FDA Releases Draft Guidance for Biosimilar Interchangeability

The FDA has released its draft guidance regarding biosimilar interchangeability, recommending that sponsors conduct 1 or more switching studies to demonstrate safety and efficacy in patients alternating between the 2 products, according to the Regulatory Affairs Professional Society.

However, requirements will vary based on the nature of the proposed interchangeable product, and may include an evaluation of data and information generated to support a demonstration of a biological product’s biosimilarity, according to the FDA.

The guidance provides an overview of important scientific considerations when demonstrating interchangeability with a reference product, the FDA stated. This includes data and information needed to support a demonstration of interchangeability; considerations for the design and analysis of a switching study, or studies, to support a demonstration of interchangeability; recommendations regarding the use of a licensed reference product in a switching study/studies; and considerations for developing presentations, container closure systems, and delivery device constituent parts for proposed interchangeable products.

The following product-dependent factors that may impact the data required to support a demonstration of interchangeability are as follows:

• Product complexity and the extent of comparative and functional characterization The FDA recommends sponsors use a stepwise approach to create data and information that address residual uncertainty about demonstrating interchangeability during product development. At each step, sponsors should evaluate the extent to which there is residual uncertainty, and also identify the next steps to address it.
• Product-specific immunogenicity risk Clinical experience with the reference product and comprehensive risk assessment may affect data needed to support biosimilarity.
• Totality of factors to consider in assessing the data and information needed to support a demonstration of interchangeability The factors need to be considered together to inform a consideration regarding residual uncertainty about data and information needed to support biosimilarity. The FDA provided the following 2 illustrative examples for sponsors to consider: “Product A has relatively low structural complexity, has been demonstrated to have meaningful fingerprint-like analytical similarity to the reference product as a part of demonstrating biosimilarity, and has a low incidence of serious adverse events related to immunogenicity. Here, data derived from an appropriately-designed switching study may be sufficient to support a demonstration of interchangeability.” “Product B has a high structural complexity, has been demonstrated to be highly similar to the reference product as a part of demonstrating biosimilarity but has no demonstration of meaningful fingerprint-like analytical similarity, and has known serious adverse events related to immunogenicity. Here, postmarketing data for the product as a licensed biosimilar, in addition to an appropriately-designed switching study, may provide additional data and information necessary to support a demonstration of interchangeability. The collection of biosimilar postmarketing data.”

According to the FDA, postmarketing data from drugs first licensed and marketed as a biosimilar without corresponding data derived from a switching study/studies, generally would be insufficient in supporting a demonstration of interchangeability. However, the agency does recognize certain circumstances where postmarketing data from a licensed biosimilar product may be a useful factor when considering the necessary data to support interchangeability.

In the context of demonstrating biosimilarity to a reference product, the FDA recommends that sponsors seek the use of data from animal or clinical studies comparing a proposed product with a non US-licensed comparator product to address.

In a switching study, however, the comparator product is used in both the active switching arm and the control non-switch arm, rather than being used only as a control.

“Thus, using a non-US-licensed comparator product generally would not be appropriate,” the FDA wrote.

The FDA strongly recommends sponsors use a US-licensed product in a switching study or studies, because of the subtle differences in levels of specific structural features between biological products licensed in non-US licensed areas. The agency warns that they could have an effect on a patient’s immune response. These differences have created uncertainty as to whether the results in a switching study using non-US licensed reference products would also be observed for a US-licensed reference product, according to the FDA.

When a product is being developed for licensure as interchangeable, sponsors should carefully consider their presentation, including the delivery device and the entire container closure system.

“For example, if the reference product is only marketed in a vial and prefilled syringe, a sponsor should not seek licensure for the proposed interchangeable product for a different presentation, such as an auto-injector,” the FDA wrote.

Sponsors seeking to develop a different presentation should discuss it with the FDA early on, because any differences could affect the determination of interchangeability.

“Because a proposed interchangeable product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product, a proposed interchangeable product with a differently designed presentation that the reference product may raise uncertainty about whether the differences in presentations would impact the ability of end users, including patients or caregivers, to appropriately use the proposed product,” according to the FDA.

The FDA recommends that sponsors use the threshold analysis to analyze the presentations to identify differences in design compared with the presentations licensed for the reference product.

If no differences are identified after the analysis, it is likely that additional data supporting the appropriate use by the end user will not be necessary. If differences are found, the sponsor should focus their efforts on whether the differences involve an external critical design attribute that could negatively impact the appropriate use by patient and caregiver end-user groups, according to the FDA. Furthermore, sponsors should seek to establish and categorize the differences.

The agency noted that not all differences in the presentations will impact product use, and that the draft simply provides sponsors with recommendations for conducting a threshold analysis in order to assess any differences.