On March 6, 2015, more than five years after the passage of the Biologics Price Competition and Innovation Act of 2009 (BPCIA), the U.S. Food and Drug Administration (FDA) approved the first U.S. biosimilar, Sandoz Inc.’s Zarxio®, a biosimilar of Amgen Inc.’s Neupogen®. Zarxio® is currently marketed outside the U.S. as Zarzio®, and has been approved in Europe since 2009. Given its foreign track record and the fact that filgrastim, the active protein agent in both Zarxio® and Neupogen®, is fairly simple compared to other biologics, Zarxio® likely presented an attractive test case for the FDA. Regardless, Zarxio’s® approval provides some general insight into the FDA’s thinking regarding biosimilars and highlights some of the remaining areas of uncertainty.
How much is enough?
During the January public hearing on Zarxio®, the FDA reiterated its position that a determination of biosimilarity will be made after considering the totality of the evidence submitted by the biosimilar applicant and that the nature and extent of the evidence required would be considered on a case-by-case basis. In general, the FDA has indicated that better structural and functional characterization of a proposed biosimilar may impact the extent of downstream testing, including human clinical testing, that is required.
Sandoz submitted a range of testing in support of its Zarxio® application, including numerous structural and functional studies, animal testing, and human testing. Given the FDA’s position that the review of biosimilar applications will be conducted on a product-by-product basis, it is difficult to draw any conclusions regarding the specific nature and extent of testing that may be required for future proposed biosimilars. That being said, Sandoz did submit a fairly large amount of data beyond the structural and functional characterization of its product, including human clinical studies with safety and efficacy endpoints, in support of its application for approval of a comparatively simple product with a history of use outside the U.S.
The FDA cares about European history
Some of the human clinical testing relied on by Sandoz included comparisons to a non-U.S. licensed reference product. Sandoz successfully demonstrated that such testing was relevant to the FDA’s determination of biosimilarity for Zarxio®, confirming the FDA’s previously articulated position that biosimilar applicants can, with sufficient supporting evidence, rely on testing performed with comparator products approved outside the U.S.
Beyond, Sandoz’s ability to rely on certain previously performed clinical studies, it was clear from the FDA’s hearing on Zarxio® that Zarzio®’s prior approval and use in Europe since 2009 had a positive impact on the committee’s decision to recommend approval of Zarxio®. At least one committee member acknowledged that Zarzio®’s prior use in Europe favorably impacted his decision to support approval of Zarxio®.
Extrapolation to other approved indications
Zarxio® was approved for all five indications for which Neupogen® is currently approved. The FDA has previously stated that with sufficient scientific justification, it would consider extrapolating clinical data supporting biosimilarity for an approved use to support determinations of biosimilarity for other uses approved for the reference product. In support of its request that Zarxio® be approved for all indications for which Neupogen® is approved, Sandoz relied on structural and functional characterization studies, pharmacokinetic and pharmacodynamic studies, and a clinical study that examined Zarxio’s® effectiveness in prophylactically treating neutropenia in patients undergoing myelosuppressive chemotherapy. Based on Sandoz’s demonstration of similarity, the FDA extrapolated its determination of biosimilarity to other approved indications for Neupogen® related to, for example, patients undergoing additional types of cancer treatments.
The BPCIA allows the FDA to designate certain biosimilars as interchangeable. The Act indicates that these interchangeable biosimilars can be substituted for the branded reference product without the intervention of the prescribing health care professional, but to date, the FDA has remained largely silent regarding interchangeables. Sandoz did not pursue an interchangeable designation for Zarxio®, and the FDA’s public hearing on Zarxio® offered no new insights as to the types of evidence that would be required to support a finding of interchangeability.
No final word on naming
The FDA has not settled on a comprehensive nonproprietary naming policy for biosimilars. For now, the FDA has assigned Zarxio® the “placeholder nonproprietary name,” “filgrastim-sndz,” but cautioned that the name “should not be viewed as reflective of the agency’s decision on a comprehensive naming policy for biosimilar and other biological products.” The FDA’s press release indicates that the agency intends to release draft guidance on the naming of current biologics and biosimilars in the near future.
Testing the limits of BPCIA in the courts
Sandoz and Amgen are involved in an ongoing legal battle over Zarxio®. On March 19, 2015, the district court denied Amgen’s motion for a preliminary injunction to block the sale of Zarxio® in the U.S. and Amgen’s request to force Sandoz to comply with the disclosure and pre-litigation procedures of the BPCIA. Slip op. at 2, 9-14. In its recent ruling, the district court acknowledged that “Sandoz did not engage in the [BPCIA] disclosure and dispute resolution process,” but stated that its non-compliance was “within its rights,” and dismissed Amgen’s conversion and unfair competition claims. Id. at 2. Specifically, with regard to Sandoz’s failure to provide its biosimilar application to Amgen or engage in the pre-litigation patent disclosure provisions, the district court noted that Sandoz “traded in the chance to narrow the scope of potential litigation with Amgen through subsection (l)’s steps, in exchange for the expediency of an immediate lawsuit. The BPCIA’s plain language and overall statutory scheme support a reading that renders this decision entirely permissible.” Id. at 12. The district court also rejected Amgen’s arguments that Sandoz prematurely provided its 180-day notice of intent of commercial marketing because it was done before Sandoz received FDA approval for its product. The district court held that while “FDA approval must precede market entry,” no such prior approval is required for providing notice of intent to engage in commercial marketing under the BPCIA. Id. at 13. Moreover, the district court concluded that adopting Amgen’s reading of the BPCIA would further extend the twelve-year period of exclusivity by an additional six months, contrary to the intent of the Act. Id. at 13-14.
In addition to the recent legal and regulatory activity related to Zarxio®, Janssen Biotech, Inc. is involved in litigation adverse to Celltrion and Hospira Inc., related to Celltrion’s attempt to secure approval for Remsima®, its proposed biosimilar of Janssen’s Remicade®. In the wake of the recent Amgen v. Sandoz decision, these litigations are also testing the bounds of the BPCIA. The FDA recently postponed a hearing, originally scheduled for March 17, 2015, on Celltrion’s Remsima® in view of pending information requests from the FDA. The next several months should be very interesting and hopefully will provide some additional insights into the effect and force of notice and disclosure provisions of the BPCIA, as well as, shedding additional light on the FDA’s biosimilar review process.