Draft guidance calls for a clear statement in the Indications and Usage section of labeling that reflects a drug’s clearance under accelerated approval on the basis of a particular surrogate or clinical endpoint. The document also includes provisions for reflecting the withdrawal of accelerated approval in labeling.

FDA is proposing changes in the Indications and Usage section of drug labeling to better reflect the conditional nature of accelerated approval.

In a draft guidance released March 24, the agency proposes language stating that a product was approved under the accelerated approval pathway on the basis of a specific surrogate or clinical endpoint. Labeling also would state that continued approval may be contingent upon verification or demonstration of clinical benefit in a post-marketing study.

The guidance also makes provisions for following up on that statement whether or not clinical benefit has been verified. If the benefit is not verified and the approval is withdrawn, the agency may require that the Indications and Usage section include a statement indicating a lack of evidence that a drug is effective or safe for the now-withdrawn indication.

The guidance, “Labeling for Human Prescription Drug and Biological Products Approved Under the Accelerated Approval Regulatory Pathway,” may be viewed both as the agency’s attempt to better explain the types of evidence underlying an accelerated approval to the medical and patient communities and to bring more uniformity to labeling for such drugs and biologics across review divisions.

Highlighting Conditions For Continued Approval

At the American Association for Cancer Research’s annual meeting in April 2013, Office of Hematology and Oncology Products Director Richard Pazdur announced that the agency was working on a labeling guidance for accelerated approval drugs. Pazdur said that although the conditional status of such products currently is reflected in labeling with a statement that clinical benefit has not been demonstrated, the language does not make clear that the drug was approved on the condition that further studies must adequately demonstrate clinical benefit.

Pazdur’s comments arose in the context of discussion about the agency’s challenges in explaining to the public why it sought withdrawal of accelerated approval forGenentech Inc.’s Avastin (bevacizumab) in metastatic breast cancer for efficacy reasons (“FDA “Regulatory Flexibility” On Accelerated Approval Must Result In Some Withdrawals” — “The Pink Sheet,” Apr. 15, 2013).

Genentech contested the Center for Drug Evaluation and Research’s request in 2010 to withdraw the claim after two confirmatory trials failed to verify the magnitude of the progression-free survival benefit seen in the initial pivotal trial. FDA Commissioner Margaret Hamburg ultimately sided with CDER in November 2011 and ordered the claim withdrawn.

Under the draft guidance, a drug’s accelerated approval status would be clearly stated in the indication statement, something that is currently not done.

The guidance states that the Indications and Usage section of labeling for accelerated approval drugs generally should describe three elements – indications, limitations of usefulness and clinical benefit uncertainty, and continued approval. The document includes examples of how these three elements would be represented in the Indications and Usage section (see box).

“For health care providers who frequently prescribe drugs approved under accelerated approval, including the term accelerated approval in the indications and usage statement is informative because it provides the framework and rationale for the other indications statement elements that are unique to drugs approved in this manner,” the guidance states.

The guidance also seems aimed at bringing some uniformity to how accelerated approval is characterized in drug labeling across FDA review divisions. While the indication statement for oncology drugs often reflects the surrogate or clinical endpoint upon which accelerated approval was granted – the same approach taken by the guidance – that is not always the case for drugs handled by other review divisions, such as the Division of Cardiovascular and Renal Products’ recent approval ofChelsea Therapeutics International Ltd.’s orthostatic hypotension drug Northera (droxidopa) (see chart).

The guidance also provides for revisions to the Indications and Usage section when clinical benefit has been confirmed in post-marketing studies.

“The indications statement should generally reflect the population and condition for which there is substantial evidence of safety and effectiveness, including any new or remaining limitations of use,” the guidance states. “The previous statements concerning limitations of usefulness and continued approval should be removed or revised, as appropriate.”

When The Indication Goes Away

The guidance’s final section on withdrawal of an accelerated approval indication may be seen as reflecting the lasting impact the Avastin breast cancer claim saga is expected to have on the expedited approval pathway.

The guidance explains the statutory and regulatory conditions under which accelerated approval may be withdrawn. If a claim is withdrawn but the drug remains approved for other indications, labeling must be revised. “For example, it may be necessary to remove information concerning the withdrawn indication from several sections (e.g., Indications and Usage, Dosage and Administration, and Clinical Studies) so that the labeling does not imply or suggest that the drug is approved for the withdrawn indication,” FDA said.

However, the guidance does not stop at simply removing information from the labeling about the now-withdrawn indication. Rather, it envisions adding information about the withdrawn claim when appropriate.

“If there is a common belief that the drug may be effective for a certain use, or if there is a common use of the drug for a condition, but the preponderance of evidence related to the use or condition shows that the drug is ineffective or that the therapeutic benefits of the drug do not generally outweigh its risks, the FDA may require that the Indications and Usage section state that there is lack of evidence that the drug is effective or safe for that use,” the guidance states. “When accelerated approval of an indication is withdrawn, the FDA may require that the labeling be revised to include a limitation of use concerning the withdrawn indication.”

In withdrawing Avastin’s metastatic breast cancer indication, the agency did not go so far as to require that the Indications and Usage section reflect a lack of evidence on the drug’s safety and efficacy in this population. Current Avastin labeling references the breast cancer population only in the Adverse Reactions section’s discussion of clinical trial patient exposure and with regard to higher rates of congestive heart failure reported in metastatic breast cancer patients, “an indication for which Avastin is not approved.”

However, Avastin’s labeling is in keeping with the guidance’s provisions on safety information for a withdrawn indication.

The agency may require a specific warning about an unapproved use if a drug is frequently prescribed for a disease or condition and such use is associated with a clinically significant risk, the guidance states.

“Because the drug was previously indicated for the now-withdrawn use and may continue to be considered for that use by some health care providers, important adverse reactions or other risks associated with the withdrawn indication may be appropriate to include in the Warnings and Precautions and/or Adverse Reactions sections of the revised labeling,” the guidance states. “The description of the risk or hazard also should be accompanied by a statement that the drug is not approved for the withdrawn indication.”

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