Regulatory Focus™ > News Articles > PhRMA: Recommended Language in FDA Accelerated Drug Labeling Guidance Misleading

PhRMA: Recommended Language in FDA Accelerated Drug Labeling Guidance Misleading

Posted 02 June 2014 | By Alexander Gaffney, RAC

PhRMA: Recommended Language in FDA Accelerated Drug Labeling Guidance Misleading

Pharmaceutical industry trade group PhRMA has come out forcefully against language contained within a draft guidance document issued in March 2014 by the US Food and Drug Administration (FDA), calling the agency's take on labeling drugs granted accelerated approval potentially confusing to patients and undercutting faith in the regulatory system.


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Drugs may be withdrawn if they fail to show subsequent benefit, or they may be granted full and unconditional approval.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 2014 final guidance document, Expedited Programs for Serious Conditions—Drugs and Biologics.]

New Guidance: 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.

So in March 2014, FDA released a new draft guidance document, Labeling for Human Prescription Drug and Biological Products Approved under the Accelerated Approval Regulatory Pathway, intended to clarify how a drug's limitations should be expressed on the drug label.

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:

  • that the drug was approved under accelerated conditions and based on a surrogate endpoint for certain indications
  • a description of what a surrogate endpoint is and its limitations
  • 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 (bevacizumab), 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.

PhRMA: 'Conditional' Language not Helpful

PhRMA, however, said it isn't a fan of the guidance as it is currently written. In comments submitted to FDA last week, the group indicated that the labeling carve-outs "could be misinterpreted to mean that products approved under the Accelerated Approval pathway have not met the statutory requirements of safety and efficacy required of all FDA-approved drugs.”

That, in turn, could create the impression that the drugs have not met FDA's standards for safety and efficacy, and thereby "undermine the intent of the Accelerated Approval pathway and recent congressional efforts to encourage its broader use," PhRMA continued.

The group noted that FDA's past statements have indicated that drugs approved under the pathway are granted full approval for marketing, and are not subject to limitations, meaning—in PhRMA's interpretation—that they have met "the same statutory standard" for approval as other drugs. The group goes on to argue that FDA's prior statements indicated that its intent was to not regard accelerated approvals as "conditional," but rather only as accelerated.

Of course, prior statements by FDA don't prevent an evolution of the agency's views—an evolution that may be driven in part by the 2011 withdrawal of Roche's Avastin for its breast cancer indication. The drug had been granted accelerated approval, but the indication was revoked when the agency determined that the full data indicated that its harms outweighed its benefits. Its approval, in other words, was very much "conditional" in effect.

‘Continued Approval’

FDA's views on whether approvals are "conditional" or just subject to heightened scrutiny (i.e. future verification) could be a source of tension in the final guidance. PhRMA, for example, said it is displeased with FDA's attempts to require the addition of a statement indicating that a drug's approval is tentative.

Consider the following labeling statement proposed by FDA:

"Continued approval for this indication may be contingent upon {either (“verification and description of clinical benefit”) or (“demonstration of” followed by identification of the particular expected clinical benefit(s) that will be the objective of the postmarketing study)} in confirmatory trials."

PhRMA said this language is "inconsistent with prior FDA goals of keeping the 'indications and usage' section of the labeling 'focused' and 'succinct.'" For example, FDA generally doesn't require a sponsor to include language about postmarketing requirements. "The primary intent of labeling is not to educate the prescriber on the regulatory process, but to provide “adequate directions for use," PhRMA wrote.

"If anything, its inclusion in the Highlights section will create the unbalanced perception that products approved under Accelerated Approval, by virtue of their approval pathway alone, are cause for concern, despite having met the full statutory standards of safety and efficacy," PhRMA concluded.

By potentially making doctors more wary of prescribing drugs approved under accelerated conditions—which are by definition intended to assist patients with life-threatening diseases—PhRMA said FDA would be acting contrary to the intent of legislators, who have recently been pressing for more rapid approvals for life-saving and –extending drugs.

The group asks for the "continued approval" language to be removed, or failing that, moved to a less prominent position in the drug labeling (e.g. the "Clinical Studies" section).


PhRMA Comments

PhRMA Statement

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