Proposal To Refuse To Approve a New Drug Application Supplement for HETLIOZ (Tasimelteon); Opportunity for a Hearing, 61337-61339 [2022-21932]
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[FR Doc. 2022–21971 Filed 10–7–22; 8:45 am]
BILLING CODE 4164–01–P
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.
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
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SUMMARY:
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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
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61337
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-201509-18/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, Kaetochi.Okemgbo@fda.hhs.gov.
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-24hour 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
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Federal Register / Vol. 87, No. 195 / Tuesday, October 11, 2022 / Notices
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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
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 § 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
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.
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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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:
(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
(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
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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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 nextday 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 § 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, thenActing 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
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Federal Register / Vol. 87, No. 195 / Tuesday, October 11, 2022 / Notices
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 § 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.
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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
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
§ 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
§ 314.200, on or before 60 days after the
date the notice is published in the
Federal Register.
As stated in § 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
§ 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 (§ 314.200(g)(6)). If a hearing is
granted, it will be conducted according
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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61339
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 §§ 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]
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DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Meeting of the Presidential Advisory
Council on HIV/AIDS
Department of Health and
Human Services, Office of the Secretary,
Office of the Assistant Secretary for
Health.
AGENCY:
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Agencies
[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]
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
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