Biosimilar Interchangeability: FDA Designation, Marketing Exclusivity, Guidance, and Future Trends

Since its introduction, the FDA’s biosimilar interchangeability designation has been a highly debated topic among healthcare industry stakeholders. Confusion regarding the interchangeability designation persists and the commercial impact is yet to be determined.

Still, the role of biosimilar interchangeability has the potential to change the accessibility of treatments for many diseases including cancers, diabetes, arthritis, psoriasis, neutropenia, retinal disorders, and more.

Thirteen biosimilars have received the interchangeability designation from the FDA, including two high-concentration, Humira biosimilars: Alvotech/Teva’s Simlandi and Sandoz’s Hyrimoz.

There have been several initiatives to eliminate barriers related to the FDA’s biosimilar interchangeability designation, including updated FDA guidance recommending that manufacturers remove the interchangeability designation from biosimilar labels.

Biologics and Biosimilars

Biologics are regulated by the FDA and are approved under the 351(a) pathway with a Biologics License Application (BLA).

A biosimilar is a biological product that is highly similar to, and has no clinically meaningful differences from, an existing FDA-approved reference product. Biosimilars are also approved via the 351(k) pathway.

Biologics that have biosimilars are often called the “reference product”. A biologic is approved based on a full evaluation of safety and efficacy data while a biosimilar is evaluated against the reference product to ensure that they are highly similar and have no clinically meaningful differences.

What is Biosimilar Interchangeability? 

According to the FDA, an interchangeable biosimilar product may be substituted for the reference product without consulting the prescriber, although this process is guided by state regulations. Interchangeability is not a clinical term, so the use of interchangeable biosimilars is not considered clinically advantageous over the use of biosimilars without the designation.

All states have legislation specific to interchangeability of biologic products. However, each state varies in the details regarding when substitution is permitted and defining how providers and patients must be notified when an interchangeable biosimilar has been used to fill a prescription. In some states, a biosimilar with an interchangeable designation from the FDA may be substituted at the point of sale without consulting the prescriber.  

Interchangeability is not as relevant for provider-administered biosimilars (e.g., those for the treatment of oncologic indications), as these products are typically obtained directly by the healthcare provider and are not dispensed by pharmacies.

Are Interchangeable Biosimilars Better than Biosimilars without the Designation? 

The same manufacturing quality standards apply to the reference biologics, biosimilars, and interchangeable biosimilars. Biosimilars, by definition, are highly similar to an FDA-approved reference product with no clinically meaningful differences between the biosimilar and the reference product. As such, interchangeable biosimilars are not considered clinically superior to biosimilars without that designation. In the U.S., interchangeability is a legal designation, not a clinical one.

In practice, biosimilars may be used in place of the reference product regardless of the interchangeable designation, because they are all highly similar. For example, the National Comprehensive Cancer Network indicates throughout its treatment guidelines that an FDA-approved biosimilar is an appropriate substitute for the reference product.

Biosimilar Interchangeability and Marketing Exclusivity

The Biologics Price Competition and Innovation Act (BPCIA) provides market exclusivity to the first interchangeable biosimilar product (first interchangeable exclusivity), which delays the FDA from granting the designation to other products for a specified time. The calculation of the first interchangeable exclusivity period is complex as it depends on the timing of specific events, such as the product’s approval and launch dates, and whether the product was involved in patent infringement litigation under the BPCIA. In certain circumstances, it is possible that the exclusivity period may expire even before the interchangeable product is launched.

The BPCIA specifically states that a subsequent interchangeable biosimilar may not be approved until the earlier if:

• 1 year after the first commercial marketing of the first interchangeable biosimilar biological product to be approved as interchangeable for that reference product;

• 18 months after:

  • a final court decision on all patents-in-suit in an action for patent infringement under subsection (l)(6) of the BPCIA that was instituted against the applicant for the first approved interchangeable biosimilar biological product; or

  • dismissal of such an action with or without prejudice; or

• 42 months after approval of the first interchangeable biosimilar biological product if the applicant for that product has been sued for patent infringement under subsection (l)(6) of the BPCIA and such litigation is still ongoing within such 42-month period; or

• 18 months after approval of the first interchangeable biosimilar biological product if the applicant for that product has not been sued under subsection (l)(6) of the BPCIA.

The FDA has indicated that it considers each reference product to be a particular combination of strength, dosage form, and route of administration, as noted in an October 2023 memorandum regarding FDA’s first interchangeable exclusivity determination for Cyltezo (Boehringer Ingelheim’s Humira biosimilar product, adalimumab-adbm). In that memorandum, the FDA focused on the application of different first interchangeable exclusivity periods to different strengths of Cyltezo, depending on when each strength received an interchangeability designation.

The potential impacts on first interchangeable exclusivity of the presentation of a biosimilar product, however, remain unclear. Presentation refers to the biosimilar product’s container closure system and any delivery device, such as a prefilled syringe, prefilled pen, or autoinjector. Notably, on April 5, 2024, the FDA approved prefilled syringes of Sandoz’s Hyrimoz (adalumumab-adaz) as interchangeable, but not autoinjectors of the same strength. The FDA has stated it plans to publish guidance on this issue by September 30, 2025.

FDA Guidance on Labeling and Switching Studies

In September 2023, the FDA released updated draft guidance on labeling for biosimilar and interchangeable biosimilar products. This guidance recommends that manufacturers remove the interchangeability designation from biosimilar labels and instead recommends the use of a “biosimilarity statement” for both biosimilar and interchangeable biosimilar products to emphasize that both are safe and effective.

This change is an attempt to educate healthcare professionals that both biosimilars and interchangeable biosimilars can be prescribed with the same confidence in safety and efficacy. The FDA also suggested that information about interchangeability would be more appropriately located in the Purple Book database of licensed biologics rather than the labeling.

In 2019, the FDA issued guidance that generally biosimilar products should have switching study data to be considered as interchangeable with the reference product.  However, no switching studies were necessary for several subsequently approved interchangeable biosimilar products, and the FDA granted the interchangeability designation based only on well-reasoned scientific justification.

On June 20, 2024, the FDA released updated draft guidance that removes switching study requirements for a biosimilar to be approved with an interchangeability designation. The updated FDA draft guidance permits manufacturers to instead choose to provide an assessment of why the comparative analytical and clinical data in the biosimilar application or supplement support that the switching standard set forth in section 351(k)(4)(B) of the Public Health Service (PHS) Act have been met. The FDA stated that since the publication of interchangeable guidance, for biosimilars approved to date, the risk of safety or diminished efficacy is insignificant following single or multiple switches between a reference product and a biosimilar product.

Case Study: Interchangeable Biosimilars to Lantus

Semglee, a biosimilar to Sanofi’s Lantus (insulin glargine), was originally FDA-approved in June of 2020 as a 505(b)(2) product under a New Drug Application (NDA) without interchangeability. In July 2021, Semglee (insulin glargine-yfgn) was approved as a biosimilar to Lantus with the interchangeable designation.

Semglee was the first approved interchangeable biosimilar in the United States. Biocon, Mylan, and Viatris, the co-manufacturers of Semglee, conducted the INSTRIDE 3 study to demonstrate that switching between Semglee and Lantus resulted in no meaningful difference in efficacy, insulin dose, safety, or immunogenicity. However, in its review of biosimilar Semglee, the FDA indicated that it did not consider the INSTRIDE 3 study design appropriate for purposes of demonstrating interchangeability because the study used hemoglobin A1c as the sole measure of efficacy.

The FDA stated that other sources of data and information submitted with the application were sufficient to demonstrate Semglee's interchangeability, although the switching study was reviewed to confirm that its results were consistent with conclusions based on the other sources. Although the study was completed, the FDA ultimately stated that it was not necessary for the interchangeability designation.

Eli Lilly’s Rezvoglar (insulin glargine-aglr), another Lantus biosimilar, was originally approved in December 2021, but Lilly delayed its launch until April 2023. In November of 2022, Rezvoglar was granted interchangeability, however, no switching study was conducted.

The FDA had stated that the information submitted as part of the BLA application adequately compared structural and functional characteristics of Rezvoglar to Lantus. Based on human pharmacokinetic and pharmacodynamic data that compared systemic exposure and glucose response rates along with a clinical immunogenicity assessment, the FDA determined that neither a clinical immunogenicity study nor a switching study were needed to support licensure of Rezvoglar as interchangeable to Lantus.

Biosimilar-to-Biosimilar Switching

An FDA guidance document indicated that, in the context of switching between products, multiple exposures to each product may potentially prime the immune system to recognize subtle differences in structural features between products.

Switching from a reference product to a biosimilar and vice versa, or from a biosimilar to another biosimilar has occurred in the real world. Thus far, there have not been widespread immunogenicity or safety concerns. However, there are limited real-world data to support biosimilar-to-biosimilar switching.

Payer Impacts

For payers, an interchangeability designation may be nice to have to facilitate pharmacist substitution, but it is not required when choosing a preferred biosimilar. This is because pharmacies are likely to communicate with a physician prior to any switch of a biologic, regardless of whether it is interchangeable or not. To date, formulary coverage has not consistently favored interchangeable biosimilar products and the interchangeability designation is not relevant to products covered under the medical benefit and obtained directly by the healthcare provider since pharmacist substitution does not occur.

Conclusion 

Since its introduction, the FDA’s interchangeability designation for biosimilars has been a controversial topic among healthcare industry stakeholders. Some believe this designation has hindered biosimilar adoption due to the misperception that noninterchangeable biosimilars are clinically inferior, and healthcare providers may wait for the interchangeable designation before prescribing biosimilars. For payers and pharmacy benefit managers (PBMs), the interchangeable designation for biosimilars may be preferable but not essential. To date, formulary coverage has not consistently favored interchangeable biosimilar products.

There has been movement by the FDA, as well as Congress, to overcome barriers related to the biosimilar interchangeability designation. Removal of the interchangeability designation may lead to an increase in biosimilar adoption, which could lower costs for patients.

However, the elimination of the interchangeability designation would have a significant impact on stakeholders across the healthcare industry and would require changes to current business practices in some cases. Physician confidence in biosimilars will need to increase substantially to reach a level similar to their current confidence in generics. Additionally, removing the interchangeability designation may impact how manufacturers negotiate pricing and offer rebates on biosimilars, which could affect formulary coverage of biosimilars and preferred product selection by payers and PBMs.

About IPD Analytics Biologic and Biosimilar Insights 

IPD Analytics tracks biologic and biosimilar approvals and launches in major markets across the globe. Pipeline monitoring and product forecasting including anticipated therapy cost, sales, and utilization are provided to help payers, providers, manufacturers, and other stakeholders keep up with this quickly changing market.

In addition, state and federal legislation on biosimilar interchangeability and substitution is closely monitored by our team of legal analysts, delivering key insights on changes coming to the biosimilar market landscape.

Learn more about how IPD Analytics helps payers, providers, and manufacturers in gathering insights and understanding these trends with our Life-Cycle Insights, Payer & Provider Insights, Market & Financial Insights, and Legislation & Government Insights platforms.