What Is a Biosimilar?

The question, of course, is how significant are those differences? If the products are different enough, an immune reaction might be provoked. “There’s no question that there is some risk of immunogenicity when molecules aren’t 100% similar,” said Aaron Hakim, a third-year Yale medical student and co-author of a 2017 JAMA article on the adoption of biosimilars for chronic disease (JAMA. 2017;317:2163-2164). “If your immune system was fine with product A but product B is slightly different, it may cause adverse effects. The drug may no longer be effective for you.”

It’s important to note that immunogenicity is a risk even with biologics, because batch-to-batch variability exists in the production of therapeutic antibodies even when biologics are produced in the same plant, by the same manufacturer, and using the same process.

An International Perspective

Europe is far ahead of the United States in adopting biologics and biosimilars. In fact, the European Medicines Agency (EMA) approved 109 biologics between 2011 and 2016, compared with the 85 approved by the FDA in that same time frame (J Allergy Clin Immunol. 2017;139:1461-1464). Thirty biosimilars have already been approved in Europe, compared with just four here in the U.S.

What accounts for the difference?

“The regulatory paradigm for the approval of biosimilars in the United States really only started with the Affordable Care Act,” Hakim said. The Biologics Price Competition and Innovation Act passed in 2010 as part of the Affordable Care Act, and it is “only in the last several months that the FDA has put out guidance for what it required to be an interchangeable biosimilar, meaning a biosimilar that can be substituted for the branded biologic, at the level of the pharmacy,” Hakim said. That document was originally expected before the end of 2015; it was January 2017 when the FDA released draft guidance for industry regarding how to demonstrate interchangeability.

In contrast, the Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Quality Issues went into effect in 2006 in Europe. There, biosimilars must be proven similar to a reference biologic in terms of safety, efficacy, and quality, but drug manufacturers do not need to conduct clinical trials as extensive as those required for approval of the original biologic. (It is expected that FDA approval of biosimilars in the U.S. will require switching studies to demonstrate that patients can alternate between the original biologic and the biosimilar without diminished efficacy or serious side effects.)