Document ID: FDA-2020-N-2029-0226
Agency: fda
Document Type: Notice
Title: Proposal To Withdraw Approval of MAKENA; Hearing
Posted Date: 2022-08-17T04:00Z

[Federal Register Volume 87, Number 158 (Wednesday, August 17, 2022)]
[Notices]
[Pages 50626-50629]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2022-17715]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2020-N-2029]

Proposal To Withdraw Approval of MAKENA; Hearing

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of hearing.

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SUMMARY: The Food and Drug Administration (FDA, Agency, or we) has 
granted a hearing on the Center for Drug Evaluation and Research's 
(CDER's) proposal to withdraw approval of MAKENA (hydroxyprogesterone 
caproate injection, 250 milligrams (mg) per milliliter (mL), once 
weekly), new drug application (NDA) 021945, held by Covis Pharma Group/
Covis Pharma GmbH (Covis). This notice provides information and details 
regarding the hearing, including the time, date, and format of the 
hearing, as well as the questions to be posed to the advisory committee 
at the hearing.

DATES: The hearing will be held virtually October 17 to 19, 2022, 
beginning at 8 a.m. Eastern Time on each day and concluding at 4 p.m. 
on Days 1 and 2 and 12:30 p.m. on Day 3. Either electronic or written 
comments on the hearing must be submitted by November 3, 2022.

ADDRESSES: The docket number for this matter is FDA-2020-N-2029. The 
docket will close on November 3, 2022. Either electronic or written 
comments on this hearing must be submitted by November 3, 2022. 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 on November 3, 2022. Comments 
received by mail/hand delivery/courier (for written/paper submissions) 
will be considered timely if they are received on or before that date. 
Comments received on or before October 11, 2022, will be provided to 
the advisory committee for consideration.
    You may submit comments as follows:

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'').

[[Page 50627]]

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-2020-N-2029 for ``Proposal to Withdraw Marketing Approval; 
Hearing.'' 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 
our 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: Rachael Vieder Linowes, Office of 
Scientific Integrity, Food and Drug Administration, 10903 New Hampshire 
Ave., Bldg. 1, Rm. 4206, Silver Spring, MD 20993; 240-402-5931, 
[email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    Section 506 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) 
(21 U.S.C. 356) provides that a drug sponsor may request to expedite 
the review and approval of a drug intended to treat an unmet need 
related to a serious or life-threatening disease or condition. Under 
the accelerated approval pathway, FDA may grant accelerated approval 
based on the drug's effect on a surrogate or an intermediate clinical 
endpoint. FDA's regulations, at Sec.  314.510 (21 CFR 314.510), require 
that accelerated approval be subject to a sponsor's engaging in further 
study ``to verify and describe [the drug's] clinical benefit, where 
there is uncertainty as to the relation of the surrogate endpoint to 
clinical benefit, or of the observed clinical benefit to ultimate 
outcome.''
    Under section 506(c)(3) of the FD&C Act, FDA may withdraw approval 
of a drug approved under this pathway if, among other reasons, the 
required study fails to verify ``the predicted effect on 
irreversibility morbidity or mortality or other clinical benefit.'' 
Under Sec.  314.530(a) (21 CFR 314.530(a)), FDA may withdraw 
accelerated approval of a drug when ``[a] postmarketing clinical study 
fails to verify clinical benefit'' or ``[o]ther evidence demonstrates 
that the drug product is not shown to be safe or effective under its 
conditions of use,'' among other circumstances.
    To initiate the process for withdrawing accelerated approval of a 
drug, the Director of CDER must provide the applicant with notice of an 
opportunity for a hearing on the proposed grounds for withdrawal under 
Sec.  314.530(b). To obtain a hearing, the applicant must, pursuant to 
Sec.  314.530(c), request one within 15 days after receiving CDER's 
notice and submit ``the data and information upon which [it] intends to 
rely at the hearing'' within 30 days thereafter.
    Pursuant to Sec.  314.530(e)(1), FDA conducts hearings under Sec.  
314.530 in accordance with part 15 (21 CFR part 15), with certain 
modifications. The key modification under Sec.  314.530(e)(1) is that 
an advisory committee is present at the hearing and provides advice and 
recommendations to the Commissioner. Under Sec.  314.530(e)(2), the 
presiding officer, the members of the advisory committee, and up to 
three representatives from both the applicant and CDER may ask 
questions of the presenters at the hearing. The presiding officer, as a 
matter of discretion, may also permit questions of presenters posed by 
others participating in the hearing upon submission of such questions 
in writing. After receiving advice and recommendations from the 
advisory committee, the Commissioner of Food and Drugs makes the final 
decision on whether to withdraw accelerated approval of the drug 
product at issue (see Sec.  314.530(f)).
    On February 3, 2011, FDA approved the NDA for MAKENA under the 
accelerated approval pathway to reduce the risk of preterm birth in 
women with a singleton pregnancy who have a history of singleton 
spontaneous preterm birth. As described in CDER's proposal to withdraw 
approval, the MAKENA NDA ``relied on evidence from the Maternal Fetal 
Medicine Unit (MFMU) Network trial (referred to as `Trial 002') for 
primary support of efficacy and safety.'' CDER granted accelerated 
approval based on the results for Trial 002. Consistent with section 
506(c)(2) of the FD&C Act and Sec.  314.510, CDER's approval letter 
required, inter alia, that the sponsor complete a postmarketing 
confirmatory study, described as ``a clinical trial of MAKENA in women 
with a singleton pregnancy who had a previous spontaneous preterm birth 
(Protocol #17P-ES-003)'' (Trial 003).
    On October 5, 2020, CDER proposed withdrawing accelerated approval 
of MAKENA and provided Covis with an opportunity to request a hearing 
on the proposal.\1\ In the proposal, CDER cited two grounds under 
section 506(c)(3) of the FD&C Act and Sec.  314.530(a) for withdrawing 
approval: (1) the confirmatory study failed to verify clinical benefit 
of the drug and (2) the evidence does not establish that the drug is 
effective under its conditions of use. CDER's proposal to withdraw 
approval also provided notice to all holders of approved abbreviated 
new drug applications (ANDAs) referencing the NDA for MAKENA (NDA 
021945) that, if the Agency withdraws

[[Page 50628]]

accelerated approval of MAKENA, CDER would proceed to withdraw approval 
of the ANDAs under 21 CFR 314.151(b)(3).
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    \1\ AMAG Pharmaceuticals, Inc. (AMAG), the sponsor of NDA 021945 
at the time, received this notice. After AMAG requested a hearing, 
Covis acquired AMAG, including NDA 021945. For efficiency, this 
notice refers to AMAG as ``Covis.''
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    On October 14, 2020, Covis timely requested a hearing and sought an 
additional 30 days in which to submit data and information in support. 
On December 4, 2020, after receiving an extension of time within which 
to do so, Covis further responded to CDER's proposal to withdraw 
accelerated approval of MAKENA. The response included data and 
information and incorporated other data and information in FDA's 
administrative files by reference.\2\
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    \2\ The presiding officer has subsequently granted requests by 
Covis to submit additional data and information that were not 
included in its December 4, 2020, submission and may do so again 
based on a showing of good cause.
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    By letter to CDER and Covis dated August 18, 2021, FDA's Chief 
Scientist granted Covis's hearing request and appointed Celia M. Witten 
as presiding officer.

II. Notice of Hearing Under Part 15 and Sec.  314.530

    This public hearing will be held in accordance with part 15 and 
Sec.  314.530. The presiding officer will conduct the hearing, and an 
advisory committee will be present at the hearing for purposes of 
considering the data and information presented by CDER and Covis with 
respect to CDER's proposal to withdraw accelerated approval of MAKENA 
and providing advice to the Commissioner of Food and Drugs on that 
proposal (see Sec.  314.530(e)).
    Under 21 CFR 15.30(f), the hearing is informal, and the rules of 
evidence do not apply. In accordance with Sec.  314.530(e)(2), however, 
only the presiding officer, the members of the advisory committee, and 
up to three representatives from CDER and Covis may pose questions to 
the advisory committee at the hearing itself. The presiding officer may 
nonetheless exercise her discretion under Sec.  314.530(e)(2) to allow 
others to propose questions by submitting them in writing for her 
consideration. In the interest of economy and efficiency, particularly 
given the virtual platform, the presiding officer has determined that 
only the holders of ANDAs referencing the NDA for MAKENA (ANDA holders) 
will be permitted to submit questions; that all proposed questions must 
be submitted to the docket for this proceeding in advance of the 
hearing; and that the questions selected will be posed to CDER and 
Covis at the close of their respective presentations (see section IV of 
this document).

III. Questions To Be Addressed at the Public Hearing

    The questions to be posed to the advisory committee at the hearing 
are as follows:
    1. For discussion and vote:
    Do the findings from Trial 003 verify the clinical benefit of 
MAKENA on neonatal morbidity and mortality from complications of 
preterm birth?
    2. For discussion and vote:
    Does the available evidence demonstrate that MAKENA is effective 
for its approved indication of reducing the risk of preterm birth in 
women with a singleton pregnancy who have a history of singleton 
spontaneous preterm birth?
    3. For discussion:
    Should FDA allow MAKENA to remain on the market? As part of that 
discussion, you may discuss:
     whether the benefit-risk profile supports retaining the 
product on the market;
     what types of studies could provide confirmatory evidence 
to verify the clinical benefit of MAKENA on neonatal morbidity and 
mortality from complications of preterm birth?
    For vote:
    Considering your responses to the previous questions both in the 
discussions and votes, should FDA allow MAKENA to remain on the market 
while an appropriate confirmatory study is designed and conducted?

IV. Participating in the Public Hearing

    Persons wishing to view the hearing may access the webcast at the 
following separate links on the respective days of the hearing:
    Day 1: https://youtu.be/EEm7pM_LgsM.
    Day 2: https://youtu.be/Nt2bcDVgpag.
    Day 3: https://youtu.be/Dal27hktzcg.
    Request for Oral Presentations: We currently expect public 
participation to occur from 2 p.m. to 4 p.m. Eastern Time on the first 
day of the hearing and from 8 a.m. to 10 a.m. on the second day. 
Persons interested in participating in the hearing by making an oral 
presentation during the 4 hours currently reserved for such 
presentations must submit requests by 11:59 p.m. Eastern Time on 
September 6, 2022, as further described below.
    If you wish to make a formal presentation or present oral comments 
during the session for public participation, you must register at the 
following link by 5 p.m. Eastern Time on September 6, 2022: https://www.surveymonkey.com/r/B72THCF. When registering, please provide 
complete contact information, including name, title, affiliation, 
address, email, and telephone number. To complete your request for an 
opportunity to make a presentation at the hearing, you must also submit 
a comment to the docket for this hearing matter (see ADDRESSES) by 
11:59 p.m. Eastern Time on September 6, 2022, and clearly indicate in 
the heading and/or cover page that your comment is a ``Request for Oral 
Presentation.''
    In the ``Request for Oral Presentation'' submitted to the public 
docket, you must identify yourself and others who will join you for 
your presentation, list the affiliation (if any) of each individual 
participating in your presentation (including your own), and request a 
specific amount of time for your presentation. You must also include a 
summary of what you plan to present at the hearing and a copy of any 
slide deck, along with any data or information on which you intend to 
rely at the hearing that is not already referenced or included in the 
public docket for this hearing matter. No commercial or promotional 
material will be permitted to be presented or distributed at the public 
hearing.
    We urge organizations with common interests to consolidate or 
coordinate their presentations. In accordance with 21 CFR 15.21(c), the 
presiding officer may require joint presentations by persons with 
common interests.
    The presiding officer will determine the amount of time allotted to 
each presenter and the approximate time each presentation is to begin 
and will select and notify participants by September 30, 2022. If you 
are notified that you will be a presenter, we encourage you to be 
online well in advance of the approximate time provided in the notice. 
Actual presentation times may vary based on how the hearing progresses.
    Proposed Questions: To propose a question to either CDER or Covis, 
an ANDA holder must submit a comment to the docket for this hearing 
matter (see ADDRESSES) by 11:59 p.m. Eastern Time on September 30, 
2022; indicate in the heading and/or cover page that the comment 
includes ``Proposed Question(s)''; and state in the submission that the 
question or questions are being proposed by a specific ANDA holder or 
someone authorized to do so on that specific ANDA holder's behalf. The 
comment should also indicate whether each proposed question is intended 
for CDER, Covis, or both.

[[Page 50629]]

    Transcripts: Please be advised that as soon as a transcript of the 
public hearing is available, it will be accessible at https://www.regulations.gov. It may also be viewed at the address where Dockets 
Management Staff is located (see ADDRESSES). A link to the transcript 
will also be available on the Agency's website.

    Dated: August 12, 2022.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2022-17715 Filed 8-16-22; 8:45 am]
BILLING CODE 4164-01-P