Regulatory Focus™ > News Articles > New FDA Guidance Explains Process Behind Safety Labeling Changes for Drugs, Biologics

New FDA Guidance Explains Process Behind Safety Labeling Changes for Drugs, Biologics

Posted 30 July 2013 | By Alexander Gaffney, RAC

The US Food and Drug Administration (FDA) has released a new guidance document pertaining to labeling changes made to pharmaceutical and biological products based on new safety information discovered after initial FDA approval, including the process of making changes and how regulators will enforce existing requirements.


It is often said that at the time of a drug's approval, relatively little is actually known about its safety. Despite advances in regulatory science and clinical trials protocols, many safety issues are only discovered in real-world settings once a product is approved and subsequently given to a larger population. In the case of some drugs, even large pre-market trials involving thousands of patients are not able to discover issues that would only come to light once the product is used by millions of patients.

Per FDA regulations under 21 CFR 314.80(c)(2) and 600.80(c)(2), manufacturers of pharmaceutical and biological products are required to submit reports of adverse drug experiences that occur after regulatory approval. Those reports are divided into two primary types: expedited and non-expedited. Expedited reports must generally be submitted to FDA within 15 days, and relate to adverse drug experiences that are serious, life-threatening or deadly.

Non-expedited reports, by contrast, encompass all adverse events that are less serious, and are generally those that would make their way into a periodic adverse drug experience report (PADER), a periodic adverse experience report (PAER), a periodic safety update report (PSUR) or a periodic benefit-risk evaluation report (PBRER)-all reporting forms used to inform regulators.

The reports are required by FDA at varying intervals, depending primarily on how new a drug product is to the market. Generally, newly approved drugs must report once per quarter for the first three years, and then annually thereafter. In addition, FDA may also learn about adverse events through its own monitoring systems like the Sentinel System.

Information into Action

But it's how these reports are ultimately used that had prompted FDA's newest guidance. Under Section 505(o)(4) of the Federal Food, Drug and Cosmetic Act (FD&C Act)-instituted in 2007 under the Food and Drug Administration Amendments Act (FDAAA)-FDA is authorized to require safety labeling changes for all drugs approved under a new drug application (NDA), biologics license application (BLA) or an abbreviated new drug application (ANDA).

Prior to the passage of the law, FDA would typically engage in negotiations with the sponsor on a voluntary basis, a process which could become protracted. In a Federal Register notice released on 29 July 2013, FDA noted that its authority at the time left it with "few tools at its disposal to end negotiations and require the changes" short of seeking to withdraw the NDA/BLA/ANDA, notifying the public of the danger directly, or seeking to find a product misbranded and initiating enforcement actions.

Under its new authority, FDA may require the submission of a labeling supplement including labeling changes if "new safety information" is brought to its attention that it "believes should be included in the labeling of the drug."

New Safety Information

But what is "new safety information," exactly? Under Section 505(o)(2)(C) of the FD&C Act, the term is defined as:

"[I]nformation derived from a clinical trial, an adverse event report, a postapproval study (including a study under section 505(o)(3)), peerreviewed biomedical literature, data derived from the postmarket risk identification and analysis system under section 505(k); or other scientific data deemed appropriate by [FDA]."

That information can either be about a serious risk or unexpected serious risk made known to FDA or the effectiveness of a risk evaluation and mitigation strategy (REMS) plan, which may require strengthening to promote safety.

Once information is received, FDA said it forms a "multidisciplinary team" to evaluate the information, all of whom work together to determine the appropriate response. FDA typically has five types of changes it can order to the drug's labeling: a Boxed Warning (also known as a black box warning), new contraindications, an updated warnings and precautions section, updated drug interactions (also known as drug-drug interactions, or DDIs) and adverse reactions.

Once a labeling change is ordered, related labeling materials, such as a Medication Guide or REMS, will also need to be updated.

The Nuts and Bolts of a Label Change

The guidance also explains some of the procedures associated with labeling changes. For example, FDA will notify application holders of any required changes through a safety labeling change notification letter. The letter will include the source of the new information, a summary of the safety issue, proposed labeling changes and further instructions regarding a response.

Upon receipt, applicants must submit a labeling change in the form of a supplemental application to their NDA, BLA or ANDA application. Alternatively, they may respond to FDA by stating that they do not believe a change to be necessary, known as a rebuttal statement. That statement should be supported by details, FDA explains in its guidance document.

Any supplement adopting all FDA-recommended changes should be submitted as a Changes Being Effected (CBE)-0 supplement, allowing the product to continue to be marketed while FDA reviews the application. Other changes will need to be submitted as a Prior Approval Supplement (PAS) requiring FDA's approval prior to the product being marketed using the new labeling convention.

All supplements should be submitted to FDA within 30 days of the initial request. In order to expedite the process, FDA says it will email or fax letters instead of mailing them. FDA will also respond to any supplement submission within 15 days to inform the sponsor of its status (either approved or, in the case of some supplements with language proposed by the sponsor, not approved).

FDA's process for responding to rebuttal statements is similar, albeit lengthier at 30 days. Sponsors will then have an additional 15 days to respond to FDA's response to the rebuttal letter. Other extensions are possible, but may not exceed 30 days after the end of the discussion period.

If an applicant does not respond to FDA at all throughout the process or not in the allotted time, FDA may issue an order requiring the labeling changes be made.

ANDAs and Multiple Applications

FDA notes that the process for ANDA holders will be slightly different if there is still an actively marketed NDA acting as that product's reference-listed drug (RLD) in the Orange Book. 

"Holders of ANDAs with a marketed NDA RLD would usually be notified by Office of Generic Drugs of the required safety labeling changes after approval of the labeling supplement for the NDA RLD," FDA wrote. "ANDA holders should submit the required labeling changes as a CBE-0 within 30 days of the date of the written notification from FDA."

There are also differences when multiple NDA or ANDA holders are affected by a safety labeling change. FDA said its policy in such cases will be to wait until all supplements and rebuttal statements are submitted to respond, and will then approve a single labeling change common to all products involved. However, an exception will be made if there is a, "well-justified, scientific rationale to support different wording for different drug labels," FDA explained.

New labeling should be available on the sponsor's website within 10 days of FDA approval, with labeling changes affixed to packaging as soon as possible. FDA said further guidance would be forthcoming on this particular requirement.

The entire guidance may be found here.

Guidance for Industry: Safety Labeling Changes -Implementation of Section 505(o)(4) of the FD&C Act

Federal Register Notice

Tags: safety, guidance

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