Last week, at their January 7, 2015 meeting, the FDA's Oncologic Drugs Advisory Committee ("ODAC") recommended the approval of Sandoz's biosimilar filgrastim application to market a version of Amgen's NEUPOGEN^® biologic drug.  As we previously reported, the Sandoz application is believed to be the first application accepted under the new biosimilar pathway created by the Biologics Price Competition and Innovation (BPCI) Act.  Moreover, the recommendation was to approve the application for use for all five requested indications.  The FDA has been slow to issue guidance of what is required to demonstrate biosimilarity.  42 U.S.C. § 262(i)(2) defines the terms "biosimilar" and "biosimilarity" to mean "(A) that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; and (B) there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product."  (42 U.S.C. § 262 is also referred to as section 351 of the Public Health Service Act, and correspondingly, biosimilar application are often referred to as "351(k) applications.").  Therefore, this case can provide insight into what regulatory hurdles other 351(k) applicants might face.  This case has also been of interest to the biotech and pharmaceutical industry because Sandoz refused to abide by the other provisions of the section 351(k), namely providing Amgen with a copy of the application submitted to the FDA 20 days after it received notification of acceptance by the FDA.  Amgen filed suit in the Northern District of California requesting, among other things, an injunction preventing Sandoz from marketing its biosimilar product (see "Court Report," November 2, 2014).

NEUPOGEN® is a 175 amino acid recombinant methionyl human granulocyte colony-stimulating factor (r-metHuG-CSF), which has been reported to be identical to the predicted natural DNA sequence of G-CSF from humans, except for the N-terminal methionine required to grow in E. coli.  Of course, because NEUPOGEN® is produced in E. coli, it also differs from human G-CSF in that it is not glycosylated.  G-CSFs act by binding 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.  NEUPOGEN® is often prescribed for cancer patients on chemotherapy at times when they are at most risk of infection because their white blood cell count is low.  The five indications found in Amgen's package insert, and requested by Sandoz, include "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."

So what does it mean to have no clinically meaningful differences?  As the FDA explained in its Briefing Document for the January 7, 2015 ODAC meeting, it recommends the use of "a stepwise approach to developing the data and information needed."  This approach "should start with extensive structural and functional characterization of both the proposed biosimilar product and the reference product . . . ."  The level of "residual uncertainty" "drives both the type and amount of data needed" from the nonclinical and clinical studies.  Sandoz's product was referred to as EP2006 because the FDA was still considering its approach to nonproprietary naming of biosimilars.  Otherwise, Sandoz sought the name "Zarxio," which is similar to the version it already sells in markets outside the U.S. -- "Zarzio."  The analytical data for EP2006 satisfied the committee that it is "highly similar to US-licensed Neupogen with the exception of protein content, which was slightly lower than that of US-licensed Neupogen."  However, Sandoz provided additional data and statistical analysis found in an addendum ODAC briefing document that addressed this low protein content, thereby alleviating the FDA's concerns.  The clinical studies included comparative PK and PD studies in normal human healthy subjects, and comparative studies "which enrolled patients with breast cancer receiving TAC chemotherapy who were randomized to receive either EP2006 or US-licensed Neupogen."  In total, Sandoz conducted five PK and PD studies and two efficacy studies to demonstrate that its drug product was safe, pure, and potent, and thereby "no clinically meaningful difference" exists.  Interestingly, Sandoz used the European Union-approved Neupogen in some of its clinical trials.  Sandoz was therefore required to "scientifically justify" the relevance of that data to US-licensed reference product.  After reviewing the justification, the FDA agreed that the data supports "a demonstration that EP2006 is biosimilar to US licensed Neupogen."

Of course, if the FDA accepts this recommendation, and there is no reason to assume that it will not, it is still possible that Sandoz will be enjoined before it is able to launch.  As alluded to above, Amgen has filed an action in the U.S. District Court for the Northern District of California based on the failure of Sandoz to follow the disclosure procedures set out in the statute.  Specifically, when the FDA accepted Sandoz's application last July, Sandoz was supposed to provide Amgen "a copy of the application submitted to the" FDA, and "such other information that describes the process or processes used to manufacture the biological product that is subject of such application" within 20 days.  42 U.S.C. § 262(l)(2) ("the . . . applicant . . . shall provide . . . .").  Sandoz chose not to do so because it did not want to share its BLA or manufacturing process with a future competitor, notwithstanding the statute's confidentiality provisions and the limitations on disclosure placed on recipients as found in the statute.  Moreover, as Sandoz alleged in paragraph 52 of its answer to Amgen's complaint, "[p]roviding the biosimilar application to the reference product sponsor is an option, not a requirement."  The basis for its position is the statutorily mandated "penalty" for not complying with the disclosure requirements:

If a subsection (k) applicant fails to provide the application and information required under paragraph (2)(A), the reference product sponsor, but not the subsection (k) applicant, may bring an action under section 2201 of Title 28, for a declaration of infringement, validity, or enforceability of any patent that claims the biological product or a use of the biological product.

42 U.S.C. § 262(l)(9)(C).  If the disclosure was mandatory, according to Sandoz, this section would be superfluous.  Of course, this comes on the heels of Sandoz's failed declaratory judgment action against Amgen, attempting to obtain patent certainty before filing an application to market a biosimilar version of Enbrel^®.  As we recently reported, the District Court for the Northern District of California dismissed the case on jurisdictional grounds as essentially premature, and the Federal Circuit affirmed.  Of course, members of the biotech patent community viewed this as another attempt by Sandoz to sidestep the requirements of the BPCIA.  This present case is still in the early stages, but we will continue to monitor it and the impact that it will have on Sandoz's application.