Document ID: FDA-2022-N-2390-0001
Agency: fda
Document Type: Notice
Title: Proposal To Refuse To Approve a New Drug Application Supplement for
HETLIOZ (Tasimelteon); Opportunity for a Hearing
Posted Date: 2022-10-11T04:00Z

[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