Author byline as per print journal: Joseph P Park¹, PhD; Gillian R Woollett², MA, DPhil

Submitted: 16 July 2024; Revised: 6 August 2024; Accepted: 8 August 2024; Published online first: 21 August 2024

Approval pathways for biosimilars and interchangeable biosimilars were first introduced in the US through enactment of Biologics Price Competition and Innovation Act of 2009 (BPCIA) (itself Title VII part of the Patient Protection and Affordable Care Act) on 23 March 2010 [1]. The interchangeability designation, unique to the US, enables pharmacists (subject to state law) to substitute the US Food and Drug Administration (FDA)-designated biosimilars for the reference product without involving the original healthcare providers (HCPs) (albeit they will be notified subsequently). As such, an interchangeability designation is about dispensing, not prescribing. The basis upon which the FDA designation is given has been a subject of much debate, and on 21 June 2024, FDA issued a Draft Guidance ‘Considerations in Demonstrating Interchangeability With a Reference Product: Update’ [2] clarifying that biosimilar sponsors may apply for the designation at any time without the previously generally required additional clinical switching studies.

Though a formal regulatory determination of interchangeability is unique to the US, the concept of biologicals interchangeability has created turmoil globally. It has raised questions in large part because of the discrepancy between the legal designation in BPCIA and the term’s common usage [3]. Some patients and healthcare providers have mistakenly considered interchangeable biosimilar products to be ‘better biosimilars’ and led to some HCPs to only feel confident switching their patient(s) to an interchangeable biosimilar, especially for those already established on the reference product. Some HCPs have suggested waiting on the designation before using biosimilars even in naïve patients. To counter this misunderstanding, FDA conducted a meta-analysis to show that fear of such switching is erroneous and has no basis in fact [4]. FDA analysed the collective experience to date with switching naïve and experienced patients between reference products and biosimilars [4] and showed that there was no evidence of altered safety of efficacy with any of the switches.

This confirms the results of others in the peer-reviewed literature [5-7] but ­coming from FDA with its greater access to data and singular professional standing is important.

Based on experience with biosimilars to date, all stakeholders can have as much confidence switching to biosimilars as they do continue to use any given biological, which will likely include switching between originator products pre- and post-manufacturing change [8]. The apparent shift in FDA’s current thinking on interchangeability is based on fundamental regulatory science and confirmed by the shared cumulative experience to date [9]; as well as the need to understand how to make biosimilars more efficiently with no compromise in quality, safety and efficacy if more patients are to be able to access them [10, 11].

Switching study or studies in one or more appropriate conditions of use was originally considered necessary to obtain an FDA designation of interchangeability as this would comply with the black letter law of the BPCIA. The showing that the risk of diminished efficacy in terms of safety from alternating or switching between the use of the biosimilar product and the reference product is not greater than the risk of using the reference product without such alternation or switch, is one of the three requirements for interchangeability designation in the statute. The data from these clinical switching studies was likely one of the reasons some patients and HCPs perceived interchangeable biosimilar products to be superior to biosimilars without the designation. Surely, one must be learning more through these additional studies, otherwise why do them [12]?

FDA originally expected that the data and information acquired from switching studies would be useful in assessing the risk, in terms of safety and diminished efficacy, of alternating or switching between the products. Afterall, it seems reasonable on first pass, that a clinical question is best answered with clinical data. This, however, is not the case when clinical studies are so insensitive compared to analytics and function tests in vitro [13, 14].

FDA updated their guidance on the need for comparative clinical study for biosimilars or interchangeable product starting with insulin in the Fall of 2019 with their publication ‘Clinical Immunogenicity Considerations for Biosimilar and Interchangeable Insulin Products’ [15]. In this draft guidance, FDA specified that the comparative clinical switching studies would not be necessary for proposed interchangeable insulin products because there is a very low residual uncertainty regarding immunogenicity and high similarity can be demonstrated based on comprehensive and robust comparative analytical assessment between the proposed interchangeable insulin product and the reference product.

Accordingly, Semglee®, the very first FDA-designated interchangeable biological in the US, referencing Lantus® (Insulin glargine), was approved in July 2021 without a clinical switching study. Subsequent to insulin, multiple products have been designated interchangeable by FDA without a clinical switching study; a decision apparently based upon low or known immunogenicity risk, or low systemic risk, from exposure – Lucentis® (ranibizumab) biosimilars (Cimerli® and Byooviz®), Stelara® (ustekinumab) biosimilar (Wezlana®), and Eylea® (aflibercept) biosimilars (Opuviz® and Yesafili®). FDA has released a draft guidance reflecting this evolved approach regarding the role of clinical switching studies in supporting the interchangeability designation [2].

Another area in which we have seen an evolution in FDA’s thinking concerns the label for the interchangeable biosimilar product. FDA initially recommend that the labelling for an interchangeable biosimilar include an interchangeability statement rather than a biosimilarity statement [16]. For the initially-approved interchangeable products, an interchangeable statement was to be included in the Highlights of the Prescribing Information with a footnote defining what it means to be an interchangeable product along with the following statement that the ‘Interchangeability of [INTERCHANGEABLE BIOSIMILAR’S PROPRIETARY NAME] has been demonstrated for the condition(s) of use, strength(s), dosage form(s), and route(s) of administration described in its Full Prescribing Information’.

FDA’s thinking has changed, as evidenced by the most recent version of the FDA’s draft guidance ‘Labeling for Biosimilar and Interchangeable Biosimilar Product’ [17]. FDA has recognized that the interchangeability designation and the interchangeability statement is not likely to be useful to the prescribers [3] as any physician can prescribe both biosimilar and interchangeable biosimilar products in place of the reference products with equal confidence that they are as safe and effective as their reference products. Consequently, FDA’s new recommendation on the labelling of interchangeable biosimilars now includes the same biosimilarity statement as the biosimilar product without the interchangeable designation. Since then, all the interchangeability statements have been removed from the labels for the interchangeable products. By removing the interchangeable statement from the label, it could also help prevent further subtle misleading promotional communication utilizing the interchangeability statement to distinguish interchangeable biosimilars from biosimilars without the interchangeability designation but also to demean any biosimilars without the designation in comparison to the reference product. The question does, however remain, why there is any biosimilar statement at all on the package insert, as the same reasoning for no difference between an interchangeable and a biosimilar, also applies between a biosimilar and its reference product [18].

While FDA’s thinking regarding interchangeability has evolved significantly over the recent years, some aspects still require clarification or remain entirely unaddressed. For example, the first interchangeable designation gets ­market exclusivity defined in specific statutory provisions in the BPCIA. These were originally intended to be an incentive to pursue the designation for those few products for which substitution was expected to be a consideration (essentially insulin, etanercept and adalimumab, the main Pharmacy Benefit of Part D biologicals in the US). However, when such market exclusivity begins, ends, and on what basis FDA is making these decisions is still obscure [19]. The first interchangeability exclusivity was expected to be granted once per reference product for the very first interchangeable biosimilar to a certain reference originator biological. Apparently, that is not FDA’s thinking today. The agency has given exclusivity specific to individual presentations, e.g. concentration and formulation. For example, more than one interchangeable Humira® (adalimumab) biosimilar has been given exclusivity based on the different presentations.

Given that this exclusivity blocks the designation for a subsequent biosimilar to the same reference product (but not the approval of such products as biosimilars), as a legal matter, the commercial implications for biosimilars sponsors are enormous. What does a provisional designation of interchangeability mean in practice? Such uncertainty is not good for further investments in biosimilars, and leaves biosimilars on the market that are interchangeable as a clinical matter but not as a legal one [3]. Moreover, the fundamental reason for granting the exclusivity, which is to compensate for additional investment, becomes more questionable especially when additional studies are not necessary [2].

Overall, in conclusion, it would appear that FDA is increasingly aware that the unique FDA provision for an interchangeability designation is neither helpful nor necessary. With more and more biosimilar products receiving the interchangeability designation, it is becoming clear that interchangeability is creating more confusion than contributing to improved access to biosimilars as originally intended. FDA does not have the authority to do away with the separate designation, but in the Agency’s technical advice to the US Congress, it has made clear that all biosimilars are necessarily interchangeable as a matter of regulatory science. This conclusion was a change proposed in the recent FDA 2025 budget proposal [20]. FDA could finally cut the longstanding gordian knot around the interchangeability designation by deeming all approved biosimilars as interchangeable with their single identified reference product. That would serve patients and their healthcare providers particularly well.

Funding sources

This research was funded by Samsung Bioepis Co Ltd.

Competing interests: JPP and GRW are employees of Samsung Bioepis Co Ltd.

Provenance and peer review: Not commissioned; externally peer reviewed.

Authors

Joseph P Park¹, PhD
Gillian R Woollett², MA, DPhil

¹Samsung Bioepis Co Ltd, 76 Songdogyoyuk-ro, Yeonsu-gu, Incheon 21987, Republic of Korea
²Samsung Bioepis US (SBUS), Washington, DC, USA

References
1. US Food and Drug Administration. Implementation of the Biologics Price Competition and Innovation Act of 2009 [homepage on the Internet]. [cited 2024 Aug 6]. Available from: https://www.fda.gov/drugs/guidance-compliance-regulatory-information/implementation-biologics-price-competition-and-innovation-act-2009
2. US Food and Drug Administration. Draft guidance for industry. Considerations in demonstrating interchangeability with a reference product: update [homepage on the Internet]. [cited 2024 Aug 6]. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/considerations-demonstrating-interchangeability-reference-product-update
3. Park JP, Jung B, Park HK, Shin D, Jun JA, Ghil J, et al. Interchangeability for biologics is a legal distinction in the USA, not a clinical one. BioDrugs. 2022;36(4):431-6.
4. Herndon TM, Ausin C, Brahme NN, Schrieber SJ, Luo M, Andrada FC, et al. Safety outcomes when switching between biosimilars and reference biologics: a systematic review and meta-analysis. PLOS ONE. 2023;18(10):e0292231.
5. Cohen HP, Blauvelt A, Rifkin RM, Danese S, Gokhale SB, Woollett G. Switching reference medicines to biosimilars: a systematic literature review of clinical outcomes. Drugs. 2018;78(4):463-78.
6. Barbier L, Ebbers HC, Declerck P, Simoens S, Vulto AG, Huys I. The efficacy, safety, and immunogenicity of switching between reference biopharmaceuticals and biosimilars: a systematic review. Clin Pharmacol Ther. 2020;108(4):734-55.
7. Cohen HP, Hachaichi S, Bodenmueller W, Kvien TK, Danese S, Blauvelt A. Switching from one biosimilar to another biosimilar of the same reference biologic: a systematic review of studies. BioDrugs. 2022;36(5):625-37.
8. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH harmonised tripartite guideline. Comparability of biotechnology/biological products subject to changes in their manufacturing process Q5E [homepage on the Internet]. [cited 2024 Aug 6]. Available from: https://database.ich.org/sites/default/files/Q5E%20Guideline.pdf
9. Guillen E, Ekman N, Barry S, Weise M, Wolff-Holz E. A data driven approach to support tailored clinical programs for biosimilar monoclonal antibodies. Clin Pharmacol Ther. 2023;113(1):108-23.
10. US Food and Drug Administration. BsUFA III Regulatory Research Pilot Program: Research Roadmap [homepage on the Internet]. [cited 2024 Aug 6]. Available from: https://www.fda.gov/media/164751/download
11. IQVIA. Biosimilars in the United States 2023-2027. Competition, Savings and Sustainability (Updated January 31, 2023) [homepage on the Internet]. [cited 2024 Aug 6]. Available from: https://www.iqvia.com/insights/the-iqvia-institute/reports/biosimilars-in-the-united-states-2023-2027
12. World Medical Association. WMA Declaration of Helsinki. Ethical principles for medical research involving human subjects. Fortaleza, Brazil [home­page on the Internet]. [cited 2024 Aug 6]. Available
from: https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/
13. Kirsch-Stefan N, Guillen E, Ekman N, Barry S, Knippel V, Killalea S, et al. Do the outcomes of clinical efficacy trials matter in regulatory decision-making for biosimilars? BioDrugs. 2023;37(6):855-71.
14. International Pharmaceutical Regulators Programme. Workshop summary report: increasing the efficiency of biosimilar development programs — reevaluating the need for comparative clinical efficacy studies. IPRP Biosimilars Working Group (BWG) [homepage on the Internet]. [cited 2024 Aug 6]. Available from: https://admin.iprp.global/sites/default/files/2024-07/IPRP_BWG_Final%20IPRP%20Scientific%20Workshop%20Summary%20Report_2024_0506.pdf
15. US Food and Drug Administration. Guidance document. Clinical immunogenicity considerations for biosimilar and interchangeable insulin products. November 2019. [homepage on the Internet]. [cited 2024 Aug 6]. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-immunogenicity-considerations-biosimilar-and-interchangeable-insulin-products
16. US Food and Drug Administration. Draft guidance. Biosimilarity and interchangeability: additional draft Q&As on biosimilar development and the BPCI Act. November 2020 [homepage on the Internet]. [cited 2024 Aug 6]. Available from: https://downloads.regulations.gov/FDA-2011-D-0611-0082/attachment_1.pdf
17. US Food and Drug Administration. Guidance document. Labeling for biosimilar and interchangeable biosimilar products. September 2023 [homepage on the Internet]. [cited 2024 Aug 6]. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/labeling-biosimilar-and-interchangeable-biosimilar-products
18. Samsung Bioepis. Labeling for biosimilar and interchangeable biosimilar products; Draft guidance for industry [Docket No. FDA-2016-D-0643] [homepage on the Internet]. [cited 2024 Aug 6]. Available from: https://www.regulations.gov/comment/FDA-2016-D-0643-0074
19. US Food and Drug Administration. Purple Book. Database of licensed biological products [homepage on the Internet]. [cited 2024 Aug 6]. Available from: https://purplebooksearch.fda.gov/
20. US Food and Drug Administration. FY25 Legislative proposals [homepage on the Internet]. [cited 2024 Aug 6]. Available from: https://www.fda.gov/media/176924/download

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