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FDA Releases New Accelerated Approval Labeling Guidance

Posted 24 March 2014 | By Alexander Gaffney, RAC

A new guidance document published by the US Food and Drug Administration (FDA) is intended to clarify how drugs approved through the accelerated approval pathway should be labeled.


FDA's accelerated approval pathway is one of several tools used to expedite the approval of medicines intended to treat serious or unmet needs.

Under Section 506(c) of the Federal Food, Drug and Cosmetic Act (FD&C Act), accelerated approval is reserved for products intended to treat or cure a "serious or life-threatening condition" based on surrogate endpoints that are "reasonably likely to predict clinical benefit."

For example, if a drug is intended to treat a deadly type of cancer and early data indicate that it has slowed the progression of the disease, it could be eligible for accelerated approval.

In addition to the severity of the disease, FDA is also supposed to take into account its rarity as well as the availability (or lack thereof) of alternative treatments. If ample FDA-approved treatments are already available, a new drug is unlikely to obtain accelerated approval unless it demonstrates a marked improvement in safety or efficacy relative to the existing treatments-a "meaningful advantage over available therapy."

It's also important to note that drugs approved through the accelerated approval pathway are given somewhat tentative approvals. "Approval under this section will be subject to the requirement that the applicant study the drug further, to verify and describe its clinical benefit, where there is uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical benefit to ultimate outcome," explains 21 CFR 314.510.

Drugs may be withdrawn if they fail to show subsequent benefit, or they may be granted full and unconditional approval.

[More information is available in FDA's 2013 guidance document, Expedited Programs for Serious Conditions--Drugs and Biologics.]

Concerns about Limitations

But since the drugs are initially approved based on incomplete data, FDA has expressed concern that consumers and healthcare providers may not fully appreciate the potential limitations of the medicine. Not all surrogate endpoints are ultimately indicative of a positive outcome.

In 2011, FDA withdrew the breast cancer indication for Roche's Avastin (bevacizumab) after complete data ultimately showed no benefit for a significant number of patients. While the drug did indeed show a surrogate benefit, the drug caused life-threatening side-effects which negated many of those benefits.

How, then, should patients and healthcare providers be made aware of the limited evidence supporting the tentative approval of drugs via the accelerated approval pathway?

New Guidance on Labeling

If FDA's new draft guidance document, Labeling for Human Prescription Drug and Biological Products Approved under the Accelerated Approval Regulatory Pathway, is any guide, it's all in the labeling.

In particular, the limitations of a drug should be made clear in its "INDICATIONS AND USAGE" section on its label. Unlike drugs granted full approval, drugs given accelerated approval must contain a "succinct description of the limitations of usefulness of the drug and any uncertainty about anticipated clinical benefits, with reference to the 'Clinical Studies' section for a discussion of the available evidence," FDA wrote.

Those "succinct descriptions" will depend upon the status of the drug, FDA notes.

For drugs which have just obtained accelerated approval, the label should state:

  1. that the drug was approved under accelerated conditions and based on a surrogate endpoint for certain indications
  2. a description of what a surrogate endpoint is and its limitations
  3. a notice that further testing is ongoing, and that continued approval is contingent upon finding the expected benefit after full data is obtained

Once those benefits have been verified, however, the labeling can be updated to remove the references to the aforementioned three points.

For drugs like Avastin, where the drug's accelerated approval is revoked but the drug remains approved for other indications, FDA explains that the labeling must also be updated to remove all mention of the now-revoked indication.

FDA also notes that "it may sometimes be appropriate to add to the labeling new information concerning the withdrawn indication," such as if it was withdrawn due to safety concerns or just a lack of evidence. Both types of labeling information may be required by FDA, it said.


Labeling for Human Prescription Drug and Biological Products Approved under the Accelerated Approval Regulatory Pathway (FR)

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