FDA Updates Select Q&As on Biosimilar Regulation

September 22, 2021

The Food and Drug Administration (FDA) updated a final guidance and a companion draft guidance (the “first draft guidance”) providing answers to questions related to the agency’s regulation of biosimilar products and its interpretation of the Biologics Price Competition and Innovation Act of 2009 (BPCIA). In doing so, FDA finalized some of the Questions and Answers (Q&As) that were previously in the first draft guidance document and moved them to the final guidance document.

A second draft guidance document, which was issued in November 2020, has additional draft Q&As. FDA plans to finalize these Q&As when it concludes its review of the comments. The guidance also may be updated to include additional draft Q&As as appropriate. (For ease of reference, FDA retains the same numbering for these Q&As as they move from draft to final form (or vice-versa).) 

While many of the changes to the final guidance and first draft guidance were editorial or stylistic in nature, the following is a summary of the more substantive changes.

Revised Final Q&As

The following Q&As were already included in the previous version of the final guidance document but were revised in the updated version.

  • Q.I.4 asks whether a proposed biosimilar product can have a delivery device or container closure that differs from its reference product. The revised answer clarifies that some design differences may be acceptable, provided the differences would not result in a condition of use, dosage form, strength, or route of administration that differs from the reference product.
  • Q.I.8 asks whether a biosimilar sponsor can use comparative animal or clinical data with a non-U.S. licensed product to support biosimilarity testing. The revised answer includes a footnote explaining that FDA will also consider non-animal testing if such testing is suitable, adequate, validated, and feasible.
  • Q.I.17 asks when a proposed biosimilar applicant should submit an initial pediatric study plan (PSP). The revised answer clarifies that the Pediatric Research Equity Act (PREA) requires the PSP to be submitted before the applicant submits the required assessments or investigation.

Draft Q&As that Have Been Finalized

FDA transferred the following Q&As from the first draft guidance document to the final guidance document and incorporated some of the suggested changes it received during the relevant comment period.

  • Q.I.16 asks how a proposed biosimilar product applicant can fulfill the requirement for pediatric assessments or investigations under PREA. The revised answer includes a definition of “pediatric extrapolation” to clarify the distinction between extrapolation in the context of a proposed biosimilar product under the PHSA and extrapolation in the context of PREA. The final answer also explains that it is possible for a biosimilar applicant to fulfill PREA requirements for an indication that is not approved for pediatric use in the reference product but its labeling includes pediatric information by including the relevant pediatric information in the labeling for the biosimilar product.
  • Q.I.20 asks about the nature and type of information that a sponsor should provide to support a postapproval manufacturing change for a licensed biosimilar product. The answer explains that a sponsor should provide sufficient data and information to demonstrate the comparability of the biosimilar product before and after the manufacturing change, including analytical comparisons of the pre-change and post-change materials as well as comparisons of postchange material to historical analytical data. The guidance recommends that in-house reference standards be included in the comparability study but that additional reference materials may be included in certain cases. The revised answer explains that international reference standards and specific impurity reference materials are examples of additional information that may be provided in such comparison studies.
  • Q.I.21 asks whether a biosimilar sponsor may seek approval for a route of administration, dosage form, or strength that differs from that of the reference product. The answer was finalized without any substantive changes.
  • Q.I.22 asks whether a biosimilar applicant may seek approval for a condition of use that has not been previously approved for the reference product. While the answer to the question remains the same, the final answer also explains that the data that must be incorporated in the biosimilar product’s labeling will depend on whether the applicant is seeking licensure for all of the conditions for use licensed for the reference product.
  • Q.I.24 asks whether an applicant may submit data and information to support approval of a product for an indication for which the reference product has unexpired orphan exclusivity. Consistent with the draft answer, the revised answer states that an applicant should submit data and information to support an indication even if there is unexpired orphan exclusivity. The revised answer, however, states that FDA will not approve the proposed product for the protected indication, but it omits an important clause that was present in the first draft guidance: “until the orphan exclusivity expires.” This was likely a mistake in drafting.

Withdrawn Q&As

FDA withdrew the following two Q&As from the first draft guidance document.

  • Q.I.23 asked whether a biosimilar applicant could obtain a letter from FDA confirming that the applicant’s study protocols contain safety protections that are comparable to an applicable Risk Evaluation and Mitigation Strategy (REMS) for the reference product to enable the applicant to access the reference product for testing. FDA withdrew this question because it intends to issue a guidance document describing how its existing process for obtaining such letters will be aligned with the framework established by the Further Consolidated Appropriations Act, 2020,[1] which addressed this issue.
  • Q.II.1 asked how FDA interprets the category of “protein (except any chemically synthesized polypeptide)” in the amended definition of “biological product” in the Public Health Safety Act. FDA withdrew this question because it has issued a final rule on the definition for the term “biological product,” which includes a definition of “protein” for this purpose.[2]

Q&As that Remain in Draft

The following Q&A was included in the previous version of the first draft guidance document and remained unchanged in the updated version. The remaining draft Q&As from the previous version of the first draft guidance document were either finalized or withdrawn.

  • Q.I.12 asks how an applicant of a proposed injectable interchangeable product can demonstrate that it has the same strength as the reference product.

The following Q&As, which are in the second draft guidance document, remain in draft form and have not yet been revised.

  • Q.I.25 asks how an applicant can submit a biologics license application (BLA) for an interchangeable biosimilar product and whether FDA will approve an application as a biosimilar if the data and information support biosimilarity but not interchangeability.
  • Q.I.26 asks how a BLA holder should proceed if it seeks licensure of its product as biosimilar to or interchangeable with another reference biological product.
  • Q.I.27 asks for recommendations for labeling of interchangeable biosimilars.
  • Q.I.28 asks whether FDA recommends that an interchangeable biosimilar include a labeling statement on interchangeability.
Comments can be submitted to the docket FDA has established for these Q&A guidance documents.

[1] Pub. L. 116-94; 21 U.S.C. § 355-2.

[2] Food & Drug Admin., Final Rule, “Definition of the Term ‘Biological Product,’” 85 Fed. Reg. 10057 (Feb. 21, 2020); 21 C.F.R. § 600.3(h)(6).