HOLZKIRCHEN, Germany—Sandoz, a Novartis company, announced today that the U.S. Food and Drug Administration (FDA) has approved Zarxio (filgrastim-sndz) for all indications included in the reference product's label. Sandoz is the first company to receive approval of a biosimilar in the U.S. through the new FDA biosimilars pathway established under the Biologics Price Competition and Innovation Act (BPCIA). The approval was based on a comprehensive package of analytical, nonclinical, and clinical data, which confirmed that Zarxio is highly similar to the U.S.-licensed reference product, Amgen’s Neupogen. The approval of Zarxio follows the unanimous positive vote in January by the Oncologic Drugs Advisory Committee in favor of recommending biosimilar filgrastim for approval in the U.S.
"The FDA approval of Zarxio marks a significant milestone for the United States healthcare system and for patients who might suffer from neutropenia," said Carol Lynch, global head of Biopharmaceuticals & Oncology Injectables at Sandoz. "As the global leader in biosimilars, we are honored to be the first company to successfully work with FDA to navigate the U.S. biosimilar pathway and we look forward to making this high-quality biosimilar available to patients in the U.S."
"Filgrastim has proven clinical value in treating patients at increased risk of neutropenia, but it is underused in the U.S. for a variety of reasons, including price," said Dr. Louis Weiner, chairman of the department of oncology and director of the Lombardi Comprehensive Cancer Center at Georgetown University. "Biosimilars have the potential to increase access and the approval of Zarxio may reduce costs to the healthcare system. The comprehensive data set supports its use in clinical practice."
The successful Sandoz pivotal head-to-head PIONEER study was the final piece of data contributing to the totality of evidence used by FDA to approve Zarxio as biosimilar to the reference product. Importantly, the data demonstrating high similarity was sufficient to allow extrapolation of use of Zarxio to all indications of the reference product. In the PIONEER study, Zarxio and the reference product both produced the expected reduction in the duration of severe neutropenia in cancer patients undergoing myelosuppressive chemotherapy (1.17 and 1.20 days for Zarxio and the reference product, respectively). The mean time to absolute neutrophil count recovery in cycle 1 was also similar (1.8 days ± 0.97 in ZARXIO arm vs. 1.7 days ± 0.81 in reference product arm). No immunogenicity or antibodies against rhG-CSF were detected throughout the study.
Marketed as Zarzio outside of the U.S., the Sandoz biosimilar filgrastim is 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.
Sandoz claims it is the global market leader with over 50 percent volume share of biosimilars approved in North America, Europe, Japan and Australia. The company currently markets three biosimilars (somatropin, filgrastim and epoetin alfa) outside the U.S.; each of which occupies the number one biosimilar position in its respective category. The Sandoz pipeline has several biosimilars across various stages of development, including five programs in Phase 3 clinical trials/filing preparation.
Biological products are generally derived from a living organism. They can come from many sources, including humans, animals, microorganisms or yeast. A biosimilar product is a biological product that is approved based on a showing that it is highly similar to an already-approved biological product, known as a reference product. The biosimilar also must show it has no clinically meaningful differences in terms of safety and effectiveness from the reference product. Only minor differences in clinically inactive components are allowable in biosimilar products.
Sandoz, Inc.’s Zarxio is biosimilar to Amgen Inc.’s Neupogen (filgrastim), which was originally licensed in 1991. Zarxio is approved for the same indications as Neupogen, and can be prescribed by a health care professional for patients with cancer receiving myelosuppressive chemotherapy; patients with acute myeloid leukemia receiving induction or consolidation chemotherapy; patients with cancer undergoing bone marrow transplantation; patients undergoing autologous peripheral blood progenitor cell collection and therapy; and patients with severe chronic neutropenia.
“Biosimilars will provide access to important therapies for patients who need them,” said FDA Commissioner Margaret A. Hamburg, M.D. “Patients and the health care community can be confident that biosimilar products approved by the FDA meet the agency’s rigorous safety, efficacy and quality standards.”
The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) was passed as part of the Affordable Care Act that President Obama signed into law in March 2010. The BPCI Act created an abbreviated licensure pathway for biological products shown to be “biosimilar” to or “interchangeable” with an FDA-licensed biological product, called the “reference product.” This abbreviated licensure pathway under section 351(k) of the Public Health Service Act permits reliance on certain existing scientific knowledge about the safety and effectiveness of the reference product, and enables a biosimilar biological product to be licensed based on less than a full complement of product-specific preclinical and clinical data.
A biosimilar product can only be approved by the FDA if it has the same mechanism(s) of action, route(s) of administration, dosage form(s) and strength(s) as the reference product, and only for the indication(s) and condition(s) of use that have been approved for the reference product. The facilities where biosimilars are manufactured must also meet FDA’s standards.
The FDA’s approval of Zarxio is based on review of evidence that included structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data and other clinical safety and effectiveness data that demonstrate Zarxio is biosimilar to Neupogen. Zarxio has been approved as biosimilar, not as an interchangeable product. Under the BPCI Act, a biological product that that has been approved as an “interchangeable” may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.
For this approval, the FDA has designated a placeholder nonproprietary name for this product as “filgrastim-sndz.” The provision of a placeholder nonproprietary name for this product should not be viewed as reflective of the agency’s decision on a comprehensive naming policy for biosimilar and other biological products, the agency noted. While the FDA has not yet issued draft guidance on how current and future biological products marketed in the United States should be named, the agency intends to do so in the near future.
Predictably, not everyone was pleased by the approval of filgrastim. “Today, the FDA approved the first biosimilar to be authorized for use in the United States, intoned a group named RetireSafe, which claims to have 400,000 supporters nationwide. “While the approval of Zarxio (a biosimilar to the reference biologic Neupogen) was no surprise (it has been approved for use for a number of years in Europe) it was very troubling considering that the FDA has not yet released guidance on critical safety measures on how a biosimilar should be named, tracked, and how the manufacturing process will be regulated, inspected and controlled. It is the precedent that this approval sets that troubles RetireSafe.”
Future biosimilars may not have the prior use information of this first biosimilar and will probably be more complicated. “It should be noted,” RetireSafe said in a statement, “that even with the background of usage in Europe this product was still NOT approved as an interchangeable replacement (meaning it could be substituted without any notification) but as a biosimilar, meaning that the drug was only similar to the reference biologic.”
According to RetireSafe, the more than 1,400 older Americans who took its survey concerning biosimilars overwhelmingly indicated that safety with these new medicines was paramount. The success of these money-saving biosimilars can only be achieved if there is a trust by both the patient and the healthcare provider that this medicine is safe. “Careening forward with biosimilar approvals without the input from those groups who represent the patients and the older Americans who are most likely to use this drug and without the guidance and regulations that will ensure that any adverse effects can be tracked is not a way to build this trust,” the group concluded.