New FDA draft guidance: Implications for simplifying interchangeability for biosimilars in the US

In its new draft biosimilar guidance for industry¹, the FDA is no longer recommending a repeated switch study to demonstrate interchangeability of biosimilars. Instead, the FDA will accept an assessment of why the comparative analytical and clinical data in the application or supplement shows that the switching standard outlined in section 351(k)(4)(B) of the Public Health Service Act has been met. Applicants with a pending biologics license application (BLA) for a proposed biosimilar can submit an amendment with such an assessment for interchangeability review. 

In this blog, we discuss how the FDA’s prior practices shaped the policy change regarding comparative data to support biosimilar switching.

Defining and determining biosimilar interchangeability  

Interchangeability of biosimilars is a concept unique to the US, introduced in the Biologics Price Competition and Innovation Act of 2009.² To grant interchangeable status, the FDA must determine that the biological product has not only been demonstrated to be biosimilar to its reference product, but in addition it can be expected to produce the same clinical result in any given patient as the reference product. If the biological product is administered more than once to an individual, it will only be deemed interchangeable if the risk (in terms of safety or diminished efficacy) of alternating or switching between the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch. To demonstrate this, FDA required a clinical study in patients to investigate repeated alternating switching between the biosimilar and reference product with equivalent PK at steady state as the primary objective. We previously noted that such switching studies are not a sensitive setting for the detection of differences in efficacy or safety.³  

The FDA’s rationale for performing these studies was that, theoretically, repeated switching could enhance the formation of anti-drug antibodies which could impact PK – although no evidence for this has been reported. Even if enhanced immunogenicity were to represent a risk, there would need to be an initial difference in immunogenic properties between the biosimilar and the reference product, which should be determinable during the initial biosimilar PK studies. Modern methods for detecting and characterizing anti-drug antibodies are extremely sensitive with a detection level well below the 100 ng/ml that the FDA guidelines quote as being the threshold for clinical relevance whereas using PK as a surrogate for immunogenicity is a rather blunt approach.⁴   

Herdon et. al. (2023) reviewed results from a total of 5,252 patients who were switched to or from a biosimilar and reference product. Safety data including deaths, serious adverse events, and treatment discontinuation showed no overall risk difference (95% CI ≥ -0.01, ≤ 0.01). Immunogenicity data showed a similar incidence of immunogenicity compared to those who were not switched, as was the case for safety data.⁵ 

Switching studies: Experience from FDA’s 13 interchangeable biosimilar approvals  

At the end of June 2024, the FDA had approved 56⁶ biosimilars of which 13 were approved as interchangeable; nine of these without clinical switching studies.⁷  

Initially, switching studies were performed on two adalimumab biosimilars^8,9 before their approval as interchangeable. A switching study was also undertaken on an insulin-glargine biosimilar¹⁰, although in this case, such a study was not considered necessary, and FDA subsequently approved another insulin-glargine biosimilar as interchangeable, along with two ranibizumab biosimilars without switching studies.¹¹ Since ranibizumab is administered into the eye, a pharmacokinetic switch study would not be feasible and therefore was not required to demonstrate interchangeability. In late 2023, FDA approved an ustekinumab biosimilar without clinical switching data, concluding that a switching study was not necessary to support a demonstration of interchangeability.¹² This was because the applicant had provided adequate data and information to support a demonstration that the risk in terms of safety or diminished efficacy of alternating or switching the ustekinumab biosimilar with US-Stelara was not greater than the risk of using US-Stelara alone. A further six of nine subsequent biosimilar approvals were approved as interchangeable, mostly without clinical switch data.  

Evolving regulatory policy on interchangeability  

In addition to no longer requiring switching studies to demonstrate interchangeability, the FDA has also revised its requirements for labeling interchangeable biosimilars. Whereas the FDA previously had specific standards for labeling of interchangeable biosimilar products, in September 2023 the Agency issued draft guidance¹³ no longer recommending that “labeling for interchangeable biosimilar products include an interchangeability statement.” Instead, the FDA now recommends that labeling for both interchangeable biosimilars and biosimilars include a “biosimilarity statement” to the effect that “PRODUCT X (monoclonal-xxxx) is biosimilar to INNOVATOR (monoclonal-yyyy)”. This is because FDA now considers it not necessary to describe the interchangeability standard as this is not required for informing the safe and effective use of the product to prescribing health care professionals.¹⁴ 

There is also a proposal for the reintroduction of the Biosimilar Red Tape Elimination Act, which recommends an amendment to the federal code that all biosimilars, upon approval, shall be deemed interchangeable.¹⁵ 

Next steps for biosimilar and biologics developers 

The FDA is accepting public comments on the new draft guidance on demonstrating interchangeability until August 20, 2024.  

To discuss your biosimilar development plans, please get in touch. Parexel’s Regulatory Consulting experts are always available to discuss your quality and clinical program and approach to optimizing your development¹⁶, as well as meeting interchangeability standards. 

References: 

1. Federal Register (2024, Jun 21). Considerations in Demonstrating Interchangeability With a Reference Product: 
   Federal Register: Considerations in Demonstrating Interchangeability With a Reference Product: Update; Draft Guidance for Industry; Availability [accessed July 4, 2024] 
2. U.S Food & Drug Administration (2016, Feb 12). Biologics Price Competition and Innovation Act of 2009: https://www.fda.gov/drugs/guidance-compliance-regulatory-information/implementation-biologics-price-competition-and-innovation-act-2009 [accessed July 4, 2024] 
3. Nick, C (2023, Sep 22). Assessing the need for comparative clinical trials in biosimilar development programs: https://www.parexel.com/insights/blog/assessing-the-need-for-comparative-clinical-trials-in-biosimilar-development-programs [accessed July 5, 2024] 
4. U.S Food & Drug Administration (2018, Feb 22) Immunogenicity Assessment for Therapeutic Protein Products: Immunogenicity Assessment for Therapeutic Protein Products | FDA [accessed July 5, 2024] 
5. Herdon, T et all (2023, Oct 3). Safety outcomes when switching between biosimilars and reference biologics: A systematic review and meta-analysis: Safety outcomes when switching between biosimilars and reference biologics: A systematic review and meta-analysis - PMC (nih.gov) [accessed July 4, 2024] 
6. U.S Food & Drug Administration (2023, Nov 2) https://www.fda.gov/drugs/biosimilars/biosimilar-product-information 
7. U.S Food & Drug Administration (2024, July 1). FDA Approves Interchangeable Biosimilar for Multiple Inflammatory Diseases: FDA Approves Interchangeable Biosimilar for Multiple Inflammatory Diseases | FDA [accessed July 9, 2024] 
8. Boehringer Ingelheim (2023, Sep 19): Switching Study Evidence | Cyltezo® (adalimumab-adbm) (boehringer-ingelheim.com) [accessed July 9, 2024] 
9. Sandoz, a Novartis Division. HYRIMOZ® ADACCESS Study [accessed July 9, 2024] 
10. Matli, M (2023, Mar 17). The First Interchangeable Biosimilar Insulin: Insulin Glargine-yfgn. Journal of Diabetes Science and Technology. The First Interchangeable Biosimilar Insulin: Insulin Glargine-yfgn - PMC (nih.gov) [accessed July 9, 2024] 
11. Niazi, S (2023, Nov 20). BioRationality: FDA Publishes Results of First Meta-Analysis to Conclude All Biosimilars Are Interchangeable. The Center for Biosimilars. BioRationality: FDA Publishes Results of First Meta-Analysis to Conclude All Biosimilars Are Interchangeable (centerforbiosimilars.com) [accessed July 10, 2024] 
12. Center for Drug Evaluation and Research. (2022, Oct 31). BIOSIMILAR MULTIDISCIPLINARY EVALUATION AND REVIEW: accessdata.fda.gov/drugsatfda_docs/nda/2024/761285Orig1s000,761331Orig1s000MultidisciplineR.pdf [accessed July 10, 2024] 
13. U.S Food & Drug Administration (2023, Sep 18). Labeling for Biosimilar and Interchangeable Biosimilar Products: Labeling for Biosimilar and Interchangeable Biosimilar Products | FDA [accessed July 4, 2024] 
14. Yim, S (2024, Jan 16). Updated FDA Labeling Recommendations for Biosimilar and Interchangeable Biosimilar Products: Updated FDA Labeling Recommendations for Biosimilar and Interchangeable Biosimilar Products | FDA 
15. Nick, C and Duda, B (2023, Aug 29). Simplifying Interchangeability for Biosimilars in the US: https://www.linkedin.com/pulse/simplifying-interchangeability-biosimilars-us-parexel/?trackingId=YO1iK9RVTrOZ2BesUYLbVA%3D%3D [accessed July 4, 2024] 
16. Nick, C. (2024). Streamlining biosimilar development based on 20 years’ experience. Expert Opinion on Biological Therapy, 1–11: https://doi.org/10.1080/14712598.2024.2314612 [accessed July 9, 2024] 

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