Zarxio’s® Approval: Some Insights and Unanswered Questions Regarding the Future of
U.S. Biosimilars
Jonathan Davies, Aaron Gleaton, Sanya Sukduang
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 Zaxio®, 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®.
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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.
Interchangeability?
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
Zarxio® is not available to the U.S. market yet as Sandoz and Amgen are involved in an ongoing
legal battle over the product. Both sides are currently awaiting a ruling on Amgen’s motion for a
preliminary injunction to block the sale of Zarxio® in the U.S. Sandoz has stated that it will not
launch Zarxio® until the earlier of a decision by the court or April 10, 2015.
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®. These
litigations are testing the bounds of the notice and disclosure provisions of the BPCIA, including
whether a biosimilar applicant is required to provide a copy of its application (and the
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consequences, if any, for failure to do so), the availability of declaratory judgment actions, and
the timing of notice related to intent to engage in commercial marketing. 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 valuable insights.
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