USFDA Draft Guidance on Safety Labeling Changes: Streamlining Section 505(o)(4) Implementation

Sharan Murugan
Sep 21
3 min read

On September 19, 2025, the U.S. Food and Drug Administration (FDA) released its revised draft guidance, “Safety Labeling Changes—Implementation of Section 505(o)(4) of the FD&C Act,” updating the industry on requirements and procedures for making post-approval safety-related labeling changes (SLCs). This revision reflects statutory updates and FDA’s current procedures to ensure timely, effective communication of new safety information.

New Safety Information (NSI): Data from clinical trials, adverse event reports, literature, postmarketing studies, or other scientific sources revealing serious risk, unexpected serious risk, or reduced effectiveness not previously contained in the labeling.

Section 505(o)(4) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) authorizes the FDA to require application holders of certain drugs to make labeling changes based on new safety information (NSI) that becomes available after the drug's approval. This includes information related to serious risks, unexpected serious risks, or reduced effectiveness under prescribed conditions of use.

The provision applies to:

Prescription drug products with approved NDAs (New Drug Applications) under section 505(b).
Prescription drug products with approved ANDAs (Abbreviated New Drug Applications) under section 505(j), if the reference listed drug (RLD) is not currently marketed.
Biological products with approved BLAs (Biologics License Applications) under section 351 of the Public Health Service Act.

Section 505(o)(4) does not apply to nonprescription (over-the-counter) drugs or marketed unapproved drugs. It requires application holders to update labeling unless approval of the application has been withdrawn or the biologics license has been revoked.

When FDA identifies new safety information about serious risks or reduced effectiveness (such as via postmarketing studies, adverse event reports, or literature), the agency can mandate changes to product labeling.

FDA SLC Process: How It Works

1. Notification

FDA sends an SLC notification letter to all relevant application holders, describing the source and nature of the new information and the proposed labeling changes.
When multiple holders are impacted, the FDA coordinates simultaneous notification and discussions.

2. Applicant Response

Holders must submit, within 30 calendar days, either:
- A supplement with proposed labeling changes
- A detailed “rebuttal statement” if they do not agree with the need for changes

3. FDA Review & Discussion

If proposed changes match FDA's language, approval can occur swiftly (goal: within 45 days).
Alternative proposals or rebuttal statements prompt a discussion period (up to 30 days, extendable if needed), after which FDA will either approve changes or issue an SLC order.

4. SLC Order

If no agreement is reached or no response is received, the FDA can issue a formal SLC order, specifying the final text and requiring implementation via a “changes-being-effected” (CBE-0) supplement within 15 days.
SLC order letters are posted publicly.

5. Dispute Resolution

Application holders may appeal via the formal FDA dispute process, but must initiate this within 5 days of receiving the order.
Failure to comply can result in statutory violation, misbranding designation, civil penalties, or further enforcement.

Timelines & Transparency

Supplement or rebuttal must be submitted within 30 days of notification.
Labeling approval (if agreed) typically within 45 days.
Labeling changes must appear on the sponsor’s website within 10 days post-approval.
SLC order letters and approved labeling updates are posted on the FDA website; notification letters may be posted if public interest is high.

Enforcement

Failure to comply can result in severe consequences:

Civil monetary penalties (up to $250,000 per violation; $1 million total per proceeding)
Product seizure or injunction
Drug considered misbranded and prohibited from interstate commerce.

Stakeholders should review the full guidance and comment within 60 days of Federal Register publication. Staying compliant with SLC requirements ensures the safety of patients and the integrity of the U.S. drug supply.