Accelerated Approval: Adcomm Should Always Precede Withdrawal Proposal, US FDA Says

The US Food and Drug Administration intends to convene an advisory committee when its drug or biologic centers are considering withdrawal of an accelerated approval product.

A new draft guidance on accelerated approval also codifies the practice of naming other product center leaders as decision-makers in the disputes.

The guidance, released on 5 December, describes the expedited withdrawal procedures established by the Food and Drug Omnibus Reform Act (FDORA), as well as the criteria for determining the effect on a surrogate endpoint is reasonably likely to predict clinical benefit and confirmatory trial expectations.

The expedited withdrawal procedures give a sponsor who declines to voluntarily remove an accelerated approval product from the market the right to submit a written appeal. The sponsor also may request a meeting with the commissioner or their designee and seek an adcomm unless one previously has considered the issues.

Adcomm First, Then Withdrawal Proposal

The agency generally expects a withdrawal proposal will be issued by the product center that granted accelerated approval. When data or other information raise concerns that one or more criteria for withdrawal may have been met, center officials should discuss their concerns with the sponsor and try to seek a resolution, which may include voluntary withdrawal.

If the center is considering whether to propose withdrawal, it should convene an adcomm to request advice on whether any of the withdrawal criteria have been met and any other issues that may be relevant, the guidance states.

“Doing so will provide an opportunity for a robust, public discussion of the issues and will provide the committee’s advice to the center before the center decides whether to propose withdrawing approval,” the agency said.

The agency recently held adcomms on two “dangling” accelerated approval products.

In September, a committee overwhelmingly voted that available evidence did not verify the benefit of Intercept’s Ocaliva (obeticholic acid) in primary biliary cholangitis and the drug’s benefit-risk profile was not favorable. The FDA subsequently issued a complete response letter on Intercept’s bid to convert from accelerated to regular approval, although the agency has not yet issued a formal withdrawal proposal.

In November, panelists said the confirmatory trial for AstraZeneca’s anticoagulant reversal agent Andexxa (andexanet) did not demonstrate a clinical benefit and the drug had an unfavorable risk-benefit profile. However, committee members seemed reluctant to pull the drug from the market.

When an adcomm is convened, “FDA strongly recommends that a sponsor submit, if it had not already, any data and evidence and any objections to withdrawal that the sponsor considers relevant so that they may be considered at this stage,” the guidance states.

Codifying Existing Practice

Calling an adcomm before a withdrawal proposal has been the standard practice to date, but FDORA allowed the agency to skip the public meeting once a formal withdrawal request is made, which helps streamline the process.

The agency has withdrawn an accelerated approval over the sponsor’s objection three times: the breast cancer claim for Genentech’s Avastin (bevacizumab), Covis’ preterm birth prevention drug Makena (hydroxyprogesterone caproate) and Oncopeptides’ multiple myeloma drug Pepaxto (melphalan flufenamide).

The agency convened an adcomm prior to a formal withdrawal proposal in all three cases. Before the FDORA procedures were implemented, a sponsor could request a public hearing on the center’s proposal regardless of whether an adcomm already had considered the issues. Consequently, public hearings involving an adcomm occurred for both Avastin and Makena, lengthening the withdrawal process.

Pepaxto is the only drug withdrawn using the FDORA expedited withdrawal procedures. Center for Biologics Evaluation and Research Director Peter Marks, who was the commissioner’s designee and made the final decision, described the new process as more streamlined than prior withdrawals.

Under the expedited procedures, if an adcomm had been convened on the issues related to the proposed withdrawal, a sponsor’s request for another panel meeting should be denied, the guidance states.

Tapping Other Center Directors To Help

Then-CBER Director Karen Midthun was the hearing officer in the Avastin dispute, and FDA Commissioner Margaret Hamburg made the final decision. CBER Deputy Director Celia Witten served as the hearing officer for Makena, with FDA Commissioner Robert Califf and then-Chief Scientist Namandjé Bumpus jointly making the final withdrawal decision.

“Upon a finding on appeal that the studies do not verify clinical benefit of the drug or the available evidence does not show the drug to be safe and effective under the conditions of use in the approved labeling, the commissioner/designee generally intends to withdraw accelerated approval in the absence of unusual circumstances.”

FDA

The draft guidance formalizes the roles of the chief scientist and other product center leaders in the withdrawal process.

If a designee is needed, the commissioner generally intends to designate the FDA’s chief scientist or one of the center directors from CBER, the Center for Drug Evaluation and Research, or the Oncology Center of Excellence, who was not involved in the withdrawal proposal, the guidance states.

The commissioner or their designee may select a team of advisers who have not participated in the proposed withdrawal.

“Generally, for consistency and efficiency, if a designee is selected, the designee for the written appeal will be the same as the designee for the meeting with the sponsor,” the guidance states. “If a designee becomes unable to act for any reason, a new designee may be selected by the commissioner.”

The final decision of the commissioner or their designee should be based on information filed in the docket for the withdrawal proceeding or that the sponsor submitted to the new drug application or biologics license application file, as well as the record of any advisory committee meeting.

“Upon a finding on appeal that the studies do not verify clinical benefit of the drug or the available evidence does not show the drug to be safe and effective under the conditions of use in the approved labeling, the commissioner/designee generally intends to withdraw accelerated approval in the absence of unusual circumstances,” the guidance states.