On January 17, 2017, the U.S. Food and Drug Administration released a nonbinding draft Guidance for Industry, Considerations in Demonstrating Interchangeability With a Reference Product, for comment purposes. This draft Guidance builds on the Agency's ongoing efforts to implement the Biologics Price Competition and Innovation Act (BPCIA) of 2009. The Guidance 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." This Guidance is the first that the Agency has provided on interchangeability and indicates the Agency's willingness to consider interchangeability, in certain and demonstrable circumstances. Similar to the biosimilar context, the Agency contemplates a product-specific approach that considers the totality of the evidence provided by a sponsor to assess the interchangeability of a proposed biologic product.

An interchangeable product, under the BPCIA, must be (1) "biosimilar to the reference product"; (2) "expected to produce the same clinical result as the reference product in any given patient"; and (3) "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 is not 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." Additionally, the Guidance notes the Agency'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 conditions of use of the reference product when possible. (Emphasis added.)

The 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) "recommendations regarding the use of a U.S.-licensed reference product in a switching study or studies"; and (4) "considerations for developing presentations, container closure systems, and delivery device constituent parts."

The Guidance first discusses the totality of factors impacting the type and amount of data-as well as information-needed for demonstrating interchangeability. These factors include structural complexity, product specific risks, and biosimilar post-marketing data. As with a biosimilarity determination, the Agency'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.)

The Agency believes that interchangeable applications will "include data from a switching study or studies in one or more appropriate conditions of use in order" to satisfy the third requirement for interchangeable status-"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 is not greater than the risk of using the reference product without such alternation or switch." The FDA notes that in the context of an interchangeability determination, the comparator product must be used in both the active and control switching arm, and thus, only a US-licensed comparator product should be used. The Agency also notes that sponsors may 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.

As an example, the Agency provides that a sample Product A, which has a low structural complexity, fingerprint-like analytical similarity to the reference product, and a low incidence of adverse events, would have a low burden to prove interchangeability. Therefore, data from a switching study alone may be enough to demonstrate interchangeability. As a counter example, Product B, which has a more complex structure, no fingerprint-like similarity, and known adverse effects, would have a higher burden under this nonbinding Guidance. Here, postmarketing data, in addition to switching studies and other evidence, may be needed for an interchangeability determination.

Comments to this draft Guidance will be due by March 19, 2017-60 days from the date of the proposed Guidance's publication in the Federal Register.