FDA announced a new revised draft guidance which “is being updated and reissued in draft to, among other things, include the addition of information related to Congress’ 2018 changes to the definition of adverse drug experience regarding reduced effectiveness and make other changes to reflect current Agency processes and procedures regarding safety labeling changes. This draft guidance revises and, when finalized, will replace the guidance for industry entitled “Safety Labeling Changes—Implementation of Section 505(o)(4) of the FD&C Act” issued in July 2013.” It is interesting to note that “Section 505(o)(4) does not apply to nonprescription (over-the-counter) drugs regulated under the 54 FD&C Act or to marketed unapproved drugs.”

The revised guidance, which can be found here, addresses how, when and who must make the revised label changes.  FDA announces many new safety and labeling changes (SLC) frequently and posts them on the FDA website.  Those changes typically address new safety or efficacy changes that are made for products by NDA or BLA application holders.  Generic manufacturers are required to keep up with these changes and revise their drug product labeling according to the text provided in the announced NDA or BLA changes which are published by the Agency.

In addition, there are times when the NDA or BLA drug product have been withdrawn for reasons other than safety or efficacy  where the FDA will require ANDA applicants to make certain changes and FDA will notify the ANDA applicants of those safety labeling changes (SLCs) arising from current data received and evaluated by the FDA and mandate that the generic applicant make those changes.  The guidance identifies the specific step that the application holder (whether it be NDA, BLA or ANDA holders) needs to take to update their labeling to comply with the changes required.

The guidance also provides a new definition of new safety information as:

“information derived from a clinical trial, an adverse event report, a postapproval study (including a study under section 505(o)(3)), peer reviewed biomedical literature, data derived from the postmarket risk identification and analysis system under section 505(k); or other scientific data deemed appropriate by [FDA]” about: (A) A serious risk or an unexpected serious risk associated with use of the drug that [FDA] has become aware of (that may be based on a new analysis of existing information) since the drug was approved, since the risk evaluation and mitigation strategy [REMS] was required, or since the last assessment of the approved [REMS] for the drug, or (B) The effectiveness of the approved [REMS] for the drug obtained since the last assessment of [the REMS].”

In general, the FDA will provide information on a required SLC notification letter to all applicants in situations where the NDA or BLA has been withdrawn and there are approved ANDAs, or where FDA identifies a general safety label or efficacy change to NDA or BLA holders, when there are multiple applicants for similar therapeutic classes of products and where the change should be applied. The notification letter will contain:

  • The source from which the new safety information was derived, unless such information is the confidential commercial information of another application holder,
  • A brief description of the new safety information (e.g., a serious risk, or an unexpected serious risk associated with the use of the drug, or the effectiveness of the REMS),
  • Proposed labeling changes, and
  • Instructions regarding the circumstances in which the application holder should respond by submitting proposed labeling changes as a prior approval supplement (PAS) or as a changes being effected (CBE-0 supplement).

The guidance also includes information on:

  • How Should an Application Holder Respond to an SLC Notification Letter
  • How Will FDA Review the Required Labeling Supplement or Rebuttal Statement
  • How the Agency will review Labeling Supplements
  • SLC Actions and Time Frame
  • When Should New Labeling with SLCs Be Available

The guidance document also contains other enforcement information, potential fines for not adhering or not complying with required label changes and outlines procedures to take if there is disagreement with the Agency on the proposed changes that need to be made.