Interchangeability of biosimilars in the EU, clarity?

A joint statement is just that, a joint statement

On April 21st, 2023, the European Medicines Agency (EMA) and the Heads of Medicines Agencies (HMA) issued an updated joint statement on the interchangeability of biosimilars approved in the EU. The core is:

HMA and EMA consider that once a biosimilar is approved in the EU it is interchangeable, which means the biosimilar can be used instead of its reference product (or vice versa) or one biosimilar can be replaced with another biosimilar of the same reference product. Interchange should only take place after careful consideration of the approved conditions of use (i.e., consulting the most recent product information)[1].

There is also a Questions and Answers document[2], where some important questions are answered. One of those questions is Question 3.

The answer is a clear “No”. Because, it is left to the Member States to decide if a particular product for another that is biosimilar to it. EMA and HMA merely issued a scientific document to say that, in their view, there are no scientific obstacles to switch – even multiple switches – between a reference product and a biosimilar. Does it matter?

Before the previous version of this statement was issued in September 2022, many EU Member States had already allowed substitution and switching, and I am not sure this guidance will change much. In the US, FDA still sees interchangeability as something that requires data, as can be read in their guidance document[3] where it is written in the general principles: FDA expects that sponsors will submit data and information to support a showing that the proposed interchangeable product can be expected to produce the same clinical result as the reference product in all of the reference product’s licensed conditions of use.

FDA’s definition is little different from the EU, in that in 351(i)(3) of the PHS Act[4] requires that interchangeability means that the reference product must be able to be substituted without intervention of the prescriber of the original product, but still this difference in assessment and requirements between FDA and EMA is quite striking, I think. A major difference is of course that EMA has assessed and approved more than 80 biosimilars since 2006, whereas FDA only has 40 approved since the first approval in 2016 and only 3 are deemed interchangeable in October 2022. EMA simply has more experience with biosimilars.

But, does it matter?

The goal of regulation is of course to protect public health. And, as I have always interpreted it, part of the European philosophy of regulation is that what is good for Polish patients, is also good for Dutch patients, or German or Spanish patients. FDA requires a pretty in-depth study program before they are comfortable saying a product can be interchangeably used and there is no need for a healthcare provider to take another look. In Europe on the other hand, a statement is issued saying that any biosimilar can be interchangeably used – including multiple switches – but the individual member states can still do what they think is good for them. A Dutch patient in Spain may not be able to get the same treatment as they would get in Estonia, simply because Spain looks at this issue differently.

Does this statement provide the clarity that is needed and is it a good idea to paint with a broad brush when biologics can be so different even depending on the exact process used? Do differences in immunogenicity translate to differences in adverse reactions? Is the potency of a biosimilar drug always the same as that of an originator? I don't think it necessarily is, but without evidence it'll be hard to judge. And I think that results obtained in the past, may not be a good predictor for the future.

references

[1] https://www.ema.europa.eu/documents/public-statement/statement-scientific-rationale-supporting-interchangeability-biosimilar-medicines-eu_en.pdf

[2] https://www.ema.europa.eu/en/documents/other/qa-statement-scientific-rationale-supporting-interchangeability-biosimilar-medicines-eu_en.pdf

[3] https://www.fda.gov/regulatory-information/search-fda-guidance-documents/considerations-demonstrating-interchangeability-reference-product-guidance-industry

[4] https://uscode.house.gov/view.xhtml?req=title:42%20section:262%20edition:prelim)#:~:text=(3)%20The%20term,the%20reference%20product.