CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 22-395 PHARMACOLOGY REVIEW(S) Reviewer: L. S. Leshin NDA 22-395 DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH PHARMACOLOGY/TOXICOLOGY REVIEW AND EVALUATION ADDENDUM NDA NUMBER: 22-395 SERIAL NUMBER: 000 DATE RECEIVED BY CENTER: Oct 13, 2008 PRODUCT: Qutenza™ (Capsaicin Dermal Patch 8%) INTENDED CLINICAL POPULATION: Patients with neuropathic pain associated with postherpetic neuralgia (PHN) SPONSOR: NeurogesX Inc. DOCUMENTS REVIEWED: SD-22, received July 31, 2009 REVIEW DIVISION: Division of Anesthesia, Analgesia, and Rheumatology Drug Products (HFD-170) PHARM/TOX REVIEWER: L.S. Leshin, DVM, PhD PHARM/TOX SUPERVISOR: A. Wasserman, PhD DIVISION DIRECTOR: B. Rappaport, MD PROJECT MANAGER: T. Clayton 1 Reviewer: L. S. Leshin NDA 22-395 EXECUTIVE SUMMARY I. Recommendations A. Recommendation on approvability Approve (no change from the original review) B. Recommendation for nonclinical studies None (no change from the original review) C. Recommendations on labeling Refer to the original review. There are no new changes in labelling. II. Regulatory background During the initial review of the 6-month transgenic mouse carcinogenicity study a request (IND 63354, May 13, 2009) for a DSI inspection was submitted to examine the extensive discrepancies in the study methodology and results. The inspection group was aware that this study was not essential for approval since the proposed drug would be administered once with possible retreatment at 3 month intervals. Nevertheless, they were able to (b) (4) inspect the contract lab, that conducted the study (Report 7215-150, Oct 6 2006) titled "26-Week Dermal Oncogenicity Study with trans Capsaicin in TgAC Hemizygous Mice." The study was amended and resubmitted (submission July 30, 2009 SD-22 received July 31, 2009) to address the items raised as FDA-483 observations from the FDA surveillance audit of (b) (4) (b) (4) between July 20 and July 22, 2009. The audit is not filed with this application in DARRTS at this time. III. Summary of nonclinical findings While a number of critical items were corrected (see Appendix), the underlying problems of the study are still present, making the interpretation of the data problematic. These include a high level of papillomas in the untreated control group (negative controls), upon necropsy not all masses were histologically examined, and there is a trend of increasing papilloma with dose when pooled across sex (there is no obvious mechanistic reason why dose groups should not be pooled). For these reasons, the study is still unacceptable. The carcinogenicity section of the label will indicate that adequate carcinogenic studies have not been conducted. Recall that for the proposed administration frequency, a carcinogenicity study is not essential for approval. 2 Reviewer: L. S. Leshin NDA 22-395 Appendix: Revised Information Provided to Study 7215-150, 26-Week Dermal Oncogenicity Study with trans Capsaicin in TgAC Hemizygous Mice The major findings of the audit were: • The conclusions in the final report regarding carcinogenicity of the test article are based on a tabulation of masses (Appendix 6-“Weekly Incidence of Dermal Masses”), which includes masses at sites remote from the treatment sites. Specifically, each page of Appendix 6 states “Note: Numbers indicate the total number of skin masses on the treated site each week”. The “treated site” for the animals in this study is defined in the study protocol as an “area approximately 2 cm x 2 cm of dorsal skin at the intrascapular region”. However, as identified in the final report Appendix 11, “Individual Anatomic Pathology Data”, the number of dermal masses often include masses found at sites other than at the treatment site. • There was no formal statistical analysis of the tumor data in the final report. • The final report did not include a description of all circumstances that may have affected the quality or integrity of the data. Specifically, the final report includes data to indicate that 77 of the 350 animals in the study (22%) died prior to completing the 26-week dosing period. There is no discussion in the final report regarding the impact on the study outcomes to having so many study animals die during the study, and no discussion as to the possible cause or relationship of the deaths to the study treatment. • The final study report did not include the signed and dated reports of each of the individual scientists or other professionals involved in the study. The Applicant provided the following revisions in the amended final report of July 29, 2009: • There were numerous administrative changes, including signatures, quality assurance inspections, amendments, etc. • A statistical report was included, with more detailed statistical methods and analyses. • Clarification of data entries for statistical analysis was provided. • A pathology report was included. • Survival figures were included and a discussion of animal mortality was included. • The abstract was revised. • The title and footnote of Appendix 6 was corrected and clarified. The number of papillomas by study week were subdivided into locations in which they were observed. • A table relating weeks of study to times for various events in the study was included. 3 Reviewer: L. S. Leshin NDA 22-395 Signatures: Reviewer Signature ___________________________________ L. S. Leshin, D.V.M., Ph.D. Supervisor Signature_____________________________ Concurrence Yes ___ No A. Wasserman, Ph.D. 4 Application Submission Type/Number Type/Number Submitter Name Product Name -------------------- -------------------- -------------------- ------------------------------------------ NDA-22395 ORIG-1 NEUROGESX INC NGX-4010 (CAPSAICIN PATCH 8%) --------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------- /s/ ---------------------------------------------------- LAWRENCE S LESHIN 10/27/2009 ADAM M WASSERMAN 10/27/2009 DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH Supervisory Pharmacologist Memorandum NDA NUMBER: 22-395 SERIAL NUMBER: 000 DATE RECEIVED BY CENTER: 13-OCT-2008 PRODUCT: Qutenza (Capsaicin) patch INTENDED CLINICAL POPULATION: Neuropathic pain associated with Postherpetic Neuralgia SPONSOR: NeurogesX REVIEW DIVISION: Division of Anesthesia, Analgesia and Rheumatology Products (HFD-170) PHARM/TOX REVIEWER: L. Steven Leshin, DVM, Ph.D. PHARM/TOX SUPERVISOR: Adam Wasserman, Ph.D. DIVISION DIRECTOR: Bob Rappaport, M.D. PROJECT MANAGER: Tanya Clayton EXECUTIVE SUMMARY I. BACKGROUND A. Regulatory Summary (Pharmacology/Toxicology) The present NDA submission submitted by NeurogesX pertains to Qutenza®, a topical patch containing 8% capsaicin (179 mg) in adhesive which is to be used for managing the neuropathic pain of postherpetic neuralgia. The present application proposes up to 4 (20 x 14 cm; 280 cm2) patches may be applied by a practitioner over painful intact skin areas once every 3 months or greater depending on the return of pain to the site. Capsaicin, existing as the natural trans format, is a significant component of various hot pepper plants and is the main active ingredient in chili peppers used in foods as well as in the defensive weapon “pepper spray” where deployment into mucous membranes of eyes, nose and mouth is profoundly irritating. It is not an approved drug product but is marketed in various forms under a tentative final monograph for external analgesic drug products (proposed for 21 CFR 348.12) published in the Federal Register (February 8, 1983; Volume 48 No. 27). This tentative monograph section (Irritants that do not produce redness) applies to topical counterirritants which allow concentrations of capsaicin in capsaicin-related products are acceptable of 0.025 to 0.25%. This in practice has “supported” unapproved topical creams such as Zostrix (0.025%) and Zostrix HP (0.075%) marketed for mild to moderate pain of rheumatoid arthritis or osteoarthritis and myalgia while a recent addition (Zostrix Neuropathy Cream) contains 0.25% capsaicin in an unknown concentration of lidocaine as part of a “Lidocare” vehicle which is marketed for the treatment of postherpetic neuropathic pain. The current product proposed for marketing approval represents a markedly higher concentration than all currently marketed and unapproved products. II. S UMMARY OF NONCLINICAL FINDINGS A. Brief overview of nonclinical findings General pharmacology Capsaicin at high concentrations as used in Qutenza is designed to act as an agonist at epidermal nerve fiber TRPV1 (transient receptor potential vanilloid, type 1) receptors at levels sufficient to cause “defunctionalization” (i.e. calcium-overload-induced local degeneration) of the peripheral ends of these nerve fibers. Capsaicin activates TRPV1 receptors which are non-selective cation channels (though preferring calcium) located on sensory neurons that serve as molecular polymodal integrators of a number of environmental stimuli including heat and protons. Importantly, TRPV1 receptor channels are capable of being functional upregulated or sensitized by protein kinases activated by a number of receptors