FDA Issued Draft Guidance on Interchangeability

BioSimilars Patent Dance

BioSimilars Patent DanceToday, the FDA announced the availability of a draft guidance on biosimilar interchangeability, entitled “Considerations in Demonstrating Interchangeability With a Reference Product,” which is currently available on FDA’s website.  The official announcement is scheduled to be published in the Federal Register tomorrow, January 18, 2017.

This guidance provides an overview of scientific considerations for demonstrating the interchangeability of a biosimilar product to its reference product, including the following highlights:

Data and information needed to support a demonstration of interchangeability.
Interchangeability requires a showing that a proposed product “can be expected to produce the same clinical result as the reference product in any given patient.”  Though the FDA recognizes that a sponsor may seek licensure for fewer than all conditions of use for which the reference product is licensed, FDA expects sponsors to submit data and information demonstrating interchangeability in all of the reference product’s (RP’s) licensed indications.  Moreover, the FDA recommends that a sponsor seek licensure for all of the reference product’s licensed conditions where possible.

The FDA will generally consider the totality of the evidence, including analytical similarity and risk of immunogenicity.  Interchangeability is considered along a spectrum, where products with low structural complexity may have low residual uncertainty regarding interchangeability due to high analytical similarity with a reference product, and thus may require less data.

For products used more than once, the FDA expects data from switching studies in one or more appropriate conditions of use; post-marketing data alone will generally not suffice.  However, post-marketing data may be useful in lowering residual uncertainty about interchangeability.

FDA will permit sponsors to extrapolate data and information supporting a demonstration of interchangeability in one condition of use to the remaining conditions of use for which the reference product is licensed.  Sponsors should provide sufficient scientific justification for extrapolating interchangeability data from one condition of use to others.

Considerations for the design and analysis of switching studies to support a demonstration of interchangeability.
Switching studies are generally required where a biological product is intended to be used more than once.  FDA advises sponsors intending to develop a proposed interchangeable product to meet with FDA to discuss their proposed product development plan. If a sponsor does not intend to conduct a switching study, the sponsor must provide a scientific justification.

According to FDA, appropriate endpoints for switching studies generally will be the impact of switching on clinical pharmacokinetics (PK) and pharmacodynamics (PD).  Switching studies also should consider the following: (1) study design and analysis, considering sample size, number and duration of switches, and PK, PD, and immunogenicity sampling; (2) study population (though not recommended, the FDA allows the use of different patient populations in a switching study, including healthy patients, where it is clinically and ethically appropriate to do so); (3) choosing a condition of use that would support subsequent extrapolation of data to other conditions of use; and (4) choosing a route of administration that best assesses a patient’s immune response.

Recommendations regarding the use of U.S.-licensed reference products in switching studies.
The FDA strongly recommends the use of a U.S.-licensed reference product in switching studies, even though biosimilarity may be established with a non-U.S. licensed comparator.  Because the goal for a switching study is to determine a biosimilar product’s interchangeability with a U.S.-licensed reference product, it would not be appropriate to establish interchangeability with a product that patients will not receive in the U.S.

Considerations for developing presentations, container closure systems, and delivery device constituent parts for proposed interchangeable products.
Because an interchangeable product may be substituted for the reference product without the intervention of a health care provider who prescribed the reference product, the sponsor should carefully consider the presentation of the product.

Where more than minor differences exist in the presentation of the product, the sponsor should consider conducting comparative use human factors studies, which assess any differences in the use error rate between the reference product and the proposed interchangeable product.  Considerations for such studies are provided in Appendix A to the guidance.

Comments on the draft guidance may be submitted to Docket No. FDA-2017-D-0154.  FDA will consider any comments submitted within 60 days of the draft guidance’s publication in the Federal Register before it begins working on the final version of the guidance.