The Biologics Price Competition and Innovation Act of 2009 (BPCIA) was passed as part of health reform signed into law by President Obama in March 2010. The BPCIA created an abbreviated pathway for regulatory approval of biologic medicinal products that are “biosimilar” to or “interchangeable” with an already FDA-approved biologic product. The abbreviated pathway permits the biosimilar applicant to rely on the safety and effectiveness of the approved product, enabling a biosimilar product to gain FDA approval based on less than a full complement of preclinical and clinical data. Although nearly five years have passed since the BPCIA was enacted, the BPCIA regulatory pathway has been much slower to take shape than its European counterpart. 2015 promises to be a landmark year, with the first biosimilar in U.S. history expected to be approved next month.

Europe’s abbreviated pathway for the approval of biosimilar medicinal products preceded the BPCIA and quickly took form. It was enacted in 2004. In 2005, a year later, the European Medicines Agency (EMA) issued its guidance for the development of biosimilar medicinal products. In 2006, the EMA approved its first biosimilar product. In 2007, five additional biosimilar products were approved. There are now 19 approved biosimilar products in 6 different classes of biologics: epoetins, filgrastims, growth hormones, follitropins, monoclonal antibodies, and insulins. The EMA has publishedproduct-specific guidances for the development of biosimilars in each of these classes.

In the U.S., the FDA did not issue its first guidance on the implementation of the BPCIA pathway until 2012. Biosimilar applicants did not submit any applications for approval of biosimilar products for another two years, instead spending the time on laying the groundwork for their applications. FDAreported that although it received no biosimilar applications in 2013, it received 93 submissions for biosimilars in development that year and completed 81 actions related to these submissions. FDA held numerous meetings with biosimilar applicants.

In 2014, biosimilar applicants submitted the first applications for approval of biosimilar products in the U.S. Four applications were submitted in 2014 by four manufacturers: Sandoz, Celltrion, Apotex and Hospira. The first application was submitted in May 2014 by Sandoz and the last in December by Hospira. The FDA accepted the first three applications for review in 2014 and Hospira’s application from December this month.

These first four applications fall into three product classes of varying complexity. Sandoz’s application is for the simplest product, a biosimilar version of Amgen’s Neupogen (filgrastim). It is a small protein with no sugar attachments (glycosylation) that is made in bacterial cells. Apotex submitted an application for a biosimilar version of Amgen’s Neulasta (pegfilgrastim), an improved long-lasting version of Neupogen. Neulasta consists of Neupogen with a covalently bound polyethylene glycol (PEG) molecule that allows Neulasta to be administered less frequently than Neupogen. The next most complex product is Hospira’s proposed biosimilar of Amgen’s Epogen (epotein alpha). Epogen, although a small protein, has complex glycosylation and is made in mammalian cells. Celltrion’s and Hospira’s application for a proposed biosimilar of Janssen’s Remicade monoclonal antibody is by far the most complex of the products being considered. It is large and has a complex structure and glycosylation.

In January of this year, FDA staff concluded that Sandoz’s proposed product is a biosimilar of Neupogen, i.e., that it is highly similar to Neupogen with no clinically meaningful differences. FDA found that Neupogen should be approved for all five indications of Neupogen as Sandoz requested. Sandoz had conducted a pivotal clinical trial for only one of the five indications of Neupogen but FDA concluded that based on the totality of the evidence it was scientifically justified to extrapolate the clinical data submitted by Sandoz to all five of Neupogen’s indications. Extrapolation is highly significant as it shortcuts the need for clinical trials for each of the indications and reduces the time and expense of approval. In the case of Neupogen, Amgen obtained approval for one indication in 1991 but did not have approval for all five of Neupogen’s indications until 1998.

On January 7, the Oncologic Drugs Advisory Committee met and agreed with FDA’s finding that Sandoz’s product is a biosimilar of Neupogen. The FDA Advisory Committee also unanimously recommended approval of the product for all five of Neupogen’s indications. Sandoz’s product will be the first U.S. biosimilar. Its approval is expected as early as March and Sandoz has said that it intends to launch immediately. Whether Sandoz will be able to do so depends on the litigation pathway created under the BPCIA and Amgen’s lawsuit against Sandoz to enforce the BPCIA’s litigation provisions.

FDA’s review of the next three biosimilar applications will provide important information on the requirements for biosimilarity and extrapolation for more complex biologics. FDA has scheduled an Advisory Committee meeting for the proposed biosimilar of Remicade, the most complex of the products, for March 17. In addition, half a dozen new biosimilar applications are expected to be filed this year. Even though many regulatory and policy questions remain, it is clear that the BPCIA regulatory pathway is beginning to take shape. With the unanimous recommendation to approve Sandoz’s biosimilar of Neupogen, 2015 will undoubtedly be a historic year for biosimilars in the U.S.