FDA's Biosimilar Playbook: Merging Biosimilarity with Interchangeability

Policy Impetus and Background 

Health care costs, including the therapeutic products used in patient care and treatment, remain a primary focus in the United States, and the costs associated with biologic products are no exception. Bipartisan policy efforts have sought to accelerate biosimilar approvals as a means, at least in part, to reduce drug prices. The market appetite for biosimilar products —development and use—has been influenced by the regulatory pathway these products face, among several other factors.  

For biosimilar products, FDA has historically required human clinical studies with efficacy endpoints to demonstrate biosimilarity and interchangeability with the reference product. An August 2025 study by the Eastern Research Group, Inc. ("2025 ERCI study") for the Department of Health and Human Services ("HHS") found that these requirements have increased biosimilar development time and costs and that the distinction between "biosimilar" and "interchangeable" has contributed to "poorer market uptake [of biosimilars] in the United States compared to [generic drugs]" by suggesting the two-tiered system correlates to perceived differences in safety/efficacy.  

FDA has been progressively moving to influence the speed with which biosimilars get to market. In October 2025, FDA entered a new chapter in such effort, stating that it is taking "significant action to make it faster and less costly to develop biosimilar medicines" and plans "to make it easier for biosimilars to be developed as interchangeable with brand-name biologics, helping patients and pharmacists choose lower-cost options more easily." As discussed in our recent Alert, "FDA Proposes to Remove Comparative Efficacy Studies to Accelerate Biosimilar Development," on October 29, 2025, FDA issued draft guidance ("biosimilarity draft guidance") proposing that clinical studies with efficacy endpoints (comparative efficacy studies or "CES") may not be necessary to demonstrate biosimilarity.  

This builds on FDA's June 2024 interchangeability draft guidance, which proposes that clinical switching studies between a reference product and a proposed biosimilar are generally no longer needed to demonstrate interchangeability. Both draft guidance documents focus on therapeutic proteins (e.g., monoclonal antibodies) and rely on the significant experience that FDA has acquired with biosimilars and the precision of modern analytical methods as bases for shifting away from the need to undertake human efficacy and switching clinical trials. 

FDA's Blurring of Biosimilar and Interchangeable Biosimilar Under the BPCIA 

The Biologics Price Competition and Innovation Act of 2010 ("BPCIA") created the biosimilar pathway and defines a "biosimilar" as a "biological product [that] is highly similar to the reference product notwithstanding minor differences in clinically inactive components" and for which "there are no clinically meaningful differences … in terms of the safety, purity, and potency of the product." 42 U.S.C. § 262(i)(2).  

An abbreviated Biologics License Application ("aBLA") must include, among other things, information demonstrating that the proposed biological product is biosimilar to a reference product based on data derived from: "(aa) analytical studies…; (bb) an assessment of toxicity…; and (cc) a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency in 1 or more appropriate conditions of use…." 42 U.S.C. 262(k)(2)(A)(i)(I). However, the statute also allows FDA to waive any of the data in clause (i)(I) it determines is "unnecessary." 42 U.S.C. 262(k)(2)(A)(ii). FDA relies on this authority to propose removing CES to demonstrate biosimilarity. Biosimilarity Draft Guidance at p. 1. 

In the biosimilarity draft guidance, FDA explains that modern analytical tools can more sensitively detect and characterize differences between a proposed biosimilar and its reference product, making CES generally unnecessary to show biosimilarity, particularly for therapeutic proteins. Consistent with that view, FDA indicates that when comparative analytical data show high similarity, a well-designed human PK similarity study and an immunogenicity assessment may be sufficient to evaluate whether there are clinically meaningful differences between the proposed biosimilar and the reference product. While CES may still be needed in limited cases—such as for intravitreally administered products, or where a comparative clinical study with a clinically relevant endpoint other than efficacy may be informative—the biosimilarity draft guidance makes CES the exception rather than the rule for therapeutic proteins.  

The biosimilarity draft guidance complements FDA's September 2025 final guidance, which discusses factors to consider in performing comparative analytical assessment to support a demonstration of biosimilarity to a therapeutic protein reference product.  

The BPCIA permits an interchangeability designation for biosimilars that meet additional statutory criteria, namely when the data in an aBLA is sufficient to demonstrate that: (i) the biosimilar can be expected to have the same clinical result as the reference product in any given patient; and (ii) switching between the biosimilar and the reference product does not present greater risk than using the reference product in terms of safety or diminished efficacy. 42 U.S.C. 262(k)(4). Historically, FDA recommended dedicated switching studies to support interchangeability. However, the interchangeability draft guidance reflects FDA's evolved thinking, stating that given the precision of current analytical methods and accumulated experience showing the risk from switching is insignificant, clinical switching studies are generally no longer needed to demonstrate interchangeability.  

Impact of Merging Interchangeability with Biosimilarity on Substitution and FIE 

If the two draft guidance documents are finalized as written—and recognizing that when finalized, guidance documents represent FDA's current thinking on a topic and that alternative approaches may be used if the approach satisfies the requirements of the applicable statutes and regulations—the requirements for demonstrating biosimilarity and interchangeability would for practical purposes be the same for at least therapeutic protein products. This makes FDA's proposal significant because of the advantages for a biosimilar being designated "interchangeable."  

First, an interchangeable designation "means that the biological product may be substituted for the reference product without the intervention of the health care provider." 42 U.S.C. 262(i)(3). Thus, pharmacist substitution, which is governed by state law, can more easily occur. With interchangeability enabling such substitution, there is an expectation of greater prescriber familiarity and comfort with biosimilar products. The U.S. Federal Trade Commission commented favorably that removing switching study expectations "would lower barriers to entry, simplify the approval process, help to dispel the false impression of separate safety and efficacy standards for interchangeables and other biosimilars, and foster increased competition in biologic marketplaces."  

Moreover, the 2025 ERCI study concluded that designating all approved biosimilars as interchangeable would materially increase expected net present value ("ENPV") and that eliminating CES "can lead to cost savings and an increase in lifetime ENPV in large markets." 

Second, the BPCIA provides exclusivity for the first approved interchangeable of a reference product. First interchangeable exclusivity ("FIE") bars FDA from approving another interchangeable for the earlier of one year after first commercial marketing or for defined periods (18 to 42 months after approval) depending on the status and outcomes of patent litigation. 42 U.S.C. 262(k)(6). However, this merging of biosimilarity with interchangeability could materially affect who secures FIE. Under the current framework—which recommends switching studies to demonstrate interchangeability but recognizes business or use-case reasons not to pursue the designation—FDA makes an interchangeability designation only if the applicant explicitly requests it in its biosimilar application. That request, in turn, defines the pool of applications eligible for FIE. However, this construct may soon change.  

In the press conference announcing these changes, FDA Commissioner Marty Makary stated that FDA believes "all biosimilars should be interchangeable," raising the possibility that FDA could begin approving biosimilars as interchangeable, irrespective of whether the applicant requests that designation. HHS Secretary Robert F. Kennedy, Jr. added that HHS will apply "the same procedure that is used for small molecule drugs" to biosimilars but excluded vaccines from the proposals to waive clinical studies because they lack placebo-controlled, randomized safety trials.  

If FDA does begin approving all biosimilars (other than vaccines) as interchangeable, FIE could shift from the first approved biosimilar that requested interchangeability to the first approved biosimilar to a reference product. This may result in companies altering their launch sequences of biosimilars or intensifying their development efforts for certain biosimilars as they race to be the first approved. Although reducing the clinical burden for biosimilars and approving them as interchangeables may encourage more biosimilar entries, FIE may end up delaying rather than accelerating access to the second and subsequent biosimilars for products that would not have requested an interchangeable designation.  

Commissioner Makary has stated that FDA plans to finalize both the biosimilarity and the interchangeability draft guidance documents within the first half of 2026 to further align the biosimilars pathway with the generics model. Despite these changes, biosimilars remain distinct from generics in important ways, and biologic-specific challenges will continue to influence development and market strategies. These considerations will be addressed further in the next installment of this series.