On May 10, 2019, the FDA issued final Guidance titled, “Considerations in Demonstrating Interchangeability With a Reference Product,” the purpose of which is 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.” This final Guidance builds on the FDA’s January 2017 draft guidance of the same name and public comments submitted in response to that draft Guidance. Analyses of the draft Guidance and comments can be found here and here, respectively.

To be interchangeable with a reference product under the BPCIA, the biological product 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.” Further, “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.”

Like the 2017 draft, the final Guidance addresses the amount and type of data and information necessary to show interchangeability (including considerations relating to switching studies), the development of presentations for proposed interchangeable products, and postmarketing safety. The final Guidance, however, differs in several ways from the draft Guidance.

For example, 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 what data and information is likely to be needed to demonstrate interchangeability. Where 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 similar in nature and frequency to the reference product, then “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, additional postmarketing data for the product as a licensed biosimilar as well as a switching study may be required to demonstrate interchangeability 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.

The draft and final Guidance also differ regarding the identity of the appropriate comparator reference product to use in switching studies. Previously, the draft Guidance stated that “using a non-U.S.-licensed comparator product generally would not be appropriate” and that the “FDA strongly recommends that sponsors use a U.S.-licensed reference product in a switching study.” The final Guidance now outlines a path for using non-U.S.-licensed comparator products in a switching study. Specifically, a sponsor may use a non-U.S.-licensed reference product so long as it can provide “adequate data and information to establish a ‘bridge’ between the non-U.S.-licensed comparator and the U.S.-licensed reference product” to justify the relevance of the data obtained to a demonstration of interchangeability. But 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 FDA indicated that multiple exposures to each product in a switching study “may potentially prime the immune system to recognize subtle differences in structural features between products,” potentially increasing an overall immune response.

Regardless of the choice of comparator, for products intended to be administered to an individual more than once, the FDA views a switching study or studies as necessary in most instances to demonstrate interchangeable status. Both the draft Guidance and final Guidance are similar in this regard, with the final Guidance including an illustrative example of a switching study design. The Agency also provided more detailed information with respect to the safety and immunogenicity assessments that should be evaluated in a switching study.

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.

A more in-depth analysis of the FDA’s final guidance can be found here. Readers also are encouraged to read the final Guidance, also available on FDA’s website.