The comment period for FDA’s draft guidance Considerations in Demonstrating Interchangeability With a Reference Product closed on Friday, May 19, 2017. Innovators, biosimilar makers, patients, healthcare providers and other stakeholders have weighed in on the long-awaited guidance. Interchangeable biosimilars, unlike other biosimilars, may be substituted for the innovator product without the intervention of the healthcare provider who prescribed the innovator product. FDA’s guidance for interchangeable biosimilars is thus particularly important to stakeholders. This post, Part I of a three-part series, provides an overview of the key provisions of the guidance. Parts II and III will focus on the comments from stakeholders and open issues.

FDA issued its interchangeability guidance in January 2017 shortly before the Trump administration took office. The guidance provides FDA’s current thinking on the data and information needed to demonstrate interchangeability in accordance with the Biologics Price Competition & Innovation Act of 2009 (BPCIA). While FDA approved the first biosimilar in March 2015 and issued its first draft guidance to industry on biosimilars in 2012, FDA had not addressed how it expects biosimilar makers to show that a product is interchangeable with an innovator product. In December 2015, AbbVie, an innovator company, filed a citizen petition requesting that FDA establish a standard for interchangeability determinations under the BPCIA. Though FDA denied AbbVie’s petition at the same time it released its guidance this January, inviting AbbVie to provide comments to the guidance instead, the guidance takes into account AbbVie’s proposals.

Statutory Framework

The BPCIA provides that an interchangeable product is a biosimilar that may be substituted for the innovator product (also known as a reference product) by a pharmacist without the intervention or permission of the health care provider who prescribed the reference product. 42 U.S.C. § 262(i)(3). For a biological product to be considered interchangeable, it must be “biosimilar to the reference product “ and “expected to produce the same clinical result as the reference product in any given patient.” § 262(k)(4). In addition, “for a biological product that is administered more than once to an individual”—as would be the case for a biologics used to treat any chronic condition—§ 262(k)(4) requires that “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.”

FDA’s Case-by-Case Approach

In its draft guidance, FDA says that the data and information necessary to support a demonstration of interchangeability needs to be determined on a case-by-case basis. According to FDA, a variety of product-dependent factors may determine what data and information is needed. These include a product’s structural and functional complexity, the extent to which analytical characterization addresses uncertainty regarding interchangeability, product-specific immunogenicity risk, and post-marketing data from the licensed biosimilar product.

Switching Studies for Interchangeability

FDA expects that a switching study or studies in one or more conditions of use will be needed for products that are intended to be administered more than once in order to satisfy the statutory requirement for interchangeable products. FDA explains that “[t]he main purpose of a switching study or studies is to demonstrate that the risk in terms of safety or diminished efficacy of alternating or switching between use of the proposed interchangeable product and the reference product is not greater than the risk of using the reference product without such alternation or switch.”

In its discussion of switching studies, FDA focused on immunogenicity concerns due to switching between a reference product and a proposed interchangeable product. FDA explains that the primary endpoint of a switching study should assess the impact of switching or alternating between the use of the proposed interchangeable product and the reference product on clinical pharmacokinetics and pharmacodynamics, as those assessments are most likely to be sensitive to changes in immunogenicity and/or exposure.

FDA also states that a switching study should begin with a lead-in period of treatment with the reference product, followed by a randomized two-arm period. The two-arm period has a switching arm, with switching between the proposed interchangeable product and the reference product, and a non-switching arm that continues to receive the reference product. According to the guidance, the switching arm is expected to incorporate at least two separate exposure periods to each of the two products (the reference and the proposed interchangeable products). In other words, FDA expects at least three switches. The last switch should be from the reference product to the proposed interchangeable product.

FDA further explains that, although using a non-U.S.-licensed reference product is generally acceptable for the purpose of demonstrating biosimilarity, “a non-U.S.-licensed comparator product generally would not be appropriate in a switching study.” The guidance states that “FDA strongly recommends that sponsors use a U.S.-licensed reference product in a switching study or studies.” This is consistent with the position FDA articulated in its first draft guidelines for biosimilars back in February 2012. The reason is that the reference product plays a different role in switching studies than it does it biosimilarity studies. In biosimilarity studies, the reference product is simply a control. In switching studies, by contrast, the question becomes whether one product will affect the immune system’s response to another product when the switch occurs. Because the goal of the switching studies is to determine interchangeability with a reference product available to U.S. patients, establishing interchangeability with a product not licensed in the U.S. or that is subtly different from the U.S. product may not achieve that goal.

The guidance provides that a single integrated two-part study could be used both to: (1) support a demonstration of biosimilarity—that is, to show no clinically meaningful differences between the reference product and the proposed product, and (2) evaluate the impact of switching between the reference product and the proposed product to determine interchangeability. For such an integrated study to be acceptable, following the time point for demonstrating biosimilarity between the two products, the subjects in the reference product arm should be further re-randomized into a non-switching arm and a switching arm.

Extrapolation for Untested Conditions of Use

As AbbVie had advocated in its citizen petition, FDA expects sponsors to submit data and information to show that the proposed interchangeable product can be expected to produce the same clinical result as the reference product in all of the reference product’s licensed conditions of use even if the biosimilar maker seeks approval for fewer than all conditions of use for which the reference product is licensed. FDA also recommends that the biosimilar maker seek licensure for all of the reference product’s licensed conditions of use.

FDA states, however, that the data and information needed to show that the interchangeable product “can be expected to produce the same clinical result as the reference product in any given patient” as set forth in the BPCIA “will likely not involve additional clinical studies other than those necessary to support other elements of demonstrating interchangeability.” Instead, FDA will allow extrapolation from data and information sufficient to demonstrate interchangeability in an appropriate condition of use to one or more additional conditions of use for which the reference product is licensed. The biosimilar maker must, however, scientifically justify extrapolating the data to support each additional condition of use by addressing, for example, the mechanisms of action in each condition of use and the immunogenicity risk of the product in different patient populations who may be taking the proposed product for different conditions of use.

Presentations for Interchangeable Products

Separately, the draft guidance states that the data and information needed to show interchangeability may be affected by the proposed product’s “presentation,” defined as the container closure system and/or delivery device constituent part of the product (such as a vial, pre-filled syringe, or an auto-injector). Generally the presentation must be the same for an interchangeable product as for the reference product, but a biosimilar maker intending to develop an alternative presentation should discuss its proposal with FDA.