When a pharmaceutical product or medical device is approved by the Food and Drug Administration (FDA), it must be given an appropriate label, which contains information about the use of the product or device. The label is usually a package insert that is placed inside of the product, and includes detailed information about the clinical data, proper uses or “on-label uses,” risks and benefits of a particular drug or device, and other information that FDA requires. At times, after the FDA has approved a product or device, subsequent testing or data has caused companies to revise a product label to include new uses for a product that were once considered “off-label,” and to advise consumers and health care practitioners of new warnings and safety issues associated with a product or device.
In the past, FDA requested that holders of applications for approved products make labeling changes related to safety after approval to address serious risks. FDA learned of the potential for such serious risks from a variety of sources including, but not limited to monitoring of Adverse Event Reporting System (AERS) or Vaccine Adverse Event Reporting System (VAERS) in-boxes, Safety-related data in a new drug application (NDA), biologics licensing application (BLA), supplements, or investigational new drug application (IND), FDA inspections and investigations, including postmarketing adverse drug experience (ADE) inspections, and Meta-analyses of safety information, or new analyses of previously submitted information.
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. If the application holder did not respond to FDA’s request or did not agree with the requested labeling changes, the Agency 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.
Notify the public about the safety information through mechanisms such as a 72 Public Health Advisory or notification on the FDA Web site describing the safety information and the need for labeling changes.
Take appropriate enforcement action.
Food and Drug Administration Amendments Act of 2007
Recognizing the limitations of FDA’s authority in this area, Congress passed the Food and Drug Administration Amendments Act of 2007 (FDAAA), which were signed into law on September 27, 2007(Public Law 110-85). Specifically, Section 901 of Title IX of FDAAA amended added section 505(o)(4), which authorizes FDA to require and, if necessary, order labeling changes if FDA becomes aware of new safety information that becomes available after approval, which FDA believes should be included in the labeling of the drug or biological product.
Section 505(o)(4) 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. Consequently, FDA recently released a Guidance to address the requirements and rules created by this new section. Section 505(o)(4) of the Act authorizes FDA to require safety labeling changes for the following products:
Prescription drug products with an approved NDA under section 505(b) of the Act biological drug products with an approved 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 section 505(o)(4) safety labeling changes provisions 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 to marketed unapproved drugs.
What pharmaceutical and medical device manufacturers should take away from this guidance is that FDA will now have the power to order a company to change its label after reviewing safety data, and if the process described below is not followed by a company, significant monetary and legal penalties may follow. Below is a full summary of the guidance.
New Safety Information
For the purposes of section 505(o), FDA noted that the term new safety information is defined as “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 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”, or
“The effectiveness of the approved [REMS] for the drug obtained since the last assessment of [the REMS]”.
According to the FDA Guidance, a “serious risk” is defined as “a risk of a serious adverse drug experience.” A “serious adverse drug experience” is an adverse drug experience that results in —
- Death;
- An adverse drug experience that places the patient at immediate risk of death from the adverse drug experience as it occurred (not including an adverse drug experience that might have caused death had it occurred in a more severe form);
- Inpatient hospitalization or prolongation of existing hospitalization;
- A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; or
- A congenital anomaly or birth defect; or
- Putting a patient at jeopardy for a medical/surgical intervention to prevent an adverse outcome
Once FDA has learned about the potential for new safety information (from some of the sources noted above), FDA may derive new safety information through various means, including but not limited to:
- 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
Once information is gathered, 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). If the safety information is relevant to more than one member of a drug class, FDA expects that review staff will identify the affected class members and review staff in all relevant review divisions and offices will be part of the team.
Within CDER, the Office of Generic Drugs (OGD), the Unapproved Drugs Coordinator, and the Office of Compliance (OC) may also be notified, as appropriate. The team’s discussions and evaluations of the new safety information may include, but are not limited to, presentations at internal Agency meetings, Drug Safety Oversight Board meetings, or Advisory Committee meetings.
Safety Label Changes Required Under 505(o)(4)?
The Guidance noted that for labeling changes that are not required and reviewed under section 505(o)(4), application holders may continue to submit labeling supplements using standard procedures. FDA expects that information that meets the standard of new safety information that should be included in labeling under section 505(o)(4), will include, but is not limited to, information that would be described in new or revised language in the following sections of the professional labeling:
- Boxed warnings
- Contraindications
- Warnings and precautions
- Drug interactions
- Adverse reactions
FDA expects that information that results in changes made only to the adverse reaction section, but does not warrant inclusion in other sections of labeling (such as warnings and precuations), would not normally trigger required safety labeling changes under section 505(o)(4). FDA also anticipates that minor editorial changes to any part of the labeling would not trigger required safety labeling changes under section 505(o)(4).
FDA expects that all labeling changes that address new safety information about serious risks that affect a class of drugs will be required under the authority of section 505(o)(4) of the Act.
If certain changes to the professional labeling are required under section 505(o)(4), other changes to the product labeling, including changes to an existing Medication Guide or creation of a new Medication Guide, may also be required to ensure that all labeling for the product is consistent. Medication Guides are part of the product labeling, and are also potential elements of a REMS.
FDA Procedures, Notifications
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). If the new safety information applies to more than one application holder, FDA plans to send a letter to each holder of an approved NDA, BLA, and ANDA without a marketed NDA RLD on the same day. Holders of approved NDAs, BLAs, and ANDAs without a marketed NDA RLD will also be notified and required to make the changes if approval of the application has not been formally withdrawn by Federal Register notice. 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
- Instructions regarding the circumstances in which the application holder should respond by submitting proposed labeling changes as a prior approval supplement4 or a changes-being-effected supplement5
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
- 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 notification letter applies to only one application and the application holder submits a supplement proposing the labeling changes identical to those that FDA included in the notification letter, the application holder should submit a changes-being-effected supplement. In all other situations, the application holder should submit a prior approval supplement to propose labeling changes that reflect the new safety information.
In the notification letter, FDA will provide information about whether application holders should submit proposed labeling changes as a prior approval or a changes-being-effected supplement.
Following notification, the labeling supplement or rebuttal statement must be submitted within 30 calendar days of the date that the notification letter is issued. FDA plans to forward copies of safety labeling change letters (including notification letters and orders) via fax or e-mail so that they will be received on the date the document is issued.
The application holder’s prior approval supplement may contain proposed edits or counterproposals to the language recommended by FDA, with the rationale for the changed wording.
FDA Review of Label Changes
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.
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 revised language in the supplement can be approved or requires further discussion, and proceed as follows:
If the proposed revised 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 that will begin on the date that FDA receives the application holder’s submission and will last no more than 30 calendar days (unless an extension is warranted).
- 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.
- If FDA does not agree with the application holder’s proposed labeling changes and FDA and the application holder cannot reach consensus, FDA may order the application holder to make the required labeling changes.
- If more than one drug in a class is affected, including ANDA products, FDA will send approval letters to all affected application holders of NDAs, BLAs, and ANDAs without a marketed NDA RLD, on the same day.
Rebuttal Statements
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. The process and timing above for supplements is the same for rebuttal statements.
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 will be warranted when a 30-day discussion period may not suffice to adequately address all outstanding issues. For example, the labeling change may involve a drug class or the supplement may contain significantly revised language. In such cases, before the conclusion of the discussion period, FDA may notify the application holder in writing that the 30-day discussion period has been extended and, when possible, briefly state the reason(s) for the extension.
Other Provisions
FDA’s reasons may include, but are not limited to, the need to consider and discuss the application holder’s alternative language, consider additional information, obtain consensus at a higher level within CDER or CBER or among involved offices, or receive input from the Drug Safety Oversight Board or other advisory committees.
For class labeling changes, it is FDA’s policy that labeling decisions should wait until all supplements 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 from all application holders and to consider the differences and commonality between products, FDA anticipates that a 30-day extension of the discussion period may be warranted. FDA does not anticipate more than one extension to the 30-day discussion period for most labeling changes.
If the application holder does not submit a prior approval 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 may issue an order directing that the labeling be changed.
Holders of ANDAs with a marketed NDA RLD will 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 changes-being-effected supplement within 30 days of the date of the written notification from FDA.
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 may issue an order to change the product labeling. FDA may also issue an order if a supplement or rebuttal statement is not submitted within 30 calendar days of the date of the notification letter.
FDA anticipates that orders for labeling changes will be rare and that such actions will first involve discussion with the appropriate CDER or CBER senior managers.
Order letters will be issued within 15 calendar days of the conclusion of the 30-day discussion period (or extension, if applicable). FDA plans to include the following in the order letters:
- Approval of any sections of labeling on which the application holder and FDA reached agreement
- A Complete Response action for the sections of labeling on which the application holder and FDA cannot agree
- A brief explanation why the application holder’s proposed labeling changes or rebuttal do not adequately address the new safety information
- An order to submit a changes-being-effected supplement within 15 calendar days of the date of the order for specified changes to the sections of labeling on which the application holder and FDA cannot agree (FDA plans to include specific wording for these required labeling changes in the order letter)
After the application holder submits the changes-being-effected supplement, FDA intends to promptly review the supplement, and if it addresses the new safety information adequately as directed, FDA will approve the supplement, generally within 15 calendar days of receipt. As with other approval letters, the document will be posted on the FDA Web site.
Alternatively, instead of submitting a changes-being-effected supplement, the application holder may appeal the order through formal dispute resolution procedures within 5 calendar days of the date of the order. If the application holder does not submit a supplement within 15 calendar days of the date of the order and does not initiate dispute resolution within 5 calendar days of the date of the order, the application holder will be in violation of the statute. This may result in enforcement actions, described below.
FDA expects that new approved labeling will be available on the application holder’s Web site within 10 calendar days of approval. FDA acknowledges that incorporating labeling changes into printed material included in new 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 package inserts, PPIs, and Medication Guides.
Safety labeling changes notification letters that apply to more than one application may be posted on the FDA 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 until the resulting supplement is approved.
All safety labeling changes order letters may be posted on the FDA Web site.
Enforcement and Penalties
An application holder may appeal an order to make a safety labeling change using the usual FDA dispute resolution procedures. The application holder must make its appeal of the order within 5 calendar days. Similarly, for appeals to higher levels, such as the Center Director, application holders should appeal a written determination made by a previous level within 5 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 timeframe.
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 calendar days of the date of that determination. If the labeling supplement is not submitted within 15 days, the application holder will be in violation of the statute.
Enforcement action for a violation of 505(o)(4) could result in one or more of the following:
- Violations of the requirements for safety labeling changes may result in unapproved new drug charges. A responsible person may not introduce or deliver into interstate commerce the drug involved if the applicant is in violation of section 505(o) safety labeling changes requirements
- Violations of the requirements for safety labeling changes may result in misbranding charges. Failure to comply with section 505(o)(4) causes a product to be misbranded
An application holder that violates safety labeling changes requirements may be subject to civil monetary penalties of up to $250,000 per violation, but no more than $1 million for all violations adjudicated in a single proceeding. These penalties increase if the violation continues more than 30 days after FDA notifies the application holder of the violation. The penalties double for the following 30-day period and continue to double for subsequent 30-day periods, up to $1 million per period and $10 million for all violations adjudicated in a single proceeding. In determining the amount of a civil penalty, FDA will consider the application holder’s efforts to correct the violation
Such violations may also be subject to additional enforcement action, including but not limited to seizure of the product and injunction.
Comments and suggestions regarding this draft document should be submitted within 90 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Comments can be submitted to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with Docket No. FDA–2011–D–0164, which is listed in the Federal Register.