[Federal Register Volume 88, Number 164 (Friday, August 25, 2023)]
[Notices]
[Pages 58282-58284]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2023-18320]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2023-N-3167]


Notice of Opportunity for Public Comment on Proposal To Withdraw 
Approval of New Drug Application for PEPAXTO, Equivalent to 20 
Milligrams Base per Vial

AGENCY: Center for Drug Evaluation and Research, Food and Drug 
Administration, HHS.

[[Page 58283]]


ACTION: Notice of opportunity for public comment.

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SUMMARY: The Center for Drug Evaluation and Research (CDER) of the Food 
and Drug Administration (FDA, the Agency) is proposing to withdraw 
approval of PEPAXTO (melphalan flufenamide) for injection, equivalent 
to (EQ) 20 milligrams (mg) BASE/VIAL, once every 28 days, new drug 
application (NDA) 214383, held by Oncopeptides AB (Oncopeptides). This 
notice is intended to provide an opportunity for public comment on 
CDER's proposed withdrawal of PEPAXTO, in accordance with the expedited 
withdrawal of approval procedures described in the Federal Food, Drug 
and Cosmetic Act (FD&C Act).

DATES: Either electronic or written comments on this proposal to 
withdraw PEPAXTO must be submitted by September 25, 2023.

ADDRESSES: You may submit comments as follows. Please note that late, 
untimely filed comments will not be considered. The https://www.regulations.gov electronic filing system will accept comments until 
11:59 p.m. Eastern Time at the end of September 25, 2023. Comments 
received by mail/hand delivery/courier (for written/paper submissions) 
will be considered timely if they are received on or before that date.

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2023-N-3167 for ``Notice of Opportunity for Public Comment on 
Proposal To Withdraw Approval of New Drug Application for PEPAXTO, 
Equivalent to 20 Milligrams Base per Vial.'' Received comments, those 
filed in a timely manner (see ADDRESSES), will be placed in the docket 
and, except for those submitted as ``Confidential Submissions,'' 
publicly viewable at https://www.regulations.gov or at the Dockets 
Management Staff between 9 a.m. and 4 p.m., Monday through Friday, 240-
402-7500.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852, 240-402-7500.

FOR FURTHER INFORMATION CONTACT: Anuj Shah, Center for Drug Evaluation 
and Research, Food and Drug Administration, 10903 New Hampshire Ave., 
Bldg. 51, Rm. 6224, Silver Spring, MD 20993-0002, 301-796-2246.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA approved NDA 214383 for PEPAXTO on February 26, 2021, under the 
accelerated approval pathway (section 506(c) of the FD&C Act (21 U.S.C. 
356(c)) and 21 CFR part 314, subpart H) for use in combination with 
dexamethasone for the treatment of adult patients with relapsed or 
refractory multiple myeloma who have received at least four prior lines 
of therapy and whose disease is refractory to at least one proteasome 
inhibitor, one immunomodulatory drug, and one CD38-directed monoclonal 
antibody (triple class refractory).\1\
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    \1\ Most patients in the United States with relapsed disease 
will have been exposed to lenalidomide (an immunomodulatory agent), 
a proteasome inhibitor, corticosteroids, and an anti-CD38 monoclonal 
antibody after one or two lines of treatment, and retreatment with 
previously used agents or agents in the same class of drug can be 
effective.
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    NDA 214383 relied on evidence from Trial OP-106 (ClinicalTrials.gov 
NCT number, NCT02963493), also known as HORIZON, a single-arm, open-
label, phase 2 multicenter clinical trial that enrolled patients with 
relapsed or refractory multiple myeloma and who received at least two 
lines of prior therapy including an immunomodulatory drug and a 
proteasome inhibitor. The primary endpoint was overall response rate 
(ORR),\2\ as assessed by the investigator.
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    \2\ ORR was defined as the proportion of patients with a best 
confirmed response of stringent complete response, complete 
response, very good partial response, or partial response according 
to the International Myeloma Working Group Uniform Response 
Criteria.
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    At the time of approval under the accelerated approval pathway, the 
applicant was required to conduct an appropriate post-approval study to 
verify and describe the clinical benefit of PEPAXTO.\3\ CDER has 
determined

[[Page 58284]]

withdrawal of approval is warranted because the required post-approval 
confirmatory trial failed to verify clinical benefit and because 
available evidence demonstrates PEPAXTO is not shown to be safe or 
effective under its conditions of use. The Oncologic Drugs Advisory 
Committee (ODAC) convened on September 22, 2022, to discuss issues 
related to this proposed withdrawal. The ODAC voted 14 to 2 that the 
benefit-risk profile of melphalan flufenamide was not favorable for the 
currently indicated patient population. For additional background, 
please refer to CDER's letter to Oncopeptides Re: Section 506(c)(3)(B) 
Notice of Proposed Withdrawal of Approval; PEPAXTO (melphalan 
flufenamide) for injection; NDA 214383 (``Notice to Oncopeptides of 
Proposed Withdrawal of PEPAXTO'') and CDER's Proposed Withdrawal of 
PEPAXTO Decisional Memorandum, available at Docket No. FDA-2023-N-3167, 
https://www.regulations.gov.
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    \3\ Section 506(c)(2)(A)(i) of the FD&C Act (as renumbered by 
the Consolidated Appropriations Act of 2023 (Pub. L. 117-328); see 
also 21 CFR 314.510.
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II. Legal Standard for Withdrawal of Approval

    Section 506(c) of the FD&C Act, as amended most recently by the 
Consolidated Appropriations Act of 2023 (Pub. L. 117-328), describes 
the accelerated approval of new drug applications and the procedures 
and authority governing expedited withdrawal of approval. FDA has the 
legal authority to use the expedited procedures to withdraw approval of 
a product that has received accelerated approval if, among other 
reasons, ``a study required to verify and describe the predicted effect 
on irreversible morbidity or mortality or other clinical benefit of the 
product fails to verify and describe such effect or benefit'' (section 
506(c)(3)(A)(ii) of the FD&C Act) or ``other evidence demonstrates that 
the product is not shown to be safe or effective under the conditions 
of use.'' (section 506(c)(3)(A)(iii) of the FD&C Act.)

III. Explanation for the Proposed Withdrawal

    CDER proposes to withdraw approval of PEPAXTO because the required 
confirmatory study, Trial OP-103, also known as OCEAN, failed to verify 
clinical benefit and because available evidence demonstrates PEPAXTO is 
not shown to be safe or effective under its conditions of use. More 
specifically, the results failed to show that PEPAXTO had a significant 
effect on the primary endpoint of progression-free survival. 
Furthermore, the observed median overall survival was 5.3 months 
shorter in the PEPAXTO arm compared to the control arm. After 
considering all the available data and the discussion at the ODAC held 
in September 2022, CDER recommends withdrawing the accelerated approval 
for PEPAXTO. Please refer to CDER's ``Notice to Oncopeptides of 
Proposed Withdrawal of PEPAXTO'' and ``Proposed Withdrawal of PEPAXTO 
Decisional Memorandum'' for additional explanation.

IV. Opportunity for Public Comment on CDER's Proposal To Withdraw 
Approval of PEPAXTO

    In accordance with the expedited withdrawal of approval procedures 
described in section 506(c)(3)(B)(ii) and (iii) of the FD&C Act, CDER 
is providing an opportunity for public comment on its proposal to 
withdraw approval of NDA 214383 (PEPAXTO) through the issuance of a 
Federal Register Notice. FDA will consider any such public comments it 
receives in making its decision on CDER's proposal to withdraw approval 
of NDA 214383 (PEPAXTO) and make available on its website and in the 
public docket a summary of such comments and FDA's response to them.

    Dated: August 21, 2023.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2023-18320 Filed 8-24-23; 8:45 am]
BILLING CODE 4164-01-P