The EU’s take on the class of medicines known as biosimilars is a slight variation of what is seen in the US, where there are two distinct types: Follow-on biologics that are biosimilar, or "expected to produce the same clinical result as the reference product," and ones that are "interchangeable," or able to be switched with their reference product.
Arguments over interchangeability in the US (from whether pharmacists should be allowed to switch a biologic for its biosimilar without a doctor’s notification, to whether interchangeable biosimilars might be perceived as "better" or "safer" than their non-interchangeable counterparts) were somewhat resolved by the US Food and Drug Administration’s (FDA) issuance of draft guidance in January on what should be submitted to support an interchangeable application.
The draft makes clear that switching studies to help gain this designation "should evaluate changes in treatment that result in two or more alternating exposures (switch intervals) to the proposed interchangeable product and to the reference product." Study design, types of data and other considerations are also included in that draft, though no biosimilars have been approved by FDA so far as interchangeable.
What About Interchangeability in the EU?
But are biosimilars in the EU interchangeable even if the region does not use the "interchangeable" designation like in the US? Several officials from the Finnish Medicines Agency, Netherlands’ Medicines Evaluation Board, the Norwegian Medicines Agency, Germany’s Paul-Ehrlich-Institut and others offer a simple retort: Yes.
"Our conclusion is that biosimilars licensed in the EU are interchangeable," they wrote in an opinion piece published in BioDrugs in January.
But it’s also not that simple because the EU and US look at interchangeablity differently.
In the US, the authors said, "interchangeability is defined in the legislation [the Biologics Price and Competition Innovation Act] and corresponds to automatic substitution in the EU terminology, where interchangeability means changing one medicine for another that is expected to achieve the same clinical effect in a given clinical setting and in any patient on the initiative, or with the agreement of, the prescriber. Thus, the European type of interchangeability is not a legal but a scientific and medical term."
Officially, however, the EU does not even have a position, the authors wrote, "Instead, several national regulatory
authorities, including the Dutch Medicines Evaluation
Board (MEB), the Finnish Medicines Agency Fimea,
Healthcare Improvement Scotland, the Irish Health Products
Regulatory Authority, and Paul Ehrlich Institute in
Germany, have already taken national positions to endorse
the interchangeability of biosimilars under the supervision
of the prescriber."
And though the EU might turn its nose up at the US concept of having two different types of biosimilars (the authors noted that the region has "no plans to introduce new legal or regulatory requirements for interchangeability studies and thus create two classes of biosimilars"), there is "ongoing discussion on the need for specific interchangeability studies in the EU."
Discussions in the US and EU on this concept of "interchangeability" also come down to matters of safety, or as the EU authors concluded: "a switch between comparable versions of the same active substance approved in accordance with EU legislation is not expected to trigger or enhance immunogenicity. On the basis of current knowledge, it is unlikely and very difficult to substantiate that two products, comparable on a population level, would have different safety or efficacy in individual patients upon a switch."
And though there are examples of harmful immunogenicity being triggered by a switch, the authors noted: "Interestingly, the current examples of switch-related immunological adverse drug reactions were found to be caused by differences between drug formulations as well as by improper storage and transport conditions but not by differences in active substances as often suggested in the public discussion on interchangeability and risk of immunogenicity."
They also offered the "most prominent example of a rare immunological problem," anti-epoetin antibody-induced pure red cell aplasia (PRCA) in more than 200 patients with chronic kidney disease who were switched from a previous to a new version of Johnson & Johnson’s Eprex (epoetin alfa) "after a simultaneous change in the product formulation and the administration route."
Interchangeability of Biosimilars: A European Perspective