The US Food and Drug Administration (FDA) on Tuesday released for public consultation its long-awaited draft guidance detailing the agency's expectations for demonstrating biosimilar interchangeability.

The guidance, which was initially expected to be published before the end of 2015, recommends that sponsors looking to get a biosimilar approved as interchangeable with its reference product conduct one or more switching studies to show that patients can alternate between the two products safely and without diminished efficacy.

Background: Biosimilars and Interchangeability

While the US has lagged behind Europe in terms of approving biosimilars, FDA is beginning to narrow the gap and there are biologics approved in the EU as biosimilars that are not considered as such in the US.

Since 2015, the agency has approved four biosimilars under section 351(k) of the Public Health Service Act (PHS Act)—Sandoz' Zarxio (filgrastim-sndz), Pfizer's and Celltrion's Inflectra (infliximab-dyyb), Sandoz' Erelzi (etanercept-szzs) and Amgen's Amjevita (adalimumab-atto)—compared to more than 20 biosimilars that have been approved in Europe.

However, for both drugmakers and health systems, interchangeability is seen as a major benefit to biosimilar development, as section 351(i) of the PHS Act allows for interchangeable biosimilars to be substituted for their reference product at the pharmacy level.

Demonstrating Interchangeability

While the draft guidance focuses on presenting recommendations regarding the data and information needed to support interchangeability, as well as considerations for switching study design and analysis, FDA is clear that its requirements will vary based on the product submitted.

"There is no single data package that will work for all proposed interchangeable products," writes Leah Christl, associate director for therapeutic biologics in the Office of New Drugs at the Center for Drug Evaluation and Research (CDER).

As such, Christl says biosimilar sponsors should consult with FDA early on to discuss their plans to demonstrate interchangeability.

In the draft guidance, FDA discusses a number of these considerations. For instance, FDA says sponsors should consider an array of factors when determining the type and amount of data to support a demonstration of interchangeability, including product complexity and product-specific immunogenicity risk.

Additionally, FDA says sponsors should consider the "totality of factors" for their product to determine the amount and type of data that will be required to demonstrate interchangeability, and gives the following two examples:

• "Product A has relatively low structural complexity, has been demonstrated to have meaningful fingerprint-like analytical similarity to the reference product as 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 high structural complexity, has been demonstrated to be highly similar to the reference product as 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."

Switching Studies

According to FDA, switching studies should be designed to determine whether alternating between a biosimilar and its reference product two or more times impacts the safety or efficacy of the treatment course.

However, the agency notes that if the product is only intended to be administered once, sponsors may instead provide a justification for not needing to conduct a switching study.

"If an apparent difference in immune response or adverse events is noticed between the switching and non-switching arms of the study…it would raise concerns as to whether the proposed interchangeable product is interchangeable, regardless of whether the proposed interchangeable product or the reference product or the switching of the two products actually caused the event," FDA writes.

FDA also says that sponsors may use extrapolated data to support interchangeability for multiple indications if a sponsor is able to provide adequate scientific justification for doing so.

"Differences between conditions of use…do not necessarily preclude extrapolation," FDA writes. However, the agency says that sponsors should address any differences in relevant factors (mechanism of action, pharmacokinetics, pharmacodynamics, biodistribution, immunogenicity, toxicity) in their justification.

Contrary to its advice for conducting biosimilarity studies, FDA says that sponsors conducting switching studies should use a US-licensed reference product, as the reference product in a switching study plays a different role versus a biosimilarity study.

"Rather than being used only as a control, the comparator product is used in a switching study in both the active switching arm and the control non-switching arm," FDA writes. "Thus, using a non-US-licensed comparator product generally would not be appropriate."

According to FDA, "subtle differences" between biological products licensed in different regions could have an effect on patients' immune response. These differences, FDA says, create uncertainty as to whether the results of a switching study using a non-US-licensed reference product would hold true for a US-licensed reference product.

Presentations

FDA also says that sponsors should carefully consider their product presentation, including the delivery device and container closure system, as differences in presentation may affect FDA's determination of interchangeability.

In general, FDA says that sponsors should not try to get an interchangeable biosimilar approved with a different type of presentation than the reference product.

"For example, if the reference product is only marketed in a vial and a prefilled syringe, a sponsor should not seek licensure for the proposed interchangeable product for a different presentation, such as an auto-injector," FDA writes, noting that sponsors wishing to develop a different presentation should discuss doing so with FDA early on.

"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 than the reference product may raise uncertainty about whether the difference in presentations would impact the ability of end users, including patients or caregivers," FDA writes.

However, the agency says that not all differences in product presentation will have an impact on a product's use, and the draft provides sponsors with recommendations for conducting a threshold analysis for assessing the differences.

Draft Guidance: Considerations in Demonstrating Interchangeability With a Reference Product

Christl: From our perspective: Interchangeable biological products