Recently, the Food and Drug Administration (FDA) released a Guidance for Industry: “Safety Labeling Changes —Implementation of Section 505(o)(4) of the FD&C Act“. The guidance provides information on the implementation of section 505(o)(4) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355(o)(4)), which was added by section 901 of the Food and Drug Administration Amendments Act of 2007 (FDAAA). Section 505(o)(4) authorizes FDA to require certain drug and biological product application holders to make safety-related labeling changes based on new safety information that becomes available after approval of the drug or biological product.
For questions about the effect of any portion of this guidance, contact Kristen Everett, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Building 22, room 6484, Silver Spring, MD 20993.
I. Section 505(o)(4)
Section 505(o)(4) of the Act authorizes FDA to require safety labeling changes for the following products:
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Prescription drug products with an approved new drug application (NDA) under section 505(b) of the Act
- Biological products with an approved biologics license application (BLA) under section 351 of the Public Health Service Act (the PHS Act) (42 U.S.C. 262)
- Prescription drug products with an approved abbreviated new drug application (ANDA) under section 505(j) of the Act, if the NDA reference listed drug (RLD) is not currently marketed
The safety labeling changes provisions in section 505(o)(4) apply to the above-listed products, including products that are not marketed, unless approval of the NDA, BLA, or ANDA has been withdrawn in the Federal Register.
Section 505(o)(4) does not apply to nonprescription (over-the-counter) drugs approved under an NDA or ANDA or to marketed unapproved drugs.
II. BACKGROUND
Before the enactment of FDAAA, FDA had the ability to request safety-related changes to the labeling of approved drug products. Upon the enactment of FDAAA, FDA received express authority to require safety labeling changes in certain circumstances as described in the guidance.
A. Past Practice
In the past, FDA requested that holders of applications for approved products make labeling changes related to safety to address serious risks. FDA typically learned of the potential for such serious risks from a variety of sources, including FDA’s adverse events reporting systems. In most cases, application holders responded to these requests for labeling changes by negotiating appropriate language with FDA staff to address the concerns and then submitting a supplement or amended supplement to obtain approval of the changes. Negotiations were often protracted, and FDA had few tools at its disposal to end negotiations and require the changes.
Before FDAAA, if the application holder did not respond to FDA’s request or did not agree with the requested labeling changes, FDA could take the following actions:
- FDA could initiate proceedings to withdraw approval of the drug — an action not normally desirable if some patients were benefitting from the drug despite its risks.
- FDA could notify the public about the safety information through mechanisms such as Public Health Advisories or notifications on the FDA web site describing the safety information and the need for labeling changes.
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If in FDA’s judgment the absence of the new safety information from the drug’s label rendered the product misbranded, FDA could take appropriate enforcement action.
Congress recognized the limitations of FDA’s authority in this area and, in FDAAA, gave FDA new authorities to require safety labeling changes in certain circumstances.
B. New FDAAA Authorities and Requirements
On September 27, 2007, the President signed FDAAA (Public Law 110-85). Section 901 of Title IX of FDAAA amended the FD&C Act by adding new section 505(o). Section 505(o)(4) authorizes FDA to require and, if necessary, order labeling changes if FDA becomes aware of new safety information that FDA believes should be included in the labeling of the drug. Section 505(o)(4) of the FD&C Act imposes time frames for application holders to submit and for FDA staff to review such changes, and gives FDA new enforcement tools to bring about timely and appropriate safety labeling changes.
III. IMPLEMENTATION OF SAFETY LABELING CHANGES UNDER FDAAA
A. What is New Safety Information?
1. What Does New Safety Information Mean?
Section 505(o)(2)(C) of the FD&C Act states that, for the purposes of section 505(o), the phrase new safety information has the meaning given in section 505-1(b) of the FD&C Act (21 U.S.C. 355-1(b)), which defines new safety information as “information derived from a clinical trial, an adverse event report, a post approval study (including a study under section 505(o)(3)), peer reviewed biomedical literature, data derived from the post market risk identification and analysis system under section 505(k); or other scientific data deemed appropriate by [FDA]” about:
- “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” (emphasis added), or
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“The effectiveness of the approved [REMS] for the drug obtained since the last assessment of [the REMS].”
It is FDA’s view that the statutory definition of new safety information is broad to enable FDA to require application holders to add information about serious risks to the labeling of a drug when the Agency determines that such information should be included.
2. How Does FDA Learn About New Safety Information?
FDA may learn about new safety information from many sources, including, but not limited to, those listed in Appendix A. Once FDA has learned about the potential for new safety information, FDA may derive new safety information through various means, including, but not limited to, the following:
- A new analysis of existing information
- An assessment of the risks and benefits of the drug as it pertains to a new use of the drug, a new indication for the drug, or the use of the drug in a new population
- Information on the effectiveness of a previously approved REMS obtained since the last assessment of that REMS
3. How Will FDA Evaluate the New Safety Information?
FDA will form a multidisciplinary team to evaluate information that may be new safety information that should be incorporated into a drug’s labeling under section 505(o)(4).
B. What Types of Safety Labeling Changes Could Be Required Under Section 505(o)(4)?
FDA expects that information that meets the standard of new safety information that should be included in labeling, thereby triggering safety labeling changes under section 505(o)(4), generally will include, but is not limited to, information that would be described in new or revised language in the following sections of the prescribing information:
- BOXED WARNINGS
- CONTRAINDICATIONS
- WARNINGS AND PRECAUTIONS
- DRUG INTERACTIONS
- ADVERSE REACTIONS
FDA expects that labeling changes that address new safety information about serious risks associated with a drug, including those that affect a class of drugs, will be required under the authority of section 505(o)(4) of the FD&C Act.
IV. PROCEDURES
A. How Will FDA Notify Application Holder(s) of Required Safety Labeling Changes?
Once FDA has determined that there is new safety information that should be included in labeling, FDA plans to send a safety labeling change notification letter (notification letter) to the application holder(s). A holder of an approved NDA, BLA, or ANDA without a marketed NDA reference listed drug (RLD) will be notified and required to make the safety labeling changes, unless approval of the application has been formally withdrawn in a Federal Register notice. If the new safety information applies to more than one application holder, FDA plans to send a letter on the same day to each holder of an approved NDA, BLA, and/or ANDA without a marketed NDA RLD.
FDA will include the following information in the notification letter:
- The source from which the new safety information was derived
- A brief description of what the new safety information is about (a serious risk or an unexpected serious risk associated with the use of the drug, or the effectiveness of the REMS)
- Proposed labeling changes
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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 supplement
B. How Should Application Holders Respond to a Notification Letter?
Section 505(o)(4)(B)(i) and (ii) states that, after receiving notification of the required safety labeling changes, the application holder(s) must either:
- submit a supplement with proposed labeling changes to reflect the new safety information; or
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notify FDA that it does not believe a labeling change is warranted and submit a statement detailing the reasons why such a change is not warranted (a rebuttal statement).
If the application holder submits a supplement proposing labeling changes identical to those that FDA included in the notification letter, the application holder may submit a supplement – changes-being-effected (CBE-0). In all other situations, the application holder(s) should submit prior approval supplement to propose alternative labeling changes that reflect the new safety information.
C. How Will FDA Review the Required Labeling Supplement or Rebuttal Statement?
Section 505(o)(4)(C) of the Act directs FDA to “promptly review and act upon” a safety labeling changes supplement or rebuttal statement responding to a notification letter.
1. Meaning of Promptly Review and Act
This section describes the process FDA intends to use to review labeling supplements and rebuttal statements, the actions that FDA will take, and the time frame in which FDA expects to take those actions.
a. Labeling Supplements
When an application holder submits a labeling supplement, FDA’s review team will conduct a preliminary review of the supplement, consider whether the proposed language in the supplement can be approved or requires further discussion, and proceed as follows:
- If the proposed language can be approved without changes, FDA will approve the supplement promptly and notify the application holder by sending a supplement approval letter. For supplements that propose acceptable wording, FDA’s goal is to take action within 30 calendar days of receipt of the supplement.
- If the proposed revised language cannot be approved without changes, the Agency will initiate a discussion period to review and discuss the proposed revisions (section 505(o)(4)(C)). The discussion period will begin on the date that FDA receives the application holder’s submission and last no more than 30 calendar days (unless an extension is warranted) (section 505(o)(4)(D)).
- If the notification letter was issued for more than one application, and one or more application holders in the class submit proposed language that differs from what FDA included in the notification letter, FDA will inform all application holders that received a notification letter that a discussion period will be initiated to review and consider alternative wording that was submitted. The discussion period will begin on the date that FDA receives the application holder’s submission and last no more than 30 calendar days (unless an extension is warranted) (section 505(o)(4)(D)).
Within 15 calendar days of the conclusion of the 30-day discussion period (and any extension period, if applicable), FDA will proceed as follows:
- If FDA and the application holder reach consensus on the proposed labeling, FDA will notify the application holder by sending a supplement approval letter.
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If FDA does not agree with the application holder’s proposed labeling changes and FDA and the application holder cannot reach consensus, under section 505(o)(4)(E), FDA can order the application holder to make the required labeling changes (see section IV.E for further discussion of safety labeling changes orders).
b. Rebuttal Statements
Similar to the process for supplements, when an applicant submits a rebuttal statement, FDA’s review team will conduct a preliminary review of the rebuttal statement, consider whether FDA accepts the application holder’s reasons why labeling changes are not warranted or whether the rebuttal statement requires further discussion, and proceed as follows:
- If FDA accepts the application holder’s reasons why labeling changes are not warranted, FDA will promptly notify the application holder. In such situations, FDA’s goal is to take action within 30 calendar days of receipt of the rebuttal statement.
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If FDA does not accept the application holder’s reasons why labeling changes are not warranted, the Agency will initiate a discussion period (section 505(o)(4)(C)). The discussion period would begin on the date that FDA receives the application holder’s rebuttal statement and last no more than 30 calendar days (unless an extension is warranted) (section 505(o)(4)(D)). If the sponsor agrees to submit a labeling supplement during the discussion period, the supplement should be submitted before the end of the discussion period (and any extension period, if applicable), and FDA will follow the procedure as outlined above.
Within 15 calendar days of the conclusion of the 30-day discussion period (and any extension period, if applicable), FDA will proceed as follows:
- If FDA and the application holder reach consensus on the reasons why labeling changes are not needed, FDA will notify the application holder.
- If FDA does not agree with the application holder’s rebuttal statement and FDA and the application holder cannot reach consensus on the submission of a labeling supplement, under section 505(o)(4)(E), FDA can order the application holder to make the required labeling changes (see section IV.D for further discussion of safety labeling changes orders).
2. Additional Information on Review Procedures
The following sections provide additional information on FDA’s review procedures for safety labeling changes supplements or rebuttal statements responding to a notification letter.
a. 30-Day Discussion Periods and Extensions
If FDA does not agree with the wording in the submitted supplement or the reasoning of the rebuttal statement, FDA must initiate discussions that do not extend for more than 30 days after the receipt of the submission (section 505(o)(4)(C) and (D)).
Under section 505(o)(4)(D), FDA may extend the discussion period for more than 30 days, if FDA determines that an extension of the discussion period is warranted. FDA expects that an extension of the discussion period (usually for another 30 days) will be warranted when a 30-day discussion period may not suffice to adequately address all outstanding issues.
b. Failure to Respond to a Notification Letter
If the application holder does not submit a labeling supplement or a rebuttal statement within 30 calendar days of the date of the notification letter, the application holder will be considered to have forfeited the review and discussion period, and FDA can issue an order directing that the labeling be changed (see section IV.D for further discussion of safety labeling changes orders).
c. Labeling Change Notifications for ANDAs with a Marketed NDA RLD
Holders of ANDAs with a marketed NDA RLD would usually be notified by OGD of the required safety labeling changes after approval of the labeling supplement for the NDA RLD. ANDA holders should submit the required labeling changes as a supplement- changes-beingeffected (CBE-0) within 30 days of the date of the written notification from FDA.
3. Additional Information on Review Procedures for Safety Labeling Changes that Affect More than One Application
a. Labeling Supplements, Rebuttal Statements, and Discussion Period(s)
For class labeling changes, it is FDA’s policy that labeling decisions should wait until all supplements and rebuttal statements submitted within 30 days of notification have been reviewed. FDA intends to approve a labeling change common to all class members on the same day unless there is a well-justified, scientific rationale to support different wording for different drug labels. To carefully review supplements and rebuttal statements from all application holders and to consider the differences and commonalities between products, FDA anticipates that a 30-day extension of the discussion period may be warranted.
b. Failure to Respond to a Notification Letter
One or more application holders in a class may fail to respond to the notification letter within the required 30-day time frame, or may fail to respond at all, while others submit labeling supplements or rebuttal statements within the required 30-day time frame.
D. How Will FDA Issue an Order for Labeling Changes?
If, at the conclusion of the 30-day discussion period (or extension, if applicable), FDA determines that the application holder’s proposed labeling changes do not adequately address the new safety information or finds unacceptable the application holder’s reasons why the labeling changes are not warranted, FDA can issue an order to change the product labeling (section 505(o)(4)(E)). FDA can also issue an order if a supplement or rebuttal statement is not submitted within 30 calendar days of the date of the notification letter.
E. When Should New Labeling Be Available?
FDA expects that new approved labeling will be available on the application holder’s Web site within 10 calendar days of approval of the labeling supplement, or FDA’s receipt of a changes being-effected labeling supplement. In addition, approved updates to labeling are posted on FDA’s Web site.
FDA acknowledges that incorporating labeling changes into printed material included in drug shipments usually requires more time than incorporating changes to a Web site. FDA intends to issue guidance outlining its expectations regarding time frames for the availability of labeling changes for printed package inserts, patient package inserts, and Medication Guides.
F. Will Safety Labeling Changes Letters Be Disclosed?
Safety labeling changes notification letters that apply to more than one application will be posted on FDA’s Web site to provide rapid communication to the public of a serious safety risk. Notification letters that apply to a single application are considered confidential commercial information and are not posted; however, the resulting supplement is approved and posted.
All safety labeling changes order letters may be posted on FDA’s Web site.
V. DISPUTE RESOLUTION
An application holder may appeal an order to make a safety labeling change using the usual dispute resolution procedures (guidance for industry on Formal Dispute Resolution: Appeals Above the Division Level) (see section 505(o)(4)(F) of the Act). The appeal should be submitted as correspondence to the NDA, BLA, or ANDA.
Under section 505(o)(4)(F), the application holder must make its appeal of the order within days of receiving that order. FDA has interpreted “5 days” to mean “5 calendar days.” Appeals received by FDA later than 5 calendar days after the date that the order letter was received will not be entertained. Similarly, for appeals to higher levels, such as the Center Director, application holders should appeal a written determination made by a previous level within calendar days of receiving that determination. The dispute process will be considered to be concluded if an appeal of a written determination is not received within this time frame.
At the conclusion of the dispute resolution process, if FDA determines that a labeling supplement is required, the labeling supplement must be submitted within 15 days of the date of that determination (section 505(o)(4)(G)). FDA has interpreted “15 days” to mean “15 calendar days.” If the labeling supplement is not submitted within 15 days, the application holder will be in violation of the statute.
VI. ENFORCING REQUIREMENTS FOR SAFETY LABELING CHANGES
Section 902 of FDAAA gave FDA authority to enforce the section 505(o)(4) requirements for safety labeling changes. If the responsible person or, when applicable, the holder of the approved application under section 505(j) neither submits a supplement within 15 calendar days of the date of a safety labeling change order nor initiates dispute resolution within 5 days, the responsible person or application holder will be in violation of section 505(o)(4) of the Act. In addition, if at the conclusion of any dispute resolution process, the Secretary determines that a supplement must be submitted and such supplement is not submitted within 15 days of the date of the determination, the responsible person or application holder will be in violation of section 505(o)(4) of the Act.