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Time for Regulators to Acknowledge That Biosimilars Are Interchangeable, Paper Argues


"We argue that the default should be that biosimilars are interchangeable, unless there is compelling evidence otherwise," write Hans C. Ebers, PhD, of Biogen, and Hubb Schellekens, MD, PhD, of Utrecht University.

Differences in the US and European understandings of the term “interchangeability” as it relates to biosimilars has been the cause of a great deal of discussion in recent years. In the European context, the ability to switch between biosimilars and their reference products (or among other biosimilars of the same product) is a medical matter, and switches typically occur at the discretion of the prescribing physician, not the pharmacist. In the US context, interchangeability is a designation granted by the FDA that will allow for a biosimilar to be substituted for its reference product at the pharmacy level under applicable state laws.

However, interchangeability, argues a recent feature in Drug Discovery Today, is at its heart a product characteristic that allows one medicine to be exchanged for another while producing the same clinical effect, regardless of whether that exchange takes the form of switching or pharmacy-level substitution. Given the body of evidence supporting biosimilars, and to boost confidence in these drugs, write Hans C. Ebers, PhD, of Biogen, and Hubb Schellekens, MD, PhD, of Utrecht University, regulators should acknowledge that biosimilars are, in fact, interchangeable.

One of the FDA’s stated concerns about switching between biosimilars and their reference products has been the risk of increased immunogenicity. However, the authors point out, immunogenicity has been extensively assessed over the past 15 years, and “there are no data” in more than 16,000 papers published on the immunogenicity of biologics that would point to a link between switching and immunogenicity, and there is no reason to believe that switching between a biosimilar and its reference would pose a higher risk than using 2 different batches of the same reference.

Ebers and Schellekens also point out that the FDA’s requirement that biosimilar developers hoping for interchangeability designations produce clinical data in the form of studies involving multiple switches is not required in the European Union; given the state-of-the-art methods used to demonstrate biosimilarity, any residual uncertainty “will be very small” and would take infeasibly large studies to address.

The authors also point out the FDA’s recommendation that bridging studies may be needed to establish the similarity of US- and EU-licensed reference products; given that products also undergo manufacturing changes over their independent life cycles, “This could imply that clinical studies confirming continued interchangeability could be required following manufacturing changes that affect quality attributes.”

Finally, write Ebers and Schellekens, current evidence on switching suggests that the nocebo effect, whereby patients experience negative outcomes as a result of negative beliefs or expectations about a therapy, is a driver of differing discontinuation rates between patients who switch to a biosimilar and those who remain on a reference product. The nocebo effect, they point out, is not unique to biologic drugs; regulators should take official positions on the interchangeability of biosimilars in order to boost prescriber confidence that will, in turn, help limit the impact of nocebo on patient outcomes.

The authors conclude that, based on available data, “there is no reason to doubt that biosimilars are interchangeable and that the risk of increased immunogenicity of switching to a biosimilar is no greater than switching between two batches of any biologic. We argue that the default should be that biosimilars are interchangeable, unless there is compelling evidence otherwise.”

There may be reasons to limit substitution at the pharmacy level, such as differences in device design that could lead to inappropriate use of a medication, they write, but a harmonized regulatory position on interchangeability will “allow the discussion to focus on questions that are most relevant when switching to biosimilars, such as ways to reduce nocebo effects.”


Ebbers HC, Schellekens H. Are we ready to close the discussion on the interchangeability of biosimilars? [published online June 26, 2019] Drug Discov Today. doi: 10.1016/j.drudis.2019.06.016.

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