Biosimilars and interchangeable products
- The FDA was first authorized to develop a pathway for the approval of biosimilar products in 2010 under the Biologics Price Competition and Innovation (BPCI) Act. Biosimilars are biological products that are highly similar to a previously approved biological product and have “no clinically meaningful” differences relative to the original reference product. Because of the complexities involved in the production of biological products from living organisms, there are minor differences between a reference product and its biosimilars. Hence, they are similar, but not identical to, the reference product.
- Legally, the FDA’s finding that a product is biosimilar does not automatically imply that a product is “interchangeabile” with the product on which it is based. The FDA requires extensive testing to support the approval of a biosimilar product, including comparative clinical studies and other human research. For a biosimilar to be considered “interchangeable,” additional rigorous testing, which may include “switching” studies, is required.
- Interchangeable products are a subset of biosimilars that are demonstrated to produce the same clinical result as the reference product in any given patient. In practice, the biggest difference between interchangeable products and biosimilars are that pharmacists can substitute interchangeable biosimilars without consulting the prescriber (though different state laws may apply). Thus, switching studies must confirm that the biosimilar product is expected to produce the same clinical result as the reference product in any given patient, and that alternating or switching between the biosimilar and reference products will not cause any ill effects.
Regulatory context: Promotional labeling
- In general, the labeling for biosimilars and interchangeable products is expected to be similar—though not identical—to that of their reference products. For instance, it would be acceptable for a biosimilar’s labeling to differ from its reference product for the purpose of providing information necessary to inform its safe and effective use (e.g., regarding its administration, preparation, storage, or safety). In 2018, the FDA published a detailed guidance on labeling requirements for biosimilar products. It explained that products should be declared as biosimilar near the top of the Highlights of Prescribing Information section, with an asterisk to a specific, agency-provided statement explaining the meaning of “biosimilar.” The guidance also briefly explained how labeling should be handled for biosimilar products that are approved for fewer indications than the reference product. While FDA stated that biosimilar product labeling should generally not mention any indications that the reference product—but not the biosimilar product—are approved for in the biosimilar product’s labeling, an exception would be if necessary to ensure safe use. However, the 2018 guidance it did not offer advice for interchangeable product labeling.
- Similarly, the FDA published a Q&A-style guidance in early 2020 explaining how these concepts could be extended to the development of promotional labeling for biosimilar products. For context, while prescription drug products are required to comply with FDA’s regulatory requirements around labeling and approval (see 21 CFR 201), promotional materials and advertisements are regulated differently (under 21 CFR 202.1(1)(2)). For these types of materials, FDA’s Office of Prescription Drug Promotion (OPDP) is primarily concerned with ensuring that advertisements are not “false or misleading,” that they include important information about a product’s benefits and risks, and present information in a way that is comprehensible to its intended audience. Like the 2018 guidance, the Q&A on promotional materials did not indicate if or how the development of these materials might differ when it comes to interchangeable products.
- The FDA published recommendations for interchangeable products separately in a completely new guidance, issued two years later. The November 2020 document, entitled Biosimilarity and Interchangeability: Additional Draft Q&As on Biosimilar Development and the BPCI Act, clarified that, for the most part, labeling for interchangeable products should follow the same guidance proposed for other biosimilars. It also stated that no biosimilar or interchangeable products should include a description of or data from clinical studies conducted to support a demonstration of biosimilarity or interchangeability. Additionally, it provided specific “Interchangeable Product (IP)” language to be used in place of the “biosimilar” explainer language provided in the 2018 guidance. However, the guidance didn’t offer recommendations on promotional materials.
- Recently, in September 2023, the FDA released an updated draft guidance on labeling for biosimilar and interchangeable products, suggesting a dramatic change in approach. Among other changes, this guidance proposed eliminating the distinction between “biosimilar” and “interchangeable” in the product labeling. The draft guidance provided language stating that all products, whether biosimilar or interchangeable, be referred to as “biosimilar” on the product label, with a general definition explaining the term biosimilar. According to the document, the agency no longer recommends the use of the term “interchangeable” in any portion of the labeling, nor does it provide a definition for this term. [ Read AgencyIQ’s analysis of this guidance here.]
Today, FDA published a revised version of the Q&A guidance on promotional labeling.
- Today, FDA’s Office of Prescription Drug Promotion (OPDP) released a new version of its February 2020 Q&A draft guidance on the development of promotional labeling for biosimilar and interchangeable products. According to OPDP, the update is intended to fulfill an obligation made by FDA to issue guidance on this topic per the BsUFA III commitment letter. The Office also highlighted that the revised draft now includes “additional recommendations, an example of an interchangeable biosimilar product, and clarifying editorial changes.”
- The scope of the guidance has been adjusted slightly. To start, though the guidance previously offered additional context to sponsors regarding biological reference products and biosimilars, the updated draft also touches on advertising and promotional labeling for interchangeable biosimilars as well. As interchangeable products are a subset of biosimilars, the previous draft still mentioned that its recommendations applied to interchangeable products, however it lacked recommendations specific to interchangeable products only. In addition to describing FDA’s definition of an interchangeable product, the guidance newly adds that “Interchangeable biosimilar products may be substituted for the reference product without the intervention of the prescribing health care provider (HCP).”
- Secondly, the new draft shifts away from using the term “promotional materials” and now refers to “promotional communications” throughout. Whereas the phrase “promotional materials” carried a certain, tangible connotation; FDA’s subtle switch to the term “promotional communications” seems to more accurately encompasses the full range of promotional strategies used in the 21st century. In line with this change, the detailed explanations of what FDA considers to be “promotional labeling” and “advertisements” that were previously included in a footnote in the introductory section have been trimmed down. In particular, the guidance no longer comments on the potential intentions of sponsors in choosing to develop these materials. Likewise, the list of potential forms that advertisements might take (e.g., published in journals, magazines, other periodicals, or broadcast via radio, television, and telephone communication systems) has been omitted in the new copy, likely to signal flexibility in the application of these terms.
- There is one new Q&A included in the revised guidance on postmarketing reporting requirements. The newly added Question #9 specifically asks: “Are promotional communications for reference products and biosimilar products subject to postmarketing reporting requirements?” Yes, responds FDA. Sponsors should submit a completed copy of Form FDA 2253, plus any “specimens of mailing pieces and any other labeling or advertising devised for promotion of the reference product or biosimilar product” at the time of its initial publication or dissemination. For additional advice on this topic, the guidance directs readers to FDA’s 2014 guidance on the submission of interactive promotional media for currently marketed products. Note: Even though FDA has newly addressed this issue in its own question, some of this advice was included in the answer for Question #8 (How can firms request FDA review of draft promotional materials for reference products and biosimilar products before their dissemination?).
- As a whole, the guidance emphasizes the importance of tying any information contained within promotional materials to the correct product. As was explained in the previous draft and has now been made clearer, each and every specific claim or study that is referenced in promotional labeling should be accurately connected to the product for which that specific information applies to. The reason for this is that “Correctly and specifically identifying the relevant biological product or products in promotional communications can help prevent presentations that are inaccurate because they attribute data or information to the wrong product,” the guidance states. Furthermore, “It can also help the audience identify which product or products are the subject of a particular presentation in a promotional communication.” Importantly, as promotional labeling might address a reference product, a biosimilar product, or collectively address some combination of biosimilar product(s) and/or reference product(s); it’s important that the applicable products be identified in each instance where new information is being provided within a promotional communication.
- Can information about a biosimilar product be included in promotional materials, even if it isn’t specifically included in the product’s actual FDA-approved labeling? Yes, the guidance confirms. It also provides an example of the types of information this might apply to: “studies that supported the demonstration of biosimilarity between the biosimilar product and the reference product.” If a sponsor wishes to include this type of information, the guidance states that the promotional communications should still adhere to the principles outlined in its 2018 guidance on medical product communications. While this topic was previously addressed in the same question and answer combination (Question #4), the information has been framed slightly differently in the new copy. As the previous wording was a bit hard to follow, it’s likely that the heavy edits made to this duo was intended to clarify FDA’s stance.
- Don’t disparage non-interchangeable products – or your biosimilar competition. As before, the FDA advises sponsors (Q&A #6) to maintain accuracy when preparing promotional materials. In addition to providing accurate information about the specific product being promoted, this also means avoiding making potentially inaccurate claims about other products. It clarifies, “When multiple products are licensed as biosimilar to and interchangeable with or biosimilar to but not interchangeable with the same reference product, promotional communications should avoid representing or suggesting that any of these products (i.e., the reference product, any interchangeable biosimilar product(s), or any non-interchangeable biosimilar product(s)) are less safe or effective than each other for their approved uses based on their licensure pathways.” It goes on to explain that promotional communications for a reference product should dually avoid “representing or suggesting that a biosimilar product is less safe or effective than the reference product because the biosimilar product has not been licensed as interchangeable with the reference product.”
- Product consistency: An interesting addition made to page 8 of the guidance is regarding manufacturing and product quality. As before, FDA notes that its decision to approve a biosimilar product means that the Agency has determined the product is “highly similar to the reference product” and that there are no clinically meaningful differences between the reference and biosimilar product “in terms of safety, purity, and potency.” The new draft adds that “It is both normal and expected for biological products to have minor differences between batches. This means that biologics generally cannot be copied exactly, and that is why biosimilar products may not be identical to their corresponding reference product.”
- Finally, as was mentioned in the Federal Register notice, the draft now provides an example of a scenario where promotional communications are being developed for an interchangeable product (but are used incorrectly). This example appears in the response to Question #7. This new example offers an example of a company promoting an interchangeable product. “Promotional communications for HILEZEO state that, unlike patients using OMPIRAM, patients using HILEZEO can be assured of HILEZEO’s safety and effectiveness because HILEZEO is licensed as interchangeable with CLAREXANT while OMPIRAM is not.” The FDA explains that this presentation would be misleading, as it suggests that, “because HILEZEO is licensed as interchangeable with CLAREXANT and OMPIRAM is not, HILEZEO is superior in safety and effectiveness to OMPIRAM.”
Looking ahead: What does the future hold for biosimilar and interchangeable products?
- In September 2023, the FDA surprised many by announcing its intent to eliminate the distinction between “biosimilar” and “interchangeable” in product labeling. By way of explanation for this shift in policy, the guidance stated that “It has become clear that an applicant may choose to submit a single 351(k) biologics license application (BLA) seeking to license both biosimilar and interchangeable biosimilar products. Draft labeling for such applications would need to address both biosimilar and interchangeable biosimilar products, and the status of a particular product within such a BLA can change over time, for example, as relevant exclusivities expire. Determining how to appropriately label such products and keep labeling up to date without causing undue confusion has proven challenging.” To address this issue, FDA stated its new recommendations would be a standard ‘biosimilarity statement’ to be included in the labeling for both interchangeable products and biosimilars. Information regarding interchangeability would remain available only in the Purple Book: Database of Licensed Biological Products.
- The reactions to this shift in policy were varied. Overall, most stakeholders acknowledged a general state of confusion and misinformation regarding biosimilars, most of which relates to a lack of clarity regarding the meaningful distinction between biosimilarity and interchangeability. In response, an array of arguments were made both for and against maintaining “interchangeability” as a unique regulatory distinction. [Read Agency IQ’s breakdown of the comments submitted here]
- What about FDA’s obligations per the Biosimilar User Fee Amendments of 2022 (BsUFA III) agreement? FDA’s September guidance was intended to fulfill a BsUFA III requirement to “publish draft guidance on labeling for interchangeable biosimilar biological products.” However, it ironically used the opportunity to instead, seemingly diminish the status of interchangeable products in comparison to other biosimilars. The same can be said for this new guidance, equally intended to fulfill a BsUFA III obligation for the FDA to “publish a draft guidance on promotional labeling and advertising considerations for interchangeable biosimilar biological products.” Despite adding in a two-sentence example on the application of FDA’s biosimilar promotional labeling requirements to interchangeables, the new guidance makes few recommendations regarding interchangeability, indicating that the FDA doesn’t intend to support companies hoping to make note of any perceived differences.
- Comments on the revised draft are requested by June 25, 2024.
Featuring prior research by Chelsey McIntyre.
To contact the author of this item, please email Rachel Coe.
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