Notice2024-12564
Proposal To Refuse To Approve a New Drug Application Supplement for HETLIOZ (Tasimelteon); Opportunity for a Hearing
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Published
June 7, 2024
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Director of the Center for Drug Evaluation and Research (Center Director) at the Food and Drug Administration (FDA or Agency) is proposing to refuse to approve a supplemental new drug application (sNDA) submitted by Vanda Pharmaceuticals, Inc. (Vanda), for HETLIOZ (tasimelteon) capsules, 20 milligrams (mg), in its present form. This notice summarizes the grounds for the Center Director's proposal and offers Vanda an opportunity to request a hearing on the matter.
Full Text
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<title>Federal Register, Volume 89 Issue 111 (Friday, June 7, 2024)</title>
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[Federal Register Volume 89, Number 111 (Friday, June 7, 2024)]
[Notices]
[Pages 48647-48649]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2024-12564]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2022-N-2390]
Proposal To Refuse To Approve a New Drug Application Supplement
for HETLIOZ (Tasimelteon); Opportunity for a Hearing
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Director of the Center for Drug Evaluation and Research
(Center Director) at the Food and Drug Administration (FDA or Agency)
is
[[Page 48648]]
proposing to refuse to approve a supplemental new drug application
(sNDA) submitted by Vanda Pharmaceuticals, Inc. (Vanda), for HETLIOZ
(tasimelteon) capsules, 20 milligrams (mg), in its present form. This
notice summarizes the grounds for the Center Director's proposal and
offers Vanda an opportunity to request a hearing on the matter.
DATES: Either electronic or written requests for a hearing must be
submitted by July 8, 2024; submit data, information, and analyses in
support of the hearing and any other comments by August 6, 2024.
ADDRESSES: You may submit hearing requests, documents in support of the
hearing, and any other comments as follows. Please note that late,
untimely filed requests and documents will not be considered. The
<a href="https://www.regulations.gov">https://www.regulations.gov</a> electronic filing system will accept
hearing requests until 11:59 p.m. Eastern Time at the end of July 8,
2024, and will accept documents in support of the hearing and any other
comments until 11:59 p.m. Eastern Time at the end of August 6, 2024.
Documents received by mail/hand delivery/courier (for written/paper
submissions) will be considered timely if they are received on or
before these dates.
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'').
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-2022-N-2390 for ``Proposal To Refuse To Approve a New Drug
Application Supplement for HETLIOZ (Tasimelteon); Opportunity for a
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
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 <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: Christopher Koepke, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Silver Spring, MD 20993, 301-651-7695,
<a href="/cdn-cgi/l/email-protection#e3a08b918a90978c938b8691cda88c86938886a3858782cd8b8b90cd848c95"><span class="__cf_email__" data-cfemail="47042f352e343328372f2235690c2822372c2207212326692f2f3469202831">[email protected]</span></a>.
SUPPLEMENTARY INFORMATION:
I. Proposal To Refuse To Approve sNDA 205677-012
FDA approved new drug application 205677 for HETLIOZ (tasimelteon)
capsules for treatment of non-24-hour sleep-wake disorder on January
31, 2014, and for treatment of Smith-Magenis syndrome in patients 16
years of age and older on December 1, 2020. On May 4, 2023, Vanda
submitted sNDA 205677-012 for HETLIOZ (tasimelteon) capsules, 20 mg, as
an efficacy supplement proposing to add a new indication for the
treatment of insomnia characterized by difficulties with sleep
initiation.
To support an indication for the treatment of insomnia
characterized by difficulties with sleep initiation, Vanda referred to
three studies, Study 3101, Study 3104, and Study 3107, as primary
support for demonstrating substantial evidence of effectiveness. The
application proposes that Studies 3101, 3104, and 3107 together; Study
3104 alone; or Study 3104 with confirmatory evidence, provides
substantial evidence of effectiveness for the proposed conditions of
use.
On March 4, 2024, the Office of Neuroscience in the Center for Drug
Evaluation and Research (CDER) issued a complete response letter to
Vanda under Sec. 314.110(a) (21 CFR 314.110(a)) stating that sNDA
205677-012 could not be approved in its present form because the
application does not provide substantial evidence of effectiveness for
tasimelteon and does not demonstrate that the drug is safe for the
treatment of insomnia characterized by difficulties with sleep
initiation. The complete response letter described the specific
deficiencies that led to this determination and, where possible,
recommended ways that Vanda might remedy these deficiencies. Those
deficiencies are summarized below.
(1) Studies 3101 and 3107 are not adequate and well-controlled for
[[Page 48649]]
insomnia disorder because the design excluded subjects with insomnia
disorder, and scientific evidence was not provided to demonstrate that
changes in healthy volunteers without insomnia disorder would
correspond to a similar degree of response in patients with insomnia
disorder (see 21 CFR 314.126(b)(3)).
(2) The application does not include adequate subjective, patient-
reported data to demonstrate clinical benefit associated with the
polysomnogram findings in Study 3104. Only one subjective endpoint at
an early timepoint was found to be nominally significant; no other
secondary endpoints were nominally significant, and none were
statistically significant. Endpoints derived from patient-reported
outcome measures are necessary to demonstrate that the change in sleep
latency measured by polysomnogram is perceptible to the patient and
that the patient experiences a measurable subjective improvement in
symptoms.
(3) The results of Studies 3101 and 3107 do not demonstrate
statistically or nominally significant improvements on subjective sleep
latency. Furthermore, they are not adequate to provide substantiation
of the effect of a drug used for insomnia, which is a chronic
indication, because they were single-dose studies in healthy subjects
that excluded subjects with insomnia.
(4) The application does not provide longer-term efficacy data to
demonstrate that this treatment would be effective for long-term use in
this chronic condition.
(5) The application does not provide data to support effectiveness
in patients 65 years of age and older with insomnia disorder, who are
within the intended patient population according to the proposed
conditions of use.
(6) The application does not provide long-term safety data in
adults of all ages with insomnia disorder. In addition, the application
provided insufficient data to support safety in patients 65 years and
older with insomnia disorder.
(7) With respect to the proposals that Study 3104 alone, or with
confirmatory evidence, is sufficient to demonstrate substantial
evidence of effectiveness, the application does not establish either.
Even if Study 3104 did not have the deficiencies described in the
complete response letter and summarized above, and even if a single
adequate and well-controlled study could be sufficient for the proposed
conditions of use, Study 3104 lacks the features of a study that could
alone provide substantial evidence of effectiveness. In addition, the
confirmatory evidence proposed in the application (i.e., to provide
evidence of effectiveness for closely related approved indications,
mechanistic data, or the effectiveness of members of the same
pharmacological class as tasimelteon) would be insufficient.
These deficiencies preclude a finding that the application provides
substantial evidence of effectiveness for tasimelteon or that the
application demonstrates that tasimelteon is safe, for the treatment of
insomnia characterized by difficulties with sleep initiation. The
complete response letter stated that to address the deficiencies, Vanda
would need to submit at least one positive, adequate, and well-
controlled study that addresses the deficiencies described in the
complete response letter.
The complete response letter stated that Vanda is required either
to resubmit the application, fully addressing all deficiencies listed
in the letter, or take other actions available under Sec. 314.110
(i.e., withdraw the application or request an opportunity for a
hearing).
Following the complete response letter, in a letter dated April 11,
2024, Vanda indicated that it wished to receive approval of its
application or a notice of opportunity for a hearing. For the reasons
described above, FDA cannot approve the application in its current
form; thus, we are issuing this notice of opportunity for a hearing.
II. Notice of Opportunity for a Hearing
For the reasons stated above and as explained in the March 4, 2024,
complete response letter, notice is given to Vanda and all other
interested persons that the Center Director proposes that FDA issue an
order refusing to approve sNDA 205677-012 on the grounds that the
application fails to meet the criteria for approval under section
505(d) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21
U.S.C. 355(d)) because there is a lack of substantial evidence that the
drug is effective, and the drug has not been shown to be safe, for
treatment of insomnia characterized by difficulties with sleep
initiation (sections 505(d)(4) and 505(d)(5) of the FD&C Act).\1\
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\1\ Section 505(d) of the FD&C Act provides that FDA shall
refuse to approve an application if, among other reasons, ``upon the
basis of the information submitted to him as part of the
application, or upon the basis of any other information before him
with respect to such drug, he has insufficient information to
determine whether such drug is safe for use under such conditions''
or ``there is a lack of substantial evidence that the drug will have
the effect it purports or is represented to have under the
conditions of use prescribed, recommended, or suggested in the
proposed labeling thereof[.]'' (Sections 505(d)(4) and 505(d)(5) of
the FD&C Act.)
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Vanda may request a hearing before the Commissioner of Food and
Drugs (the Commissioner) on the Center Director's proposal to refuse to
approve sNDA 205677-012. Pursuant to Sec. 314.200(c)(1) (21 CFR
314.200(c)(1)), if Vanda decides to seek a hearing, it must file: (1) a
written notice of participation and request for a hearing on or before
30 days after the notice is published in the Federal Register and (2)
the studies, data, information, and analyses relied upon to justify a
hearing, as specified in Sec. 314.200, on or before 60 days after the
date the notice is published in the Federal Register.
As stated in Sec. 314.200(g), a request for a hearing may not rest
upon mere allegations or denials but must present specific facts
showing that there is a genuine and substantial issue of fact that
requires a hearing to resolve. We note in this regard that because CDER
proposes to refuse to approve sNDA 205677-012 based on the multiple
deficiencies summarized above, any hearing request from Vanda should
address all those deficiencies. Failure to request a hearing within the
time provided and in the manner required by Sec. 314.200 constitutes a
waiver of the opportunity to request a hearing. If a hearing request is
not properly submitted, FDA will issue a notice refusing to approve
sNDA 205677-012.
The Commissioner will grant a hearing if there exists a genuine and
substantial issue of fact or if the Commissioner concludes that a
hearing would otherwise be in the public interest (see Sec.
314.200(g)(6)). If a hearing is granted, it will be conducted according
to the procedures provided in 21 CFR parts 10 through 16 (see 21 CFR
314.201).
Paper submissions under this notice of opportunity for a hearing
should be filed in one copy, except for those submitted as
``Confidential Submissions'' (see ``Written/Paper Submissions'' and
``Instructions'' in ADDRESSES). Except for data and information
prohibited from public disclosure under 21 U.S.C. 331(j) or 18 U.S.C.
1905, submissions may be seen in the Dockets Management Staff Office
between 9 a.m. and 4 p.m., Monday through Friday, and on the internet
at <a href="https://www.regulations.gov">https://www.regulations.gov</a>. This notice is issued under section
505(c)(1)(B) of the FD&C Act and Sec. Sec. 314.110(b)(3) and 314.200.
Dated: May 31, 2024.
Douglas C. Throckmorton,
Deputy Director, Center for Drug Evaluation and Research.
[FR Doc. 2024-12564 Filed 6-6-24; 8:45 am]
BILLING CODE 4164-01-P
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