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204684Orig1s000 CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 204684Orig1s000 MEDICAL REVIEW(S) Clinical Investigator Financial Disclosure Review Template Application Number: 204684 Submission Date(s): September 27, 2012 and April 19, 2013 Applicant: Paladin Therapeutics, Inc. Product: IMPAVIDO (miltefosine) Reviewer: Hala Shamsuddin, M.D. Date of Review: February 24, 2014 Covered Clinical Study (Name and/or Number): Study 3154 Study 3168 Study Z020a and b Study SOTO Study Z022 Dutch PK study Was a list of clinical investigators provided: Yes X No (Request list from applicant) Total number of investigators identified: Six (6) Number of investigators who are sponsor employees (including both full-time and part-time employees): None Number of investigators with disclosable financial interests/arrangements (Form FDA 3455): Six (6) If there are investigators with disclosable financial interests/arrangements, identify the number of investigators with interests/arrangements in each category (as defined in 21 CFR 54.2(a), (b), (c) and (f)): Compensation to the investigator for conducting the study where the value could be influenced by the outcome of the study: None Significant payments of other sorts: None Proprietary interest in the product tested held by investigator: None Significant equity interest held by investigator in sponsor of covered study: None Is an attachment provided with details Yes X No (Request details from of the disclosable financial applicant) interests/arrangements: Is a description of the steps taken to Yes X No (Request information minimize potential bias provided: from applicant) Number of investigators with certification of due diligence (Form FDA 3454, box 3) None Is an attachment provided with the NA No (Request explanation Reference ID: 3464181 reason: from applicant) Discuss whether the applicant has adequately disclosed financial interests/arrangements with clinical investigators as recommended in the guidance for industry Financial Disclosure by Clinical Investigators. Also discuss whether these interests/arrangements, investigators who are sponsor employees, or lack of disclosure despite due diligence raise questions about the integrity of the data: - If not, why not (e.g., study design (randomized, blinded, objective endpoints), clinical investigator provided minimal contribution to study data) - If yes, what steps were taken to address the financial interests/arrangements (e.g., statistical analysis excluding data from clinical investigators with such interests/arrangements) Briefly summarize whether the disclosed financial interests/arrangements, the inclusion of investigators who are sponsor employees, or lack of disclosure despite due diligence affect the approvability of the application. Reviewer’s Comments The financial disclosure statement from the sponsor was submitted with the original NDA on September 27, 2012. The NDA was resubmitted on April 19, 2013 after refuse to file was issued. No new clinical studies were conducted in the interim between the original submission and re-submission. Certification was submitted that the sponsor had not entered into any financial arrangements with any of the clinical investigators whereby the value of compensation to the investigator could be affected by the outcome of the study as defined in 21CFR 54.2(a). Certification was provided that none of the listed investigator disclosed a proprietary interest in the product or significant equity in the sponsor as defined in 21 CFR 54.2(b) and (c), and that no listed investigator received significant payments of other sorts 21CFR (f). The applicant for NDA 204684 has adequately disclosed financial interests/arrangements with the clinical investigators. Reference ID: 3464181 --------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------- /s/ ---------------------------------------------------- HALA H SHAMSUDDIN 03/04/2014 Reference ID: 3464181 NDA 204684 SN006 Miltefosine (Impavido®) Clinical Review NDA 204684 SDN 006 Type of Review Priority Submit Date April 19, 2012 Received Date April 19, 2013 PDUFA Goal Date December 19, 2013 Office of Antimicrobial Products (OAP) Office/ Division Division of Anti-Infective Products (DAIP) Reviewer Hala Shamsuddin MD Team Leader Thomas Smith MD Product Miltefosine Established Name Trade Name Impavido® Therapeutic Class Anti-Parasitic, Anti-Protozoal Sponsor Paladin Therapeutics Formulation Oral Capsule 50 mg Dosing Regimen 50 mg twice or three times a day (Target Dose 2.5mg/kg/day) • Treatment of Visceral Leishmaniasis caused by L. donovani Indications • Treatment of Mucosal Leishmaniasis • Treatment of Cutaneous Leishmaniasis caused by L. braziliensis, L. guyanensis and L. panamensis Intended Individuals ≥12 Years of Age Population 1 Reference ID: 3417098 NDA 204684 SN006 Miltefosine (Impavido®) Contents Recommendations/Risk Benefit Assessment ................................................................ 8 Recommendation on Regulatory Action ..............................................................................8 Risk Benefit Assessment .....................................................................................................8 Visceral Leishmaniasis Due to L. donovani ............................................................................................ 8 Cutaneous Leishmaniasis Due to Members of the Subgenus L. Viannia .............................................. 9 Mucosal Leishmaniasis Due to Members of the Subgenus L. Viannia .................................................. 9 Recommendations for Post-market Risk Evaluation and Mitigation Strategies .....................9 Recommendations for Post-market Requirements and Commitments ............................... 10 Executive Summary ................................................................................................... 10 Leishmaniasis .................................................................................................................. 10 Miltefosine ...................................................................................................................... 11 Summary of Efficacy ......................................................................................................... 12 VL Caused by L. donovani .................................................................................................................... 12 CL Due to Members of the Subgenus Viannia .................................................................................... 18 ML Due to Members of the Subgenus Viannia ................................................................................... 22 Summary of Safety ........................................................................................................... 23 Visceral Leishmaniasis ........................................................................................................................ 23 Cutaneous Leishmaniasis .................................................................................................................... 26 Ophthalmic Effects .............................................................................................................................. 28 Reproductive Effects ........................................................................................................................... 29 Cardiac Safety ..................................................................................................................................... 31 Introduction and Regulatory Background .................................................................. 31 Leishmaniasis .................................................................................................................. 31 Product Information ........................................................................................................ 34 Tables of Currently Available Treatments for Proposed Indications ................................... 34 Availability of Proposed Active Ingredient in the United States ......................................... 38 Summary of Pre-Submission Regulatory Activity Related to Submission ............................ 38 Other Relevant Background Information .......................................................................... 39 Ethics and Compliance with Good Clinical Practices ................................................... 39 Submission Quality and Integrity ...................................................................................... 39 Compliance with Good Clinical Practices ........................................................................... 40 Financial Disclosures ........................................................................................................ 40 Significant Efficacy/Safety Issues Related to Other Review Disciplines ....................... 40 2 Reference ID: 3417098 NDA 204684 SN006 Miltefosine (Impavido®) Chemistry, Manufacturing and Controls............................................................................ 40 Clinical Microbiology ........................................................................................................ 41 In vitro Activity ...................................................................................................................................
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