In September, the U.S. Food and Drug Administration issued Final Guidance entitled "Questions and Answers on Biosimilar Development and the BPCI Act: Guidance for Industry," and Draft Guidance entitled "New and Revised Draft Q&As on Biosimilar Development and the BPCI Act (Revision 2)."
The Final Guidance provides its Answers in final form, having been subject to the notice and comment requirements for FDA Guidances and originally promulgated as Questions and Answers on Biosimilar Development and the BPCI Act (April 2015) and New and Revised Draft Q&As on Biosimilar Development and the BPCI Act (Revision 2) (December 2018). The Answers are classified into three groups: biosimilarity or interchangeability; provisions related to the requirement to submit a BLA for a "biological product"; and exclusivity.
The Answers in the initial section of this Final Guidance on Biosimilarity or Interchangeability track the draft Guidance, involving sources of information regarding development programs for both biosimilar and interchangeable products (Question I.1), meetings with FDA (Q.I.2), formulation, delivery device or container differences (which "may be acceptable"; Q.I.3 and Q.I.4), and licensure for fewer than all administration routes, "presentations," or conditions of use (yes to all; Q.I.5, Q.I.6, and Q.I.7). Further Final Answers provide an extensive discussion of use of comparative animal or clinical data for non-U.S-licensed products (with a series of potential issues to be addressed and factors to be considered; Q.I.8), and specific answers on drug-drug interactions and cardiac delay studies (which may need to be addressed to the extent they were relevant to the reference product; Q.I.9). The Guidance also describes "how long and in what manner" samples of biological products should be retained in comparative clinical PK/PD studies (Q.I.10) and what is to be considered "publicly available information" regarding the information used to establish that a reference product is "safe, pure, and potent" and included in a 351(k) application (Q.I.13). Further subject to Final Answer status are the requirements for dosage forms for injectable biosimilars (distinguishing between an "injection" meaning in liquid form and "for injection" meaning a lyophilized powder; Q.I.18), the requirements for importing non-U.S.-licensed product for bridge studies (and whether a separate IND is required; Q.I.19), and the "nature and type of information" needed related to post-approval manufacturing changes for a licensed biosimilar product (Q.I.20).
In addition to these more general Questions, the Guidance includes Final Answers on requirements under the Pediatric Research Equity Act (Q.I.15, Q.I.16, and Q.I.17), and to the question of whether a biosimilar applicant can seek approval for an indication wherein the reference product has unexpired orphan exclusivities (Q.I.24) (and in this regard the Guidance in the Exclusivity section provides information for how a biosimilar applicant can determine whether a reference produce has any such unexpired orphan exclusivity by reference to FDA's Orphan Drug Product database; see "Search Orphan Drug Designations and Approvals"; Q.III.2).
Questions receiving a negative final answer include whether a biosimilar applicant can seek approval for an administration route, dosage form, or strength different from the reference product (Q.I.21) or a condition of use (Q.I.22).
Some questions did not receive final determinations; these include Q.I.11 (which had been withdrawn with a reference to Guidance entitled "Scientific Considerations in Demonstrating Biosimilarity to a Reference Product"); Q.I.12, which was published in "New and Revised Draft Q&As on Biosimilar Development and the BPCI Act (Revision 3)" (see below); and Q.I.23, which has been withdrawn with no further comment nor explanation. And some Questions have been superseded by other Guidances, such as the standards for establishing interchangeability (Q.I.14) (see "FDA Issues Final Guidance Regarding Biosimilar Interchangeability").
In Section II regarding questions relating to requirements for submitting a Biologic License Application for a biological product, the Guidance provides clarification concerning what FDA will consider the same product class (Q.II.2). For antibody-drug conjugates, the Guidance directs these compounds be submitted as a BLA (Q.II.3), citing section 503(g) of the FD&C Act, Transfer of Therapeutic Biological Products to the Center for Drug Evaluation and Research (June 30, 2003), available here; and Intercenter Agreement Between the Center for Drug Evaluation and Research and the Center for Biologics Evaluation and Research (October 31, 1991), available here. Question Q.II.1 was withdrawn regarding the meaning of the term "protein" during the transition period for drugs approved prior to March 23, 2010.
The final section of the Guidance concerns Exclusivity and permits an applicant for a BLA under section 351(a) to apply for reference product exclusivity under section 351(k)(7) (Q.III.1).
Despite being a "Final" Guidance, this one contains two Notices, the first surrounded by a black box stating:
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the title page.
Second, each page of the Guidance contains the label that it "Contains Nonbinding Recommendations."
Issued on the same day, the FDA provided a Draft Guidance (see above) that is limited to Question 12 from the Final Guidance and having an Answer to this Question:
Q.I.12 How can an applicant demonstrate that its proposed injectable biosimilar 145 product or proposed injectable interchangeable product has the same 146 "strength" as the reference product? (repeated from the December 2018 Guidance)
The Answer cites Section 351(k)(2)(A)(i)(IV) to the effect that a biosimilar applicant must demonstrate that the "strength" of a proposed biosimilar (or interchangeable) product is the same as the reference biologic product, based on data, and analytical similarity assessment. As in many prior Guidances, this one counsels that an applicant should discuss their approach with FDA prior to implementing it and provide an "adequate scientific basis" for their approach.
Specifically with regard to an injection-based product, the Guidance counsels comparison for "the same total content of drug substance" and "the same concentration of drug substance." Biosimilar drug products provided as bulk solids should contain information on the concentration of drug when constituted or reconstituted as an injection and that it is the same as for the reference biologic drug product.
As with other draft Guidances, this one contains the statement (surrounded by a black box) that:
This draft guidance, when finalized, will represent the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the title page.
And like the Final version of the Q&As, each page of the Guidance contains the label that it "Contains Nonbinding Recommendations."
