On Friday, February 23, 2024, FDA introduced its last resolution to withdraw the approval of Pepaxto (melphalan flufenamide), which was accepted in February 2021 together with dexamethasone for the therapy of grownup sufferers with relapsed or refractory a number of myeloma (RRMM) who’ve obtained a minimum of 4 prior strains of remedy and whose illness is refractory to a minimum of one proteasome inhibitor, one immunomodulatory agent, and one CD38-directed monoclonal antibody. That is the third withdrawal of an accelerated approval FDA has carried out, following Avastin in 2011 and Makena in 2023. Notably, this resolution marks the primary use of the brand new expedited procedures for withdrawal of an accelerated approval that have been enacted within the Meals and Drug Omnibus Reform Act of 2022 (FDORA). Previous to FDORA’s enactment, the statute didn’t present particulars on the withdrawal procedures apart from providing a chance for a casual listening to.
With out commenting on the deserves of the choice, it’s an fascinating window into how FDA might use these new procedures in apply. All in all, the brand new expedited procedures took about 7 months from proposal to withdrawal. In contrast, the 2 earlier 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 accepted primarily based on total response price (ORR) and length of response (DOR) in a subpopulation of topics with RRMM who had obtained 4 prior strains of remedy and whose illness was refractory to 1 proteasome inhibitor, one immunomodulatory agent, and one CD38-directed monoclonal antibody (reflective of the accepted inhabitants) in a single-arm Section 2 research. Because the approval was granted utilizing the accelerated approval pathway, the approval was topic to a postmarketing requirement to confirm and describe the medical advantage of the drug in a Section 3 trial. The confirmatory trial was to have a main endpoint of progression-free survival (PFS) and secondary endpoints together with ORR and total survival (OS).
Oncopeptides subsequently carried out a randomized, managed Section 3 trial evaluating Pepaxto and dexamethasone to pomalidomide and dexamethasone. This trial didn’t meet its main endpoint of enchancment in PFS utilizing the pre-specified evaluation and appeared to indicate a detrimental impact on OS. In September 2022, CDER convened a gathering of the Oncology Medication Advisory Council (ODAC), which voted 14-2 that the benefit-risk profile of Pepaxto was not favorable for the indicated inhabitants.
In December 2022, FDORA was enacted. Amongst different issues, it revised the provisions referring to accelerated approval at 21 U.S.C. § 356(c) to explain particular expedited procedures to withdraw an accelerated approval if sure situations are met, together with the place a required confirmatory research fails to confirm and describe the anticipated medical profit or the place proof demonstrates the product shouldn’t be proven to be secure or efficient underneath the situations of use. The brand new procedures embrace the availability of due discover and a proof for a proposed withdrawal, a chance for a gathering with the Commissioner or the Commissioner’s designee, a chance for a written attraction, a chance for public remark, and the convening of an advisory committee if requested and no such committee had beforehand suggested FDA on the related points. Nevertheless, the timelines for these procedures weren’t specified by the regulation. FDORA additionally directed FDA to problem draft steering on the subject of the brand new expedited procedures for withdrawal of accelerated approval not later than 18 months following enactment and a last steering 1 yr after the shut of the general public remark interval on the draft steering. FDA has not but revealed draft steering; nevertheless, the statutory deadline to take action is June 2024.
On July 7, 2023, armed with these new procedures, CDER notified Oncopeptides that it proposed expedited withdrawal of Pepaxto as a result of the postapproval research didn’t confirm medical profit and since Pepaxto was not proven to be secure or efficient underneath its situations of use (the paperwork mentioned herein are revealed within the docket here). As dictated by FDORA, the discover supplied the chance for a gathering and/or written attraction, which the discover acknowledged must be submitted inside 30 days. The discover defined that if Oncopeptides determined to attraction the proposal to withdraw, there could be a chance for public remark. It additionally acknowledged that, for the reason that ODAC had already met to debate the related points, Oncopeptides was not entitled to a different advisory committee assembly. If Oncopeptides determined to not attraction, the discover inspired the corporate to request a voluntary withdrawal of approval and to waive the procedural choices within the new statutory language. Furthermore, if Oncopeptides didn’t reply inside 15 enterprise days both requesting voluntary withdrawal of approval or notifying FDA of its intent to submit a written attraction, FDA would deem Oncopeptides to have waived the brand new procedures. The discover was accompanied by an in depth clarification of the justification for CDER’s dedication, as required by FDORA, drafted by the evaluate division to the CDER Director, Dr. Patrizia Cavazzoni.
Earlier than the 15-business day window expired, Oncopeptides submitted a notification to FDA of its intent to file a written attraction inside 30 days of receipt of the unique notification. Moreover, Oncopeptides requested a gathering with the Commissioner or the Commissioner’s designee. In response, Commissioner Dr. Robert Califf designated CBER Director, Dr. Peter Marks, to function the Commissioner’s designee for each the attraction and the chance for a gathering.
On August 4, 2023, Oncopeptides submitted its attraction. In an August 9, 2023, letter, Dr. Marks notified each CDER and Oncopeptides of the paperwork, together with CDER’s discover and clarification and Oncopeptides’s attraction doc, that will be submitted to the to-be-opened docket with the required discover for public touch upon the proposed withdrawal. Dr. Marks additionally requested that CDER submit a response to Oncopeptides’s attraction by September 8, 2023, and acknowledged that his crew would work to coordinate a gathering with the events following this response.
On September 8, 2023, CDER submitted its response. The subsequent doc within the docket is a letter from Dr. Marks referring to an upcoming October 2, 2023, joint (digital) assembly with CDER and Oncopeptides. The letter described the mechanics and timing of the assembly, laying out a 2-hour agenda, with 50 minutes devoted to a presentation by Oncopeptides. The events submitted extra arguments previous to the assembly that have been posted within the docket. Moreover, the docket incorporates the slides that have been utilized by CDER and Oncopeptides through the assembly. The docket additionally incorporates a quick abstract of the assembly.
On February 23, 2024, Dr. Marks issued his final decision, which concluded that the grounds for withdrawing approval have been met. The justification for his resolution was that the confirmatory research didn’t affirm medical profit, and the accessible proof demonstrated that Pepaxto was not proven to be secure or efficient underneath its situations of use. Both of those situations could be enough grounds for withdrawal of the approval. A piece of the ultimate resolution letter addressed a proposal made by Oncopeptides that Pepaxto stay available on the market, probably with a narrower indication, whereas additional research have been carried out. Dr. Marks’s letter cited the earlier expertise with Avastin’s withdrawal in figuring out that this was opposite to legislative intent. Furthermore, the letter famous that whether or not Pepaxto was secure and efficient for a narrower indication was outdoors the scope of the statutory foundation for withdrawing accelerated approval; the query was whether or not it ought to stay available on the market as presently accepted and labeled.
With FDORA in place and designed to offer a structured and expedited course of for withdrawal of an accelerated approval, it’s a secure wager that this isn’t the final we are going to see of this course of. Nevertheless, FDORA left quite a bit to FDA interpretation, and with the deadline for the draft steering a number of months away, this case might present a window into FDA’s pondering. For instance, in deciding this attraction, Dr. Marks finally mixed the assembly and the written attraction right into a single course of. In principle, an organization might request one or the opposite, nevertheless it seems cheap that we’d see this sooner or later. The desk beneath may additionally present a information for timing for a future attraction. Of be aware, the truth that Oncopeptides was not eligible for a further advisory committee assembly doubtless made this course of sooner than it would in any other case have been.
Timeline of Key Occasions
Occasion | Date (days from discover of proposed withdrawal) |
CDER discover and clarification of proposed withdrawal | July 7, 2023 |
Oncopeptides notification of intent to file written attraction and requesting assembly | July 26, 2023 (13 enterprise days)* |
Oncopeptides submission of written attraction | August 4, 2023 (28 days)** |
CDER announcement in Federal Register of alternative for public remark | August 25, 2023 (49 days) |
CDER response to attraction | September 8, 2023 (63 days) |
Assembly with Commissioner’s designee | October 2, 2023 (87 days) |
Ultimate Determination | February 23, 2024 (231 days) |
*FDA’s deadline was 15 enterprise days
**FDA’s deadline was 30 days