Life Science Compliance Update

March 24, 2015

District Court Denies Amgen’s Motion for Preliminary Injunction to Prevent Marketing of Sandoz’s Biosimilar Zarxio

Biosimilar pic

The first U.S. biosimilar is one step closer to entering the marketplace. Last week, U.S. District Judge Richard Seeborg of the Northern District of California denied Amgen's request for a preliminary injunction to block Sandoz from selling its version of Neupogen. The Food and Drug Administration approved Sandoz’s biosimilar application for “Zarxio” earlier this month.

Amgen had argued that Sandoz should have provided its Biologic License Application and manufacturing plans within 20 days after the FDA accepted the application, in accordance with the "patent dance" procedure laid out in the biosimilar statute. Amgen also argued that Sandoz should have provided six-months notice of its plans to market an FDA approved biosimilar. 

Judge Seeborg’s concluding remarks sums up his view:

“As the twelve-year exclusivity period for Neupogen long ago expired, there exists no substantive bar to market entry for Sandoz’s biosimilar filgrastim—and, consequently, no basis on which Amgen is entitled to injunctive relief or other remedies for disadvantages it may suffer due to market competition from Sandoz.”

Background

Sandoz’s biosimilar of Neupogen is the first application to be approved using the new biosimilar pathway created by the Biologics Price Competition and Innovation Act (BPCIA). This path allowed Sandoz to reduce the costs associated with bringing its drug to market if they could show their Neupogen-copy was “biosimilar” to the already approved product.  Sandoz announced last July that the FDA had accepted its biosimiar application.

Under the 351(k) pathway, so-named because of the statute provision, the law also lays out a detailed “patent dance." The provisions in the law coordinate how the reference product manufacturer and the potential biosimilar manufacturer would handle a web of complicated legal issues associated with the biosimilar, in effect, copying the reference product.

The statute states that “20 days after…the application has been accepted for review, the subsection (k) applicant…shall provide to the reference product sponsor a copy of the application submitted to the Secretary under subsection (k).” Thus, after approval, Sandoz had 20 days to provide Amgen with a copy of its filing, as well as other manufacturing details. Amgen would then have 60 days to return a list of patents it could claim that Amgen had infringed, and those it would be willing to license. After a few rounds of information exchanges, the statute indicates that the companies must begin “good faith negotiations” to identify the patents to be tested in lawsuits.

No Patent Dance

Amgen alleged that Sandoz never even started the patent resolution procedures. According to Amgen, Sandoz received notice that FDA accepted the company’s 351(k) application, but refused to engage in the disclosure deadline that should have happened within 20 days of that acceptance. On October 24, 2014, Amgen filed a complaint in the District Court for the Northern District of California alleging that Sandoz unlawfully refused to engage in the "patent dance," and sought injunctive relief. 

Furthermore,  Sandoz notified Amgen in July 2014 that it would begin commercially marketing its biosimilar likely by the second quarter of 2015. Amgen argued that Sandoz would instead have to delay its marketing until 180-days after FDA eventually approved the product. Amgen relied on the BCPIA provision stating: "The subsection (k) applicant shall provide notice to the reference product sponsor not later than 180 days before the date of the first commercial marketing of the biological product licensed under subsection (k)." Amgen focused on the "licensed" language to argue that Sandoz's notice must come after FDA approved the product--thus Sandoz would have to wait 180-days after March 6, 2015, so at least until September 6, to finally market Zarxio. 

District Court Denies Injunction

Sandoz countered Amgen's preliminary injunction, arguing that the BCPIA patent dance outlined in the statute was not mandatory, but optional. Sandoz also argued that biosimilar manufacturers should not have to wait for FDA to approve their product before giving notice to the reference product manufacturer. 

Judge Seeborg agreed, focusing on the statute's language (including dissecting the use of the words "shall" and "may"). "Congress intended merely to encourage use of the statute's dispute resolution process in favor of litigation, where practicable, with the carrot of a safe harbor for applicants who otherwise would remain vulnerable to suit," Seeborg wrote in his March 19th opinion. "The statute contains no stick to force compliance in all instances, and Amgen does not identify any basis to impute one."

Compliance with the patent dance “allows an applicant to enjoy a temporary safe harbor from litigation and, potentially, to resolve or narrow patent disputes outside court proceedings," he noted. The statute is only “required,” when “the parties elect to take advantage of their benefits.” 

In siding with Sandoz on the 180-day provision argument, Judge Seeborg seemed convinced that Amgen had already enjoyed enough exclusivity and didn't need an extra six months. "Because the FDA cannot license a biosimilar until twelve years after approval of a reference product, Amgen’s reading would tack an unconditional extra six months of market exclusivity onto the twelve years reference product sponsors already enjoy," he noted.  "Had Congress intended to make the exclusivity period twelve and one-half years, it could not have chosen a more convoluted method of doing so. Moreover, Congress presumably could have been far more explicit had it intended for infringement suits to commence only once a biosimilar receives FDA approval."

He concluded: "It was, therefore, not wrongful for Sandoz to give Amgen its 180 days’ notice prior to first commercial marketing...in July 2014, in advance of receiving FDA approval."

Download Judge Seeborg's BCPIA Opinion

FDA Law Blog, which has covered the patent provisions in the BCPIA in several comprehensive articles, states that the decision could have wide-ranging implications: “the victory scored by Sandoz, if upheld, could forever alter the biosimilars landscape in the U.S. by affirming that the complex patent resolution procedures under the BPCIA (which some might say are a disincentive to seeking approval of a highly similar biosimilar or interchangeable biosimilar biological product) are not the only game in town.”

March 06, 2015

FDA Approves Sandoz's Zarxio, The First Biosimilar Approved in the U.S.

Biosimilar pic

Today, the Food and Drug Administration approved Zarxio (filgrastim-sndz), the first biosimilar product approved in the U.S. Sandoz, Inc.’s Zarxio is biosimilar to Amgen Inc.’s Neupogen (filgrastim), which was originally licensed in 1991. The approval comes two months after an FDA advisory committee recommended Zarxio as biosimilar to Neupogen for all five of the intended indications. 

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--in this case Neupogen. 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.

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.

FDA issued the following statement in their press release: 

“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 the 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 demonstrates 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.

The most common expected side effects of Zarxio are aching in the bones or muscles and redness, swelling or itching at injection site. Serious side effects may include spleen rupture; serious allergic reactions that may cause rash, shortness of breath, wheezing and/or swelling around the mouth and eyes; fast pulse and sweating; and acute respiratory distress syndrome, a lung disease that can cause shortness of breath, difficulty breathing or increase the rate of breathing.

They also have a temporary nonproprietary name for the biosimilar product, and announced naming guidance is expected soon: 

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. 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.

---

The FDA's approval of Zarxio shows that the agency is serious about approving biosimilars, especially considering they approved the product without naming guidance.  As noted above, "filgrastim-sndz" is a "placeholder nonproprietary name." 

Zarxio is not necessarily the first filgrastim product to compete with Neupogen. In 2013, FDA approved Teva's product Granix (tbo-filgrastim), but under the tradition Biologics License Application (BLA) pathway. Granix is marketed as Tevagrastim in the European Union, where the product is indeed classified as biosimilar to Amgen's Neupogen. 

With Sandoz's product being the first down the 351(k) path, it will be interesting to follow the litigation between Amgen and Sandoz. Amgen has filed a preliminary injunction to stop Sandoz from marketing Zarxio until a court decides whether the company violated the BCPIA's procedure for information exchanges related to patent infringement.  FDA Law Blog notes that a hearing on the outstanding Motion for Preliminary Injunction and Motions for Judgment on the Pleadings is scheduled for March 13, 2015 at 10:00 AM. 

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