In what is thought to be the first application accepted under the new biosimilar pathway created by the Biologics Price Competition and Innovation (BPCI) Act, Sandoz announced last Thursday that the U.S. Food and Drug Administration (FDA) has accepted its application to market a version of the protein filgrastim. Sandoz, a Novartis Group company, already markets a biosimilar filgrastim outside the U.S. under the brand name ZARZIO®. The reference product is Amgen's NEUPOGEN®, a 175 amino acid recombinant methionyl human granulocyte colony-stimulating factor (r-metHuG-CSF), which Amgen reports is identical to the predicted natural DNA sequence of G-CSF from humans, except for the N-terminal methionine required to grow in E. coli. In addition, because NEUPOGEN® is produced in E. coli, it differs from human G-CSF because it is not glycosylated. G-CSFs bind to specific cell-surface receptors, thereby acting on hematopoietic cells to stimulate proliferation, differentiation commitment, and some end-cell functional activation. Endogenous G-CSF is produced by monocytes, fibroblasts, and endothelial cells and regulates the production of neutrophils within the bone marrow. According to the Amgen's package insert, NEUPOGEN® has several indications, including "to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever"; "for reducing the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of adults with AML"; "to reduce the duration of neutropenia and neutropenia-related clinical sequelae‚ e.g.‚ febrile neutropenia in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by marrow transplantation"; "for the mobilization of hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis"; and "for chronic administration to reduce the incidence and duration of sequelae of neutropenia (eg‚ fever‚ infections‚ oropharyngeal ulcers) in symptomatic patients with congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia."
Of course, the pharmaceutical industry has been watching these developments closely, and everyone has been wondering when, or even if, a biosimilar application would be accepted. The BPCI Act was signed into law over four years ago as part of the Affordable Care Act, and with each passing year, there has been questions whether any company would take advantage of this new system. The FDA did not help matters in 2012 when it released its draft guidance for implementing the follow-on biologic drug pathway mandated by the statute. In the first place, the FDA was very slow in providing its draft guidance. It took about two years for the initial draft guidance in 2012, and in fact it was not until earlier this year, nearly an additional two years later, that the FDA followed up with new draft guidance (see "FDA Releases Draft Guidance on Biosimilars"). Moreover, it appeared that the FDA's requirements to show that a drug is either "biosimilar" or "interchangeable" have been too vague, and ultimately might end up being too onerous. As a result, the concern was that it might be simpler for a company to file a new Biologics License Application ("BLA") instead of a "follow-on" application pursuant to the statute.
One of the main issues is in differentiating whether a follow-on drug is merely "biosimilar," or whether it is "interchangeable." According to the FDA, a biosimilar drug is a biological product that is highly similar to a reference product with no clinically meaningful differences in terms of safety, purity, and potency. Interchangeability, on the other hand, means that a biological product is biosimilar, can be expected to produce the same clinical result in any given patient, and the safety and reduced efficacy risks of alternating or switching are not greater than with repeated use of the reference product. Of course, interchangeability is the desired goal necessary to make the new system work.
Even though Sandoz's filgrastim application was the first announced (by Sandoz) to be accepted by the FDA, it is currently not possible to be certain that it was because such information is not made publically available by the FDA. Instead, according to the statutory scheme, the application filer and the reference product sponsor are required to participate in a series of exchanges after acceptance to determine which patents are necessary to litigate. It is only after this process is concluded that a lawsuit can be filed by the reference product sponsor. This process can take on the order of half a year. Therefore, we might not know for sure whether the filgrastim application is the first such application until sometime early next year. We will, of course, continue to monitor the case and provide any updates as they occur.