4748 Federal Register / Vol. 90, No. 10 / Thursday, January 16, 2025 / Notices 

your animal patients, what factors have 

influenced your decision (e.g., legal 

issues surrounding cannabis, safety 

concerns, effectiveness concerns, 

product quality concerns, not found a 

need, etc.)? If you do not use or 

recommend hemp-derived cannabis 

products for your animal patients for 

reasons other than effectiveness 

concerns, are there any indications and 

species for which you believe they 

could be effective and why? 

Dated: January 10, 2025. 

P. Ritu Nalubola, 

Associate Commissioner for Policy. 

[FR Doc. 2025–00945 Filed 1–15–25; 8:45 am] 

BILLING CODE 4164–01–P 

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, tereza.hess@fda.hhs.gov. 

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) 


ddrumheller on DSK120RN23PROD with NOTICES1
Federal Register / Vol. 90, No. 10 / Thursday, January 16, 2025 / Notices 4749 

post hoc pooled analyses of Study 2301 

and Study 3301, Group 1; (2) an openlabel 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 § 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 multiplicitycontrolled 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 repeatdose 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 § 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. 


ddrumheller on DSK120RN23PROD with NOTICES1
4750 Federal Register / Vol. 90, No. 10 / Thursday, January 16, 2025 / Notices 

1Section 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. 

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

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 

§ 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 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 

§ 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 § 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: 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 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

[Docket No. FDA–2000–D–0187] 

Recommendations To Reduce the Risk 

of Transfusion-Transmitted Malaria; 

Draft Guidance for Industry; 

Availability 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Notice of availability. 

SUMMARY: The Food and Drug 

Administration (FDA, Agency, or we) is 

announcing the availability of a draft 

document entitled ‘‘Recommendations 

To Reduce the Risk of TransfusionTransmitted Malaria.’’ The draft 

guidance document provides blood 

establishments that collect blood and 

blood components with FDA’s revised 

recommendations to reduce the risk of 

transfusion-transmitted malaria (TTM). 

The guidance recommends selectively 

testing blood donations from donors at 

risk for malaria using an FDA-licensed 

donor screening nucleic acid test (NAT) 

for Plasmodium species (spp.), the 

causative agents of malaria. The draft 

guidance, when finalized, is intended to 

supersede the document entitled 

‘‘Recommendations To Reduce the Risk 

of Transfusion-Transmitted Malaria,’’ 

dated December 2022. 

DATES: Submit either electronic or 

written comments on the draft guidance 

by March 17, 2025 to ensure that the 

Agency considers your comment on this 

draft guidance before it begins work on 

the final version of the guidance. 

ADDRESSES: You may submit comments 

on any guidance at any time as follows: 

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– 

2000–D–0187 for ‘‘Recommendations To 

Reduce the Risk of TransfusionTransmitted Malaria.’’ Received 

comments will be placed in the docket 

and, except for those submitted as 

‘‘Confidential Submissions,’’ publicly 

viewable at https://www.regulations.gov 


ddrumheller on DSK120RN23PROD with NOTICES1