FDA Accepts Apotex’s Neupogen Biosimilar Application: Raises Issues of How the Agency Will Address Exclusivity, Previous Warning Letters to Apotex
Apotex Inc. has announced that as of February 13, 2015, the FDA has accepted for filing the company’s application for filgrastim, a biosimilar version of Amgen’s Neupogen. The product was jointly developed with Intas Pharmaceuticals Ltd. Filgrastim is used to help cancer patients taking chemotherapy to fight infections and fever by boosting white blood cell count. This is the fifth application submitted through the 351(k) abbreviated approval pathway created by the Biosimilar Price Competition and Innovation Act (BPCIA), and the second biosimilar submitted by Apotex.
This latest Neupogen biosimilar application is noteworthy for several reasons.
Sandoz’s Neupogen Biosimilar Application Has Already Been Accepted and Recommended by FDA Advisory Committee
Apotex is a few months late with its Neupogen application on the 510(k) pathway. The FDA accepted Sandoz’ biosimilar application to Neupogen last year, and the biosimilar received unanimous support of FDA’s Oncologic Drugs Advisory Committee on January 7, 2015.
An important distinction, however, is that the term “interchangeability“ is a higher standard than biosimilarity, and indicates that the biosimilar may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product. Biosimilars can be approved as stand-alone products, but the end goal of this biosimilar pathway is interchangeability–recognition that the new product is essentially “equal” to the original biologic.
The problem is that FDA has not yet released guidance on interchangeability. Apotex’s biosimilar application for Neupogen highlights the need for such guidance because the biosimilar pathway provides exclusivity periods for the first interchangeable biologic product:
(6) EXCLUSIVITY FOR FIRST INTERCHANGEABLE BIOLOGICAL PRODUCT.—Upon review of an application submitted under this subsection relying on the same reference product for which a prior biological product has received a determination of interchangeability for any condition of use, the Secretary shall not make a determination…that the second or subsequent biological product is interchangeable for any condition of use until the earlier of—
(A) 1 year after the first commercial marketing of the first interchangeable biosimilar biological product to be approved as interchangeable for that reference product
If Sandoz’s biosimilar for Neupogen is indeed approved and found to be interchangeable, what would be the status of Apotex’s product? FDA is planning to release interchangeability guidance later this year.
UPDATED, 2/19/2015, 5:45 pm: Sandoz has highlighted that its current application is for approval of “EP2006” (their application name for the Neupogen biosimilar) as specifically a biosimilar and not as an interchangeable biologic. Thus, we will have to wait to see the exclusivity issue play out and also await future guidance by FDA on interchangeability
Looking abroad, it is perhaps unsurprising that Neupogen has multiple biosimilar potentials. Apotex is one of nine manufacturers that have a filgrastim biosimilar product approved by the European Medicines Agency, the regulatory body for approval of medicines in the European Unions. There have been 22 total biosimilars approved by EMA, so filgrastim makes up a large portion of available biosimilars overseas.
View the full list of biosimilars approved in Europe online at GaBi, the Generics and Biosimilars Initiative.
FDA Warning Letters to Apotex
Apotex has on numerous occasions been disciplined by the FDA based on “significant deviations from U.S. current good manufacturing practice (CGMP) regulations.” It will be interesting to see how much FDA takes previous Warning Letters into account in reviewing this application.
Most recently, on January 30, 2015, FDA’s Warning Letter was sent after inspectors visited an Apotex Indian plant. “Ongoing quality-control problems prompted the FDA to send several warning letters in recent years and, at one point, issue an import alert that prevented the drug maker from shipping medicines to the U.S,” wrote Ed Silverman in his Pharmalot coverage of the enforcement activity. “FDA notes that Apotex failed to ensure that laboratory records included complete data from tests that are needed to ensure compliance with manufacturing standards; disregarded failing test results, and retested samples that initially failed to meet specifications.”
Here are links to all five Warning Letters, all relating to CGMP transgressions:
Neupogen Biosimilar is Apotex’s Second 510(k) Application
Apotex is the only company to date to have two biosimilar applications currently under active review by FDA—filgrastim and, from December 2014, pegfilgrastim, a biosimilar of Amgen’s Neulasta, a long acting form of Neupogen.
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In other biosimilar news, on March 17, FDA’s Arthritis Advisory Committee will discuss Celltrion’s proposed biosimilar to Janssen Inc.’s Remicade. Celltrion’s biosimilar was approved in Europe in September of 2013.
But Sandoz stated explecitely in their brief that that the clinical studies were not to support application for interchangeability designation.
Thank you for the comment, the article has been updated to reflect it