FDA Safety Labeling Requirements
By Brian Bollwage, VP of global regulatory affairs, Theorem Clinical Services
Background
Prior to 2007, the U.S. Food and Drug Administration’s labeling authority was limited; the agency could only request changes to the labeling of approved drug products. That changed, however, with the enactment of the Food and Drug Administration Amendments Act of 2007, in particular, section 505(o)(4). In that section, the FDA was given new authority to require safety labeling changes for approved drugs.
This means the FDA can now order labeling changes if it becomes aware of new safety information that it believes should be included in the labeling of a drug. This article summarizes the FDA’s thinking in this regard, as indicated by its guidance released in recent weeks.
The FDA’s Scope
Section 505(o)(4) authorizes the FDA to require safety labeling changes for: 1) prescription drug products with an approved new drug application (NDA); 2) biological products with an approved biologics license application (BLA); and, 3) prescription drug products with an approved abbreviated new drug application (ANDA) when the reference listed drug is not currently marketed.
It is also important to note that the FDA’s authority extends beyond just new products entering the market. The agency’s authority to compel labeling changes remains in effect throughout the life of the product unless approval of the NDA, BLA or ANDA has been officially withdrawn in the Federal Register.
New Safety Information
The obvious question then is this: What exactly constitutes new safety information that can prompt the FDA to require labeling changes? The answer is quite broad. Information derived from a clinical trial, an adverse event report, a post-approval study, peer-reviewed biomedical literature as well as data derived from the post-market risk identification and analysis system or other scientific data may all be considered new safety information. Sponsors, therefore, must take a broad-based view of what sources of information might potentially lead to safety label changes.
Typical Labeling Changes
The FDA expects that new safety information may necessitate changes to the following sections of a drug or biologic prescribing information:
- Boxed warnings
- Contraindications
- Warnings and precautions
- Drug interactions
- Adverse reactions
In addition, changes to medication guides as an element of a risk evaluation and mitigation strategy (REMS) are to be included.
However, the FDA does not expect that all label changes related to safety will be required to be implemented under 505(o)(4). For example, the FDA expects information that results in changes only to the adverse reaction section would not trigger required safety labeling changes under 505(o)(4), but rather that such changes would be submitted via the standard NDA/BLA supplement routes described in 21 CFR 314.70 and 601.12.
Process for Label Changes
When the FDA decides safety label changes are required, it will send a notification letter to the relevant application holder. Each holder of an NDA, a BLA or an ANDA without a marketed NDA reference listed drug (RLD) will be notified via letter on the same day.
The FDA’s letter will describe:
- The source of the safety information
- The safety information itself
- The FDA’s proposed label changes
- The FDA’s instructions regarding submission type, i.e., prior approval supplement or changes-being-effected supplement
Sponsors, in turn, can respond to the letter in one of two ways. Sponsors may agree with the FDA and submit a supplement to their NDA, BLA or ANDA. In the alternative, sponsors may notify the FDA that a label change is not warranted (rebuttal). In either case, sponsors are expected to respond to the relevant application within 30 calendar days.
The FDA’s goal is to take action within 30 days of receipt of a safety labeling supplement. In the event that a rebuttal is submitted, this will open a 30-day discussion period within which the FDA will further evaluate the sponsor’s position and determine whether the label change is indeed necessary. Extensions to the discussion period are permissible at the FDA’s discretion. At the conclusion of the 30-day discussion period, the FDA has the authority to issue an order to compel the required labeling changes. The FDA anticipates that it will be rare when such directed orders are needed, but it is worth remembering that a directed order is an available alternative for FDA action.
Implementation of New Labels
The FDA expects application holders to post safety labeling changes to their websites within 10 days. However, the FDA has recognized that incorporating label changes into printed materials will take more time, and the agency has indicated it intends to further consider this matter and update its guidance regarding timing in the future. However, it should be noted that revisions to print materials should be expedited for both regulatory and liability considerations.
Conclusion
While Congress expanded the FDA’s authority in 2007 to give it the ability to require changes on prescription drug safety labels, it wasn’t until recently that the FDA issued its guidance, which provides the agency’s current thinking on this topic. It is important that sponsors be aware of the possibility of required label changes and have a process in place to efficiently respond should they receive notification from the FDA — particularly given the FDA’s intent to quickly expedite any required changes.
About the Author:
Brian Bollwage, JD, is vice president of global regulatory affairs for Theorem Clinical Services, a leading, global provider of comprehensive clinical research and development services. In a career spanning more than 30 years with almost all of it focused on regulatory affairs, Bollwage is a leading authority on regulatory law.