The unanimous recommendation by the Oncologic Drugs Advisory Committee (ODAC) for FDA approval of Sandoz's biosimilar filgrastim (EP2006; Zarxio)?the first biosimilar filing to be accepted in the United States? moves the biosimilar product tantalizingly close to FDA approval. Furthermore, ODAC recommended approval of EP2006 for all indications for which the reference product (Amgen's Neupogen) is approved, confirming that indication extrapolation is a realistic prospect in the United States. The FDA is expected to make a final decision in the coming months. However, questions still remain regarding Sandoz's refusal to engage in the Biologics Price Competition and Innovation Act (BPCIA) ?patent dance? and the implications that this might have on the launch of EP2006. We still question the absence of FDA guidance documents in light of these forward-looking events.

First ODAC review of a biosimilar
In what was a litmus test of the U.S. biosimilars approval process, the ODAC met on January 7, 2014, to discuss whether EP2006 was highly similar to U.S.-licensed Neupogen and if, based on the totality of the evidence, EP2006 should be approved as a biosimilar for each of the five indications for which Neupogen is approved in the United States, as shown below:

  • Prevention of febrile neutropenia in cancer patients receiving myelosuppressive chemotherapy
  • Reducing the duration of neutropenia in patients with acute myeloid leukemia receiving induction or consolidation chemotherapy
  • Reducing the duration of neutropenia in cancer patients receiving bone marrow transplant
  • Stem cell mobilization in patients undergoing peripheral blood progenitor cell collection and therapy
  • Severe chronic neutropenia

Sandoz's ODAC presentation
Sandoz presented data from two pivotal studies that compared EP2006 to U.S.-licensed Neupogen: a clinical pharmacokinetic/pharmacodynamic study conducted in 28 healthy volunteers (EP06-109) and a safety and efficacy study conducted in 218 breast cancer patients receiving myelosuppressive chemotherapy (EP06-302). In addition, the company established an analytical data bridge between U.S.- and EU-approved Neupogen, which enabled inclusion of clinical data produced as part of EP2006's EU clinical development. All of the supportive studies using EU-approved Neupogen had been conducted in healthy volunteers. Sandoz was also able to draw upon the worldwide postmarketing experience with Zarzio when making its case for U.S. approval. Sandoz justified indication extrapolation for EP2006 based on several key factors including demonstration of analytical and functional similarity between EP2006 and Neupogen and the existence of a single, well-understood mechanism of action (MOA) of filgrastim across all indications.

Interestingly, while Sandoz's EP06-302 study included repeated switching between EP2006 and Neupogen, the company highlighted that its current application was for approval of EP2006 as a biosimilar and not as an interchangeable biologic. The BPCIA legislates for interchangeable biologics that can be automatically substituted by pharmacists for the reference brand product without prior physician consent. The FDA has not yet published guidance on interchangeability; however, the agency has indicated that, at least initially, a two-step process is desired with a biosimilar product first approved as a biosimilar, followed by an application for approval as an interchangeable biologic. Sandoz did indicate that it expects to use the positive switching data for a future application to secure interchangeable designation that would enable pharmacists to substitute Neupogen for EP2006 without physician consent. FDA guidance on interchangeability due in 2015 will aid in determining how impactful Sandoz's positive switching data is likely to be for approval as an interchangeable biologic.

Indication extrapolation
While the advisory committee's recommendation is a positive sign that the FDA will permit indication extrapolation, as per the agency's guidance, developers working on monoclonal antibody (MAb) biosimilars such as infliximab and rituximab will need to build strong justification for extrapolation. In many instances the MOA of MAbs is not fully understood and it can differ between indications. A good example is Celltrion's infliximab biosimilar. In the EU, it was approved for the same six indications as the reference product Remicade based on clinical data in ankylosing spondylitis and rheumatoid arthritis. However, Health Canada considered that in vitro differences between Celltrion's infliximab biosimilar and Remicade in antibody-dependent cell-mediated cytotoxicity (ADCC) NK cell-mediated assays could translate to potential significant differences between the products when used in Crohn's disease (CD) and ulcerative colitis (UC) where the MOA may involve ADCC. This led to Health Canada's decision not to approve Celltrion's infliximab biosimilar in CD and UC, where ADCC is relevant. Biosimilar developers will have to understand the data requirements different regulators have for indication extrapolation. Furthermore, the refusal of one regulator to grant indication extrapolation may negatively impact the commercial opportunity of the product in regions where the regulator did grant indication extrapolation by promoting wariness amongst physicians prescribing for that indication.

An unexpected occurrence during the ODAC meeting was a moment of focus from the committee on the price of EP2006 and whether it would be lower than Neupogen. In many ways, this cuts to the heart of the matter with regards to biosimilars?will these products offer physicians, payers, and patients lower-cost biologics and fulfill the clear mandate for which the biosimilar pathway in the United States has been established? Sandoz's answer revealed the complexities that need to be considered with drug pricing in the U.S. healthcare system. The company indicated that EP2006 could be priced at parity with Neupogen, but its net cost would be lower based on other mechanisms such as rebates.

Next steps
The role of the advisory committee is to provide independent advice and recommendations to the FDA. However, their recommendations are non-binding, and any final decisions remain with the FDA. A final FDA decision on Sandoz's EP2006 is expected by May 2015, should the FDA meet their review performance goal for biosimilar applications (i.e. 70% of all 2014 biosimilar applications being reviewed within ten months), although Sandoz has indicated that approval could occur even earlier in Q1 2015.

While Sandoz has proposed the U.S. brand name of Zarxio for EP2006, it is not yet approved by the FDA as such, and many unanswered questions remain regarding how non-proprietary names for U.S. biosimilars should be structured. The FDA was due to publish guidance on labeling for biosimilar biologic products in 2014, which we expect to address naming; however, the guidance document is now listed in the agency's publication schedule for 2015. Many who follow the industry, including the Biosimilars Advisory Service team, would like to see this guidance published prior to the approval of EP2006. Biosimilar naming has been a contentious issue in the United States, with proponents for and against biosimilars having distinct a non-proprietary name than the reference product. It has been argued that distinct non-proprietary names are necessary for pharmacovigilance purposes, in order to identify and trace biological products and correctly assign adverse events. Proponents against distinct non-proprietary names maintain that distinct non-proprietary names will harm access to reimbursement and competition, and that other means of identification such as brand names or national drug codes are sufficient for pharmacovigilance.

Further barriers to entry?
Even with FDA approval, Sandoz may have difficulties launching EP2006 in the United States, with looming litigation with Amgen that claims that Sandoz has not followed the rules of the BPCIA. The BPCIA lays out a procedural approach for biosimilar applicants to follow. In the initial step, the biosimilar applicant should submit the biosimilar application and details of the manufacturing process to the reference brand sponsor within 20 days of the biosimilar application being accepted by the FDA. Amgen claims that Sandoz has refused to undertake this initial step. Amgen filed a complaint against Sandoz in October 2014, alleging infringement of patent US6162427 (a method for using Neupogen to treat a disease requiring peripheral stem cell transplantation in a patient), conversion (use of Amgen's demonstration of safety, purity, and potency of Neupogen), and unfair competition. The complaint also highlighted that Amgen could not be certain that other patents were not being infringed on in lieu of Sandoz's biosimilar dossier. The outcome of this litigation is closely watched by those in the biosimilar community, since it will determine the future relevance of the BPCIA ?patent dance?.

Anees Malik is a senior business insights analyst on of the Biosimilars Advisory Service team at Decision Resources Group.

Hristina Ivanova is a research associate on the Oncology and Biosimilars Advisory Service teams at Decision Resources Group.

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