`
`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`208745Orig1s000
`
`
`OTHER REVIEW(S)
`
`

`

` 12/31/2015
`(completed)
` 12/31/2018
` 2/28/2019
` MM/DD/YYYY
`
`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
`
`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:
`
`208745
`Plecanatide
`3117-1: Determine the appropriate plecanatide treatment dose for
`pediatric patients with chronic idiopathic constipation (CIC) who are 12
`years to less than 18 years of age by assessing the safety and efficacy of
`once daily oral plecanatide in an eight (8) week, proof-of-concept,
`dose-ranging with sparse pharmacokinetic (PK) sampling study.
`
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`
`
`Adult studies of plecanatide are completed and ready for approval in chronic idiopathic
`constipation. However, there exists an unmet need for therapies for pediatric patients with
`chronic idiopathic constipation.
`
`
`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 1/19/2017
`
`Page 1 of 4
`
`Reference ID: 4043971
`
`

`

`Through the evaluation of the safety, efficacy, and pharmacokinetics, the goal of this dose ranging
`study is to assess the appropriate dose of plecanatide in pediatric patients with chronic idiopathic
`constipation who are 12 years to less than 18 years of age.
`
`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.
` 8 week
`This study is a
`treatment study, with sparse PK sampling, to evaluate the safety and efficacy of once
`daily oral plecanatide for the treatment of pediatric patients with chronic idiopathic
`constipation who are 12 years to less than 18 years of age.
`
`PMR/PMC Development Template
`
`Last Updated 1/19/2017
`
`Page 2 of 4
`
`Reference ID: 4043971
`
`(b)(4)
`
`

`

`Required
` Observational pharmacoepidemiologic study
` Registry studies
` Primary safety study or clinical trial
` Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
` Thorough Q-T clinical trial
` Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology)
` Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
` Pharmacokinetic studies or clinical trials
` Drug interaction or bioavailability studies or clinical trials
` Dosing trials
`Continuation of Question 4
`
`
` Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`
` Meta-analysis or pooled analysis of previous studies/clinical trials
` Immunogenicity as a marker of safety
` Other (provide explanation)
`
`
`
`
`Agreed upon:
` Quality study without a safety endpoint (e.g., manufacturing, stability)
` Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease, background
`rates of adverse events)
` Clinical trials primarily designed to further define efficacy (e.g., in another condition, different disease
`severity, or subgroup) that are NOT required under Subpart H/E
` Dose-response study or clinical trial performed for effectiveness
` Nonclinical study, not safety-related (specify)
`
` Other
`
`
`
`5. Is the PMR/PMC clear, feasible, and appropriate?
` Does the study/clinical trial meet criteria for PMRs or PMCs?
` Are the objectives clear from the description of the PMR/PMC?
` Has the applicant adequately justified the choice of schedule milestone dates?
` Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine feasibility,
`and contribute to the development process?
`
`
`
`
`
`
`
`
`
` Check if this form describes a FDAAA PMR that is a randomized controlled clinical trial
`
`If so, does the clinical trial meet the following criteria?
`
` There is a significant question about the public health risks of an approved drug
` There is not enough existing information to assess these risks
` Information cannot be gained through a different kind of investigation
` The trial will be appropriately designed to answer question about a drug’s efficacy and safety, and
` The trial will emphasize risk minimization for participants as the protocol is developed
`
`PMR/PMC Development Template
`
`Last Updated 1/19/2017
`
`Page 3 of 4
`
`Reference ID: 4043971
`
`

`

`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 1/19/2017
`
`Page 4 of 4
`
`Reference ID: 4043971
`
`

`

`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:
`
`208745
`Plecanatide
`3117-2: Determine the appropriate plecanatide treatment dose for
`pediatric patients with chronic idiopathic constipation (CIC) who are 6
`years to less than 12 years of age by assessing the safety and efficacy of
`once daily oral plecanatide in an eight (8) week, proof-of-concept,
`dose-ranging with sparse pharmacokinetic (PK) sampling study.
`
` 12/31/2018
` 12/31/2020
` 2/28/2021
` MM/DD/YYYY
`
`
`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 studies of plecanatide are completed and ready for approval in chronic idiopathic
`constipation. However, there exists an unmet need for therapies for pediatric patients with
`chronic idiopathic constipation.
`
` This study will follow the completion of planned dose-ranging, sparse PK sampling, efficacy and
`
`safety study in chronic idiopathic constipation pediatric patients 12 to years to less than 18 years
`of age.
`
`
`2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is a
`FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new safety
`information.”
`
`PMR/PMC Development Template
`
`Last Updated 1/19/2017
`
`Page 1 of 4
`
`Reference ID: 4043971
`
`

`

`Through the evaluation of the safety, efficacy, and pharmacokinetics, the goal of this dose ranging
`study is to assess the appropriate dose of plecanatide in pediatric patients with chronic idiopathic
`constipation who are 6 years to less than 12 years of age.
`
`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.
` 8 week
`This study is a
`treatment study, with sparse PK sampling, to evaluate the safety and efficacy of once
`daily oral plecanatide for the treatment of pediatric patients with chronic idiopathic
`constipation who are 6 years to less than 12 years of age.
`
`PMR/PMC Development Template
`
`Last Updated 1/19/2017
`
`Page 2 of 4
`
`Reference ID: 4043971
`
`(b)(4)
`
`

`

`Required
` Observational pharmacoepidemiologic study
` Registry studies
` Primary safety study or clinical trial
` Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
` Thorough Q-T clinical trial
` Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology)
` Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
` Pharmacokinetic studies or clinical trials
` Drug interaction or bioavailability studies or clinical trials
` Dosing trials
`Continuation of Question 4
`
`
` Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`
` Meta-analysis or pooled analysis of previous studies/clinical trials
` Immunogenicity as a marker of safety
` Other (provide explanation)
`
`
`
`
`Agreed upon:
` Quality study without a safety endpoint (e.g., manufacturing, stability)
` Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease, background
`rates of adverse events)
` Clinical trials primarily designed to further define efficacy (e.g., in another condition, different disease
`severity, or subgroup) that are NOT required under Subpart H/E
` Dose-response study or clinical trial performed for effectiveness
` Nonclinical study, not safety-related (specify)
`
` Other
`
`
`
`5. Is the PMR/PMC clear, feasible, and appropriate?
` Does the study/clinical trial meet criteria for PMRs or PMCs?
` Are the objectives clear from the description of the PMR/PMC?
` Has the applicant adequately justified the choice of schedule milestone dates?
` Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine feasibility,
`and contribute to the development process?
`
`
`
`
`
`
`
`
`
` Check if this form describes a FDAAA PMR that is a randomized controlled clinical trial
`
`If so, does the clinical trial meet the following criteria?
`
` There is a significant question about the public health risks of an approved drug
` There is not enough existing information to assess these risks
` Information cannot be gained through a different kind of investigation
` The trial will be appropriately designed to answer question about a drug’s efficacy and safety, and
` The trial will emphasize risk minimization for participants as the protocol is developed
`
`PMR/PMC Development Template
`
`Last Updated 1/19/2017
`
`Page 3 of 4
`
`Reference ID: 4043971
`
`

`

`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 1/19/2017
`
`Page 4 of 4
`
`Reference ID: 4043971
`
`

`

`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:
`
`208745
`Plecanatide
`3117-3: Confirm the efficacy and safety of plecanatide treatment in
`pediatric patients with chronic idiopathic constipation (CIC) who are 6
`years to less than 18 years of age by performing a randomized, double-
`blind, placebo-controlled, parallel group, 12 week treatment study.
`
` 12/31/2018
` 12/31/2021
` 2/28/2022
` 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
`
`
`
`Adult studies of plecanatide are completed and ready for approval in chronic idiopathic
`constipation. However, there exists an unmet need for therapies for pediatric patients with
`chronic idiopathic constipation.
`
`
`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 1/19/2017
`
`Page 1 of 4
`
`Reference ID: 4043971
`
`

`

`The goal of this phase 3 study is to determine the effect (efficacy and safety) of plecanatide in the
`treatment of pediatric patients with chronic idiopathic constipation who are 6 to less than 18 years
`of age.
`
`This study will follow the completion of planned dose-ranging, sparse PK sampling, proof-of-
`concept studies of pediatric patients with chronic idiopathic constipation ages 6 to 18 years of age.
`
`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.
`A confirmatory randomized, double-blind, placebo-controlled, parallel group study will
`be required to evaluate the safety and efficacy of once daily oral plecanatide for 12 weeks
`for the treatment of pediatric patients with chronic idiopathic constipation who are 6 years
`to less than 18 years.
`
`PMR/PMC Development Template
`
`Last Updated 1/19/2017
`
`Page 2 of 4
`
`Reference ID: 4043971
`
`

`

`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 1/19/2017
`
`Page 3 of 4
`
`Reference ID: 4043971
`
`

`

`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 1/19/2017
`
`Page 4 of 4
`
`Reference ID: 4043971
`
`

`

`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:
`
`208745
`Plecanatide
`3117-4: Determine the appropriate plecanatide treatment dose for
`pediatric patients with chronic idiopathic constipation (CIC) who are 2
`years to less than 6 years of age by assessing the safety and efficacy of
`once daily oral plecanatide in an eight (8) week, proof-of-concept,
`dose-ranging with sparse pharmacokinetic (PK) sampling study.
`
` 12/31/2020
` 12/31/2022
` 2/28/2023
` MM/DD/YYYY
`
`
`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 studies of plecanatide are completed and ready for approval in chronic idiopathic
`constipation. However, there exists an unmet need for therapies for pediatric patients with
`chronic idiopathic constipation.
`
`Initiation of the trial is contingent on the determination that it is safe to proceed in patients 2
`years to less than 6 years of age. This will be determined on completion and evaluation of the
`results from a biopsy GC-C receptor expression study to assess the ontogeny of the GC-C
`receptor in pediatric patients, which will be required under 505(o) and dose finding clinical
`studies in patients greater than 6 years to less than 18 years .
`
`
`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 1/19/2017
`
`Page 1 of 4
`
`Reference ID: 4043971
`
`

`

`Through the evaluation of the safety, efficacy, and pharmacokinetics, the goal of this dose
`ranging study is to assess the appropriate dose of plecanatide in pediatric patients with chronic
`idiopathic constipation who are 2 years to less than 6 years of age.
`
`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.
` 8 week
`This study is a
`treatment study, with sparse PK sampling, to evaluate the safety and efficacy of once
`daily oral plecanatide for the treatment of pediatric patients with chronic idiopathic
`constipation who are 2 years to less than 6 years of age.
`
`PMR/PMC Development Template
`
`Last Updated 1/19/2017
`
`Page 2 of 4
`
`Reference ID: 4043971
`
`(b)(4)
`
`

`

`Required
` Observational pharmacoepidemiologic study
` Registry studies
` Primary safety study or clinical trial
` Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
` Thorough Q-T clinical trial
` Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology)
` Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
` Pharmacokinetic studies or clinical trials
` Drug interaction or bioavailability studies or clinical trials
` Dosing trials
`Continuation of Question 4
`
`
` Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`
` Meta-analysis or pooled analysis of previous studies/clinical trials
` Immunogenicity as a marker of safety
` Other (provide explanation)
`
`
`
`
`Agreed upon:
` Quality study without a safety endpoint (e.g., manufacturing, stability)
` Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease, background
`rates of adverse events)
` Clinical trials primarily designed to further define efficacy (e.g., in another condition, different disease
`severity, or subgroup) that are NOT required under Subpart H/E
` Dose-response study or clinical trial performed for effectiveness
` Nonclinical study, not safety-related (specify)
`
` Other
`
`
`
`5. Is the PMR/PMC clear, feasible, and appropriate?
` Does the study/clinical trial meet criteria for PMRs or PMCs?
` Are the objectives clear from the description of the PMR/PMC?
` Has the applicant adequately justified the choice of schedule milestone dates?
` Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine feasibility,
`and contribute to the development process?
`
`
`
`
`
`
`
`
`
` Check if this form describes a FDAAA PMR that is a randomized controlled clinical trial
`
`If so, does the clinical trial meet the following criteria?
`
` There is a significant question about the public health risks of an approved drug
` There is not enough existing information to assess these risks
` Information cannot be gained through a different kind of investigation
` The trial will be appropriately designed to answer question about a drug’s efficacy and safety, and
` The trial will emphasize risk minimization for participants as the protocol is developed
`
`PMR/PMC Development Template
`
`Last Updated 1/19/2017
`
`Page 3 of 4
`
`Reference ID: 4043971
`
`

`

`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 1/19/2017
`
`Page 4 of 4
`
`Reference ID: 4043971
`
`

`

`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:
`
`208745
`Plecanatide
`3117-5: Confirm the efficacy and safety of plecanatide treatment in
`pediatric patients with chronic idiopathic constipation (CIC) who are 2
`years to less than 6 years of age by performing a randomized, double-
`blind, placebo-controlled, parallel group, 12 week treatment study.
`
` 12/31/2022
` 12/31/2025
` 2/28/2026
` 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
`
`
`
`Adult studies of plecanatide are completed and ready for approval in chronic idiopathic
`constipation. However, there exists an unmet need for therapies for pediatric patients with
`chronic idiopathic constipation.
`
`The study will not be initiated until it has been determined that it is safe to proceed in patients 2
`years to less than 6 years of age. This will be determined on completion and evaluation of the
`results from the biopsy GC-C receptor expression study which will be required under 505(o) to
`assess the ontogeny of the GC-C receptor in pediatric patients and the planned dose finding
`clinical studies in patients greater than 6 years to less than 18 years.
`
`
`
`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 1/19/2017
`
`Page 1 of 4
`
`Reference ID: 4043971
`
`

`

`The goal of this phase 3 study is to determine the efficacy and safety of plecanatide in the
`treatment of pediatric patients with chronic idiopathic constipation who are 2 years to less than 6
`years of age. This study would follow the completion of a planned dose-ranging, sparse PK
`sampling, proof-of-concept study in pediatric patient with chronic idiopathic constipation ages 2
`to less than years of age.
`
`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 adv