This draft guidance update is based on updated information and experience following the issuance of the FDA’s interchangeability guidance for industry in 2019 (Considerations in Demonstrating Interchangeability With a Reference Product) [2].

In the US, according to the Biologics Price Competition and Innovation Act of 2009 (BPCI Act), only a biological that has been approved as interchangeable may be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product [3]. Acquiring this status requires the inclusion of a switching study or studies, intended to support a demonstration that a biological product is interchangeable with a reference product. These studies can cost millions of dollars and delay biosimilar market access.

By early 2019, 45 US states have passed the biosimilar substitution laws that permit or require pharmacists to dispense an interchangeable biological product in certain situations [3].

Since publication of the interchangeability guidance in 2019, the FDA’s scientific approach to when a switching study, or studies, may be needed to support a demonstration of interchangeability has evolved. A recent systematic review and meta-analysis by FDA [4] has found that no differences in the risk of death, serious adverse events, and treatment discontinuations between participants who switched between biosimilars and reference products and participants who did not switch. Additionally, now, analytical tools can accurately evaluate the structure and effects biological products, both in the laboratory (in vitro) and in living organisms (in vivo) with more precision and sensitivity than switching studies. Overall, since the initial interchangeability guidance was published, FDA states that for all approved biosimilars, the risk of safety or diminished efficacy is insignificant following single or multiple switches between a reference and a biosimilar product.

In light of this, the new draft guidance seeks comment on a revised approach where such studies will generally not be required. This supports US Republican Senator for Utah, Mike Lee’s ‘Biosimilar Red Tape Elimination Act’ [5], which was put forward in 2023 and aimed to amend the federal code to state that all biosimilars that receive FDA approval are, by definition, interchangeable and do not require switching studies.

Such a move in the US would follow suit with Europe and the UK. The European Medicines Agency (EMA), after studying over 10 years of data on biosimilars, found no difference in ‘nature, severity or frequency of adverse events between biosimilars and their reference medicines’ and on 19 September 2022, EMA and the Heads of Medicines Agencies issued a joint statement confirming that biosimilar medicines approved in the European Union (EU) are interchangeable with their reference medicines or with an equivalent biosimilar (see EMA calls for biosimilar interchangeability across the EU) [6]. The UK’s Medicines and Healthcare products Regulatory Agency issued a revised guidance in November 2022 that outlined the same position on interchangeability as EMA [7].

In fact, FDA has granted provisional determination for interchangeability designation to Pyzchiva (ustekinumab-ttwe), the latest biosimilar approval [8].

FDA has released the draft for a comment period of 60 days, i.e. until 20 August 2024. Comments can be submitted online at https://www.regulations.gov/docket/FDA-2017-D-0154/document, or in written form, and can be mailed to Dockets Management, Food and Drug Administration, 5630 Fishers Lane, Rm 1061, Rockville, MD 20852, USA. All written comments should reference the docket no. FDA-2017-D-0154.

Related articles
US Senate clarifies status of interchangeable biosimilar exclusivity

Different approaches to the interchangeability of biosimilars

References
1. U.S. Food and Drug Administration. Considerations in demonstrating interchangeability with a reference product: update. June 2024 [homepage on the Internet]. [cited 2024 Jul 23]. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/considerations-demonstrating-interchangeability-reference-product-update
2. GaBI Online - Generics and Biosimilars Initiative. FDA issues final guidance on interchangeable biologicals [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2024 Jul 23]. Available from: www.gabionline.net/guidelines/FDA-issues-final-guidance-on-interchangeable-biologicals
3. GaBI Online - Generics and Biosimilars Initiative. 45 US states have passed biosimilar substitution laws [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2024 Jul 23]. Available from: www.gabionline.net/policies-legislation/45-US-states-have-passed-biosimilar-substitution-laws
4. Schrieber S. Switches between biosimilars and their reference products. Generics and Biosimilars Initiative Journal (GaBI Journal). 2023;12(3):106. doi:10.5639/gabij.2023.1203.016
5. GaBI Online - Generics and Biosimilars Initiative. Updated Biosimilar Red Tape Elimination Act introduced by Senator Lee [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2024 Jul 23]. Available from: : www.gabionline.net/policies-legislation/updated-biosimilar-red-tape-elimination-act-introduced-by-senator-lee
6. GaBI Online - Generics and Biosimilars Initiative. EMA calls for biosimilar interchangeability across the EU [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2024 Jul 23]. Available from: www.gabionline.net/biosimilars/general/ema-calls-for-biosimilar-interchangeability-across-the-eu
7. GaBI Online - Generics and Biosimilars Initiative. UK updates guidance to allow biosimilars interchangeability [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2024 Jul 23]. Available from: www.gabionline.net/guidelines/uk-updates-guidance-to-allow-biosimilars-interchangeability
8. GaBI Online - Generics and Biosimilars Initiative. FDA approves third ustekinumab biosimilar Pyzchiva [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2024 Jul 23]. Available from: www.gabionline.net/biosimilars/news/fda-approves-third-ustekinumab-biosimilar-pyzchiva

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