DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration Silver Spring MD 20993 NDA 208159 NDA APPROVAL Wellstat Therapeutics Attention: Michael K. Bamat, PhD 930 Clopper Rd. Gaithersburg, MD 20878 Dear Dr. Bamat: Please refer to your New Drug Application (NDA) dated July 10, 2015, and your amendments, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for Vistogard® (uridine triacetate), Oral Granules. This new drug application provides for the use of Vistogard® (uridine triacetate), Oral Granules for the emergency treatment of adult and pediatric patients: • following a fluorouracil or capecitabine overdose regardless of the presence of symptoms, or • who exhibit early-onset, severe or life-threatening toxicity affecting the cardiac or central nervous system, and/or early-onset, unusually severe adverse reactions (e.g., gastrointestinal toxicity and/or neutropenia) within 96 hours following the end of fluorouracil or capecitabine administration. This approval includes the following limitation of use: Vistogard® is not recommended for the non-emergent treatment of adverse reactions associated with fluorouracil or capecitabine because it may diminish the efficacy of these drugs. The safety and efficacy of Vistogard® initiated more than 96 hours following the end of fluorouracil or capecitabine administration have not been established. We have completed our review of this application, as amended. It is approved, effective on the date of this letter, for use as recommended in the agreed-upon labeling text and with the minor editorial revisions listed below/indicated in the enclosed labeling. o Correct approval date added to the Patient Package Insert Reference ID: 3859286 NDA 208159 Page 2 WAIVER OF HIGHLIGHTS SECTION We are waiving the requirements of 21 CFR 201.57(d)(8) regarding the length of Highlights of prescribing information. This waiver applies to all future supplements containing revised labeling unless we notify you otherwise. CONTENT OF LABELING As soon as possible, but no later than 14 days from the date of this letter, submit the content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA automated drug registration and listing system (eLIST), as described at: http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content of labeling must be identical to the enclosed labeling (text for the package insert and text for the patient package insert,). Information on submitting SPL files using eLIST may be found in the guidance for industry SPL Standard for Content of Labeling Technical Qs and As, available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U CM072392.pdf. The SPL will be accessible via publicly available labeling repositories. CARTON AND IMMEDIATE CONTAINER LABELS We acknowledge your November 30, 2015, submission containing final printed carton and container labels. ADVISORY COMMITTEE Your application for uridine triacetate was not referred to an FDA advisory committee because outside expertise was not necessary; there were no controversial issues that would benefit from advisory committee discussion. REQUIRED PEDIATRIC ASSESSMENTS Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration are required to contain an assessment of the safety and effectiveness of the product for the claimed indication(s) in pediatric patients unless this requirement is waived, deferred, or inapplicable. Reference ID: 3859286 NDA 208159 Page 3 Because this drug product for this indication has an orphan drug designation, you are exempt from this requirement. Furthermore, this product is appropriately labeled for use in all relevant pediatric populations. Therefore, no additional pediatric studies are needed at this time. POST MARKETING COMMITMENT (PMC) We remind you of your postmarketing commitment: 3001-1 A retrospective analysis of the drug product manufacturing process development to further examine the relationship particle size distribution and dissolution. Interbatch and intrabatch variability in dissolution is observed, but the cause has not been established. This analysis will provide data that will lead to more consistent quality in the drug product. The timetable you submitted on November 16, 2015, states that you will conduct this study according to the following schedule: Final Protocol Submission: Final Report Submission: 02/2016 08/2016 Submit clinical protocols to your IND 039571 for this product. Submit nonclinical and chemistry, manufacturing, and controls protocols and all postmarketing final reports to this NDA. In addition, under 21 CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii) you should include a status summary of each commitment in your annual report to this NDA. The status summary should include expected summary completion and final report submission dates, any changes in plans since the last annual report, and, for clinical studies/trials, number of patients entered into each study/trial. All submissions, including supplements, relating to these postmarketing commitments should be prominently labeled “Postmarketing Commitment Protocol,” “Postmarketing Commitment Final Report,” or “Postmarketing Commitment Correspondence.” PROMOTIONAL MATERIALS You may request advisory comments on proposed introductory advertising and promotional labeling. To do so, submit, in triplicate, a cover letter requesting advisory comments, the proposed materials in draft or mock-up form with annotated references, and the package insert, Medication Guide, and patient PI (as applicable) to: OPDP Regulatory Project Manager Food and Drug Administration Center for Drug Evaluation and Research Office of Prescription Drug Promotion 5901-B Ammendale Road Beltsville, MD 20705-1266 Reference ID: 3859286 NDA 208159 Page 4 Alternatively, you may submit a request for advisory comments electronically in eCTD format. For more information about submitting promotional materials in eCTD format, see the draft Guidance for Industry (available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U CM443702.pdf). As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the package insert, at the time of initial dissemination or publication, accompanied by a Form FDA 2253. Form FDA 2253 is available at: http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf. Information and Instructions for completing the form can be found at: http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. For more information about submission of promotional materials to the Office of Prescription Drug Promotion (OPDP), see: http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm. METHODS VALIDATION We have not completed validation of the regulatory methods. However, we expect your continued cooperation to resolve any problems that may be identified. REPORTING REQUIREMENTS We remind you that you must comply with reporting requirements for an approved NDA (21 CFR 314.80 and 314.81). MEDWATCH-TO-MANUFACTURER PROGRAM The MedWatch-to-Manufacturer Program provides manufacturers with copies of serious adverse event reports that are received directly by the FDA. New molecular entities and important new biologics qualify for inclusion for three years after approval. Your firm is eligible to receive copies of reports for this product. To participate in the program, please see the enrollment instructions and program description details at: http://www.fda.gov/Safety/MedWatch/HowToReport/ucm166910.htm. POST APPROVAL FEEDBACK MEETING New molecular entities and new biologics or drugs in the PDUFA V program qualify for a post approval feedback meeting. Such meetings are used to discuss the quality of the application and to evaluate the communication process during drug development and marketing application review. The purpose is to learn from successful aspects of the review process and to identify areas that could benefit from improvement. If you would like to have such a meeting with us, call the Regulatory Project Manager for this application. Reference ID: 3859286 NDA 208159 Page 5 PDUFA V APPLICANT INTERVIEW FDA has contracted with Eastern Research Group, Inc. (ERG) to conduct an independent interim and final assessment of the Program for Enhanced Review Transparency and Communication for NME NDAs and Original BLAs under PDUFA V (‘the Program’). The PDUFA V Commitment Letter states that these assessments will include interviews with applicants following FDA action on applications reviewed in the Program. For this purpose, first-cycle actions include approvals, complete responses, and withdrawals after filing. The purpose of the interview is to better understand applicant experiences with the Program and its ability to improve transparency and communication during FDA review. ERG will contact you to schedule a PDUFA V applicant interview and provide specifics about the interview process. Your responses during the interview will be confidential with respect to the FDA review team. ERG has signed a non-disclosure agreement and will not disclose any identifying information to anyone outside their project team. They will report only anonymized results and findings in the interim and final assessments. Members of the FDA review team will be interviewed by ERG separately. While your participation in the interview is voluntary, your feedback will be helpful to these assessments. If you have any questions, call Jeannette O’Donnell, Regulatory Project Manager, at (240) 402-4978 or email: Jeannette.Odonnell@fda.hhs.gov. Sincerely, {See appended electronic signature page} Geoffrey Kim, MD Director Division of Oncology Products 1 Office of Hematology and Oncology Products Center for Drug Evaluation and Research Enclosure(s): Content of Labeling Carton and Container Labeling Reference ID: 3859286 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------GEOFFREY S KIM 12/11/2015 Reference ID: 3859286