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[Federal Register Volume 90, Number 10 (Thursday, January 16, 2025)]
[Notices]
[Pages 4748-4750]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2025-01027]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2024-N-5933]

Proposal to Refuse to Approve a New Drug Application for 
TRADIPITANT; 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 new drug application (NDA) 
submitted by Vanda Pharmaceuticals, Inc. (Vanda), for TRADIPITANT 
capsules, 85 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 February 18, 2025; submit data, information, and analyses 
in support of the hearing and any other comments by March 17, 2025.

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 February 
18, 2025, and will accept documents in support of the hearing and any 
other comments until 11:59 p.m. Eastern Time at the end of March 17, 
2025. 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-2024-N-5933 for ``Proposal To Refuse To Approve a New Drug 
Application for TRADIPITANT; 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: Tereza Hess, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Silver Spring, MD 20993, 202-768-5659, 
[email protected].

SUPPLEMENTARY INFORMATION:

I. Proposal To Refuse To Approve NDA 218489

    Vanda submitted NDA 218489 for TRADIPITANT capsules, 85 mg, on 
September 18, 2023, pursuant to section 505(b)(1) of the Federal Food, 
Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355(b)(1)). Vanda proposed 
that TRADIPITANT capsules be indicated for ``the treatment of [symptoms 
of] or [nausea in] in gastroparesis.''
    To support a demonstration of substantial evidence of 
effectiveness, Vanda referred to two randomized, double-blind, placebo-
controlled studies (Study 2301 and Study 3301, Group 1), and the 
following additional data submitted as confirmatory evidence: (1)

[[Page 4749]]

post hoc pooled analyses of Study 2301 and Study 3301, Group 1; (2) an 
open-label study (Study 3301, Group 2); (3) data from individual 
patient expanded access uses; and (4) two studies in a different 
condition (Study 2401 and Study 3401 in motion sickness). Further, 
Vanda proposed that Study 2301 alone and Study 3301 alone each meet the 
standard for substantial evidence of effectiveness. To support a 
demonstration of the safety of TRADIPITANT for the treatment of 
gastroparesis, Vanda referred to the clinical studies described above 
and to nonclinical studies, including in vitro studies using new 
alternative methods, that have been completed.
    On September 18, 2024, the Office of Immunology and Inflammation 
(OII) in CDER issued a complete response letter to Vanda under Sec.  
314.110(a) (21 CFR 314.110(a)) stating that NDA 218489 could not be 
approved in its present form because the application does not provide 
substantial evidence of effectiveness for TRADIPITANT and does not 
demonstrate that the drug is safe for the proposed conditions of use. 
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. The following deficiencies in Study 3301, Group 1, and Study 
2301 preclude a finding of substantial evidence of effectiveness:
    a. The results of Study 3301, Group 1 (a phase 3 study) did not 
demonstrate a statistically significant difference between TRADIPITANT 
and placebo for the primary endpoint of the change from baseline to 
Week 12 in biweekly average nausea severity, nor did they demonstrate a 
nominally significant difference on nausea severity for any of the 2-
week intervals assessed. In addition, there were no nominally 
significant differences between TRADIPITANT and placebo for the 
multiplicity-controlled secondary endpoints that assessed individual 
signs and symptoms of gastroparesis, nor for other clinically relevant 
endpoints such as nausea-free days. The estimated difference between 
TRADIPITANT and placebo for these endpoints was generally close to 
zero, except for the nausea-free days endpoint, which numerically 
favored placebo at Week 12.
    b. The post hoc analyses of the results of Study 3301, Group 1 did 
not demonstrate a consistent benefit in reduction of nausea nor do they 
overcome the lack of efficacy observed on the multiple prespecified 
endpoints in Study 3301, Group 1. These post hoc analyses were neither 
controlled for multiplicity nor prespecified in the statistical 
analysis plan (SAP). The lack of both control for multiplicity and 
prespecification for the post hoc analyses greatly increases the chance 
of erroneously concluding a drug has an effect on an outcome when no 
effect exists, which is especially problematic in the context of a 
trial that did not demonstrate statistical significance on the primary 
endpoint and multiplicity-controlled secondary endpoints, such as Study 
3301, Group 1.
    c. Although the results of Study 2301 (a phase 2 study) 
demonstrated a statistically significant difference in the primary 
endpoint of change from baseline to Day 28 (Week 4) in the weekly 
average of individual daily nausea severity scores, the results were 
not persuasive because there were methodological shortcomings with the 
analysis that could bias results (e.g., use of methods not in 
accordance with those described (or specified) in the SAP) and 
statistical analyses that addressed these concerns were not robust with 
respect to missing data assumptions. In addition, although several of 
the secondary endpoints were reported as having nominally statistically 
significant results at Day 28 (Week 4), these analyses were not 
controlled for multiplicity. The secondary efficacy endpoints also had 
the same methodological shortcomings as the primary efficacy endpoint. 
Furthermore, these results from Study 2301 were not supported by Study 
3301, Group 1 as the latter did not achieve statistical significance on 
primary and secondary endpoints that were similar to those assessed in 
Study 2301, including at Week 4.
    2. The data submitted as confirmatory evidence are not sufficient 
to constitute confirmatory evidence of either Study 3301, Group 1 or 
Study 2301. The post hoc pooled analyses of Study 3301, Group 1 and 
Study 2301 do not provide independent substantiation of the results of 
Study 2301; rather, the results of the post hoc analyses are driven by 
Study 2301. Additionally, the data and analysis provided from open-
label sources (i.e., Study 3301 Group 2, and individual patient 
expanded access use) are limited in their ability to support 
conclusions related to symptomatic improvement. Further, studies from 
the ongoing motion sickness program are not appropriate sources of 
additional efficacy data to provide confirmatory evidence for 
gastroparesis.
    3. The application does not establish that data from either Study 
3301, Group 1 or Study 2301 demonstrate substantial evidence of 
effectiveness on its own. As noted above, Study 3301, Group 1 did not 
achieve statistical significance on primary and secondary endpoints 
that were similar to those assessed in Study 2301, including at Week 4. 
Study 2301 does not provide substantial evidence of effectiveness as a 
single adequate and well-controlled trial due to the methodological 
shortcomings and limitations of the results of the trial.
    4. The clinical safety data submitted with the application are 
inadequate to characterize the safety of TRADIPITANT for treating 
patients with gastroparesis. The clinical safety database included 
controlled clinical trial data that were limited to 12 weeks in 
duration. Additional longer-term safety data are needed, in part, to 
inform the safe use of the drug because gastroparesis is a chronic 
condition that necessitates ongoing daily use or recurrent intermittent 
treatment over months to years in most patients.
    5. The nonclinical safety data submitted with the application are 
inadequate to characterize the safety of TRADIPITANT for treating 
patients with gastroparesis. The provided in vitro studies along with 
the provided animal studies did not adequately characterize the long-
term safety of TRADIPITANT to inform risk to humans.
    These deficiencies preclude a finding that the application provides 
substantial evidence of effectiveness for TRADIPITANT, and that the 
application demonstrates that TRADIPITANT is safe, for the proposed 
conditions of use. The complete response letter stated that to address 
the deficiencies, OII recommends that Vanda leverage existing data to 
inform the design of two new adequate and well-controlled trials in 
adults with idiopathic or diabetic gastroparesis. OII also recommended 
that Vanda conduct a chronic repeat-dose toxicity study in a nonrodent 
species, which would support the clinical trials longer than 12 weeks 
in duration.
    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 November 
25, 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, CDER cannot approve the application in its current 
form; thus, we are providing Vanda with this notice of opportunity for 
a hearing.

[[Page 4750]]

II. Notice of Opportunity for a Hearing

    For the reasons stated above and as explained in the September 18, 
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 NDA 218489 under section 505(c) of the FD&C 
Act, 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, and the drug has 
not been shown to be safe, for the proposed conditions of use, 
including for the proposed indication of ``the treatment of [symptoms 
of] or [nausea in] in gastroparesis'' (sections 505(d)(4) and 505(d)(5) 
of the FD&C Act).\1\
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    \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.
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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 NDA 218489. 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 NDA 218489 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 NDA 
218489.
    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: January 13, 2025.
Patrizia Cavazzoni,
Director, Center for Drug Evaluation and Research.
[FR Doc. 2025-01027 Filed 1-15-25; 8:45 am]
BILLING CODE 4164-01-P
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