The evolving regulatory landscape of biosimilars and the concept of ‘interchangeability’ in the US, is explored in the GaBI Journal article, ‘US interchangeability designation: are we ready to cut the Gordian knot?’ [1].
The US’s interchangeability designation permits pharmacist-level substitution of a biosimilar without involving the original prescriber, though prescribers are notified afterward. Importantly, this designation pertains to dispensing, not prescribing. The designation was introduced through the Biologics Price Competition and Innovation Act (BPCIA) of 2009 [2].
Here, the paper’s authors Gillian R Woollett, MA, DPhil, and Joseph P Park, PhD both of Samsung Bioepis, note that initially, FDA guidance required additional clinical switching studies to obtain this designation. However, the authors explain that in June 2024, the FDA released updated draft guidance indicating that these studies are no longer generally necessary. Sponsors may now apply for interchangeability at any time, and the FDA will assess risk based on totality of evidence, primarily grounded in analytical and functional data, rather than relying on clinical switching studies.
The paper emphasizes that while interchangeability is a legal designation in the US, its use has led to global misunderstanding. Many healthcare providers and patients have erroneously viewed interchangeable biosimilars as superior to standard biosimilars. This has delayed biosimilar adoption in some settings. In response, the FDA conducted a meta-analysis, which confirmed no clinically significant safety or efficacy differences when switching between biosimilars and their reference products. Details of this analysis have recently been explored by Michael S Reilly of Alliance for Safe Biologic Medicines and gastroenterologist Ralph D McKibbin [3, 4].
The authors highlight how the FDA's evolving stance is based on accumulating scientific evidence and experience and aligns with the need to make biosimilars more accessible without compromising quality. For example, the first interchangeable biosimilar, Semglee (insulin glargine), was approved in 2021 without switching studies [5], setting a precedent. Since then, several biosimilars have received interchangeability designations without such studies, including those referencing Lucentis, Stelara, and Eylea.
FDA’s perspective on biosimilar labelling has also shifted. Initially, interchangeable products were labelled with a specific interchangeability statement. However, the latest guidance recommends harmonizing labelling between biosimilars and interchangeable biosimilars, removing the interchangeability statement to avoid misleading promotional claims or unfounded differentiation.
Nevertheless, the authors identify lingering regulatory ambiguities. One key concern is how the FDA interprets and applies interchangeability exclusivity, originally intended as a single reward for the first interchangeable version of a reference product. Instead, exclusivity has been granted for different presentations, e.g., concentrations or formulations, of the same reference product. This has created confusion and commercial uncertainty, as legal exclusivity can block the designation of other biosimilars despite their clinical equivalence.
In conclusion, the authors argue that FDA's technical and scientific position has evolved to recognize that all biosimilars are, in effect, interchangeable as a matter of clinical practice and regulatory science. However, the legal distinction remains entrenched. The FDA cannot unilaterally eliminate the designation, but it has recommended in its 2025 budget proposal that all approved biosimilars be deemed interchangeable [4, 6]. The authors suggest this would help resolve confusion, remove commercial disincentives, and better serve patients and providers alike.
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LATIN AMERICAN FORUM
The objective of GaBI’s Latin American Forum is to provide you with all the latest news and updates on developments of generic and biosimilar medicines in Latin America in Spanish. View the latest headline article: Estudios de eficacia clínica en biosimilares: ¿siguen siendo necesarios? Browse the news in the Latin American Forum! Register to receive the GaBI Latin American Forum newsletter. Inform colleagues and friends of this new initiative.
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El objetivo del Foro Latinoamericano de GaBI es brindarle las últimas noticias y actualizaciones sobre desarrollos de medicamentos genéricos y biosimilares en América Latina en español. Ver el último artículo de cabecera: Estudios de eficacia clínica en biosimilares: ¿siguen siendo necesarios? !Explore las noticias en el Foro Latinoamericano! Regístrese para recibir el boletín informativo GaBI Foro Latinoamericano. Informe a colegas y amigos sobre esta nueva iniciativa.
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References
1. Park JP, Woollett GR. US interchangeability designation: are we ready to cut the Gordian knot?. Generics and Biosimilars Initiative Journal (GaBI Journal). 2024;13(3):161-3. doi:10.5639/gabij.2024.1303.035
2. GaBI Online - Generics and Biosimilars Initiative. FDA publishes final Q&A on biosimilar development and the BPCI Act[www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2025 Jun 5]. Available from: www.gabionline.net/policies-legislation/fda-publishes-final-q-a-on-biosimilar-development-and-the-bpci-act
3. Reilly MS, McKibbin RD. Misinformation about interchangeable biosimilars undermines US health policy, physician confidence, and patient health. Generics and Biosimilars Initiative Journal (GaBI Journal). 2024;13(2):55-60. doi:10.5639/gabij.2024.1302.009
4. GaBI Online - Generics and Biosimilars Initiative. Are interchangeable biosimilars at risk? [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2025 Jun 5]. Available from: www.gabionline.net/biosimilars/research/are-interchangeable-biosimilars-at-risk
5. GaBI Online - Generics and Biosimilars Initiative. FDA approves first interchangeable insulin glargine biosimilar [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2025 Jun 5]. Available from:
www.gabionline.net/biosimilars/news/fda-approves-first-interchangeable-insulin-glargine-biosimilar
6. Reilly MS, McKibbin RD, Schneider PJ, Spiegel A. Biosimilar Red Tape Elimination Act (S.2305): weakening FDA regulatory standards for biosimilars, undermining physician confidence and jeopardizing patient health. Generics and Biosimilars Initiative Journal (GaBI Journal). 2025;14(1): Epub ahead of print.
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