EU APPROACH TO BIOSIMILARS

The European Union has led the way in issuing regulatory guidance for nonclinical and clinical development of biosimilars. The EU provided the Directives in 2003/63/EC and 2004/27/EC, that provided the legal catalyst required to develop biosimilar products (6, 7). The European Directives defined that a biosimilar medicine is similar to a biological medicine that has already been authorized (i.e., the biological reference medicine). In 2005, the EU developed a science-based regulatory guidance framework to ensure high-quality biosimilar drugs and issued its first EU regulatory guidance, Guideline on Similar Biological Medicinal Products, followed by two more guidelines in 2006: Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Quality Issues, and Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Nonclinical and Clinical Issues (8–10).

The EU currently has three overarching biosimilar guidance and product-class specific guidelines in areas including, epoetins, filgrastims, insulins, growth hormones, alfa interferons, mAbs, beta-interferons, follitropins, and low-molecular-weight heparins (8–16). These guidelines are principles for biosimilar drug development and apply to all biological medicinal products to include biobetters (17). Additional guidance, such as Guideline on Immunogenicity Assessment of Biotechnology-derived Therapeutic Proteins, includes both biotechnology-derived and biological (biosimilar) medicinal products (18).

The approach taken by the US has been quite different than the EU, because a legal pathway in the US lagged six years behind the first such guidance in the EU. In February 2012, FDA issued draft regulatory guidance to support market approval for biosimilars (19). This guidance followed the passage of the Biologics Price Competition and Innovation Act of 2009 (BPCIA) and was signed into law by President Obama in March 2010 with the aim to create an abbreviated regulatory approval pathway in the US for biologic products demonstrated to be highly similar or interchangeable with an FDA-licensed reference biologic product (20).

The delay in developing a regulatory pathway in the US compared with the EU has caused delay of biosimilars entering the US market. For example, Teva Pharmaceutical's submission of a BLA for XM02, a biosimilar filgrastim, was finally approved by FDA in an original BLA and was not approved as a biosimilar to Neupogen (filgrastim), and Teva is prohibited from marketing the drug in the US until late 2013 (21, 22). In contrast, Teva's biosimilar filgrastim, Tevagrastim, was approved in the EU in September 2008 as a biosimilar to the reference product, Neupogen (23, 24).

Before FDA guidance was released, many pharmaceutical and biotechnology companies were moving forward on different paths for market approval based on EU biosimilar regulatory guidance. While the new FDA guidance will provide a much clearer regulatory pathway for biotherapeutics, many questions remain as to how these complex drug-development programs should navigate the various regulatory hurdles. There is an ongoing debate as to whether biosimilar or biobetter drugs will result in less financial spend and time to market. Only time will tell how this story will play out.

Christina Satterwhite, PhD, is director of laboratory sciences, Preclinical Services, at Charles River Laboratories.