Europe and FDA guidance on biosimilar interchangeability


The number of approvals for biosimilar products is steadily increasing in Europe, the USA, and other regions to combat the economic burden of originator biologics on healthcare systems and patients. More and more originator biological products are losing market exclusivity, and this has led to an increasing number of biosimilar products being available on the market. The European Medicines Agency (EMA) has been ahead of the US Food and Drug Administration (FDA) in terms of approvals. As of June 2018, the EMA has given approval to 43 biosimilar products versus 11 products by the FDA.1,2,3 The FDA still does not have a clear pathway when it comes to approving biosimilar products, leading to limited approvals, whereas the EMA has developed general as well as product specific guidelines. There have been concerns about safety, efficacy, and similarity of these biosimilars to the reference products, especially monoclonal antibodies, bringing interchangeability of these biosimilars with their originator products. Currently, the EMA and FDA have different approaches regarding interchangeability.1

EMA Guidance

In European countries, the substitution of a reference medicine by a biosimilar is encouraged for the treatment of treatment-naïve patients while a more cautious approach is used for substitution in patients already on reference products.1Interchangeability, switching, and substitution of a reference medicine by its biosimilar is not regulated by the EMA. These fall within the remit of European Union (EU) member states.4 As such, the EMA recently released an information guide for healthcare professionals. In the context of biosimilars and reference medicines, it is important for healthcare professionals to be aware of the terminology when referring to the practices of interchangeability and substitution in the EU.4

Interchangeability refers to the possibility of exchanging one medicine for another medicine that is expected to have the same clinical effect. This could mean replacing a reference product with a biosimilar (or vice versa) or replacing one biosimilar with another. Replacement can be done by:

• Switching, when the prescriber decides to exchange one medicine for another medicine with the same therapeutic intent.4
• Substitution (automatic), the dispensing of one medicine instead of another equivalent and interchangeable medicine at the pharmacy level without consulting the prescriber.4

EMA and Member States’ Responsibilities

When the EMA carries out the scientific review of a biosimilar, the evaluations do not include recommendations on whether the biosimilar is interchangeable with the reference medicine, and thus whether the reference medicine can be switched or substituted with the biosimilar.4

The decision on whether to allow the interchangeable use and substitution of the reference biological medicine and biosimilar is taken at the national level. Information on the scientific evaluation performed by the EMA’s scientific committees is available on the EMA’s website and could be used to support decisions.4

FDA Guidance

In 2017, the FDA released draft guidance on biosimilar interchangeability entitled “Considerations in Demonstrating Interchangeability with a Reference Product”.5 According to the guidance, sufficient information showing that a biosimilar product “can be expected to produce the same clinical result as the reference product in any given patient” has to be provided to get approval for interchangeability.Moreover, an adequately powered switching study should be performed in a patient population. Such a study would be a parallel arm, with one treatment arm alternating at least three times between the reference and the biosimilar product (multiple switching) and the other arm continuing with the reference product.1,5

When applicable studies involving pharmacokinetics and pharmacodynamics as primary endpoints while immunogenicity and safety as secondary endpoints should be undertaken. Based on these studies, if the FDA approves the product as interchangeable then the substitution can be done at pharmacist level depending on the state regulations. However, to date, the FDA has not granted interchangeability (or biosimilarity) to any biosimilar.1,5

Differences in Regulations

In the EU, the EMA has given decision-making authority regarding interchangeability or substitution to each national agency in its member states. Not all member states have succeeded in releasing a guideline for interchangeability, however, all the states carry a common opinion that a thorough comparability study would be sufficient, and that clinical studies specifically for interchangeability or substitution are not a mandate. In contrast, the FDA differs and has asked for clinical studies for interchangeability or substitution to be carried out.1,4,5

There is much ambiguity and lack of standardisation revolving around interchangeability of biosimilars with reference products. Due to concerns of safety and efficacy, however there is an agreement that switching, or substitution should be a cautious approach made under medical supervision by healthcare professionals.1

Building for Biosimilars

With an attempt to rebalance pharmaceutical budgets, the use of biosimilars is highly encouraged in Europe. Furthermore, because of the financial and economic crisis, many European member states have adopted strategies to balance the national budgets with special focus on healthcare and encouraged the use of biosimilars. It is therefore important to adopt a strategy which will facilitate this process while reinforcing the confidence of all stakeholders. To gain this confidence, real-world data from a large pool of the patient population from observational or registry studies must be collected. In addition, long-term follow-up must be performed with these patients to understand the effect on immunogenicity, and physicians must be major leads in such studies, with a view to help collate data to reflect the effectiveness of biosimilars.



1Noce A, Ernst M. Switching from Reference to Biosimilar Products: An Overview of the European Approach and Real-World Experience So Far. EMJ. 2018;3[3]:74-81.
2European Medicines Agency. European public assessment reports. 2018
3U.S. Food and Drug Administration. Biosimilar product information. 2018.
4European Medicines Agency. Biosimilars in the EU: Information guide for healthcare professionals. 2017.
5U.S. Food and Drug Administration. Considerations in demonstrating interchangeability with a reference product. 2017.