[Federal Register Volume 87, Number 195 (Tuesday, October 11, 2022)]
[Notices]
[Pages 61337-61339]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2022-21932]
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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 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 November 10, 2022; submit data, information, and analyses
in support of the hearing and any other comments by December 12, 2022.
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 November
10, 2022, and will accept documents in support of the hearing and any
other comments until 11:59 p.m. Eastern Time at the end of December 12,
2022. 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: Kaetochi Okemgbo, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 6224, Silver Spring, MD 20993, 301-796-
1546, [email protected].
SUPPLEMENTARY INFORMATION:
I. Proposal To Refuse To Approve sNDA 205677-004
FDA approved new drug application (NDA) 205677 for HETLIOZ
(tasimelteon) for treatment of non-24-hour sleep-wake disorder on
January 31, 2014. On October 16, 2018, Vanda submitted sNDA 205677-004
for HETLIOZ (tasimelteon) capsule, 20 mg, as an efficacy supplement
proposing to add a new indication for the treatment of jet lag
disorder. Jet lag disorder is recognized by the International
Classification of Sleep Disorders as a circadian rhythm sleep-wake
disorder
[[Page 61338]]
resulting from a mismatch between an individual's internal circadian
clock and the local time, most frequently occurring in response to
rapid travel across time zones (Ref. 1). Jet lag disorder is
characterized by daytime fatigue, general malaise, memory difficulties,
difficulty staying alert, problems with concentration and decision-
making, and gastrointestinal symptoms (e.g., constipation or diarrhea)
(Ref. 1). Although symptoms of jet lag are common, all of the following
criteria must be met for a diagnosis of jet lag disorder:
(1) There is a complaint of insomnia or excessive daytime
sleepiness, accompanied by a reduction of total sleep time, associated
with transmeridian jet travel across at least two time zones.
(2) There is associated impairment of daytime function, general
malaise, or somatic symptoms (e.g., gastrointestinal disturbance)
within 1 to 2 days after travel.
(3) The sleep disturbance is not better explained by another
current sleep disorder, medical or neurological disorder, mental
disorder, medication use, or substance use disorder (Ref. 1).
Therefore, substantial evidence of efficacy of tasimelteon for the
treatment of jet lag disorder would include sufficient evidence to show
that the drug will have an effect on: (1) insomnia or excessive daytime
sleepiness, accompanied by a reduction of total sleep time, associated
with transmeridian jet travel across at least two time zones and (2) an
associated impairment of daytime function, general malaise, or somatic
symptoms within 1 to 2 days after travel, as those symptoms are
described in the diagnostic criteria for a diagnosis of jet lag
disorder.\1\
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\1\ In contrast, when appropriate, clinically meaningful
evidence that a drug has an effect on certain symptoms of a
multisymptom condition such as jet lag disorder may support an
indication limited to those particular symptoms. Because Vanda did
not propose such an indication in its sNDA, FDA did not consider
whether the data show substantial evidence of effectiveness for a
more limited use.
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On August 16, 2019, the former Division of Psychiatry Products,
Office of Drug Evaluation I (Division),\2\ issued a complete response
letter to Vanda under Sec. 314.110(a) (21 CFR 314.110(a)) stating that
sNDA 205677-004 could not be approved in its present form because the
application does not provide substantial evidence of efficacy for
tasimelteon for the treatment of jet lag disorder. The complete
response letter described the specific deficiencies that led to this
determination and, where possible, recommended ways that Vanda might
remedy these deficiencies. The following is a summary of these
deficiencies:
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\2\ This division is now the Division of Psychiatry within the
Office of Neuroscience in the Office of New Drugs (OND) of FDA's
Center for Drug Evaluation and Research (CDER).
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(1) There was inadequate justification for the primary endpoints
for the pivotal clinical trials, Study VP-VEC-162-3101 (Study 3101) and
VP-VEC-162-3107 (Study 3107). The primary endpoint in Study 3101 was
latency to persistent sleep as measured by polysomnogram. Latency to
persistent sleep is defined as the length of time that elapsed between
lights out and the point of 10 minutes of solid (persistent) sleep. The
primary endpoint in Study 3107 was total sleep time in the first two-
thirds of the night as measured by polysomnogram. Both latency to
persistent sleep and total sleep time in the first two-thirds of the
night provide objective assessments of sleep on 1 night after a sleep
advance cycle, but the supplement did not demonstrate how these primary
endpoints assess the fundamental sleep disturbances associated with jet
lag disorder.
(2) The clinical trials did not prespecify type I error control for
subjective endpoints. Additionally, there was insufficient support for
the relevance of the exploratory subjective endpoints to the diagnosis
of jet lag disorder. Subjective endpoints can be important to FDA's
analysis of whether objective endpoints are clinically meaningful.\3\
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\3\ Here, irrespective of subjective endpoints, the supplement
failed to demonstrate that the objective endpoints used in Study
3101 and Study 3107 were clinically meaningful for the reasons
discussed in deficiency (1).
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(3) Studies 3101 and 3107 each focused on only one jet lag-related
symptom and one direction of travel in healthy subjects. Other
important aspects required for a diagnosis of the disorder (i.e.,
associated impairment of daytime function, general malaise, or somatic
symptoms (e.g., gastrointestinal disturbance)) were not evaluated in
these studies.
(4) Studies 3101 and 3107 did not include sufficient data, such as
baseline polysomnograms, to determine each individual's reaction to the
sleep advance within the protocol or the effects of the drug.
(5) There are inadequate data to demonstrate effectiveness of the
drug when administered according to the dosing and administration
information in the proposed labeling, i.e., for 1 or more nights,
depending on the number of time zones traveled and the duration of the
stay. Studies 3101 and 3107 were single-dose studies that did not
demonstrate the effectiveness of repeat dosing of tasimelteon for jet
lag disorder.
(6) There are inadequate data to inform a recommendation on the
optimal night to dose the drug, and whether dosing on multiple nights
is more effective than dosing on a single night.
(7) There are inadequate data to characterize the use of the study
drug with a sleep-delay cycle (westward travel as outgoing or
incoming). The only data presented simulate eastward travel by sleep
advance.
(8) The assessment of next-day functioning appears to be based on
the driving study (Study VP-VEC-162-1201) and a subjective assessment
of sleepiness, i.e., the Karolinska Sleepiness Scale. The Karolinska
Sleepiness Scale is not fit-for-purpose for the proposed indication,
and the driving study, which enrolled healthy subjects without sleep
advance, does not assess the range of functional impairments associated
with jet lag disorder. Thus, the assessment of next-day functioning is
inadequate.
These deficiencies preclude a finding of substantial evidence of
effectiveness for the treatment of jet lag disorder. The complete
response letter stated that to address the deficiencies, Vanda should
conduct at least one additional adequate and well-controlled study. FDA
encouraged Vanda to meet with the Division to discuss and reach
agreement on the design of a study or studies that would address the
deficiencies. 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). Applicable regulations, including 21 CFR
10.75, also provide a mechanism for applicants to obtain formal review
of one or more decisions reflected in a complete response letter (see
Ref. 2).
On January 3, 2020, Vanda submitted a formal dispute resolution
request (FDRR) concerning the complete response letter. Dr. Billy Dunn,
then-Acting Director of the Office of Neuroscience, denied the FDRR by
correspondence dated August 4, 2020, based on his determination that
the application did not provide substantial evidence of effectiveness
for tasimelteon for treatment of jet lag disorder. In addition to the
bases provided in the complete response letter, Dr. Dunn noted that
only one study relied upon by Vanda to support the approval of the
supplement, Study VP-VEC-162-2102 (Study 2102), evaluated individuals
[[Page 61339]]
with a history of jet lag disorder. The other studies were conducted in
healthy individuals with no evidence of experiencing jet lag disorder.
Dr. Dunn evaluated Study 2102 and the other study submitted by Vanda as
supportive evidence, Study VP-VEC-162-2101, and concluded that they
were small phase 2 studies with design and methodological limitations.
He also noted that jet lag disorder presents a series of complaints and
symptoms beyond sleep disturbances and daytime sleepiness, and the
sleep disturbances of jet lag disorder typically persist over several
days. Because Studies 3101 and 3107 lacked robust assessment of
important additional endpoints that might have been able to address
these characteristics of jet lag disorder, Dr. Dunn concluded the data
submitted do not support a finding of substantial evidence of
effectiveness of tasimelteon for treatment of jet lag disorder. He also
denied Vanda's requests: (1) for the Division to consider a narrower
indication for treatment of insomnia and daytime sleepiness in jet lag
disorder, because that request was raised after the complete response
letter and therefore was outside the scope of the dispute resolution
process and (2) for FDA to convene an Advisory Committee to answer the
question of whether the supplement had provided substantial evidence of
effectiveness, because he found no scientific questions that would have
been appropriate for consideration by an Advisory Committee.
Vanda submitted another FDRR on September 2, 2020, for review of
the Office of Neuroscience denial. Dr. Mary Thanh Hai, then-Acting
Deputy Director of the Office of New Drugs (OND), denied the second
FDRR on behalf of OND by correspondence dated October 21, 2020, based
on her determination that the application did not provide substantial
evidence of effectiveness for tasimelteon for treatment of jet lag
disorder. Dr. Thanh Hai noted that the regulatory history of this
development program revealed very clear advice from FDA on the study
population and recommended endpoints for clinical trials to support a
marketing application for the treatment of jet lag disorder. She also
agreed with Dr. Dunn's denial of Vanda's requests regarding a narrower
indication and convening an Advisory Committee.
On July 1, 2022, Vanda submitted a request for an opportunity for a
hearing under Sec. 314.110(b)(3) on whether there are grounds under
section 505(d) of the Federal Food, Drug, and Cosmetic Act (FD&C Act)
(21 U.S.C. 355(d)) for denying approval of sNDA 205677-004.
II. Notice of Opportunity for a Hearing
For the reasons stated above and as explained in further detail in
the August 16, 2019, complete response letter and the August 4, 2020,
and October 21, 2020, FDRR denials, notice is given to Vanda and all
other interested persons that the Center Director proposes to issue an
order refusing to approve sNDA 205677-004 on the grounds that the
application fails to meet the criteria for approval under section
505(d) of the FD&C Act because there is a lack of substantial evidence
that the drug is effective for treatment of jet lag disorder (section
505(d)(5) of the FD&C Act).\4\
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\4\ Section 505(d)(5) of the FD&C Act provides that FDA shall
refuse to approve an NDA supplement if ``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[.]'' For
the reasons explained in this notice, CDER has concluded that the
data and information submitted in the supplement do not show that
the drug is effective for the proposed conditions of use.
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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 205677-004. 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 205677-004 based on the multiple
deficiencies summarized above, any hearing request from Vanda must
address all of 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 205677-004.
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 (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 (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.
III. References
The following references marked with an asterisk (*) are on display
at the Dockets Management Staff (see ADDRESSES) and are available for
viewing by interested persons between 9 a.m. and 4 p.m., Monday through
Friday; they also are available electronically at https://www.regulations.gov. References without asterisks are not on public
display at https://www.regulations.gov because they have copyright
restriction. Some may be available at the website address, if listed.
References without asterisks are available for viewing only at the
Dockets Management Staff. FDA has verified the website addresses, as of
the date this document publishes in the Federal Register, but websites
are subject to change over time.
1. Sateia, M., ``Jet Lag Disorder,'' International Classification of
Sleep Disorders, 3rd ed., Illinois: American Academy of Sleep
Medicine, pp. 220-224, 2014.
* 2. FDA Guidance for Industry and Review Staff, ``Formal Dispute
Resolution: Sponsor Appeals Above the Division Level,'' November
2017, (available at https://www.fda.gov/media/126910/download),
accessed August 30, 2022.
Dated: October 4, 2022.
Jacqueline Corrigan-Curay,
Principal Deputy Center Director, Center for Drug Evaluation and
Research.
[FR Doc. 2022-21932 Filed 10-7-22; 8:45 am]
BILLING CODE 4164-01-P