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FDA Rejects Hospira’s EPO Biosimilar Application

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After the FDA approved the first U.S. biosimilar, Sandoz’s Zarxio (filgrastim-sndz), earlier this year, many predicted that the floodgates would open for biosimilar products.  That has not been the case.  No other U.S. biosimilar product has been approved.  In addition, Pfizer recently announced that Hospira’s application (now owned by Pfizer) for a biosimilar version of Amgen’s Epogen (EPO) had been rejected, and that it intends to resubmit its application to FDA in the first half of 2016.

EPO is a more complex biologic product than Sandoz’s Zarxio.  It is made in genetically engineered mammalian cells as opposed to bacteria.  It is larger than Zarxio and it has sugar molecules (glycosylation) attached to it.  Glycosylation is variable and depends on how the product is made and the cells that are used to make it.  Because biosimilars are made in living cells, rather than chemically synthesized in a laboratory the way small molecule drugs are, they can at best be similar to the approved biologic product.  They cannot be identical.  Further, the more complex the protein is (such as through the addition of sugars or due to increased size), the greater the potential differences from the approved product may be and the harder it is to fully characterize those differences.

Hospira filed an abbreviated Biologics License Application (aBLA) for its proposed biosimilar of Amgen’s EPO in December 2014.  FDA accepted Hospira’s application for review in February 2015.  In September 2015, Amgen sued Hospira in the District of Delaware under the Biologics Price Competition and Innovation Act of 2009 (BPCIA) in connection with Hospira’s proposed biosimilar EPO product.  In its complaint, Amgen said that Hospira could have marketing approval for its proposed biosimilar by November 2015.  FDA’s performance goal is to act on most regulatory applications for approval of biosimilar products within a 10-month period.  FDA met its performance goal here but it did not result in the approval of Hospira’s aBLA.  Rather, as Pfizer announced last week, FDA issued a complete response letter on October 16 denying the application.  While the details of FDA’s letter are not public, Pfizer indicated that it will resubmit an application to FDA during the first half of 2016, and that it expects FDA to act on its resubmitted application in the second half of 2016.  (FDA’s performance goal is to act on most resubmitted applications for biosimilar products within six months.)

Sandoz’s Zarxio, by contrast, sailed through the regulatory approval process.  Sandoz filed its aBLA on May 8, 2014.  On January 7, 2015, FDA’s Oncologic Drugs Advisory Committee met to review Zarxio and unanimously recommended its approval as a biosimilar of Amgen’s Neupogen.  Zarxio, unlike EPO, is one of the simplest of proteins.  FDA approved Sandoz’s Zarxio for marketing on March 6, 2015.  It approved Zarxio for all five of Neupogen’s indications (although Sandoz had only provided clinical data for one) and did so within its 10-month performance goal.

FDA’s recent rejection of Hospira’s proposed biosimilar EPO suggests that Zarxio’s approval may ultimately provide little guidance for more complex products.  In addition, significant marketing history outside the U.S. does not guarantee approval here.  Hospira’s EPO (trade name Retacrit) had been approved in Europe as a biosimilar of Amgen’s Epogen since 2007, but nonetheless was rejected in the U.S. for now.  Given the complexity of many biosimilars, it seems quite unlikely that the floodgates are about to open for these products.