Notice2022-17715
Proposal To Withdraw Approval of MAKENA; Hearing
Primary source
Metadata and text below are from the Federal Register, a public-domain U.S. government work. Always verify the official published version before relying on it for any legal matter.
Published
August 17, 2022
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
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.
Full Text
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<title>Federal Register, Volume 87 Issue 158 (Wednesday, August 17, 2022)</title>
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[Federal Register Volume 87, Number 158 (Wednesday, August 17, 2022)]
[Notices]
[Pages 50626-50629]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[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
<a href="https://www.regulations.gov">https://www.regulations.gov</a> 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:
<bullet> Federal eRulemaking Portal: <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to <a href="https://www.regulations.gov">https://www.regulations.gov</a>
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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
<bullet> 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:
<bullet> 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.
<bullet> 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a> or at the Dockets Management Staff between 9 a.m.
and 4 p.m., Monday through Friday, 240-402-7500.
<bullet> 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
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: <a href="https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf">https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf</a>.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to <a href="https://www.regulations.gov">https://www.regulations.gov</a> 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,
<a href="/cdn-cgi/l/email-protection#621003010a03070e4c0e0b0c0d150711220406034c0a0a114c050d14"><span class="__cf_email__" data-cfemail="aedccfcdc6cfcbc280c2c7c0c1d9cbddeec8cacf80c6c6dd80c9c1d8">[email protected]</span></a>.
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:
<bullet> whether the benefit-risk profile supports retaining the
product on the market;
<bullet> 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: <a href="https://youtu.be/EEm7pM_LgsM">https://youtu.be/EEm7pM_LgsM</a>.
Day 2: <a href="https://youtu.be/Nt2bcDVgpag">https://youtu.be/Nt2bcDVgpag</a>.
Day 3: <a href="https://youtu.be/Dal27hktzcg">https://youtu.be/Dal27hktzcg</a>.
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: <a href="https://www.surveymonkey.com/r/B72THCF">https://www.surveymonkey.com/r/B72THCF</a>. 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>. 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
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