For regulatory and human factors teams developing combination products, understanding how FDA reviewers engage with the Use-Related Risk Analysis is critical to planning realistic submission timelines and anticipating deficiency cycles. The URRA sits at the intersection of human factors engineering, medication error prevention, and labeling strategy, making it one of the more scrutinized documents in a drug-device or biologic-device application package.
This analysis reviews publicly available FDA review records from CDER and CBER to characterize how frequently and in what contexts DMEPA and human factors reviewers have required sponsors to revise or resubmit a URRA during BLA and NDA review actions over the past five years. The examples and patterns documented here are drawn from Drugs@FDA review packages across a range of combination product types and therapeutic areas.
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Has FDA (DMEPA) ever required revisions to a Use-Related Risk Analysis (URRA) in a BLA or NDA review? Yes, routinely.
Short answer
Yes. Across FDA drug and biologics review records from mid-2021 through mid-2026, FDA's human factors and medication-error reviewers repeatedly asked sponsors to revise, update, or resubmit the Use-Related Risk Analysis (URRA) as part of an NDA or BLA action. This is a common, documented review outcome for combination products (drug-device and biologic-device), not a rare event. The examples below are drawn directly from the review documents in Drugs@FDA and CDER/CBER review sets 124567891011.
A terminology note before the findings: "URRA" is FDA/CDER terminology. The division that owns this review is DMEPA, the Division of Medication Error Prevention and Analysis (Office of Medication Error Prevention and Risk Management, CDER). We read the question's "DEMPA" as DMEPA, since DMEPA is the group that authors the URRA assessments quoted here; the human factors deficiencies are also raised by CDER/CBER human factors reviewers. All instances located are FDA CDER/CBER review records.
What a URRA is and why it gets revised
A URRA is the sponsor's systematic analysis of the tasks a user performs with a product, the use errors or task failures that could occur, and the potential clinical harm from each. FDA reviewers use it to decide whether a human factors (HF) validation study is needed and to drive changes to the user interface, the device design, and the Instructions for Use (IFU). When reviewers find that hazards and risks do not align, that critical tasks are miscategorized, that a redesigned interface is not reflected, or that mitigations are not demonstrated, they ask the sponsor to update the URRA and, frequently, to run or repeat an HF study. Requests appear both in approval/advisory correspondence and in the human factors and medication-error review memos.
Documented instances (mid-2021 to mid-2026)
| Product | Application | Approx. approval date | What FDA asked regarding the URRA |
|---|---|---|---|
| Zimhi (naloxone HCl injection) | NDA 212854 | Oct 2021 | Submit an updated comprehensive URRA reflecting the redesigned user interface (addition of an automatically deploying needle safety element) 1 |
| Furoscix (furosemide, On-Body Infusor) | NDA 209988 | Oct 2022 | Update the Hazard Analysis and referenced risk documentation so hazards and risks align and each risk's mitigation is shown; discrepancy noted in the use-related risk analysis 2 |
| Ycanth (cantharidin topical) | NDA 212905 | Jul 2023 | Re-categorize tasks (previously called non-critical) as critical tasks in an updated URRA; add mitigations for the broken-ampule use issues and conduct an additional HF validation study 7 |
| Mekinist (trametinib oral solution) | NDA 217513 | Mar 2023 | Based on the URRA/HF study, revise IFU content (relocate/repeat oral syringe storage information; clarify disposal information) 10 |
| Hepzato (melphalan HCl, Hepatic Delivery System) | NDA 201848 | Aug 2023 | HF data did not support safe/effective use; provide root-cause analyses, implement mitigations, and update the use-related risk analysis 8 |
| Bimzelx (bimekizumab-bkzx, autoinjector/PFS) | BLA 761151 | Oct 2023 | Based on the URRA, revise IFU statements (increase prominence of the "second click" instruction; revise the complete-dose instruction) 9 |
| Entyvio Pen (vedolizumab) | BLA 761133 | Sep 2023 | Revise the user interface (device design, labeling, IFU) based on root-cause analyses of use-related issues, then submit another HF validation study 11 |
| Agamree (vamorolone oral suspension) | NDA 215239 | Oct 2023 | DMEPA recommended submitting an updated URRA and an HF study to address product settling after reconstitution and the risk of inconsistent dosing 6 |
| Winrevair (sotatercept-csrk) | BLA 761363 | Mar 2024 | Based on the URRA, revise specific IFU steps (vial bubble-check wording; air-draw figures/steps) 4 |
| Vyalev (foscarbidopa/foslevodopa) | NDA 216962 | Oct 2024 | Based on the URRA, omitted/incorrect critical tasks carry risk of loss of mobility or under/overdose; update the URRA if the interface is revised, and add labeling mitigations (e.g., alarm troubleshooting guide) 5 |
Selected detail
Zimhi (NDA 212854). In the approval action, FDA tied the URRA update directly to a required device change: "Modify your device to include an automatically deploying needle safety element to decrease the risk of needlestick injury... Submit your updated comprehensive use-related risk analysis (URRA) taking into consideration the changes to the user interface." 1
Furoscix (NDA 209988). Reviewers found the sponsor's hazard and risk analyses did not illustrate mitigation and did not align: "Your Hazard and Risk Analyses... do not clearly illustrate how you mitigate each of your risks. Please update your Hazard Analysis and other referenced risk documentation..." and "Please update your risk documentation to ensure your hazards and risks align." A discrepancy in the use error analysis (the use-related risk analysis) was specifically flagged for correction 2.
Ycanth (NDA 212905). FDA disagreed with the sponsor's task criticality classifications: certain tasks "should be re-categorized as critical tasks in your updated URRA," and, because the sponsor "did not propose any additional mitigation strategies to address the use issues (e.g., reducing the force required to break the ampule)," reviewers called for additional mitigations and a further HF validation study 7.
Agamree (NDA 215239). This is an explicit DMEPA-driven request: because the product could settle if not injected quickly after reconstitution, leading to inconsistent dose administration, "DMEPA recommended submission of an updated Use-Related Risk Analysis (URRA) and a Human Factors study to demonstrate that any proposed labeling changes adequately addresses this issue." 6
Winrevair (BLA 761363). Reviewers used the URRA to justify concrete IFU edits, for example revising the vial step heading to "Wait for bubbles in the vial to go away," and adding warning figures for the air-draw step "Based on the use-related risk analysis (URRA)..." 4
Vyalev (NDA 216962). The URRA framed the harm analysis ("Based on the URRA, if this task is omitted or not performed correctly there is risk of... loss of mobility"), and FDA instructed: "If your user interface is revised in response to the CR, you should update your use-related risk analysis (URRA)..." along with labeling mitigations such as an alarm troubleshooting guide 5.
The mirror image: URRA accepted, only the IFU revised
Not every review ends in a URRA revision. In some 2025 CBER reviews of injectable products, reviewers accepted the sponsor's URRA and justification and agreed no HF validation study was needed for licensure, asking only for targeted IFU edits ("Please revise your Instructions for Use to address this concern") rather than a URRA revision. This distinction matters: FDA will sign off on a URRA and still direct labeling changes, so a request to "revise the IFU" is not the same finding as a request to "revise the URRA."
Patterns worth noting for submission strategy
- The most common trigger is a change to the user interface or device constituent part. FDA's standing expectation is that any post-advice interface change is reflected in an updated URRA before the HF data determination is finalized 15.
- Task criticality disputes are a recurring flashpoint. If FDA disagrees that a task is non-critical, it will ask for the URRA to re-classify it, which can cascade into a new or repeated HF validation study 7.
- "Hazards and risks must align, and mitigations must be shown." A URRA that lists hazards without traceable mitigations is a documented deficiency 28.
- The URRA is the stated basis for IFU wording. Reviewers cite the URRA when directing specific IFU edits (step wording, figures, warnings, storage/disposal placement) 4910.
- Requests appear in multiple document types: approval/advisory letters, the DMEPA/medication-error review, and the human factors review, as well as multidiscipline review memos 278.
Scope and limitations
- Jurisdiction and terminology: "URRA" is FDA (CDER/DMEPA) terminology. This memo covers FDA NDA and BLA review records only; EMA and other authorities use human factors/usability engineering under IEC 62366 with different document names and were not the subject of this search. If you want a parallel look at EMA usability assessments or Health Canada/TGA human factors expectations, that is a separate query.
- Date window: results are limited to review records dated from July 2021 through the present (July 2026). Several products had earlier review cycles (for example, Ycanth had a prior action cycle), so a URRA revision request can predate the final approval date shown.
- Retrieval method: findings come from keyword and application-number searches of review-document text, then confirmed page-by-page against each product's own review PDF. Combination-product reviews share boilerplate URRA advisory language, so each quotation above was tied back to the specific product's review document rather than to generic template text.
- This is a representative, not exhaustive, list. The underlying corpus returns many more combination-product reviews containing URRA discussion; the ten to eleven products here are confirmed, clearly-worded instances.