CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`208341Orig1s000
`
`
`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 #
`
`Product Name:
`
`PMR/PMC Description:
`
`208341
`
`EPCLUSA; sofosbuvir and velpatasvir fixed dose combination tablet
`
`Conduct a study to evaluate the pharmacokinetics, safety and treatment
`response (using sustained virologic response) of sofosbuvir and velpatasvir in
`pediatric subjects 12 through less than 18 years of age with chronic hepatitis
`C virus infection
`
` 6/30/2016
` 3/31/2019
` 9/30/2019
` N/A
`
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`Study 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 trials are completed and ready for approval. The review team met with the Pediatric Review
`Committee (PeRC) on May 11, 2016. 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 6/24/2016
`
`Page 1 of 4
`
`Reference ID: 3951086
`
`

`

`The goal of the deferred pediatric study is to evaluate the safety, efficacy (assessed as sustained virologic
`response), and pharmacokinetics of
`“M" sofosbuvir and velpatasvir in
`children ages 12 through less than 18 years of age with chronic hepatitis C infection.
`one)
`
`agreement with the Applicant’s overall pediatric plan.
`
`The Division is in general
`
`3.
`
`Ifthe study/clinical trial is a PMR. check the applicable regulation.
`Ifnot a PMR, skip to 4.
`
`— Which regulation?
`El Accelerated Approval (subpart H/E)
`[3 Animal Efficacy Rule
`XI Pediatric Research Equity Act
`I: FDAAA required safety study/clinical trial
`
`—
`
`If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
`[3 Assess a known serious risk related to the use of the drug?
`l:l Assess signals of serious risk related to the use of the drug?
`l:l 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:
`
`l:l Analysis of spontaneous p_ostmarketing 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 {we 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 sufiicient
`to assess this known serious risk, or has been established but is nevertheless not sufficient to assess
`
`or identify a serious risk
`
`l:l 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 {we if: a study will not be sufficient to identify or assess a serious
`risk
`
`[:I Clinical uial: 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.
`
`A clinical study is required to evaluate the pharmacokinetics. safety and treatment response (using
`sustained virologic response) of sofosbuvir and velpatasvir in pediatric subjects 12 through less
`
`than 18 years of age with chronic hepatitis C infection.
`
`PMR/PMC Development Template
`
`Last Updated 6040016
`
`Page 2 of 4
`
`Reference ID: 3951 086
`
`

`

`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 6/24/2016
`
`Page 3 of 4
`
`Reference ID: 3951086
`
`

`

`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 6/24/2016
`
`Page 4 of 4
`
`Reference ID: 3951086
`
`

`

`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:
`
`208341
`
`EPCLUSA; sofosbuvir and velpatasvir fixed dose combination tablet
`
`Conduct a study to evaluate the pharmacokinetics, safety and treatment
`response (using sustained virologic response) of sofosbuvir and velpatasvir in
`pediatric subjects 3 through less than 12 years of age with chronic hepatitis C
`virus infection
`
` 6/30/2016
` 10/31/2020
` 4/30/2021
` 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 trials are completed and ready for approval. The review team met with the Pediatric Review
`Committee (PeRC) on May 11, 2016. 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 6/24/2016
`
`Page 1 of 4
`
`Reference ID: 3951086
`
`

`

`The goal of the deferred pediatric study is to evaluate the safety, efficacy (assessed as sustained virologic
`response), and pharmacokinetics of
`mm sofosbuvir and vel atasvir in
`children ages 3 through less than 12 years of age with chronic hepatitis C infection
`m’
`
`he Division is in general agreement with the Applicant’s overall pediatric plan.
`
`3.
`
`Ifthe study/clinical trial is a PMR. check the applicable regulation.
`Ifnot a PMR, skip to 4.
`
`— Which regulation?
`
`:l Accelerated Approval (subpart H/E)
`:l Animal Efficacy Rule
`XI Pediatric Research Equity Act
`:I FDAAA required safety study/clinical trial
`
`—
`
`—
`
`
`
`If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
`:I Assess a known serious risk related to the use of the drug?
`:] Assess signals of serious risk related to the use of the drug?
`:I 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:
`
`:1 Analysis of spontaneous p_ostmarketing adverse events?
`Do not select the above study/clinical trial (we 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
`
`El 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 Me if. a study will not be sufficient to identify or assess a serious
`risk
`
`I: 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 hmnan 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.
`
`A clinical study is required to evaluate the pharmacokinetics. safety and treatment response (using
`sustained virologic response) of sofosbuvir and velpatasvir in pediatric subjects 3 through less
`
`than 12 years of age with chronic hepatitis C infection.
`
`Required
`
`[:| Observational pharmacoepidemiologic study
`l:| Registry studies
`
`PMR/PMC Development Template
`
`Last Updated 64’244’2016
`
`Page 2 of 4
`
`Reference ID: 3951 086
`
`

`

` 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 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.
`
`PMR/PMC Development Template
`
`Last Updated 6/24/2016
`
`Page 3 of 4
`
`Reference ID: 3951086
`
`

`

`_______________________________________
`(signature line for BLAs)
`
`PMR/PMC Development Template
`
`Last Updated 6/24/2016
`
`Page 4 of 4
`
`Reference ID: 3951086
`
`

`

`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:
`
`208341
`Sofosbuvir/velpatasvir (EPCLUSATM)
`
`Conduct a drug interaction study to evaluate the interaction between
`sofosbuvir/velpatasvir and atorvastatin.
`
` 09/30/2016
` 05/31/2017
` 02/28/2018
` 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
`
`
`
`The results from the rosuvastatin study indicate that velpatasvir can significantly increase the
`concentration of substrates of organic anion transporting polypeptides (OATP) and breast cancer
`resistance protein (BCRP), such as atorvastatin. Although the results from the rosuvastatin drug
`interaction study cannot be directly extrapolated to atorvastatin, there is a mechanistic basis for a
`potentially clinically significant interaction with atorvastatin (a commonly used statin). Furthermore, a
`serious safety risk (rhabdomyolysis) has been identified in postmarketing reports with use of
`ledipasvir/sofosbuvir and atorvastatin. Based on the evidence from in vitro studies, ledipasvir and
`velpatasvir may have similar drug interaction potential for inhibition of OATP1B and BCRP transport, so
`the potential exists for sofosbuvir/velpatasvir to increase atorvastatin exposures, leading to serious adverse
`events. Thus, a PMR is needed to study the interaction between sofosbuvir/velpatasvir and atorvastatin in
`order to derive appropriate dosing recommendations for concomitant use.
`
`
`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 6/24/2016
`
`Page 1 of 4
`
`Reference ID: 3951086
`
`

`

`As described in Section 1, coadministration of sofosbuvir/velpatasvir with atorvastatin is expected to
`increase the concentrations of atorvastatin, which is associated with increased risk of myopathy, including
`rhabdomyolysis. During the sofosbuvir/velpatasvir NDA review, we became aware of postmarketing
`reports for ledipasvir/sofosbuvir, which identified a serious safety risk (rhabdomyolysis) associated with
`use of ledipasvir/sofosbuvir and atorvastatin. Based on the in vitro drug interaction potential results,
`rosuvastatin-velpatasvir drug-drug interaction results, as well as the postmarketing reports for
`ledipasvir/sofosbuvir, we believe it is necessary to further investigate the potential for a drug-drug
`interaction between sofosbuvir/velpatasvir and atorvastatin. The objective for this PMR study is to
`evaluate the pharmacokinetic based drug interaction potential. The results from this study will help
`determine a clinical management plan, if warranted.
`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.
`The study is a pharmacokinetic drug interaction study. The study will be conducted in healthy
`volunteers.
`
`
`
`PMR/PMC Development Template
`
`Last Updated 6/24/2016
`
`Page 2 of 4
`
`Reference ID: 3951086
`
`

`

`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 6/24/2016
`
`Page 3 of 4
`
`Reference ID: 3951086
`
`

`

`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 6/24/2016
`
`Page 4 of 4
`
`Reference ID: 3951086
`
`

`

`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 208341
`
`EPCLUSA; sofosbuvir and velpatasvir fixed dose combination tablet
`
`Submit the final clinical report and datasets for the ongoing trial GS-US-342-
`1202 (ASTRAL-5), titled “A Phase 3, Open-label Study to Investigate the
`Efficacy and Safety of Sofosbuvir/GS-5816 Fixed Dose Combination for 12
`weeks in Subjects with Chronic Hepatitis C Virus (HCV) and Human
`immunodeficiency Virus (HIV)-1 Coinfection,” to provide safety data in HIV-
`1/HCV co-infected subjects receiving sofosbuvir and velpatasvir concurrently
`with HIV antiretroviral therapy.
`
`
`Study/Trial Completion:
`Final Report Submission:
`Other:
`
`
`
`
` 8/31/2016
` 12/31/2016
` N/A
`
`
`PMR/PMC Schedule Milestones:
`
`
`
`
`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
`
`
`
`GS-US-342-1202 (ASTRAL-5) is a Phase 3, open-label trial evaluating the safety and efficacy of
`sofosbuvir and velpatasvir (SOF/VEL) for 12 weeks in subjects with chronic HCV infection and HIV-1
`co-infection. The study is ongoing during review of the NDA.
`
`Data obtained from GS-US-342-1202 will provide safety data in subjects receiving SOF/VEL
`concurrently with HIV antiretroviral 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
`
`Last Updated 6/24/2016
`
`Page 1 of 4
`
`Reference ID: 3951086
`
`

`

`Obtain safety data in subjects receiving SOF/VEL concurrently with HIV antiretroviral therapy and obtain
`dosing recommendations for HCV/HIV-1 co-infected patients.
`
`Several phase 1 drug-drug interaction studies were conducted to evaluate the effects of co-administration of
`SOF/VEL with antiretroviral agents. Notable results from these trials include:
`• Significant reductions in VEL AUC when coadministered with efavirenz. Since lower VEL
`exposures may result in lack of efficacy, co-administration of SOF/VEL with EFV containing
`regimens is not recommended.
`Increases in tenofovir exposures when SOF/VEL is coadministered with a tenofovir containing
`regimen. This effect was most notable when the antiretroviral regimen also contained ritonavir or
`cobicistat. It is unclear whether the increased tenofovir exposure increases risk of tenofovir-
`associated toxicity, particularly renal toxicity.
`
`•
`
`
`Study GS-US-342-1202 (ASTRAL 5) is an ongoing trial evaluating the safety and efficacy of SOF/VEL in
`HCV/HIV coinfected subjects. Submission of the final clinical report and datasets are identified as a PMR
`in order to provide safety data in subjects receiving SOF/VEL concurrently with HIV antiretroviral therapy
`and to provide dosing recommendations for HCV/HIV-1 co-infected patients.
`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.
`
`PMR/PMC Development Template
`
`Last Updated 6/24/2016
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`Page 2 of 4
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`Reference ID: 3951086
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`

`This trial is an ongoing phase 3 trial in HCV/HIV-1 coinfected subjects
`
`
`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
`
`PMR/PMC Development Template
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`Last Updated 6/24/2016
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`Page 3 of 4
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`Reference ID: 3951086
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`

` 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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`Last Updated 6/24/2016
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`Page 4 of 4
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`Reference ID: 3951086
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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 #
`
`Product Name:
`
`PMR/PMC Description:
`
`208341
`
`EPCLUSA; sofosbuvir and velpatasvir fixed dose combination tablet
`
`Conduct a trial in hepatitis C virus genotype 3 infected subjects with cirrhosis
`treated with sofosbuvir and velpatasvir to determine if the addition of
`ribavirin improves the efficacy (i.e., sustained virologic response rate) and
`reduces the rate of virologic failure.
`
`
`Study/Trial Completion:
`Final Report Submission:
`Other:
`
`
`
`
` 6/30/2017
` 6/30/2018
` N/A
`
`
`PMR/PMC Schedule Milestones:
`
`
`
`
`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
`
`
`
`PMR/PMC Development Template
`
`Last Updated 6/24/2016
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`Page 1 of 4
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`Reference ID: 3951086
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`

`

`The results of the ASTRAL-3 trial demonstrate that treatment with 12 weeks of sofosbuvir and velpatasvir
`(SOF/VEL) for subjects with HCV GT3 provides superior SVR12 rates than the comparator, SOF + RBV
`for 24 weeks: 95% versus 8