[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]
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
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\
---------------------------------------------------------------------------
\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 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