CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`209241Orig1s000
`
`
`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.
`
`209241, Ingrezza (valbenazine) 40mg Capsules
`
`Conduct an in vitro study to assess the induction potential of NBI-136110 on
`CYP2B6 enzyme.
`
`Final Protocol Submission:
`
`Study/Trial Completion:
`Final Report Submission:
`Other:
`
`
` 12/30/2017
`
` 07/30/2018
` 12/30/2018
` MM/DD/YYYY
`
`
`NDA/BLA #
`Product Name:
`
`PMR/PMC Description:
`
`PMR/PMC Schedule Milestones:
`(PMR 3177-1)
`
`
`
`
`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
`
`
`
`NBI-136110 is not an active metabolite of valbenazine. But it is a major circulation moiety. This in-vitro
`study will be used to test induction potential of NBI-136110 on CYP2B6 enzyme and so the study can 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.”
`
`The Drug Interaction Guidance recommends evaluation of CYP enzyme induction potential for the major
`circulating moieties. The induction potential of NBI-136110 has not been evaluated for CYP2B6. The goal
`is to assess the in-vitro induction potential of NBI-136110 on CYP2B6 enzyme.
`
`PMR/PMC Development Template
`
`Last Updated 4/6/2017
`
`Page 1 of 3
`
`Reference ID: 4082546
`
`

`

`
`
`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.
`In-vitro drug interaction study using human biomaterials
`
`
`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
`
`Last Updated 4/6/2017
`
`Page 2 of 3
`
`Reference ID: 4082546
`
`

`

`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
`In-vitro drug interaction study using human biomaterials
`
`
`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
`
`Last Updated 4/6/2017
`
`Page 3 of 3
`
`Reference ID: 4082546
`
`

`

`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:
`(PMR 3177-2)
`
`209241, Ingrezza (valbenazine) 40mg Capsules
`
`Conduct a pharmacokinetic trial to quantify the impact of CYP2D6 inhibition
`on the exposures of the parent compound and major metabolites, either in the
`presence of a strong CYP2D6 inhibitor or in subjects who are CYP2D6 poor
`metabolizers (PMs)..
`
` 11/30/2017
` 12/30/2018
` 08/30/2019
` MM/DD/YYYY
`
`
`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 TD patient population who are CYP2D6 poor metabolizers (PM) or taking CYP2D6 inhibitors as
`comedication are relatively small. However, increased active metabolite (NBI-98782) exposure is
`anticipated in this group of patients. It is important to optimize dose in this population. It would be
`appropriate to collect data on subjects in the presence of a strong CYP2D6 inhibitor or on subjects who are
`CYP2D6 poor metabolizers (PMs) 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 4/6/2017
`
`Page 1 of 4
`
`Reference ID: 4082546
`
`

`

`CYP2D6 is considered as a major metabolic enzyme for the active metabolite NBI-98782. However, there
`is no dedicated drug-drug interaction study in the presence of a strong CYP2D6 inhibitor to quantify the
`impact of increase in exposures of NBI-98782 in the current submission. Additionally, the precise-
`magnitude of the difference in exposures of NBI-98782 of CYP2D6 PMs and non-PMs was inconclusive
`because the observed trends varied between significantly higher exposures in a few individuals and no
`difference in exposures.
`
`
`
`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 will be a pharmacokinetic trial to quantify the impact of CYP2D6 inhibition on the
`exposures of the parent compound and major metabolites, either in the presence of a strong
`CYP2D6 inhibitor or in subjects who are CYP2D6 poor metabolizers (PMs).
`
`
`
`PMR/PMC Development Template
`
`Last Updated 4/6/2017
`
`Page 2 of 4
`
`Reference ID: 4082546
`
`

`

`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
`Study pharmacokinetics in subjects either in the presence of a strong CYP2D6 inhibitor or in
`subjects who are CYP2D6 poor metabolizers (PMs)
`
`
`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 4/6/2017
`
`Page 3 of 4
`
`Reference ID: 4082546
`
`

`

`
`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 4/6/2017
`
`Page 4 of 4
`
`Reference ID: 4082546
`
`

`

`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.
`
`209241, Ingrezza (valbenazine) 40mg Capsules
`
`Conduct a pharmacokinetic trial to assess exposure differences of the parent
`compound and major metabolites in patients with severe renal impairment and
`matching subjects with normal renal function receiving the same dose.
`
` 12/30/2017
` 12/30/2018
` 08/30/2019
` MM/DD/YYYY
`
`
`NDA/BLA #
`Product Name:
`
`PMR/PMC Description:
`(PMR# 3177-3)
`
`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 TD patient population with severe renal impairment is relatively small. However, increased active
`metabolite (NBI-98782) exposure is anticipated in patients with severe renal impairment. It is important to
`optimize dose in this population. It would be appropriate to collect data on subjects with renal
`
`impairment 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.”
`
`Significant increase in exposure of a CYP2D6 substrate in patients with severe renal impairment has been
`reported. CYP2D6 is considered as a major metabolic enzyme for the active metabolite NBI-98782.
`Exposure change of NBI-98782 has not been assessed in the current program. Lack of this information will
`not ensure a safe use of valbenazine in severe renal impairment patients.
`
`PMR/PMC Development Template
`
`Last Updated 4/6/2017
`
`Page 1 of 3
`
`Reference ID: 4082546
`
`(b) (4)
`
`

`

`
`
`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 will be a pharmacokinetics trial in subjects with severe renal impairment. The study will be
`conducted in subjects with severe renal impairment
`
`
`
`
`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
`
`Last Updated 4/6/2017
`
`Page 2 of 3
`
`Reference ID: 4082546
`
`(b) (4)
`
`

`

`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
`Study pharmacokinetics in subjects with severe renal impairment
`
`
`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
`
`Last Updated 4/6/2017
`
`Page 3 of 3
`
`Reference ID: 4082546
`
`

`

`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:
`(PMR# 3177-4)
`
`209241, Ingrezza (valbenazine) 40mg Capsules
`
`Evaluate the potential for clinical dependence and withdrawal symptoms
`associated with valbenazine. Implement the following assessments in a
`current or future study in which subjects will receive valbenazine treatment
`(40 and 80 mg/day) for at least four consecutive weeks: Administer
`withdrawal scales, assess for withdrawal-related AEs, and monitor vital signs
`on the last day of treatment, day 1 off-treatment, every other day thereafter for
`the first week, and then 2-3 times weekly for two additional weeks.
`
` 01/31/2018
` 01/31/2019
` 01/31/2020
` MM/DD/YYYY
`
`
`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
`
`
`
`This PMR to evaluate for withdrawal symptoms was driven by the lack of evaluation of short-term (e.g.,
`days to weeks) withdrawal symptoms in clinical trials and the theoretical concern based on animal
`findings of increased activity at trough drug levels. It is not a pre-approval requirement because the lack of
`safety findings four weeks post-withdrawal suggests the concerns are not substantial enough to delay
`market entry for the first treatment for tardive dyskinesia.
`
`
`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 4/6/20173/28/2017
`
`Page 1 of 4
`
`Reference ID: 4082546
`
`

`

`Existing human clinical studies do not assess for the existence of short-term withdrawal symptoms
`following valbenazine discontinuation. Rodent studies found increased activity at trough drug levels. It is
`important to assess whether there are any short-term withdrawal symptoms in humans so appropriate
`information could be added to product labeling.
`
`
`
`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.
`Visits and assessments will be added to the end of existing clinical studies (NBI-98854-1304 and
`-1402) for patients who have not yet completed study participation.
`
`
`
`PMR/PMC Development Template
`
`Last Updated 4/6/20173/28/2017
`
`Page 2 of 4
`
`Reference ID: 4082546
`
`

`

`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)
`Additional visits and assessments will be included for ongoing clinical studies.
` 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
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`Last Updated 4/6/20173/28/2017
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`Page 3 of 4
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`Reference ID: 4082546
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`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 4/6/20173/28/2017
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`Page 4 of 4
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`Reference ID: 4082546
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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/BLA #
`Product Name:
`
`PMR/PMC Description:
`(PMC# 3177-5)
`
`209241, Ingrezza (valbenazine) 40mg Capsules
`
`
`Perform a randomized controlled trial to assess whether a higher dose would
`confer additional therapeutic benefit. You may consider a design in which
`subjects with an inadequate response to valbenazine 80 mg are randomized to
`continue the 80 mg dose or receive a higher dose. Depending on findings from
`the clinical pharmacology study evaluating the effect of CYP2D6 inhibition
`on plasma concentrations, CYP2D6 poor metabolizers may be excluded from
`this trial to reduce the risk for exposure-related adverse events such as QT
`prolongation.
`
` 03/2019
` 03/2023
` 03/2024
` MM/DD/YYYY
`
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`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 Clinical Pharmacology and Clinical reviews both concluded that there may be a potential for an
`improved benefit/risk ratio with a higher dose of valbenazine in some patients. It would not be reasonable
`to institute this as a pre-approval requirement, as it would delay market entry for the first treatment for
`tardive dyskinesia.
`
`
`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
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`Last Updated 4/6/2017
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`Page 1 of 4
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`Reference ID: 4082546
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`Clinical pharmacology dose/exposure/response analyses, a clear dose-response relationship for response to
`40 mg vs. 80 mg daily, and the existence of a substantial proportion of patients with residual TD symptoms
`suggests trial of a higher dose may be warranted for evaluating the benefit/risk ratio.
`
`
`
`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