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 § 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 ( printed 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 § 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 (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.