FDA Flexes its New FDORA Muscles in Withdrawing an Accelerated Approval

February 29, 2024By Mark A. Tobolowsky & Michelle L. Butler

On Friday, February 23, 2024, FDA announced its final decision to withdraw the approval of Pepaxto (melphalan flufenamide), which was approved in February 2021 in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma (RRMM) who have received at least four prior lines of therapy and whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one CD38-directed monoclonal antibody.  This is the third withdrawal of an accelerated approval FDA has performed, following Avastin in 2011 and Makena in 2023.  Notably, this decision marks the first use of the new expedited procedures for withdrawal of an accelerated approval that were enacted in the Food and Drug Omnibus Reform Act of 2022 (FDORA).  Prior to FDORA’s enactment, the statute did not provide details on the withdrawal procedures other than offering an opportunity for an informal hearing.

Without commenting on the merits of the decision, it is an interesting window into how FDA may use these new procedures in practice.  All in all, the new expedited procedures took about 7 months from proposal to withdrawal.  In contrast, the two previous withdrawals, Makena in 2023 and Avastin in 2011, took 30 months and 11 months, respectively.

The Pepaxto NDA, which was submitted by Oncopeptides AB (Oncopeptides), was approved based on overall response rate (ORR) and duration of response (DOR) in a subpopulation of subjects with RRMM who had received 4 prior lines of therapy and whose disease was refractory to one proteasome inhibitor, one immunomodulatory agent, and one CD38-directed monoclonal antibody (reflective of the approved population) in a single-arm Phase 2 study.  As the approval was granted using the accelerated approval pathway, the approval was subject to a postmarketing requirement to verify and describe the clinical benefit of the drug in a Phase 3 trial.  The confirmatory trial was to have a primary endpoint of progression-free survival (PFS) and secondary endpoints including ORR and overall survival (OS).

Oncopeptides subsequently conducted a randomized, controlled Phase 3 trial comparing Pepaxto and dexamethasone to pomalidomide and dexamethasone.  This trial did not meet its primary endpoint of improvement in PFS using the pre-specified analysis and appeared to show a detrimental effect on OS.  In September 2022, CDER convened a meeting of the Oncology Drugs Advisory Council (ODAC), which voted 14-2 that the benefit-risk profile of Pepaxto was not favorable for the indicated population.

In December 2022, FDORA was enacted.  Among other things, it revised the provisions relating to accelerated approval at 21 U.S.C. § 356(c) to describe specific expedited procedures to withdraw an accelerated approval if certain conditions are met, including where a required confirmatory study fails to verify and describe the predicted clinical benefit or where evidence demonstrates the product is not shown to be safe or effective under the conditions of use.  The new procedures include the provision of due notice and an explanation for a proposed withdrawal, an opportunity for a meeting with the Commissioner or the Commissioner’s designee, an opportunity for a written appeal, an opportunity for public comment, and the convening of an advisory committee if requested and no such committee had previously advised FDA on the relevant issues.  However, the timelines for these procedures were not specified by the law.  FDORA also directed FDA to issue draft guidance on the topic of the new expedited procedures for withdrawal of accelerated approval not later than 18 months following enactment and a final guidance 1 year after the close of the public comment period on the draft guidance.  FDA has not yet published draft guidance; however, the statutory deadline to do so is June 2024.

On July 7, 2023, armed with these new procedures, CDER notified Oncopeptides that it proposed expedited withdrawal of Pepaxto because the postapproval study failed to verify clinical benefit and because Pepaxto was not shown to be safe or effective under its conditions of use (the documents discussed herein are published in the docket here).  As dictated by FDORA, the notice offered the opportunity for a meeting and/or written appeal, which the notice stated should be submitted within 30 days.  The notice explained that if Oncopeptides decided to appeal the proposal to withdraw, there would be an opportunity for public comment.  It also stated that, since the ODAC had already met to discuss the relevant issues, Oncopeptides was not entitled to another advisory committee meeting.  If Oncopeptides decided not to appeal, the notice encouraged the company to request a voluntary withdrawal of approval and to waive the procedural options in the new statutory language.  Moreover, if Oncopeptides did not respond within 15 business days either requesting voluntary withdrawal of approval or notifying FDA of its intent to submit a written appeal, FDA would deem Oncopeptides to have waived the new procedures.  The notice was accompanied by a detailed explanation of the justification for CDER’s determination, as required by FDORA, drafted by the review division to the CDER Director, Dr. Patrizia Cavazzoni.

Before the 15-business day window expired, Oncopeptides submitted a notification to FDA of its intent to file a written appeal within 30 days of receipt of the original notification.  Additionally, Oncopeptides requested a meeting with the Commissioner or the Commissioner’s designee.  In response, Commissioner Dr. Robert Califf designated CBER Director, Dr. Peter Marks, to serve as the Commissioner’s designee for both the appeal and the opportunity for a meeting.

On August 4, 2023, Oncopeptides submitted its appeal.  In an August 9, 2023, letter, Dr. Marks notified both CDER and Oncopeptides of the documents, including CDER’s notice and explanation and Oncopeptides’s appeal document, that would be submitted to the to-be-opened docket with the required notice for public comment on the proposed withdrawal.  Dr. Marks also requested that CDER submit a response to Oncopeptides’s appeal by September 8, 2023, and stated that his team would work to coordinate a meeting with the parties following this response.

On September 8, 2023, CDER submitted its response.  The next document in the docket is a letter from Dr. Marks referring to an upcoming October 2, 2023, joint (virtual) meeting with CDER and Oncopeptides.  The letter described the mechanics and timing of the meeting, laying out a 2-hour agenda, with 50 minutes dedicated to a presentation by Oncopeptides.  The parties submitted additional arguments prior to the meeting that were posted in the docket.  Additionally, the docket contains the slides that were used by CDER and Oncopeptides during the meeting.  The docket also contains a brief summary of the meeting.

On February 23, 2024, Dr. Marks issued his final decision, which concluded that the grounds for withdrawing approval were met.  The justification for his decision was that the confirmatory study did not confirm clinical benefit, and the available evidence demonstrated that Pepaxto was not shown to be safe or effective under its conditions of use.  Either of these conditions would be sufficient grounds for withdrawal of the approval.  A section of the final decision letter addressed a proposal made by Oncopeptides that Pepaxto remain on the market, potentially with a narrower indication, while further studies were conducted.  Dr. Marks’s letter cited the previous experience with Avastin’s withdrawal in determining that this was contrary to legislative intent.  Moreover, the letter noted that whether Pepaxto was safe and effective for a narrower indication was outside the scope of the statutory basis for withdrawing accelerated approval; the question was whether it should remain on the market as currently approved and labeled.

With FDORA in place and designed to provide a structured and expedited process for withdrawal of an accelerated approval, it is a safe bet that this is not the last we will see of this process.  However, FDORA left a lot to FDA interpretation, and with the deadline for the draft guidance several months away, this case may provide a window into FDA’s thinking.  For example, in deciding this appeal, Dr. Marks ultimately combined the meeting and the written appeal into a single process.  In theory, a company may request one or the other, but it appears reasonable that we would see this in the future.  The table below may also provide a guide for timing for a future appeal.  Of note, the fact that Oncopeptides was not eligible for an additional advisory committee meeting likely made this process faster than it might otherwise have been.

Timeline of Key Events

EventDate (days from notice of proposed withdrawal)
CDER notice and explanation of proposed withdrawalJuly 7, 2023
Oncopeptides notification of intent to file written appeal and requesting meetingJuly 26, 2023 (13 business days)*
Oncopeptides submission of written appealAugust 4, 2023 (28 days)**
CDER announcement in Federal Register of opportunity for public commentAugust 25, 2023 (49 days)
CDER response to appealSeptember 8, 2023 (63 days)
Meeting with Commissioner’s designeeOctober 2, 2023 (87 days)
Final DecisionFebruary 23, 2024 (231 days)

*FDA’s deadline was 15 business days

**FDA’s deadline was 30 days