CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 2051230rig1s000 OTHER PMR/PMC Development Template This template should be completed by the PMR/PMC Development Coordinator and included for each PMR/PMC in the Action Package. NDA Product Name: 205123 simeprevir PMR Description: Conduct a trial to evaluate the pharmacokinetics, safety and treatment response (using sustained virologic response) of simeprevir as a component of a combination antiviral treatment regimen in pediatric subjects 3 through 17 years of age with chronic hepatitis C. PMR/PMC Schedule Milestones: Final Protocol Submission: Trial Completion: Final Report Submission: Other: 05/31/2018 07/31/2021 12/31/2021 MM/DD/YYYY 1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a pre-approval requirement. Check type below and describe. Unmet need Life-threatening condition Long-term data needed Only feasible to conduct post-approval Prior clinical experience indicates safety Small subpopulation affected Theoretical concern Other Treatment for pediatric chronic hepatitis C patients 3 through 17 years of age 2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is a FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new safety information.” PMR/PMC Development Template Reference ID: 3410400 Last Updated 11/20/2013 Page 1 of 4 This is one of the trials that will be used to fulfill PREA requirements. The goal of the trial is to evaluate pharmacokinetics, safety and antiviral activity of simeprevir as a component of a combination antiviral treatment regimen in pediatric patients (3 to 17 years old) with chronic hepatitis C . 3. If the study/clinical trial is a PMR, check the applicable regulation. If not a PMR, skip to 4. - Which regulation? Accelerated Approval (subpart H/E) Animal Efficacy Rule Pediatric Research Equity Act FDAAA required safety study/clinical trial - If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply) Assess a known serious risk related to the use of the drug? Assess signals of serious risk related to the use of the drug? Identify an unexpected serious risk when available data indicate the potential for a serious risk? - If the PMR is a FDAAA safety study/clinical trial, will it be conducted as: Analysis of spontaneous postmarketing adverse events? Do not select the above study/clinical trial type if: such an analysis will not be sufficient to assess or identify a serious risk Analysis using pharmacovigilance system? Do not select the above study/clinical trial type if: the new pharmacovigilance system that the FDA is required to establish under section 505(k)(3) has not yet been established and is thus not sufficient to assess this known serious risk, or has been established but is nevertheless not sufficient to assess or identify a serious risk Study: all other investigations, such as investigations in humans that are not clinical trials as defined below (e.g., observational epidemiologic studies), animal studies, and laboratory experiments? Do not select the above study type if: a study will not be sufficient to identify or assess a serious risk Clinical trial: any prospective investigation in which the sponsor or investigator determines the method of assigning investigational product or other interventions to one or more human subjects? 4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the study or trial will be performed in a subpopulation, list here. Pediatric subjects 3 through 17 years of age with chronic hepatitis C PMR/PMC Development Template Reference ID: 3410400 Last Updated 11/20/2013 Page 2 of 4 Required Observational pharmacoepidemiologic study Registry studies Primary safety study or clinical trial Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety Thorough Q-T clinical trial Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology) Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety) Pharmacokinetic studies or clinical trials Drug interaction or bioavailability studies or clinical trials Dosing trials Continuation of Question 4 Additional data or analysis required for a previously submitted or expected study/clinical trial (provide explanation) Meta-analysis or pooled analysis of previous studies/clinical trials Immunogenicity as a marker of safety Other (provide explanation) Agreed upon: Quality study without a safety endpoint (e.g., manufacturing, stability) Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease, background rates of adverse events) Clinical trials primarily designed to further define efficacy (e.g., in another condition, different disease severity, or subgroup) that are NOT required under Subpart H/E Dose-response study or clinical trial performed for effectiveness Nonclinical study, not safety-related (specify) Other 5. Is the PMR/PMC clear, feasible, and appropriate? Does the study/clinical trial meet criteria for PMRs or PMCs? Are the objectives clear from the description of the PMR/PMC? Has the applicant adequately justified the choice of schedule milestone dates? Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine feasibility, and contribute to the development process? Check if this form describes a FDAAA PMR that is a randomized controlled clinical trial If so, does the clinical trial meet the following criteria? There is a significant question about the public health risks of an approved drug There is not enough existing information to assess these risks Information cannot be gained through a different kind of investigation The trial will be appropriately designed to answer question about a drug’s efficacy and safety, and The trial will emphasize risk minimization for participants as the protocol is developed PMR/PMC Development Template Reference ID: 3410400 Last Updated 11/20/2013 Page 3 of 4 PMR/PMC Development Coordinator: This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine the safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug quality. _______________________________________ (signature line for BLAs) APPEARS THIS WAY ON ORIGINAL PMR/PMC Development Template Reference ID: 3410400 Last Updated 11/20/2013 Page 4 of 4 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------VICTORIA L TYSON 11/20/2013 Reference ID: 3410400 PMR/PMC Development Template This template should be completed by the PMR/PMC Development Coordinator and included for each PMR/PMC in the Action Package. NDA Product Name: PMR Description: 205123 simeprevir Collect long-term safety data for subjects enrolled in the pediatric simeprevir safety, pharmacokinetics and efficacy trial. Data collected should include at least 3 years of follow-up in order to characterize the long-term safety of simeprevir in pediatric subjects, including growth assessment, sexual maturation and characterization of simeprevir resistance-associated substitutions in viral isolates from subjects failing therapy. PMR/PMC Schedule Milestones: Final Protocol Submission: Trial Completion: Final Report Submission: Other: 08/31/2019 07/31/2024 01/31/2025 MM/DD/YYYY 1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a pre-approval requirement. Check type below and describe. Unmet need Life-threatening condition Long-term data needed Only feasible to conduct post-approval Prior clinical experience indicates safety Small subpopulation affected Theoretical concern Other Long-term safety data in pediatric subjects treated in the simeprevir safety, pharmacokinetics and efficacy trial. 2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is a FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new safety information.” PMR/PMC Development Template Reference ID: 3411624 Last Updated 11/22/2013 Page 1 of 4 This is one of the trials that will be used to fulfill PREA requirements. 3. If the study/clinical trial is a PMR, check the applicable regulation. If not a PMR, skip to 4. - Which regulation? Accelerated Approval (subpart H/E) Animal Efficacy Rule Pediatric Research Equity Act FDAAA required safety study/clinical trial - If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply) Assess a known serious risk related to the use of the drug? Assess signals of serious risk related to the use of the drug? Identify an unexpected serious risk when available data indicate the potential for a serious risk? - If the PMR is a FDAAA safety study/clinical trial, will it be conducted as: Analysis of spontaneous postmarketing adverse events? Do not select the above study/clinical trial type if: such an analysis will not be sufficient to assess or identify a serious risk Analysis using pharmacovigilance system? Do not select the above study/clinical trial type if: the new pharmacovigilance system that the FDA is required to establish under section 505(k)(3) has not yet been established and is thus not sufficient to assess this known serious risk, or has been established but is nevertheless not sufficient to assess or identify a serious risk Study: all other investigations, such as investigations in humans that are not clinical trials as defined below (e.g., observational epidemiologic studies), animal studies, and laboratory experiments? Do not select the above study type if: a study will not be sufficient to identify or assess a serious risk Clinical trial: any prospective investigation in which the sponsor or investigator determines the method of assigning investigational product or other interventions to one or more human subjects? 4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the study or trial will be performed in a subpopulation, list here. Pediatric subjects 3 through 17 years of age PMR/PMC Development Template Reference ID: 3411624 Last Updated 11/22/2013 Page 2 of 4 Required Observational pharmacoepidemiologic study Registry studies Primary safety study or clinical trial Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety Thorough Q-T clinical trial Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology) Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety) Pharmacokinetic studies or clinical trials Drug interaction or bioavailability studies or clinical trials Dosing trials Continuation of Question 4 Additional data or analysis required for a previously submitted or expected study/clinical trial (provide explanation) Meta-analysis or pooled analysis of previous studies/clinical trials Immunogenicity as a marker of safety Other (provide explanation) Agreed upon: Quality study without a safety endpoint (e.g., manufacturing, stability) Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease, background rates of adverse events) Clinical trials primarily designed to further define efficacy (e.g., in another condition, different disease severity, or subgroup) that are NOT required under Subpart H/E Dose-response study or clinical trial performed for effectiveness Nonclinical study, not safety-related (specify) Other 5. Is the PMR/PMC clear, feasible, and appropriate? Does the study/clinical trial meet criteria for PMRs or PMCs? Are the objectives clear from the description of the PMR/PMC? Has the applicant adequately justified the choice of schedule milestone dates? Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine feasibility, and contribute to the development process? Check if this form describes a FDAAA PMR that is a randomized controlled clinical trial If so, does the clinical trial meet the following criteria? There is a significant question about the public health risks of an approved drug There is not enough existing information to assess these risks Information cannot be gained through a different kind of investigation The trial will be appropriately designed to answer question about a drug’s efficacy and safety, and The trial will emphasize risk minimization for participants as the protocol is developed PMR/PMC Development Template Reference ID: 3411624 Last Updated 11/22/2013 Page 3 of 4 PMR/PMC Development Coordinator: This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine the safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug quality. _______________________________________ (signature line for BLAs) APPEARS THIS WAY ON ORIGINAL PMR/PMC Development Template Reference ID: 3411624 Last Updated 11/22/2013 Page 4 of 4 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------VICTORIA L TYSON 11/22/2013 Reference ID: 3411624 PMR/PMC Development Template This template should be completed by the PMR/PMC Development Coordinator and included for each PMR/PMC in the Action Package. NDA# Product Name: 205123 simeprevir PMR Description: Submit the final study report and datasets from the ongoing clinical trial TMC435HPC3005, entitled “A Phase 3, Randomized, DoubleBlind, Double Dummy, Placebo-Controlled Study Conducted in the Asia-Pacific Region to Investigate the Efficacy, Pharmacokinetics, Safety and Tolerability of TMC435 vs. Placebo as Part of a Treatment Regimen Including Peginterferon alfa-2a and Ribavirin in Treatmentnaïve, Genotype 1 Hepatitis C-Infected Subjects.” PMR/PMC Schedule Milestones: Trial Completion: Final Report Submission: 02/28/2015 7/31/2015 During application review, explain why this issue is appropriate for a PMR/PMC instead of a pre-approval requirement. Check type below and describe. Unmet need Life-threatening condition Long-term data needed Only feasible to conduct post-approval Prior clinical experience indicates safety Small subpopulation affected Theoretical concern Other Existing clinical data indicate that simeprevir exposures are higher in people with East Asian ancestry compared to those without East Asian ancestry due to physiological characteristics (e.g. lower hepatic levels of the metabolizing enzyme CYP3A). In Phase 1 studies, mean simeprevir exposures (AUC) were 2- to 3-fold higher in healthy subjects of East Asian descent compared to healthy Caucasian subjects. In Phase 3 studies evaluating simeprevir 150 mg QD, mean simeprevir exposures were 3.4-fold higher in HCV-infected patients of East Asian descent compared to the pooled Phase 3 population. However, the number of East Asian patients evaluated in the Phase 3 trials was very small (n=15, 1.9%) and the safety data for the range of exposures expected in the East Asian patient subpopulation are limited. At the time of approval, no simeprevir dose will be recommended for patients of East Asian descent due to the paucity of safety data. While some studies have suggested that the incidence of HCV infection is higher in Asian Americans compared to Americans of other ethnic backgrounds, the size of the HCVinfected Asian American subpopulation is relatively small (Kim et al. J Clin Gastroenterology 2013) and simeprevir pharmacokinetics, safety, and efficacy in patients of East Asian descent could be more efficiently evaluated in a trial conducted in East Asia. These data would inform simeprevir dose recommendations for patients with East Asian ancestry. PMR/PMC Development Template Reference ID: 3410407 Last Updated 11/20/2013 Page 1 of 4 1. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is a FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new safety information.” Analysis of the Phase 3 clinical trial data suggests that there is a positive relationship between simeprevir exposures and the frequency of adverse events (including rash, photosensitivity, pruritus, dyspnea, and increased bilirubin). The elevated simeprevir exposures observed in people with East Asian ancestry, the limited amount of safety data in HCV-infected patients of East Asian descent, and the increased risk of AEs associated with high simeprevir exposures are review issues and collectively underscore the need for further evaluation of simeprevir in patients with East Asian ancestry. Trial HPC3005 is an evaluation of the pharmacokinetics, safety, and efficacy of simeprevir 100 and 150 mg QD in HCV-infected patients in China and Korea. The results of this trial will inform a dose selection for HCV-infected patients with East Asian ancestry that provides the most favorable risk-benefit ratio. 2. If the study/clinical trial is a PMR, check the applicable regulation. If not a PMR, skip to 4. - Which regulation? Accelerated Approval (subpart H/E) Animal Efficacy Rule Pediatric Research Equity Act FDAAA required safety study/clinical trial - If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply) Assess a known serious risk related to the use of the drug? Assess signals of serious risk related to the use of the drug? Identify an unexpected serious risk when available data indicate the potential for a serious risk? - If the PMR is a FDAAA safety study/clinical trial, will it be conducted as: Analysis of spontaneous postmarketing adverse events? Do not select the above study/clinical trial type if: such an analysis will not be sufficient to assess or identify a serious risk Analysis using pharmacovigilance system? Do not select the above study/clinical trial type if: the new pharmacovigilance system that the FDA is required to establish under section 505(k)(3) has not yet been established and is thus not sufficient to assess this known serious risk, or has been established but is nevertheless not sufficient to assess or identify a serious risk Study: all other investigations, such as investigations in humans that are not clinical trials as defined below (e.g., observational epidemiologic studies), animal studies, and laboratory experiments? Do not select the above study type if: a study will not be sufficient to identify or assess a serious risk Clinical trial: any prospective investigation in which the sponsor or investigator determines the method of assigning investigational product or other interventions to one or more human subjects? 3. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the study or trial will be performed in a subpopulation, list here. PMR/PMC Development Template Reference ID: 3410407 Last Updated 11/20/2013 Page 2 of 4 The randomized controlled safety, efficacy, and pharmacokinetic trial is currently ongoing in HCV-infected patients China and Korea (i.e. patients with East Asian ancestry) and will evaluate safety, efficacy, and systemic simeprevir exposures following administration of placebo or simeprevir 100 or 150 mg QD in combination with pegylated interferon alfa and ribavirin. Required Observational pharmacoepidemiologic study Registry studies Primary safety study or clinical trial Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety Thorough Q-T clinical trial Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology) Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety) Pharmacokinetic studies or clinical trials Drug interaction or bioavailability studies or clinical trials Dosing trials Continuation of Question 4 Additional data or analysis required for a previously submitted or expected study/clinical trial (provide explanation) This trial is currently ongoing; the final CSR is expected in Feb 2015. Meta-analysis or pooled analysis of previous studies/clinical trials Immunogenicity as a marker of safety Other (provide explanation) Agreed upon: Quality study without a safety endpoint (e.g., manufacturing, stability) Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease, background rates of adverse events) Clinical trials primarily designed to further define efficacy (e.g., in another condition, different disease severity, or subgroup) that are NOT required under Subpart H/E Dose-response study or clinical trial performed for effectiveness Nonclinical study, not safety-related (specify) Other 4. Is the PMR/PMC clear, feasible, and appropriate? Does the study/clinical trial meet criteria for PMRs or PMCs? Are the objectives clear from the description of the PMR/PMC? Has the applicant adequately justified the choice of schedule milestone dates? Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine feasibility, and contribute to the development process? Check if this form describes a FDAAA PMR that is a randomized controlled clinical trial If so, does the clinical trial meet the following criteria? There is a significant question about the public health risks of an approved drug PMR/PMC Development Template Reference ID: 3410407 Last Updated 11/20/2013 Page 3 of 4 There is not enough existing information to assess these risks Information cannot be gained through a different kind of investigation The trial will be appropriately designed to answer question about a drug’s efficacy and safety, and The trial will emphasize risk minimization for participants as the protocol is developed PMR/PMC Development Coordinator: This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine the safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug quality. _______________________________________ (signature line for BLAs) APPEARS THIS WAY ON ORIGINAL PMR/PMC Development Template Reference ID: 3410407 Last Updated 11/20/2013 Page 4 of 4 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------VICTORIA L TYSON 11/20/2013 Reference ID: 3410407 PMR/PMC Development Template This template should be completed by the PMR/PMC Development Coordinator and included for each PMR/PMC in the Action Package. NDA Product Name: 205123 simeprevir PMR Description: Conduct a study to determine the phenotypic susceptibility of TMC435 against: L356F, V406I, or V629I expressed in genotype 1a replicon cultures, individually and in combination with Q80K R24W, K213R, T358F, P574A, P574S, T610I, or V629I expressed in genotype 1b replicon cultures PMR/PMC Schedule Milestones: Final Report Submission: 7/31/ 2014 1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a pre-approval requirement. Check type below and describe. Unmet need Life-threatening condition Long-term data needed Only feasible to conduct post-approval Prior clinical experience indicates safety Small subpopulation affected Theoretical concern Other The emergence of these substitutions was infrequent and the association between these substitutions and reduced efficacy or virologic failure is unclear. 2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is a FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new safety information.” PMR/PMC Development Template Reference ID: 3410409 Last Updated 11/20/2013 Page 1 of 4 The goal of the nonclinical study is to determine if expression of these substitutions is associated with a reduction in simeprevir susceptibility in HCV replicon cultures. If so, then these substitutions may be identified in the label as potentially resistance-associated. 3. If the study/clinical trial is a PMR, check the applicable regulation. If not a PMR, skip to 4. - Which regulation? Accelerated Approval (subpart H/E) Animal Efficacy Rule Pediatric Research Equity Act FDAAA required safety study/clinical trial - If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply) Assess a known serious risk related to the use of the drug? Assess signals of serious risk related to the use of the drug? Identify an unexpected serious risk when available data indicate the potential for a serious risk? - If the PMR is a FDAAA safety study/clinical trial, will it be conducted as: Analysis of spontaneous postmarketing adverse events? Do not select the above study/clinical trial type if: such an analysis will not be sufficient to assess or identify a serious risk Analysis using pharmacovigilance system? Do not select the above study/clinical trial type if: the new pharmacovigilance system that the FDA is required to establish under section 505(k)(3) has not yet been established and is thus not sufficient to assess this known serious risk, or has been established but is nevertheless not sufficient to assess or identify a serious risk Study: all other investigations, such as investigations in humans that are not clinical trials as defined below (e.g., observational epidemiologic studies), animal studies, and laboratory experiments? Do not select the above study type if: a study will not be sufficient to identify or assess a serious risk Clinical trial: any prospective investigation in which the sponsor or investigator determines the method of assigning investigational product or other interventions to one or more human subjects? 4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the study or trial will be performed in a subpopulation, list here. Phenotypic analysis in HCV replicon culture. PMR/PMC Development Template Reference ID: 3410409 Last Updated 11/20/2013 Page 2 of 4 Required Observational pharmacoepidemiologic study Registry studies Primary safety study or clinical trial Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety Thorough Q-T clinical trial Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology) Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety) Pharmacokinetic studies or clinical trials Drug interaction or bioavailability studies or clinical trials Dosing trials Continuation of Question 4 Additional data or analysis required for a previously submitted or expected study/clinical trial (provide explanation) Meta-analysis or pooled analysis of previous studies/clinical trials Immunogenicity as a marker of safety Other (provide explanation) Agreed upon: Quality study without a safety endpoint (e.g., manufacturing, stability) Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease, background rates of adverse events) Clinical trials primarily designed to further define efficacy (e.g., in another condition, different disease severity, or subgroup) that are NOT required under Subpart H/E Dose-response study or clinical trial performed for effectiveness Nonclinical study, not safety-related (specify) Other 5. Is the PMR/PMC clear, feasible, and appropriate? Does the study/clinical trial meet criteria for PMRs or PMCs? Are the objectives clear from the description of the PMR/PMC? Has the applicant adequately justified the choice of schedule milestone dates? Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine feasibility, and contribute to the development process? Check if this form describes a FDAAA PMR that is a randomized controlled clinical trial If so, does the clinical trial meet the following criteria? There is a significant question about the public health risks of an approved drug There is not enough existing information to assess these risks Information cannot be gained through a different kind of investigation The trial will be appropriately designed to answer question about a drug’s efficacy and safety, and The trial will emphasize risk minimization for participants as the protocol is developed PMR/PMC Development Template Reference ID: 3410409 Last Updated 11/20/2013 Page 3 of 4 PMR/PMC Development Coordinator: This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine the safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug quality. _______________________________________ (signature line for BLAs) APPEARS THIS WAY ON ORIGINAL PMR/PMC Development Template Reference ID: 3410409 Last Updated 11/20/2013 Page 4 of 4 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------VICTORIA L TYSON 11/20/2013 Reference ID: 3410409 PMR/PMC Development Template This template should be completed by the PMR/PMC Development Coordinator and included for each PMR/PMC in the Action Package. NDA # Product Name: PMC Description: 205123 simeprevir Submit the final study report and datasets for trial HPC3001, entitled, “A Phase 3, Randomized, Double-Blind Trial to Evaluate the Efficacy, Safety and Tolerability of TMC435 versus Telaprevir, both in Combination with PegIFNα-2a and Ribavirin, in Chronic Hepatitis C Genotype-1 Infected Subjects who were Null or Partial Responders to Prior PegIFNα and Ribavirin Therapy.” PMR/PMC Schedule Milestones: Trial Completion: Final Report Submission: 6/30/2014 12/31/2014 1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a pre-approval requirement. Check type below and describe. Unmet need Life-threatening condition Long-term data needed Only feasible to conduct post-approval Prior clinical experience indicates safety Small subpopulation affected Theoretical concern Other This is an ongoing trial evaluating simeprevir versus telaprevir (an approved direct-acting antiviral) in combination with pegylated interferon and ribavirin in null and partial responders previously treated with peginterferon/ribavirin therapy. 2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is a FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new safety information.” PMR/PMC Development Template Reference ID: 3410415 Last Updated 11/20/2013 Page 1 of 4 This Phase 3 trial is evaluating efficacy and safety of simeprevir in combination with pegylated interferon and ribavirin in prior non-responders (null and partial responders) to pegylated interferon and ribavirin therapy. The trial results are needed to confirm efficacy and safety in previously submitted phase 2b trial in this population. 3. If the study/clinical trial is a PMR, check the applicable regulation. If not a PMR, skip to 4. - Which regulation? Accelerated Approval (subpart H/E) Animal Efficacy Rule Pediatric Research Equity Act FDAAA required safety study/clinical trial - If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply) Assess a known serious risk related to the use of the drug? Assess signals of serious risk related to the use of the drug? Identify an unexpected serious risk when available data indicate the potential for a serious risk? - If the PMR is a FDAAA safety study/clinical trial, will it be conducted as: Analysis of spontaneous postmarketing adverse events? Do not select the above study/clinical trial type if: such an analysis will not be sufficient to assess or identify a serious risk Analysis using pharmacovigilance system? Do not select the above study/clinical trial type if: the new pharmacovigilance system that the FDA is required to establish under section 505(k)(3) has not yet been established and is thus not sufficient to assess this known serious risk, or has been established but is nevertheless not sufficient to assess or identify a serious risk Study: all other investigations, such as investigations in humans that are not clinical trials as defined below (e.g., observational epidemiologic studies), animal studies, and laboratory experiments? Do not select the above study type if: a study will not be sufficient to identify or assess a serious risk Clinical trial: any prospective investigation in which the sponsor or investigator determines the method of assigning investigational product or other interventions to one or more human subjects? 4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the study or trial will be performed in a subpopulation, list here. This is a Phase 3 trial that is currently ongoing. PMR/PMC Development Template Reference ID: 3410415 Last Updated 11/20/2013 Page 2 of 4 Required Observational pharmacoepidemiologic study Registry studies Primary safety study or clinical trial Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety Thorough Q-T clinical trial Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology) Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety) Pharmacokinetic studies or clinical trials Drug interaction or bioavailability studies or clinical trials Dosing trials Continuation of Question 4 Additional data or analysis required for a previously submitted or expected study/clinical trial (provide explanation) Meta-analysis or pooled analysis of previous studies/clinical trials Immunogenicity as a marker of safety Other (provide explanation) Agreed upon: Quality study without a safety endpoint (e.g., manufacturing, stability) Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease, background rates of adverse events) Clinical trials primarily designed to further define efficacy (e.g., in another condition, different disease severity, or subgroup) that are NOT required under Subpart H/E Dose-response study or clinical trial performed for effectiveness Nonclinical study, not safety-related (specify) Other 5. Is the PMR/PMC clear, feasible, and appropriate? Does the study/clinical trial meet criteria for PMRs or PMCs? Are the objectives clear from the description of the PMR/PMC? Has the applicant adequately justified the choice of schedule milestone dates? Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine feasibility, and contribute to the development process? Check if this form describes a FDAAA PMR that is a randomized controlled clinical trial If so, does the clinical trial meet the following criteria? There is a significant question about the public health risks of an approved drug There is not enough existing information to assess these risks Information cannot be gained through a different kind of investigation The trial will be appropriately designed to answer question about a drug’s efficacy and safety, and The trial will emphasize risk minimization for participants as the protocol is developed PMR/PMC Development Template Reference ID: 3410415 Last Updated 11/20/2013 Page 3 of 4 PMR/PMC Development Coordinator: This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine the safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug quality. _______________________________________ (signature line for BLAs) APPEARS THIS WAY ON ORIGINAL PMR/PMC Development Template Reference ID: 3410415 Last Updated 11/20/2013 Page 4 of 4 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------VICTORIA L TYSON 11/20/2013 Reference ID: 3410415 PMR/PMC Development Template This template should be completed by the PMR/PMC Development Coordinator and included for each PMR/PMC in the Action Package. NDA Product Name: 205123 simeprevir PMC Description: Submit the final study report and datasets for trial TMC435HPC2002, entitled, “An Exploratory Phase 2a, Randomized, Open-Label Trial to Investigate the Efficacy and Safety of 12 weeks or 24 weeks of TMC435 in Combination with PSI-7977 with or without Ribavirin in Chronic Hepatitis C Genotype 1 Infected Prior Null Responders to Peginterferon/Ribavirin Therapy or HCV Treatment-Naïve Subjects.” PMR/PMC Schedule Milestones: Study/Trial Completion: Final Report Submission: Other: 02/28/2014 10/31/2014 MM/DD/YYYY 1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a pre-approval requirement. Check type below and describe. Unmet need Life-threatening condition Long-term data needed Only feasible to conduct post-approval Prior clinical experience indicates safety Small subpopulation affected Theoretical concern Other This is an ongoing trial evaluating an interferon-free regimen in prior peginterferon/ribavirin null responders and treatment-naïve patients 2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is a FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new safety information.” PMR/PMC Development Template Reference ID: 3410419 Last Updated 11/20/2013 Page 1 of 4 The goal of the trial is to evaluate efficacy and safety of interferon-free regimen of simeprevir plus PS7977 (sofosbuvir) plus or minus ribavirin in patients with chronic hepatitis C. 3. If the study/clinical trial is a PMR, check the applicable regulation. If not a PMR, skip to 4. - Which regulation? Accelerated Approval (subpart H/E) Animal Efficacy Rule Pediatric Research Equity Act FDAAA required safety study/clinical trial - If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply) Assess a known serious risk related to the use of the drug? Assess signals of serious risk related to the use of the drug? Identify an unexpected serious risk when available data indicate the potential for a serious risk? - If the PMR is a FDAAA safety study/clinical trial, will it be conducted as: Analysis of spontaneous postmarketing adverse events? Do not select the above study/clinical trial type if: such an analysis will not be sufficient to assess or identify a serious risk Analysis using pharmacovigilance system? Do not select the above study/clinical trial type if: the new pharmacovigilance system that the FDA is required to establish under section 505(k)(3) has not yet been established and is thus not sufficient to assess this known serious risk, or has been established but is nevertheless not sufficient to assess or identify a serious risk Study: all other investigations, such as investigations in humans that are not clinical trials as defined below (e.g., observational epidemiologic studies), animal studies, and laboratory experiments? Do not select the above study type if: a study will not be sufficient to identify or assess a serious risk Clinical trial: any prospective investigation in which the sponsor or investigator determines the method of assigning investigational product or other interventions to one or more human subjects? 4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the study or trial will be performed in a subpopulation, list here. This is a Phase 2a clinical trial that is currently ongoing. PMR/PMC Development Template Reference ID: 3410419 Last Updated 11/20/2013 Page 2 of 4 Required Observational pharmacoepidemiologic study Registry studies Primary safety study or clinical trial Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety Thorough Q-T clinical trial Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology) Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety) Pharmacokinetic studies or clinical trials Drug interaction or bioavailability studies or clinical trials Dosing trials Continuation of Question 4 Additional data or analysis required for a previously submitted or expected study/clinical trial (provide explanation) Meta-analysis or pooled analysis of previous studies/clinical trials Immunogenicity as a marker of safety Other (provide explanation) Agreed upon: Quality study without a safety endpoint (e.g., manufacturing, stability) Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease, background rates of adverse events) Clinical trials primarily designed to further define efficacy (e.g., in another condition, different disease severity, or subgroup) that are NOT required under Subpart H/E Dose-response study or clinical trial performed for effectiveness Nonclinical study, not safety-related (specify) Other 5. Is the PMR/PMC clear, feasible, and appropriate? Does the study/clinical trial meet criteria for PMRs or PMCs? Are the objectives clear from the description of the PMR/PMC? Has the applicant adequately justified the choice of schedule milestone dates? Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine feasibility, and contribute to the development process? Check if this form describes a FDAAA PMR that is a randomized controlled clinical trial If so, does the clinical trial meet the following criteria? There is a significant question about the public health risks of an approved drug There is not enough existing information to assess these risks Information cannot be gained through a different kind of investigation The trial will be appropriately designed to answer question about a drug’s efficacy and safety, and The trial will emphasize risk minimization for participants as the protocol is developed PMR/PMC Development Template Reference ID: 3410419 Last Updated 11/20/2013 Page 3 of 4 PMR/PMC Development Coordinator: This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine the safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug quality. _______________________________________ (signature line for BLAs) APPEARS THIS WAY ON ORIGINAL PMR/PMC Development Template Reference ID: 3410419 Last Updated 11/20/2013 Page 4 of 4 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------VICTORIA L TYSON 11/20/2013 Reference ID: 3410419 PMR/PMC Development Template This template should be completed by the PMR/PMC Development Coordinator and included for each PMR/PMC in the Action Package. NDA# Product Name: PMR/PMC Description: 205123 simeprevir Submit the final study report and datasets for trial TMC435-TiDP16C212, entitled, “A Phase 3 Open-Label Study to Evaluate the Safety, Tolerability and Efficacy of TMC435 Plus PegIFNα-2a (Pegasys®) and Ribavirin (Copegus®) Triple Therapy in Chronic Hepatitis C Genotype-1 Infected Subjects who are Co-Infected with Human Immunodeficiency Virus Type 1 (HIV-1).” PMR/PMC Schedule Milestones: Final Study Report: Other: 05/31/2014 MM/DD/YYYY 1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a pre-approval requirement. Check type below and describe. Unmet need Life-threatening condition Long-term data needed Only feasible to conduct post-approval Prior clinical experience indicates safety Small subpopulation affected Theoretical concern Other There are currently no direct acting antiviral drugs approved for treatment of the HIV/HCV coinfected population. 2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is a FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new safety information.” PMR/PMC Development Template Reference ID: 3410422 Last Updated 11/20/2013 Page 1 of 4 This trial (currently ongoing) would provide safety and efficacy information on the combination of simeprevir with peginterferon-alfa and ribavirin in the population of HIV-HCV co-infected patients. Individuals co-infected with HIV/HCV have a greater risk of progression to cirrhosis or decompensated liver disease than HCV-mono-infected patients. This accelerated rate is magnified in HIV/HCV-co-infected patients with low CD4 counts. 3. If the study/clinical trial is a PMR, check the applicable regulation. If not a PMR, skip to 4. - Which regulation? Accelerated Approval (subpart H/E) Animal Efficacy Rule Pediatric Research Equity Act FDAAA required safety study/clinical trial - If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply) Assess a known serious risk related to the use of the drug? Assess signals of serious risk related to the use of the drug? Identify an unexpected serious risk when available data indicate the potential for a serious risk? - If the PMR is a FDAAA safety study/clinical trial, will it be conducted as: Analysis of spontaneous postmarketing adverse events? Do not select the above study/clinical trial type if: such an analysis will not be sufficient to assess or identify a serious risk Analysis using pharmacovigilance system? Do not select the above study/clinical trial type if: the new pharmacovigilance system that the FDA is required to establish under section 505(k)(3) has not yet been established and is thus not sufficient to assess this known serious risk, or has been established but is nevertheless not sufficient to assess or identify a serious risk Study: all other investigations, such as investigations in humans that are not clinical trials as defined below (e.g., observational epidemiologic studies), animal studies, and laboratory experiments? Do not select the above study type if: a study will not be sufficient to identify or assess a serious risk Clinical trial: any prospective investigation in which the sponsor or investigator determines the method of assigning investigational product or other interventions to one or more human subjects? 4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the study or trial will be performed in a subpopulation, list here. Phase 3 open-label clinical trial. PMR/PMC Development Template Reference ID: 3410422 Last Updated 11/20/2013 Page 2 of 4 Required Observational pharmacoepidemiologic study Registry studies Primary safety study or clinical trial Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety Thorough Q-T clinical trial Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology) Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety) Pharmacokinetic studies or clinical trials Drug interaction or bioavailability studies or clinical trials Dosing trials Continuation of Question 4 Additional data or analysis required for a previously submitted or expected study/clinical trial (provide explanation) Meta-analysis or pooled analysis of previous studies/clinical trials Immunogenicity as a marker of safety Other (provide explanation) Agreed upon: Quality study without a safety endpoint (e.g., manufacturing, stability) Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease, background rates of adverse events) Clinical trials primarily designed to further define efficacy (e.g., in another condition, different disease severity, or subgroup) that are NOT required under Subpart H/E Dose-response study or clinical trial performed for effectiveness Nonclinical study, not safety-related (specify) Other 5. Is the PMR/PMC clear, feasible, and appropriate? Does the study/clinical trial meet criteria for PMRs or PMCs? Are the objectives clear from the description of the PMR/PMC? Has the applicant adequately justified the choice of schedule milestone dates? Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine feasibility, and contribute to the development process? Check if this form describes a FDAAA PMR that is a randomized controlled clinical trial If so, does the clinical trial meet the following criteria? There is a significant question about the public health risks of an approved drug There is not enough existing information to assess these risks Information cannot be gained through a different kind of investigation The trial will be appropriately designed to answer question about a drug’s efficacy and safety, and The trial will emphasize risk minimization for participants as the protocol is developed PMR/PMC Development Template Reference ID: 3410422 Last Updated 11/20/2013 Page 3 of 4 PMR/PMC Development Coordinator: This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine the safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug quality. _______________________________________ (signature line for BLAs) APPEARS THIS WAY ON ORIGINAL PMR/PMC Development Template Reference ID: 3410422 Last Updated 11/20/2013 Page 4 of 4 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------VICTORIA L TYSON 11/20/2013 Reference ID: 3410422 SEALD Director Sign-Off Review of the End?of?Cycle Prescribing Information: Outstanding Format De?ciencies Product Title1 TRADENAMETM (simeprevir) capsules, for oral use Applicant anssen Products, LP Application] Supplement Number NDA 205123 Type of Application Original . . treatment of chronic hepatitis (C HC) infection as a component of a Ind1cat10n(s) . . . . . combmatron treatment regimen Of?ce/Division Division Project Manager Victoria Tyson Date FDA Received Application March 28, 2013 Goal Date November 28, 2013 Date PI Received by SEALD November 19, 2013 SEALD Review Date November 19, 2013 SEALD Labeling Reviewer Elizabeth Donohoe Acting SEALD Division Director Sandra Kweder 1 Product Title that appears in draft agreed-upon prescribing information (PI) This Study Endpoints and Labeling Development (SEALD) Director sign-off review of the end-of-cycle, prescribing information (PI) for important format items reveals outstanding format de?ciencies that should be corrected before taking an approval action. After these outstanding format de?ciencies are corrected, the SEALD Director will have no objection to the approval of this PI. The Selected Requirements of Prescribing Information (SRPI) is a checklist of 42 important format PI items based on labeling regulations [21 FR 201 .56(d) and 201.57] and guidances. The word ?must? denotes that the item is a regulatory requirement, while the word ?should? denotes that the item is based on guidance. Each SRPI item is assigned with one of the following three responses: 0 NO: The PI does not meet the requirement for this item (de?ciency). 0 YES: The PI meets the requirement for this item (not a de?ciency). 0 This item does not apply to the speci?c PI under review (not applicable). Reference ID: 3409515 Selected Requirements of Prescribing Information Highlights See Appendix A for a sample tool illustrating the format for the Highlights. HIGHLIGHTS GENERAL FORMAT and HORIZONTAL LINES IN THE PI YES NO 1. Highlights (HL) must be in a minimum of 8-point font and should be in two-column format, with ½ inch margins on all sides and between columns. Comment: 2. The length of HL must be one-half page or less (the HL Boxed Warning does not count against the one-half page requirement) unless a waiver has been granted in a previous submission (e.g., the application being reviewed is an efficacy supplement). Instructions to complete this item: If the length of the HL is one-half page or less, then select “YES” in the drop-down menu because this item meets the requirement. However, if HL is longer than one-half page:  For the Filing Period:  For efficacy supplements: If a waiver was previously granted, select “YES” in the dropdown menu because this item meets the requirement.  For NDAs/BLAs and PLR conversions: Select “NO” because this item does not meet the requirement (deficiency). The RPM notifies the Cross-Discipline Team Leader (CDTL) of the excessive HL length and the CDTL determines if this deficiency is included in the 74day or advice letter to the applicant.  For the End-of-Cycle Period:  Select “YES” in the drop down menu if a waiver has been previously (or will be) granted by the review division in the approval letter and document that waiver was (or will be) granted. Comment: HL is > 1/2 page; see page 2 of the Labeling Review Tool (LRT) for suggestions on how to reduce the HL length. YES 3. A horizontal line must separate HL from the Table of Contents (TOC). A horizontal line must separate the TOC from the FPI. Comment: YES 4. All headings in HL must be bolded and presented in the center of a horizontal line (each horizontal line should extend over the entire width of the column as shown in Appendix A). The headings should be in UPPER CASE letters. Comment: 5. White space should be present before each major heading in HL. There must be no white space NO between the HL Heading and HL Limitation Statement. There must be no white space between the product title and Initial U.S. Approval. See Appendix A for a sample tool illustrating white space in HL. Comment: White space is missing before the Product Title heading. YES 6. Each summarized statement or topic in HL must reference the section(s) or subsection(s) of the Full Prescribing Information (FPI) that contain more detailed information. The preferred format SRPI version 3: October 2013 Reference ID: 3409515 Page 2 of 10 Selected Requirements of Prescribing Information is the numerical identi?er in parenthesis at the end of each summarized statement or topic. Comment: YES 7. Section headings must be presented in the following order in HL: Section Required/Optional 0 Highlights Heading Required 0 Highlights Limitation Statement Required 0 Product Title Required 0 Initial U.S. Approval Required 0 Boxed Warning Required if a BOXED WARNING is in the FPI - Recent Major Changes Required for only certain changes to Pl* 0 Indications and Usage Required 0 Dosage and Administration Required 0 Dosage Forms and Required 0 Contraindications Required (if no contraindications must state ?None.?) 0 Warnings and Precautions Not required by regulation, but should be present 0 Adverse Reactions Required 0 Drug Interactions Optional 0 Use in Specific Populations Optional 0 Patient Counseling Information Statement Required 0 Revision Date Required RMC only applies to the BOXED WARNING. INDICATIONS AND USAGE. DOSAGE AND ADMINISTRATION. CONTRAINDICATIONS. and WARNINGS AND PRECAUTIONS sections. Comment: HIGHLIGHTS DETAILS Highlights Heading YES 8. At the beginning of HL, the following heading must be bolded and should appear in all UPPER CASE letters: OF PRESCRIBING Comment: Highlights Limitation Statement NO 9. The bolded HL Limitation Statement must include the following verbatim statement: ?These highlights do not include all the information needed to use (insert name of drug product) safely and effectively. See full prescribing information for (insert name of drug product).? The name of drug product should appear in UPPER CASE letters. Comment: should be inserted in place of Product Title in Highlights YES 10. Product title must be bolded. Comment: Initial U.S. Approval in Highlights NO 11. Initial U.S. Approval in HL must be bolded, and include the verbatim statement ?Initial U.S. Approvalz? followed by the 4-digit year. Comment: The 4-digityear is missing and should read: "2013 SRPI version 3: October 2013 Page 3 0f 10 Reference ID: 3409515 Selected Requirements of Prescribing Information N/A N/A N/A N/A N/A N/A N/A YES N/A Boxed Warning (BW) in Highlights 12. All text in the BW must be bolded. Comment: 13. The BW must have a heading in UPPER CASE, containing the word “WARNING” (even if more than one warning, the term, “WARNING” and not “WARNINGS” should be used) and other words to identify the subject of the warning (e.g., “WARNING: SERIOUS INFECTIONS and ACUTE HEPATIC FAILURE”). The BW heading should be centered. Comment: 14. The BW must always have the verbatim statement “See full prescribing information for complete boxed warning.” This statement should be centered immediately beneath the heading and appear in italics. Comment: 15. The BW must be limited in length to 20 lines (this includes white space but does not include the BW heading and the statement “See full prescribing information for complete boxed warning.”). Comment: Recent Major Changes (RMC) in Highlights 16. RMC pertains to only the following five sections of the FPI: BOXED WARNING, INDICATIONS AND USAGE, DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, and WARNINGS AND PRECAUTIONS. RMC must be listed in the same order in HL as the modified text appears in FPI. Comment: 17. The RMC must include the section heading(s) and, if appropriate, subsection heading(s) affected by the recent major change, together with each section’s identifying number and date (month/year format) on which the change was incorporated in the PI (supplement approval date). For example, “Warnings and Precautions, Acute Liver Failure (5.1) --- 9/2013”. Comment: 18. The RMC must list changes for at least one year after the supplement is approved and must be removed at the first printing subsequent to one year (e.g., no listing should be one year older than revision date). Comment: Indications and Usage in Highlights 19. If a product belongs to an established pharmacologic class, the following statement is required under the Indications and Usage heading in HL: “(Product) is a (name of established pharmacologic class) indicated for (indication)”. Comment: Dosage Forms and Strengths in Highlights 20. For a product that has several dosage forms (e.g., capsules, tablets, and injection), bulleted subheadings or tabular presentations of information should be used under the Dosage Forms and Strengths heading. SRPI version 3: October 2013 Reference ID: 3409515 Page 4 of 10 Selected Requirements of Prescribing Information Comment: YES YES NO Contraindications in Highlights 21. All contraindications listed in the FPI must also be listed in HL or must include the statement “None” if no contraindications are known. Each contraindication should be bulleted when there is more than one contraindication. Comment: Adverse Reactions in Highlights 22. For drug products other than vaccines, the verbatim bolded statement must be present: “To report SUSPECTED ADVERSE REACTIONS, contact (insert name of manufacturer) at (insert manufacturer’s U.S. phone number) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch”. Comment: Patient Counseling Information Statement in Highlights 23. The Patient Counseling Information statement must include one of the following three bolded verbatim statements that is most applicable: If a product does not have FDA-approved patient labeling:  “See 17 for PATIENT COUNSELING INFORMATION” If a product has FDA-approved patient labeling:  “See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling”  “See 17 for PATIENT COUNSELING INFORMATION and Medication Guide” Comment: The statement currently reads: "See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient information." and should read: "See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling." NO Revision Date in Highlights 24. The revision date must be at the end of HL, and should be bolded and right justified (e.g., “Revised: 9/2013”). Comment: The date is missing and should read: "11/2013". SRPI version 3: October 2013 Reference ID: 3409515 Page 5 of 10 Selected Requirements of Prescribing Information Contents: Table of Contents (TOC) See Appendix A for a sample tool illustrating the format for the Table of Contents. 25. The TOC should be in a two-column format. Comment: YES 26. The following heading must appear at the beginning of the TOC: “FULL PRESCRIBING INFORMATION: CONTENTS”. This heading should be in all UPPER CASE letters and bolded. Comment: N/A 27. The same heading for the BW that appears in HL and the FPI must also appear at the beginning of the TOC in UPPER CASE letters and bolded. Comment: YES 28. In the TOC, all section headings must be bolded and should be in UPPER CASE. Comment: YES 29. In the TOC, all subsection headings must be indented and not bolded. The headings should be in title case [first letter of all words are capitalized except first letter of prepositions (through), articles (a, an, and the), or conjunctions (for, and)]. Comment: YES 30. The section and subsection headings in the TOC must match the section and subsection headings in the FPI. Comment: YES 31. In the TOC, when a section or subsection is omitted, the numbering must not change. If a section or subsection from 201.56(d)(1) is omitted from the FPI and TOC, the heading “FULL PRESCRIBING INFORMATION: CONTENTS” must be followed by an asterisk and the following statement must appear at the end of TOC: “*Sections or subsections omitted from the full prescribing information are not listed.” Comment: YES SRPI version 3: October 2013 Reference ID: 3409515 Page 6 of 10 Selected Requirements of Prescribing Information Full Prescribing Information (FPI) FULL PRESCRIBING INFORMATION: GENERAL FORMAT YES 32. The bolded section and subsection headings in the FPI must be named and numbered in accordance with 21 CFR 201.56(d)(1) as noted below (section and subsection headings should be in UPPER CASE and title case, respectively). If a section/subsection required by regulation is omitted, the numbering must not change. Additional subsection headings (i.e., those not named by regulation) must also be bolded and numbered. BOXED WARNING 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Labor and Delivery 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance 9.2 Abuse 9.3 Dependence 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.4 Microbiology (by guidance) 12.5 Pharmacogenomics (by guidance) 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION NO Comment: 33. The preferred presentation for cross-references in the FPI is the section (not subsection) heading followed by the numerical identifier. The entire cross-reference should be in italics and enclosed within brackets. For example, “[see Warnings and Precautions (5.2)]” or “[see Warnings and Precautions (5.2)]”. SRPI version 3: October 2013 Reference ID: 3409515 Page 7 of 10 Selected Requirements of Prescribing Information N/A Comment: Two places in the FPI (Section 1 and subsection 12.4) cross-reference "Pharmacogenomics" where "Clinical Pharmacology" (12.5) should be cross-referenced. Multiple places (2.1, 2.4, 2.5, 5.6, 7, 7.3 [including the heading of Table 5 and its corresponding legend], 8.5, 8.6, 8.7, 8.8, 10) cross-reference "Pharmacokinetics" and should cross-reference "Clinical Pharmacology"(12.3). In subsection 5.2, Patient Counseling Information (17.2) is cross-referenced; this should be removed as prescribers should only be directed to sections with more detailed information and there is no subsection "17.2". Section 6 cross-references "Pregnancy" and should cross-reference "Use in Specific Populations" (8.1). Subsection 12.3 cross-references "Use in Special Populations" under 'Hepatic Impairment' and 'Race' where "Use in Specific Populations" should be cross-referenced. 34. If RMCs are listed in HL, the corresponding new or modified text in the FPI sections or subsections must be marked with a vertical line on the left edge. Comment: FULL PRESCRIBING INFORMATION DETAILS FPI Heading YES N/A N/A N/A YES 35. The following heading must be bolded and appear at the beginning of the FPI: “FULL PRESCRIBING INFORMATION”. This heading should be in UPPER CASE. Comment: BOXED WARNING Section in the FPI 36. In the BW, all text should be bolded. Comment: 37. The BW must have a heading in UPPER CASE, containing the word “WARNING” (even if more than one Warning, the term, “WARNING” and not “WARNINGS” should be used) and other words to identify the subject of the Warning (e.g., “WARNING: SERIOUS INFECTIONS and ACUTE HEPATIC FAILURE”). Comment: CONTRAINDICATIONS Section in the FPI 38. If no Contraindications are known, this section must state “None.” Comment: ADVERSE REACTIONS Section in the FPI 39. When clinical trials adverse reactions data are included (typically in the “Clinical Trials Experience” subsection of ADVERSE REACTIONS), the following verbatim statement or appropriate modification should precede the presentation of adverse reactions: “Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.” Comment: N/A 40. When postmarketing adverse reaction data are included (typically in the “Postmarketing Experience” subsection of ADVERSE REACTIONS), the following verbatim statement or appropriate modification should precede the presentation of adverse reactions: SRPI version 3: October 2013 Reference ID: 3409515 Page 8 of 10 Selected Requirements of Prescribing Information “The following adverse reactions have been identified during post-approval use of (insert drug name). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.” Comment: YES YES PATIENT COUNSELING INFORMATION Section in the FPI 41. Must reference any FDA-approved patient labeling in Section 17 (PATIENT COUNSELING INFORMATION section). The reference should appear at the beginning of Section 17 and include the type(s) of FDA-approved patient labeling (e.g., Patient Information, Medication Guide, Instructions for Use). Comment: 42. FDA-approved patient labeling (e.g., Medication Guide, Patient Information, or Instructions for Use) must not be included as a subsection under section 17 (PATIENT COUNSELING INFORMATION). All FDA-approved patient labeling must appear at the end of the PI upon approval. Comment: APPEARS THIS WAY ON ORIGINAL SRPI version 3: October 2013 Reference ID: 3409515 Page 9 of 10 Selected Requirements of Prescribing Information Appendix A: Format of the Highlights and Table of Contents SRPI version 3: October 2013 Reference ID: 3409515 Page 10 of 10 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------ELIZABETH A DONOHOE 11/19/2013 ERIC R BRODSKY 11/19/2013 I agree. Eric Brodsky, SEALD labeling team leader, signing for Sandra Kweder, Acting SEALD Director. Reference ID: 3409515 FOOD AND DRUG ADMINISTRATION Center for Drug Evaluation and Research Office of Prescription Drug Promotion ****Pre-decisional Agency Information**** Memorandum Date: October 28, 2013 To: Victoria Tyson, Regulatory Project Manager Division of Antiviral Products (DAVP) From: Kemi Asante, PharmD, Regulatory Review Officer Office of Prescription Drug Promotion (OPDP) Subject: NDA 205123 – TRADENAME (simeprevir) Capsules As requested in DAVP’s consult dated April 22, 2013, OPDP has reviewed the simeprevir prescribing information (PI), patient package insert (PPI) and carton/container labeling. OPDP’s comments on the PI are provided directly below in the proposed substantially complete version of the PI sent via email by DAVP on September 18, 2013. Please note that comments on the PPI will be provided under separate cover as a collaborative review between OPDP and the Division of Medical Policy Programs (DMPP). We have no comments on the draft carton/container labeling accessed from the following EDR location, \\CDSESUB1\EVSPROD\NDA205123\205123.enx. Thank you for your consult. If you have any questions please contact me at 301-7967425 or at Kemi.Asante@fda.hhs.gov. 66 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page 1 Reference ID: 3397068 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------OLUWASEUN A ASANTE 10/28/2013 Reference ID: 3397068 Department of Health and Human Services Public Health Service Food and Drug Administration Center for Drug Evaluation and Research Office of Medical Policy PATIENT LABELING REVIEW Date: October 28, 2013 To: Debra Birnkrant, MD Director Division of Antiviral Products (DAVP) Through: LaShawn Griffiths, MSHS-PH, BSN, RN Associate Director for Patient Labeling Division of Medical Policy Programs (DMPP) Barbara Fuller, RN, MSN, CWOCN Team Leader, Patient Labeling Division of Medical Policy Programs (DMPP) From: Sharon R. Mills, BSN, RN, CCRP Senior Patient Labeling Reviewer Division of Medical Policy Programs (DMPP) Kemi Asante, Pharm.D. Regulatory Review Officer Office of Prescription Drug Promotion (OPDP) Subject: Review of Patient Labeling: Patient Package Insert (PPI) Drug Name (established name): TRADENAME (simeprevir) Dosage Form and Route: Capsules for oral use Application Type/Number: NDA 205123 Applicant: Janssen Research & Development, LLC Reference ID: 3397304 1 INTRODUCTION On March 28, 2013, Janssen Research & Development, LLC submitted for the Agency’s review an original New Drug Application (NDA) 205123 for TRADENAME (simeprevir) Capsules. The proposed indication for TRADENAME (simeprevir) Capsules is for the treatment of chronic hepatitis C (CHC) genotype 1 infection, in combination with peginterferon alfa and ribavarin, in adults with compensated liver disease (including cirrhosis). This collaborative review is written by the Division of Medical Policy Programs (DMPP) and the Office of Prescription Drug Promotion (OPDP) in response to a request by the Division of Antiviral Products (DAVP) on April 23, 2013, and April 22, 2013, respectively, for DMPP and OPDP to review the Applicant’s proposed Patient Package Insert (PPI) for TRADENAME (simeprevir) Capsules. 2 3 MATERIAL REVIEWED • Draft TRADENAME (simeprevir) Capsules PPI received on March 28, 2013, revised by the Review Division throughout the review cycle, and received by DMPP and OPDP on October 18, 2013. • Draft TRADENAME (simeprevir) Capsules Prescribing Information (PI) received on March 28, 2013 revised by the Review Division throughout the review cycle, and received by DMPP and OPDP on October 18, 2013. • Approved Incivek (telaprevir) comparator labeling dated April 25, 2013, and approved Victrelis (boceprevir) comparator labeling dated September 18, 2013. REVIEW METHODS To enhance patient comprehension, materials should be written at a 6th to 8th grade reading level, and have a reading ease score of at least 60%. A reading ease score of 60% corresponds to an 8th grade reading level. In our review of the PPI the target reading level is at or below an 8th grade level. Additionally, in 2008 the American Society of Consultant Pharmacists Foundation (ASCP) in collaboration with the American Foundation for the Blind (AFB) published Guidelines for Prescription Labeling and Consumer Medication Information for People with Vision Loss. The ASCP and AFB recommended using fonts such as Verdana, Arial or APHont to make medical information more accessible for patients with vision loss. We have reformatted the PPI document using the Verdana font, size 11. In our collaborative review of the PPI we have: • simplified wording and clarified concepts where possible • ensured that the PPI is consistent with the Prescribing Information (PI) • removed unnecessary or redundant information Reference ID: 3397304 4 • ensured that the PPI meets the criteria as specified in FDA’s Guidance for Useful Written Consumer Medication Information (published July 2006) • ensured that the PPI is consistent with the approved comparator labeling where applicable. CONCLUSIONS The PPI is acceptable with our recommended changes. 5 RECOMMENDATIONS • Please send these comments to the Applicant and copy DMPP and OPDP on the correspondence. • Our collaborative review of the PPI is appended to this memorandum. Consult DMPP and OPDP regarding any additional revisions made to the PI to determine if corresponding revisions need to be made to the PPI. Please let us know if you have any questions. 14 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page Reference ID: 3397304 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------SHARON R MILLS 10/28/2013 OLUWASEUN A ASANTE 10/28/2013 BARBARA A FULLER 10/28/2013 LASHAWN M GRIFFITHS 10/28/2013 Reference ID: 3397304 Department of Health and Human Services Public Health Service Food and Drug Administration Center for Drug Evaluation and Research Office of Surveillance and Epidemiology Office of Medication Error Prevention and Risk Management Label, Labeling and Packaging Review Date: October 3, 2013 Reviewer: Morgan Walker, PharmD, MBA Division of Medication Error Prevention and Analysis Team Leader: Jamie Wilkins Parker, PharmD Division of Medication Error Prevention and Analysis Drug Name and Strength: Sovriad (Simeprevir) 150 mg Capsules Application Type/Number: NDA 205123 Applicant/sponsor: Janssen OSE RCM #: 2013-844 *** This document contains proprietary and confidential information that should not be released to the public.*** Reference ID: 3384136 Contents 1 Introduction................................................................................................................. 1 1.1 2 Methods and Materials Reviewed............................................................................... 1 2.1 3 Labels and Labeling....................................................................................................... 1 Medication Error Risk Assessment............................................................................. 2 3.1 4 Product Information ....................................................................................................... 1 Labeling Risk Assessment ............................................................................................. 2 Conclusions and Recommendations ........................................................................... 2 Appendices.......................................................................................................................... 4 Reference ID: 3384136 1 INTRODUCTION This review evaluates the proposed container label and insert labeling for Sovriad (Simeprevir) 150 mg Tablets, NDA 205123 for areas of vulnerability that could lead to medication errors. 1.1 PRODUCT INFORMATION The following product information is provided in the April 12, 2013 submission. Active Ingredient: Simeprevir Indication of Use: the treatment of chronic hepatitis (CHC) genotype 1 infection, in combination with peginterferon alfa and ribavirin, in adult patients with compensated liver disease (including cirrhosis) who are treatment-naive or who have failed previous interferon therapy (pegylated or non-pegylated) with or without ribavirin. 0 Route of Administration: Oral Dosage Form: Capsule Strength: 150 mg Dose and Frequency: one capsule of 150 mg taken orally once daily with food 0 How Supplied: Bottles of 28 capsules and bottles of 7 capsules (emergency supply) 0 Storage: Store in the original bottle in order to protect from light. Do not store above 0 Container and Closure System: The container closure system for commercial supply is a (4) high density polyethylene (HDPE) bottle (W) (4) 2 METHODS AND MATERIALS REVIEWED 2.1 LABELS AND LABELING Using the principles of hrunan factors and Failure Mode and Effects Analysis,1 along with post marketing medication error data, the Division of Medication Error Prevention and Analysis (DMEPA) evaluated the following: 0 Container Labels submitted April 12, 2013 (Appendix A) 0 Insert Labeling submitted April 12, 2013 1 Institute for Healthcare Improvement (IHI). Failure Modes and Effects Analysis. Boston. Reference ID: 3384136 3 MEDICATION ERROR RISK ASSESSMENT 3.1 LABELING RISK ASSESSMENT DMEPA reviewed the proposed insert labeling and container labels. We find that the insert labeling does not contain any vulnerabilities that may pose risks for medication errors to occur at this time. However, after review of the container labels, we have identified the following vulnerabilities that may pose a risk for medication errors to occur:  The proposed proprietary name and established name is in all upper case instead of title case.  The proposed proprietary name is difficult to read .  The established name is not prominent enough and difficult to read .  The strength statement is too prominent and competes with prominence of the proposed proprietary name.  The alert on the side panel is important information and should be on the principal display panel (PDP).  The dosage form “capsule” is presented as part of the strength statement. It is customary to present the dosage form next to the established name.  Emergency supply statement is inappropriate. 4 (b) (4) (b) (4) CONCLUSIONS AND RECOMMENDATIONS DMEPA concludes that the insert labeling is acceptable from a medication error perspective. However, the proposed container labels can be improved to increase the readability and prominence of important information on the label to promote the safe use of the product. Based on this review, DMEPA recommends the following be implemented prior to approval of this NDA: A. Comments to the Applicant a. Ensure that the proposed proprietary name and established name is title case and not in all uppercase lettering for ease of readability. b. Increase the prominence of the established name so that it is commiserate with the proprietary name taking into account all pertinent factors including typography, layout, contrast and other printing features per 21 CFR 201.10(g)(2). c. Move the “Each capsule contains…” statement from the PDP to the side panel and replace with the “Alert…” statement that is currently located on the side panel as this statement provides important information to patients. 2 Reference ID: 3384136 d. Relocate the dosage form “capsule” to the established name statement “simeprevir” as the following demonstrates, since the dosage form is part of the established name: (Simeprevir) Capsules 150 mg If you have further questions or need clarifications, please contact Danyal Chaudhry, project manager, at 301-796-3813. APPEARS THIS WAY ON ORIGINAL 3 Reference ID: 3384136 APPENDICES APPENDIX A. DATABASE DESCRIPTIONS FDA Adverse Event Reporting System (FAERS) The FDA Adverse Event Reporting System (FAERS) is a database that contains information on adverse event and medication error reports submitted to FDA. The database is designed to support the FDA's post-marketing safety surveillance program for drug and therapeutic biologic products. The informatic structure of the database adheres to the international safety reporting guidance issued by the International Conference on Harmonisation. Adverse events and medication errors are coded to terms in the Medical Dictionary for Regulatory Activities (MedDRA) terminology. The suspect products are coded to valid tradenames or active ingredients in the FAERS Product Dictionary (FPD). FDA implemented FAERS on September 10, 2012, and migrated all the data from the previous reporting system (AERS) to FAERS. Differences may exist when comparing case counts in AERS and FAERS. FDA validated and recoded product information as the AERS reports were migrated to FAERS. In addition, FDA implemented new search functionality based on the date FDA initially received the case to more accurately portray the follow up cases that have multiple receive dates. FAERS data have limitations. First, there is no certainty that the reported event was actually due to the product. FDA does not require that a causal relationship between a product and event be proven, and reports do not always contain enough detail to properly evaluate an event. Further, FDA does not receive reports for every adverse event or medication error that occurs with a product. Many factors can influence whether or not an event will be reported, such as the time a product has been marketed and publicity about an event. Therefore, FAERS data cannot be used to calculate the incidence of an adverse event or medication error in the U.S. population. Appendix B: Container Labels (b) (4) 4 Reference ID: 3384136 Reference ID: 3384136 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------JAMIE C WILKINS PARKER on behalf of MORGAN A WALKER 10/17/2013 JAMIE C WILKINS PARKER 10/17/2013 Reference ID: 3384136 MEMORANDUM DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH ______________________________________________________________________________________________________________________________ CLINICAL INSPECTION SUMMARY DATE: September 20, 2013 TO: Victoria Tyson, Regulatory Health Project Manager Adam Sherwat, M.D. Clinical Reviewer Division of Antiviral Drug Products FROM: Antoine El-Hage, Ph.D. Good Clinical Practice Assessment Branch Division of Good Clinical Practice Compliance Office of Scientific Investigations THROUGH: Susan Thompson, M.D. Team Leader Good Clinical Practice Assessment Branch Division of Good Clinical Practice Compliance Office of Scientific Investigations Kassa Ayalew, M.D., M.P.H. Acting Branch Chief Good Clinical Practice Assessment Branch Division of Good Clinical Practice Compliance Office of Scientific Investigations SUBJECT: Evaluation of Clinical Inspections NDA: 205-123 APPLICANT: Janssen Research & Development, LLC. DRUG: TMC435 (Simepravir) NME: Yes THERAPEUTIC CLASSIFICATION: Priority review INDICATION: Treatment of chronic hepatitis C, genotype 1 infection in treatment naïve and experienced adults with compensated liver disease including cirrhosis. Reference ID: 3378839 Page 2 – Clinical Inspection Summary/NDA 205-123 CONSULTATION REQUEST DATE: April 15, 2013 DIVISION ACTION GOAL DATE: November 22, 2013 INSPECTION SUMMARY GOAL DATE: August 28, 2013; extended to September 28, 2013 PDUFA DATE: November 28, 2013 I. BACKGROUND: TMC 435, formerly known as TMC345350, is a NS3/4N protease inhibitor (PI) and has been developed for treatment of chronic hepatitis C virus (HCV) infection. The applicant is seeking the following indication: the treatment of chronic hepatitis C (CHC) genotype 1 infection, in combination with peginterferon alfa and ribavirin, in adult patients with compensated liver disease (including cirrhosis) who are treatment-naïve or who have failed previous interferon therapy (pegylated or non-pegylated) with or without ribavirin. This product must not be used as monotherapy. Two pivotal studies in HCV-infected relapsed subjects were submitted in support of the application. Protocols: TMC435-HPC3007 entitled “A Phase III Randomized, Double-Blind, PlaceboControlled Study to Investigate the Efficacy, Safety and Tolerability of TMC435 vs. Placebo as Part of a Treatment Regimen Including Peginterferon Alfa-2a and Ribavirin in Hepatitis C, Genotype 1 Infected Subjects Who Relapsed After Previous Interferon-Based Therapy” (PROMISE) and TMC435-TiDP16-C216 entitled “A Phase III Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Efficacy, Safety and Tolerability of TMC435 vs. Placebo as Part of a Treatment Regimen Including Peginterferon Alfa-2a (Pegasys) and Ribavirin (Copegus)or Peginterferon Alfa-2b (Peginterferon) and Ribavirin (Rebetol) in Treatment Naïve, Genotype 1, Hepatitis C, Infected Subjects” (QUEST-2) Investigational Drug HCV is a leading cause of liver disease worldwide and has become a focus of considerable medical research. More than 50% of HCV infections become chronic and may lead to the development of liver fibrosis, cirrhosis, and hepatocellular carcinoma. Complications of liver disease due to HCV are the leading cause of liver failure requiring liver transplantation. Current therapies are based on peginterferon-alfa (PegIFN alpha) in combination with ribavirin (RBV). This combination yielded a sustained virologic response in approximately 45% of treatment naïve subjects infected with genotype 1 HCV. In addition to the limited efficacy on genotype 1 HCV, this combination has significant side effects and is poorly tolerated in some subjects. Tibotec Inc has developed TMC435 (simeprevir), because of a need for new compounds that may overcome the disadvantages of current HCV therapy. In recent clinical studies, new investigational drugs acting directly on the virally encoded protease target have demonstrated significant reduction in HCV ribonucleic acid (RNA) levels and improved SVR rates can be achieved when administered in combination with PegIFN alpha and RBV. The HCV-encoded NS3/4A protease is essentially for viral replication and multidisciplinary discovery research Reference ID: 3378839 Page 3 – Clinical Inspection Summary/NDA 205-123 has led to new specific and potent NS3/4A protease inhibitors (PIs), including TMC 435. TMC 435 was developed as an oral solution or as a capsule formulation. In HCV-infected subjects, the t1/2 was approximately 41 hours, a profile that supports a once daily dosing regimen, and the lack of a relevant effect of food on the extent of absorption of TMC following an oral capsule. TMC435 (simeprevir) an NME, is currently being reviewed in support of an application for treatment of HCV infected naïve and relapsed subjects. Safety and efficacy in support of the application are based partially on 12–week data from TMC435-TiDP16-C216, a phase 3 trial comparing TMC 435 vs placebo in treatment–naïve genotype 1 HCV- infected subjects. Protocol TMC-435-HPC3007 The objective of this study was to demonstrate the superiority of TMC 435 versus placebo a part of a treatment regimen including PegIFN alpha-2a and RBV, with respect to the proportion of subjects with sustained viral response (SVR) 12 weeks after planned end of treatment (SVR12) as defined below: 1) At the actual end of treatment (EOT)  HCV RNA levels <25 IU/mL undetectable AND 2) At the time point of SVR12 (i.e., 12 weeks after the planned EOT)  HCV RNA levels <25 IU/mL undetectable OR  HCV RNA levels <25 IU/mL detectable The secondary objectives of this study were: 1) to demonstrate the superiority of TMC 435 versus placebo a part of a treatment regimen including PegIFN alpha-2a and RBV, with respect to the proportion of subjects with SVR 24 weeks after planned end of treatment (SVR24), and 2) to compare the incidence of on-treatment failure in the TMC435 and placebo treatment groups. This protocol was a randomized, double-blind, placebo–controlled, 2-arm, multicenter, phase III study to compare the efficacy, tolerability and of TMC 435 versus placebo as part of a treatment regimen including PegIFNalfa-2a and RBV in adult HCV, genotype 1 infected subjects who received at least 24 weeks of an Peg IFN-based therapy and relapsed within 1 year after the last medication intake. The study consisted of a screening period with a maximum duration of 6 weeks, a response–guided 24 or 48 week (TMC435 treatment group) or 48-week (control group) treatment period, and a post-therapy follow-up period for up to 72 weeks after the start of treatment. A target of 375 subjects with documented chronic genotype 1 HCV infection, who relapsed and have a screening plasma HCV RNA level of > 10,000 IU/mL were be randomly assigned in a 2:1 ratio to receive TMC435 or placebo, stratified by HCV genotype 1 subtype and IL28B genotype. Reference ID: 3378839 Page 4 – Clinical Inspection Summary/NDA 205-123 Protocol TMC-435-TiDP16-C216HP This protocol was a randomized, double-blind, placebo–controlled, 2-arm, multicenter, phase III study to compare the efficacy, tolerability and of TMC 435 versus placebo as part of a treatment regimen including PegIFNalfa-2a/RBV or PegIFNalpha-2b/ RBV in adult naïve subjects with genotype 1 HCV infection. The study consisted of a screening period with a maximum duration of 6 weeks, a response–guided 24 or 48 week (TMC435 treatment group) or 48-week (control group) treatment period, and a post-therapy follow-up period for up to 72 weeks after the start of treatment. The objective of this study was to demonstrate the superiority of TMC 435 versus placebo a part of a treatment regimen including PegIFN alpha-2b and RBV, with respect to the proportion of subjects with sustained viral response (SVR) 12 weeks after planned end of treatment (SVR) 12 weeks after planned end of treatment (SVR12) as defined below: 1) At the actual end of treatment (EOT)  HCV RNA levels <25 IU/mL undetectable AND 2) At the time point of SVR12 (i.e., 12 weeks after the planned EOT)  HCV RNA levels <25 IU/mL undetectable OR  HCV RNA levels <25 IU/mL detectable The secondary objectives of this study were: 1) to demonstrate the superiority of TMC 435 versus placebo a part of a treatment regimen including PegIFN alpha-2a and RBV, or PegIFN alfa-2b/RBV, with respect to the proportion of treatment naïve genotype1 HCV-infected subjects with SVR 24 weeks after planned end of treatment (SVR24), and 2) to compare the incidence of on-treatment failure in the TMC435 and placebo treatment groups. The review division requested inspection of four clinical investigators two domestic and two foreign site inspections in support of this NDA which includes the above protocols. The consult to OSI states, “The sites were selected on the basis of the relatively large enrollment of subjects, high treatment responders, protocol violations, and significant primary efficacy results pertinent to decision-making”. Reference ID: 3378839 Page 5 – Clinical Inspection Summary/NDA 205-123 II. RESULTS (by protocol/site): District Name of CI/Address/ and Site # Protocol #s and # of Subjects Inspection Dates Final Classification Dallas Eric Lawitz, M.D. Alamo Medical Research 621 Camden St. Ste 202 San Antonio TX 78215 Site# US00897 TMC 435HPC3007 13 subjects 5/1724/2013 VAI Los Angeles Franco Felizarta, M.D. The Office of Franco Felizarta 3535 San Dimas St. Suite 24 Bakersfield CA 93301 Site # US00643 TMC 435HPC3007 12 subjects 5/2024/2013 VAI Foreign Andrzej Horban, M.D. 37 Wolska Street Warszawa 01-201 Poland Site# PL0005 Ewa Janczewska-Kazak, M.D. UI Koscielna 5 Czeladz 41-250 Poland Site#PL00027 TMC435-TiDPC216 14 subjects 6/2427/2013 Pending (preliminary classification NAI) TMC435-TiDPC216 17 subjects 9/1620/2013 Pending (preliminary classification NAI) Foreign Key to Classifications NAI = No deviations VAI = Deviation(s) from regulations OAI = Significant deviations from regulations. Data unreliable. Pending = Preliminary classification based on e-mail communication from the field; the EIR has not been received from the field and complete review of EIR is pending. An inspection summary addendum will be generated if conclusions change upon receipt and review of the EIRs. 1. Eric Lawitz, M.D. San Antonio TX 78215 a. What Was Inspected: At this site, 13 subjects were screened, and four subjects were reported as screen failures. Nine (9) subjects were randomized into the study, one subject withdrew, and eight subjects completed the study. Review of the Informed Consent Documents, for all subjects records reviewed, verified that subjects signed informed consent forms prior to enrollment. The medical records/source documents for all subjects were reviewed. The review included consent forms, drug accountability records, vital signs, IRB files, laboratory results, financial disclosure statement, inclusion/exclusion criteria, and use of Reference ID: 3378839 Page 6 – Clinical Inspection Summary/NDA 205-123 concomitant medications. Source documents for all subjects were compared to case report forms and data listings, to include primary efficacy endpoint and adverse events. b. General observations/commentary: At the conclusion of the inspection, no Form FDA 483 was issued to Dr. Lawitz. However, our investigation found that the clinical investigator did not follow the protocol inclusion/exclusion criteria. Study protocol TMCHPC3007 prohibits the use of CYP inducers according to the protocol. Subject 3007-6448 was on concomitant prohibited medication (Provigil 100mg) for fatigue at the pre-study and throughout the study. The clinical investigator agreed with the observation and stated that in the future when in doubt he will consult with the sponsor for additional information. The medical records reviewed were found to be in order, organized, and the data verifiable. There were no deaths and no evidence of underreporting of adverse events. There were no known limitations to the inspection. c. Assessment of Data Integrity: With the exception of the item noted above, the records reviewed were found to be organized and the data verifiable. The data in support of the clinical efficacy and safety at Dr. Lawitz’s site are considered reliable and acceptable in support of the application. 2. Franco Felizarta, M. D. Bakersfield CA 93301 a. What Was Inspected: At this site, a total of 13 were screened and 4 subjects were reported as screen failures. Forty three subjects were randomized, and four subjects were reported as screen failures. Nine (9) subjects were randomized into the study, and nine subjects completed the study. Review of the Informed Consent Documents, for all subjects reviewed, verified that subjects signed consent forms prior to enrollment except for Subject 3007-6072. The medical records/source data for all subjects enrolled were reviewed which included consent forms, drug accountability records, vital signs, laboratory results, IRB records, adverse events, prior and current medications, and inclusion/exclusion criteria. There was no evidence of under-reporting of adverse events. Source documents were compared to CRFs and data listings for primary efficacy endpoints and adverse events listing. There was no evidence of under-reporting of adverse events at this site. b. General Observations/Commentary: At the conclusion of the inspection, a one item Form FDA 483 was issued to Dr. Felizarta. Our investigation noted that the clinical investigator did not follow the protocol inclusion criteria. Study protocol TMC435-HPC3007 required that each subject must give written consent before performance of any study related activity. Subject 3007-6072 underwent screening procedures prior to signing a consent form approved by the IRB. The clinical investigator agreed with the observation and stated that the consent form signed by the subject was from a sister study approved by the IRB. The medical records reviewed were found to be in order, organized, and the data verifiable. There were no known limitations to the inspection. Reference ID: 3378839 Page 7 – Clinical Inspection Summary/NDA 205-123 c. Assessment of Data Integrity: With the exception of the item noted above, the data generated at Dr. Felizarta’s site in support of the clinical efficacy and safety are considered acceptable and may be used in support of the pending application. 3. Andrzej Horban, M.D. Warszaw, Poland a. What Was Inspected: At this site, a total 14 subjects were screened, 14 subjects were randomized into the study, and 14 subjects completed the study. Review of the Informed Consent Documents, for all subjects records reviewed, verified that all subjects signed consent forms prior to enrollment. The medical records/source documents for five subjects were reviewed for primary/secondary endpoints and informed consent including medical notes being translated form Polish to English. The medical records/source documents for three subjects were reviewed excluding medical notes being translated. Even though the study site was blinded to efficacy endpoints, the field investigator was able to verify documentation of subject visits, sample collection and the contract lab performing the HCV RNA analysis. The review included drug accountability records, vital signs, IRB files, laboratory tests, inclusion/exclusion criteria, and use of concomitant medications. Source documents for subjects were not verified/compared to case report forms and data listings for the primary efficacy endpoints. However, our field investigator was able to verify adverse events reporting. b. General Observations/Commentary: At the conclusion of the inspection, no Form FDA 483 was issued to Dr.Horban. The medical records reviewed were found to be in order, organized, and certain data were verifiable. There were no deaths and no evidence of under-reporting of adverse events. There were no known limitations to the inspection. c. Assessment of Data Integrity: The data submitted in support of the clinical efficacy and safety at Dr. Horba’s site are considered reliable and appear acceptable in support of the pending application. 4. Ewa Janeczewska-Kazak, M.D. Czelade 41-250, Poland a. What Was Inspected: At this site, a total 17 subjects were screened, two subjects were reported as screen failures, 15 subjects were randomized into the study, and 11 subjects completed the study. Review of the Informed Consent Documents, for all subjects records reviewed, verified that all subjects signed consent forms prior to enrollment. The medical records/source documents for 15 subjects were reviewed for primary/secondary endpoints and informed consent including medical notes being translated from Polish to English. The medical records/source documents for 15 subjects were reviewed. The review included drug accountability records, vital signs, IRB files, laboratory test results, inclusion/exclusion criteria, and use of concomitant medications. Reference ID: 3378839 Page 8 – Clinical Inspection Summary/NDA 205-123 Source documents for all subjects were compared to case report forms and data listings for the primary efficacy endpoints. However, there was a third party unblinded monitor to review the primary efficacy endpoint and write a note to the site for determination of successful/acceptable primary efficacy endpoint results. This procedure was completed according to the protocol. b. General Observations/Commentary: At the conclusion of the inspection, no Form FDA 483 was issued to Dr.Janczewska-Kazak. The medical records reviewed were found to be in order, organized, and certain data were verifiable. There were no deaths and no evidence of under-reporting of adverse events. There were no known limitations to the inspection. c. Assessment of Data Integrity: The data submitted in support of the clinical efficacy and safety at Dr. Janczewska-Kazak’s site are considered reliable and appear acceptable in support of the pending application. III. OVERALL ASSESSMENT OF FINDINGS AND GENERAL RECOMMENDATIONS Three clinical investigator sites were inspected in support of this application. The inspections of Drs. Lawitz and Felizarta revealed minor regulatory violations, and the classifications for these inspections are noted above as Voluntary Action Indicated (VAI). The classification for the inspection of Drs. Horban and Janczewska-Kazak are pending with No Action Indicated (NAI). The final classification for Dr. Horban’s and Janczewska’s sites will be determined upon review of the establishment inspection reports (EIR). An inspection summary addendum will be generated if conclusions change upon receipt and review of the EIR. While minor observations were identified during the inspection of Drs. Lawitz and Felizarta, the findings are not likely to critically impact primary efficacy and safety analyses; therefore, OSI does not consider the effect of the violations on overall data integrity to be significant. Overall, the data submitted from these three sites are considered acceptable in support of the pending application. {See appended electronic signature page} Antoine El-Hage, Ph.D. Good Clinical Practice Assessment Branch Division of Good Clinical Practice Compliance Office of Scientific Investigations CONCURRENCE: {See appended electronic signature page} Susan Thompson, M.D. Team Leader Good Clinical Practice Assessment Branch Reference ID: 3378839 Page 9 – Clinical Inspection Summary/NDA 205-123 Division of Good Clinical Practice Compliance Office of Scientific Investigations {See appended electronic signature page} Kassa Ayalew, M.D., M.P.H. Acting Branch Chief Good Clinical Practice Assessment Branch Division of Good Clinical Practice Compliance Office of Scientific Investigations Reference ID: 3378839 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------ANTOINE N EL HAGE 09/26/2013 KASSA AYALEW 09/26/2013 Reference ID: 3378839 MEMORANDUM DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH ____________________________________________________________________________ DATE: September 16, 2013 TO: Debra B. Birnkrant, M.D. Director, Division of Antiviral Products Office of Antimicrobial Products FROM: Xikui Chen, Ph.D. Pharmacologist Division of Bioequivalence and GLP Compliance Office of Scientific Investigations THROUGH: Sam H. Haidar, Ph.D., R.Ph. Chief, Bioequivalence Branch Division of Bioequivalence and GLP Compliance Office of Scientific Investigations (OSI) and William H. Taylor, Ph.D. Director Division of Bioequivalence and GLP Compliance Office of Scientific Investigations SUBJECT: Review of EIRs Covering NDA 205-123, Simeprevir Capsules, sponsored by Janssen Research and Development, LLC At the request of the Division of Antiviral Products, the Division of Bioequivalence and GLP Compliance (DBGLPC) conducted inspections of the following study: Study Number: Study Title: Reference ID: 3374148 TMC435HPC1002 “A Phase I, open-label, randomized, 3-panel, 3-way crossover trial in healthy adult subjects to assess the relative bioavailability of TMC435 following administration of 2 liquid formulations or 2 different capsule concept formulations compared to the Phase III 150 mg capsule, and to assess the effect of food on the bioavailability of TMC435 following administration of the liquid formulations” Page 2 NDA 205-123, Simeprevir Capsules The audits included thorough examination of study records, facilities, and equipment, and interviews and discussions with the firms' managements and staff. Clinical Site: The inspection of the clinical portion was conducted by ORA Investigator mm mm. Following the inspection mm Form was i (Attachment the response from so to the inspectional findings on Se 2013 (Att 2). The Form observations, on response, and the reviewer's evaluations 1? You failed to retain reserve samples for the test article and reference standards used to conduct the bioequivalence study TMC435HPC1002. The remaining test articles and reference standards used for this trial were returned to the Sponsor at the end of trial. The return of study supplies were picked up by the courier on 16Ju1y2012, according to the WW Record of Return of Study Supplies to Sponsor form. so responded that this study does not meet the requirements FR or The study compared the relative bioavailability of two pediatric formulations (a solution and a suspension) defined as test articles, with the II testing capsule of TMC435 as reference standard. forwards the claim by the sponsor Janssen that they are king approval of the solution or suspension formulations (4) and will not do so in the future [Reference is not aware when Janssen made these decisions relative to the timing of the proposed design on processes. Batch 1 @w on G019 we Both batches of G019 have the same formulation as the phase capsule of TMC435 tested in study TMC435HPC1002. defers to DAVP and OCP to decide whether all or part of study TMC435HPC1002 should be considered as a definitive bioavailability/bioequivalence study, for which reserve samples would be required. Reference ID: 3374148 Page 3 NDA 205?123, Simeprevir Capsules 2.You did not retain documentation showing you reported deviations in PK (pharmacokinetic) sample collection times when they were collected from subjects outside the signed Window Allowance Agreement. Study protocol No. TMC435HPC1002, approved date 21FE32012, Section 17.1 indicates [that] when departures from the protocol occur, contact with the sponsor must be made as soon as possible to discuss the situation and agree on an appropriate course of action. Mmprovided an email [Reference which concluded that all PK sampling time deviations, including those outside the Window Allowance Agreement, were minor and not major protocol deviations, and that there was no impact on trial data or subject safety. defers to DAVP and OCP to evaluate the impact of the sampling time deviations. Bioanalytical Site: The inspectio Investigator MW mm mm Following the inspection MW), Form ssued (Attachment 3) a response from to the inspectional finding on mm' 2013 (Atta The Form observation, response, and the reviewer's evaluation 1? For Study TMC435HPC1002, analytical run #18 did not include dilution quality control (QC) samples in measurements of TMC435 for 5/5 clinical plasma samples, with concentrations that were above the upper limit of quantification (ULOQ). In the response, MW reported a 2?fold dilution linearity experiment using control samples with concentrations above ULOQ. The results for accuracy and precision are within the acceptance criteria for the experiment and listed in Amendment 2 of partial validation report number Quality control samples were used for evaluating dilution linearity, because the study plasma samples were not available. The data for 5 study samples with concentrations above ULOQ, Reference ID: 3374148 Page 4 – NDA 205-123, Simeprevir Capsules assayed with 2-fold dilution, are acceptable based on the results of the dilution linearity experiment. Conclusion: Following the above inspections, this DBGLPC reviewer recommends the following: • DAVP and OCP should determine whether Study TMC435HPC1002 should be considered as a definitive bioavailability/ bioequivalence study, for which reserve samples would be required. Without the reserve samples, the study would not be acceptable for review as a definitive study. The study is acceptable for other limited purposes, such as comparing manufacturing lots. • The bioanalytical data from study TMC435HPC1002 are acceptable for review, if the clinical data are accepted by DAVP and OCP. APPEARS THIS WAY ON ORIGINAL Reference ID: 3374148 Page 5 – NDA 205-123, Simeprevir Capsules Final Classifications: (b) (4) VAI: VAI: CC: CDER OSI PM TRACK OSI/DBGLPC/Taylor/Haidar/Bonapace/Choi/Skelly/Dejernett/Chen/CF OND/ODE4/DAVP/Victoria Tyson/Birnkrant (b) (4) Draft: XC 9/13/2013 Edit: MFS 9/13/2013; WHT 9/13/2013 OSI: BE File # 6455; O:\BE\EIRCOVER\205123.jan.sim.doc ECMS: Cabinets/CDER_OC/OSI/Division of Bioequivalence & Good Laboratory Practice Compliance/Electronic Archive/BEB FACTS: 1514697 35 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page Reference ID: 3374148 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------XIKUI CHEN 09/16/2013 MICHAEL F SKELLY 09/16/2013 Skelly signing on behalf of Dr. Haidar WILLIAM H TAYLOR 09/17/2013 Reference ID: 3374148 RPM FILING REVIEW (Including Memo of Filing Meeting) To be completed for all new NDAs, BLAs, and Ef?cacy Supplements [except SE8 (labeling change with clinical data) and SE9 (manufacturing change with clinical data] Application Information NDA 205123 NDA Supplement Ef?cacy Supplement Type SE- BLA Supplement Proprietary Name: TBD (Sovriad conditionally granted under IND: submitted to NDA and under review) Established/Proper Name: Simeprevir. TMC435 Dosage Form: Capsule 150 mg Applicant: Janssen Reasearch Development. LLC Agent for Applicant (if applicable): Date of Application: March 28. 2013 Date of Receipt: March 28. 2013 Date clock started after UN: PDUFA Goal Date: November 28. 2013 Action Goal Date (if different): November 22. 2013 Filing Date: May 27. 2013 Date of Filing Meeting: April 22. 2013 Chemical Classi?cation: (1.2.3 etc.) (original NDAs only) 1 Proposed indication: treatment of chronic hepatitis genotype 1 infection, in combination with peginterferon alfa and ribavirin, in adult patients with compensated liver disease, including cirrhosis, who are treatment-naive or who have failed previous interferon therapy (pegylated or non-pegylated) with or without ribavirin Type of Original NDA: IXI 505(b)(1) AND (if applicable) J: 505(b)(2) Type of NDA Supplement: 505(b)(1) El 505(b)(2) If 505(b)(2): Dra? the ?505(b)(2) Assessment? review found at: eer .- and refer to Appendix A for further information. Review Classi?cation: Standard Priority If the application includes a complete response to pediatric WR, review classification is Priority. Tropical Disease Priority I a tro ical disease riori ?rei?ievi' voucher was submitted review - - t) Rev1ew Voucher classi?cation is Priority. Resubmission after withdrawal? I Resubmission after refuse to ?le? Part 3 Combination Product? El Convenience kit/Co-package El Pre-?lled drug delivery device/system (syringe. patch. etc.) (01110? the 0f Pre-?lled biologic delivery device/ system (syringe. patch. etc.) comwmm?" (OCP) 01?3" Device coated/impregnated/combined with drug 0" a? Im" ?Cem? El Device coated/impregnated/combined with biologic Separate products requiring cross-labeling IX Drug/Biologic El Possible combination based on cross-labeling of separate products Other (drug/device/biological product) Version: 3/25/13 1 Reference ID: 3304642 El Fast Track Designation PMC response Breakthrough Therapy Designation PMR response: Rolling Review [505(0)] Orphan Designation PREA deferred pediatric studies [21 CF CFR El switch. Full Accelerated approval con?rmatory studies (21 CFR El switch. Partial 314.510/21 CFR 601.41) Direct-to-OTC Animal rule postmarketing studies to verify clinical bene?t and safety (21 CFR 314.610/21 CFR 601.42) Other: Collaborative Review Division (if OTC product): List referenced IND Number(s): 75391 Goal Dates/Product Names/Classi?cation Properties YES NO NA Comment PDUFA and Action Goal dates correct in tracking system? If no, ask the document room staff to correct them immediately. These are the dates used for calculating inspection dates. Are the proprietary. established/proper. and applicant names Som'ad-trade name correct in tracking system? granted 9/20/ 12 under IND 75391: submitted to the If no, ask the document room staff to make the corrections. Also, NDA 4/ 12/2013 ask the document room staff to add the established/proper name to the supporting if not already entered into tracking system. Is the review priority (S or P) and all appropriate classi?cations/properties entered into tracking system chemical classi?cation. combination product classi?cation. 505 orphan d?lg)? For supplements, check the New Application and New Supplement Notification Checklists for a list of all classifications4oroperties at: hmM/in side. (do. usinessProce sSuggort/ucml 63969. In a If no, ask the document room staff to make the appropriate entries. Application Integrity Policy YES NO NA Comment Is the application affected by the Application Integrity Policy Check the AIP list at: If yes. explain in comment colunm. If affected by AIP. has been noti?ed of the submission? If yes, date noti?ed: User Fees YES NO NA Comment Is Form 3397 (User Fee Cover Sheet) included with authorized signature? Version: 3/25/ 13 2 Reference ID: 3304642 User Fee Status Payment for this application: If a user fee is required and it has not been paid (and it Paid is not exempted or waived), the application is El Exempt (orphan. govermnent) unacceptable for filing following a 5-day grace period. Waived small business. public health) Review stops. Send Unacceptable for Filing (07V) letter Not required and contact user fee staff Payment of other user fees: If the firm is in arrears for other fees (regardless of Not ill arrears whether a user fee has been paid for this application), In arrears the application is unacceptable for ?ling (5-day grace period does not apply). Review stops. Send UN letter and contact the user fee staff 505(b)(2) YES NO NA Comment Ef?cacy Supplements only) Is the application for a duplicate of a listed drug and eligible for approval under section 5050) as an Is the application for a duplicate of a listed drug whose only difference is that the extent to which the active ingredient(s) is absorbed or otherwise made available to the site of action is less than that of the reference listed drug [see 21 CFR Is the application for a duplicate of a listed drug whose only difference is that the rate at which the proposed product?s active ingredient(s) is absorbed or made available to the site of action is tulintentionally less than that of the listed drug [see 21 CFR If you answered yes to any of the above questions, the application may be refused for filing under 21 FR Contact the 505(b)(2) review staff in the Immediate Of?ce of New Drugs Is there miexpired exclusivity on any drug product containing the active moiety 5-year. 3-year. orphan. or pediatric exclusivity)? Check the Electronic Orange Book at: If yes. please list below: Application No. Drug Name Exclusivity Code Exclusivity Expiration If there is unexpired, 5?_vear evclusivitv remaining on the active moiety for the proposed drug product, a 505 (2) application cannot be submitted until the period of exclusivity expires (unless the applicant provides paragraph IV patent certi?cation; then an application can be submitted fouryears after the date of approval. Pediatric exclusivity will extend both of the time??ames in this provision by 6 months. 21 CFR Unexpired, 3- year exclusivity may block the approval but not the submission of a 5 05 application. Exclusivity YES NO NA Comment Does another product (same active moiety) have orphan exclusivity for the same indication? Check the Orphan Drug Version: 3/25/ 13 3 Reference ID: 3304642 Designations and Approvals list at: If another product has orphan exclusivity. is the product considered to be the same product according to the orphan drug de?nition of sameness [see 21 CFR If yes, consult the Director, Division of Regu latory Po 1 i Q, 11, 01770? 0f Regulatory Policy Has the applicant requested 5-year or 3-year Waxman-Hatch exclusivity? efficacy supplements only) If yes. years requested: 5 Note: An applicant can receive exclusivity without requesting it; therefore, requesting exclusivin? is not required. Is the proposed product a single enantiomer of a racemic drug previously approved for a different therapeutic use (NDAs only If yes. did the applicant: elect to have the single enantiomer (contained as an active ingredient) not be considered the same active ingredient as that contained in an already approved racemic drug. and/or request exclusivity pursuant to section 505(11) of the Act (per Section 1113)? If yes, contact Mary Ann Holovac, Director of Drug Information, Format and Content All paper (except for COL) All electronic Do not check mixed submission if the only electronic component Mixed (paper/electronic) is the content of labeling (COL). CTD Mixed If mixed (paper/electronic) submission, which parts of the application are submitted in electronic format? Overall Format/Content YES NO NA Comment If electronic submission, does it follow the guidance?1 If not, explain waiver granted). Index: Does the submission contain an accurate comprehensive index? Is the submission complete as required under 21 CFR 314.50 e?icaev supplements) or lulder 21 FR 601.2 efficacv supplements) including: http://wuw Version: 3/25/ 13 4 Reference ID: 3304642 legible English (or translated into English) pagination navigable hyperlinks (electronic submissions only) If no. explain. BLAs only: Companion application received if a shared or divided manufacttuing arrangement? If yes. BLA Forms and Certi?cations Electronic fonns and certi?cations with electronic signatures (scanned, digital, or electronic similar to BART S, e. are acceptable. Othenrise,_paperfonns and certi?cations with hand-written signatures must be included. arms include: user fee cover sheet (3397), application form (35 6h), patent information (3542a), ?nancial disclosure (3454/3455), and clinical trials (36 74); Certifications include: debarment certi?cation, patent certi?cation?), ?eld copy certi?cation, and pediatric certi?cation. Application Form YES NO NA Comment Is fonn FDA 35611 included with authorized signature per 21 CFR If foreign applicant, a US. agent must sign the form [see 21 FR Are all establislnnents and their registration numbers listed 011 the form/attached to the form? Patent Information YES NO NA Comment ef?cacy supplements only) Is patent information submitted on form FDA 3542a per 21 CFR Financial Disclosure YES NO NA Comment Are fmancial disclosm?e forms FDA 3454 and/or 3455 included with authorized signature per 21 CFR and Forms must be signed by the APPLICANT, not an Agent [see 21 CFR Note: Financial disclosure is required for bioequivalence studies that are the basis for approval. Clinical Trials Database YES NO NA Comment Is fonn FDA 3674 included with authorized signature? If yes, ensure that the application is also coded with the supporting document category, ?Form 36 74. Version: 3/25/ 13 5 Reference ID: 3304642 If no, ensure that language requesting submission of the form is included in the acknowledgement letter sent to the applicant Debarment Certi?cation YES NO NA Comment Is a correctly worded Debarment Certi?cation included with authorized signature? Certification is not required for supplements if submitted in the original application; If foreign applicant, bo_th the applicant and the US. Agent must sign the certi?cation [per Guidance for Industry: Submitting Debarment erti?cations]. Note: Debarment Certi?cation should use wording in Act Section 306(k)(1) ?[Name of applicant] hereby certi?es that it did not and will not use in any capacity the services of any person debarred under section 306 of the Federal Food, Drug, and Cosmetic Act in connection with this application. Applicant may not use wording such as, 0 the best of my Field Copy Certi?cation YES NO NA Comment ef?cacy supplements only) For paper submissions only: 15 a Field Copy Certi?cation (that it is a true copy of the CMC teclmical section) included? Field opy Certification is not needed if there is no CMC technical section or if this is an electronic submission (the Field Of?ce has access to the EDR) If maroon ?eld copy jackets from foreign applicants are received, return them to CDR for delivery to the appropriate ?eld office. Controlled Substance/Product with Abuse Potential YES NO NA Comment For NMEs: Is an Abuse Liability Assessment. including a proposal for scheduling. submitted per 21 FR If yes, date consult sent to the Controlled Substance Sta?: For non-NMEs: Date of consult sent to Controlled Substance Staff Version: 3/25/ 13 Reference ID: 3304642 Pediatrics YES NO NA Comment PREA Meeting- 9/2 5/20 1 3 Does the application trigger If yes, notify RPM meeting is requiredf Note: NDAs/BLAs/e?icacv supplements for new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration trigger PREA. All waiver defeiral requests, pediatric plans, and pediatric assessment studies must be reviewed bv prior to approval of the If the application triggers PREA. are the required pediatric assessment studies or a full waiver of pediatric studies included? If studies or full waiver not included, is a request for full PPSR: waiver of pediatric studies OR a request for partial waiver Partial waiVer-Less and/or deferral with a pediatric plan included? than 3 years Of age Deferral-3 years of age to less than 18 If no, request in 74-day letter years of age If a request for full waiver/partial waiver/deferral is included. does the application contain the certi?cation(s) required by FDCA Section 5053(a)(3) and If no, request in 74-day letter BPCA (N efficacy supplements only): Is this submission a complete response to a pediatric Written Request? If yes, notify Pediatric Exclusivity Board RPM (pediatric exclusivity determination is required)3 Proprietary Name YES NO NA Comment Is a proposed proprietary name submitted? submitted yes, ensure that the application is also coded with the supporting document category, ?Proprietary Name/Request for Review. REMS YES NO NA Comment Is a REMS submitted? If yes, send consult to and notify via the CDER 0S1 RMP mailbox Prescription Labeling Not applicable Check all types of labeling submitted. Package Insert (PI) Patient Package Insert (PPI) Instructions for Use (IFU) 2 http:// inside fda. govz9003/ DER/Of?ceofN 3 http:// inside fda. govz9003/ DER/Of?ceotN 7.11tm Version: 3/25/ 13 7 Reference ID: 3304642 Medication Guide (MedGuide) El Carton labels Immediate container labels Diluent El Other (specify) YES NO NA Comment Is Electronic Content of Labeling (COL) submitted in SPL format? If no, request applicant to submit SPL before the ?ling date. Is the PI submitted in PLR format?4 If PI not submitted in PLR format. was a waiver or deferral requested before the application was received or in the submission? If requested before application was submitted. what is the status of the request? If no waiver or deferral, request applicant to submit labeling in PLR format before the ?ling date. All labeling (PI. PPI. MedGuide. IFU. carton and irmnediate container labels) consulted to MedGuide. PPI. IFU (plus PI) consulted to (send WORD version If available) Carton and immediate container labels. PI. PPI sent to and appropriate CMC review office (OBP or ONDQAW OTC Labeling Not Applicable Check all types of labeling submitted. El Outer carton label Immediate container label Blister card Blister backing label El Consumer Information Lea?et (CIL) Physician sample Consumer sample Other (specify) YES NO NA Comment Is electronic content of labeling (COL) submitted? If no, request in 74-day letter. Are arnrotated speci?cations submitted for all stock keeping units If no, request in 74-day letter. If representative labeling is submitted. are all represented SKUs de?ned? 4 http://inside 2 5 5 7 6 Version: 3/25/13 8 Reference ID: 3304642 If no, request in 74-day letter. A11 labeling/packaging. and cmrent approved Rx PI (if switch) sent to Other Consults YES NO NA Comment Are additional consults needed? IFU to DRH: QT skin rash: study report to QT Interdisciplinary Review Team) Validation 0f manufacturing - . . controls and If yes, spew/j, eonsult(s) and date(s) sent. analytical methods Meeting Minutes/SPAS YES NO NA Comment End-of Phase 2 meeting(s)? Date(s): October 18. 2010. September 15. 201 1 If yes, distribute minutes before ?ling meeting Pre-NDA/Pre-BLA/Pre-Supplement meeting(s)? Date(s): August 2. 2012. January 30. 2013 If yes, distribute minutes before ?ling meeting Any Special Protocol Assessments Date(s): If yes, distribute letter and/or relevant minutes before ?ling meeting Version: 3/25/ 13 9 Reference ID: 3304642 ATTACHMENT MEMO OF FILING MEETING DATE: April 22, 2013 BLA/NDA/Supp #: 205123 PROPRIETARY NAME: TBD (proposed name Sovriad under review) ESTABLISHED/PROPER NAME: Simeprevir, TMC435 DOSAGE FORM/STRENGTH: 150 mg, Capsules APPLICANT: Janssen Research & Development, LLC PROPOSED INDICATION: in combination with pegylated interferon alfa and ribavirin for the treatment of chronic hepatitis C genotype 1 infection in adults with compensated liver disease including cirrhosis who are treatment-naïve or who have failed previous interferon therapy (pegylated or non-pegylated) with or without ribavirin BACKGROUND: TMC435, simeprevir, is an NS3/4A protease inhibitor, a 150 mg capsule proposed for administration once daily in combination with pegylated interferon alfa and ribavirin for 12 weeks, followed by response-guided therapy for 12 or 36 weeks of P/R, based on the response at Week 4. Clinical trials to support the indication were conducted at several sites in the U.S. and in foreign countries under IND 75391. The NDA includes additional pharmacogenomics and deep sequencing data from trials C205 and C206 that were conducted in treatment-naïve and treatment-experienced, genotype 1 CHC subjects. The NDA also includes Phase 1, 2, PK, BA, BE and drug-drug interaction trials and Janssen has ongoing studies in CHC/HIV co-infected subjects (C212) and in treatment-naïve and treatment-experienced patients infected with Genotype 4. The NDA includes a request for priority review designation. The trade name Sovriad was granted under the IND on September 20, 2012 and a request for review was submitted to the NDA for review on April 12, 2013. The goal date for response is July11, 2013. A pediatric development plan is included in the NDA along with a request for waiver of pediatric studies for children under 3 years of age and a deferral for children 3 to less than 18 years of age. Administratively the NDA is complete and is being managed under PDUFA V-The Program. There were no agreements made at the application’s pre-submission meeting regarding late submission components. The following changes were highlighted under PDUFA V: • Version: 3/25/13 Reference ID: 3304642 Filing Letter-Date of the Internal MidCycle Meeting 10 0 Post Teleconference Late-Cycle Meeting An Advisory Committee Meeting is scheduled for October 24. 2013. REVIEW TEAM: Discipline/Organization Names Present at ?ling meeting? (Y or N) Regulatory Project Management RPM: Victoria Tyson Elizabeth Thompson. MS Cross-Discipline Team Leader (CDTL) Mary Singer. MD. Clinical Reviewer: Adam Sherwat. MD TL: Mary Singer. MD. Social Scientist Review (for OTC Reviewer: products) TL: OTC Labeling Review (for OTC Reviewer: products) TL: Clinical Microbiology (for antimicrobial Reviewer: Damon Deming. products) Eric Donaldson. TL: Julian O?Rear, Version: 3/25/13 11 Reference ID: 3304642 Clinical Pharmacology Biostatistics Nonclinical (Pharmacology/Toxicology) Statistics (carcinogenicity) Reviewer: Leslie Chinn, Ph.D. Y TL: Islam Younis, Ph. D. N Reviewer: Yanming Yin, Ph.D. Y TL: Fraser Smith, Ph.D. Y Reviewer: Janice Lansita, Ph.D. Y TL: Hanan Ghantous, Ph.D., DABT N Celia Cruz, Ph.D.-Drug Product Chunchun Zhang, PhD.Drug Substance Stephen Miller, Ph.D. Rapti Madurawe, Ph.D. Y Y Y N Reviewer: Danyal Chaudhry Y TL: Franklin Stephenson N Reviewer: Carolyn Yancey Y TL: Kendra Worthy N Reviewer: TL: Immunogenicity (assay/assay validation) (for BLAs/BLA efficacy supplements) Reviewer: TL: Product Quality (CMC) Reviewer: TL: Quality Microbiology (for sterile products) CMC Labeling Review Reviewer: TL: Reviewer: TL: Facility Review/Inspection Reviewer: TL: OSE/DMEPA (proprietary name) OSE/DRISK (REMS) OC/OSI/DSC/PMSB (REMS) Reviewer: TL: Version: 3/25/13 Reference ID: 3304642 12 Version: 3/25/13 Reference ID: 3304642 APPEARS THIS WAY ON ORIGINAL 13 Bioresearch Monitoring (051) Reviewer: Antoine El Hage TL: Susan Leibenhaut Controlled Substance Staff (CSS) Reviewer: TL: Other reviewers Other attendees FILING MEETING DISCUSSION: GENERAL 0 505(b)(2) ?ling issues: 0 Is the application for a duplicate of a listed diug and eligible for approval under section 5050) as an 0 Did the applicant provide a scienti?c ?bridge" demonstrating the relationship between the proposed product and the referenced literature? Describe the scienti?c bridge studies): Not Applicable YES NO DYESEINO 0 Per reviewers. are all parts in English or English translation? If no. explain: 0 Electronic Submission comments List comments: Not Applicable CLINICAL Comments: Not Applicable FILE El REFUSE TO FILE Review issues for 74-day letter 0 Clinical study site(s) inspections(s) needed? If no, explain: IXIYES Version: 3/25/ 13 Reference ID: 3304642 14 • Advisory Committee Meeting needed? Comments: If no, for an NME NDA or original BLA , include the reason. For example: o this drug/biologic is not the first in its class o the clinical study design was acceptable o the application did not raise significant safety or efficacy issues o the application did not raise significant public health questions on the role of the drug/biologic in the diagnosis, cure, mitigation, treatment or prevention of a disease • Abuse Liability/Potential Comments: • If the application is affected by the AIP, has the division made a recommendation regarding whether or not an exception to the AIP should be granted to permit review based on medical necessity or public health significance? YES Date if known: October 24, 2013 NO To be determined Reason: Not Applicable FILE REFUSE TO FILE Review issues for 74-day letter Not Applicable YES NO Comments: CLINICAL MICROBIOLOGY Not Applicable FILE REFUSE TO FILE Comments: deep sequencing data trials C205 and C206 Review issues for 74-day letter CLINICAL PHARMACOLOGY Not Applicable FILE REFUSE TO FILE Comments: pharmacogenomics data submitted for trials C205 and C206 • Clinical pharmacology study site(s) inspections(s) needed? Review issues for 74-day letter BIOSTATISTICS Not Applicable FILE REFUSE TO FILE BA and analytical Site Comments: Version: 3/25/13 Reference ID: 3304642 YES NO Review issues for 74-day letter 15 NONCLINICAL (PHARMACOLOGY/TOXICOLOGY) Not Applicable FILE REFUSE TO FILE Review issues for 74-day letter Comments: APPEARS THIS WAY ON ORIGINAL Version: 3/25/13 Reference ID: 3304642 16 IMMUNOGENICITY (BLAs/BLA efficacy supplements only) Not Applicable FILE REFUSE TO FILE Review issues for 74-day letter Comments: PRODUCT QUALITY (CMC) Not Applicable FILE REFUSE TO FILE Comments: Review issues for 74-day letter Environmental Assessment Not Applicable • Categorical exclusion for environmental assessment (EA) requested? YES NO If no, was a complete EA submitted? YES NO If EA submitted, consulted to EA officer (OPS)? YES NO Comments: Quality Microbiology (for sterile products) • Was the Microbiology Team consulted for validation of sterilization? (NDAs/NDA supplements only) Not Applicable YES NO Comments: Facility Inspection Not Applicable • Establishment(s) ready for inspection? YES NO ƒ Establishment Evaluation Request (EER/TBP-EER) submitted to OMPQ? YES NO Comments: EES submitted Facility/Microbiology Review (BLAs only) Not Applicable FILE REFUSE TO FILE Comments: Review issues for 74-day letter Version: 3/25/13 Reference ID: 3304642 17 CMC Labeling Review Comments: Review issues for 74-day letter APPLICATIONS IN THE PROGRAM (PDUFA V) (N ME NDAs/Original BLAs) 0 Were there agreements made at the application?s El YES pie-submission meeting (and documented in the IE N0 minutes) regarding certain late submission components that could be submitted within 30 days after receipt of the original application? If so. were the late submission components all El YES submitted within 30 days? El NO 0 What late submission components. if any, arrived after 30 days? 0 Was the application otherwise complete upon YES submission. including those applications where there NO were no agreements regarding late submission components? 0 Is a comprehensive and readily located list of all YES clinical sites included or referenced in the NO application? 0 Is a comprehensive and readily located list of all IE YES manufacturing facilities included or referenced in the N0 application? REGULATORY PROJECT MANAGEMENT Signatory Authority: Ed Cox/J eff Murray Date of Mid-Cycle Meeting (for NME in ?the Program" PDUFA V): Jlme 20. 2013 21" Century Review Milestones (see attached) (listing review milestones in this document is optional): Version: 3/2 5/ 3 18 Reference ID: 3304642 Comments: REGULATORY The application is iuisuitable for ?ling. Explain why: The application. on its face. appears to be suitable for ?ling. Review Issues: No review issues have been identi?ed for the 74-day letter. Review issues have been identi?ed for the 74-day letter. List (optional): Review Classi?cation: Standard Review Priority Review ACTIONS ITEMS Ensure that any updates to the review priority (S or P) and classi?cations/properties are entered into tracking system chemical classi?cation. combination product classi?cation. 505(b)(2). orphan drug). If RTE. notify everybody who already received a consult request. OSE PM. and Product Quality PM (to cancel If ?led. and the application is under AIP. prepare a letter either granting (for signature by Center Director) or denying (for signature by ODE Director) an exception for review. supplements: If ?led. send 60-day ?ling letter If priority review: 0 notify sponsor in writing by day 60 (For supplements: include in 60-day ?ling letter: For supplements: see CST for choices) 0 notify OMPQ (so facility inspections can be scheduled earlier) Send review issues/no review issues by day 74 Conduct a PLR format labeling review and include labeling issues in the 74-day letter Update the PDUFA DARRTS page (for NME NDAs in the Program) EIXIIZIE supplements: Send the Product Information Sheet to the product reviewer and the Facility Information Sheet to the facility reviewer for completion. Ensure that the completed forms are forwarded to the CDER RMS-BLA Superuser for data entry into RMS-BLA one month prior to taking an action [These sheets may be formd in the CST eRoom at: 1685f El Other Version: 3/25/13 19 Reference ID: 3304642 Version: 3/25/13 Reference ID: 3304642 APPEARS THIS WAY ON ORIGINAL 20 Appendix A (NDA and NDA Supplements only) NOTE: The term "original application" or "original NDA" as used in this appendix denotes the NDA submitted. It does not refer to the reference drug product or "reference listed drug." An original application is likely to be a 505(b)(2) application if: (1) it relies on published literature to meet any of the approval requirements, and the applicant does not have a written right of reference to the underlying data. If published literature is cited in the NDA but is not necessary for approval, the inclusion of such literature will not, in itself, make the application a 505(b)(2) application, (2) it relies for approval on the Agency's previous findings of safety and efficacy for a listed drug product and the applicant does not own or have right to reference the data supporting that approval, or (3) it relies on what is "generally known" or "scientifically accepted" about a class of products to support the safety or effectiveness of the particular drug for which the applicant is seeking approval. (Note, however, that this does not mean any reference to general information or knowledge (e.g., about disease etiology, support for particular endpoints, methods of analysis) causes the application to be a 505(b)(2) application.) Types of products for which 505(b)(2) applications are likely to be submitted include: fixed-dose combination drug products (e.g., heart drug and diuretic (hydrochlorothiazide) combinations); OTC monograph deviations (see 21 CFR 330.11); new dosage forms; new indications; and, new salts. An efficacy supplement can be either a (b)(1) or a (b)(2) regardless of whether the original NDA was a (b)(1) or a (b)(2). An efficacy supplement is a 505(b)(1) supplement if the supplement contains all of the information needed to support the approval of the change proposed in the supplement. For example, if the supplemental application is for a new indication, the supplement is a 505(b)(1) if: (1) The applicant has conducted its own studies to support the new indication (or otherwise owns or has right of reference to the data/studies), (2) No additional information beyond what is included in the supplement or was embodied in the finding of safety and effectiveness for the original application or previously approved supplements is needed to support the change. For example, this would likely be the case with respect to safety considerations if the dose(s) was/were the same as (or lower than) the original application, and. (3) All other “criteria” are met (e.g., the applicant owns or has right of reference to the data relied upon for approval of the supplement, the application does not rely Version: 3/25/13 Reference ID: 3304642 21 for approval on published literature based on data to which the applicant does not have a right of reference). An efficacy supplement is a 505(b)(2) supplement if: (1) Approval of the change proposed in the supplemental application would require data beyond that needed to support our previous finding of safety and efficacy in the approval of the original application (or earlier supplement), and the applicant has not conducted all of its own studies for approval of the change, or obtained a right to reference studies it does not own. For example, if the change were for a new indication AND a higher dose, we would likely require clinical efficacy data and preclinical safety data to approve the higher dose. If the applicant provided the effectiveness data, but had to rely on a different listed drug, or a new aspect of a previously cited listed drug, to support the safety of the new dose, the supplement would be a 505(b)(2), (2) The applicant relies for approval of the supplement on published literature that is based on data that the applicant does not own or have a right to reference. If published literature is cited in the supplement but is not necessary for approval, the inclusion of such literature will not, in itself, make the supplement a 505(b)(2) supplement, or (3) The applicant is relying upon any data they do not own or to which they do not have right of reference. If you have questions about whether an application is a 505(b)(1) or 505(b)(2) application, consult with your OND ADRA or OND IO. Version: 3/25/13 Reference ID: 3304642 22 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------VICTORIA L TYSON 05/07/2013 ELIZABETH G THOMPSON 05/07/2013 Reference ID: 3304642 REGULATORY PROJECT MANAGER PHYSICIAN’S LABELING RULE (PLR) FORMAT REVIEW OF THE PRESCRIBING INFORMATION To be completed for all new NDAs, BLAs, Efficacy Supplements, and PLR Conversion Supplements Application: 205123 Application Type: New NDA Name of Drug: TBD (simeprevir) Capsule Applicant: Janssen Research & Development, LLC Submission Date: March 28, 2013 Receipt Date: March 28, 2013 1.0 Regulatory History and Applicant’s Main Proposals NDA 205123 was submitted March 28, 2013 and is both a Type 1 NME and Type 4 New Combination. This proposed indication is for the treatment of genotype 1 hepatitis C infection, in combination with peginterferon alfa and ribavirin, in adult patients with compensated liver disease (including cirrhosis) who are treatment naïve or who failed previous interferon therapy (pegylated or non-pegylated) with or without ribavirin. 2.0 Review of the Prescribing Information (PI) This review is based on the applicant’s submitted Microsoft Word format of the PI. The applicant’s proposed PI was reviewed in accordance with the labeling format requirements listed in the “Selected Requirements for Prescribing Information (SRPI)” checklist (see the Appendix). 3.0 Conclusions/Recommendations SRPI format deficiencies were identified in the review of this PI. For a list of these deficiencies see the Appendix. RPM PLR Format Review of the PI: Last Updated May 2012 Reference ID: 3299731 Page 1 of 8 4.0 Appendix Selected Requirements of Prescribing Information (SRPI) The Selected Requirement of Prescribing Information (SRPI) version 2 is a 48-item, drop-down checklist of critical format elements of the prescribing information (PI) based on labeling regulations (21 CFR 201.56 and 201.57) and labeling guidances. Highlights (HL) YES YES YES YES YES GENERAL FORMAT 1. Highlights (HL) must be in two-column format, with ½ inch margins on all sides and in a minimum of 8-point font. Comment: 2. The length of HL must be less than or equal to one-half page (the HL Boxed Warning does not count against the one-half page requirement) unless a waiver has been is granted in a previous submission (i.e., the application being reviewed is an efficacy supplement). Instructions to complete this item: If the length of the HL is less than or equal to one-half page then select “YES” in the drop-down menu because this item meets the requirement. However, if HL is longer than one-half page: ¾ For the Filing Period (for RPMs) ƒ For efficacy supplements: If a waiver was previously granted, select “YES” in the dropdown menu because this item meets the requirement. ƒ For NDAs/BLAs and PLR conversions: Select “NO” in the drop-down menu because this item does not meet the requirement (deficiency). The RPM notifies the CrossDiscipline Team Leader (CDTL) of the excessive HL length and the CDTL determines if this deficiency is included in the 74-day or advice letter to the applicant. ¾ For the End-of Cycle Period (for SEALD reviewers) ƒ The SEALD reviewer documents (based on information received from the RPM) that a waiver has been previously granted or will be granted by the review division in the approval letter. Comment: 3. All headings in HL must be presented in the center of a horizontal line, in UPPER-CASE letters and bolded. Comment: 4. White space must be present before each major heading in HL. Comment: 5. Each summarized statement in HL must reference the section(s) or subsection(s) of the Full Prescribing Information (FPI) that contains more detailed information. The preferred format is SRPI version 2: Last Updated May 2012 Reference ID: 3299731 Page 2 of 8 Selected Requirements of Prescribing Information (SRPI) YES the numerical identifier in parenthesis [e.g., (1.1)] at the end of each information summary (e.g. end of each bullet). Comment: 6. Section headings are presented in the following order in HL: Section Required/Optional Required • Highlights Heading Required • Highlights Limitation Statement Required • Product Title Required • Initial U.S. Approval Required if a Boxed Warning is in the FPI • Boxed Warning Required for only certain changes to PI* • Recent Major Changes Required • Indications and Usage Required • Dosage and Administration Required • Dosage Forms and Strengths Required (if no contraindications must state “None.”) • Contraindications Not required by regulation, but should be present • Warnings and Precautions Required • Adverse Reactions Optional • Drug Interactions Optional • Use in Specific Populations • Patient Counseling Information Statement Required Required • Revision Date * RMC only applies to the Boxed Warning, Indications and Usage, Dosage and Administration, Contraindications, and Warnings and Precautions sections. YES Comment: 7. A horizontal line must separate HL and Table of Contents (TOC). Comment: HIGHLIGHTS DETAILS YES YES YES Highlights Heading 8. At the beginning of HL, the following heading must be bolded and appear in all UPPER CASE letters: “HIGHLIGHTS OF PRESCRIBING INFORMATION”. Comment: Highlights Limitation Statement 9. The bolded HL Limitation Statement must be on the line immediately beneath the HL heading and must state: “These highlights do not include all the information needed to use (insert name of drug product in UPPER CASE) safely and effectively. See full prescribing information for (insert name of drug product in UPPER CASE).” Comment: Product Title 10. Product title in HL must be bolded. Comment: Initial U.S. Approval YES SRPI version 2: Last Updated May 2012 Reference ID: 3299731 Page 3 of 8 Selected Requirements of Prescribing Information (SRPI) 11. Initial U.S. Approval in HL must be placed immediately beneath the product title, bolded, and include the verbatim statement “Initial U.S. Approval:” followed by the 4-digit year. Comment: N/A N/A N/A N/A N/A N/A N/A N/A N/A Boxed Warning 12. All text must be bolded. Comment: 13. Must have a centered heading in UPPER-CASE, containing the word “WARNING” (even if more than one Warning, the term, “WARNING” and not “WARNINGS” should be used) and other words to identify the subject of the Warning (e.g., “WARNING: SERIOUS INFECTIONS”). Comment: 14. Must always have the verbatim statement “See full prescribing information for complete boxed warning.” centered immediately beneath the heading. Comment: 15. Must be limited in length to 20 lines (this does not include the heading and statement “See full prescribing information for complete boxed warning.”) Comment: 16. Use sentence case for summary (combination of uppercase and lowercase letters typical of that used in a sentence). Comment: Recent Major Changes (RMC) 17. Pertains to only the following five sections of the FPI: Boxed Warning, Indications and Usage, Dosage and Administration, Contraindications, and Warnings and Precautions. Comment: 18. Must be listed in the same order in HL as they appear in FPI. Comment: 19. Includes heading(s) and, if appropriate, subheading(s) of labeling section(s) affected by the recent major change, together with each section’s identifying number and date (month/year format) on which the change was incorporated in the PI (supplement approval date). For example, “Dosage and Administration, Coronary Stenting (2.2) --- 3/2012”. Comment: 20. Must list changes for at least one year after the supplement is approved and must be removed at the first printing subsequent to one year (e.g., no listing should be one year older than revision date). Comment: Indications and Usage YES SRPI version 2: Last Updated May 2012 Reference ID: 3299731 Page 4 of 8 Selected Requirements of Prescribing Information (SRPI) 21. If a product belongs to an established pharmacologic class, the following statement is required in the Indications and Usage section of HL: [(Product) is a (name of class) indicated for (indication)].” Comment: YES NO NO YES YES Dosage Forms and Strengths 22. For a product that has several dosage forms, bulleted subheadings (e.g., capsules, tablets, injection, suspension) or tabular presentations of information is used. Comment: Contraindications 23. All contraindications listed in the FPI must also be listed in HL or must include the statement “None” if no contraindications are known. Comment: Applicant only listed contraindications for the coadministered products and did not indicate any contraindications for simprevir. Applicant will be asked to state "None" if no contraindications to simeprevir are known. 24. Each contraindication is bulleted when there is more than one contraindication. Comment: See comment above. Applicant should list bullet each contraindication. Adverse Reactions 25. For drug products other than vaccines, the verbatim bolded statement must be present: “To report SUSPECTED ADVERSE REACTIONS, contact (insert name of manufacturer) at (insert manufacturer’s U.S. phone number) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch”. Comment: Patient Counseling Information Statement 26. Must include one of the following three bolded verbatim statements (without quotation marks): If a product does not have FDA-approved patient labeling: • “See 17 for PATIENT COUNSELING INFORMATION” If a product has FDA-approved patient labeling: • “See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.” • “See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.” Comment: YES Revision Date 27. Bolded revision date (i.e., “Revised: MM/YYYY or Month Year”) must be at the end of HL. Comment: Contents: Table of Contents (TOC) SRPI version 2: Last Updated May 2012 Reference ID: 3299731 Page 5 of 8 Selected Requirements of Prescribing Information (SRPI) YES YES YES N/A YES YES YES YES GENERAL FORMAT 28. A horizontal line must separate TOC from the FPI. Comment: 29. The following bolded heading in all UPPER CASE letters must appear at the beginning of TOC: “FULL PRESCRIBING INFORMATION: CONTENTS”. Comment: 30. The section headings and subheadings (including title of the Boxed Warning) in the TOC must match the headings and subheadings in the FPI. Comment: 31. The same title for the Boxed Warning that appears in the HL and FPI must also appear at the beginning of the TOC in UPPER-CASE letters and bolded. Comment: 32. All section headings must be bolded and in UPPER CASE. Comment: 33. All subsection headings must be indented, not bolded, and in title case. Comment: 34. When a section or subsection is omitted, the numbering does not change. Comment: 35. If a section or subsection from 201.56(d)(1) is omitted from the FPI and TOC, the heading “FULL PRESCRIBING INFORMATION: CONTENTS” must be followed by an asterisk and the following statement must appear at the end of TOC: “*Sections or subsections omitted from the Full Prescribing Information are not listed.” Comment: Full Prescribing Information (FPI) YES YES YES GENERAL FORMAT 36. The following heading must appear at the beginning of the FPI in UPPER CASE and bolded: “FULL PRESCRIBING INFORMATION”. Comment: 37. All section and subsection headings and numbers must be bolded. Comment: 38. The bolded section and subsection headings must be named and numbered in accordance with 21 CFR 201.56(d)(1) as noted below. If a section/subsection is omitted, the numbering does not change. Boxed Warning 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS SRPI version 2: Last Updated May 2012 Reference ID: 3299731 Page 6 of 8 Selected Requirements of Prescribing Information (SRPI) 6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Labor and Delivery 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance 9.2 Abuse 9.3 Dependence 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.4 Microbiology (by guidance) 12.5 Pharmacogenomics (by guidance) 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Comment: YES YES N/A N/A N/A 39. FDA-approved patient labeling (e.g., Medication Guide, Patient Information, or Instructions for Use) must not be included as a subsection under Section 17 (Patient Counseling Information). All patient labeling must appear at the end of the PI upon approval. Comment: 40. The preferred presentation for cross-references in the FPI is the section heading (not subsection heading) followed by the numerical identifier in italics. For example, [see Warnings and Precautions (5.2)]. Comment: 41. If RMCs are listed in HL, the corresponding new or modified text in the FPI sections or subsections must be marked with a vertical line on the left edge. Comment: FULL PRESCRIBING INFORMATION DETAILS Boxed Warning 42. All text is bolded. Comment: 43. Must have a heading in UPPER-CASE, containing the word “WARNING” (even if more than one Warning, the term, “WARNING” and not “WARNINGS” should be used) and other words to identify the subject of the Warning (e.g., “WARNING: SERIOUS INFECTIONS”). SRPI version 2: Last Updated May 2012 Reference ID: 3299731 Page 7 of 8 Selected Requirements of Prescribing Information (SRPI) N/A NO YES Comment: 44. Use sentence case (combination of uppercase and lowercase letters typical of that used in a sentence) for the information in the Boxed Warning. Comment: Contraindications 45. If no Contraindications are known, this section must state “None”. Comment: Applicant only listed contraindications for the coadministered products and did not indicate any contraindications for simprevir. Applicant will be asked to state "None" if no contraindications to simeprevir are known. Adverse Reactions 46. When clinical trials adverse reactions data is included (typically in the “Clinical Trials Experience” subsection of Adverse Reactions), the following verbatim statement or appropriate modification should precede the presentation of adverse reactions: “Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.” Comment: N/A 47. When postmarketing adverse reaction data is included (typically in the “Postmarketing Experience” subsection of Adverse Reactions), the following verbatim statement or appropriate modification should precede the presentation of adverse reactions: “The following adverse reactions have been identified during post-approval use of (insert drug name). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.” Comment: YES Patient Counseling Information 48. Must reference any FDA-approved patient labeling, include the type of patient labeling, and use one of the following statements at the beginning of Section 17: • “See FDA-approved patient labeling (Medication Guide)” • “See FDA-approved patient labeling (Medication Guide and Instructions for Use)” • “See FDA-approved patient labeling (Patient Information)" • “See FDA-approved patient labeling (Instructions for Use)" • “See FDA-approved patient labeling (Patient Information and Instructions for Use)” Comment: Comment will be sent to sponsor to remove italized font. SRPI version 2: Last Updated May 2012 Reference ID: 3299731 Page 8 of 8 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------SAMMIE G BEAM 04/26/2013 ELIZABETH G THOMPSON 04/26/2013 Reference ID: 3299731