Dek: Sponsors should seek early discussions with FDA to ensure an effective and efficient process for demonstrating the interchangeability of a chosen biologic product.

On May 9, 2019, FDA issued final guidance, Considerations in Demonstrating Interchangeability with a Reference Product (1). This article provides a concise summary of the guidance, which is intended to assist sponsors in demonstrating that a proposed therapeutic protein product is interchangeable with a reference product for the purposes of submitting a marketing application or supplement under section 351(k) of the Public Health Service Act (PHS Act) (42 U.S.C. 262(k)) (2).

The terms interchangeable and interchangeability, as defined in section 351(i) of the PHS Act, mean that “the biological product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product”. To date, no such interchangeable products have been approved by FDA.

Section 351(k)(4) of the PHS Act provides that, upon review of an application submitted under section 351(k) or any supplement to such application, FDA will determine that the biological product is interchangeable with the reference product if FDA determines that the information submitted in the application or the supplement is sufficient to show that the biological product “is biosimilar to the reference product” and “can be expected to produce the same clinical result as the reference product in any given patient” and that “for a biological product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch”.

Factors impacting the type and amount of data and information needed

As a general principle, FDA intends to consider the totality of the evidence on a case-by-case basis. A stepwise approach is recommended for sponsors to generate data and information. This should allow the sponsor to raise questions and address uncertainty about how to demonstrate interchangeability at each stage of product development. Due to the complexity of the products covered by the new guidance, FDA recommends that sponsors meet with the agency early and often.

The current guidance provides several factors that may impact the type and amount of data and information needed to support a demonstration of interchangeability:

  • The product’s degree of structural and functional complexity may influence the extent of clinical data needed. For example, products that act on multiple targets, or act in less-defined biological pathways, or have certain structural features that are specifically expected to impact interchangeability may require more clinical data. For more complex products, it may be important to provide data sets that include highly sensitive analytics and sequential analytical methods. These data sets can identify molecules with different combinations of attributes and provide a comprehensive assessment of the relationships between attributes.
  • Clinical experience with the reference product and comprehensive product risk assessments may also affect the data and information needed to support a demonstration of interchangeability.
  • For products that have been previously licensed and marketed as a biosimilar, some post-marketing data is typically available from post-marketing surveillance and other post-marketing studies. Without corresponding data from the switching studies, post-marketing data alone is generally not sufficient to support a demonstration of interchangeability, but it may supplement the switching studies in certain situations. Post-marketing data may also be helpful as a factor when considering what additional data must be generated to demonstrate interchangeability.

Data and information needed to support a demonstration of interchangeability


To show that the product is biosimilar to a reference product, as required in section 351(k)(4)(A)(i) of the PHS Act, the sponsor can refer to its biosimilar licensure if there is one, or make a demonstration of biosimilarity, which would include, in part, a showing that the product meets the highly similar standard.

The data and information necessary to meet the section 351(k)(4)(A) standard may include: identification and analysis of critical quality attributes; analysis of the mechanism of action in each condition of use; analysis of any differences in pharmacokinetics and biodistribution in different patient populations; analysis of any differences in the immunogenicity risk in different patient populations; analysis of any differences in toxicities in each condition of use and in each patient population; and information on other factors that affect safety and efficacy.


FDA will generally expect a switching study or studies to support a showing for each of the statutory criterion in section 351(k)(4)(B) of the PHS Act. Sponsors should provide a justification if they believe that a switching study is not necessary for their product. For biological products that are not intended to be administered to an individual more than once, a switching study is generally not needed, although the focus of the current guidance is protein treatments that are typically administered recurrently.

A switching study or studies should evaluate changes in treatment that result in two or more alternating exposures (switch intervals) to the proposed interchangeable product and to the reference product. Design requirements of the switching study will be determined on a case-by-case basis. An example is depicted in the May 9, 2019 guidance (1).

Study endpoints. FDA recommends that the primary endpoints in a switching study should include a comparison of pharmacokinetic (PK) and/or pharmacodynamic (PD) parameters between the switching arm and non-switching arm following the final switch. Sponsors need to demonstrate the suitability of the PK and PD assays they develop. In cases where PK and/or PD are not adequately sensitive endpoints, sponsors are expected to propose and justify selected endpoints other than PK or PD measures. In addition to PK/PD, descriptive assessments of immunogenicity and safety are also expected.

A switching study may also incorporate the evaluation of efficacy endpoints, although they are generally not as sensitive as PK/PD endpoints.

Study design and analysis. The guidance discusses several considerations in the design of a dedicated switching study: sample size, which should generally be based on PK considerations; number and duration of switches; when to sample PK, PD, and immunogenicity; and study analysis.

If a sponsor is considering a single study to show both biosimilarity and interchangeability, then an integrated two-part study design may be appropriate. After the end of the first part of the study on biosimilarity, the subjects in the reference product arm should be re-randomized for the second part of the study on interchangeability. An integrated study needs to be adequately powered to evaluate both the endpoints for biosimilarity and interchangeability.

Study population. Sponsors should provide scientific justification to demonstrate that the study population for switching studies is adequately sensitive to detect the impact of switching. FDA generally recommends that sponsors use patients in switching studies. When considering using healthy subjects, the sponsor should weigh the benefit of exposing healthy subjects to the biologic products and the risk of having them develop antibodies, which may in turn preclude them from being able to receive the treatment in the future.

Conditions of use to be studied. A sponsor may obtain licensure only for a condition(s) of use for which the reference product is licensed. Sponsors should consider studying a condition of use that would support subsequent extrapolation of data to other conditions of use (e.g., to minimize the cost and duration of studies for other conditions where interchangeability is sought).

Route of administration. If a product is approved for more than one route of administration, sponsors should study the more immunogenic route (e.g., subcutaneous rather than intravenous), as this will better assess how a patient’s immune system response will impact the clinical performance of the product, including changes in safety risk and efficacy.

Non-US-licensed comparator. It is possible to use a non-US-licensed comparator in a switching study, as long as the sponsor supports the choice of comparator by providing adequate data and information to establish a “bridge” between the non-US-licensed comparator and the US-licensed reference product and thereby justify the relevance of the data obtained using the non-US-licensed comparator.

Extrapolation of data. If the proposed product meets the requirements for licensure as an interchangeable product for one condition of use, the sponsor may seek licensure for one or more additional conditions of use for which the reference product is licensed. To support the extrapolation of data, the sponsor needs to provide sufficient scientific justification addressing; for example, the following issues for the tested and extrapolated conditions of use: mechanisms of action; differences in PK, PD, and biodistribution of the product; differences in immunogenicity risk; differences in toxicities; and any other factors that may affect safety or efficacy.

Considerations for developing “presentations” for proposed interchangeable products

A product’s presentation typically includes, in addition to the active therapeutic protein, a container system and potentially a delivery device. A container system refers to the sum of packaging components that together contain and protect the dosage form. A delivery device is used as a medium or carrier for administering a pharmaceutical product to a patient.

A sponsor developing an interchangeable product generally should not seek licensure for a presentation for which the reference product is not licensed. However, a sponsor can discuss other possibilities with FDA.

As applicable, a general description of the presentation should be provided in the chemistry, manufacturing, and controls section of the application, including delivery device constituent part design and development information.

The sponsor should submit data and information supporting the appropriate use and performance testing of the delivery device constituent part of the proposed interchangeable product.

Post-marketing safety monitoring

Post-marketing safety monitoring for interchangeable products should account for the following features:

  • Any particular safety or effectiveness concerns associated with the use of the reference product and its class, the development and clinical experience with the proposed interchangeable product (if already marketed outside the United States), the specific condition of use and patient population, and patient exposure in the interchangeability development program
  • Adequate pharmacovigilance mechanisms.

FDA will require post-market safety surveillance on a risk-adjusted basis (3). FDA may also require a post-marketing study or a clinical trial to evaluate certain safety risks.


Through its guidance, FDA has provided much-needed general principles and factors to consider in determining what kind of data are needed to comply with the 351(k)(4) pathway. FDA has also identified certain specific features to consider in developing and presenting data to FDA when seeking approval for an interchangeable product. Given the complexity of biologic products and the distinct features contributing to the interchangeability assessment for different products, however, sponsors are still facing uncertainties that will need to be addressed on a case-by-case basis. Therefore, as the agency has repeatedly emphasized in its guidance, sponsors should seek early discussions and continue to work closely with FDA at every stage of the process to ensure an effective and efficient process for demonstrating the interchangeability of a chosen biologic product.