Proposal To Refuse To Approve a New Drug Application Supplement for HETLIOZ (Tasimelteon); Opportunity for a Hearing, 48647-48649 [2024-12564]

Download as PDF Federal Register / Vol. 89, No. 111 / Friday, June 7, 2024 / Notices ddrumheller on DSK120RN23PROD with NOTICES1 However, section 1865(a)(1) of the Act provides that, if a provider entity demonstrates through accreditation by a Centers for Medicare & Medicaid Services (CMS) approved national Accrediting Organization (AO) that all applicable Medicare conditions are met or exceeded, we will deem those provider entities as having met the requirements. Accreditation by an AO is voluntary and is not required for Medicare participation. If an AO is recognized by the Secretary of the Department of Health and Human Services (the Secretary) as having standards for accreditation that meet or exceed Medicare requirements, any provider entity accredited by the national accrediting body’s approved program would be deemed to meet the Medicare conditions. A national AO applying for approval of its accreditation program under part 488, subpart A, must provide CMS with reasonable assurance that the AO requires the accredited provider entities to meet requirements that are at least as stringent as the Medicare conditions. Our regulations concerning the approval of AOs are set forth at §§ 488.4 and 488.5. The regulations at § 488.5(e)(2)(i) require AOs to reapply for continued approval of its accreditation program every 6 years or sooner as determined by CMS. Community Health Accreditation Partner’s (CHAP’s) current term of approval for their hospice accreditation program expires February 24, 2025. II. Approval of Deeming Organizations Section 1865(a)(2) of the Act and our regulations at § 488.5 require that our findings concerning review and approval of a national AO’s requirements consider, among other factors, the applying AO’s requirements for accreditation; survey procedures; resources for conducting required surveys; capacity to furnish information for use in enforcement activities; monitoring procedures for provider entities found not in compliance with the conditions or requirements; and ability to provide CMS with the necessary data for validation. Section 1865(a)(3)(A) of the Act further requires that we publish, within 60 days of receipt of an organization’s complete application, a notice identifying the national accrediting body making the request, describing the nature of the request, and providing at least a 30-day public comment period. We have 210 days from the receipt of a complete application to publish notice of approval or denial of the application. The purpose of this proposed notice is to inform the public of the CHAP VerDate Sep<11>2014 17:23 Jun 06, 2024 Jkt 262001 request for continued approval of its hospice accreditation program. This notice also solicits public comment on whether the CHAP’s requirements meet or exceed the Medicare conditions of participation (CoPs) for hospices. III. Evaluation of Deeming Authority Request CHAP submitted all the necessary materials to enable us to make a determination concerning its request for continued approval of its hospice accreditation program. This application was determined to be complete on April 20, 2024. Under section 1865(a)(2) of the Act and our regulations at § 488.5 (Application and re-application procedures for national AO) our review and evaluation of CHAP will be conducted in accordance with, but not necessarily limited to, the following factors: • The equivalency of CHAP’s standards for hospices as compared with CMS’ hospice CoPs. • CHAP’s survey process to determine the following: ++ The composition of the survey team, surveyor qualifications, and the ability of the organization to provide continuing surveyor training. ++ The comparability of CHAP’s processes to those of state agencies, including survey frequency, and the ability to investigate and respond appropriately to complaints against accredited facilities. ++ CHAP’s processes and procedures for monitoring hospices, which are found out of compliance with CHAP’s program requirements. These monitoring procedures are used only when CHAP identifies noncompliance. If noncompliance is identified through validation reviews or complaint surveys, the SA monitors corrections as specified at § 488.9. ++ CHAP’s capacity to report deficiencies to the surveyed facilities and respond to the facility’s plan of correction in a timely manner. ++ CHAP’s capacity to provide CMS with electronic data and reports necessary for effective validation and assessment of the organization’s survey process. ++ The adequacy of CHAP’s staff and other resources, and its financial viability. ++ CHAP’s capacity to adequately fund required surveys. ++ CHAP’s policies with respect to whether surveys are announced or unannounced, to ensure that surveys are unannounced. ++ CHAP’s policies and procedures to avoid conflicts of interest, including the appearance of conflicts of interest, PO 00000 Frm 00098 Fmt 4703 Sfmt 4703 48647 involving individuals who conduct surveys or participate in accreditation decisions. ++ CHAP’s agreement to provide CMS with a copy of the most current accreditation survey, together with any other information related to the survey as we may require (including corrective action plans). IV. Collection of Information Requirements This document does not impose information collection requirements, that is, reporting, recordkeeping, or third-party disclosure requirements. Consequently, there is no need for review by the Office of Management and Budget under the authority of the Paperwork Reduction Act of 1995 (44 U.S.C. 3501 et seq.). V. Response to Comments Because of the large number of public comments, we normally receive on Federal Register documents, we are not able to acknowledge or respond to them individually. We will consider all comments we receive by the date and time specified in the DATES section of this preamble, and, when we proceed with a subsequent document, we will respond to the comments in the preamble to that document. The Administrator of the Centers for Medicare & Medicaid Services (CMS), Chiquita Brooks-LaSure, having reviewed and approved this document, authorizes Vanessa Garcia, who is the Federal Register Liaison, to electronically sign this document forpurposes of publication in the Federal Register. Vanessa Garcia, Federal Register Liaison, Centers for Medicare & Medicaid Services. [FR Doc. 2024–12495 Filed 6–6–24; 8:45 am] BILLING CODE 4120–01–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 SUMMARY: E:\FR\FM\07JNN1.SGM 07JNN1 48648 Federal Register / Vol. 89, No. 111 / Friday, June 7, 2024 / Notices 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. 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. DATES: 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. ADDRESSES: ddrumheller on DSK120RN23PROD with NOTICES1 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’’). VerDate Sep<11>2014 17:23 Jun 06, 2024 Jkt 262001 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-201509-18/pdf/2015-23389.pdf. Docket: For access to the docket to read background documents or the PO 00000 Frm 00099 Fmt 4703 Sfmt 4703 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, Christopher.Koepke@fda.hhs.gov. 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 SmithMagenis 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 § 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 E:\FR\FM\07JNN1.SGM 07JNN1 ddrumheller on DSK120RN23PROD with NOTICES1 Federal Register / Vol. 89, No. 111 / Friday, June 7, 2024 / Notices 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 singledose 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 wellcontrolled 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 VerDate Sep<11>2014 17:23 Jun 06, 2024 Jkt 262001 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 § 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 Vanda may request a hearing before the Commissioner of Food and Drugs 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.) PO 00000 Frm 00100 Fmt 4703 Sfmt 9990 48649 (the Commissioner) on the Center Director’s proposal to refuse to approve sNDA 205677–012. 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 205677–012 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 § 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 § 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 §§ 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 E:\FR\FM\07JNN1.SGM 07JNN1

Agencies

[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.

-----------------------------------------------------------------------

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\
---------------------------------------------------------------------------

    \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.)
---------------------------------------------------------------------------

    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
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