[Federal Register Volume 89, Number 111 (Friday, June 7, 2024)]
[Notices]
[Pages 48647-48649]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[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 
https://www.regulations.gov 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:
     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-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 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: Christopher Koepke, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Silver Spring, MD 20993, 301-651-7695, 
[email protected].

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 https://www.regulations.gov. 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