Proposal to Refuse to Approve a New Drug Application for TRADIPITANT; Opportunity for a Hearing

<NOTICE> DEPARTMENT OF HEALTH AND HUMAN SERVICES <SUBAGY>Food and Drug Administration</SUBAGY> <DEPDOC>[Docket No. FDA-2024-N-5933]</DEPDOC> <SUBJECT>Proposal to Refuse to Approve a New Drug Application for TRADIPITANT; Opportunity for a Hearing</SUBJECT> <HD SOURCE="HED">AGENCY:</HD> Food and Drug Administration, HHS. <HD SOURCE="HED">ACTION:</HD> Notice. <SUM> <HD SOURCE="HED">SUMMARY:</HD> 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. </SUM> <DATES> <HD SOURCE="HED">DATES:</HD> 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. </DATES> <HD SOURCE="HED">ADDRESSES:</HD> 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 <E T="03">https://www.regulations.gov</E> 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. <HD SOURCE="HD2">Electronic Submissions</HD> Submit electronic comments in the following way: • <E T="03">Federal eRulemaking Portal: https://www.regulations.gov</E> . Follow the instructions for submitting comments. Comments submitted electronically, including attachments, to <E T="03">https://www.regulations.gov</E> 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 <E T="03">https://www.regulations.gov</E> . • 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”). <HD SOURCE="HD2">Written/Paper Submissions</HD> Submit written/paper submissions as follows: • <E T="03">Mail/Hand Delivery/Courier (for written/paper submissions):</E> 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.” <E T="03">Instructions:</E> 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 <E T="02">ADDRESSES</E> ), will be placed in the docket and, except for those submitted as “Confidential Submissions,” publicly viewable at <E T="03">https://www.regulations.gov</E> 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 <E T="03">https://www.regulations.gov</E> . 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: <E T="03">https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf</E> . <E T="03">Docket:</E> For access to the docket to read background documents or the electronic and written/paper comments received, go to <E T="03">https://www.regulations.gov</E> 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. <FURINF> <HD SOURCE="HED">FOR FURTHER INFORMATION CONTACT:</HD> Tereza Hess, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993, 202-768-5659, <E T="03">tereza.hess@fda.hhs.gov</E> . </FURINF> <SUPLINF> <HD SOURCE="HED">SUPPLEMENTARY INFORMATION:</HD> <HD SOURCE="HD1">I. Proposal To Refuse To Approve NDA 218489</HD> 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) 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 § 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 en ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Preview showing 10k of 18k characters. Full document text is stored and available for version comparison. ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━