This fall marks the tenth anniversary of the effective date of the European Medicines Agency’s Guideline on Similar Biological Medicinal Products. As this blog noted previously, the EU’s biosimilar pathway both preceded the U.S. pathway created in 2010 and came into use more quickly. Over the past ten years, the EMA has approved 19 biosimilars under the guidelines, corresponding to 6 different reference drugs, in six categories of biologics: epoetins, filgrastims, follitropins, growth hormones, insulins, and monoclonal antibodies.  The EMA’s Committee for Medicinal Products for Human Use recently recommended granting marketing authorization for a biosimilar of Enbrel, a dimeric fusion protein, which would constitute a seventh category.  Although the U.S., with its larger and more homogenous pharmaceutical market, is unlikely to follow the exact same path as Europe, the European experience is relevant in assessing the future of biosimilars in the United States.

Biosimilar Products Approved by the EMA as of December 7, 2015 (1)

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Market adoption of biosimilars

Unlike generic small-molecule drugs, which generally replace brand-name drugs once they are approved, adoption of biosimilars in the EU has been mixed, ranging greatly between countries and between products.  This is because while the authorization to market biosimilars is provided centrally by the EMA, each country retains control over substitution policies, i.e. recommendations as to whether a biosimilar should be used interchangeably with its reference medicine.  Thus, for example, a recent study by the IMS Institute for Healthcare Informatics found that biosimilar penetration in 2013 for G-CSF (filgrastim) ranged from 2% of treatment days in Belgium to nearly 100% in Croatia, Czech Republic, Hungary, and Romania. The IMS study attributes differences in the uptake of biosimilars—and differences in price competition—to local practices, practices in turn influenced by national funding schemes and the actions of payers.

Product Specific Guidelines

The EMA has established specific guidelines detailing requirements for regulatory approval for each of the categories of biosimilars currently approved, as well as for biosimilar products containing interferon alpha, interferon beta and low-molecular-weight heparins. Category-based guidelines are valuable in the development of standards for biologics, since the complexity of structure and glycosylation differs greatly across categories of biologic products. In the next several years, as the FDA considers applications for biosimilars of varying types, we can expect that the U.S. will begin to develop category-specific policies as well.

Naming schemes for biosimilars

In Europe, biosimilars are generally referred to by their trade names, which are different from those of the brand-name reference drug, but the non-proprietary names of European biosimilars are identical to those of their reference drug.  For instance, the European packaging for Zarzio (the European trade name for Zarxio) identifies the product by that trade name and by its International Nonproprietary Names name, filgrastim. Filgrastim is the same INN name used for the reference product, Neupogen, even though the two products are (bio)similar rather than identical. The FDA’s recently issued draft guidance, by contrast, requires the addition of a randomly-assigned suffix for all biologic products.  It results in different non-proprietary names for biosimilars and their reference drugs. Under the proposed U.S. naming scheme, for example, Zarxio will be identified as “filgrastim-bflm,” while Neupogen will be assigned the name “filgrastim-jcwp.”

The next several years:

The U.S. has taken a more cautious pace to the approval of biosimilar medications than the EU took in its first few years. While the U.S. biosimilar statute became law in 2010 and the FDA’s first guidance on biosimilars was released in 2012, to date only one product (Zarxio) has been approved in the U.S. as a biosimilar. The number of biosimilar applications pending FDA review indicates that the next several years may be a time of rapid development in the regulation of U.S. biosimilars – although the FDA’s most recent publicly announced decision, rejecting Hospira’s application for a biosimilar version of Amgen’s Epogen (EPO), suggests that the FDA is taking a cautious approach and will not approve a proposed biosimilar even when it is already marketed in the EU.  It remains to be seen to what extent the U.S. regulatory pathway follows the contours of the European model.