Establishing interchangeability for biosimilars in the US

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The European Commission held a Stakeholder Event on Biosimilar Medicinal Products in Brussels, Belgium on 5 May 2017. During this event Dr Hans Ebbers of the Medicines Evaluation Board (MEB/CBG) in The Netherlands discussed how interchangeability for biosimilars is established in the US.

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The US has a somewhat different approach to establishing interchangeability compared to Europe. The regulatory position is different in the US, because the US Food and Drug Administration (FDA) has jurisdiction to classify biosimilars as ‘interchangeable’, and this designation then enables substitution at the pharmacy level without the consent of the prescribing physician – provided that state legislature permits such substitution and that the prescribing physician has not indicated in the prescription form that the prescribed product must not be substituted [1].

The US legal pathway for biosimilars does not define the weight of evidence required to fulfil the requirement that an interchangeable biosimilar product ‘can be expected to produce the same clinical result as the reference product in any given patient’ and ‘the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch’ [1].

Generally sponsors will be expected to conduct a switching study, see Figure 1.

Figure 1: Possible study design for switching studies

Fig 1 GW 3164G

rand: randomized.

For a switching study in the US:

  • A non-US product would generally not be appropriate
  • Pharmacokinetics/trough levels as primary endpoint in switching studies
  • Considerable focus on differences in presentation and device

–     May need to be addressed in Human Factors studies

FDA released draft guidance on the interchangeability of biosimilars with their reference biologicals in January 2017 [2]. The comment period on the guidance ended on 19 May 2017 [3]. Questions not answered in the guidance include:

  • What to do with manufacturing changes? Originator or biosimilar
  • How to deal with other interchangeable biosimilars?

FDA has indicated that biosimilarity must first be established before any studies into interchangeability can be performed. Once biosimilarity has been established drugmakers can then decide whether to further pursue interchangeability or not. This approach, however, has raised questions as to what would happen if a product was deemed not interchangeable [4].

Dr Hans Ebbers stated that the views expressed in his presentation are the personal views of the author and are not to be understood or quoted as being made on behalf of, or reflecting the position of the CBG or any other regulatory agency, or one of its committees or working parties.

Related articles
Interchangeability and switching study designs for biosimilars

Establishing interchangeability for biosimilars

1. Ebbers HC, Chamberlain P. Interchangeability. An insurmountable fifth hurdle? Generics and Biosimilars Initiative Journal (GaBI Journal) 2014;3(2):88-93. doi:10.5639/gabij.2014.0302.022
2. GaBI Online - Generics and Biosimilars Initiative. FDA issues draft guidance on biosimilar interchangeability []. Mol, Belgium: Pro Pharma Communications International; [cited 2018 Jan 12]. Available from:
3. GaBI Online - Generics and Biosimilars Initiative. FDA extends comment period for interchangeability guidance []. Mol, Belgium: Pro Pharma Communications International; [cited 2018 Jan 12]. Available from:
4. GaBI Online – Generics and Biosimilars Initiative. FDA gives some insight into biosimilar pathway []. Mol, Belgium: Pro Pharma Communications International; [cited 2018 Jan 12]. Available from:

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Posted 12/01/2018 by Paul Declerck
Interchangeability approach in the US is the most appropriate approach

First posted 12/1/2018 ---
Very nice presentation of Dr Ebbers with very useful information. As commented on a very similar post I want to point out that in the discussion on interchangeability/switching/substitution the EMA as well as many authors provide an erroneous definition of interchangeability. Indeed, whereas ‘switching’ and ‘substitution’ refer to a “practice” (of the physician and the pharmacist, respectively) ‘interchangeability’ does not refer to a medical practice but actually refers to a property of two drugs. Two drugs are interchangeable if changing one drug for the other is expected to achieve the same clinical effect in a given clinical setting and in any patient. And, important in the context of biosimilars, one should also take into account that the designation of ‘interchangeable’ can only be attributed if also alternating (i.e., back-and-forth) between the two drugs does not affect either the safety or the efficacy in any patient. This is also the reason why the approach of the FDA with respect to the requirements for the designation of ‘interchangeable’ is scientifically correct [1]. ---

[1] Declerck Paul, Endrenyi Laszlo, Chow Shein-Chung (2017). Interchangeability, Switchability, and Substitution of Biosimilar Products. In: Endrenyi Laszlo, Declerck Paul, Chow Shein-Chung (Eds.),
Biosimilar Drug Product Development, (Chapter 10, pp 283-296) CRC Press.

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