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FDA Finalizes Guidance on Interchangeable Biosimilars


The FDA has released its long-awaited final guidance on demonstrating interchangeability of a biosimilar with its reference.

The FDA has released its long-awaited final guidance on demonstrating interchangeability of a biosimilar with its reference.

The guidance is intended to help biosimilar developers demonstrate that their products are interchangeable with a reference biologic for the purposes of submitting their marketing applications or supplementing them under the Public Health Service Act. A designation of interchangeability will allow a product to be substituted for its reference at the pharmacy level in the United States.

The guidance explains that the data and information needed to meet the legal standard for interchangeability, which shows that the proposed interchangeable product “can be expected to produce the same clinical result as the reference product in any given patient,” will vary by case. The required data may include:

  • Identification and analysis of critical quality attributes
  • Identification of analytical differences and an analysis of the potential clinical impact of such differences
  • An analysis of the mechanism of action in each condition of use
  • An analysis of differences in expected pharmacokinetics (PK) and biodistribution in different patient populations
  • An analysis of differences in expected immunogenicity risk
  • An analysis of differences in expected toxicity
  • Information on factors that could affect safety or efficacy

Data Considerations

Data and information should include a scientific justification as to why any differences detected do not preclude a demonstration of interchangeability. According to the guidance, data and information under the “can be expected to produce the same clinical result as the reference product in any given patient” legal standard are not likely to involve additional clinical studies (other than those that support other elements of demonstrating interchangeability).

The guidance also explains that, for products administered more than 1 time to a patient, the agency expects that data from switching studies in 1 or more conditions of use will be required to meet the legal standard that holds the application show that the risk of safety issues or diminished efficacy from alternating or switching treatments is not greater than the risk of continued treatment with the reference.

Notably, the interchangeable product’s sponsor does not have to seek interchangeability for all indications of the reference product, though the agency recommends doing so.

The kinds of data needed to support an interchangeability application will be influenced by a variety of factors, including product complexity and the extent of comparative and functional characterization. Clinical data required for products that have single targets may be fewer than those required for those products that act on multiple (or less defined) pathways. Structural features that impact patient response may also impact the extent of data needed.

Data sets with highly sensitive analytics or sequential analytical methods that can identify molecules with attributes like different charge variants or glycoforms, as well as a comprehensive assessment of the relationships between those attributes, can provide information that reduces uncertainty about interchangeability. The FDA says “These approaches could be of greater importance for more complex products because these products would have a larger number of attributes and thus a potential for greater uncertainty regarding interchangeability,” and says that advances in analytics could allow for analytical characterization that impacts the amount of data needed for an interchangeability demonstration. Other key issues will affect the data needed, including the product-specific immunogenicity risk; products that have known impacts on immune response may need more data.

The guidance does note that the FDA’s current thinking does not support using postmarketing data from already approved biosimilars—without corresponding data from prospective, controlled switching studies—to show interchangeability. “We generally would not expect postmarketing data to provide sufficient information related to the impact on clinical [PK] and pharmacodynamics (PD) of switching or alternating between the use of the proposed interchangeable product and the reference product, which we think are important study endpoint considerations.”

However, postmarketing data may be helpful in considering which data are needed to support a demonstration, and some postmarketing surveillance data from a biosimilar may be helpful in building the totality of the evidence for interchangeability.

Study Considerations

Switching studies to support interchangeability should evaluate changes in treatment that arise after 2 or more alternating switch intervals. If a sponsor does not think a switching study is necessary, the FDA expects a justification to be provided. Switching studies for products that would be administered only once would not usually be required.

The primary endpoint of the switching study should assess the impact of alternating between the products on clinical PK and PD, if available, as these are likely to be sensitive to detecting changes in exposure or activity. PD measures may be particularly useful as short-term, sensitive indications of potential impacts. The study should also assess safety and immunogenicity, while efficacy endpoints would be supportive. Samples from patients in different arms of the study should be assessed using the same assays.

Study Design

A dedicated switching study with a lead-in period of treatment with the reference, followed by a randomized 2-arm period (with 1 arm incorporating a switch and the other comprising continuous treatment) may be appropriate, but the sample size should be based on PK considerations. Additionally, intersubject variability in PD should be considered. The number and duration of switches should take into account the clinical consideration of the condition being treated, the dose of the product, and the duration of exposure that would be expected to cause concern.

Generally, the switch arm should incorporate 3 switches at a minimum, with each switch crossing over to the alternate product. The final switch should be from the reference to the proposed interchangeable. A comparative assessment should take place during the final exposure after a washout period of at least 3 half lives. To capture a full PK profile, intensive sampling should be performed during the final exposure period. The timing of PD and immunogenicity sampling will need justification.

In studies of intravenously administered drugs, AUCtau will be considered a primary study endpoint. For subcutaneous product studies, Cmax and AUCtau will be considered as co-primary endpoints.

For studies that have an integrated design that proposed to demonstrate biosimilarity and interchangeability at once, a 2-part design may be warranted. Following time points for evaluation of biosimilarity, subjects in the reference arm may be rerandomized in the second part of the study to a non-switching arm or a switching arm. Such a study would need to be powered to the appropriate endpoints, including PD and PK.

The population for these studies should be adequately sensitive to detect differences (and should be part of a license condition of use), and that population may be different from the one used to support licensure of the reference. If using healthy volunteers, sponsors should weigh the benefit and risks of exposing individuals to the product.

A product approved for more than 1 route of administration may be studied in the setting that will best allow for assessment of immune response and its potential to impact clinical performance.


In order for interchangeability to be extrapolated for additional indications, the sponsor will need to provide scientific justification that addresses the mechanism of action, differences in expected PK or biodistribution, differences in expected immunogenicity, differences in expected toxicity, or other factors that could affect safety and efficacy.

Comparator Products

Sponsors who want to use data from a switching study with an ex-US comparator product would have to provide bridging data between the US and ex-US reference products. The type and extent of the bridging data needed may be more extensive than is required for demonstrations of biosimilarity, the guidance indicates, because the different comparator products may have “subtle differences” in structural features, impurities, or formulation that are relevant in the context of switching.


The FDA encourages sponsors to communicate with the agency early on the topic of presentation, and notes that sponsors should generally not seek licensure for a presentation or device that is not licensed for the reference.

Postmarketing Safety Monitoring

Finally, postmarketing surveillance should consider safety or efficacy concerns associated with the reference or class, as well as the interchangeable product in its development or clinical use, condition of use, patient population, and patient exposure, and adequate pharmacovigilance must be in place.

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