On Friday May 10, the FDA published the much-anticipated final version of the guidance document Considerations in Demonstrating Interchangeability with a Reference Product.  We did a general post here  and, while recognizing the final version is similar (highly similar?) to the previous draft from January 2017, a careful review (as outlined here) found several useful and potentially significant changes in the final guidance.

  • The final guidance is more definitive about the need for clinical studies to establish interchangeability. (However, was there ever really any question about this before?)
  • Section V.A.3, Totality of Factors to Consider in Assessing the Data and information Needed to Support a Demonstration of Interchangeability, no longer includes the absence of a meaningful “fingerprint-like” analytical similarity as a factor that would lead to a need for post-marketing data from the product’s use as a biosimilar to support a demonstration of interchangeability. (Presumably, any product with high structural complexity and whose reference product has a history of rare, life-threatening adverse events would need to include post-marketing safety data to support a proposal for interchangeability.)
  • The final guidance specifically states that the same bioanalytical methods should be used for testing PK and PD samples from the switching and non-switching arms of the clinical switching study. It also states that the validation of these assays should demonstrate that they perform similarly for both the proposed interchangeable product and the reference product.
  • The final guidance added a paragraph in Section VI.A.1 Study Endpoints stating that “In cases where PK and/or PD are not adequately sensitive endpoints (e.g., products with limited systemic exposure, or for which PD effects are not measurable), sponsors are expected to propose and justify selected endpoints other than PK or PD.”
  • Section VI.A.2.a Dedicated Switching Study Design adds the incidence of immunogenicity and its consequences as factors to consider when determining the subject sample size for a switching study. In addition, this section has been modified to specify the primary endpoints for a PK switching study for an intravenously administered drug to be AUCtau.  For a subcutaneously administered drug, AUCtau and Cmax should be co-primary endpoints.  With regards to PD studies, this section now includes a requirement for sponsors to propose appropriate margins and statistical analyses for their assessment.
  • In Section VI.A.2.b Integrated Study Design, the recommendation in the draft guidance for “continuing of the proposed product arm (non-switching proposed product arm) from the inception of the study, through the duration of the switching portion of the integrated study, to the completion of the study” has been removed from the final guidance.
  • Section VII, which was named Use of a U.S.-Licensed Reference Product in a Switching Study or Studies, has been renamed, Considerations Regarding the Comparator Product in a Switching Study or Studies. This renaming is a prelude to a significant change in the guidance.  While the draft guidance lays out the argument against using a non-U.S.-licensed reference product and strongly recommended that sponsors use a U.S.-licensed reference product in switching studies, the final guidance repeats the concerns with using a non-U.S.-licensed reference product, but opens the door a wee bit by saying that “FDA believes that when supported by adequate data and information, it may be reasonable to use a non-U.S.-licensed comparator in a switching study.”  Of course, the big question in this regard is, “what constitutes adequate data and information?”
  • Not too surprising is the culling down of Section VIII Considerations for Developing Presentations for Proposed Interchangeable Products. The draft guidance had a subsection of “General Considerations” and then went into great detail about threshold analyses for device components.  The final guidance has scrapped the details (as well as an Appendix on Comparative Human Factors Studies) and simply presents the general considerations and recommends that sponsors have early discussions with the FDA regarding their specific product presentation.

All in all, this final version provides greater clarity of the FDA’s expectations for the studies that sponsors will need to perform and the data that they will need to submit to their BLAs when requesting a designation of “interchangeable” with the reference product.  However, this field is still so new and still developing, and no guidance will eliminate the need for good communication with the Agency as a firm plans to move into this market.