FDA Approves First Biosimilar

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In a landmark decision, FDA approved Zarxio, making it the first biosimilar product in the United States.

FDA approved Sandoz’s Zarxio (filgrastim-sndz) on March 6, 2015. The approval is a groundbreaking decision, as Sandoz is the first pharmaceutical company to have a biosimilar product approved in the United States. Known as Zarzio outside of the US, Sandoz says its biosimilar filgrastim is already available in more than 60 countries worldwide, has generated more than 7.5 million patient-days of exposure, and is "the most widely used filgrastim in Europe."

The medication is now approved in the US for all five of the same indications as Amgen’s Neupogen (filgrastim), including for patients receiving myelosuppressive chemotherapy, with acute myeloid leukemia receiving chemoptherapy, with cancer undergoing bone marrow transplantation, for those receiving autologous peripheral blood progenitor call collection and therapy, and for patients with neutropenia. The approval trails a unanimous positive vote in January 2015 from FDA’s Oncologic Drugs Advisory Committee. To date, there are a total of five 351(k) applications that are publicly disclosed, including the one for Zarxio, said Leah Christl, associate director for therapeutic biologics and biosimilars in the Office of New Drugs (OND), Center for Drug Evaluation and Research (CDER), during a March 6, 2015 media briefing held by FDA.

The decision by the regulatory body comes five years after the passage of the Biologics Price Competition and Innovation Act of 2009 (BPCIA), part of the Affordable Care Act that was signed into law in March 2010. The abbreviated pathway enables “a biosimilar biological product to be licensed based on less than a full complement of product-specific preclinical and clinical data,” according to the FDA statement accompanying the announcement.

The data on Zarxio submitted to FDA included information on structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data, and other clinical safety and effectiveness data-all of which support Zarxio’s use in clinical practice, said Dr. Louis Weiner, chairman of the department of oncology and director of the Lombardi Comprehensive Cancer Center at Georgetown University, in a Novartis press release. "Filgrastim has proven clinical value in treating patients at increased risk of neutropenia, but it is underused in the US for a variety of reasons, including price,” he said. Biosimilars are expected to produce savings of 20–30% from innovator prices. As a result of these savings, “Biosimilars are likely to create greater competition in the medical marketplace,” said Christl in an FDA Consumer update, released the same day as the Zarxio approval notification.

Christl said in January 2015 that a major drug development concern with biosimilars is addressing analytical differences. She said that some biopharma companies fail to establish a strong foundation of analytical data to ensure sufficient similarity, and may have to redo pharmacology studies and other trials as a result.

Biosimilar, but not interchangeable
While the approval is based on strong evidence, says FDA, the agency is careful to state that the biosimilarity designation does not imply interchangeability. A manufacturer can submit additional data to FDA post-approval for a product to be considered for an interchangeable status. In the March 6 briefing, John Jenkins, MD, director, Office of New Drugs confirmed that Sandoz did not request approval for Zarxio as an interchangeable product.

Although it is still up to a prescriber to make the decision whether a patient is administered Neupogen or switched to Zarxio, said Jenkins, FDA is not engaged in those decisions. Christl pointed out that the practice of pharmacy is driven by state laws and state boards of pharmacy, but a pharmacist or pharmacy benefit manager representative could call a subscriber to suggest a drug switch if the state would allow it.

It was implied by speakers at the March 6 meeting that switching from one drug to another may be the focus of the forthcoming draft guidance on interchangeability. The formation of drug-specific antibodies seems to be the primary concern, and it will likely be important to ensure that switching does not introduce immunogenicity.


Still no comprehensive naming policy
The naming of a biosimilar has been a hot topic and a point of contention for many manufacturers and healthcare providers alike. For now, FDA is using a “placeholder” nonproprietary name-filgrastim-sndz-to identify the product, but the agency does not mean for this to indicate it has made a decision on a comprehensive naming policy, as the agency notes it has not yet released guidance on how future biologics shall be named. Jenkins said it is not unusual for a product to contain a prefix or suffix in its name, and mentioned tbo-filgrastim (Teva’s Granix) as an example, although he emphasized that tbo-filgrastim is not a biosimilar, but a related biologic to Neupogen. A draft guidance on the naming of biosimilars is in the works, presenters said, and the naming convention may or may not change.

Also due to be released is a draft guidance on biosimilar labeling, presenters said. Ann Farrell, MD, division director, Division of Hematology Products (DHP) of FDA said that while one would expect Neupogen and Zarxio to behave the same way based on clinical studies, any changes to the labels “refer to product-specific issues for Zarxio.” Not all of the data that are submitted to FDA to prove biosimilarity are necessary for the prescriber to see to suggest those products, she said.

Manufacturing considerations
While Novartis says no immunogenicity or antibodies against rhG-CSF were detected throughout the head-to-head PIONEER study, immunogenicity issues can be introduced at the production level, a fact that is not lost on FDA, which pointed out in its written announcement that the facilities where biosimilars are manufactured must meet its standards. In fact, FDA said in a briefing earlier this year that six batches of the EU-approved Neupogen used in the Zarxio clinical trials were “lower in protein content than the comparator products and do not meet statistical equivalence.” The dilution was said to have likely occurred at the fill-and-finish stage of manufacturing. These manufacturing differences could result in problems such as aggregation and could have the potential to create immune responses.

Legal issues linger
Amgen has alleged that Sandoz purposely did not share with Amgen its 351(k) biologics license application (BLA) for filgrastim, its manufacturing processes, and dossier for the product within the time allotted by the BPCIA. Amgen is suing Sandoz for patent infringement (covering a method of using filgrastim to treat a disease requiring peripheral stem cell transplantation), unfair competition, and conversion, and tried to prevent the product from going through the FDA regulatory process until Amgen gave Sandoz permission to use the license for the product. The efforts by Amgen to prevent FDA action did not seem to stick, however-when answering a question about the naming of Zarxio, Jenkins commented in the March 6 call that “From an FDA standpoint, [Sandoz] can launch and market whenever they make that decision.”

Future advisory meetings
There may not be as much fanfare for future biosimilar applications as there has been for Zarxio. When asked if advisory meetings for biosimilars will continue to be occur, Jenkins noted the number of advisory meetings on 351(k) applications are expected to decrease as time goes on.