FDA Requirements for URRA Revisions in BLA and NDA Reviews

By Rhizome Team

Use-Related Risk Analysis (URRA) documents are critical components of drug and biologics applications, providing systematic evaluations of risks associated with product use. The FDA regularly reviews these documents as part of their comprehensive assessment of new drug applications (NDAs) and biologics license applications (BLAs).

Understanding when and why the FDA requires revisions to URRA submissions helps manufacturers prepare more robust risk analyses and anticipate potential regulatory feedback. This insight enables companies to proactively address user interface risks and human factors considerations before they become regulatory obstacles.

Here we examine documented instances from recent FDA reviews where revisions to URRA submissions were explicitly required, providing practical guidance for manufacturers preparing their own use-related risk analyses.

Want to read the citations or ask Rhizome a follow-up question? Schedule a call

Has the FDA or DEMPA every required revisions to a URRA as reported in a BLA or NDA review in the last five years?

Answer

Comprehensive Answer:

Yes, the FDA has required revisions, clarifications, or updates to Use-Related Risk Analyses (URRAs) as reported in Biologics License Application (BLA) and New Drug Application (NDA) reviews within the last five years. Multiple documented cases demonstrate that the FDA—often through the Division of Medication Error Prevention and Analysis (DMEPA)—has requested applicants to revise, update, or clarify their URRA submissions during the regulatory review process. However, some sources note that in certain cases, the FDA only requested clarification or confirmation rather than explicit revisions. There are no documented instances in the provided sources of the European Medicines Agency (EMA) or DEMPA (if distinct from DMEPA) requiring such revisions.

Key Examples:

  1. DUVYZAT (givinostat hydrochloride, NDA, 2023):

    • The FDA issued an Information Request (IR) specifically asking the applicant to submit an updated URRA categorizing each task as critical or non-critical. The applicant responded with an updated URRA, demonstrating a clear requirement for revision during the NDA review process 19.

  2. SELARSDI (ustekinumab-aekn, BLA, 2024):

    • The FDA stated they were "unable to fully review your URRA" and requested a table specifying revisions made to the URRA, including reasons and impacts. The applicant provided the requested documentation, indicating a requirement for clarification and documentation of URRA revisions 1.

  3. RYKINDO (risperidone, NDA, 2024):

    • The FDA requested an updated URRA and additional detail regarding clinical harms associated with identified errors, requiring the applicant to revise and expand the URRA 3.

  4. AGAMREE (vamorolone, NDA 215239, 2023):

    • The FDA requested an updated URRA to include risk analysis for a specific Instructions for Use (IFU) statement. The applicant submitted the revised URRA, fulfilling the FDA's request 10.

  5. ZIMHI (NDA 212854, 2022):

    • After requesting a device modification, the FDA required the applicant to submit an updated and comprehensive URRA reflecting changes to the user interface, explicitly demonstrating a requirement for URRA revision 23.

  6. YESAFILI (BLA 761274, 2024):

    • The FDA discussed the need to request a URRA from the applicant due to changes in product classification and device component, indicating that URRA submissions or revisions may be required when product configurations change 21.

  7. XACDURO (sulbactam-durlobactam, NDA 216974, 2023):

    • The FDA requested clarification on whether the URRA and product user interface were identical between submissions. The applicant confirmed no changes; thus, no revision was required in this instance, but the process demonstrates FDA scrutiny of URRA content 1425.

  8. OMVOH (mirikizumab):

    • The FDA referenced previous URRA reviews and confirmed that recommendations were implemented, suggesting that URRA revisions or updates are a routine part of the review process when issues are identified 22.

  9. Trelstar (triptorelin pamoate, NDA supplement):

    • The FDA required submission of a comprehensive URRA as part of a postmarketing commitment, with the protocol subject to FDA review. However, in this case, the FDA ultimately did not require further revisions to the URRA 9.

Summary of Findings and Conflicting Interpretations:

  • Majority View: The FDA has, on multiple occasions, required applicants to revise, update, or clarify their URRA as part of BLA or NDA reviews, especially when product changes, deficiencies, or user interface modifications are identified 131019212223.
  • Clarification vs. Revision: In some cases, the FDA requested only clarification or confirmation (e.g., XACDURO, Trelstar), and did not require an actual revision to the URRA 91425. However, the overall evidence supports that revisions are sometimes explicitly required.
  • DMEPA Involvement: Where DMEPA is involved, their review often leads to requests for additional information, clarification, or revision of the URRA.
  • EMA/DEMPA: No evidence was found in the provided sources that the EMA or DEMPA (if distinct from DMEPA) required URRA revisions in the last five years.

References:
1 SELARSDI BLA Review (2024)
3 RYKINDO NDA Review (2024)
9 Trelstar NDA Supplement Review
10 AGAMREE NDA 215239 Review (2023)
1425 XACDURO NDA 216974 Review (2023)
19 DUVYZAT NDA Review (2023)
21 YESAFILI BLA 761274 Review (2024)
22 OMVOH Review
23 ZIMHI NDA 212854 Review (2022)

Conclusion:
The FDA has required revisions, updates, or clarifications to URRAs as part of BLA and NDA reviews within the last five years, particularly when product changes or deficiencies are identified. While some cases only involved clarification, there are multiple documented instances where explicit URRA revisions were mandated. No such requirements were documented for EMA or DEMPA in the provided sources.