Safety label guidance: Commenters want clarity, transparency, and assurances

Industry, patient groups, and academics seek more clarity from the US Food and Drug Administration (FDA) regarding its plans to require drug and biologic manufacturers to update their labeling after detecting safety signals. Several industry and research advocacy groups have written to the agency regarding a recent draft guidance that outlines its process for requiring safety labeling changes (SLC), asking for more details on how the agency arrives at its decisions and what information it will disclose publicly.

In September, FDA published a draft guidance outlining what safety information companies should include in their labeling if they detect serious safety issues post-approval. The guidance would update 2013 guidance on the same topic to include new authorities granted to the agency under the 2018 Substance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment for Patients and Communities Act (SUPPORT Act) (RELATED: Safety labeling: FDA proposes updated guidance on postmarket changes, Regulatory Focus, 18 September 2025).

The new law gave FDA additional authorities to require manufacturers of approved new drug applications (NDA), abbreviated new drug applications (ANDA), and biologics license applications (BLAs) to inform users about postmarket safety information. The updated draft guidance outlines what SLC manufacturers should include with certain products.

The Pharmaceutical Research and Manufacturers of America (“PhRMA”) wrote to FDA asking it to clarify language that the agency cannot use section 505(o)(4) to narrow product indications. The group expressed concern about proposed language in the draft guidance that SLCs may permit “new or revised language in any section of the Prescribing Information.”

"Narrowing an indication is, in effect, partially withdrawing the previously applicable approval of the approved drug," said PhRMA. "Congress has created a separate mechanism by which FDA must conduct such withdrawals: the section 505(e) process. If Congress intended to alter FDA’s ability to modify or withdraw indications, Congress would have amended section 505(e) directly.”

PhRMA emphasized that Congress expressly limited the SLCs to boxed warnings, contraindications, warnings, precautions, or adverse reactions, or new effectiveness information in the SUPPORT Act and did not state that it applies to indications as well. It noted that lawmakers did consider H.R. 5811, which would have given FDA the authority to require changes to indications, but ultimately rejected the proposal.

PhRMA also asked FDA to clarify what new information would trigger an SLC letter to manufacturers. It stated that the proposed language in the draft guidance is overly expansive and requested that the agency explicitly specify that such information must be both new and reliably related to a serious risk concern. It also requested more details on when serious risks from reduced effectiveness would trigger an SLC letter.

PhRMA stated that it is concerned that the process outlined by FDA for triggering an SLC letter may not provide sufficient opportunity for all parties involved to engage with the agency in situations where an SLC affects multiple application holders. It stated that it is concerned the agency removed language from its 2013 guidance and asked the agency to acknowledge that class labeling may not be appropriate in situations where there is a sound scientific basis for differential labeling of different drugs within a class.

The drug lobby group also asked FDA to clarify that it will not rigidly apply the SLC timelines to deny application holders an opportunity to engage with regulators when there are multiple applicants.

"Each application holder should independently decide whether to respond to the SLC with a labeling supplement or a rebuttal statement," said PhRMA. "Closing the discussion period automatically on the same date for all application holders disadvantages any application holder who chooses to exercise their statutory right to rebut the SLC notification, because that application holder necessarily has less time to prepare and submit a labeling supplement compared to application holders who file supplements.

"PhRMA is also concerned that applicants may be ordered to apply labeling changes based on a language drafted by one or more other application holders," the group added.

Another concern for PhRMA is that it says FDA changed several SLC timelines compared to the 2013 guidance without providing explanations. It lists four major changes, including the fact that the agency now states it will act on supplements that propose acceptable wording to the SLC and respond to rebuttal statements within 45 days, up from the previously stated 30 days in the guidance.

Furthermore, PhRMA requested that the FDA not publicly announce SLC notifications or orders until the statutory process has been completed.

"The Agency’s public announcement creates the appearance of finality, even if discussion between the application holder and the Agency is still ongoing," said PhRMA. "Additionally, a premature announcement causes unnecessary public confusion and reputational harm to the product if the Agency ultimately decides against ordering a labeling change.

"PhRMA is concerned that announcing SLC notifications or orders before the statutory process is complete undermines an application holder’s rebuttal and appeal rights under the FDCA and its due process rights; an application holder has no meaningful opportunity to respond, rebut, or appeal the Agency’s decision before FDA’s view that the labeling must change is announced to the world," said the group.

Furthermore, PhRMA asked FDA to revise the draft guidance to clarify how it designates confidential commercial information (CCI), said the agency should communicate with application holders before sending them an SLC notification letter, allow application holders to voluntarily trigger a 505(o)(4) process, asked that notification letters provide more than a brief description of new information, and clarify how it plans to address public health threat provisions.

The Association for Accessible Medicines (AAM) also commented on the guidance, noting that while it addresses biologics, it does not address biosimilars. The group said that FDA provides details for generic drug manufacturers that they would be notified if there is an SLC to the reference listed drug (RLD), as they would be required to make the same change within 30 days of the written notification. However, the group stated that having such a process for biosimilars would not only be contrary to Section 351 of the Public Health Service Act, but it would also create inefficiencies and confusion.

"While there is no statutory same labeling requirement, the biosimilar framework cannot be reconciled with the introduction into a biosimilar’s labeling of safety (including reduced effectiveness) information that is new or different from its reference product," said AAM.

"Instead, FDA should clarify in the final guidance that, like when a generic has a marketed RLD, FDA will inform the biosimilar manufacturer once the reference product labeling has been approved," the group added. "The biosimilar will then have 30 days to submit a Category A supplement, which would incorporate the relevant safety information from the reference product labeling."

The Yale Collaboration for Regulatory Rigor, Integrity, and Transparency (CRRIT) asked FDA to include a summary of the assessment that outlines why the agency determined that an SLC is required. The group said the summary would be like the Data Summary sections that the agency often includes in safety communications to detail the evidence it used to support its decision

"A similar approach would strengthen SLC notification letters," said the group. "Not all SLCs will result in an FDA safety communication, and even when such communications are issued, the level of detail made public can vary and sometimes is insufficient.

"Thus, incorporating a concise summary of FDA’s assessment directly into the SLC notification letter would meaningfully enhance transparency not only for application holders, but also for patients, clinicians, and the broader public who rely on clear, timely information about emerging safety information," it added.

CRRIT also raised concerns that it was unclear how FDA plans to use its existing surveillance system to evaluate potential safety signals and develop labeling changes based on the information. The group said its evaluation of the FDA Adverse Event Reporting System (FAERS) surveillance found that none of the regulatory actions for the safety signals were supported by a publicly accessible evaluation
of FDA's Sentinel Initiative.

"This gap underscores the need for clearer public documentation of how FDA interprets and weighs emerging safety information, thereby enabling clinicians and patients to make informed treatment decisions," said CRRIT. "Including a comprehensive summary of that assessment within the SLC notification letter would significantly enhance transparency and provide clearer insight into the basis for FDA’s determination."

CRRIT also asked FDA to provide public explanations for when it grants manufacturers an extension on the discussion period to implement an SLC and clarify when it cannot provide such an explanation. The group said the explanations would promote procedural transparency. Furthermore, while FDA has said it will not publish SLC notification letters because they may include commercially confidential information (CCI), the group encouraged the agency to publish the letters with CCI redacted to provide the public with more transparency.

"Earlier in the draft guidance, FDA specifies that such letters generally include the source of new safety information, a brief description of that information, proposed labeling changes, and instructions regarding how an application holder should respond," said CRRIT. "As this material is not inherently commercially confidential, these notification letters should be released publicly.

"Routine publication of SLC notification letters, with appropriate redaction of commercially confidential details, could improve transparency, facilitate academic and clinical research, and inform the public and other stakeholders about the basis for labeling revisions," the group added. "This would provide patients and clinicians with timely information around proposed changes from FDA regarding safe and appropriate use of therapeutics that would then inform clinical decision-making and patient choice."

Safety label guidance: Commenters want clarity, transparency, and assurances

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