On May 10, 2019, the U.S. Food and Drug Administration (FDA) released nonbinding final Guidance for Industry, Considerations in Demonstrating Interchangeability With a Reference Product, that 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.” With the exception of some modifications discussed below, the final Guidance largely tracks the recommendations of the FDA’s proposed draft Guidance on interchangeability, released January 17, 2017.

An interchangeable product, under the BPCIA, must be (1) “biosimilar to the reference product” and (2) “expected to produce the same clinical result as the reference product in any given patient.” In addition, “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” cannot be “greater than the risk of using the reference product without such alternation or switch.” If deemed interchangeable, the approved biologic product “may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.”

Conditions of Use

The final Guidance notes the FDA’s expectation that “sponsors will submit data and information to support a showing 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,” and recommends that sponsors “seek licensure for all of the reference product’s licensed conditions of use when possible.” (Emphasis added.) As in the draft Guidance, the final Guidance continues to permit sponsors to provide justification of interchangeability of multiple indications from extrapolated data, provided that the risk of safety or diminished efficacy in the alternating products can be assessed.

Data and Considerations Supporting Interchangeability

The final Guidance addresses the following areas in a therapeutic protein interchangeable development program: (1) “data and information needed to support a demonstration of interchangeability”; (2) “considerations for the design and analysis of a switching study or studies”; (3) “considerations regarding the comparator product in a switching study or studies”; and (4) “abbreviated considerations for developing presentations, container closure systems, and delivery device constituent parts.”

The final Guidance first discusses the totality of factors impacting the type and amount of data and information needed for demonstrating interchangeability. These factors include structural complexity, the extent of structural and functional characterization, product-specific risks, and biosimilar post-marketing data. As with a biosimilarity determination, the FDA’s evaluation of these factors will determine the amount of additional evidence necessary. For those products that have already been licensed as biosimilar, “that licensure may be referenced to support a showing for this statutory criterion for demonstrating interchangeability.” Additionally, the Agency currently believes that meeting the “expected to produce the same clinical result” requirement “will likely not involve additional clinical studies other than those necessary to support other elements of demonstrating interchangeability.” (Emphasis added.)

Unlike the draft Guidance, the final Guidance no longer uses the term “fingerprint-like” to characterize the similarity between a proposed interchangeable product and its reference product. Instead, the FDA provided further detail in two examples to illustrate the data and information likely required to demonstrate interchangeability. In the first example, the proposed interchangeable product and the reference product have relatively low structural complexity, the reference product has no history of inducing severe immune responses, and the proposed interchangeable product, in clinical studies, has a low incidence of serious adverse immunogenic events that are similar in nature and frequency to those observed with the reference product. In this first situation, “sufficiently extensive comparative analytical data demonstrating high similarity to the reference product” and an “appropriately designed dedicated switching or integrated study” may be sufficient to demonstrate interchangeability. In contrast, where the proposed interchangeable product and the reference product have high structural complexity and the reference product has a history of rare, life-threatening adverse immunogenic events, postmarketing data in addition to a switching study may be required to demonstrate interchangeability.

Switching Studies

Interchangeable applications for a biological product that is administered more than once to an individual generally will be expected to “include data from a switching study or studies in one or more appropriate conditions of use” to show 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.” The final Guidance provides new, additional information with respect to the safety and immunogenicity assessments that should be evaluated in a switching study.

The draft and final Guidance further differ in their discussions of the appropriate comparator reference product for use in interchangeable switching studies. Previously, the draft Guidance emphasized that “using a non-U.S.-licensed comparator product generally would not be appropriate” and strongly recommended the use of a U.S.-licensed reference product in a switching study. The final Guidance softens this position by specifically contemplating the use of a non-U.S.-licensed comparator products in switching studies where “adequate data and information to establish a ‘bridge’ between the non-U.S.-licensed comparator and the U.S.-licensed reference product” is provided. That being said, the final Guidance cautions that the type and extent of such “bridging data” needed “may be different or more extensive than is needed in other contexts in which a non-U.S.-licensed comparator is used.”

The final Guidance also omits several sections of the draft Guidance directed towards considerations for developing container closure systems and delivery device constituent parts for proposed interchangeable products found in the earlier draft, including draft guidance on threshold analyses and comparative use human factor studies.