CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`205834Orig1s000
`
`
`OTHER REVIEW(S)
`
`

`

`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/BLA #
`Product Name:
`
`NDA 205834
`Ledipasvir/sofosbuvir
`
`PMR/PMC Description:
`
`Submit an interim study report and datasets for GS-US-334-0122
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`Study/Trial Completion:
`Final Report Submission:
`Other:
`
`completed
`07/31/2017
`07/31/2018
`
`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 ongoing trial GS-US-248-0122, entitled, “A Long Term Follow-up Registry for Subjects
`Who Achieve a Sustained Virologic Response to Treatment in Gilead-Sponsored Trials in
`Subjects with Chronic Hepatitis C Infection”, with the three year follow-up data from: GS-US-
`337-0102 (ION-1), GS-US-337-0109 (ION-2), GS-US-337-0108 (ION-3) will collect the follow-
`up data for three years to assess the durability of treatment response, hence needs to be done post-
`approval.
`
`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
`
`Last Updated 9/26/2014
`
`Page 1 of 4
`
`Reference ID: 3635710
`
`

`

`An interim study report from the ongoing trial GS-US-248-0122, entitled, “A Long Term Follow-
`up Registry for Subjects Who Achieve a Sustained Virologic Response to Treatment in Gilead-
`Sponsored Trials in Subjects with Chronic Hepatitis C Infection”, with the three year follow-up
`data from: GS-US-337-0102 (ION-1), GS-US-337-0109 (ION-2), GS-US-337-0108 (ION-3) will
`provide long-term data on the durability of treatment response.
`
`The primary objective of this registry is to assess the durability of sustained virologic response
`(SVR) following treatment in a Gilead-sponsored trial. The secondary objectives of this registry
`are to determine whether subsequent detection of HCV RNA in subjects who relapse following
`SVR, represents the re-emergence of pre-existing virus, the development of resistance mutations,
`or whether it is due to re-infection; to assess clinical progression of liver disease; and to screen for
`the development of hepatocellular carcinoma (HCC). Once enrolled, subjects will be followed for
`up to 3 years. Visits will occur at Baseline and then at Weeks 24, 48, 72, 96, 120 and 144. At
`each visit, subjects will have blood drawn for plasma HCV RNA quantification, liver function
`tests, platelets, coagulation test, α-fetoprotein, and a quality of life survey will be completed.
`If HCV RNA is detected, the subject will have a repeat blood sample drawn for confirmation. If
`HCV RNA is confirmed the subject will be withdrawn from the Registry. If the confirmed HCV
`RNA is > 1000 IU/ml, viral sequence analysis will be performed.
`
`The listed three trials are the Phase 3 registrational trials supporting dosing and administration
`recommendations.
`
`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
`
`PMR/PMC Development Template
`
`Last Updated 9/26/2014
`
`Page 2 of 4
`
`Reference ID: 3635710
`
`

`

`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.
`Submit an interim study report from the ongoing study GS-US-248-0122, entitled, “A
`Long Term Follow-up Registry for Subjects Who Achieve a Sustained Virologic
`Response to Treatment in Gilead-Sponsored Trials in Subjects with Chronic Hepatitis C
`Infection”, with the three year follow-up data from: GS-US-337-0102 (ION-1), GS-US-
`337-0109 (ION-2), GS-US-337-0108 (ION-3)
`
`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?
`
`PMR/PMC Development Template
`
`Last Updated 9/26/2014
`
`Page 3 of 4
`
`Reference ID: 3635710
`
`

`

`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 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)
`
`PMR/PMC Development Template
`
`Last Updated 9/26/2014
`
`Page 4 of 4
`
`Reference ID: 3635710
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`LINDA C ONAGA
`09/26/2014
`
`WILLIAM B TAUBER
`09/26/2014
`
`Reference ID: 3635710
`
`

`

`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/BLA #
`Product Name:
`
`PMR/PMC Description:
`
`NDA 205834
`Ledipasvir/sofosbuvir fixed dose combination tablet
`
`Conduct a study to evaluate the pharmacokinetics, safety and treatment
`response (using sustained virologic response) of ledipasvir/sofosbuvir in
`pediatric subjects 3 through 17 years of age with chronic hepatitis C
`
` 0714/2014
` 6/30/2018
` 2/28/2019
` N /A
`
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`Study/Trial Completion:
`
`Final Report Submission:
`
`Other:
`
`
`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
`
`
`
`Adult studies are completed and ready for approval. The review team met with the Pediatric Review
`Committee (PeRC) on August 6, 2014. The PeRC agreed with the Division to grant a deferral for pediatric
`patients aged 3 through 17 years because the product is ready for approval in adults.
`
`
`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
`
`Last Updated 9/8/2014
`
`Page 1 of 4
`
`Reference ID: 3631501
`
`

`

`The study is a deferred pediatric trial under PREA to evaluate the pharmacokinetics, safety and treatment
`response (using sustained virologic response) of ledipasvir/sofosbuvir for the treatment of chronic hepatitis
`C virus (HCV) infection in pediatric subjects 3 through 17 years of age. The Division is in general
`agreement with the Applicant’s overall pediatric plan.
`
`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.
`
`Conduct a study to evaluate the pharmacokinetics, safety and treatment response (using sustained
`virologic response) of ledipasvir/sofosbuvir in pediatric subjects 3 through 17 years of age with
`chronic hepatitis C.
`
`
`
`PMR/PMC Development Template
`
`Last Updated 9/8/2014
`
`Page 2 of 4
`
`Reference ID: 3631501
`
`

`

`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
`
`Last Updated 9/8/2014
`
`Page 3 of 4
`
`Reference ID: 3631501
`
`

`

`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)
`
`PMR/PMC Development Template
`
`Last Updated 9/8/2014
`
`Page 4 of 4
`
`Reference ID: 3631501
`
`

`

`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/BLA #
`Product Name:
`
`PMR/PMC Description:
`
`NDA 205834
`Ledipasvir/sofosbuvir fixed dose combination tablet
`
`Collect and analyze long-term safety data for subjects enrolled in the pediatric
`ledipasvir/sofosbuvir safety, pharmacokinetic and efficacy study. Data
`collected should include at least 3 years of follow-up in order to characterize
`the long-term safety of ledipasvir/sofosbuvir including growth assessment,
`sexual maturation and characterization of ledipasvir/sofosbuvir resistance
`associated substitutions in viral isolates from subjects failing therapy.
`
` 05/2014
` 2/28/2023
` 8/31/2023
` N/A
`
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`Study/Trial Completion:
`
`Final Report Submission:
`
`Other:
`
`
`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
`
`
`
`Adult studies are completed and ready for approval. This PMR will provide long-term safety data in
`pediatric subjects treated in the ledipasvir/sofosbuvir safety, pharmacokinetic and efficacy study.
`
`
`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
`
`Last Updated 9/8/2014
`
`Page 1 of 4
`
`Reference ID: 3631501
`
`

`

`The study is a deferred pediatric study under PREA for the treatment of chronic hepatitis C virus (HCV)
`infection in pediatric subjects 3 through 17 years of age. The study will collect and analyze long-term
`safety data for subjects enrolled in the pediatric ledipasvir/sofosbuvir safety, pharmacokinetic and efficacy
`study. Data collected should include at least 3 years of follow-up in order to characterize the long-term
`safety of ledipasvir/sofosbuvir including growth assessment, sexual maturation and characterization of
`ledipasvir/sofosbuvir resistance associated substitutions in viral isolates from subjects failing therapy.
`
`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. Long-term safety data for
`subjects enrolled in the pediatric ledipasvir/sofosbuvir safety, pharmacokinetic and efficacy study
`should include at least 3 years of follow-up in order to characterize the long-term safety of
`ledipasvir/sofosbuvir including growth assessment, sexual maturation and characterization of
`ledipasvir/sofosbuvir resistance associated substitutions in viral isolates from subjects failing
`therapy.
`
`
`
`PMR/PMC Development Template
`
`Last Updated 9/8/2014
`
`Page 2 of 4
`
`Reference ID: 3631501
`
`

`

`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
`
`Last Updated 9/8/2014
`
`Page 3 of 4
`
`Reference ID: 3631501
`
`

`

`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)
`
`PMR/PMC Development Template
`
`Last Updated 9/8/2014
`
`Page 4 of 4
`
`Reference ID: 3631501
`
`

`

`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 205834
`Ledipasvir/sofosbuvir fixed dose combination tablet
`
`Ledipasvir 2-year rat carcinogenicity study
`
` Completed
` Completed
` 12/31/2015
` N/A
`
`
`NDA/BLA #
`Product Name:
`
`PMR/PMC Description:
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`Study/Trial Completion:
`
`Final Report Submission:
`
`Other:
`
`
`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 applicant should submit the final report for the ledipasvir 2-year carcinogenicity study in
`rats.
`
`
`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.”
`
`Ledipasvir will be administered for up to 24 weeks in certain HCV populations. Therefore,
`carcinogenicity studies are required and should be submitted to the NDA.
`
`PMR/PMC Development Template
`
`Last Updated 9/8/2014
`
`Page 1 of 3
`
`Reference ID: 3631501
`
`

`

`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.
`2 year carcinogenicity study in rats
`
`
`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
`
`PMR/PMC Development Template
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`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 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)
`
`PMR/PMC Development Template
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`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 205834
`Ledipasvir/sofosbuvir fixed dose combination tablet
`
`Ledipasvir mouse carcinogenicity study
`
` Completed
` N/A
` 01/31/2015
` N/A
`
`
`NDA/BLA #
`Product Name:
`
`PMR/PMC Description:
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`Study/Trial Completion:
`
`Final Report Submission:
`
`Other:
`
`
`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 applicant should submit the final report for the ledipasvir 26-week carcinogenicity study in
`rasH2 mice.
`
`
`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.”
`
`Ledipasvir will be administered for up to 24 weeks in certain HCV populations. Therefore,
`carcinogenicity studies are required and should be submitted to the NDA.
`
`PMR/PMC Development Template
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`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 analy