense a biosimilar when receiving a prescription for the branded biologic and whether the biosimilar will reduce patient costs and have lower prices. The FDA noted that it does not oversee the substitution of pharmaceuticals, which are determined by state pharmaceutical boards. Of note is that Sandoz did not apply for licensure of EP2006 as being interchangeable. There was a discussion that most states have passed laws that will require a pharmacist to contact the prescribing physician to obtain permission to dispense a non-interchangeable biosimilar in lieu of a prescribed branded biologic. With respect to costs and prices, Sandoz represented that the costs for EP2006 would be less, but that it was unable to determine whether pricing would be lower at this time due to the numerous factors that impact pricing.

Ultimately, the ODAC Committee unanimously voted for licensure of EP2006 for all five indications. The only area of concern expressed by the ODAC Committee was regarding a discrepancy in the results of study EP06-302 between Sandoz’s presentation and the FDA’s presentation. Of particular concern was whether the discrepancy indicated the presence of clinically meaningful differences between EP2006 and Neupogen. When viewed in view of the totality of the data presented, the ODAC Committee concluded that the potential differences evidenced by this discrepancy were not clinically meaningful. The final vote was 14 yes, 0 no, and 0 abstentions.

We expect that the FDA will license EP2006 in the near future, which will also require resolution of outstanding issues such as the naming convention to be used for biosimilars. However, the sale of Zarxio® could be complicated and/or delayed by Amgen’s citizen petition and its pending lawsuit against Sandoz for failure to comply with the BPCIA. See Left Without a Partner: Amgen Sues Sandoz for Refusing to Dance in Accordance with BPCIA Patent Procedures.

Notes:
[1] All references to Neupogen® are to the US–licensed version of the biologic.