Today, the U.S. Food and Drug Administration (FDA) published final guidance titled "Safety Labeling Changes — Implementation of Section 505(o)(4) of the Federal Food, Drug, and Cosmetic Act," implementing its authority under the Food and Drug Administration Amendments Act of 2007 (FDAAA). Due to what had been a protracted process of making label updates to reflect new safety information, this section of FDAAA granted FDA the authority to require NDA, BLA, and ANDA holders (but only where the NDA is no longer marketed) to make safety labeling changes. This guidance does not apply to over-the-counter drugs marketed under a NDA or ANDA, nor does it apply to marketed unapproved drugs.
FDA can only order label updates where it becomes aware of "new safety information," which is broadly defined as including any information derived from a clinical trial, an adverse event report, a postapproval study, peer-reviewed biomedical literature, data derived from the postmarket risk identification and analysis system, or any other scientific data deemed appropriate by FDA involving: (1) a serious risk or an unexpected serious risk associated with use of the drug that FDA has become aware of since approval of the drug or any associated risk evaluation and mitigation strategy (REMS); or (2) the effectiveness of the approved REMS for the drug obtained since the last assessment of the REMS.
In order to evaluate whether a safety labeling update should be required, FDA will form a multidisciplinary team to evaluate information that may be new safety information pulling appropriate resources from the Center for Drug Evaluation and Research (CDER). FDA expects that new information ordered to appear in labeling typically would appear in the following sections: Boxed Warnings, Contraindications, Warnings and Precautions, Drug Interactions, and Adverse Reactions. However, FDA states in the Guidance that changes to the Adverse Reactions section of the labeling but which would not impact other sections, such as Warnings or Precautions, typically would not trigger required safety labeling changes under this authority.
FDA notes in its Guidance that its use of this authority could include class labeling updates addressing new safety information. In addition, the Guidance states that label changes could necessitate changes to or creation of a Medication Guide or updates to REMS.
FDA will notify application holders of required changes via a "notification letter" which will outline: the source from which the new safety information was derived; a brief description of the new safety information (a serious risk or an unexpected serious risk associated with the use of the drug, or the effectiveness of the REMS); its 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 or as a changes-being-effected (CBE) supplement. After receiving a notification letter, application holders must respond within 30 calendar days with either a labeling supplement submission or a rebuttal response. If the changes reflected in the supplement are identitical to those FDA has ordered, a CBE-0 should be submitted, whereas if the proposed changes are not identical to those FDA has ordered, a prior approval supplement should be filed. Where application holders propose "acceptable" but modified wording, FDA expects to approve those supplements within 30 calendar days, otherwise FDA expects to negotiate acceptable rewording within the same 30 calendar days time frame. FDA also expects to take action on rebuttal statements within 30 calendar days and initiate a 30-day "discussion period" if the agency disagrees with the application holder's rebuttal. Within 15 days of the close of this discussion period, FDA can either agree that no update is warranted or use its authority to require and order the labeling change.
FDA expects that it will rarely have to order a labeling change after the close of a discussion period and expects application holders will cooperate in this process. Revised labeling reflecting the "new safety information" must appear on the company website within 10 calendar days of approval of the labeling supplement. FDA states in its Guidance that it understands it will take longer to update printed materials and states that it will issue further guidance outlining its expectations for acceptable time frames for executing printed material updates. Only notification letters that apply to more than one application holder (e.g., class labeling updates) will be posted on the FDA website.
Additional information can be found in FDA's Guidance document at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM250783.pdf. Application holders would be wise to carefully review and understand FDA's process outlined in this final Guidance.
Julie Tibbets is a partner in the Food, Drug & Device/FDA Practice of Alston & Bird LLP where she focuses her practice on advising manufacturers of drugs, biologics, and medical devices on marketing, medical affairs, and health care professional related matters and interactions. This publication is intended to be informational and does not constitute legal advice regarding any specific situation. This material may also be considered attorney advertising under court rules of certain jurisdictions. Julie can be reached at julie.tibbets@alston.com or at 202.239.3444.